Exploring Brain Functional Anatomy with Positron Tomography - Symposium No. 163

EXPLORING BRAIN FUNCTIONAL ANATOMY WITH POSITRON TOMOGRAPHY

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Ciba Foundation Symposium 163

EXPLORING BRAIN FUNCTIONAL ANATOMY WITH POSITRON TOMOGRAPHY A Wiley-Interscience Publication

1991

JOHN WlLEY & SONS Chichester

. New York

. Brisbane

. Toronto . Singapore

OCiba Foundation 1991 Published in 1991 by John Wiley & Sons Ltd. Baffins Lane, Chichester West Sussex PO19 IUD,England All rights reserved. No part of this book may be reproduced by any means, or transmitted, or translated into a machine language without the written permission of the publisher.

Olher Wiley Edilorial Offices John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA Jacaranda Wiley Ltd, G.P.O.Box 859, Brisbane, Queensland 4001, Australia John Wiley & Sons (Canada) Ltd, 22 Worcester Road, Rexdale, Ontario M9W 1L1, Canada John Wiley & Sons (SEA) Pte Ltd, 37 Jalan Pemimpin 05-04, Block B. Union Industrial Building, Singapore 2057 Suggested series entry for library catalogues: Ciba Foundation Symposia Ciha Foundation Symposium 163 x + 287 pages, 42 figures, 14 tables

Library of Congress Cataloging-in-PublicationData Exploring brain functional anatomy with positron tomography. p. cm.-(Ciba Foundation symposium; 163) Editors: Derek J. Chadwick (organizer) and Julie Whelan. “Symposium on Exploring Brain Functional Anatomy with Positron Tomography, held at the Ciba Foundation, London, 12-14 March 1991”Contents p. “A Wiley-Interscience Publication.” Includes bibliographical references and indexes. ISBN 0 471 92970 0 1. Brain-Tomography-Congresses. 2. Brain-MetabolismCongresses. 3. Cerebral circulation-Congresses. 1. Chadwick, Derek. 11. Whelan, Julie. 111. Symposium on Exploring Brain Functional Anatomy with Positron Tomography (1991: Ciba Foundation) IV. Series. 1DNLM: 1. Brain-metabolism-congresses. 2. Brain-radionuclide imaging-congresses. 3. Tomography, Emission-Computed-congresses. W3 C161F v. 163/WL 141 E96] QP376.E93 1991 612.8 ’ 2-dc20 DNLM/DLC 91-40214 for Library of Congress ClP British Library Cataloguing in Publication Duta A catalogue record for this book is available from the British Library ISBN 0 471 92970 0 Phototypeset by Dobbie Typesetting Limited, Tavistock, Devon. Printed and bound in Great Britain by Biddles Ltd., Guildford.

Contents Symposium on Exploring Brain Functional Anatomy with Positron Tomography, held at the Ciba Foundation, London 12-14 March 1991 The topic of the symposium was proposed by Professor Richard Frackowiak Editors: Derek J. Chadwick (Organizer) and Julie Whelan R. Porter Introduction

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R. C. Collins* Basic aspects of functional brain metabolism Discussion 16

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H. Iida, I. Kanno and S. Miura Rapid measurement of cerebral blood flow with positron emission tomography 23 Discussion 37 General discussion Brain energy metabolism: cell body or synapse? Oxidative metabolism in brain 5 1

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D. W. Townsend Optimization of signal in positron emission tomography scans: present and future developments 57 Discussion 69 K. J. Friston, P. M. Grasby, C. D. Frith, C. J. Bench, R. J. Dolan, P. J. Cowen, P. F. Liddle and R. S. J. Frackowiak The neurotransmitter basis of cognition: psychopharmacological activation studies 76 Discussion 87 J. C. Mazziotta, D. Valentino, S. Grafton, F. Bookktein, C. Pelizzari, G. Chen and A. W. Toga Relating structure to function in vivo with tomographic imaging 93 Discussion 101 *In Professor Collins’ unavoidable absence his paper was presented by Professor John Mazziotta. V

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Contents

P. E. Roland and R. J. Seitz Positron emission tomography studies of the somatosensory system in man 113 Discussion 120 P. T. Fox and J. V. Pardo Does inter-subject variability in cortical functional organization increase with neural ‘distance’ from the periphery? 125 Discussion 140

S. Zeki A thought experiment with positron emission tomography 145 Discussion 154 M. Corbetta, F. M. Miezin, G. L. Shulman and S. E. Petersen Selective attention modulates extrastriate visual regions in humans during visual feature discrimination and recognition 165 Discussion 175 C. D. Frith Positron emission tomography studies of frontal lobe function: relevance to psychiatric disease 181 Discussion 191 M. E. Raichle Memory mechanisms in the processing of words and wordlike symbols 198 Discussion 204

R. J. Wise, U. Hadar, D. Howard and K. Patterson Language activation studies with positron emission tomography 218 Discussion 228

R. S. J. Frackowiak, C. Weiller and F. Chollet The functional anatomy of recovery from brain injury 235 Discussion 244

J. C. Baron Testing cerebral function: will it help the understanding or diagnosis of central nervous system disease? 250 Discussion 26 1

Final general discussion 265

R. Porter Summing-up 275 Index of contributors 278 Subject index 280

Participants J. C. Baron Centre Cyceron, INSERM U. 320, BP 5027, Bd Henri Becquerel, F-14021 Caen Cedex, France S. F. Cappa Clinica Neurologica, Universita di Brescia, Neurologia I1 Spedali Civili, Piazzale Ospedale 1, 1-25125 Brescia, Italy

F. Chollet Department of Neurology, HBpital Purpan, F-31059 Toulouse, France R. C. Collins* UCLA Department of Neurology, Reed Neurological Research Center, 710 Westwood Plaza, Los Angeles, CA 90024-1769, USA M. Corbetta Department o f Neurology & Neurological Surgery, Washington University School of Medicine, Box 81 11, 660 South Euclid Avenue, St Louis, MO 63110, USA

A. C. Evans Positron Imaging Laboratories, McConnell Brain Imaging Centre, Montreal Neurological Hospital & Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4

P. T. Fox Research Imaging Center, The University of Texas Health

Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7800, USA

R. S. J. Frackowiak MRC Cyclotron Unit, Hammersmith Hospital, Ducane Road, London W12 OHS, UK K. J. Friston** MRC Cyclotron Unit, Hammersmith Hospital, Ducane Road, London W12 OHS, UK *Professor Collins was unable to attend the symposium. His paper was presented by Professor Mazziotta. **Present address: Neurosciences Institute, 1230 York Avenue, New York, NY 100021, USA. vii

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Participants

C. D. Frith Division of Psychiatry, Clinical Research Centre, Watford Road, Harrow, Middlesex, HA1 3UJ, UK B. Gulyas Department of Clinical Neurophysiology, Karolinska Hospital, Box 60500, S-104 01 Stockholm 60, Sweden

H. Iida Research Institute of Brain & Blood Vessels, Senshu-KubotaMachi, Akita City 010, Japan M. Jeannerod Vision et Motricitt, INSERM U. 94, 16 Avenue du Doyen LCpine, F-69500 Bron, France

T. Jones PET Methods Section, MRC Cyclotron Unit, Hammersmith Hospital, Ducane Road, London W12 OHS, UK N. A. Lassen Department of Clinical PhysiologicaVNuclear Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark E. T. MacKenzie Centre Cyceron. INSERM U. 320, BP 5027, Bd Henri Becquerel, F- 14021 Caen Cedex, France

J. C. Mazziotta Department of Neurology, UCLA School of Medicine, University of California, Los Angeles, CA 90024-1769, USA R. E. Passingham Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford OX1 3UD, UK F. Plum Department of Neurology, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021, USA R. Porter (Chairman) Faculty of Medicine, Monash University, Clayton, Melbourne, Victoria 3168, Australia

M. E. Raichle Division of Radiation Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA P. E. Roland Department of Clinical Neurophysiology, Karolinska Hospital, Box 60500, S-104 01 Stockholm 60, Sweden L. Sokoloff Laboratory for Cerebral Metabolism, National Institute of Mental Health, Building 36, Room lAO5, National Institutes of Health, Bethesda, MD 20892, USA

Participants

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D. W. Townsend Division of Nuclear Medicine, HBpital Cantonal, University of Geneva, CH-1211 Geneva 4, Switzerland E. K. Warrington Department of Clinical Neuropsychology, The National Hospital, Queen Square, London WClN 3BG, UK R. J. Wise PET Clinical Group, Westminster & Charing Cross Hospital, Reynolds Building, St Dunstan’s Road, London W6 8RP, UK S. Zeki Department of Anatomy and Developmental Biology, University College London, Gower Street, London WClE 6BT, UK

Introduction Robert Porter Faculty of Medicine, Monash University, Clayton, Melbourne, Victoria 3 168, Australia

Historically, the exploration of brain functional anatomy has used the methods of clinicopathological correlation. Enormous difficulties and great uncertainty surround the interpretation of the signs and symptoms which seem t o be associated with damage or disease of localized brain regions. Broca’s contribution established the fact of anatomical localization of function within the cerebral cortex in 1861, even though, as Marie later demonstrated, his description of the extent of the lesion in his aphasic patient was incomplete. Hughlings Jackson’s studies of patients with partial epileptic seizures led him to draw conclusions about the structural organization of motor functions within the cerebral cortex which were soon shown to exist in the living, normal brain, when electrical stimulation of the cerebral cortex revealed the ordered nature of the functional representation of movement. Foerster, already a respected clinical neurologist, began to perform neurosurgical operations in the early 1920s. In the process of providing treatment for his patients, he seems to have regarded each operation as a n opportunity to conduct a physiological experiment and to study functional anatomy. Many of his observations on the interpretation of these experiments and his conclusions about the functions of different regions of the cerebral cortex in movement performance, deduced from both stimulation and ablation experiments, are summarized in his Hughlings Jackson lecture in 1935. From this work and from the observations of Penfield and his co-workers, who utilized the opportunity provided by operative excision of cerebral tumours, vascular malformations, or epileptic foci, to stimulate the exposed surface of the cerebral cortex electrically in conscious patients and to record the resulting effects in elaborate detail, have come most of our general views of human brain functional anatomy (Fig. 1). Almost all of this information relates to surface topography: the surface of the brain has been the only part accessible both to the surgeon’s scalpel and to his stimulating electrode. Moreover, and creating a problem for those developing theories of functional anatomy, some influence of the fact that the subjects were all suffering disorders which required surgical intervention could have distorted the findings towards those created by pathology rather than to observations about normal physiology. Even the earlier methods of study of regional cerebral blood flow, which could be applied to normal human subjects, 1

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FIG. 1. Schematic diagram of the functional anatomy of the human brain, as depicted in summarizing the observations of Penfield & Boldrey (1937). (Reproduced with permission of Macmillan Publishing Company from The cerebral cortex of man by Penfield & Rasmussen. Copyright 1950 Macmillan Publishing Company; copyright renewed 01978 Theodore Rasmussen.)

allowed information about the flow through only the most superficial structures to be used as a gauge of increased or decreased local metabolism, resulting from more, or less, functional neuronal and synaptic activity in the region. Positron emission tomography (PET), whether used to study regional cerebral blood flow or to examine directly the regional metabolism or transmitter turnover of the brain, can, by its very nature, allow deep as well as superficial regions of the brain to be examined. Methods of illustrating blood flow or metabolism in these deep structures have been developed which allow tomographic sections to be constructed by computer and to reveal functional activities in deep, previously hidden regions. Yet we shall still need to validate the precise relationships between oxygen consumption, glucose metabolism, blood flow changes and neuronal interactions which describe these phenomena quantitatively (Fig. 2).

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Introduction

NERVE SIGNAL TRANSMISSION

FIG. 2. This schematic diagram illustrates the deductive steps that are involved in interpreting changes in glucose metabolism or blood flow as modifications of neuronal activity which must have occurred in regions of the brain. Although oxygen consumption and blood flow are linked, the temporal relationships between changes in these following alterations in nerve signal transmission are poorly understood, and the precise neurophysiologicalcauses of the energy debt, and such things as the quantitative metabolic costs of excitation and inhibition at synapses, are still debated.

How has the evidence obtained with these new techniques, in normal human subjects and in those with disordered brain function, advanced our knowledge of the functional anatomy of the human brain? Which aspects of any global neuronal function, that can be separately described, are in fact localized, where are these localized, and what are the biochemical mechanisms used for that localization? That is what we are here to discuss. However, we shall also have to attempt to evaluate the techniques themselves, to examine the influence of the methods used on the functional anatomical information that they make available to us. Have we significantly advanced our knowledge beyond that

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available from the results of electrical stimulation or other studies? What are the limitations of the techniques? What is the spatial resolution of the method of measurement and does this vary with the different positron emitters that are used to probe different metabolic events? How could spatial resolution be improved? A major problem for the study of analysable function has been the temporal resolution of all our methods of studying the human brain, apart from the realtime measures of electrical or magnetic changes produced by the nervous tissue itself during the performance of that function. Can the real-time evaluation of function be analysed, using modifications of PET, and what are the approaches that could be adopted to relate changing metabolic events directly, and temporally, to functional states, even while these are occurring? A part of the programme of this symposium must deal with the technique itself and with the sophisticated computer manipulation of measures of the coincidence of events. But the several brain functions, to the study of which the method is applied, also need our consideration. Some of those functions are ones in which there is an opportunity to control the stimulus and to analyse the details of the response. Human vision is a case in point. Already we know a great deal about the functional anatomy and the psychophysics of vision. In relation to other aspects of human brain function we have less ability to control the physiological events whose underlying regional metabolic changes we wish to analyse. Learning and memory and language are cases in point. It is surely to address these more complex questions that we need to apply new research tools, and we should not be daunted by the difficulties of interpreting the results of our studies. Finally, is there a clinical role for these investigations in the understanding of disorder in the human brain, and what is the role of PET in diagnosis? Are there examples, other than the localization of a difficult-to-detect epileptic focus, of the application of PET in patient management? We shall hear about the role of PET in following recovery from brain injury and in assessing frontal lobe function with relevance to psychiatric illness. Is this an indication that the routine monitoring of brain status in some clinical conditions may employ these methods in the future? As a neurophysiologist, I shall be interested to learn whether we have evidence of changes in regional function during development, as learned patterns of behaviour are established; or as the nervous system ages and the functional capacities of the human brain decline. Where do these changes during development or during ageing manifest themselves, and what is their biochemical basis? At this exciting stage of the development of this technique and its applications, the questions that can be raised outnumber the answers that have yet been provided. At this symposium, however, we have the opportunity to exchange views on the latest evidence that is available, to speculate on its meaning, and to project our thinking into the future and into the unknown.

Introduction

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References Penfield W, Boldrey E 1937 Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain 60:389-443 Penfield W, Rasmussen AT 1950 The cerebral cortex of man. A clinical study of localisation of function. Macmillan, New York

Basic aspects of functional brain metabolism Robert C. Collins

Department of Neurologyp Reed Neurological Research Center, UCLA School of Medicine, Los Angeles, CA 90024, USA

Abstract. Brain energy metabolism and blood flow are greatest in neuropil where there is a high density of oxidative enzymes and capillaries. Here fluctuations in synaptic potentials cause the greatest demand on metabolism through the continuous need to pump ions to maintain membrane charge. A transient increase in functional activity within a pathway causes an increase in energy metabolism followed by an increase in blood flow. The vascular response is biphasic, with an initial increase followed by a plateau phase. The site and magnitude of the response reflect the quality and intensity of the stimulus. Prolonged changes in functional activity within a pathway cause a reorganization of energy metabolizing

enzymes and vascular architecture.

1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 6-22

The last several years have witnessed important advances in the use of positron emission tomography for the study of functional anatomy in humans. New techniques and experimental strategies can now provide partial localization of simple and complex sensory processing (Fox et a1 1987a,b, Lueck et a1 1989), aspects of language (Petersen et a1 1988, 1990) and selected cognitive functions (Posner et a1 1988, Pardo et a1 1991). This progress has largely come from improvement in temporal resolution, which means that it is now possible to study blood flow changes in brain functional activity in time windows of 40 seconds (Raichle et a1 1983). In addition, improvements in tomographic design now permit studies of glucose utilization in small zones and structures in brain, such as the superior colliculus and the cerebellar dentate nucleus (Spinks et a1 1988). Finally, advances in image analysis have allowed subtraction of one image from another-permitting the subtraction of different behavioural states from each other (Fox et a1 1988). This has allowed the separation of experimental states from control conditions, as well as the localization of more complex brain functions either ‘parallel’ to simple functions, or in a hierarchical relation to them. The studies underlying these advances are the subject of this symposium. 6

Functional brain metabolism

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TABLE 1 Experimental approaches to functional anatomy ~

Technique

Species

Lesion analysis

Humans and Loss of behaviour after damage to a site animals indicates its contribution to the missing

The epileptic focus

The stimulating electrode The recording electrode

Metabolic mapping

Function

behaviour Focal seizures crudely evoke the functional properties of a site and its circuits Animals The evoked behaviour reveals the functional properties of the stimulated site and its circuits (primarily motor system) Changes in neuronal firing, linked to Animals receptive field stimuli or movement, localize sites and patterns of functional organization Humans and Regional changes in blood flow and energy metabolism localize sites of animals physiological activation Humans

Definitions of functional anatomy are highly dependent on the method of analysis (Table 1). Ultimately there must be some congruence between the various approaches to determining the brain sites and systems activated during selected behaviours. Congruence is high for simple behaviours; for example, all methods agree on the localization of primary visual cortex. The identification of distributed systems underlying complex behaviours will require comparison of results obtained using many different procedures. It is important to define how each method is limited by the sensitivity and capacity of its measurements, if we are to identify false negatives and positives. In order to understand these issues for metabolic mapping it is necessary to appreciate basic aspects of the anatomy, physiology and biochemistry that underlie functional brain changes.

Functional architecture of brain The distribution of blood vessels throughout the brain follows a few common principles of design (Bar 1980). For laminated structures like cerebral cortex, hippocampus and the olfactory bulb, surface arteries break up into arterioles that penetrate at right-angles into the brain. The distribution of penetrating arterioles is non-random on cerebral cortex and reflects functional organization, such as the whisker fields in the rodent’s somatosensory cortex (Pate1 1983). Feeding capillaries branch off from the penetrating arterioles to supply capillary networks within horizontal laminae. The penetrating arterioles lie in register with the vertical orientation of ascending cortical dendrites, whereas capillary

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networks become differentially distributed to supply functional subspecializations along or within horizontal laminae. The variation in capillary density throughout brain shows a high correlation ( r = 0.88, P
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The functional architecture of the brain thus reflects a highly heterogeneous pattern of metabolic and vascular structures distributed t o serve different intensities of function. Zones with high densities of cytochrome oxidase activity and capillaries have the highest rates of glucose utilization and blood flow in the resting or control state. These zones would have a higher steady state of synaptic activity-ion pumping-energy utilization than other areas, regardless of the behavioural function subserved. Some zones that are relatively poor in oxidative metabolism and capillary supply are relatively rich in glycolytic enzymes. The separation of these zones is best appreciated in archaecortex and palaeocortex (Fig. 1). Activation of functional zones Simple sensory stimulation has proved to be the best experimental paradigm for studying basic aspects of functional activation of brain. Using the visual system of rat, Miyaoka et a1 (1979) found a quantitative relationship between the intensity of light and the magnitude of glucose utilization in visual centres. We (Toga & Collins 1981) found a linear relationship between the frequency of photoflash stimulation and increasing glucose utilization in rat superior colliculus. The lateral geniculate nucleus and visual cortex did not show a robust response to this type of stimulus, however, reflecting the fact that on-off receptive field signals project primarily to the superior colliculus. This indicates the importance of stimulus quality in activating functional zones. Moving bars and gratings are very poor activating visual stimuli for rodents, but very potent stimuli for cats and primates. Similarly, electrical stimulation of a peripheral nerve is not as potent a stimulus as the natural use of a nerve’s function, such as the tactile-kinaesthetic exploration of an object. Stimulation of the median nerve (R. C. Collins & M. E. Raichle, unpublished observations) does not produce as great an increase in focal somatosensory blood flow and metabolism as either passive vibration (Fox et a1 1987b) or active object manipulation (Ginsberg et a1 1988). Stimulus frequency is also an important variable when activating brain. Stimulation of rat forelimb motor cortex (500 Hz, 20 ms train stimuli) produced a linear increase in glucose utilization in first-order projections (e.g. caudate) with rates up t o 60 stimuli/minute, but no further increase up to 180/minute (Collins et a1 1986). By contrast, metabolism continued to increase linearly in second-order projections in globus pallidus and substantia nigra. This indicates that functional zones have different capacities for responding t o high frequency electrical stimulation. There can also be a dissociation between blood flow and metabolism at high rates of stimulation. Whereas glucose utilization increases linearly in rat superior colliculus with photoflash up to 32/s, blood flow only increases up to 8/s (Sundermann et a1 1985). Photoflash stimulation in man likewise causes an increase in visual cortex blood flow up to 8 stimuli/s, with

Collins

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a

FIG. I. Segregation of energy metabolizing enzymes and capillaries in laminated brain structures. (a) Olfactory bulb. The anatomical inputs into the histological fields are diagrammed at the top of the figure. (A) shows histological staining using thionin. There is a high density of capillaries (B), cytochrome oxidase activity (C), and lactate dehydrogenase activity (D) in the glomerular zone (GL). Cytochrome oxidase and capillaries are also high in the external plexiform layer (EPL) where lactate dehydrogenase is low. Histological layers: olfactory nerve layer (ONL), glomerular layer (GL), external plexiform layer (EPL), mitral body layer (MBL), inner plexiform layer (IPL) and granule layer (GRL). Other abbreviations: C, centrifugal fibres; AON, fibres from anterior olfactory nucleus; AC, fibres from anterior commissure.

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b

FIG. 1. Segregation of energy metabolizing enzymes and capillaries in laminated brain structures, (b) Olfactory cortex. (A) shows histological staining using thionin. Compare the density of capillaries (B), cytochrome oxidase activity (C) and lactate dehydrogenase activity (D) among the histological fields. All three are relatively high in zone IA, which receives input from the lateral olfactory tract (LOT). Cytochrome oxidase activity and capillary density fall in zone IB, which receives association fibres (ASSOC.) from the prepiriform cortex. (Fig. 1 from Borowski & Collins 1989a by permission of Alan R. Liss, Inc.)

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a falling off in response beyond that (Fox & Raichle 1984). These results indicate the capacity of a system to follow repetitive stimuli. The dissociation of flow and metabolism and the decremental blood flow response at high stimulus rates (and in pathological conditions) probably reflect the unnatural properties of the stimulus condition. Simply put, the functional architecture of the nervous system was not designed to process stimuli at unnaturally high frequencies or intensities. The site and magnitude of response reflect the quality and intensity of stimuli in the real world. The sequence of responses in functional zones upon activation has become better clarified with the introduction of new techniques and experimental strategies. High resolution optical imaging techniques allow the visualization of sequential changes in cortical blood flow and metabolism in vivo in response to afferent stimulation (Grinvald et a1 1988). Charge-capture devices are used to measure changes in the reflectance of light from cortex at different wave lengths of stimulation. Extremely small signals can be detected at high spatial resolution, using signal averaging and image analysis techniques. The method has allowed the study of changes within the functional zones tuned to ocular dominance, orientation and colour (Ts’o et al 1990, Frostig et a1 1990). The arrival of a sensory volley into a cortical zone causes an activity-dependent change in light absorbance when illumination at 600-639nm is used. This is thought to reflect shifts in oxygen delivery at capillaries or changes in the state of cytochromes and/or NADH. This event is followed quickly by changes in absorbance with illumination at 570 nm, which reflects an increase in haemoglobin or blood volume. Studies using high resolution optical imaging thus confirm that physiological activation of brain activates metabolism first, then blood flow. Using a different approach, Ngai et a1 (1988) have also found a delay in the blood flow response to afferent stimulation. These investigators stimulated rat sciatic nerve and measured changes in the diameter of pial arterioles. Of interest, they found a frequency-dependent response, with maximal arteriolar dilatation at 5 Hz (0.15 V, 0.5 ms) with a decrement at higher rates. The vascular response was both delayed, beginning a few seconds after the onset of stimulation, and biphasic, with a rapid 2-3 second maximal 150% dilatation followed by a prolonged plateau (1 16%). Vasodilatation usually outlasted the stimulus by several seconds. The origin of the vascular response remains unclear. Although neurotransmitter receptors have been found on arterioles and capillaries, their precise physiological role remains uncertain (see review, Collins 1987). The delay and biphasic nature of the response suggests the release of a metabolic substance that causes an immediate maximal response, followed by a wash-out of the stimulus. Adenosine (Morii et a1 1987) and nitrous oxide (Moncada et a1 1988) are two possible chemical substances that could play a role in the vascular response. Because afferent sensory stimuli first activate middle layers of cortex, it is unclear how metabolic signals here are communicated to surface arterioles.

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Various hypotheses are being tested that include intercellular electrotonic coupling within a vascular tree (Segal & Duling 1986) and delivery-diffusion of metabolites from veins leaving an activated zone to dilate incoming arterioles (Hester 1990). Plasticity of functional architecture The quantity of energy-related enzymes in sensory pathways is dependent upon the quantity of stimulation. Sensory deprivation causes a decrease in the mitochondria1 oxidative enzyme cytochrome oxidase in sensory pathways in animals and man (Dietrich et al 1981, Horton & Hedley-Whyte 1984; for review, Wong-Riley 1989). Lesions or impulse blockade of central pathways will also cause changes in energy-related enzymes in terminal fields. When lesions (Borowski & Collins 1989b) or reversible impulse blockade (Collins & Borowski 1991) are induced in the perforant pathway into the hippocampus, a decrease occurs in cytochrome oxidase activity in the outer two-thirds of the dentate gyrus. At the same time there is an increase and expansion of the lactate dehydrogenaserich zone of the inner third of the dentate gyrus. This occurs as the commissural pathway sprouts and expands. These studies indicate that the location and density of energy metabolism enzymes are determined by the distribution and activity of specific pathways. Sensory stimulation can cause an increase in components of functional metabolism. An increase in whisker activity in rodents causes changes in energyrelated enzymes in cortical barrels (Dietrich et a1 1982). Extensive physical treadmill exercise in rats causes an increase in capillary density in forelimb zones in the cerebellum (Black et a1 1990). By contrast, motor learning in rats causes an increase in synaptogenesis in these same zones, but no increase in capillary density. These studies indicate that prolonged intense repetitive use of synapses result in the production of more enzyme and capillaries to serve energy needs, while learning entirely new behaviours results in new synapses with an expansion of the existing functional architecture. There are several implications from these experiments in animals for positron emission tomography (PET) studies in man. First, the pattern and intensity of resting metabolism and blood flow depend upon the exact behaviour of the subject ‘at rest’. This must be defined and controlled carefully. Considerable variance will occur between control subjects unless sensory, motor and internal stimuli are precisely matched. Second, considering the plasticity of functional architecture, there will always be an irreducible variance that will reflect the different histories of individuals. Learning and training are experiential factors that sculpt the functional architecture of brain. For these reasons, each subject will be his best control for comparing subtle differences in functional states. In addition, knowing the comparative differences in functional metabolic maps among individuals of different functional skills would be instructive. ,

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Finally, functional maps can be changed. Learning new skills should a d d new features, while intense training should increase the magnitude of responses. PET studies could provide a n opportunity to localize, define and study unique attributes of the human brain.

References Auker CR, Mesler RM, Carpenter DO 1983 Apparent discrepancy between single unit activity and [ I4C]deoxyglucose labeling in optic tectum of the rattlesnake. J Neurophysiol 49: 1504- 1516 Bar T 1980 The vascular system of the cerebral cortex. Adv Anat Embryo1 Cell Biol 59: 1-65 Black JE, Isaacs KR, Anderson BJ, Alcantara AA, Greenough WT 1990 Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc Natl Acad Sci USA 875568-5572 Borowski IW, Collins RC 1989a Metabolic anatomy of brain: a comparison of regional capillary density, glucose metabolism, and enzyme activities. J Comp Neurol 288~401-413 Borowski IW, Collins RC 1989b Histochemical changes in enzymes of energy metabolism in the dentate gyrus accompany deafferentation and synaptic reorganization. Neuroscience 33:253-262 Collins RC 1987 Physiology-metabolism-bloodflow couples in brain. In: Raichle ME, Powers WJ (eds) Cerebrovascular diseases. Raven Press, New York, p 149-163 Collins RC, Borowski IW 1991 Metabolic architecture of brain, oxidative and glycolytic systems. In: Ingvar DH, Lassen NA, Raichle ME, Friberg L (eds) Brain work 11. Munksgaard, Copenhagen (Alfred Benzon Symposium 3 l), in press Collins RC, Santori EM, Der T, Toga AW Lothman EW 1986 Functional metabolic mapping during forelimb movement in rat. I. Stimulation of motor cortex. J Neurosci 6~448 -462 Dietrich WD, Durham D, Lowry OH, Woolsey TA 1981 Quantitative histochemical effects of whisker damage on single identified cortical barrels in the adult mouse. J Neurosci 1:929-935 Dietrich WD, Durham D, Lowry OH, Woolsey TA 1982 ‘Increased’ sensory stimulation leads to changes in energy-related enzymes in the brain. J Neurosci 2:1608-1613 Fox PT, Raichle ME 1984 Stimulus rate dependence of regional cerebral flow in human striate cortex, demonstrated by positron emission tomography. J Neurophysiol 51:1109-1121 Fox PT, Miezin FM, Allman JM, Van Essen DC, Raichle ME 1987a Retinotopic organization of human visual cortex mapped with positron-emission tomography. J Neurosci 7:913-922 Fox PT, Burton H, Raichle ME 1987b Mapping human somatosensory cortex with positron emission tomography. J Neurosurg 67:34-43 Fox PT, Mintun ME, Reiman EM, Raichle ME 1988 Enhanced detection of focal brain responses using intersubject brain averaging and change-distribution analysis of subtracted PET images. J Cereb Blood Flow Metab 8:642-653 Frostig RD, Lieke EE, Ts’o DY, Grinvald A 1990 Cortical functional architecture and local coupling between neuronal activity and the microcirculation revealed by in vivo high-resolution optical imaging of intrinsic signals. Proc Natl Acad Sci USA 87:6082-6086

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Ginsberg MD, Chang JY, Kelley RE et all988 Increase in both cerebral glucose utilization and blood flow during execution of a somatosensory task. Ann Neurol 23: 152- 160 Grinvald A, Frostig RD, Lieke E, Hildesheim R 1988 Optical imaging of neuronal activity. Physiol Rev 68:1285-1366 Hester RL 1990 Venular-arteriolar diffusion of adenosine in hamster cremaster microcirculation. Am J Physiol 258:H1918-1924 Horton JC, Hedley-Whyte ET 1984 Mapping of cytochrome oxidase patches and ocular dominance columns in human visual cortex. Philos Trans R SOCLond B Biol Sci 304:255-272 Livingstone M, Hubel D 1988 Segregation of form, color, movement, and depth: anatomy, physiology, and perception. Science (Wash DC) 240:740-749 Lueck CJ, Zeki S, Friston KJ et all989 The colour centre in the cerebral cortex of man. Nature (Lond) 340:386-389 Mata M, Fink DJ, Gainer H et al 1980 Activity dependent energy metabolism in rat posterior pituitary primarily reflects sodium pump activity. J Neurochem 34:213-215 Miyaoka M, Shinohara M, Batipps M, Pettigrew KD, Kennedy C, Sokoloff L 1979 The relationship between the intensity of the stimulus and the metabolic response in the visual system of the rat. SOCNeurosci Abstr 5:411 Moncada S, Radomsk MW, Palmer MJ 1988 Endothelium-derived relaxing factor. Biochem Pharmacol 37:2495-2501 Morii S, Ngai AC, KO KR, Winn HR 1987 Role of adenosine in regulation of cerebral blood flow: effects of theophylline during normoxia and hypoxia. Am J Physiol 253 :H165-H175 Ngai AC, KO KR, Morii S, Winn HR 1988 Effect of sciatic nerve stimulation on pial arterioles in rats. Am J Physiol 254:H133-H139 Pardo JV, Fox PT, Raichle ME 1991 Localization of a human system for sustained attention by positron emission tomography. Nature (Lond) 34951 -64 Patel U 1983 Non-random distribution of blood vessels in the posterior region of the rat somatosensory cortex. Brain Res 289:65-70 Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME 1988 Positron emission tomographic studies of cortical anatomy of single-word processing. Nature (Lond) 331:585-589 Petersen SE, Fox PT, Snyder AZ, Raichle ME 1990 Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science (Wash DC) 249:1041-1044 Posner MI, Petersen SE, Fox PT, Raichle ME 1988 Localization of cognitive operations in the human brain. Science (Wash DC) 240:1627-1631 Raichle ME, Martin WRW, Herscovitch P, Mintun MA, Markham J 1983 Blood flow measured with intravenous H2150. J Nucl Med 24:790-798 Segal SS, Duling BR 1986 Flow control among microvessels coordinated by intercellular conduction. Science (Wash DC) 2342368-870 Spinks TJ, Jones T, Dilardi MC, Heather JD 1988 Physical performance of the latest generations of commercial positron scanners. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 35:721-725 Sundermann R, Gitelman D, Toga AW, Collins RC 1985 There is a loose relationship between cerebral blood flow and metabolism during visual stimulation. SOCNeurosci Abstr 11:1125 Toga AW, Collins RC 1981 Metabolic response of optic centers to visual stimuli in albino rat: anatomical and physiological considerations. J Comp Neurol 199:443-464 Tootell RBH, Silverman MS, Hamilton SL, De Valois RL, Switkes E 1988a Functional anatomy of macaque striate cortex. 111. Color. J Neurosci 8:1569-1593 Tootell RBH, Silverman MS, Hamilton SL, Switkes E, De Valois RL 1988b Functional anatomy of macaque striate cortex. V. spatial frequency. J Neurosci 8:1610- 1624

16

Collins

Ts’o DY, Frostig RD, Lieke EE, Grinvold A 1990 Functional organization of primate visual cortex revealed by high resolution optical imaging. Science (Wash DC) 249~417-420 Wong-Riley MTT 1989 Cytochrome oxidase: an endogenous metabolic marker for neuronal activity. Trends Neurosci 12:94- 101 Zeki S 1991 A century of cerebral achromatopsia. Brain 113:1721-1778

DISCUSSION

Porter: Let me invite discussion on any of the issues raised in Dr Collins’ paper, and perhaps particularly on the nature of the changes that have been described in relation to plasticity of function. Zeki: I am interested in a problem with respect to colour vision. Two apparently contradictory results have been obtained. One is a temporary loss of colour vision in cases of arterial insufficiency, coupled to falling attacks. The general view is that this loss is due to some deficiency in the arterial system which supplies the occipital lobe. It is transient, and the subjects recover their colour vision quickly (within hours). One could account for this recovery by saying that the blobs of the striate cortex, which are metabolically very active and have a good blood supply, are much more susceptible to an arterial insufficiency than are the metabolically less active interblobs. Against that is the well-documented fact that subjects with carbon monoxide poisoning commonly have a selective sparing of colour vision. Several studies have described this independently. Yet one would expect that the blobs, which are much more susceptible to hypoxia than the interblobs, would be much more impaired than the latter in carbon monoxide poisoning. Mazziotta [replying f o r Dr CollinsJ: This is certainly a paradox. One possibility is a non-uniform effect of injury across the brain. We know that sublethal carbon monoxide poisoning produces selective neuroanatomical damage to different parts of the brain; globus pallidus is damaged more than cortex. Similarly, regions of hypoperfusion will have a distribution of susceptibility to ischaemia which seems t o be more related to vascular supply and watershed zones. However, from the point of view of colour vision centres which might be neuroanatomically distinct, as opposed to the initial colour system in the visual (calcarine) cortex, which is distributed uniformly, although in a non-random fashion, according to the blobs, it is difficult t o explain those two facts that you describe. One might have to consider the secondary areas where colour vision is organized as neuroanatomically distinct operations. Zeki: Is it established that areas of high metabolic activity in the cerebral cortex, such as the stripes of V2 or the blobs of V1, are richer in blood supply than metabolically less active subregions? Is the capillary bed richer? Porter: Surely Dr Collins’ presentation would suggest that this is so, but there is currently no published work that addresses these questions directly.

Functional brain metabolism

17

Mazziotta: In the example of the hippocampal dendritic organization that Dr Collins gave (p 8), the implication is of an increased capillary density. Raichle: I wonder if the data are not simply lacking. Tom Woolsey, in exciting preliminary work on the mouse whisker barrel (Woolsey et a1 1990), has begun to look at the capillary architecture and the different layers of the cortex, and has shown glomeruli of capillaries in certain layers. This is some of the first detailed work related to this kind of organization of the cortex. I am not aware that it has been done with the blobs and interblobs. If it hasn’t, it would be extremely interesting to know if similar types of vascular organization accompany functionally organized areas. Zeki: What happens in the barrel fields? Raichle: The mouse whisker barrels are not only more vascular, but if you look at them in a cross-section of the cortex, the vascular pattern changes as you go through the layers; there is almost a glomerulus-like structure of the capillaries in layer four. It is highly specialized. One would guess that the blobs have something similar. Porter: Professor Zeki, do you have a comment yourself about the paradox that you raised? Zeki: No; I am very puzzled by it. I think the facts are correct, but I have not been able to reach a conclusion. Plum: The clinical circumstances of carbon monoxide poisoning are tricky, because the process produces an impure mixture of hypoxia and oligaemia. We are accustomed to attributing to carbon monoxide a pure effect of anoxaemia on the brain, but in fact there is also a profound effect on cardiovascular output. In all probability, for example, the striatal ischaemia that so often occurs is due to hypotension and focal underperfusion, rather than an even-handed hypoxia distributed equally across all brain areas. Whether the double vascular supply from middle and posterior cerebral artery origins to the occipital pole provides relative sparing to certain groups of neurons, I do not know. Nevertheless, I would have thought that the striate cortex, being supplied by the terminal branches of both arteries, might very well share with the basal ganglia a selective vulnerability to hypoperfusion in the face of systemic hypotension. In this respect, then, human carbon monoxide poisoning may not represent a satisfactory model by which to judge the effects of pure hypoxaemia on the occipital cortex. Raichle: I have often wondered whether there is a differential susceptibility to hypoxia in the area of the blobs. Where one is dealing with more reversible levels of hypoxia, one might wonder whether there is a differential diminution in the ability to perceive colour. I am not aware of such studies, but they must have been done. Zeki: I haven’t seen such a case myself, but from the literature, although colour vision is not unaffected after carbon monoxide poisoning, it is much less affected than other visual attributes. Such patients often have to use colour to identify objects, which they therefore identify wrongly.

18

Discussion

Plum: Dr Mazziotta, is the lactate dehydrogenase concentration proportionally elevated in relation to other cortical areas, or is it simply that cytochrome oxidase is relatively deficient, in the areas of high LDH concentration? Mazziotta: I am uncertain about the absolute values. It is simply a map of the relative difference between the two enzymes. Plum: The implication of my question was an attempt to find out what is the biological advantage of the increased LDH concentrations. Mazziotta: If the particular area of brain is primarily operating on glycolysis, rather than oxidative metabolism, this could be important. Plum: I’m sorry, I still don’t understand the advantage. Sokoloff: The biological advantage would be under conditions of special stress. The glycolytic enzymes that are usually present in brain tissue are in considerable excess of their normal physiological use. It is estimated that the use of hexokinase is about 2-5% of its total capacity in the brain in normal conditions. The brain, however, more than any other organ, has the capacity to increase its rate of glycolysis. In complete anoxia, for example, there is about a 10-fold increase in glycolytic rate, and lactate accumulates because of conversion of pyruvate to lactate by lactate dehydrogenase. This great capacity for increasing its glycolytic rate could be an advantage under conditions in which there is a deficiency of oxygen. In normal conditions, LDH may not have much to do, but its biological value is in the protection it offers against special periods of stress due to the lack of oxygen, when it serves as a reservoir for oxidative substrates when the oxygen is restored. Also, glycolysis itself provides some ATP generation, though less then oxidative metabolism. Raichle: Could you speculate why LDH is differentially distributed, as Bob Collins has shown? Are the areas where it seems to be proportionately greater also those areas that would be more phasically active? SokolofJ I could only speculate teleologically. LDH may be highest in regions that may have the greatest danger of becoming deficient in oxygen, under certain circumstances, and also in regions with normally high rates of energy metabolism. Porter: Do we know whether the enzyme measurements relate to synaptic organizations, or to glial structures? There is a considerable difference in the distribution of synaptic complexes and glial arrangements within the brain regions shown to have high concentrations of the different enzymes. Do we understand the significance of those differences in terms of neuronal or synaptic function? Sokoloff: This is not known. In general, the enzymes of energy metabolism correlate well with blood flow rates of the brain regions and also with energy metabolism rates (Friede 1966, Turek et a1 1986). We also found a good rankorder correlation between the density of capillary surfaces that Craigie (1920) had described and the local rates of blood flow in the brain (Sokoloff 1961). At about that time, Friede (1966), working on a histochemical assay of succinate

Functional brain metabolism

19

dehydrogenase, found a good correlation between the distribution of this Krebs cycle enzyme and rates of blood flow, and also with capillary density. So there seems to be a correlation. Whether it has to do with glial or neuronal elements is still unresolved. Frackowiak: It is of special interest to those who are studying the brain using positron tomography to have clear the evidence that the majority of the energy is consumed at the synaptic terminals, particularly in relation to some of the features discussed in Dr Collins’ paper relevant to the plasticity of the brain; because that implies synaptic change of a rather more permanent nature, and opens up the possibility that one can measure those plastic changes. Such changes need not be initiated only as a result of development, or injury, but also as a result of learning, or changes of a pharmacological nature. I therefore wonder how strong the evidence is, and if we know what proportion of the energy metabolism is due to synaptic activity. Sokoloff: I can’t give you a quantitative estimate of how much is due to synaptic activity and how much t o the metabolic activity going on in neuronal and glial cell bodies, but the evidence that the function-related changes in energy metabolism are primarily in synaptic regions of the brain is strong, and I have some data on this (see General discussion, p43). Porter: Another, related matter concerns the time scale of the plastic changes in synaptic density and in enzymic distribution that were illustrated in the experimental study on rats. Do we know the time scale of the increases in activity of different enzymes with plastic changes in brain function? Mazziotta: In the study of Black et a1 (1990) it was in the order of weeks. There are also interesting human data, from changes in children, where the ‘plasticity clock’ may be running at a higher rate. These children were having a portion of the brain removed, because of epilepsy. We were able to observe reorganization of the remaining structures- cerebellar changes and ipsilateral and contralateral hemispheric changes-at various time intervals, where the structure is still present but its activity falls. On Dr Plum’s earlier question about the value of having high activity of glycolytic enzymes in certain brain areas, I can think of another possibility. In a neuronal system like the hippocampus, the distal neuropil zone is high in capillaries, glucose utilization and cytochrome oxidase, and the proximal perikaryon zone has elevated LDH activity. If one were suddenly to lower the substrate supply to that whole system, what would survive is the proximal zone, high in LDH. If you wanted to protect the system with any chance of regeneration, it seems reasonable that you would want to protect the cell body and proximal axon and dendritic tree. Those elements might then allow for a subsequent sprouting or reorganization, following the extreme conditions. Plum: Why protect it with the least efficient enzyme? Mazziotta: If the system is going to be most susceptible to losses in oxygen, that would provide the reason. If you are saying that the only chance of survival is via carbohydrates, then anaerobic enzyme systems should predominate.

20

Discussion

Sokoloff: One possibility is that the neuron can lose its terminals, and the terminals will regenerate, but if the cell body is destroyed, then the terminals and functional usefulness of the cell body can’t be regenerated. Plum: Barbiturate anaesthesia reduces by about 63% the overall oxidative uptake of the cerebral cortex. Using PET technology, Blacklock et al (1987) measured 2-deoxyglucose uptake in patients with brain tumours. The resulting values showed a 67% reduction in cortical grey matter uptake-a reduction similar to that found in the human chronic vegetative state by Levy et a1 (1987). Given the pharmacology of barbiturates and the profound reduction in energy metabolism, one could infer that synaptic blockade was largely responsible for the decline in glucose consumption. Wise: I am interested in the question, raised in Dr Collins’ paper, of the tendency of blood flow to increase when you give an intermittent stimulus up to a certain rate, and then to fall off rapidly as the stimulus rate increases (Fox & Raichle 1984). Does the organism still appreciate that the stimulus is in fact intermittent, beyond the range when blood flow starts to fall, or does it then appreciate the stimulus (photoflash) as a continuous stimulus? Fox: The falling-off of blood flow occurs well before flicker fusion; all the subjects in that experiment can appreciate the stimulus as flickering above 50 Hz, whereas the blood flow begins to decline by 32Hz (Fox & Raichle 1984). Frackowiak: Can we consider the question of blood flow, and the metabolism of oxygen and of glucose and their relationship? When we think about the synaptic terminals, where cytochrome oxidase concentration is highest, and where the majority of the energy consumption that is associated with brain function is expended, we are led to believe, through the results of Dr Raichle’s laboratory, that glucose and oxygen consumption are profoundly uncoupled. How is that explained, in evolutionary or functional or biochemical terms? Raichle: The observations in our laboratory, on both the visual and the somatosensory systems (Fox & Raichle 1986, Fox et a1 1988), and now the corroborative evidence in humans from magnetic resonance spectroscopy (personal communication, J. W. Prichard & R. G. Shulman, Yale University), all suggest that under the stimulus conditions that we use, there is an uncoupling of glucose and oxygen consumption, but there’s no obvious explanation for this. One could of course generalize and say that this is a general principle and at whatever level the system is going to perform this way, but we don’t have direct evidence for that. Another possibility is that with the kind of stimuli being used, or the rate at which they are presented, one pushes the system to a point where it resorts to this ‘uncoupled’ behaviour; if one stimulated at a lower rate, and produced blood flow changes that are more commonly seen with the kind of activation studies that will be discussed here, and instead of changes in flow of 40-50% in the local area, we produced flow changes of 5-lo%, the same uncoupling might not occur. We don’t have an answer to that.

Functional brain metabolism

21

Frackowiak: If I may speculate further, to try to resolve this puzzling phenomenon, might it be that the changes in blood flow and glucose metabolism that you see are not due to what is happening within the synapse itself, but rather due to cellular elements that lie around the synapse and help maintain its functional integrity? We may be seeing an in vivo ‘amplification system’ which is convenient for us working with PET, but which in itself is an indirect marker of synaptic firing, to which it is coupled through mechanisms which are not understood. Raichle: Yes. It seems to me that some very interesting experiments could be done here. The blob-interblob system might be ideally suited to that, because you have systems or areas that segregate according to their enzymic ‘anatomy’, and we have means through stimuli to turn various components of this on differentially (for example, see Livingstone & Hubel 1987). It might lend itself to looking at this coupling in different elements within an area. One might expect to find that, depending upon which parts of the system are differentially stimulated, you get more, or less, oxidative metabolism. This is also speculation, but it’s certainly an experiment that can be designed and probably executed. Roland: There is one piece of evidence missing when we discuss whether high frequency stimulation of the sensory system would involve a greater increase in blood flow throughout the frequency range, as you imply. This evidence concerns the postsynaptic potentials, which we don’t know about. We do not know about the excitatory and inhibitory postsynaptic potentials after such stimulation. I am not aware of any data which tell us to what extent the integrated EPSPs in the dendritic tree of neurons in such a stimulated area do increase at high frequency stimulation. This is the evidence that we have to consider in order to interpret why the blood flow decreases at a higher stimulus frequency and why the glucose consumption seems to increase when measured with 2-deoxyglucose. Collins [author’s note added in proof]: A recent study of the vascularization of primate visual cortex is of interest (Zheng et a1 1991). There is an increased density of radial vessels (20-50 pm) and capillaries in cytochrome oxidase-rich blobs compared to interblobs in area 17, and in cytochrome oxidase-rich stripes compared to interstripes in area 18. Within cortex the capillary density is greatest in lamina IVc. These findings support the observation that capillaries and oxidative enzymes are distributed in support of high resting functional activity. References Black JE, Isaacs KR, Anderson BJ, Alcantara AA, Greenough WT 1990 Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc Natl Acad Sci USA 875568-5572 Blacklock JB,Oldfield EH, DiChiro G et a1 1987 Effect of barbiturate coma on glucose utilization in normal brain versus gliomas. Positron emission tomography studies. J Neurosurg 67:11-75

22

Discussion

Craigie EH 1920 On the relative vascularity of various parts of the central nervous system of the albino rat. J Comp Neurol 31:429-464 Fox PT, Raichle ME 1984 Stimulus rate dependence of reigonal cerebral flow in human striate cortex, demonstrated by positron emission tomography. J Neurophysiol 5 1:1 109- 1 121

Fox PT, Raichle ME 1986 Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci USA 83:1140-1144 Fox PT, Raichle ME, Mintun MA, Dence C 1988 Nonoxidative glucose consumption during focal physiologic neural activity. Science (Wash DC) 241:462-464 Friede RL 1966 Topographic brain chemistry. Academic Press, New York Levy DE, Sidtis JJ, Rottenberg DA et a1 1987 Differences in cerebral blood flow and glucose utilization in vegetative versus locked-in patients. Ann Neurol 22:673-682 Livingstone MS, Hubel DH 1987 Psychophysical evidence for separate channels for the perception of form, color, movement and depth. J Neurosci 7:3416-3468 Sokoloff L 1961 Local cerebral circulation at rest and during altered cerebral activity induced by anesthesia or visual stimulation. In: Kety SS, Elkes J (eds) The regional chemistry, physiology and pharmacology of the nervous system. Pergamon Press, Oxford, p 107-117 Turek TJ, Hawkins RA, Wilson JE 1986 Correlation of hexokinase and basal energy metabolism in discrete regions of brain. J Neurochem 46:983-985 Woolsey TA, Rovainen CM, Robinson 0 1990 Videomicroscopy of flow in single blood vessels in mouse barrel cortex in vivo. SOCNeurosci Abstr 16:25 Zheng D, LaMantia A-S, Purves D 1991 Specialized vascularization of the primate visual cortex. J Neurosci 11 :2622-2629

Rapid measurement of cerebral blood flow with positron emission tomography Hidehiro lida, lwao Kanno and Shuichi Miura Research Institute for Brain & Blood Vessels-Akita,6- 10 Senshu Kubota-Machi, Akita City, 010 Japan

Abstract. The intravenous administration of H2150 makes possible the quantitative evaluation of regional changes in cerebral blood flow (CBF) during various neuronal activations in man. Many variations on this technique have been proposed. We have compared bolus and slow administration procedures and short and long scan lengths. For a short scan period this study suggests that the bolus injection procedure (with a scan length of 60-120 seconds) provides better CBF count statistics and less sensitivity to errors in the input function than the slow infusion procedure. For a long scan length ( > 3 min) the slow infusion procedure is recommended. Continuation of H2I5Oinfusion allows prolongation of the scan length, which enables us to obtain sufficient CBF statistics (the statistical error may be negligibly small if a sufficient amount of H2150 is infused). Another advantage of the slow infusion method may be related to the fluctuation of CBF during the scan period. If CBF fluctuates during this period the slow infusion procedure is expected to provide an average estimate of CBF, whereas the bolus injection procedure provides an estimate (an average over 10 seconds) of CBF which is more sensitive to short-term variations. The feasibility of using I5O, inhalation t o measure regional CBF has also been investigated. By means of a dynamic H,I5O scan which measures the regional distribution volume of water and a static C150 emission scan which measures blood volume prior to the 150,scan, both CBF and cerebral metabolic rate for oxygen (CMRO,) have been accurately measured by the I5O, scan for various physiological conditions. The application of this technique in a human study confirmed the uncoupling of CBF and CMRO, during motor and visual activation.

1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 23-42

The use of the 150isotope of oxygen and positron emission tomography (PET) enables us to measure regional changes in physiological function in living humans because of its short half-life (approximately 2 min). A number of studies have used HzI5Oto detect regional changes in cerebral blood flow (CBF) (Fox et a1 1984, Lammertsma et a1 1990, Friston et a1 1990) and have used the short-period inhalation of gaseous 1502 to make rapid measurements of the regional cerebral 23

lida et a1

24

metabolic rate for oxygen (CMR02) (Mintun et a1 1984, Meyer et a1 1987, Holden et a1 1988). There have been some variations in these techniques, with different rates of administration of tracer and different scanning periods. This article describes studies of the effects of changing the rate of administration and the scan length on the measurement of CBF by H2lS0autoradiography (see below). We have compared bolus or slow administrations and short or long scan lengths. An optimal procedure will then be discussed which has the following aims: (1) to maximize the available counts within a limited short scan period, (2) to minimize effects of non-linearity between CBF and PET-integration counts due to clearance of H2150 from the brain, (3) to minimize effects of errors in the input function (delay and dispersion in the peripherally sampled arterial radioactivity curve), and (4) t o minimize the effects of fluctuating CBF during the scan. Secondly, we have investigated the feasibility of using a short period inhalation of 1502 to measure regional CBF and CMROl simultaneously. This technique has been used in a study of neuronal activation in man. Methods H2lS0 autoradiography

Theory. On the basis of the single-compartment model (Kety 1951), integration of the tissue radioactivity for the scan period [0, TI is given by:

(fp + A ) “ d t ioTCi(t)dt= ~orf.C‘o(t)*e~ where the asterisk denotes the convolution integral, C&) is the arterial input function, Ci(t) the tissue concentration curve, f,regional CBF, p , the partition coefficient, and A the decay constant of 150.Thus, using the measured arterial input function, tissue concentration, and a fixed value of p of 0.80 (mllml), equation (I) can be solved for CBF (f)(Raichle et al 1983, Howard et al 1983, Kanno et al 1984, 1987, Iida et a1 1986, Lammertsma et al 1990). This holds for any H2150 administration speed or scan length. Scan length providing minimum statistical noise. A simulation study has investigated the optimum scan length which minimized statistical uncertainty (i.e. maximized signal-to-noise ratio) in the CBF values calculated for given tracer administration procedures. This simulation addressed both the limited counts in the original PET image and the non-linearity of the relationship between CBF value and the H2ISO accumulation. The simulation was performed for two input functions described in Fig. 1, which were obtained from typical studies in humans with a bolus injection and a continuous (slow) infusion over 3.5 min of H2”O. The statistical error in CBF (ACBF) was estimated according to equation (2),

25

Rapid cerebral blood flow measurement

(AI/$)/f

--

CBF

where Z is the integration of the head curve (I=S,Tci(t) dt), and Waf is the slope of the table of the integration versus CBF. The statistical noise of the integration (AZ) was estimated using equation (1) according to the known statistical relationship, AIocfl. This calculation was done for various scanning periods with CBF values of 0.2, 0.5 and 0.8 ml/min per g. A study was also performed in a volunteer listening to white noise at rest. H2150was given t o the subject eight times at 10-min intervals (four times as a bolus injection and a further four times by slow infusion over a 2-min time period). After each of the H2150administrations a dynamic scan was performed and autoradiographic CBF images were calculated for various scan lengths. A standard deviation of the CBF values (ACBF) and the ratio (ACBF/CBF) were then calculated for each pixel of the CBF images. Effects of delay a n d dispersion in the input function on CBF. The effects of delay and dispersion on the calculated CBF values were evaluated for both the bolus and slow administration procedures. First, integration of the tissue radioactivity curve was calculated according to equation (1) (values of f= 0.5 ml/min per g and p = 0.8 ml/ml were assumed) for various integration

150000

-E

-

'

Bolus

-

injection

100000 -

. v)

n 0

50000

0

-

I . '

'

.

I

..

"'

".

(a1

'

I

.

.

.

'

(b)

FIG. 1. Typical input functions for a bolus injection of H2150(a) and slow infusion of H,I5O over 3.5 min (b) obtained from typical human studies. These curves were used for all simulations. Curves are not corrected for the radioactivity decay.

lida et al

26

periods using both typical bolus and slow input functions. By shifting (delaying) the assumed input function, CBF values were calculated, and errors due to delay were evaluated for various scanning periods. Secondly, the assumed input function was dispersed with a dispersion function assumed to 6e a single exponential function (Iida et a1 1986). CBF values were calculated, and errors due to dispersion were evaluated for various scanning periods. Contribution of transient CBF to total integration. The integrated PET counts are a result of a summation of all the contributions of transient CBF over a short period of time during the scan. In order to estimate this contribution to the total integration when the scanning length and the administration speed are given, the left side of equation (1) has been expanded into a transient domain as a product of a contribution weight, w(t), and transient CBF (equation 3). ioTCi(t)dt= joTw(t)*CBF(t)dt

(3)

The contribution weight is estimated as follows. In conditions of constant CBF, the amount of H2150 extracted into the brain tissue at a certain time, t , is proportional to the temporary arterial concentration, Ca(t), and this radioactivity stays in the tissue, with physical decay and clearance by CBF. The contribution weight (contribution of extracted H2150 at time t to the total integration) is, then, expressed as in equation (4):

This has been estimated for both bolus and slow administration procedures with various scanning periods for f = 0.5 ml/min per g and p = 0.8 ml/ml. CBF and CMROzdetermination by lSO2inhalation Description of the technique. A method has been developed for measuring CBF and CMR02 simultaneously by a single PET scan with a short-period, and its applicability to repeat cerebral activation continuous inhalation of 1502, studies has been investigated. This technique was based on fitting CBF and CMR02, which are defined by Mintun's model (Mintun et a1 1984), to a tissue curve. To complement this technique, the determination measured 1502 of two additional quantities is required before the 1 5 0 2 scans, namely the regional distribution volume of water ( Vd) by a dynamic H2150scan and the regional blood volume (V,) by a static C150 scan. Therefore, dynamic 1502 scans can be repeated to measure CBF and C M R 0 2 for a number of physiological conditions (e.g. at rest and during behavioural activation). The scan is estimated using the arterial H2I50concentration curve during the 1502

Rapid cerebral blood flow measurement

27

whole-blood radioactivity curve by approximating the production of the arterial H2150 by a single rate constant model.

Validation of the technique. In order to validate this technique against our reference method, we performed dynamic H2I5O and dynamic 1 5 0 2 scans together with a static C150scan for two conditions, namely at rest and during motor activation (finger opposition). CBF was calculated by fitting to the dynamic H2150 data, and CMR02 was obtained according to the combined fitting technique (i.e. simultaneous fitting of three parameters of CBF, CMR02 and V, to the dynamic H2150and l S 0 2 curves). These values of CBF and CMR02 were then compared with results from the present technique (i.e. determination of CBF and CMR02 from the I5O2data alone, in which values of Vd and VB were measured at rest by the dynamic H2150 and static C150 scans, respectively). Data obtained from the primary motor cortex region from four healthy volunteers were analysed. The scanner used was a CTI PET scanner (Model 931 09/12 Knoxville, TN, USA) at Hammersmith Hospital, London (Spinks et a1 1988). Application of the technique. The applicability of this technique to a neuronal activation study was tested. The protocol employed was visual stimulation by the use of a flickering visual display (8 Hz). The study was performed on four healthy volunteers, and data were collected from the primary visual cortex region. A set of paired scans of dynamic H2150,dynamic I5O2 and static C150 was made under a resting eyes-closed condition; thereafter, single dynamic 1502 scans were performed twice during the flicker activation, to measure both CBF and CMR02. The inhalation period of 1502 was approximately 1.5 min and the length of the dynamic scan was 4.5 min. The first scan was started 1 min after the start of flickering; the second scan began 20 min after the flickering began. The scanner used was Headtome-IV installed in Akita-Noken, Japan (Iida et a1 1989b). Results Figure 2 shows global H2150 head time-activity curves of a typical slice obtained from a bolus injection and a slow infusion study. The radioactivity concentration increases rapidly after the bolus injection of H2150,and then is maintained at almost the same level during a slow tracer clearance. In the slow infusion study, the tracer level increases slowly according to a ramp function. Figure 3 shows the results of the simulation, showing errors in the calculated CBF values (ACBF/CBF) due to statistical noise in the original PET image. The errors were plotted as a function of the scan length. For the bolus administration (a), there was an optimum scan length which gave minimum statistical error. Minimum error was obtained when the scan length was between

lida et al

28

E

\

Is( u

FIG. 2. Global H,150 head time-activity curves (true coincidence counting rates of a typical brain slice) obtained from a typical bolus injection and 3.5-min slow infusion study. After the bolus injection the head time-activity curve reaches the maximum level rapidly and maintains almost the same level. On the other hand, after the slow infusion, the head time-activity curve increases monotonically.

60 and 120 s for a CBF range of 50-80 ml/min per 100 g, and longer than 120 s for a CBF of 20ml/min per 1OOg. On the other hand, for the slow administration (b), the error decreased monotonically as scan length increased (as long as the infusion continued). When this simulation was done for the same integration counts of the input function (integrating over 0-600 s), the bolus injection and the slow infusion gave the same minimum value of the error. The statistical error (standard deviation divided by the average CBF [ACBF/CBF] ) is summarized in Table 1. The values were calculated as an average of the grey and white matter regions for various scan lengths. As can be seen, the data were consistent with results from the simulation study. Errors in the calculated CBF values due to delay and dispersion of the arterial curve are shown in Tables 2 and 3 respectively. Results are presented for both the bolus injection and the slow infusion procedures. As can be seen, larger errors are caused by the delay and dispersion for the shorter scan length. Smaller errors were seen in the bolus injection procedure than in the slow infusion procedure, with the exception of a scan length of less than 20 seconds. These errors were not dependent on the CBF values assumed in the simulation. Figure 4 shows the results of the simulation, which represent the weights of the contribution of transient CBF to the total integration of the tissue curve.

29

Rapid cerebral blood flow measurement 0.04

.

0.04

- .. I5

:

O'03;

0.02

0.02

-

0.01

0.01

-

L

: m m

.

-

*

, . - .

Vd = 0.80 m h l

t . . . . , . . . . , . . . . l 200 300

0

0.00

100

0

.

---

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.

0

a

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. . . . ' . .

'

100

Time (sec)

.

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200

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.

Time (sec)

. .

300

cb)

(a1

FIG. 3. Results of the simulation which represents effects of choosing different scan lengths on the statistical error in the H,I5O autoradiographic CBF values. The errors (ACBF/CBF Yo) were presented for bolus (a) and slow (b) administration procedures. In these simulations, the two input functions were normalized to give the same integration counts (integrating over 0-600 s), corresponding to the same total administration dose. TABLE 1 Results from a volunteer PET study, representing the statistical error in CBF (standard deviation divided by average of CBF: ACBFKBF, 070) in the HZi5O autoradiographic method for various scan lengths

Scan length (s) Bolus injection Slow infusion

Structure

40

60

90

120

I80

Grey matter White matter Grey matter White matter

12.0 27.9

11.0 22.4 14.2 27.9

11.1 17.9 11.1 21.6

12.8 17.3 10.3 14.7

13.8 14.2

-

1.0

@lo 070

10.8

In the bolus injection study (a), these weights have a sharp peak, corresponding

t o the peak of the arterial input function, and independent of the scan length. By

contrast, in the slow infusion study (b), the weights are broad, covering almost the whole scanning period chosen. Figure 5 compares CBF and CMR02 values obtained by the present technique with the reference method (separate determination) for the motor

30

lida et al

TABLE 2 Results of simulation: Vo errors in the H,'50 autoradiographic CBF due to the delay of the arterial time-activity curve Scan length (s)

DeIay

20

(S)

Bolus injection Slow infusion

+3 -3 +3 -3

74.0 -45.0 44.9 -39.0

40

19.0

- 15.0

22.9 -21.2

60

90

7.6 -7.8 16.9

5.1 -5.7 10.0 -10.2

-15.2

120

180

4.0 -3.7 8.2 -8.1

2.9 -2.6 5.8 -5.8

Vo Vo

Notes: Delay of the arterial time-activity curve induced overestimation in the calculated CBF, and vice versa. The errors caused by the ambiguous delay adjustment were symmetrical concerning the direction of the shift of the arterial curve. The effects of CBF on this error were negligible at a CBF range between 20 and 80 ml/min per 100 g.

TABLE 3 Results of simulation: errors in the H,'50 autoradiographic CBF due to the dispersion in the arterial input function

___

Bolus injection

Slow

infusion

Dispersion Scan length (s) time constant (S) 20 40 3

43.0 71.2 34.0 56.7

5

3 5

20.0 26.3 24.2 38.5

~

60

90

120

180

11.8 15.8 16.3 21.0

6.4 9.5 10.8 15.4

4.5 8.0 8.1 11.1

3.2 % 5.3 5.9 070 7.4

~.

.__

Notes: Dispersion of the arterial curve induced overestimation in the calculated CBF, and this error was increased rapidly as the scan length was shortened. The effects of CBF on this error were negligible at a CBF range between 20 and 80 ml/min per 100 g.

activation study. When the measured Vd values were used, consistent values of both CBF and CMR02 were obtained when compared with the reference method: CBF values of 0.56 f0.16 compared to 0.53 f0.11 ml/min per ml for the resting condition, and 0.64 f0.12 compared to 0.63 f0.13 ml/min per ml for the activated condition, and CMR02 values of 0.0399 f0.0043 compared to 0.0387 f0.0048 at rest, and 0.0414 k 0.0059 compared to 0.0407 k 0.0054 ml/ min per ml during the activation. On the other hand, when the assumed value of vd was used, CBF values were dependent on the v d value (see Fig. 5a): the resting (activated) CBF values were 0.95 k 0.42 (1.09 +_ 0.39), 0.60 f 0.20 (0.67 k 0.17) and 0.36 0.09 (0.40 k 0.07) ml/min per ml for assumed vd values of 0.98, 0.80 and 0.60ml/ml, respectively. In contrast, the value of CMR02 was not sensitive to the assumed value of Vd used, as shown in Fig. 5(b): the resting (activated) CMR02 values were 0.0412 f0.0045 (0.433 k 0.0050), 0.0392k 0.0041 (0.0405f0.0056) and 0.0377 k 0.0043 (0.0386 f 0.0059) ml/min per ml for assumed v d values of 0.98, 0.80 and 0.60ml/ml, respectively.

+

Rapid cerebral blood flow measurement

... ,

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60

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Scanlength(sec) .

I

- ; !\ \ -i t'

.I'

-

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120 240 300

004-

L

Time (sec)

(a)

Time (sec)

0.4

FIG. 4. Results of the simulation representing the contribution weights of transient CBF values in the total integration. Data are shown for a bolus injection procedure (a) and for a 3.5-min slow infusion procedure (b). Weights are normalized so that the total integration of each curve is unity.

Results from the visual activation study are shown in Table 4 as the percentage increase in CBF and CMR02 caused by flicker activation for 1 min and 20 min after the start of the stimulation. Discussion

Advantages of a bolus injection Because most PET scanners have limiting characteristics at high count rates (due to the deadtime and the non-negligible random coincidence events), the square function (rather than a ramp function) tissue response curve would give the maximum total counts within a limited short period. This curve is nearly achieved by the bolus administration, as can be seen from Fig. 2. The total head time-activity curve is almost flat after the bolus injection during the first short period, while it increases continuously in the slow infusion procedure. Thus, when a short scan period (e.g. c 1-2 min) is required to measure the CBF over short time scales, the bolus injection technique provides better statistics than the slow infusion technique. Another advantage of using a bolus injection is related to the error sensitivity of the delay and dispersion in the input function. As shown in Tables 2 and 3,

lida et al

32

N

0 U

FIG. 5 . (a) Comparison of CBF values at rest and during activation (finger opposition) obtained by fitting to the dynamic HzL50 curve (reference) with those from the I5O, inhalation study. Values were consistent when measured values of v d were used in the I5O, (Vd=meas.), though 1502 CBF was sensitive to the v d used in the calculation, as shown in the right three columns. (b) Comparison of CMROz values at rest and during activation obtained by paired fitting to the dynamic lSOzand dynamic H,150 data (reference) with those obtained by the present technique. In contrast to the CBF determination, the present technique was not sensitive to the v d values used, and yielded results consistent with the reference methods, both at rest and during activation.

Rapid cerebral blood flow measurement

33

TABLE 4 Results from the simultaneous determination

of CBF and CMRO, by an flicker activation

Subject

150,

inhalation during the

% increase in CBF

Yo increase in CMROz

One min after the start of flickering 1 2 3

48.3 21.3 24.0 4 9.5 Average and SD 25.82 16.3

20.3 3.6 4.3 3.7 8.0k8.2

20min after the start of flickering 26.5 30.8 21.3 4 15.7 Average and SD 23.6k6.6

1 2 3

18.0 0.3 1.2 3.4 7.2 2 7.7

both delay and dispersion induced smaller errors in the bolus injection procedure than in the slow infusion technique. In addition, adjustment for the delay would be more accurate for the bolus injection than for the slow infusion, because of the sharp rise in the input and the tissue curves (Iida et a1 1988). Thus, the need to minimize the effects due to delay and dispersion also favours the bolus injection procedure. In deciding the scan length for obtaining maximum statistical accuracy in CBF estimation for the bolus injection procedure, it is important to consider two factors: (1) the non-linearity between CBF and PET counts when scanning for long periods (due to the effects of equilibration between areas of high and low CBF; Volkow et a1 1991), and (2) the statistical errors in the original raw image when scanning for short periods. In the present study, scan length has, therefore, been optimized so as to minimize the statistical error in CBF, but not in the integration counts. This process included correcting for the nonlinearity between CBF and the PET counts. The present study also included effects of tissue heterogeneity, because the Vd value of 0.80ml/ml was used, which empirically corrected for the tissue heterogeneity and provided constant CBF values independent of scan length (Iida et a1 1989a). This study suggested choosing a scan length of approximately 60-120 seconds in order to obtain the minimum statistical error in CBF estimation for a CBF range of 50-80 ml/min per 100 g. For smaller CBF rates (20 ml/min per 100 g), the optimum scan length was longer than this.

34

lida et al

Advantages of slo w infusion As discussed above, the bolus injection procedure is recommended in order to obtain maximum counts when a short scan length is chosen (e.g. < 1-2 min). However, when a long scan period is appropriate (e.g. > 3 min), the bolus injection technique is limited in value because of the equilibration between the high and low CBF regions, and the consequent reduction in statistical accuracy occurs (see Fig. 3a and Table 1). In this situation, the slow infusion procedure provides better count statistics. Continuation of Hz”O infusion allows prolongation of the scan length. By infusing sufficient amounts of H2150and scanning for a long period, the statistical error in CBF may be negligibly small (i.e. ACBF/CBF z 0). However, the following two points should be mentioned. (1) When the bolus and slow administration procedures were compared under the condition of the same administration dose (i.e. the same integration counts of the input functions), the minimum value of ACBF/CBF was found to be about the same as shown in Fig. 3, indicating that the prolongation of the infusion period with a prolonged scan length is not an essential solution for improving the statistics in CBF estimates, when the total dose administered is limited. (2) The choice of a long scan period is not suitable for repeating measurements in a variable number of stimulated conditions. Recently, a number of cerebral activation studies have been done based on normalizing the whole-brain CBF to a certain value (e.g. 50 ml/min per 100 g) and using subtraction techniques to detect the location of the changes (Fox et a1 1984, 1988, Friston et a1 1990). In applying this technique especially to cerebral activation studies involving cognitive tasks, it might be important to average the cerebral activity over the period of the scan to remove phasic changes in CBF due to repeated task performance or habituation. As shown from the comparison in Fig. 4, the total integration is almost determined by the first 20 seconds in the bolus injection procedure (the full-width of the half-maximum of the contribution weights is approximately 10 s). Hence, the calculated CBF is likely to vary depending o n the timing of the peak of the H2I5Oinput. On the other hand, in the slow infusion procedure, the contribution weights cover the whole scan period. Therefore, if this hypothesis (CBF fluctuation during the scan) is true, a slow infusion is expected to provide a more stable response for cognitive activation paradigms by averaging a fluctuating CBF. Further study of the range and frequency of CBF fluctuation is needed in order to evaluate this effect.

Feasibility of using ”0, The use of 1502 inhalation was found to be feasible for the determination of CBF. This technique provided both CBF and CMROz values which were consistent with the reference methods, and was applicable to the human neuronal

Rapid cerebral blood flow measurement

35

activation study. The results suggest an uncoupling between CBF and CMR02 during the visual activation (1 min and 20 min of continuous flicker stimulation), However, the determination of CBF by this technique depends on choosing an adequate value of Vd. Assuming a different value of v d resulted in very different values for CBF, as shown in Fig. 5 . Since the v d value is underestimated compared with the expected true partition coefficient of water, and this is caused by the tissues heterogeneity (Huang et al 1987, Iida et al 1989b), the v d value is dependent on the selected region-of-interest. Therefore, the Vd value had to be measured by the H2150 dynamic scan for each regionof-interest. In contrast, CMR02 was not sensitive to the vd values used, indicating that Vd measurement is not necessary for CMR02 determination alone.

Conclusion In the calculation of CBF by using H p O , the present study suggests the following conclusions. (1) Given repeated rapid measurements of CBF in various activated conditions using a short scan length, the bolus injection procedure provides better count statistics than the slow infusion procedure. (2) Choosing a scan length of between 60 and 120 seconds provides minimum statistical error in CBF estimation using the bolus injection procedure. (3) If a long scan length is chosen (e.g. > 3 rnin), the slow infusion procedure gives better count statistics in CBF than the bolus injection procedure. (4) When the H21S0is infused continuously, prolongation of the scan length improves the statistical accuracy of the CBF estimate. ( 5 ) Errors due to delay’ and dispersion are smaller in the bolus injection procedure than in the slow administration procedure. (6) The slow infusion procedure provides a CBF value which is averaged over the scan period, while the bolus injection procedure provides a momentary CBF value (average for approximately 10 seconds), which may be dependent on the timing of the H p O injection and the CBF fluctuation. The feasibility of measuring CBF by 1 5 0 2 inhalation has also been confirmed, but measurement of v d is required for each region-of-interest using a dynamic H2150scan before the 1502 scan. By measuring the blood volume and the regional v d , both CBF and CMR02 can be measured by a single 1502 scan for various activated conditions. A ckno wledgemenIs We thank Dr Karl J. Friston from Hammersmith Hospital, London, for invaluable discussions and advice in the preparation of this manuscript. This work was in part supported by the Japan Heart Foundation, grant for 1990.

36

lida et al

References Fox PT, Mintun MA, Raichle ME, Herscovitch P 1984 A noninvasive approach to quantitative functional brain mapping with H2I5Oand positron emission tomography. J Cereb Blood Flow Metab 4:329-333 Fox PT, Mintun MA, Reiman EM, Raichle ME 1988 Enhanced detection of focal brain responses using intersubject averaging and change-distribution analysis of subtracted PET images. J Cereb Blood Flow Metab 8:642-653 Friston KJ, Frith CD, Liddle P F , Dolan RJ, Lammertsma AA, Frackowiak RSJ 1990 The relationship between global and local changes in PET scans. J Cereb Blood Flow Metab 10:458-466 Holden JE, Eriksson L, Roland PE, Stone-Elander S, Widen L, Kesselberg M 1988 Direct comparison of single-scan autoradiographic with multiple-scan least-squares fitting approaches t o PET CMRO, estimation. J Cereb Blood Flow Metab 8:671-680 Howard BE, Ginsberg MD, Hassel WR, Lockwood AH, Freed P 1983 On the uniqueness of cerebral blood flow measured by the in vivo autoradiographic strategy and positron emission tomography. J Cereb Blood Flow Metab 3:432-441 Huang SC, Mahoney DK, Phelps ME 1987 Quantitation in positron emission tomography. 8. Effect of nonlinear parameter estimation on functional images. J Comput Assisted Tomogr 1 1 :3 14-325 Iida H , Kanno I, Miura S, Murakami M, Takahashi K, Uemura K 1986 Error analysis of a quantitative cerebral blood flow measurement using H2I5Oautoradiography and positron emission tomography. Wth respect to the dispersion of the input function. J Cereb Blood Flow Metab 6:536-545 Iida H , Higano S, Tomura N et a1 1988 Evaluation of regional differences of tracer appearance time in cerebral tissues using I50-water and dynamic positron emission tomography. J Cereb Blood Flow Metab 8:285-288 Iida H, Kanno I, Miura S, Murakami M, Takahashi K, Uemura K 1989a A determination of the regional braidblood partition coefficient of water using dynamic positron emission tomography. J Cereb Blood Flow Metab 9:874-885 Iida H , Miura S, Kanno 1 et al 1989b Design and evaluation of Headtome-IV, a wholebody positron emission tomograph. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 36~1006-1010 Kanno I, Lammertsma AA, Heather J D et a1 1984 Measurement of cerebral blood flow using bolus inhalation of C'502 and positron emission tomography. J Cereb Blood Flow Metab 4:224-234 Kanno I, Iida H , Miura S et al 1987 A system for cerebral blood flow measurement using H2150autoradiographic method and positron emission tomography. J Cereb Blood Flow Metab 7:143-153 Kety SS 1951 The theory and applications of exchange of inert gas at the lungs and tissues. Pharmacol Res 3: 1-41 Lammertsma AA, Cunningham VJ, Deiber M-P et a1 1990 Combination of dynamic and integral methods for generating reproducible functional CBF images. J Cereb Blood Flow Metab 10:675-686 Meyer E, Tyler JL, Thompson CJ, Redies C, Diksik M, Hakim AM 1987 Estimation of cerebral oxygen utilization rate by single bolus 150z inhalation and dynamic positron emission tomography. J Cereb Blood Flow Metab 7:403-414 Mintun MA, Raichle ME, Martin WRW, Herscovitch P 1984 Brain oxygen utilization measured with 0-15 radiotracers and positron emission tomography. J Nucl Med 25~177-187 Raichle ME, Martin WRW, Herscovitch P et a1 1983 Brain blood flow measured with intravenous H,I5O. 11. Implementation and validation. J Nucl Med 24:790-798

Rapid cerebral blood flow measurement

37

Spinks TJ, Jones T, Gilardi MC et a1 1988 Physical performance of the latest generation of commercial positron scanner. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 35:721-725 Volkow ND, Mullani N, Gould LK, Adler SS, Gatley SJ 1991 Sensitivity of measurements of regional brain activation with oxygen-15-water and PET to time of stimulation and period of image reconstruction. J Nucl Med 3258-61

DISCUSSION

Jones: Dr Iida, in your simulations of optimum scanning times, did you take into account mixtures of grey and white matter? Zida: Yes, in our simulations we used a value for the distribution volume of water, 0.8, which we obtained empirically by fitting the dynamic H2I5Odata for several human studies, and not the theoretical prediction (a ratio of the water content of tissue t o blood). We expected this empirical value to be corrected for the tissue mixture, because, in a kinetic H2I5Oanalysis, the tissue mixture causes systematic underestimation in the distribution volume. If we used a theoretical value for the distribution volume, the tissue mixture caused a timedependent and falling CBF value in the autoradiographic method (see Fig. 1 on p 38). Using a fitted value, we get constant and time-independent CBF values for the cortical grey regions, even when we accumulate the data over 4.5 minutes after the bolus injection of H2150.Also for the 1502 study, we observe a timeindependent CMR02 value (which has been reported by Holden et a1 1988). On the basis of these values we presumed that tissue mixture has been taken into account in our simulations. Frackowiak: I am particularly interested in the issue of the bolus injection and the slow ramp infusion, and the distinctions you drew between them. Most people think of the alterations in brain state or the responses to the physiological stimuli that we apply, which alter flow to the brain, as very dynamic and rapid changes which rapidly habituate. That would suggest that we need to take a quick snapshot of blood flow, and perhaps use a bolus technique. Alternatively, it may be more important to average brain activity over the scanning period, to integrate all the primary local and resulting secondary blood flow changes which may themselves modulate the primary responses and arise in areas constituting a functional network that is widely distributed in the brain. Such a view might lead one to favour a smoother ramp-like administration of tracer. I think you are suggesting that there is room for both these experimental approaches at the technical level and that the choice essentially depends on the physiologist’s prediction of the response? Iida: Yes, I think that both the bolus and slow ramp infusion techniques have their own advantages, depending on the paradigm employed, but I am not sure how CBF changes during the simulation. It must be very important to know how much CBF fluctuates following and during a stimulation with cognitive tasks. Can anybody give us any information?

38

Discussion

r

0.6

0.5

-

0.4

-

0.3 0.2

O.’ 0.0

=

1

0.8 rnllrnl

1

C@pJ@ ! $U 0 0

-

0

Vd

Activated

- Resting

t‘

,

1

Vd

1.0 mllml

I

I

100

200

1 I 300

Scan length (sec)

FIG. 1 ( M a ) . Autoradiographic CBF values as a function of scan length for a visual cortex region. Values were calculated for activated and resting conditions with different values of the distribution volume ( V d ) . A Vd value of 0.8 rnl/rnl provided tirneindependent CBF values for both activated and resting conditions, while a V, value of 1.0 ml/ml provided a fall in CBF values. The statistical uncertainty is expected to be large for a short scan period because of the statistical noise, and also large for a long scan length due to the wash-out effect (i.e., a large correction for the non-linearity between the CBF and the original accumulated counts).

Raichle: Dr Winn has shown with sciatic nerve stimulation in the rat that there is an abrupt rise in blood flow and then it changes over time (Ngai et a1 1988). The time course was 10-20 seconds, so it seemed like a relatively slow response, which is another issue. When one thinks of what is called an ‘intrinsic signal’ that has been observed in work with optical techniques (Grinvald et a1 1986), which some would attribute to vascular phenomena, the onset of this ‘intrinsic signal’ is more like 200 ms after the start of the stimulus. But beyond that it has a complex wave form; it isn’t something that goes up and stays there; it sometimes comes down, and occasionally if the stimulus stops it goes below baseline and comes back up (personal communication, A. Grinvald, Rockefeller University, New York). So it’s a moving target, probably within time frames below the temporal resolution of PET scanners. We shall therefore always be faced with averaging across temporally complex vascular responses t o neural activity. Porter: Part of the difficulty is that you can’t interrogate the brain of the rat, as to what is going on during that period of time. Fox: On another issue related to your simulations of measurements comparing bolus to ramp techniques, Dr Iida, you showed us every measure except the

Rapid cerebral blood flow measurement

39

one I wanted! What happens when you have a local signal? For example, during a visual stimulus, there is an active area of very high blood flow. The tracer will wash into that area; and it will then wash out. So it will leave more quickly than in other areas, as well as enter more quickly. We have approached this by looking at signal-to-noise ratios and asking whether this area of high neural activity is high relative to the background noise. It’s clear that as you scan for longer, image quality gets better and you have a less ‘noisy’ image, but you are also losing signal, by 90 seconds. Zida: That is right. We therefore took the effect of the wash-out into account, which we called the non-linearity effect, and also the statistical noise problem. If you really want to see a maximum difference in the original accumulated image for a certain amount of CBF change, you have to choose an extremely short scanning period, but you will see a poor quality image, because only short scan lengths provide the ideal and linear relation between CBF and PET counts. In our analysis, by taking into account these two factors, we approached the optimal scan length of around 90 seconds for the bolus injection technique. For low flow, the optimal time was longer, we found, and for high flow, it was slightly shorter, though longer than 60 seconds for a physiological flow range. Jones: Dr Fox is really talking about the heterogeneity problem. If you have a piece of grey matter, and you know the correct value for the tracer’s volume of distribution ( Vd),the longer you scan, the better, statistically, until the time when equilibrium is reached for the concentration of tracer between the tissue and arterial blood. A time of 90 seconds should be about right. But with the heterogeneity question, you are recording average values, the contributions to which change because of the slower wash-out from white matter. This is really the issue Dr Fox is raising. Raichle: There’s another issue here, namely that we have been discussing measurements of blood flow, but what is often done is that people simply record radioactive counts in a particular area of interest and do not compute blood flow. The question of the time of the data collection becomes very important, because the tracer will wash out faster from the area of higher flow, as Peter Fox says. Our experience has been that the signal-to-noise properties of such a scan deteriorate as a function of time (Mintun et a1 1989). This seems surprising, because one would expect that one could integrate over this time and obtain more and more counts, and be statistically better off. But count rates are changing differently in different areas and most rapidly in areas of greatest interest. Porter: That is also a spatial-averaging issue. It’s not simply the temporal average, but also the spatial zone over which the average is computed that must be understood. Roland: I tend to agree with Peter Fox in his analysis. It is certainly true that if you use a model that is very strict, like the 133Xe-intracarotidmodel,

40

Discussion

you observe a decrease in blood flow (in m1/100g per min) measured in a dynamic way, not as integration of counts, with time. This is due, I think, to two factors. There is the high clearance seen in an active brain region, but also a low clearance from the non-active grey matter, if you are looking at exactly the same spot. The weight of the non-active grey matter for the rCBF calculation will increase as you prolong the scanning time. Zida: I agree that we have a higher clearance in activated areas than nonactivated areas, and we lose a little bit of the signal, but, on the other hand, we should not forget the noise problem. Our model provides a constant and time-independent flow value. In this condition, we looked for a scan length which minimizes the statistical fluctuation of the CBF expected value, even for an activated flow range. As for the other issue, the optimal scan length should be the same if you are looking at the original accumulated counts and count ratios, although, in the paper, we discussed only CBF values. We minimized the percentage error of CBF (ACBF/CBF) by optimizing the scan length. This is equivalent to the minimization of the percentage error of accumulated counts ( A \ ,TCi(t)dt/j ,%i(t)dt). Fox: Consider the following. I put a region-of-interest over an area of stimulus-induced activation and then compare that to the background noise levels. The background noise falls over time but the signal falls faster. Thus for detecting functional activation (but not for blood flow measurement accuracy per se), the optimal scan time is shorter than two minutes. It is more in the range of 60 seconds. Zida: No! I think you are neglecting the statistical noise problem, and you are talking about a comparison of the amplitude of signals in activated and non-activated areas. Clearly, the brain tissue gets more radioactivity, as long as the radioactivity concentration is higher in the blood than in the tissue, which happened during the first period. After this, wash-out is greater than wash-in. The wash-out, as you say, causes a reduction in the activated-to-non-activated ratio; I agree with this. However, fortunately, the rate of wash-out is slower than the rate of wash-in. Therefore, there is an advantage in extending the scan length after the cross-over point in the blood and tissue curves. By taking into account both wash-out and statistical problems, we estimated the optimal scan time, and obtained our result. What we have to think about is the fluctuation (or error!) in the expected value of the activated-to-non-activated CBF ratio, and not simply the magnitude of the ratio. Fox: That is contrary to what we found, although it seems a reasonable prediction. Mazziotta: As has been mentioned, there’s a difference between measuring blood flow and detecting a change in flow, and the statistical and modelling approaches to each are different. To find an increment in a small volume of tissue will require a distinct strategy, in terms of signal-to-noise ratio and also in terms of sampling. We know now that lower spatial resolution will enhance

Rapid cerebral blood flow measurement

41

certain aspects of detectability while at the same time producing a poorer image of the distribution of cerebral blood flow, and that some combination of approaches, where you find the site of change in one analysis of the data, can then allow you to take those coordinates and identify, in the high resolution image, the site where that response came from. I think there’s a difference between the measurement of the absolute variable, and the detection of the change in the brain. Jones: Could you comment, Dr Iida, on the optimum way of giving I5O2t o measure CMR02-as a bolus, a short inhalation period, or a prolonged inhalation period? M a : The same argument as discussed for the H p O study can be applied, apart from one point. In the I5O2inhalation study, we need to estimate the recirculating H2I5Oconcentration in the blood as a function of time. This may not be an essential problem, if we can measure this recirculating water curve precisely, maybe by centrifuging the arterial blood very quickly to get a number of plasma samples. This is boring and hard work! Therefore, in our institute at the moment, we are employing a modelling approach to simulate this curve. I think the accuracy would be reasonable, but it is preferable to minimize the absolute amount of recirculating water in the blood. From this point of view, I think a slow administration would have some advantages. Roland: Dr Iida, how do you measure the distribution volume of water, and do you think it will change over a short time period-say, a couple of minutes? I assume that you might measure the distribution volume after some time, since it takes several minutes for the Patlak plot to become horizontal. However, if the vo!ume of distribution changes during the initial time course, as the experiments of John Mazziotta and Bob Collins showed might occur, we are left with the wrong distribution volume. Zida: We measured the distribution volume of water by fitting the dynamic H2150 data, for different fitting periods. We observed that the values were significantly smaller than the expected value and changed (fell) with increasing fitting periods, even after correcting the input function for delay and dispersion. This time dependency was found to be more in regions in which we expected a larger contamination of white matter spillover into the grey matter regions (Iida et a1 1989). One of the reasons for this time dependency is, therefore, most likely to be the heterogeneity of the grey and white matter. In our data analyses and simulations, for both H2I5O and lSO2studies, we used an empirical value of the distribution volume, which was an average of the fitted value (approximately 0.80). Fortunately, within the range of change of distribution volume, we got a time-independent value for either CBF or CMR02.

Evans: In the oxygen model you are measuring blood volume as a separate step. Have you looked at any simulations of incorporating the vascular component as a free parameter in the model?

42

Discussion

Zida: We have tried this, but the problem is the limitation of the statistical accuracy, and maybe systematic accuracy too, such as inaccurate correction for delay and dispersion. When we fitted four parameters, such as the vascular component ( VB), distribution volume (I‘d), CBF and CMR02, we got very strange results. We have tried to fix Vd, because fixing other parameters such as CBF and CMROl doesn’t make sense, but the results were still strange and fluctuated very much. The value for CBF in particular changed a lot, depending on the assumed V, value. So, I think that if the data quality is improved, fitting of the vascular component might be possible. But, for the moment, it may not be satisfactory for practical use. Evans: How does that behave differentially between the bolus and ramp input? Zida: I don’t think there is a big difference between the bolus and slow administration of the tracer because, for both administration procedures, the same amount of radioactive blood comes into the field of view. Evans: I think it helps to get the radioactivity into the brain quickly, because of the better statistics on the early frames. You can get a tighter determination of the influx constant and the vascular component, and distinguish between those more easily, if you have high activity in the early frames. With a ramp input they are difficult to separate out. So there is a case for a bolus input if you want to determine the vascular component in the uptake curve and try to avoid the need for a separate scan to measure blood volume. Zida: This may be true. And also it could be easier to adjust the delay of the input function in the bolus technique. But I am not sure how much we can improve the data quality. References Grinvald A, Lieke E, Frostig RD, Gilbert CD, Wiesel TN 1986 Functional architecture of cortex revealed by optical imaging of intrinsic signals. Nature (Lond) 324:361-364 Holden JE, Eriksson L, Roland PE, Stone-Elander S, Widen L, Kesselberg M 1988 Direct comparison of single-scan autoradiographic with multiple-scan least-squares fitting approaches to PET CMRO, estimation. J Cereb Blood Flow Metab 8:671-680 Iida H, Kanno I, Miura S, Murakami M,Takahashi K, Uemura K 1989 A determination of the regional braidblood partition coefficient of water using dynamic positron emission tomography. J Cereb Blood Flow Metab 9:874-885 Mintun MA, Raichle ME, Quarles RP 1989 Length of data acquisition inversely affects ability to detect focal areas of brain activation. J Cereb Blood Flow Metab 9 (suppl I):S349 Ngai AC, KO KR, Morii S, Winn HR 1988 Effect of sciatic nerve stimulation on pial arterioles in rats. Am J Physiol 254:H133-H139

Ge neral d iscussion Brain energy metabolism: cell body or synapse?

SokolofJ We have some information on the question of what proportions of the brain’s energy are being used by the cell bodies and by the synaptic regions. When the deoxyglucose method for measuring local cerebral glucose utilization was developed (Sokoloff et a1 1977), we expected to find metabolic activity primarily in cell bodies, where neurophysiologists had presumably been recording spikes. We were surprised to find the converse. For example, in the rat hippocampus, we found a dark band in the autoradiograms that turned out to be the molecular layer, which is a synapse-rich layer, not a cell body layer (Sokoloff et a1 1977). We also studied the effects in rhesus monkeys of eye-patching (Kennedy et a1 1976). In monkey with both eyes open, we found that the most labelled layer in the striate cortex was a sublayer of layer 4, a synapse-rich layer (Fig. 1). When both eyes were patched, glucose utilization was reduced throughout the striate cortex, but the most prominent effect by far was in this synaptic layer, which almost disappeared in the autoradiograms. The implication was that not only was the metabolic rate in the synapse-rich areas higher, but these seemed to be the areas most involved in changes in functional activity. William Schwartz was interested in stressing the hypothalamic-hypophysial system (Schwartz et al 1979). He salt-loaded rats by giving them 2% NaCl to drink for several days. In the autoradiograms of the deoxyglucose studies of control rats we did not see the paraventricular (PVN) and supraoptic (SON) nuclei clearly. In the salt-loaded rats, the labelling in the posterior pituitary was increased markedly, whereas the SON and PVN were not significantly changed from normal (Fig. 2). This was a surprise because electrophysiologsts have recorded from the hypothalamo-hypophysial tract and found increased spike activity in that pathway with salt-loading. The terminal projection zone of the pathway, the posterior pituitary, showed increased energy metabolism, but in the cell bodies of the PVN and SON, the sites of origin of the pathway, we couldn’t find any significant changes in metabolism. We thought that, perhaps, the cell bodies were too dispersed and that, therefore, they could not be distinguished from the surrounding tissue in the autoradiograms. When, however, Dr Savaki studied the effects of hypotension induced by phenoxybenzamine or by blood loss, she could also turn on the PVN and SON as well as the posterior pituitary (Fig. 2D). The difference between the salt-loaded rat and the hypotensive rat was that the increase in activity in 43

General discussion

44

the hypothalamo-hypophysial pathway of the hypotensive rat is due to reflex activity from the brainstem by pathways that project to the PVN and SON. In all these brain areas we are really looking at regions that are heterogeneous with respect to cell body and synaptic elements. In the dorsal root ganglion the cell bodies are clearly separated from their processes. Dr Kadekaro electrically stimulated the sciatic nerve of anaesthetized rats at different frequencies, took

t-------(

5.0mm

Cell body or synaptic metabolism?

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out the dorsal root ganglia and lumbar cord, and autoradiographed them at the same spinal level (Kadekaro et a1 1985). There were no significant changes in glucose utilization in the cell body region of the dorsal root ganglia, but in the terminal zones of that pathway-for example, in the dorsal horn of the lumbar spinal cord-she found a quantitative relationship between frequency of stimulation and rate of glucose utilization (Fig. 3). In the resting state there is a significant amount of glucose utilization in the cell body; on stimulation at different frequencies there is no change in glucose utilization in the cell bodies, whereas in the terminal zone, where the nerve terminals of that pathway are, there is a practically linear relationship between glucose utilization and spike frequency (Fig. 4). This bothered us, and also neurophysiologists who record from cell bodies. We had other evidence indicating that the increase in energy metabolism associated with increased electrical activity is related to activation of the enzyme, Na+/K+ -ATPase, presumably to restore the ionic gradients across the neural membranes that were degraded as a result of the ion currents occurring during the spike activity (Mata et a1 1980). We wondered why cell bodies do not show increases in metabolism if they do indeed spike; if so, then the Na+K+-ATPase activity should be increased. Our neurophysiological colleagues said that they were sure that they record spikes from cell bodies. We asked if they were sure that they were not recording from the initial segments. Some have intracellular recordings, but hadn’t measured current and voltage changes at the same time. Membrane physiologists who use patch-clamp techniques told us that the perikaryonal membrane is not very excitable (Smith 1983). If so, we asked, how does the signal get across the cell body from the dendrites to the axonal side? They claimed that the transmission across the cell body was electrotonic, not true conduction by spikes, until it reaches the initial segment, where the voltage

FIG. 1 (Sokolofs). [ I4C]Deoxyglucose autoradiograms demonstrating effects of bilateral and monocular visual occlusion on local glucose utilization in striate cortex of the monkey. The greater the density (i.e., darkness) the greater is the rate of glucose utilization. A. Striate cortex from animal with both eyes open. Note heterogeneity in the laminae; the darkest lamina corresponds to layer IV. B. Striate cortex from monkey with both eyes patched. Note the general reduction in density and almost complete disappearance of the laminar heterogeneity. C. Striate cortex from animal with only right eye patched. The left half of the autoradiogram corresponds to the left hemisphere contralateral to the occluded eye. Note the alternating dark and light columns traversing the full thickness of the striate cortex; these are the ocular dominance columns. The dark bands represent the columns for the open eye; the light bands represent the columns for the patched eye and demonstrate the reduced glucose utilization resulting from the reduced visual input. The arrows point to regions of bilateral asymmetry; these are the loci of representation of the blind spots of the visual fields. (From Kennedy et al 1976.)

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General discussion

Cell body or synaptic metabolism?

47

threshold is low. There are very few voltage-dependent sodium channels in the perikaryonal membrane. We, therefore, think that most of the functionally related changes in metabolic activity seen with altered functional activity are in the nerve terminals. The cell bodies d o have a significant level of energy metabolism, but it is mostly for vegetative functions, such as axonal transport and synthesis of proteins, and is not related directly to the transmission of the signal down the pathway. Porter: So you are suggesting that the metabolic cost is the cost of ion transport at the synaptic sites? This will have both pre- and postsynaptic contributions. Sokoloff: Yes, most of the cost can be attributed to ion transport at synaptic sites. Roland: There may be another implication of your beautiful studies. As far as I understand it, the GABAergic terminals end on the proximal dendrites of the hippocampal pyramidal cells, and that is a region where you don’t find much enhancement of glucose consumption after stimulation. Would you agree too that GABAergic activity does not really increase the regional metabolic rate for glucose in ordered structures like the hippocampus? SokolofJ Yes. This brings up another point. We had found, in studies with dopamine agonists, brain areas in which glucose utilization was increased. These regions were part of the nigro-striatal pathways. For example, in the caudate nucleus, apomorphine or amphetamine increased glucose metabolism. Neuropharmacologists claimed that dopamine acts as a n inhibitory neurotransmitter in the caudate nucleus. Then why this increase in glucose utilization? We couldn’t explain that then, but now that we realize that the spike frequency in the nerve terminals determines the rate of glucose utilization in a region-of-interest, we can. The effect of firing rates in the afferent terminals determines the rate of glucose utilization, whether an excitatory or an inhibitory neurotransmitter is released. In either case, it is the effect of the electrical activity in the afferent terminals that is observed. Both inhibitory and excitatory pathways, when activated, show increased rates of glucose utilization. FIG. 2 (Sokoloffi. Effects of activation of hypothalamo-neurohypophysial pathway by salt-loading or hypotension on local cerebral glucose utilization in the rat. A. Histological sections of brain stained with cresyl violet (Nissl) and pituitary stained with toluidine blue, demonstrating positions of supraoptic nucleus (SON), paraventricular nucleus (PVN), posterior pituitary (PP), and anterior pituitary (AP). B. [ 14C]Deoxyglucose autoradiograms of brain and pituitary from normal control rat drinking only water. C. [ I4C]Deoxyglucose autoradiograms from rat given 2% NaCl to drink for five days. Note selective marked increase in density in posterior hypophysis, indicating increased glucose utilization. D. [ I4C]Deoxyglucose autoradiograms from rat made hypotensive by administration of 20 mg/kg of phenoxybenzamine, 45-60 minutes before [ I4C]deoxyglucose was given. Note selective increases in labelling of supraoptic and paraventricular nuclei and posterior pituitary. (From Schwarz et a1 1979.)

48

sections of the lumbar cord and dorsal root ganglia. The arrows point to the side of stimulation. (From Kadekaro et a1 1985.)

FIG. 3 (Sokoloff). [ I4C]Deoxyglucose autoradiograms illustrating effects of electrical stimulation of sciatic nerve at different frequencies on glucose utilization in the dorsal root ganglion (right) and lumbar spinal cord (left). A and E are cresyl violet-stained

$

General discussion T

50

40

30

4 Means?

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SEM

(n)=Number

of Animals

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0

3

Dorsal

R o o t Ganglion

(4)

(4) -1 0

I

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FREQUENCY OF STIMULATION (Hz)

FIG. 4 (Soko/off).Frequency-dependent effects of electrical stimulation of sciatic nerve on glucose utilization in dorsal root ganglion and dorsal horn of lumbar spinal cord. The error bars represent SEM. (From Kadekaro et al 1985.)

To distinguish between the two, one must look one synapse downstream; if an inhibitory neurotransmitter is released at the first synapse, one will observe reduced glucose utilization in the next synapse. If an excitatory neurotransmitter is released, then glucose utilization is increased at the next synapse. Wise: This is also the question of surface area. You say that the cell body doesn’t have many sodium channels in it, but just adjacent to the cell body (the initial segment) there is a variable amount of electrical activity. The surface area there is very small, whereas at the level of the dendrites there is a large total surface area with many ion channels. The net sum of the inhibitory and excitatory influences on the dendritic tree of an axon is transmitted through the axon hillock, but local metabolic rate will be influenced by the activity at

Oxidative metabolism in brain

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dendritic level and not by the spike rate in the axon. In other words, local metabolic rate is governed by input, not output. Sokoloff: True! Porter: And there is a huge concentration of neuropil and synapses, both excitatory and inhibitory, with glial processes around them. Sokoloff: There is a large surface-to-volume ratio in the nerve terminals. Oxidative metabolism in brain

Fox: I would like your thoughts, Dr Sokoloff, on how we might perform, at autoradiographic resolution, the counterparts of the experiments performed at low resolution with PET (Fox & Raichle 1986, Fox et a1 1988) and proton spectroscopy (Prichard et a1 1987). These studies indicate that a large fraction of the increase in brain glucose metabolism induced by neural activity is nonoxidative and, therefore, yields very little energy. We have done our best at the macroscopic level (using PET and spectroscopy). You are the expert on measuring metabolism at microscopic resolution. How should we proceed to resolve this issue? Sokoloff: My interpretation of the alleged dissociation of blood flow and glucose utilization from oxygen consumption is that there is something wrong with the oxygen consumption model and method. Fox: It has been confirmed with proton spectroscopy. Sokoloff: What were seen with proton NMR spectroscopy were increases in lactate in the brain with functional activation, something that should be expected. Pyruvate is an intermediate in the pathway of energy metabolism in the brain, and it is a substrate for the Krebs cycle. Its formation is increased whenever glycolysis is increased. A large amount of lactate dehydrogenase exists in brain tissue, and there is rapid equilibration between pyruvate and lactate, with the equilibrium favouring lactate. When pyruvate formation is stimulated, the amount of lactate increases. In rat brain there is about 1 mM lactate. By NMR, on functional activation the lactate concentration increases only to 2-3 mM. This is small compared to the flux of carbon going through the glycolytic and oxidative pathways. Think of a number of bottles connected in series, with water from the top one running into the next bottle and then into the next, and so on. That’s analgous to a metabolic pathway with many steps. One will get an increase in water level in every bottle, once the flow from the first bottle is accelerated. The fact that lactate and pyruvate increase in the brain doesn’t mean that the energy is coming from anaerobic glycolysis only. From one mole of glucose the theoretical amount of ATP generated is about 36 moles. Allowing for a lack of efficiency, this estimate is reduced to 28-30 moles. From, say, 30 moles ATP formed, only two come from glycolysis. If one stimulated glycolysis by 50%, one would add only one mole of ATP, out of 30. That doesn’t make

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General discussion

economic or biochemical sense. Moreover, the same biochemical changes that occur within a cell that turn on glycolysis will, under aerobic conditions, also turn on electron transport and oxygen consumption. Therefore, if you are telling me that you are not increasing oxygen consumption when you stimulate glucose utilization under aerobic conditions, I don’t understand it at all. Frackowiak: Have you done any autoradiography a t a cellular level, using 3H-labelled deoxyglucose, to see which cell population at the synapse is metabolically most active? Is it the synapse itself, or is it the surrounding glia? Sokoloff: No, we have not, and we don’t know, but would like to. It is possible that it is mainly glial but, if so, what are all those mitochondria doing in the nerve terminals? Jones: Going back to Peter Fox’s question, could autoradiographic methods be used to study the oxygen consumption of tissue? This would provide an independent measure of the activation of oxygen consumption and help us to understand whether there are errors in the PET methods, and where they come from. Sokoloff: I don’t know how. We do know that in vitro,in brain slices, oxygen consumption is increased by electrical stimulation or by raising the K concentration in the medium. Raichle: A group of investigators at Rutgers University suggested a means of detecting oxygenation of haemoglobin in tissue sections (Buckweitz et al 1980). One might propose looking at the variation in the A-V difference in oxygen concentration across the stimulated part of the cortex, to see if it changes, on stimulation. One would have to study something like the barrel fields in the rat or mouse cortex, to do that (Woolsey et a1 1990). Sokoloff: Lockwood’s group (Izumiyama et a1 1989) have proposed a method for measuring local oxygen consumption autoradiographically. Raichle: This method of Dr Buckweitz is autoradiographic in a sense, but using the signal that is within the tissue and fast-freezing it, using the optical properties of brain venules versus incoming arterial blood. Frackowiak: On this issue of the potential errors in the ‘autoradiographic’ oxygen method, the problem is compounded by the fact that the very few steadystate measurements of oxygen consumption and blood flow performed under conditions of activation suggest a correspondence between them. The method is exceedingly tiresome and uneconomical in terms of radiation exposure, when you are trying to do repeat measurements, and therefore is not done. We carried out one PET study some time ago, comparing an eyes-closed and eyes-open condition. The increases in blood flow posteriorly were 30% and of oxygen metabolism, 25%. That was a single observation, but it raised for us the problem of why there seemed to be a discrepancy between the rapid oxygen metabolism measurements with the bolus technique and the steady state. One explanation may be that there are a number of cellular populations in the volume of tissue that we are looking at with PET. These may differ in their capacity for oxidative +

Oxidative metabolism in brain

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metabolism, which presumably has to do with neurotransmission, and for glycolysis, which may be more concerned with other local cellular functions. Sokoloff:There is the possibility of a temporal dissociation between glucose utilization and oxygen consumption. Before more oxygen can be consumed, there must be an increased supply of oxidizable carbon and hydrogen sources. It is necessary to produce more pyruvate to oxidize more. There may be an initial increase in the supply of substrates-for example, pyruvate and lactate-to the Krebs cycle, followed by increased oxygen consumption later, or, for example, an oxygen debt like that which occurs in muscle. Is this supported by the evidence? Raichle: This is certainly the most attractive possibility, but our data do not support it. This dissociation of oxygen consumption and glucose utilization was not what we were planning to find! We thought hard about the oxygen model (Mintun et a1 1984), but of the various models used to measure oxygen consumption, this one (Mintun et a1 1984) has most empirical validation. The model is basically looking at the arteriovenous oxygen difference. It is easy to say that this model does not work properly, and I would be happy to concede, if those who make such statements provided hard data to back them up. Sokoloff: A steady-state O2 consumption method would not have that problem of temporal dissociation. Raichle: It might not be viewed as a problem, if there are temporal changes to be uncovered. SokolofJ True. I have been doing some modelling of the effects of changes in glucose concentration in the arterial plasma on the free glucose concentration in brain tissue. I tried to take into account the fact that the brain doesn’t know anything about what’s in arterial blood; it only knows what is in the capillary. Therefore, we have to attempt to determine what the brain sees. To determine or model what is happening in the capillary we need to make a large number of worrisome assumptions. We have to worry about what the local A-V difference is for glucose. This is related to its rate of metabolism, the blood flow, and arterial glucose concentration. We have also to know the gradient down the capillary. Then we have to determine how much is capillary blood, venous blood, and arterial blood in the tissue. We have also to worry about the local haematocrit. All those things are assumed in our modelling, but I don’t have much confidence in the validity of these assumptions, because I haven’t been able to carry out independent verifications of any of them. I think you have the same problem in the oxygen consumption method, and the many implicit assumptions required by the method are the places to look for problems, especially under conditions where these relationships may change. You may make reasonable assumptions for a normal state, but when you perturb the system, they may not apply. Raichle: I agree that all these models depend on assumptions. However, assumptions, clearly stated, at least lay out the issues to be addressed. And at

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the theoretical level one can look at the error propagation of these various assumptions. The model is more sensitive to some than to others. But, having said this, I would return to my position that the model used to analyse our data (Mintun et a1 1984) has been empirically validated under normal conditions and I would consider the activation we performed to be normal function. Sokoloff: Before we revise our standard biochemical thinking, we ought to examine the possibility that there is a methodological problem, rather than a fundamental error in our biochemical thinking! Raichle: To evaluate a method such as ours (Mintun et a1 1984), one needs some standard, and in this instance most of us would accept the notion of measuring the A-V difference across the brain and multiplying by the blood flow to give us the metabolic rate for oxygen. We used this standard to validate our method (Mintun et a1 1984). Such a validation, rare among PET methods, is good empirical evidence that you are accurately measuring what you intend to measure, in this case oxygen consumption, despite whatever assumptions you are making in the model. Sokoloff: There are at least 50 years of experimental data, mostly not based on hypothetical models. Investigators just measured arterial-venous differences for oxygen and glucose by very good chemical methods. In almost all conditions, except hypoglycaemia and ketosis, the oxygen-to-glucose ratios were found to lie between 5 and 6mmol/mmol: that’s hard to argue with. Raichle: Yes, but our method provides exactly the same data, except that it permits regional measurements in normal humans with PET which could not be obtained otherwise. Lassen: May I add something on this point? In epilepsy, the venous blood gets more red, so evidently blood flow overshoots. Frackowiak: Everyone, I think, accepts that flow overshoots. And we should remember that using PET we are very lucky, in that by following blood flow, which is the most convenient thing we have to measure, we obtain the highest physiological signals which remain related in some way to neural activity. But in terms of this biochemical discussion at a fundamental level, it is not this overshoot of blood flow that is the important issue. Sokoloff: Dr Plum, you studied dogs with experimental seizures and found an outpouring of lactate from the brain, but when the dogs were given artificial respiration and the musculature was blockaded with neuromuscular blocking drugs, then the lactate output was essentially reduced to normal or negligible levels, in spite of the seizure activity. Plum: As you imply, we became interested some time ago in the uncoupling that occurs between blood flow and oxidative metabolism in the stimulated brain. Wilder Penfield had remarked in 1937 that he was able to identify a discharging seizure focus in the human brain by the reddened venous blood draining the area. Our laboratory looked at the mechanisms of this dramatic uncoupling between blood flow and oxidative metabolism in a series of experiments between

Oxidative metabolism in brain

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1967 and 1975 (summarized in Plum & Duffy 1975). We used seizures of a variety of intensities as our stimulus and observed in all instances that during the seizures, blood flow increased sufficiently to exceed oxygen demand in the epileptic regions but venous C 0 2 remained constant. Calculated brain pH fell in the tissue, presumably intracellularly, but electrode-measured interstitial pH remained constant throughout the seizure. Direct tissue measurements showed modest (PcO.05)reductions in ATP but up to five-fold increases in lactate (P
References Buckweitz E, Sinha AK, Weiss HR 1980 Cerebral oxygen consumption and supply in anesthetized cat. Science (Wash DC) 209:499-501 Fox PT, Raichle ME 1986 Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci USA 83: 1140- 1144 Fox PT, Raichle ME, Mintun MA, Dence C 1988 Nonoxidative glucose consumption during focal physiologic neural activity. Science (Wash DC) 241:462-464 Izumiyama M, Kogure K, Lockwood AH, Yap E, Tewson TJ 1989 Evidence of a microcirculatory and metabolic penumbra in postischemic rat brain: a I5O autoradiography. J Cereb Blood Flow Metab 9 (suppl 1):S382 Kadekaro M, Crane AM, Sokoloff L 1985 Differential effects of electrical stimulation of sciatic nerve on metabolic activity in spinal cord and dorsal root ganglion in the rat. Proc Natl Acad Sci USA 82:6010-6013 Kennedy C, Des Rosiers MH, Sakurada 0 et a1 1976 Metabolic mapping of the primary visual system of the monkey by means of the autoradiographic [ 14C]deoxyglucose technique. Proc Natl Acad Sci USA 73:4230-4234 Mata M, Fink DJ, Gainer H et a1 1980 Activity-dependent energy metabolism in rat posterior pituitary primarily reflects sodium pump activity. J Neurochem 34:213-215 Mintun MA, Raichle ME, Martin WRW, Herscovitch P 1984 Brain oxygen utilization measured with 0-15 radiotracers and positron emission tomography. J Nucl Med 25: 177- 187

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Plum F, Duffy TE 1975 The couple between cerebral blood flow and metabolism during seizures. In: Lassen N (ed) Brain work. Alfred Benzon Symposium VIII. Munksgaard, Copenhagen, p 197-214 Prichard JW, Petroff OAC, Ogino T. Shulman RG 1987 Cerebral lactate elevation by electroshock: a 'Hmagnetic resonance study. Ann NY Acad Sci 508:54-63 Schwartz WJ, Smith CB, Davidsen L et a1 1979 Metabolic mapping of functional activity in the hypothalamo-neurohypophysial system of the rat. Science (Wash DC) 205~723-725 Smith TG Jr 1983 Sites of action potential generation in cultured neurons. Brain Res 288:381-383 Sokoloff L, Reivich M, Kennedy C et a1 1977 The [ 14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 282397-916 Woolsey TA, Rovainen CM, Robinson 0 1990 Videomicroscopy of flow in single blood vessels in mouse barrel cortex in vivo. SOCNeurosci Abstr 16:25

Optimization of signal in positron emission tomography scans: present and future developments David W. Townsend Division of Nuclear Medicine, University Hospital of Geneva, 24 rue Micheti-du-Crest, 1211 Geneva 4, Switzerland

Abstract. The absolute sensitivity of a state-of-the-art, commercial neuroPET tomograph with interplane septa is about 0.5%. This poor utilization of the available photons could be improved by increasing the intrinsic efficiency of the detection process and, more significantly, by increasing the solid angle coverage of the tomograph. While multi-ring scanners currently have an axial length of about 10 cm, the useful solid angle is limited by the presence of interplane septa. These septa reduce the acceptance rate not only of scattered photons but also of true unscattered coincidences, although in studies performed at high photon counting rates the loss of potential signal may be less important than a reduction in scatter. Removal of the septa increases the absolute sensitivity of the scanner to about 3 % , a figure which also includes an unavoidable increase in scattered photons. However, in studies performed at low photon counting rates, any increase in scattered and random (uncorrelated) coincidences resulting from septa removal may be an acceptable price to pay for the accompanying increase in signal, provided that there is a real improvement in the signal-to-noise ratio. Recently, scanners with automatically retractable septa have become commercially available, thus enabling the configuration (i.e. septa extended or retracted) to be selected according to the study to be performed. 1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 57-75

A significant number of positron emission tomography (PET) studies of the brain are carried out at low coincident photon counting rates. The reasons include the low uptake of certain positron-emitting tracers, the requirement to follow tracer concentration as a function of time to low levels, the desire to do repeat studies in a single volunteer by giving multiple small doses of tracer, and the necessity to perform studies in children, where low doses are clearly indicated. Apart from studies in patients, we may, in the future, be required to reduce the tracer levels currently administered to normal volunteers under accepted research protocols. The key to performing these and other such studies more efficiently is an improvement in the sensitivity of the imaging system. 57

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Townsend

Over the past ten years, a number of different PET camera designs have been investigated, most of which have used bismuth germanate (BGO) as the detector material. At the present time, therefore, the large majority of installed PET cameras consist of multiple rings of small BGO detectors surrounding the patient. Positioned between adjacent rings of detectors, thin lead or tungsten shields (septa) project a few centimetres into the field of view, beyond the front face of the detectors. A true coincidence is one in which the two coincident photons are unscattered and originate from a single positron annihilation. Ideally, PET images should include only true coincidences and the stack of annular septa serve (a) to limit the incident photon flux, thus reducing the probability of acquiring uncorrelated photon pairs (random coincidences) and (b) to shield the detectors from out-of-plane scattered photons. The septa, however, reduce not only the contribution from scattered and random coincidences but also that from true coincidences. PET cameras with septa acquire coincidences (true, random or scattered) between pairs of detectors if they are in the same or adjacent rings, thus limiting the effective coincidence acceptance angle in the axial direction to less than 1". In practice, this small angle is usually neglected and all coincidences are assigned to parallel two-dimensional transverse slices. Each slice can then be reconstructed independently using a standard, two-dimensional reconstruction algorithm (Herman 1980). The 2D slices can be stacked in order to recover the threedimensional distribution of tracer. The measured absolute sensitivity (that is, the ratio of the number of detected photon pairs to the total number emitted from the source in a given time) of such a camera is about 0.5% (Bailey et a1 1991a). One obvious way in which to improve this low sensitivity is to increase the maximum acceptance angle of the scanner. As a first step, this can be done by removing (retracting) the septa and allowing coincidences to be acquired between any two rings-that is, a three-dimensional or volume acquisition. Retraction of the septa increases the maximum acceptance angle to about 6", and raises the absolute sensitivity of the scanner to a little over 3%. However, while the increase in true coincidences reduces statistical noise, improving the signal-to-noise ratio in the image, there is an increase in scatter which reduces image contrast, thus reducing the signal-to-noise ratio. The net effect on the signal-to-noise ratio will have a positional dependence because the increase in true coincidences is spatially variant, being concentrated more towards the centre of the axial field of view. At the centre, the signal-to-noise ratio should be improved, whereas at the axial extremities it may even be worse than with the septa extended. A further requirement of a septa-retracted acquisition is the use of a three-dimensional (volume) reconstruction algorithm which processes the additional oblique-angle data, taking into account their non-uniform spatial distribution.

Signal optimization in PET scans

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Recently, a neuroPET scanner with automatically retractable septa has become commercially available. This scanner, an ECAT 953B (Siemens/CTI Inc, Knoxville, TN, USA), consists of 16 rings of BGO detectors. The complexity and cost of coupling these detectors to individual photomultiplier tubes has been reduced by adopting the block-detector approach (Casey & Nutt 1986). In the latest design, an array of 8 x 8 detectors, 6 mm x 6 mm in size, are cut from a single BGO block, 3 cm thick and 5 cm x 5 cm in section. The block is coupled to four photomultiplier tubes (PMTs), and the relative distribution of light between the four PMTs is used to localize the most probable detector among the 64 possible candidates. For this brain scanner, two circular arrays, each of 48 blocks, are mounted contiguously to provide 16 rings of 384 detectors per ring, covering an axial extent of 10.8cm. In this chapter, the performance of the ECAT 953B scanner will be examined, and in particular its suitability for imaging the brain at low count rates, with emphasis on factors influencing the signal-to-noise ratio in the image. Apart from retracting the septa, there are, of course, other ways in which to increase camera sensitivity, such as by improving the intrinsic efficiency of the detector unit. This could be achieved either by improving the light collection from the currently used BGO block, or by using a different detector material with a better combination of stopping power, light output and decay time. However, even if the detection process were 100% efficient, the absolute sensitivity of the 953B scanner would still be less than 5% because of the small acceptance angle (<6")subtended by the 10 cm long, 75 cm diameter, cylindrical detector geometry. Further significant improvements in sensitivity must come from an increase in acceptance angle, although this will inevitably require an increase in the number of BGO detectors in the scanner. The implications of such developments for brain imaging will be briefly discussed at the end of this chapter. Retracting the septa A scanner with n rings of detectors subdivides the 3D imaging volume into 2n - 1 two-dimensional transverse planes. These planes are either direct planes where the detectors in coincidence are in the same ring, or cross planes where the detectors are in two adjacent rings, as illustrated in Fig. 1 for a scanner with four rings. If we neglect the small acceptance angle ($), coincidence lines between detectors in two adjacent rings are assigned to the transverse cross plane mid-way between, and parallel to, the two direct planes on either side. The average sensitivities of the direct (odd) and cross (even) planes therefore differ, as shown schematically in Fig. 2a for a scanner with eight rings. Each plane is reconstructed independently using a two-dimensional reconstruction algorithm. Calibration factors account for the sensitivity variations between planes.

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Direct plane

Cross plane FIG. 1. A cross-section through a neuroPET scanner with four rings of detectors. The rings are labelled 1 to 4, and detectors (al, bl), (a2, b2) are diametricallyopposing pairs of detectors in ring 1, ring 2, etc. Direct and cross planes are indicated, and tapered septa are shown between adjacent rings. II. is the maximum acceptance angle.

When the septa are retracted, coincidences are acquired between detectors in any two rings. The number of active coincidence lines of response increases from 0.95 million to 7.86 million. However, the additional oblique coincidence lines cannot simply be assigned to specific transverse planes without introducing significant spatial distortions into the images. As these oblique lines intersect more than one transverse plane, the set of 2n- 1 planes are no longer independent and the data must be reconstructed using a fully three-dimensional reconstruction algorithm. The average sensitivity of each plane with the septa retracted is shown schematically in Fig. 2a. The sensitivity variations due to the spatial variance of the camera response function cannot be corrected by simple calibration factors, but must be taken into account by the reconstruction algorithm. The sensitivity increase arising from septa retraction, which is a maximum in the centre of the field of view, is due both to the increase in the number of measured coincidence lines of response and to the elimination of the shielding effect of the septa which overlap (shadow) the crystal faces (Fig. 1); the increase in the outer planes is, of course, due mainly to the latter effect. The effect of scattered photons and random coincidences

In practice, the situation is more complicated than that shown in Fig. 2a. Septa retraction also leads to an increase in the detection of scattered photons and random, uncorrelated coincidences. The scatter fraction (the ratio of scattered to total coincidences) increases mainly because of an increase in out-of-plane scatters which are no longer absorbed by the septa. Random coincidences

61

Signal optimization in PET scans 50

0

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(bl FIG. 2. (a) The relative (noise-free) sensitivities of the direct and cross planes for a scanner with eight rings of detectors. The sensitivities are shown for septa extended and septa retracted. With the septa extended, the cross (even) planes have higher sensitivity than the direct (odd) planes. (b) The relative sensitivities of the direct and cross planes estimated from the noise equivalent count rate, including randoms and scatter, equivalent to a tracer concentration of 0.2 pCi/ml. The sensitivities are shown for septa extended and septa retracted.

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increase because of an overall increase in the incident photon flux. To take these effects into account, the concept of noise equivalent counts (NEC) has been introduced (Derenzo 1980, Strother et a1 1990). The noise equivalent count rate at a given true coincidence rate ( T ) ,scattered coincidence rate (S) and random coincidence rate ( R ) is the coincidence rate which, in the absence of scatter and randoms, would give the same signal-to-noise ratio. The NEC is given by Strother et a1 (1990) as: NEC =

T2

+

( T + s 2R )

where R is the random coincidence rate, taking into account only coincidence lines which cross the volume containing positron activity. The factor of two arises from the increase in statistical noise introduced by the random coincidence subtraction procedure. The noise-free situation shown in Fig. 2a can be modified by using equation (1) to estimate the noise equivalent efficiency for each transverse plane, with the septa extended and retracted. The result is presented schematically in Fig. 2b for scatter and random coincidence rates corresponding to a positronemitting tracer uptake of 0.2 yCi/ml uniformly within the brain. It is evident that the real improvement in the signal-to-noise ratio due to septa retraction could be significantly less than that expected from the noise-free situation, and that for the edge planes the improvement is actually less than unity; that is, for these planes, the signal-to-noise ratio is reduced by retracting the septa. The noise equivalent count concept as presented in equation ( I ) is useful for comparing different imaging situations in the presence of varying random coincidence and scatter rates. Bailey et a1 (1991b) have measured the overall NEC for the ECAT 953B scanner with septa extended and retracted for a number of different test objects containing positron activity, and for three clinical studies. These authors define an NEC gain factor as: NEC (septa retracted)/NEC(septa extended). This ratio gives an indication of the real improvement in signal-tonoise to be expected from septa retraction. The NEC does not take into account effects arising from changes in other physical parameters of the camera, such as spatial resolution. Furthermore, systematic effects introduced either by correction procedures such as scatter deconvolution, or by the reconstruction process (artifacts), may significantly affect the final signal-to-noise ratio in the image. However, for a 2D reconstructed image, in the absence of systematic effects the NEC is proportional to the square of the signal-to-noise ratio (Strother et a1 1990), at least for simple, high-contrast objects. The same relationship has also to be established for threedimensional reconstruction; we now examine the propagation of statistical noise by the reconstruction algorithm used in this work.

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The 3D reconstruction algorithm Image reconstruction from data acquired with the septa retracted requires a fully three-dimensional reconstruction algorithm. A number of possible algorithms have been proposed in recent years (Colsher 1980, Ra et a1 1982, Defrise et a1 1987, Clack et a1 1989). The approach we have adopted in this work is a generalization to three dimensions of the standard 2D filtered backprojection algorithm (Pelc & Chesler 1979). Defrise et a1 (1990a) have shown that, with certain approximations, the coincidence data set acquired with septa retracted can be considered as a set of 2D projections of the three-dimensional tracer distribution. These 2D projections are first filtered with an appropriate function (Colsher 1980) and then the filtered projections are back-projected into the 3D image volume. This procedure is only valid if the system response function is spatially invariant. However, as we have seen (Fig. 2a), the sensitivity varies throughout the field of view. Lines of response in certain directions can be measured for a point at the centre of the field of view but not for a point at the extreme axial edge of the field, an inevitable consequence of the truncated cylindrical geometry of the scanner. To maintain the filtered back-projection approach, the response function is made spatially invariant by estimating the values of these unmeasured coincidence lines using a method first suggested by Pelc (1979) and more recently developed by Kinahan & Rogers (1989). After an initial, low statistics, 3D image has been obtained by stacking the usual 2D reconstructions of direct and cross planes, the values of the unmeasured lines of response are estimated by forward projection (integration) through this initial image. Completing the measured values with these estimates ensures that the response function is spatially invariant . The statistical properties of this algorithm have been studied by Defrise et a1 (1990b). They have shown that the variance on the reconstructed value f(x) at the centre (x = 0) of a uniform sphere (radius R) is: 2R/d var(f(0)1= - k (4) n where n is the number of coincidences per resolution element of size d, and the value of k ( $ ) depends on the maximum acceptance angle ($) of the scanner and on the reconstruction filter. For the filter used in our implementation, with $=6', k ( $ ) is approximately 0.47. This result is similar to that for the 2D reconstruction ($= 0) of a disk (Barrett & Swindell 1981), where k(0)= 0.82. Thus, at least for a uniform source of activity, statistical noise is propagated similarly by both the 2D and 3D filtered back-projection algorithms, and therefore the NEC concept applies equivalently to both 2D and 3D reconstructions. It can thus be used to compare septa-extended and septa-retracted acquisitions.

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This also means that, in principle, the noise in the 3D reconstruction should reflect the increase in statistics (true coincidences) due to septa retraction. We have estimated the statistical contribution to the reconstruction signalto-noise ratio as the ratio of the mean value ( M )to the standard deviation (a) for a region-of-interest located appropriately on the image. This ratio (SNR) can be calculated independently for each transverse plane. Note that, as with the NEC, this index does not take into account any non-statistical contributions to the image noise, such as reconstruction artifacts or systematic effects due to a scatter correction procedure. Results

We have performed a number of studies with the 953B scanner to evaluate its potential for imaging the brain (Townsend et a1 1991). Low count rate measurements made with a lower energy threshold at 380keV for a 20cm diameter cylinder (containing an activity concentration of around 0.1 pCi/ml) show that septa retraction increases the total system count rate by a factor of 7.4, which includes an increase in the scatter fraction by a factor of about three (to over 40%) (Michel et a1 1991). The real gain factor after scatter correction is only 4.7. These results depend, of course, on the particular choice of lower energy threshold. The current choice of 380 keV, which may not be optimal, is intended to maximize rejection of scattered photons without significant loss of true coincidences. Bailey et a1 (1991b) find that, for a 20cm diameter cylinder, the maximum NEC is achieved at 52000 coincidences per second (52 kcps; activity concentration 0.5 pCi/ml) with the septa retracted, compared to 74 kcps (2.5 pCi/ml) with the septa extended. Similar measurements for a 15 cm diameter cylinder show that the maximum NEC is about 150 kcps for both septa extended and septa retracted. However, with the septa retracted, this rate is achieved at only 10% of the positron-emitting activity required when the septa are extended. It is also interesting to note that with a given amount of radioactivity in the field of view, the random-to-true coincidence ratio increases (as expected) when the septa are retracted. However, for a given true coincidence rate the randoms/trues ratio is actually smaller with the septa retracted than with the septa extended. We have also acquired and reconstructed data for a uniform, 20 cm diameter, cylinder at two different radioactivity concentrations (0.08 pCi/ml and 0.31 pCi/ml). For each concentration, the cylinder was imaged for the same time with the septa extended and retracted. The data obtained with septa retracted were reconstructed using the algorithm outlined above. For each study, the SNR index was calculated for all 31 transverse planes. A SNR gain factor (the ratio of the signal-to-noise ratios) was then defined for each plane as: SNR (septa retracted)/SNR(septa extended). This factor is shown in Fig. 3 as a

Signal optimization in PET scans

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function of plane number for the two activity concentrations. The NEC gain factors were estimated to be 2.1 and 3.2 for the high and low count rate scans, respectively. Finally, Fig. 4 shows the thirty-one transverse planes from a study in which [ lSF]fluorodopa was injected in a normal volunteer. The study was done with (a) septa extended and (b) septa retracted. The scans were performed sequentially, approximately 90 minutes after injection, and each scan took five minutes. The average count rates were 1500 coincidences per second (septa extended) and 5300 coincidences per second (septa retracted).

Discussion These results suggest that real gains in sensitivity are to be achieved by retracting the septa at low counting rates. The NEC estimates show that, with the septa retracted, the useful increase in signal is limited by the contribution from increased scatter and random coincidences. A corresponding limitation is seen in the reconstructed signal-to-noise (Fig. 3), where, at high coincidence rates, the improvement may be as little as 30% in the centre of the field of view, whereas at low coincidence rates, with the same cylindrical object, the signal-to-noiseratio

o

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Townsend

FIG. 4. Thirty-one 3.4mm thick, transverse sections through the brain of a normal volunteer following an injection of 6-L- [ **F]fluorodopa. The images were obtained about 90 minutes after injection from two, five-minute, scans performed sequentially with (a) septa extended (count rate, 1500 cps) and (b) septa retracted (count rate, 5300 cps).

may be increased by more than a factor of three for the same planes. It is impressive to note that, for the 15 cm diameter cylinder, the same (maximum) NEC, and hence signal-to-noise ratio, in the image is achieved at an activity concentration of only 0.6 pCi/ml with the septa retracted compared to 6 pCi/ml with the septa extended. The situation for brain imaging is more difficult to quantify. However, Bailey et al(l991b) have estimated the NEC in a study performed with a cerebral opiate

Signal optimization in PET scans

67

ligand ( [ "C] diprenorphine). They find that the overall NEC gain factor increases from four at the start of the study to about five at the end. This significant gain is reflected in the improvement observed in the reconstructed images of the low count rate fluorodopa study (Fig. 4). The standard deviation on a region of interest within the basal ganglia is reduced by a factor of two (for the same imaging time) when the septa are retracted. These improvements in the signal-to-noiseratio, particularly at low counting rates, have been achieved by increasing the acceptance angle of a commercially available PET scanner. It is interesting to speculate to what extent the signalto-noise ratio continues to improve as the acceptance angle is further increased, either by adding more rings of detectors, or by adopting a different design (Burnham et a1 1988, Rogers et a1 1988, Muehllehner et a1 1988). In the absence of actual measurements, such a question can be addressed by simulation. The effect of the increasing scatter fraction as the angular coverage of the scanner is extended beyond the 6" subtended by the 953B scanner has recently been studied (M. Defrise, personal communication 1990). The detector material is assumed to be 100% efficient at 5 1 1 keV. At an energy threshold of 300 keV, it is found that the scatter fraction does not increase continuously but tends instead to a constant value, essentially when all scatters with an energy greater than 300 keV are detected within the extended geometrical acceptance of the scanner. In the absence of random coincidences, the NEC sensitivity tends to increase monotonically with increasing angular coverage. At an angular coverage of 50°, the scatter fraction for a 20 cm diameter uniform sphere of activity is 45%, and the total and NEC sensitivities are 34% and 11070, respectively. The problem, then, is how to correct properly for such a large scatter fraction. A completely satisfactory measurement of scatter for PET has yet to be made, and any one of the proposed correction procedures is therefore likely to introduce a systematic error which has not been taken into account by the above NEC estimates. This is in contrast to the correction for random coincidences, where measurement of a time-delayed coincidence map results in a correction procedure which, while increasing statistical noise, does not introduce systematic errors. However, the 953B scanner has the capability to acquire data simultaneously from two energy windows (e.g. the photopeak and a lower energy scatter window), and work is currently under way to investigate how best to use this information ( S . Grootoonk & C . Michel, unpubfished work 1990). When the acceptance angle of the camera is increased, the aim must therefore be to obtain a reasonable balance between the statistical and systematic error contributions. Since the former decreases as the counts increase, whereas the latter is independent of the number of counts, there will be an optimal angular coverage for which the two contributions are balanced. For low count rate studies the statistical noise factor will dominate and hence a large acceptance angle will be beneficial. For studies performed at high rates with good statistics, it will be important to limit the systematic error introduced by scatter correction to

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a level compatible with the statistical contribution. Thus, the most appropriate scanner geometry will, in general, depend upon the study t o be performed. This suggests a future scanner design incorporating a larger acceptance angle than at present, but with retractable septa to limit the scatter fraction in low statistical noise situations. The use of shorter septa may be preferred, so that, with the septa extended, the scanner can still acquire oblique coincidence lines. A reduction in the coincidence timing might also be considered. At high random coincidence rates, a reduction in the statistical noise arising from the subtraction of the random coincidence background may be more significant than any accompanying loss of signal. Conclusion We have seen that the latest generation of neuroPET cameras with retractable septa offer significant advantages for low count rate studies. For higher count rate studies, the implications are that, with septa retracted, smaller quantities of radioactive tracer than those currently used can be administered without compromising image quality. Further improvements in signal-to-noise ratio in studies of the brain can be expected by increasing the angular acceptance of the camera beyond the present maximum of f6". Care must then be taken to limit any systematic error introduced by scatter correction. Retractable septa should also be provided to ensure satisfactory scanner performance with high levels of radioactive tracer in the field of view. A ckno wledgemen ts This work is supported by the Swiss Commission for the Encouragement of Scientific Research (CERS), grant number 1922.1. I am indebted to many of my colleagues, in particular to Antoine Geissbuhler, Michel Defrise, Dale Bailey and Terry Spinks, for their help and contributions to this work. The data for Figs. 3 and 4 were acquired with the ECAT 953B scanner at the MRC Cyclotron Unit, Hammersmith Hospital under the technical direction of Dr Terry Jones, to whom I express my gratitude.

References Bailey DL, Jones T, Spinks TJ 1991a A method for measuring the absolute sensitivity of positron emission tomographic scanners. Eur J Nucl Med 18:374-379 Bailey DL, Jones T, Spinks TJ, Gilardi MC, Townsend DW 1991b Noise equivalent count measurements in a neuro-PET scanner with retractable septa. IEEE (Inst Electr Electron Eng) Trans Med Imag, in press Barrett HH, Swindell W 1981 Radiological imaging, 1st edn. Academic Press, New York Burnham C, Kaufman D, Chesler D, Stearns C, Wolfson D, Brownell G 1988 Cylindrical PET detector design. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 35:675-679 Casey ME, Nutt R 1986 A multicrystal two-dimensional BGO detector system for positron emission tomography. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 33:460-463

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Clack R, Townsend DW, Defrise M 1989 An algorithm for three-dimensional reconstruction incorporating cross-plane rays. IEEE (Inst Electr Electron Eng) Trans Med Imag 8:32-42 Colsher JG 1980 Fully three-dimensional positron emission tomography. Phys Med Biol 25: 103- I15 Defrise M, Kuijk S, Deconinck F 1987 A new three-dimensional reconstruction method for positron cameras using plane detectors. Phys Med Biol 33:43-51 Defrise M, Townsend DW, Geissbuhler A 1990a Implementation of three-dimensional image reconstruction for multi-ring positron tomographs. Phys Med Biol35: 1361- 1372 Defrise M, Townsend DW, Deconinck F 1990b Statistical noise in three-dimensional positron tomography. Phys Med Biol 35:131-138 Derenzo SE 1980 Method for optimizing side shielding in positron emission tomographs and for comparing detector materials. J Nucl Med 12:971-977 Herman GT 1980 Image reconstruction from projections, 1st edn. Academic Press, New York Kinahan PE, Rogers JG 1989 Analytic three-dimensional image reconstruction using all detected events. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 36:964-968 Michel C, Bol A, Spinks T et a1 1991 Assessment of response function in two PET scanners with and without interplane septa. IEEE (Inst Electr Electron Eng) Trans Med Imag, in press Muehllehner G, Karp JS, Mankoff DA, Beerbohm D, Ordonez CE 1988 Design and performance of a new positron emission tomograph. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 35:670-674 Pelc NJ 1979 A computerized filtered backprojection algorithm for three dimensional reconstruction. PhD thesis, Harvard School of Public Health, Boston, MA, USA, p 140 Pelc NJ, Chesler DA 1979 Utilization of cross-plane rays for three-dimensional reconstruction by filtered back-projection. J Comput Assisted Tomogr 3:385-395 Ra JB, Lim CB, Cho ZH, Hilal SK, Correll J 1982 A new true three-dimensional reconstruction algorithm for spherical positron emission tomograph. Phys Med Biol 27: 37-50 Rogers JG, Harrop R, Kinahan P et a1 1988 Conceptual design of a whole body PET machine. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 35:680-684 Strother SC, Casey M, Hoffman EJ 1990 Measuring PET scanner sensitivity: relating countrates to image signal-to-noise using noise equivalent counts. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 37:783-788 Townsend DW, Geissbuhler A, Defrise M et a1 1991 Fully three-dimensional reconstruction for a PET camera with retractable septa. IEEE (Inst Electr Electron Eng) Trans Med Imag, in press

DISCUSSION Evans: Dr Townsend, you are looking at the greatest number of counts that you can get out of one study, with septa extended or retracted, with different doses of radiation, which is basically the count rate capability of the PET system. You were showing with the NEC (noise equivalent count) curves that the maximum capability with septa out (retracted) was on the order of 150 OOO counts for the whole system, which is about what one can get now, with septa in (extended), albeit in fewer slices. You can therefore collect about the same total

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counts, dividing them up how you wish, but the limiting factor is 150000-200000 counts per second per study. So the question becomes: how useful is it that you can get the same number of counts with a fraction of the radiation dose? How practical is the benefit that you can do more repeats with the septa out, if you take into the account the facts that patients will move, and they may not maintain the same physiological status over repeated trials? Townsend: Our original interest in removing the septa was to improve the count rate in situations where one cannot increase the activity in the field of view by, for example, increasing the dose injected to the patient. We were thinking particularly of low-uptake ligand studies such as those with fluorodopa where one could even envisage retracting the septa between two frames of a dynamic study in order to compensate for isotope decay or wash-out. The application to activation studies is rather recent and we have yet to determine the optimum scanning conditions. The increased sensitivity will certainly offer the possibility to perform repeat activation studies in the same volunteer or patient-and even to study effects such as habituation. Problems arising from patient movement can, I’m sure, be solved. Evans: I am intrigued, because the attraction of taking the septa out had previously seemed to be that you could use it in cognitive subtraction paradigms, where the scatter problem is subtracted away; but it seems as though the greater benefit is the increase in NEC for [ I8F]fluorodopa studies, where you are typically doing quantitative studies and you are interested in a kinetic analysis and hence an improved signal-to-noise ratio. This somewhat turns things upside down. Townsend: Although it is true that with cognitive subtraction paradigms the scatter is essentially subtracted away, we have always taken the more general view that for 3D imaging to be successful, scatter must be properly corrected before reconstruction. We have been working on a scatter correction algorithm which involves convolving an exponential scatter function with each measured 2D projection in order to estimate the scatter distribution. This distribution is then subtracted from the measured projection before attenuation correction. The aim is not only to improve contrast but also to maintain quantitation. This same correction procedure would then be applied to, for example, the fluorodopa studies. An effective scatter correction is, I think, essential for the success of 3D imaging. Work is also continuing on estimating scatter from a dual energy window approach. Frackowiak: With cognitive studies, the main aim of trying to improve sensitivity is to carry out more measurements in a single subject. This is particularly important in trying to minimize a very potent source of variance in activation studies, which is the anatomical variance between subjects. Of equal importance is the ability to make statistically meaningful measurements in single patients suffering from a specific pathology or distribution of brain damage. If improved sensitivity allows measurement of blood flow at a fraction-say,

Signal optimization in PET scans

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a fifth-of the current radiation dose, then five times as much information can be collected within radiation administration exposure guidelines. Evans: Theoretically, yes-if the patient can stand it. Frackowiak: That’s another problem, of whether the patient moves and whether you can put the patients into the tomograph, take them out and put them in again, achieving perfect spatial realignment of the resulting blood flow scans. Evans: That is a very real problem. Jones: There is also the possibility of bringing someone back on a subsequent day to complete the series of scans and then of realigning the two data sets. With the goal of achieving higher resolution than with previous systems, d o you think this a practical proposition? Evans: It certainly is, but it has been shown by Mark Mintun that you can take images and post-hoc re-register them, if you have sufficient axial sampling in 3D; so it’s conceivable to d o that. We are talking about a great potential with true 3D acquisition, but we need to have the 3D registration sorted out. You have to assume that the patient will not be perfectly aligned if you bring him back the next day and d o the same experiment. Fruckowiak: He has the same size and shape of head, of course! The registration is therefore easier with the same subject than with a group of subjects. Evans: It’s possible to d o this, but you have to d o it in a fully threedimensional re-registration environment. Jones: What do you think of the quality of the data that Dr Townsend showed when comparing the images recorded, for the same amount of delivered activity, between septa extended and septa retracted? Evans: It looked excellent, but I am suspicious of images; I want to see the numbers. Townsend: I should emphasize that each of the studies such as the fluorodopa study shown in Fig. 4b takes 3.3 hours to reconstruct on a SUN SparcStation 2 computer. For dynamic studies we have set up a multi-frame processing tool that automatically reconstructs a full dynamic study. No user intervention is required other than to supply the data file name and the reconstruction parameters at the start. The computer will then run for one or two days without intervention being required. This way we can d o about two, 15-frame dynamic studies per week without septa. We are currently analysing quantitatively our first 3D dynamic fluorodopa scan, so the numbers are coming. Evans: These computational issues will be solved; they don’t represent any fundamental obstruction. Townsend: I agree. That’s always been our view. Evans: What about the issue of habituation? To what extent can one take advantage of the option to repeat the scan again and again on the same subject?

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Mazziotta: You have to repeat the same paradigm. The beauty of this approach is that you can have 12 or more states, depending on the radiation dose, enabling you to do different tasks, or to bring subjects back on different days, as a pathological process changes, using the same behavioural paradigm instituted at different times in the recovery or progression of illness. Multiple low dose imaging gives you the flexibility to do those things, given the threedimensional re-registration. One of the most important criteria in the latter problem is having enough axial data to do the registration and alignment. Roland: Dr Townsend, you said that if you increase the count rate you will lose the gain, and get down to a factor of one, basically, if you take the septa out and do the 3D reconstruction. I need some absolute figures here. If you do ramp injections, you don’t run into the problems that you encounter if you use the bolus injection for measuring blood flow in a short time period, which is actually what you want to do, according to Dr Iida’s paper. What is the absolute count rate that you think you can handle before losing any gain? Townsend: As I showed, the NEC with the septa retracted for a 15cm diameter cylinder peaks at about 150 OOO counts per second. The same maximum value of 150OOO counts per second is measured with the septa extended, although ten times more activity is required to achieve this rate with the septa extended than with the septa retracted. The NEC is a global figure and, as shown in Figs. 2 and 3, the signal-to-noise gain actually has an axial dependence. Thus, even though the NEC may be at the maximum, the signal-to-noise gain for slices at the edge of the axial field of view may be worse than in 2D (the gain factor is less than one) with the septa extended. This is because you have little increase in signal from septa retraction in these slices. As I showed in Fig. 3 for a 20 cm diameter cylinder, the maximum signal-to-noise gain at the centre of the field of view can vary from only 30% at high rates (200000 counts per second) to more than a factor of 3 at lower rates (60000 counts per second). Roland: But in a normal study with bolus injection of about the same amount of radioactivity that you used, I imagine you would get a higher count rate? Jones: The maximum count rate obtained when infusing 30mCi over two minutes is around 200 OOO true coincidences per second. Roland: Another point that was not addressed was the electronic ‘deadtime’ in the system. This depends, of course, on the way your scanner is built, and it doesn’t apply to 3D reconstruction; but do you have any comment, Dr Townsend? Townsend: The deadtime problem is the same as for 2D acquisitions. In principle, a deadtime correction factor is estimated and used to correct each of the 256 acquired sinograms. In practice, at the present time, this estimate is not available and the data I presented were not corrected for deadtime losses. Obviously, for a given activity in the field of view, the deadtime increases when the septa are retracted, but this effect is included in the NEC estimate.

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Evans: What sort of radioactivity dose do you envisage using, Dr Jones? Jones: We are using 30 mCi, which gives a net (NEC) gain fo three compared to when the septa are extended. In other words, the data obtained are equivalent to those obtained when 90 mCi is injected with the septa extended. Evans: We use 40 mCi in a conventional scanning system. You need to show that you can go down to, say, 20mCi before you will get an improvement in the number of studies you can do; 30 mCi is not much different from 40 mCi. You have to show that the dose is substantially smaller. Frackowiak: Dr Townsend, do you see any promising avenues in thinking about detectors, and detector materials, for improving PET systems further, or will the next advances come through cheaper, and better, electronics and decreasing the deadtime? Townsend: The ECAT 953B scanner has an absolute sensitivity with septa retracted of 3-3.3'70. We have calculated that increasing the detection efficiency to 100% would increase the scanner sensitivity to only 4.5%. The major problem is the solid angle coverage of the scanner, which is only 10 cm in length axially. Obviously, advances in detector material and light collection would also be significant, but the biggest advance will come from putting more detector material around the brain. Frackowiak: Is the advantage simply that you are increasing your gain on the outermost parts of your field of view, or is there also a gain in the centre? Townsend: It depends on the size of the axial field of view you require. Inceasing the axial length by 50% (from 10 cm to 15 cm) more than doubles the overall gain throughout the original 10cm field of view. However, you should expect the same centrally peaked sensitivity profile as I showed in Fig. 2, but now extended over 15cm instead of 1Ocm. Thus the (3D t o 2D) gain factor at the edge of the lOcm field of view should certainly be greater than one, although the factor may again be less than one at the edge of the 15 cm field of view. Raichle: I wonder whether one extension of this whole idea is not just to do three-dimensional reconstruction, but to go to spherical geometry, because then the efficiency of detection goes up dramatically. People are thinking about this; there are a number of limitations, not the least of which is the cost of such a machine. Scatter correction is a problem, but if you are talking about functional activation, you could potentially subtract the scatter away. Townsend: The data with septa retracted are acquired with scatter fractions of 30-40%, which have to be corrected. As I said before, we are working on a scatter correction algorithm based on subtracting the scatter distribution. The scatter distribution is estimated by convolving the measured 2D projections with an exponential scatter kernel. The dual energy window approach which attempts to measure scatter also appears to be promising. We have also looked at scatter in a spherical geometry. One trade-off must be to ensure that the statistical error is not disproportionately small compared with any systematic error introduced

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by the scatter correction procedure. A large acceptance angle system will essentially acquire all the out-of-plane scatter, which will result in scatter fractions of about 50%. Handling that will be quite a challenge. Raichle: Spherical geometry was considered early on, but was abandoned. But as one thinks about functional activation studies with image subtraction, where scatter could be dealt with rather directly, simply by subtraction, detection efficiency could go up by a factor of 10-20. The only problem is that you are talking of a system with thousands of detectors. The gain would be tremendous in terms of what this kind of machinery could do. Lassen: The deadtime problem become increasingly critical as you cover more and more of the brain. Everybody would like to have the sort of 3D scanner that we are hearing about by adding more rings. What are the chances of a substantial improvement in the deadtime problem that would allow us to go more logically, in terms of geometry, to the sphere? Jones: People are looking for a new crystal material. Derenzo et al (1990, 1991) have identified lead-based crystals which are faster and hence suggest less deadtime and better concidence-resolving times. These crystals will take some years to come to fruition as new detectors for use in tomographs. Raichle: Certainly it has begun to frustrate us that the standard PET machine covers only 10.5 cm and you would like 15 cm in the z axis, because what emerges from the activation studies are these tremendously distributed systems; what one hopes out of this imaging is to appreciate the geometry of such distributed systems, and it’s frustrating that you have got to leave out either the top or bottom of the brain because of inadequate sampling. One hopes that the right scanners will eventually take in the whole brain. Jones: There is a need to convince some government agency to make the large investment necessary to carry out the design and construction of a global PET system. The strategy would then be to allow researchers to come to this advanced facility to carry out experiments. Plum: An existing model of this principle has been the practice of governments to build high energy linear accelerators for shared use by multiple investigators. Raichle: Yes. It has concerned me that this work is ‘big science’; it takes not only very expensive equipment but the right kind of teams to do this work. The model of international resource facilities as used by astronomers and physicists would be an excellent model to adopt in the field of brain imaging research. For everybody, in each hospital or university, to try t o duplicate resources as they currently exist at the Hammersmith Hospital in London, or in our laboratory in St Louis, is nonsense, because the technology will stagnate. I think the right step is eventually to consolidate and have a limited number of centres, with the resources necessary, but with the obligation to support the research of investigators outside those centres with worthwhile projects. This approach has been followed successfully by the astronomers and by the physicists, and we should follow their lead.

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Porter: It will be important to identify the major biomedical ‘unknown’ that requires this sort of commitment on an international basis. It is the appeal of, and the need to have an answer to, that overriding important question, for the President of the USA, or whoever else will fund the science, that will yield the necessary determination to make sure that such resources become available. Jones: Perhaps you yourself are in the best position to identify, during this meeting, what important, unknown questions there are which could only be answered by the ‘big science’ approach-for example, the development of a subtle neuropsychological test in a psychiatric patient. Raichfe: One might begin with the argument that to take the funds currently being spent on many small centres, and consolidate them into fewer centres, would accomplish a large part of what we are talking about. Frackowiak: Professor Porter’s point is that to speculate on the technology for its own sake is probably not productive, and not a good argument for added investment, Porter: Yes. The next-generation radiotelescope has to be justified on the grounds that you are looking for something that can’t be detected in any other way, but must be out there. What is the question, that would justify the ultimate international effort to produce the superlative PET scanner? That is what we have to establish. References Derenzo, SE, Moses WW et a1 1990 Prospects for new inorganic scintillators. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 37:203-208 Derenzo SE, Moses WW, DeVol TA, Cahoonn JL, Budinger TF 1991 Discovery of lead sulfate, a new scintillator for high-rate high resolution PET. J Nucl Med 32:995 (abstr no. 5)

The neurotransmitter basis of cognition: psychopharmacological activation studies using positron emission tomography K. J. Friston*t, P. M. Grasby*, C. D.Frith*, C. J. Bench*, R. J. Dolan*, P. J. Cowens, P. F. Liddle* and R. S. J. Frackowiak*

* MRC Cyclotron Unit, Harnmersmith Hospital, Ducane Road, London W12 OHS, ?University Department of Psychiatry, Westminster and Charing Cross Medical School, Fulham Palace Road, London W6 8RF and BMRC PsychopharmacologyResearch Unit, Littlemore Hospital, Oxford, UK Abstract. The neuromodulatory effect of manipulating monoaminergic receptor function was assessed by combining a psychological and a pharmacological activation during repeated positron emission tomographic (PET) scans. The effects of buspirone (a 5-HT,, receptor partial agonist) on changes in regional cerebral blood flow (rCBF) associated with free word recall were examined. A factorial design was used to demonstrate a significant interaction (changes in rCBF brought about by psychological activation which depend on drug administration) in the left parahippocampal region. This interaction was an attenuation of increases in local neuronal activity (rCBF) related to memory function. Buspirone-induced decreases in rCBF, independent of the memory effect, were seen in the left prefrontal and parietal cortices. We suggest that combined psychological and pharmacological activation is a way of measuring direct (main) drug effects and modulatory effects on neurotransmission associated with cognitive functions (interaction). 1991 Exploring brain functional anatomy with positron tomography. Wiley. Chichester (Ciba Foundation Symposium 163) p 76-92

Data from functional positron emission tomography (PET)neuroimaging are universally interpreted with reference to models. These models range from the physiological, as in the compartmental models of radioligand binding, to the psychological-for example, ‘cognitive subtraction’ (Petersen et a1 1988). We present a model for the combined manipulation of behaviour and neurotransmitter function which uses conjoint psychological and pharmacological challenge. The nature of functional brain systems and their associated neurotransmitter systems can be inferred from studying patients with specific behavioural deficits 76

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and identifying the sites of abnormal brain physiology. These inferences are based on the ‘lesion’ model of brain dysfunction and are limited, in that neither the behavioural nor the regional brain deficit is under experimental control. PET studies of regional cerebral blood flow (rCBF) activation permit experimental control of two aspects of brain function, namely the neurocognitive processes and neurotransmitter function. We suggest that combined psychological and pharmacological challenge in the same individuals provides more information than either challenge alone. To demonstrate this point we report a study which combines (or, in terms of experimental layout, crosses) a memory task with acute administration of the novel anxiolytic drug buspirone. Crossing psychological and pharmacological treatments enables the sites of interaction to be identified. An interaction in this instance is defined as a functional (psychological) increase/decrease in local neuronal activity which can be manipulated by acute drug administration. An interaction of psychological and pharmacological effects on rCBF is taken as evidence of an association between the functional system and the neurotransmitter system(s) affected by the drug. An effect of the drug may only be evident in the presence of increased/decreased neural firing and in this way may reflect a neuromodulatory role. Neuromodulatory neurotransmitters have a widespread distribution in the brain and modify neuronal excitability, not by a direct effect on membrane resistance but by altering responsiveness to other transmitters. Monoaminergic neurotransmitters in particular have been proposed to have this neuromodulatory role: ‘. . . the ability of these transmitter systems to regulate responsivity and discharge patterns of the targets in the neocortex may well rely upon interactions with intrinsic connections and . . . other afferents’ (Bloom 1988). Similarly, Mesulam (1990) emphasizes the distinction between ‘anatomically addressed channels for transferring information content and chemically addressed pathways for modulating behavioural tone’. We chose to investigate the neuromodulating effect of the serotonergic system on neuronal activity associated with performing a memory task. The pyrimidinyl piperazine, buspirone, binds with high affinity to central 5-HTIAreceptors in the rat brain and functionally has 5-HTlApartial agonist properties. Buspirone has anxiolytic and antidepressant effects and, interestingly, does not bind to the benzodiazepine/GABA receptor complex (Traber & Glazer 1987). In animals there is substantial evidence that ~ - H T ~partial A agonists, including buspirone, reduce glucose metabolism in the hippocampus (Wree et a1 1987, Kelly et a1 1988, Grasby et a1 1990)-an area with a high density of S-HT~A receptors in rats and man. Furthermore, ~ - H T ~ receptor A activation may have a neuromodulatory role in the hippocampus. The 5-HTlAagonist ipsapirone weakly inhibits spontaneous firing in hippocampal CA1 pyramidal cells, but the increased firing rates produced by the micro-iontophoretic application of glutamate are attenuated (Sprouse & Aghajanian 1988). The more marked effect of this drug is a reduction, not of spontaneous firing, but of the

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increases brought about by an independent (glutamate) manipulation. In humans cognitive activation can be used to manipulate neural activity independently of drug administration. The cognitive activation we chose was a memory task. There is good evidence that the hippocampus has a key role in short-term memory in humans (e.g. Heit et a1 1988) and metabolic activation of the hippocampus by working memory has been demonstrated in non-human primates (Friedman & Goldman-Rakic 1988). The third link in the three-way relationship between buspirone, hippocampal firing and memory, namely that buspirone impairs memory function, has been less easy to establish. A study of the effects of repeated doses of buspirone (McKay et a1 1989a) reports a significant and sustained impairment of short-term memory but studies of the acute effects of buspirone do not (Luki et a1 1987, McKay et a1 1989b). It should be noted that memory testing in the ‘acute’ studies did not commence before 70 minutes after buspirone administration. In terms of centrally mediated neuroendocrine responses to buspirone, this is very much past the acute phase. It was our prediction that buspirone would show central, regionally selective effects on blood flow in man, particularly in the hippocampal formation. These effects would be inhibitory and would depend on increased firing brought about by a memory task. This finding would represent a significant interaction between the psychological and pharmacological treatments in, and only in, the hippocampus. This prediction was partially confirmed. Methods Subjects and study design

The subjects were six right-handed male volunteers (age 26-34) with no neurological or psychiatric history. Permission to administer radioactive substances was obtained from the local ethical committee and was approved by the Advisory Committee on the Administration of Radioactive Substances WK). Each subject was scanned six times, a 2 x 3 layout being used, involving three pairs of memory tasks, 30 mg of buspirone being given orally after the first pair. Each memory task pair comprised a baseline subspan memory task and a supraspan task. The subspan task involved nine presentations of a five-word list with immediate free recall. The supraspan task consisted of three presentations of a 15-word list, again with free recall. Presentation rate was one word per two seconds. The words chosen were high frequency, concrete words selected from the MRC Psycholinguistic Database. Performance on the task (supraspan) was recorded as the total number of correct recalls over the three presentations. To reduce differences in difficulty between the sub- and supraspan tasks we changed the 15-word list only between scans.

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The critical difference between the subspan and supraspan tasks was the degree to which words have to be remembered. Only in the supraspan task is there a requirement to recall words that are not immediately accessible from shortterm memory. Other components such as speaking, listening and attending were the same for both tasks. The inter-pair spacing was 20 minutes. There was an eight-minute interval between the subspan and supraspan task within each trial pair.

Neuroendocrine response Venous blood was taken and the neuroendocrine response to buspirone was assessed at -20, 0, 20 and 40 minutes. Buspirone was given at Omin. The prolactin response was used as a putative index of central 5-HTIAreceptor function (Cowen et a1 1990). Plasma concentrations of prolactin were determined by a previously described radioimmunoassay (Cowen et a1 1985). PET scanning We used a PET scanner (CTI model 931-08/12, Knoxville, TN, USA) whose physical characteristics have been described (Spinks et a1 1988). Scans were reconstructed using a Hanning filter with a cut-off frequency of 0.5, giving a transaxial resolution of 8.5 mm. Subjects inhaled CI5O2 at an activity of 6MBq/ml and a flow rate of 500 ml/min through a standard oxygen face mask for a period of two minutes. Dynamic PET scans were collected for a period of 3.5 min starting 0.5 min before P O 2 delivery, according to a protocol described elsewhere (Lammertsma et a1 1990). For the present study, integrated counts per pixel for the two-minute build-up phase of radioactivity in the brain during CI5O2inhalation were used (Fox & Mintun 1989).

Stereotactic normalization The 15 original scan slices (6.75 mm interplane distance) were interpolated, by bilinear interpolation, to 43 planes, in order to render the voxels (volume picture elements) approximately cubic. The intercommissural line was identified directly from the primary PET image (Friston et a1 1989) and the images were reorientated and resampled into a standard stereotactic space (Talairach & Tournoux 1988). In this space there are 26 planes with 2 x 2 x 4 mm voxels. Each image was smoothed using a Gaussian filter, 10 pixels wide. This increases the signal-to-noise ratio and accommodates normal variability in gyral anatomy. Statistical parametric mapping Global variance was removed on a pixel-by-pixel basis (Friston et a1 1990) using analysis of covariance, with global count per pixel as covariate. For every pixel

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this analysis generates adjusted means for each of the six conditions and an adjusted error variance required for comparison of these means. 'Condition' means are compared with the t statistic (Wildt & Vahtola 1978) using a contrast or weighting of the means. The resulting t-values constitute a t-value statistical parametric map (SPMtt]). The 2 x 3 layout of the experiments allowed three effects to be assessed: the main effect of memory (supraspan versus subspan), the main effect of drug (pre-drug versus post-drug), and the interaction (pre-drug supra/subspan difference versus post-drug difference). The SPM(t)reflecting the main effect of memory was used to identify regions whose rCBF increased significantly ( P < 0.001). The significance of ths SPM or profile of significant change was assessed by comparing the observed and expected number of pixels using the X-squared test of proportions (Friston et a1 1990). This subset of pixels constitutes the memory system. The interaction between memory and drug and the main effect of drug were then assessed for this subsample of pixels, and thresholded at P=O.O5. For descriptive purposes the rCBF equivalents for all 36 scans were displayed graphically for two locations of special interest.

Results Neuroendocrine responses

There was a significant increase in plasma levels of prolactin (0 min vs 40 min: t = 4.01, P = 0.004, df;8) which was evident by 20 minutes. Complete data from the first subject were not available. The prolactin responses are shown graphically in Fig. 1.

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main effects of memory

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FIG. 2 (Friston et al) Statistical parametric maps (SPMs) of the t statistic which reflects the significance of main effects of, or interaction between, memory and drug challenges to rCBF. The three projections correspond to views of the brain from behind, from the top and from the right. The brightest points along any of the three lines of view are displayed; all pixels displayed correspond to a significance of KO.001 for the main effects of memory and P<0.05 for the interaction and main effects of drug. The colour scale is arbitary; the brighter the image, the more significant the t value. The left parahippocampal region has been circled for reference. Top: the main effects of memory. This SPM{t} reflects the increases (P
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Memory performance Performance of the supraspan memory task was significantly impaired on the first post-drug trial compared to the pre-drug trial ( t = 2.91, P = 0.02, df;8). By 50 minutes this impairment had disappeared, on comparison with pre-drug performance ( t = 1.6, P=0.2, df;8). Figure 1 shows these changes in performance.

Regional cerebral activity The memory system identified by the (significant) main effects of the different memory tasks is shown in Fig. 2 (see colour plate). The number of significant pixels was far in excess of that expected (P
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The rCBF increases attributable to the immediate free recall of words implicated the left parahippocampal region, as expected. It was not surprising to see an equally profound increase in the DLPFC. Cognitive testing in nonhuman primates supports the notion that the DLPFC has a unique role in mnemonic processes implicit in delayed-response tasks. ‘By many accounts the most significant experimental discovery for understanding the functions of prefrontal cortex was the demonstration by Jacobsen that prefrontal cortex damage produced a profound and selective deficit on tests of spatial delayed response . . . Jacobsen himself stressed the mnemonic or temporal sequential processes required by the delayed response tasks’ (Goldman-Rakic 1987). A previous study of recall (Roland & Seitz 1989), which contrasted rest and recall of visual material, reported increases in rCBF in posterior parietal and bifrontal regions in a distribution not dissimilar from our present findings. Our interpretation of the effect of buspirone can only be very limited, because this was a preliminary study and was not placebo controlled. Although it is possible that non-linear time effects may have accounted for the decreased performance and hippocampal activation in the second but not the first and third trial pairs, we feel that these transient post-drug effects are probably mediated by a central action of buspirone. A number of explanations for the attenuated hippocampal activation can be provided and further studies will be needed to decide between them. Two explanations deserve discussion. It is possible that, as predicted, buspirone has a direct neuromodulatory role in the parahippocampal cortex that is mediated by its partial agonist effects at the 5-HTlA receptor. If true, this would directly implicate the 5-HT neurotransmitter system in the functional hippocampal memory system. It is equally possible that buspirone acts remotely in an area which has inputs to the parahippocampal region. This distant effect may be direct and not dependent on memory-related changes in firing (unless there is modulation of modulation). The decreases in rCBF seen in the DLPFC may be evidence of such an effect. In this regard, reduced binding of [ 3H]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin,a 5-HTlAagonist) has been reported in autopsy samples of DLPFC from patients with Alzheimer’s disease (Palmer et a1 1987), a syndrome associated with memory impairment. Action at a distance is recognized in animal models of drug effects on cerebral metabolism. ‘, , . drug/receptor interactions may be localized to the primary site, FIG. 3. rCBF equivalent changes in the left parahippocampal regions ( - 8, - 44,4 mm) and left dorsolateral prefrontal cortex (DLPFC) ( - 30, 26, 28 mm). These regions demonstrate a significant interaction and main effect of drug respectively. The data are displayed in order of the six conditions: sub-supra-sub-supra-sub-supraspan.The drug was given after the first trial pair. rCBF equivalents are based on integrated tissue counts and adjusted to a global value of 50 (ml/dl per min). The solid line is the adjusted condition mean.

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but may also result in marked changes in any number of regions with which the primary area has anatomical connections . . . for example intra-cerebral injection results in altered rates of glucose utilization one, two and three synapses away from the primary injection site’ (Kelly et a1 1988). It will be interesting to explore the possibility that the main effects of a drug, on rCBF, reflect a non-modulatory, direct effect on membrane potential (resistance) resulting in increased/decreased firing, while modulatory effects facilitate or attenuate converging input and can be localized by the interaction. Thus the reduced rCBF in DLPFC could represent a regional non-modulatory action of buspirone and the parahippocampal interaction, a separate local or primary modulatory action. Alternatively, the parahippocampal interaction could be a secondary consequence of reduced (modulatory) input from the DLPFC. These two models are depicted in Fig. 4. The direct effect of buspirone on DLPFC may not be attributable to 5-HT,* receptor-buspirone interaction. Buspirone has an active metabolite 1-(2-pyrimidinyl)piperazine(1-PP) which binds with nanomolar affinity to the

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MAIN EFFECT FIG. 4. Schematic representation of two models for the main effects and interactive effects of buspirone on rCBF. (a) Main and interactive effects in the DLPFC and parahippocampal region respectively are independent and primary. (b) The interactive effect is secondary and remote from the main effect in the DLPFC and is mediated by reduced modulatory inputs to the parahippocampal region from the DLPFC.

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a2-adrenoreceptor, where it acts as an antagonist (Bianchi & Garattini 1988). There is evidence to suggest that a2-receptors in the prefrontal cortex have a critical role in delayed response tasks. Clonidine (an a2agonist) reverses agerelated deficits in delayed-response task performance in non-human primates (Arnsten & Goldman-Rakic 1985) and this effect can be antagonized in a dosedependent manner by the adrenergic antagonist yohimbine. Furthermore, pharmacological profiles in animals with lesions restricted to the DLPFC indicate that this area may be the site of action for some of clonidine’s beneficial effects. Buspirone also binds appreciably to dopamine receptors, so an effect mediated through dopamine neurotransmission cannot be excluded in the present study. Conclusions

Combined psychopharmacological activations in humans reveal the potential neuromodulatory effects of manipulating neurotransmitter function that cannot be demonstrated by psychological or pharmacological activations alone. This combined strategy is particularly relevant for investigating the monoaminergic systems that appear to have a neuromodulatory role. Interactions and direct regional effects result from acute drug administration. It is possible that main effects of drugs, on rCBF, represent a direct non-modulatory action and that interactions represent a neuromodulatory function. These effects may be primary, local changes in neuronal firing, or secondary, remote effects in connected areas. Acknowledgements K. J. F. was supported by the Wellcome Trust. We wish to thank our colleagues and collaborators at the MRC Cyclotron Unit for making the study possible and for helpful discussions.

References Arnsten AFT, Goldman-Rakic PS 1985 a,-Adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science (Wash DC) 230: 1273-1276 Bianchi G, Garattini S 1988 Blockade of a2-adrenoreceptorsby 1-(2-pyrimidinyl)piperazine (PmP) in vivo and its relation to the activity of buspirone. Eur J Pharmacol 147:343-350 Bloom FE 1988 What is the role of the general activating systems in cortical function? In: Rakic P , Singer W (eds) Neurobiology of the neocortex. Wiley, New York, p 407-421 Cowen PJ, Gadhui, H, Godsen B, Kolakowska T 1985 Responses of prolactin and growth hormone to L-tryptophan infusion: effects in normal subjects and schizophrenic patients receiving neuroleptics. Psychopharmacology 86: 164- 169 Cowen PJ, Anderson IM, Grahame-Smith DG 1990 Neuroendocrine effects of azapirones. J Clin Psychopharmacol 10:21S-25S

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Fox PT, Mintun MA 1989 Noninvasive functional brain mapping by change-distribution analysis of averaged PET images of H,I5O tissue activity. J Nucl Med 30:141-149 Friedman HR, Goldman-Rakic PS 1988 Activation of the hippocampus and dentate gyrus by working memory: a 2-deoxyglucose study of behaving rhesus monkeys. J Neurosci 8 :4693-4706 Friston KJ, Passingham RE, Nutt JG, Heather JD, Sawle GV, Frackowiak RSJ 1989 Localization in PET images: direct fitting of the intercommissural (AC-PC) line. J Cereb Blood Flow Metab 9590-695 Friston KJ, Frith CD, Liddle PF, Dolan RJ, Lammertsma AA. Frackowiak RSJ 1990 The relationship between local and global changes in PET scans. J Cereb Blood Flow Metab 10:458-466 Goldman-Rakic PS 1987 Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In: Plum F (ed) Handbook of physiology, section 1: The nervous system, vol 5 : Higher functions of the brain. Oxford University Press, New York (American Physiological Society, Bethesda) p 373-417 Grasby PM, Sharp T, Grahame-Smith DG 1990 The effect of gepirone, ipsapirone and buspirone on local cerebral glucose utilization in the rat. Br J Pharmacol99:27 (abstr) Heit G, Smith ME, Halgren E 1988 Neural encoding of individual words and faces by the hippocampus and amygdala. Nature (Lond) 333:773-775 Kelly PAT, Davis CJ, Goodwin GM 1988 Differential patterns of local glucose utilization in response to 5-hydroxytryptamine agonists. Neuroscience 3:907-915 Lammertsma AA, Cunningham VJ, Deiber M-P et a1 1990 Combination of dynamic and integral methods for generating reproducible functional CBF images. J Cereb Blood Flow Metab 10:675-686 Luki I , Rickels K , Giedecke MA, Geller A 1987 Differential effects of the anxiolytic drugs, diazepam and buspirone, on memory function. Br J Clin Pharmacol23:207-211 McKay G, Alford C, Bhatti JZ, Curran S, Hindmarch I 1989a Repeated dose effects of buspirone and clobazam on cognitive and psychomotor performance. Med Sci Res 17:325-326 McKay G , Alford C, Bhatti JZ, Curran S , Hindmarch I 1989b Effects of acute doses of buspirone and clobazam on cognitive function and psychomotor performance. Med Sci Res 17:301-302 Mesulam MM 1990 Large scale neurocognitive networks and distributed processing for attention, language and memory. Ann Neurol 28597-61 3 Palmer AM, Middlemiss DN, Bowen DM 1987 i3H]8-0H-DPAT binding in Alzheimer's disease: an index of pyramidal cell loss? In: Dourish CT, Ahlenius S, Hutson P H (eds) Brain 5-HT,, receptors. Behavioural and neurochemical pharmacology. Ellis Horwood, Chichester, p 286-299 Petersen SE, Fox PT, Posner MI, Mintun M. Raichle ME 1988 Positron emission tomographic studies of the cortical anatomy of single-word processing. Nature (Lond) 331585-589 Roland PE, Seitz RJ 1989 Mapping of learning and memory functions in the human brain. In: Ottoson D, Rostene W (eds) Visualization of brain functions. Stockton Press, London, p 141-151 Spinks TJ, Jones T, Gilardi MC, Heather J D 1988 Physical performance of the latest generation of commercial positron scanner. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 35:721-725 Sprouse JS, Aghajanian GK 1988 Responses of hippocampal pyramidal cells to putative serotonin 5-HTlA and 5-HTlB agonists: a comparative study with dorsal neurons. Neuropharmacology 27:707-7 15 Talairach J, 'Tournoux P 1988 Co-planar stereotactic atlas of the human brain, 2nd edn. Thieme Verlag, Stuttgart

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Traber J, Glazer T 1987 S-HT,, receptor-related anxiolytics. Trends Pharmacol Sci

8:432-437 Wildt AR, Vahtola 0 1978 Analysis of covariance. (University Papers: Quantitative applications in the social sciences series, no. 12) Sage Publications, Beverly Hills, CA Wree A, Zilles K, Schleicher A, Horvath E, Traber J 1987 Effects of the S-HTIA receptor agonist ipsapirone on the local cerebral glucose utilization of the rat hippocampus. Brain Res 436:283-290

DISCUSSION

Porter: It would be helpful if you were to explain to non-users of the PET technique whether there could be a direct or local effect of the drugs you used on the vasculature itself. Friston: It is possible that local variations in the density of receptors expressed on vasculature could produce regionally specific changes in blood flow that d o not reflect regional neuronal activity. Using the effect of a drug on the increases in rCBF brought about psychological (behavioural) activation circumvents this problem, because this interaction must be dependent on neuronal activity. Cappa: Was there any activation effect of the memory span test on the baseline? Friston: There are only two conditions. The baseline was the ‘non-working’ task. Your question highlights the ‘relativity’ of cognition activation studies; there is no baseline in the sense you mean. We have indices of neuronal activity in two (cognitive) brain states and consequently we can only talk about the relative differences. There is no absolute ‘baseline’ brain state. Control tasks are devised to act as baselines for, and only for, the activation condition in question. Cappa: I am interested in the locus of activation in a memory span test, because there is some evidence, coming from studies of patients with a selective disruption of verbal short-term memory, that a lesion in the left inferior parietal lobule may be associated with a severely reduced verbal span (Warrington 1979). Did buspirone have any effect on the verbal memory span? Friston: The parietal cortices were activated bilaterally by the mnemonic component. Buspirone did not effect subspan recall performance, which was 100% in all subjects, by design. It had a deleterious effect on performance during the supraspan conditions, but only in the first post-drug trial. It would have been nice to complement the basis of this study, before starting, by completing the three-way link between the regional effects of buspirone on hippocampal formation metabolism in animals, the role of the hippocampal region in memory and the impairment of memory performance by buspirone. Unfortunately, there are no studies of the acute effects of buspirone on memory (where acute, in this context, means 20-40 minutes after administration, the time of peak neuroendocrine response). However, our limited data demonstrated this acute effect post hoc.

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Muzziotta: Can you tell us whether there are situations where you see changes in blood flow and you see purely grey matter or white matter differences? It looked as if you have a large volume of contiguous pixels that are showing flow change. Do you think that reflects neuronal activation? If so, why is there not some segregation between grey and white matter, or is there a vascular territory response (that is, the distribution of the middle cerebral or anterior choroidal arteries)? Friston: I think we are seeing not a vascular territory response, but an activation profile which reflects the functional anatomy of the brain systems activated. The signals are limited to grey matter and follow the contours of the cortical surface. These data are extremely significant and the large number of pixels displayed gives the impression of contiguous lumps, but I think this is an artifact of presentation. If a focus were seen in white matter, then we would be worried that something had gone wrong. So far we have not seen white matter activations. Ruichle: I have a question about the thresholding of your t-values, so that you can decide what is significant or not. I assume that if you established such a threshold, then made ‘rest-rest’ pairs and looked at your data, the data would fall below that cut-off point. Friston: The data presented correspond to a threshold of P
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Friston: Indeed. The profile of activations associated with memory function has been replicated twice-in a separate study combining a different drug and the identical memory tasks, and in a third study using a placebo. Raichle: Dr Friston, as a more general point, how does one distinguish between a hypothesis-generating experiment and a hypothesis-testing experiment? When one combines definition of areas within the same set of data on which one tests the statistical significance of these areas, is this not a hypothesis-generating experiment rather than a hypothesis-testing one? Friston: I think this study was hypothesis led (hypothesis testing), in the sense that buspirone has been shown to have a neuromodulatory action in the hippocampal formation in animals. There was therefore a specific prediction (that was confirmed), in and only in, this region. However, the prefrontal changes attributable to the drug (buspirone) were not predicted and these findings can only be hypothesis generating. If one thinks of a PET study as multiple, and parallel, studies of different brain areas, then it is possible to treat the results as both hypothesis testing and hypothesis generating, depending on the brain region under interrogation. Working with such large data sets means that only a limited subset of findings could have been predicted. The remainder (if any) can be used to guide the next experiment. Raichle: I was not of course implying that one type is more important then the other, because hypothesis-generating experiments are essential when one is mapping the cortex, where we are not sure where things are, but then one loses this distinction when one starts talking statistically about results, which might or might not be hypothesis-generating or testing. Zeki: Would it be true to say that there is no PET experiment which is not hypothesis testing, by definition, but some PET experiments generate hypotheses, although not all? Raichle: Yes. Zeki: There is a basic point here. An electrophysiological experiment in which one simply looks at the firing rate of cells carries an hypothesis with it, namely that a cell will respond by changing its firing rate. With PET, I get the impression that you are wedded to the notion that an increase in blood flow entails a change in cerebral activity. Raichle: I don’t disagree with that; we must assume that changes in blood flow reflect changes in neuronal activity at some level. Zeki: In anatomy, as an example, the cytoarchitectonic method is one based on the hypothesis that areas which differ in function will differ in their cytoarchitecture, and therefore if we don’t find any cytoarchitectural differences, we assume (wrongly) that these areas must have a uniform function. This is a mistake that has been made many times. This is unlike, say, the degeneration method, which is not hypothesis bound in the same way, to the extent that if you discover that a cortical area does not receive an input from the striate cortex,

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it does not follow that it has no visual function. Therefore I am wondering whether PET is not also a very much hypothesis-bound method. Porter: We might be able to debate that philosophical point; I am not sure everyone would agree with that statement! Fox: In meetings like this, in discussions of PET activation techniques and particularly statistical parametric mapping and related methods, these have been labelled as ‘only’ hypothesis-generating techniques. We have been told not to think of them as hypothesis testing unless we do some other data manipulation. For example, in your case, Dr Friston, you would be advised to restrict your analysis, to sample one region about which you have a specific hypothesis, and to throw away all the other data. I find it refreshing to see that people are now coming to the view that perhaps the same statistical approach can be both hypothesis testing and hypothesis generating, depending on the experimental design and on what’s gone before. I found it disturbing t o be told that we should throw away large amounts of our data and only analyse them in very restrictive ways. Plum: Dr Friston, if you go back in your experiment after the drug has worn off, does the subject have memory of the experiment? Friston: Yes. Plum: So the assumption is that the frontal areas retain memory of the transaction but that the retrieval instrument is selectively impaired? Friston: The ability to hold information which is relevant and of a declarative nature, over extended periods of time would not, I suspect, be affected by buspirone. The specific mnemonic component which appeared to be impaired was the holding ‘online’ of immediately relevant information which could be lost after it was no longer useful. It is possible that the hippocampus is more critically involved in mediating this ‘online’ memory than in establishing declarative memories that can be retrieved at some point in the future-a function that may require the hippocampal formation and other (prefrontal) brain systems. Plum: I am wondering whether the experiment doesn’t include two components, one of which is to test whether the memory is engrained in frontal lobe circuitry, and the second of which is to determine whether the retrieval component (i.e., the hippocampal component, or some other structure governing recall) remains connected to the frontal engram. Such a hypothesis might be testable-for example, during retraining trials-by showing different intensities of metabolic activity, compared to control, in different regions involved in the learning-retrieval process. Friston: And it would be interesting t o explore that notion with other drugs that have a more selective effect on the different components of the acquisition and retrieval of declarative memory. Plum: Exactly. You might be able to show, for example, during the amnesia induced by certain benzodiazepines such as triazolam, that working memory

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would appear to be preserved but that there would be a loss of metabolic activity in retrieval areas. Similar differences might appear during the remarkable phenomenon of transient global amnesia, in which the entrainment and retrieval of memories appears to be temporarily lost, but the banked registry of past events remains pretty much intact. Friston: I think you highlight a very powerful way of using PET, namely to demonstrate a double dissociation. For example, when considering the various components of memory function, one approach would be to demonstrate a selective and regional effect of drug A on acquisition with no effect on retrieval and, similarly, to show that drug B affects retrieval but not acquisition. In this way one could ascribe regional and neurotransmitter specificity to separable cognitive components underlying memory function. These are certainly the sorts of long-term objectives one has in mind. Corbetta: May I ask you about your behavioural task, Dr Friston? I’m not convinced that the biggest difference between the two tests is working memory. In both the subspan and supraspan tasks, subjects were presumably maintaining information online. Since the short-term memory verbal span is 7 k 2 words, the buffer was almost entirely loaded in the subspan situation, too. I wonder whether more aspecific factors, such as arousal, or difficulty, may explain your differential activation. Friston: It was precisely these extra components that we wanted to engage. The supraspan task could not be performed using only a ‘buffer’. The further cognitive components required were the essence of the activation. The common components (e.g. word perception, lexical analysis, word production) are all controlled for, as was the rate of word presentation. You use the concept of ‘difficulty’ as a confounding variable which should be accounted for. I think this needs careful justification. Firstly, because ‘difficulty’ is confounded with the change in task, it is also deeply confounded with the cognitive dimension one is trying to measure. Attempts to ‘remove difficulty differences’ must, by definition, undermine the difference of interest. Secondly, difficulty is operationally defined in terms of performance; equating performance means presenting the same task twice (unless you take a measure of performance which is quite unrelated to the cognitive component in question). I personally do not think ‘difficulty’ is a useful concept in explaining the sorts of findings we deal with. Corbetta: I think that in the two tasks the working memory component is not very different. The normal span is about seven, so the memory buffer has been loaded in both situations. The difference in PET activation may not be easily accounted for by an explanation in terms of working memory. Friston: I am sure you are right to worry about the exact nature of the difference between the two memory conditions. The simplest answer is that we tried to choose tasks that were simple, had clear parallels in non-human primate

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work, and could be tightly controlled in terms of the parameters of the executive systems involved, such as speech and listening.

Reference Warrington EK 1979 Neuropsychological evidence for multiple memory systems. In: Brain and mind. Excerpta Medica, Amsterdam (Ciba Found Symp 69) p 153-166

Relating structure to function in vivo with tomographic imaging John C. Mazziotta*t$#, Daniel Valentinot, Scott Grafton*t$§, Fred Bookstein!, Charles Pelizzari", George Chen" and Arthur W. Toga5

*Division of Nuclear Medicine, iDepartment of Radiological Sciences, $Laboratory of Nuclear Medicine and 5 Department of Neurology, UCLA School of Medicine, Los Angeles. CA 90024, !Center for Human Growth and Development, University of Michigan, Ann Arbor, MI 48 109 and Department of Radiation Oncology, University of Chicago, Chicago, IL 60637, USA

Abstract. For the normal physiological responses of the brain or the pathophysiological changes that accompany disease states to be evaluated, it is necessary to compare data sets between different imaging modalities for individual subjects. Similarly, it is important to compare data between individuals both within and across imaging modalities for individual subjects. In a collaborative project with a number of university groups we have developed a system that allows for the within-subject alignment and registration of three-dimensional data sets obtained from different modalities for the same individual. This analysis takes into account the error induced by image acquisition, registration and alignment with regard to scaling, translation and rotation. A more difficult problem is the between-subject warping of individual brain anatomy to match that of another individual or of an idealized model. If the principles of morphometrics and homologous landmarks are applied, three-dimensional brain warping can provide this type of between-subject comparison. The result of accomplishing these two tasks is a system that allows data obtained in a given individual to be compared across structure and function, as obtained from magnetic resonance imaging (MRI) and from positron emission tomography (PET), respectively. It also allows comparison of the resultant information with averaged between-subject data from populations of normal individuals or patients with specific neurological disorders. This system provides the means by which to compare quantitative data between individuals in an objective and automated fashion. 1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 93-112

As early as 1984 it was realized that a systematic, objective and standardized approach to functional image analysis would be required in order to obtain the full potential of biochemical images obtained with positron emission tomography (PET) (Mazziotta 1984). Numerous approaches to the solution of these problems have been used (Bajcsy et a1 1983, Bohm et a1 1983, Evans et a1 1988, Fox et al 1985). Through a series of international symposia on the topic, a set of optimal criteria were developed for any system which seeks to provide the means by 93

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TABLE 1 Proposed criteria for the optimal solution to the problem of PET image acquisition and analysis 1.

Reproducible

2. Accurate

3.

Independent of tracer employed

4.

Independent of spatial resolution of the instrument When possible, independent of ancillary imaging techniques Minimizes subjectivity and investigator bias Fixed assumptions about normal anatomy not required Acceptable to subjects’ level of tolerance (e.g. head holders) Performs well in serial studies of the same patient and in individual studies within a patient population Capable of evolving toward greater accuracy as information and instruments improve Reasonable in cost Equally applicable in both clinical and research settings Time efficient for both data acquisition and analysis

5.

6. 7.

8. 9. 10.

11. 12.

13.

~~

From Mazziotta & Koslow 1987.

~

~~

~

which to regionalize and quantify PET data, both within subjects and between subjects (Mazziotta & Koslow 1987) (Table 1). It became clear that t o satisfy these criteria to the greatest degree, the merger of structural information obtained from magnetic resonance imaging (MRI) or computed tomography (CT) with functional images from PET or single photon emission computed tomography (SPECT) would be required. The complete problem of image analysis, both within and between subjects, can be separated into two parts (Fig. 1). In the first portion, which we termed ‘Merger l’, one seeks to align and register data about a given subject obtained from multiple imaging modalities. The second portion of the analysis is the between-subject comparison, termed ‘Merger 2’, in which the variations of neuroanatomy between subjects are accounted for by a three-dimensional warp of structural images to form a common average or t o fit an idealized model of the human brain. These mergers will be discussed independently. It should be noted that as a result of implementing these two approaches, one may build in an idealized modela system of three-dimensional volumes of interest that can be automatically sampled without bias or subjectivity-and produce regional quantification of individual subjects across modalities or time, or of a population of subjects, within or between modalities and time.

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Relating structure to function in vivo MERGERP

MERGER1

BETWEEN SUBJECTS

WITHIN SUBJECT

BRAIN A

Slngle

3-D BRAIN

Subject

BRAIN C

t

I

A

FIG. 1. Two-step process for within-subject (Merger 1) and between-subject (Merger 2) comparisons. Details of this process are described in the text.

Merger 1

Past approaches to cross-modality image correlation typically utilized fiduciary markers in order to achieve alignment and registration. Pelizzari and Chen (Pelizzari et a1 1989) developed an approach whereby a rigid portion of the human body, for example the skull, can serve as its own fiduciary system, allowing for cross-correlation, alignment and registration of identical structures in the same subject between imaging modalities. This approach forms the basis for the within-subject image correlation termed Merger 1. The algorithm for the execution of the within-subject, Merger 1, process was originally developed by Pelizzari and Chen (Pelizzari et a1 1989) at the University of Chicago. Execution of this process results in the alignment and registration of data from different imaging modalities within the same subject. For the analysis of PET data, one typically uses MRI images for the structural component in order to maximize spatial resolution; however, correlations of any image sets that have a common surface can be processed with this approach. For example, MRI, CT, PET, SPECT or in situ cryomacrotome sections of the entire human head can be examined in this fashion (Santori et a1 1990). The basic premise of this approach is that a common three-dimensional surface obtained from two different image sets can be three-dimensionally aligned and registered. Once this fit is accomplished, alignment and registration will be achieved with an accuracy that is comparable to the spatial resolution of the imaging device with the lowest spatial resolution (Pelizzari et a1 1989). A typical PET-MRI Merger 1 correlation requires a transmission and an emission set of PET images as well as an MRI study that is highly sampled along the Z axis, using pulse sequences that maximize the grey-white and brain-cerebrospinal fluid (CSF) boundaries (e.g. TE = 30 ms, TI = 300 ms, TR = 1276 ms).

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Once these data sets have been obtained, they are corrected for distortions inherent in the image acquisition process. This step is achieved by the prior scanning of phantoms (geometric three-dimensional objects filled with material visible in each instrument) to characterize the distortions induced by each instrument. Once corrected for such distortions, a common boundary (e.g. skin, skull) is identified in the transmission PET and the MRI study. Semi-automatic software for this process exists. Contours obtained from the MRI study define a surface referred to as the ‘head’, while contours obtained from the PET transmission scan are defined as a three-dimensional ‘hat’ (Pelizzari et a1 1989). Typically the ‘hat’ is smoothed and subsampled to reduce the number and, hence, the total computational time required to fit it t o the ‘head’. The centres of gravity of the ‘head’ and the ‘hat’ are superimposed and then the ‘hat’ is fit to the ‘head’ using an iterative least-squares technique. The result of this fitting is a set of three-dimensional rotation, scaling and translation variables that describes the rigid body transformation required to re-format one data set to the other (Fig. 2) (see colour plate). Using these parameters, we re-format the PET emission data set to match the MRI data. The Merger 1 approach can be used to compare structure with structure (e.g. MRI to MRI) over time, function to function (e.g. PET to PET) over time, or structure to function (e.g. MRI to PET) at each examination interval or serially over time in a given patient. In addition, electrophysiological data from an EEG can be compared with such data sets by placing MRI-visualizable markers (i.e. fat-soluble vitamin capsules) glued to the sites of selected scalp electrodes (Jack et a1 1990). These sites will then be entered into the same registration matrix on the skin surface from the MRI data set. Re-formatted images can then be displayed side by side in two (Fig. 3) or three dimensions, or superimposed in two or three dimensions (Fig. 4) (see colour plate). Validation experiments for the Merger 1 procedure have been conducted by Pelizzari et a1 (1989). These experiments demonstrate that the accuracy and reproducibility of this technique results in alignment and registration that is spatially accurate to the level of the data obtained from the device with the lower spatial resolution. More recent studies, in which two copies of an identical image contour set were displaced by known amounts in terms of rotation, translation or scaling, resulted in realignment by the software with an accuracy of 5 3 ” for rotation, 1 pixel for translation and < I pixel for scaling. Phantom measurements (Pelizzari et a1 1989) demonstrated that the residual misfit between models of the external surface from MRI and PET transmission studies is on the order of 1.5-2.0 millimetres, averaged over the surface. Note that the transformations described here are affine, and this assumes that the surface is not elastically deformed between the acquisition of the two data sets. Relaxation of this assumption is implicit in Merger 2, discussed below. Merger 1 also assumes that the coordinate transformation which optimally matches the surface, as visualized in the two scans, may be used to transform

FIG. 2 (Mazziotta et al) Three-dimensional surface contour fitting with alignment and registration matrix. Solid lines demonstrate surface contours of the ‘head’ obtained from MRI while the dotted lines indicated the same boundary obtained from the PET transmission images. These two three-dimensional data sets were fit using the iterative approach described by Pelizzari et a1 (1989). The transformation matrix indicates the disparities between the original two data sets in terms of scaling, translation and rotation for each of the three axes. After the determination of this transformation matrix, PET data are re-formatted and sliced to match the MRI data set (see Fig. 3). (Reprinted from Mauiotta et a1 1991 with permission of Raven Press.)

(B)

FIG. 4 (Mazziotta et al) Three-dimensional volume rendering of structure and function. (A) Dorsolateral surface of the head and cerebral cortex. The MRI data are presented

in grey scale and the PET data in a colour scale, with red being the highest metabolic rate for glucose and blue being the lowest. Note the anatomical detail of the facial and cranial structures including the sylvian fissure, central sulcus, cerebellum and temporal pole. (B) Midsagittal three-dimensional rendering displayed using the same principles as in (A). Note the head of the caudate nucleus, medial surface of the thalamus, parieto-occipital fissure, calcarine fissure, fourth ventricle, brainstem and cerebellum. Such images allow for the multidimensional display of structural and functional information in a single composite image that is easily recognizable and interpretable by clinical or basic neuroscientists. (Reprinted from Mazziotta et a1 1991 with permission of Raven Press.)

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FIG. 3. Re-formatted, aligned and registered MRI (left) and PET (right) data from the same subject. The PET data have been re-formatted to match the level, slice and scaling of the MRI image. Note the close concordance in the shape and position of the caudate nuclei, thalami and cortical folds. These data can be displayed side by side, as here, or superimposed in two or three dimensions (see Fig. 4).

internal coordinates-that is, the internal anatomy is rigidly fixed with respect to the surface. Both assumptions are well satisfied for brain imaging. Currently, the software required to accomplish Merger 1 runs on a SUN Sparc Workstation. Merger 2

Merger 2 is designed to deform the three-dimensional brain structure from one subject to match that of another, of a common average, or of an idealized model of the brain. This three-dimensional warping provides a single standardized coordinate system for all brain structures. This coordinate system can be thought of as an atlas, or standard brain. The coordinate system is then deformed or warped to fit the forms observed in each individual subject. As a result of this process, one can generate a three-dimensional brain atlas which itself is an

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average of a population of individuals rather than a haphazardly acquired single specimen. Warping functions called ‘homology maps’ (Bookstein 1991) go beyond the rigid motion transformations of Merger 1. Generally, they take the form of exact interpolants between scattered geometric features that are ‘known’ to correspond between forms. One very useful algebraic form for this interpolant is the thin-plate spline developed in the literature of surface interpolation and modified to apply the warping by Bookstein (1989). This technique can be extended to data for more complex situations, such as curves on surfaces, and this is a primary effort in the morphometric research designed to achieve the functions of Merger 2. Warping cannot preserve both densities and counts in the image sets. This leads to the problem of what to hold invariant under the transformation. This issue will require considerable experience with correlates of images after deformation. Three-dimensional volume renderings (Fig. 4) of the human cortex are being used to evaluate such results as well as to determine the appropriate homologous landmarks of the cerebral cortex. Currently, homologous landmarks have been obtained from a single set of two-dimensional, midsagittal MRI brain images. Through the use of Merger 2 procedures, an average image from 14 normal subjects has been produced (Fig. 5). This image demonstrates that distortions induced by warping are accurate for portions of the brain with abundant landmarks, such as the brainstem and diencephalon. Areas with fewer landmarks (such as the cerebral cortex) are less accurately warped and result in a blurring of the image in the composite average (Fig. 5 ) . A further reason for consistency in the brainstem and diencephalon may be the fact that these structures are phylogenetically older and perhaps less variable in terms of their structure in the human brain, whereas the cortical structures are the most recent to evolve and are known to be highly variable, not only between subjects but also between left and right hemispheres. Simultaneously with the acquisition of data from Merger 1 and its transformation with Merger 2, stereotactic (Talairach et a1 1967, Fox et a1 1985) and statistical (Clark et a1 1985) approaches can be applied to these data sets. This opportunity should provide a good test of the validity of a wide variety of regionalization methods-a goal that is intended as part of this project. Complete validation will also include the prediction and localization of functional stimuli, as has already been proposed and employed by Fox and colleagues (1985). Conclusions Functional and structural images are not equivalent. Despite the fact that functional images obtained with high resolution PET instruments of biological processes such as glucose metabolism appear to demonstrate structural

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FIG. 5 . Composite midsagittal MRI image obtained from 14 normal subjects after unwarping of 13 landmarks obtained in the individual studies. Landmarks were indicated by the white circles. Note that the brainstem, cerebellar and diencephalic structures are sharply focused, indicating the accuracy of the warping and, perhaps, the minimal variability of these structures between subjects. Note further the blurring of cortical regions outside the zone where a high density of landmarks was provided. This may result from the lack of landmarks in the cortical areas as well as the greater variability of cortical structures between subjects. Landmarks for cortical regions have now been identified and this process is being extended to three dimensions. The image unwarping/averaging algorithm was provided by Fred Bookstein, at the University of Michigan, with the assistance of William Jaynes. (From Thin plate splines and analysis of biological shape; videotape 1990.)

neuroanatomy, they are actually functional images superimposed on structural neuroanatomy. PET investigators have always related functional images to discrete anatomical brain regions. As spatial resolution has continued to improve in PET, this has been done with increasing confidence. However, many tracers which bind to specific subsystems of the brain (such as 6-L- [ I*F]fluorodopa and [ "C] raclopride) produce images of specific neurochemical systems in the brain and indicate very little in the way of neuroanatomical features. Thus, the idea that increasing spatial resolution in PET will solve image analysis problems is erroneous. Complex analytical systems, such as the one described here, will

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undoubtedly be used t o regionalize a n d standardize functional image d a t a to a n optimal format. It is the aim of these efforts t o provide a system that is optimal in terms of the criteria described in Table 1. At the same time, this approach must be practical in terms of acquisition time and t h e comfort of the subject, as well as the requirements for data processing a n d data management. The Merger 1 system is now complete and fulfils those criteria. The Merger 2 approach is being developed and validated. Initial results obtained using two-dimensional midsagittal MRI images are promising. The extension of the homologous landmark set to the cerebral hemispheres in multiple dimensions is now under way, with the aim of determining the feasibility o f applying this approach to the entire intracranial contents. It is hoped that through these methods the analysis of biochemical, pharmacological and physiological information from functional images can be achieved with the greatest accuracy and reproducibility. T h e net result of these efforts should be an approach which maximizes the usefulness of functional image data.

Acknowledgements This work was supported, in part, by NIMH grant MH37916, NINDS grant NS 15654, NIH grant RR05956, NSF grant DIR-8908174 and DOE contract DEAC03SF7600012. The authors wish to acknowledge the efforts of H. K. Huang, DSc, Duffy Cutler and Ed Hoffman, PhD. They gratefully acknowledge the efforts of Lee Griswold in the preparation of the figures and Laurie Carr in the preparation of the manuscript.

References

Bajcsy R, Lieberson R, Reivich M, Berggren BM, Olsson L 1983A computerized system for the elastic matching of deformed radiographic images to idealized atlas images. J Comput Assisted Tomogr 7:618-625 Bohm C, Greitz T, Kingsley D, Berggren BM, Olsson L 1983 Adjustable computerized stereotaxic brain atlas for transmission and emission tomography. Am J Neuroradiol &I31-133 Bookstein FL 1989 Principal warps: thin-plate splines and the decomposition of deformations. IEEE (Inst Electr Electron Eng) Trans Pattern Anal & Machine Intelligence 11:567-585 Bookstein FL 1991 Morphometric tools for landmark data. Cambridge University Press, New York & Cambridge Clark C, Carson R, Kessler R et a1 1985 Alternate statistical models for the examination of clinical data positron emission tomography/fluorodeoxyglucosedata. J Cereb Blood Flow Metab 5:142-150 Evans AC, Beil C, Marrett S, Thompson CJ. Hakim A 1988 Anatomical-functional correlation using an adjustable MRI-based region of interest atlas with positron emission tomography. J Cereb Blood Flow Metab 8513-530 Fox PT, Perlmutter JS, Raichle ME 1985 A stereotactic method of anatomical localization for positron emission tomography. J Comput Assisted Tomogr 9: 141- 153 Jack CR, Marsh WR, Hirschorn KA 1990 EEG scalp electrode projection onto 3D surface rendered images of the brain. Radiology 176:413-418

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Mazziotta JC 1984 Physiologic neuroanatomy: new brain imaging methods present a challege to an old discipline. J Cereb Blood Flow Metab 4:481-483 Mazziotta JC, Koslow SH 1987 Assessment of goals and obstacles in data acquisition and analysis from emission tomography: report of a series of international workshops. J Cereb Blood Flow Metab 7 (suppl): Sl-S31 Mazziotta JC, Pelizzari CC, Chen GT, Bookstein FL, Valentino D 1991 Regions of interest: the relationship between structure and function in the brain. J Cereb Blood Flow Metab 11 (suppl): A51 -A56 Pelizzari CA, Chen GTY, Spelbring DR, Weichselbaum RR, Chen CT 1989 Accurate three-dimensional registration of CT, PET and/or MR images of the brain. J Comput Assisted Tomogr 13:20-26 Santori EM, Quintana J, Mazziotta JC, Valentino D, Payne BA, Toga AW 1990 Threedimensional digital atlas for Mucucu nemestrinu. SOCNeurosci Abstr 16:246 Talairach J, Szikla G, Tournoux P et a1 1967 Atlas d’anatomie sttrtotaxique du telenckphale. Paris, Masson

DISCUSSION Passingham: Are you undertaking a cytoarchitectural analysis of the human brain, Dr Mazziotta? There are significant disagreements between the maps produced by Brodmann (1925) and von Economo (1929). We lack an agreed cytoarchitectural analysis of the human brain. Mazziotta: I agree fully that the current sets of cytoarchitectural information are confusing. But I won’t commit myself to building a cytoarchitectural map because, as Professor Zeki said earlier, there are things that lie outside the domain of cytoarchitecture. What we are doing now is developing the tools whereby we can build the map of any given anatomical or functional variable. Cytoarchitecture is one of the most labour-intensive procedures if one attempts to examine a population of brains. But in given regions of brain, where there is activation, one could go to the ‘sliced’ post mortem specimens, and apply analysis to that area, and then merge that data set with a set of activation studies. So I would not want to contemplate the systematic re-establishment of the cytoarchitectural or other chemical-architectural systems. But it is important to have the tools to do that, for local experiments designed to answer local questions. Passingham: It is odd that we are talking about the functional anatomy of the human brain when we are so ignorant about the structural anatomy. Porter: We need to remember that Campbell (1905), before von Economo, undertook that very labour-intensive task and produced diagrams of the brain areas which he could define as being histologically different on a series of serial sections through the whole human cerebral cortex. These anatomical descriptions still, in my view, stand the test of subsequent investigations. Zeki: This is so only with the understanding that the cytoarchitectonic areas defined by Campbell and by everyone else since have turned out to be incorrect,

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to the extent that they don’t indicate functional subdivisions. I don’t think anyone would go by cytoarchitectonic maps exclusively now. In primate brains, it’s obvious that the interesting axis of organization is a tangential one, parallel to the cortical surface. So in our studies of the monkey brain we have devised three-dimensional programmes that allow us to open up a gyrus and look at a sulcus as if we were flying over it. This seems preferable to the two-dimensional maps which we also developed, which have the disadvantage that topography is lost. Are there techniques currently being used, not necessarily for MRI but just to obtain a three-dimensional map of the human cerebral cortex, in which you can keep the topographical relationships intact, but you can look into a sulcus from any angle? Mazziotta: That is an interesting question; three-dimensionality is important in understanding where you are in the brain. We have considered several approaches. In one, we dissolve the cortex away, down to the white matter, so that we have a place to put the PET cortical responses. A second approach is to take a midsagittal image of the brain and dissolve all subcortical white matter structures away until you reach the cortex from the inside out-looking at the inside of the walnut shell, as it were. You can look at cortical responses in deep sulci, by rotating that shape. Of course, the anatomical appearance of that inside-out structure is not very recognizable. Another approach is to do partial dissolving, to create an artificial ‘atrophy’; you shrink down, or dissolve, the outer pixels of the cortex, which allows you to see further into the sulci. Zeki: If you were to take a contour line through layer 4, which is present almost everywhere, could you not d o it like that? It would take twice as long as it does in the macaque monkey. Mazziotta: I don’t see why it couldn’t be done, if I understand what you are describing. Fox: What would you use to create that boundary? In magnetic resonance imaging, the CSF-grey boundary and the grey-white boundary stand out. Layer 4 might be a problem. Mazziotta: You wouldn’t have layer 4 to go by; you would have to use some arbitrary position through the width of the cortex, assuming that you were normal to the cortex in the direction of your dissolving. So it’s not a trivial issue. It would require that the magnetic resonance image had the signature of brain grey matter, so it might involve multiple scanning sequences to get enough data to be able to say that something is going to be an image of grey matter, or an image of cortex. GuIydx In the Karolinska Institute’s PET Center we use the computerized brain atlas (CBA) of Torgny Greitz and Christian Bohm for the analysis of MR and PET images (Bohm et a1 1983, 1985, 1986, 1991, Seitz et a1 1990, Greitz et a1 1991a,b). The CBA includes a standard ‘master’ brain, and images of individual brains can be adjusted in shape and size to this standard brain. For the standardization procedure we use as landmarks the contours of the cerebral

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and cerebellar surfaces and those of the ventricular system. After standardizing dozens of MR images of individual brains, we have found that certain anatomical structures exhibit more stability with respect to their appearance and anatomical localization than others. Phylogenetically ‘ancient’ sulci (such as the central sulcus, the precentral and postcentral sulci, the calcarine sulcus, or the parietooccipital sulcus) exhibit less anatomical variation than sulci which may be phylogenetically younger and specific to the human brain (e.g. sulci in the prefrontal cortex or those in the lateral superior part of the occipital lobe). In a recent investigation we standardized 12 individual brains and measured the differences between the anatomical localizations of major structures in the occipital lobe of the individual brains and those of the CBA standard brain. Measurements were made at 1 cm intervals along the contours. The average difference in the case of the cerebral surface contours in the occipital lobe was 3.17k 1.40 (SD)mm, for the calcarine sulcus 1.96f2.16mm, and for the parieto-occipital sulcus 1.86 k 2.22mm. Nevertheless, it was almost impossible to identify additional sulci on the occipital surface being present in all individual brains and showing stereotactic stability throughout all the subjects. These data may support earlier observations by anatomists on the anatomical stability of gyral patterns in the human brain, namely that certain primordial structures are more stable than others (Connolly 1950,Talairach et a1 1967,Ono et a1 1990). Have you had a similar experience, Dr Mazziotta? Mazziotta: The best answer to that question comes from teachers of neuroanatomy: when one describes the brain, consistent items are fissures; they are identifiable. But they are not consistent in position, shape and direction. In our between-subject study we had to be able to rely on our ability to find a given midsagittal structure; it had nothing to do with consistency or identifiability outside that domain. We are now systematically looking for objects, shapes, or neuroanatomical landmarks, that a relatively naive individual could recognize reliably. It would be best if those landmarks had some other basis-neuroembryological, or as a growth centre- where we learn about the history of how the brain developed or evolved as key points, and homologous points between brains, in a given species. Fox: One could interpret your image of the crisp brainstem and the blurred cortex (Fig. 5 ) as simply indicating that in relation to the cerebral hemispheres, the brainstem is quite variable in position. If you fix the hemispheres relative to the anterior and posterior commissures, the averaged MRI images created by the groups in Stockholm, Montreal and elsewhere do show sulcal markings. So it is not so clear that the stereotactic approach is flawed. Professor Zeki brought up the idea of opening a sulcus, to see where the PET activation is. I suspect that the resolution of PET is not good enough for this to provide new information. Mazziotta: I agree that one can interpret the averaging in this way, with brainstem varying in its orientation in different people, with a resultant blurring

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of the cerebrum. That’s not to imply that stereotaxy doesn’t work. Clearly, you can operate it with a certain degree of accuracy and find expected structures. How good is it? These kinds of combined approaches may lead to answers to that question. In any of these systems, sites close to or between centres of the origin of the coordinate system will be best preserved, so that volume of tissue is going to be most accurately depicted. With regard to spatial resolution and the problem that Professor Zeki posed, there is certainly no point in localizing beyond the limits of the technique making the measurement. While it might not be possible to identify a focal activation at a given point in the depth of a sulcus, on one side or the other, one might be able to say that there is a difference in two different activations between the two sides. If you had a motor activation task, where the subject did something with a given finger, and you saw a site of activation in the cortex, you might not be able to say whether that was motor or sensory, or a combination of the two, using current PET resolution. If you could re-create that movement passively, so you had only a proprioceptive input (which is no small challenge), you might see that that site was now at a different point from the original one. You would then have the question of whether the first was a combination of motor and sensory, and the second task, pure sensory. Nevertheless, small differences might be of interest in the kind of issue that Professor Zeki raised. Zeki: Dr Fox is being much too pessimistic about this. The resolution of PET will improve quite a lot. Mazziotta: The other feature of this issue, and one reason we are so interested in primate studies, is the assumption that blood flow or metabolism and electrophysiology are matched. Our goal is to do combined experiments in the same animal, with electrophysiological recording in the behaving animal during PET scans. The kinds of instruments required, as well as the animal PET scanner, should help to resolve some of these questions, although they have their own complexities when you record from a small volume of tissue and scan from a larger volume. Evans: In your averaged images, were any cortical landmarks attempted? It is extremely difficult to track them down. Mazziotta: No. As I said, I didn’t feel confident in identifying cortical landmarks. The two that we attempted in cortical regions were the occipital pole and the frontal pole, so we only had that small inferior portion of the cerebrum identified. Evans: We attempted to identify some cortical landmarks (see below, p 106). This will be a serious problem with tomographic displays. Cortical surface display, and the facility for tagging specific cortical landmarks on such a display, would be very helpful. Passingham: We found the occipital and frontal poles difficult to identify reliably. I imagine that there is some ‘slop’ in your method?

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Mazziotta: We used a sagittal image where the aqueduct was in focus and then chose the anteriormost and posteriormost points. They need not be the true occipital and frontal pole in that brain. Raichle: As this discussion is unfolding, I get a sense that MR is marching along getting better and better, and PET likewise, and we keep pasting the two together. But why couldn’t we use them more interactively, particularly using MR anatomy to constrain PET functional image data? Because magnetic resonance imaging will always lead PET in terms of spatial resolution, and if one is doing within-subject averaging, particularly when thinking about activation responses, where we subtract one image from another, perhaps we could then use the two methods interactively, to guide the PET reconstruction process by prior anatomical information from MRI. Mazziotta: There’s no doubt about that. This is part of the benefit of having a means of bringing structure and function together; then you can constrain the analysis of the PET. Zeki: What is meant by using ‘prior anatomical information’ in the reconstruction process, Dr Raichle? Raichle: It’s a rather simple concept. The resolution, for example, of PET is presumably not going to become as good as that of MRI, so you impose your PET image on an MR slice, and, if you look at it carefully, some of the data will spill out over the edge, because the resolutions of the two processes are different, You could ‘trim’ the edge of your PET image to fit the MRI, but this is hardly the best way to deal with the difference in spatial resolution of the two techniques, because you know that the PET data didn’t come from outside the brain, but from inside. So if one knows the properties by which the image has been reconstructed, one could use that to put the data ‘back into the brain’, guided by the anatomy as displayed by MRI. This sort of process creates noise, so it isn’t without cost, but it has been raised in the area of looking at brains with atrophy, which is where we first thought about this issue. To extend it further to the issue of cortical responses to functional activity, one might consider trying to constrain that activity to grey matter, assuming that it didn’t come from outside the brain and that the contribution from the underlying white matter is significantly less than that of the grey matter. I don’t know how far you can take this, but certainly activity outside the brain doesn’t belong there. We have a great deal of information in the MRI, and simply overlaying PET and snipping around the edges doesn’t take advantage of the kind of information available. Jones: An additional application of NMR, again from the constraining point of view, is to use it to guide the reconstruction process for areas that one wants information about. Reconstruction techniques exist which have signal-to-noise ratio advantages compared to current back-projection methods but which take days to process the data recorded from the whole brain. There are also computationally sophisticated methods to correct for scatter, using Monte Carlo

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simulation techniques. These could also be applied to NMR-selected regionsof-interest within the brain. Raichle: Dr Jones refers to the maximum likelihood algorithms, which at one point took 17 hours for the reconstruction of an image, but with computer technology today, this takes 15 minutes or so. These kinds of algorithms lend themselves to this kind of ‘prior anatomical information’, basically putting the activity back in the brain from whence it came. Zeki: Could 1 suggest a not improbable scenario? Suppose we study someone’s vision by PET and MRI. Then he or she dies and leaves the brain to us. We section that brain and look at its cytochrome oxidase content. We have a reasonable way of determining the extent of V1 and V2 from the cytochrome oxidase architecture. If you do have such a coincidence of circumstances, you will need a highly detailed reconstruction of the occipital lobe, but one that would be really worthwhile if you had obtained prior information with PET and MRI studies. Raichle: There is a great opportunity for interaction here, and there are people thinking about how to deal with these things mathematically. Lassen: Dr Mazziotta, I can’t understand why you try to superimpose the deoxyglucose map on the MRI map, because with a deoxyglucose map in the non-activated state you have no landmarks. If the eye or the fingers were moving, you would see the location of the corresponding active areas. Wouldn’t this be a more meaningful way of mapping identical structures, by saying that in this subject and that subject, or in this or that state, we have the finger moving and use its area as an internal standard? Muzziotta: This is simply an example. One thing we are beginning to see is whether there is a correspondence between functional and anatomical landmarks. Lussen: But we already know that no perfect agreement can be expected. It is known from stimulation of the exposed cortex that the hand area can be found not to lie at a completely constant place, relative to gross anatomical landmarks. Mazziotta: Is there consistency between functional sites in the brain, once the variance in the anatomy has been taken out of it? We don’t know that. Evans: In Montreal, we have been grappling with the problem of inter-subject variability. We have transformed MRI data from 16 normal subjects into stereotaxic space using both the conventional linear scaling approach and a nonlinear warping algorithm (Bookstein 1989). The algorithm has been implemented in three dimensions and, using an interactive 3D pointer, we identified 26 distributed landmarks throughout each brain and in a ‘master’ brain. I agree with you that it is very difficult to identify cortical landmarks but, since this is the area where we most need to reduce variability, we went t o some lengths to obtain such landmarks. The combined use of the 3D display interface and the Talairach atlas allowed us search for a specific landmark by its Talairach coordinates in each of three orthogonal image planes, rather than by vague terms such as ‘frontal pole’. These point ensembles from each data set were used to

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define either a direct non-linear mapping or a best (least-square sense) linear mapping from each individual brain volume to the master space. We found (Evans et a1 1991) that the average image using the non-linear model was significantly sharper than that obtained by the conventional model, with a residual variability of 6-7 mm left over after the linear step. We hope that this will manifest itself in the averaged PET subtraction image as an increased signalto-noise ratio, but that remains to be seen. Frackowiak: It seems to me, from what I have heard here so far, and from our own experience, that in functional mapping experiments at present one is obliged to average across subjects, and in that case there is no need for anatomical information from any structural scanning. This is because the resoIution of the PET scanners at the moment is so good, in relative terms, and perfectly adequate, because we know that there is an inter-subject variability in gyral anatomy that is considerable, and that obliges us to smooth the flow maps for averaging in any case. Because of the variation in size and shape of individual brains we must re-orient and re-sample the blood flow data from subjects into a standard space. We use an excellent stereotactic atlas, which may bear no relationship to reality, but is organized around a standard set of coordinates that identify structures, in the standard space. We can therefore all work within this common reference and identify the average position of structures, give them coordinates, and communicate our data. Where MRI or CT scanning come into their own in relation to PET is in the single-subject study. The finer structural resolution may help us to overcome difficulties with the absolute quantitation and assignment of activation foci to individual gyri or their banks which are a result of the poorer intrinsic spatial resolution of the PET-derived blood flow maps. The other way in which structural scanning will be of major importance to PET studies is in the functional investigation of subjects in whom the brain anatomy is distorted in some way, developmentally or pathologically. But if we are talking about mapping the brain in groups of subjects, this degree of precision is in my opinion not especially useful, and I doubt whether it’s necessary to go to those lengths. Porter: You are saying something very similar to Dr Lassen, namely that if you are looking at functional mapping, it doesn’t have to be superimposed on structural diagrams or physical geography; it is sufficient to use the functional definition of an activated location. Frackowiak: The study of individuals as opposed to groups of subjects requires a reason. One reason may be that the individual has a disease, or that questions more profound than simply asking ‘where is there a change of blood flow across different brain states?’ are being asked. You may for example want to quantify that change. Then you do need to know which structure you are in, and its dimensions in each subject. Such a question requires a data analytical approach which differs from the pixel-by-pixel methods designed to interrogate the whole brain with no a priori assumptions. The simplest method is to use

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region-of-interest techniques, designed to answer questions from a few anatomical regions, or only one. It has taken PET some time to escape from the constraints of region-of-interest analysis in activation studies, but there are reasons for going back to those techniques to answer specific questions. Mazziotta: There is some validity to that view, but there’s also the question that, for a given study, or a population study, you need a way into the standardized space. Your way in is for the functional correlate of neuroanatomy that you can see, in a blood flow or a metabolic image. If you attempt that with a fluorodopa image, you will lose those landmarks; so you will not have the usual way into the coordinate space. Again, when you have a battery of studies with different tracers in a given individual, this is another example of where you need a way into your deformed space, and the entry ticket could be one MRI image, which would be the key to that space from any vantage point that you immediately or subsequently add. Fox: I would look at the studies that Dr Mazziotta and Dr Evans are showing us as addressing an even more fundamental question-namely, what are the rules by which functions are mapped onto the cortex? Only by applying these techniques subject by subject shall we discover the relationship between functional maps and the gyral architecture. We know, from stimulation studies in the primary sensory and motor cortices, that there is a relationship. But once we move out of those areas, we don’t know how rigid the relation is between sulci and gyri and functional anatomy. So I would look at the sort of tools that various laboratories are providing us with as a way of starting to address the rules by which function is organized in the brain. Porter: There may also be the possibility of an extension to ask what are the biochemical mechanisms that underly the establishment of those connectivities and their functional relationships. We haven’t touched upon this yet; although we discussed biochemistry as the basis of PET measurements, we didn’t talk about it in terms of its contribution to regional functional organization and the establishment of that organization during development or learning. Roland: On the issue of putting landmarks on the cortex in order to achieve a re-formatted or standardized image of gyri and sulci, it must be a suboptimal procedure. The ideal way would be to use the whole brain surface, and even those parts buried in the sulci, and to use that as the whole ‘convolute’ to reshape your brain. On the issue of why one should use anatomical strategies, there are many reasons. The first is that by using anatomical information in a single individual in MR scans, one has the possibility of looking at calculations of local recovery coefficients. One also has the opportunity, from a series of MR scans in a population, to evaluate a mean response in a group of subjects doing the same test. Secondly, I think we are not so much interested in where the activation in a particular subject is, unless we are studying pathology in a single case for

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some special reason. We are interested in the extent to which the functional maps that we are generating can be generalized across subjects. To do this, we need a common reference; we cannot just rely on functional localization. There is another point, that most groups tend to localize activations to a single point, where they record maximum change. Another approach might be that the responses could be extended over areas, and it would be relevant to question how big V1 or V2 is; how far does it extend? One will then need an anatomical reference model. The best we have is the cortex itself as a ‘global landmark’. We haven’t addressed the cortical nuclei yet. The thalamus is a fairly heterogeneous structure and it certainly matters where you are in the thalamus. If you want to make sense of the whole thing, you need a very good alignment in order to solve the localization problems in the cortex, and subcortically . Zeki: I accused Dr Fox earlier of being too pessimistic, but now I suggest that it is no use thinking that one will learn the rules of how t o map a function in the cortex by PET or by MRI; you need to do that with electrophysiology. In other words, for example, you are not going to get, by imaging, information as has been obtained on the primary visual cortex of the amount of cortex that would be required to map one degree of the field of view; nor would imaging give, at present, information on how colour, or motion, is mapped in the cortex. These would have to be studied electrophysiologically. This is why I think the idea of combining electrophysiology with PET is more useful than deceiving oneself that one will get any idea of the rules by which you map functions in the brain through these imaging techniques. Fox: I think you slightly misinterpret what I suggest! Let me give an example of where we could learn a great deal about the way in which maps evolved and the relationship between functional maps and surface anatomy. Many areas of the brain, particularly the frontal operculum and posterior inferior frontal lobe, have been described as areas of very high anatomical variability; the gyral patterns are far from consistent there. Suppose, however, that the functional areas show good consistency in Talairach (coordinate) space, the implication being that functions are not so much bound to a particular surface landmark, but have a validity within the overall structure of the brain. That is, the foldings of the surface could be random, but over the entire surface, the maps are fairly consistent. I would take this as having developmental implications which would give us guidelines to begin to think how the maps develop. But this is not to say that we know the neural circuitry by which a given process is performed, from PET data. Zeki: We should clarify what we mean by maps. We are talking about rather different kinds here. Fox: When we can designate within a functional brain area the lips, the hand, the toes, we have a map! Zeki: That is a topographic map.

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Fox: Yes. It’s not a circuit diagram of a process! Plum: It seems to me that in these discussions we are groping for rules of how the brain works, not simply for fixed maps which tell us where it works. As Professor Porter pointed out in his Introduction, it is roughly 135 years since Broca provided the first, firm anatomical example of a focal brain injury associated with a specific psychological dysfunction. Understanding of the focal origins of many psychological activities has increased at an astonishing rate during the past 30 years, thanks to the development of a variety of methods that permit the study of altered brain function in living human beings. Experimental animal findings have tended to follow the discoveries made in humans, rather than the opposite order being the case. Later, this symposium will approach the even more abstract activities of the cerebrum which are neither primarily sensory nor primarily motor, but represent behavioural combinations of these. Such findings, although extraordinarily interesting, nevertheless must be respected for their limitations. We will be taught a little about where the brain does its business, but we still will understand very little about how it works its way on the cellular level, and we will know almost nothing at all about why. Professor Zeki is one of the few persons in this room who has moved from psychology to electrophysiology to metabolic mapping in order to answer an important question about how an important subsection of the brain works. My guess is that the next decade will see the large research teams represented here increasingly extend their collaborations to include investigators working at the cellular and subcellular level of neurobiology in efforts to reduce neuropsychology to the molecular level. Perhaps the kinds of national programmes that were discussed earlier (p 74) can facilitate such an approach. Jones: Peter Fox stressed the need to identify gyral structure. Analysis tends to be based on differences between various states of activation. We seem to have forgotten that within the raw data there is a great deal of information on the functional structure of the brain itself. We already use the AC-PC line within recorded data to obtain landmarks of cerebral structure. Maybe we should make more use of this and delineate other structures of the cerebral tissues for individual subjects. We could, for example, integrate the total scan data from the repeat studies in a given subject to provide a high quality map of functional anatomy. Using this, we could contemplate data processing such as edge-finding and resolution recovery methods. Frackowiak: I hate to disagree with Professor Plum, or with Professor Zeki! But Professor Zeki told me quite distinctly that the demonstration of functional specialization was a demonstration of a very fundamental principle of the organization of the brain, and I believe he has also told me that PET is the only way this could be done in man. So that is one example. Another example of mechanism was shown by Karl Friston earlier, who took an area which is associated with a given cognitive behaviour and, by

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manipulation of the pharmacology, was able to associate a neurotransmitter system with the modulation of a neuronal pathway and a modification of behaviour . Thirdly, we have also been able, by looking at blood flow data across different aspects or degrees of a system-specificbehaviour, to look at how the blood flows in different and anatomically distant brain areas correlate-in other words, how they connect in functional terms-and how they interact in the context of activation of a particular behavioural system. All those are ways of establishing mechanistic rules; they are simply at the level of system analysis and represent a method for understanding the ‘top-down’ organization of behaviour, which must interact with the ‘bottom-up’ approach of the electrophysiologist. This philosophy explains our approach to the role of PET in understanding and elucidating brain mechanisms in man. Plum: I don’t think our views differ. What I was trying to say is that your remarkable findings cannot, at present, be subjected to the kind of microanalytic chemistry, pharmacology and physiology that one would like to see. Until online methods are developed for doing that kind of chemistry, it’s going to be difficult to make conclusions at the cellular-molecular level. Evans: Referring to Richard Frackowiak’s question, of what is the point of the anatomical correlation with the activation data in a group study, much of the discussion has been about research in normal brains, but if the PET field is to move forward, we have to be able to do these studies in individual brains, and in those with space-occupying lesions, where all notions of standardized space fall apart. I think this is where the field is going. Frackowiak: I agree with that! References Bohm C , Greitz T, Kingsley D, Berggren BM, Olsson L 1983 Adjustable computerized stereotaxic brain atlas for transmission and emission tomography. A m J Neuroradiol 4 9 3 1 -733 Bohm C, Greitz T, Kingsley D, Berggren BM, Olsson L 1985 A computerized individually variable stereotaxic brain atlas. In: Greitz T, Ingvar DH, Widen L (eds) The metabolism of the human brain studied with positron emission tomography. Raven Press, New York Bohm C, Greitz T, Blomqvist G et a1 1986 Applications of a computerized adjustable brain atlas in positron emission tomography. Acta Neuroradiol Suppl 369:449-452 Bohm C, Greitz T, Seitz R, Eriksson L 1991 Specification and selection of regions of interest (ROls) in a computerized brain atlas. J Cereb Blood Flow Metab 11:A64-68 Bookstein FL 1989 Principal warps: thin-plate splines and the decomposition of deformations. IEEE (Inst Electr Electron Eng) Trans Pattern Anal & Machine Intelligence 11567-585 Brodmann K 1925 Vergleichende Lokalisationslehre der Grosshirnrinde, 2nd edn. J A Barth, Leipzig Campbell AW 1905 Histological studies on the localisation of cerebral function. Cambridge University Press, London

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Connolly CJ 1950 External morphology of the primate brain. CC Thomas, Springfield, IL Evans AC, Dai W, Collins L, Neelin P, Marrett S 1991 Warping of a computerized 3-D atlas to match brain image volumes for quantitative neuroanatomical and functional analysis. Proceedings of the International Society of Optical Engineering (SPIE): Medical Imaging V, February 1991 Greitz T, Holte S, Bohm C et a1 1991a A data base library as a diagnostic aid in neuroimaging. Neuroradiol Suppl 33:2-4 Greitz T. Bohm C, Holte S, Eriksson L 1991b A computerized brain atlas: construction, anatomical content, and some applications. J Comput Assisted Tomogr 15:26-38 Ono M, Kubik S, Abernathey CD 1990 Atlas of the cerebral sulci. Thieme Verlag, Stuttgart Seitz RJ, Bohm C, Greitz T et a1 1990 Accuracy and precision of the computerized brain atlas programme (CBA) for localization and quantification in positron emission tomography. J Cereb Blood Flow Metab 10:443-357 Talairach J, Szikla G, Tournoux P et a1 1967 Atlas d’anatomie stCrCotaxique du telenckphale. Masson, Paris von Economo C 1929 The cytoarchitectonics of the human cerebral cortex. Oxford University Press, London

Positron emission tomography studies of the somatosensory system in man P. E. Roland and R. J. Seitz* PET Division, Neurobuilding, Karolinska Hospital, S- 10401, Stockholm, Sweden and *Department of Neurology, Heinrich-Heine Universitat Dusseldorf, 4000 Diisseldorf 1, Germany

Abstract. Activity in the human somatosensory system was measured by regional cerebral blood flow (rCBF) and by the binding of ["Clnimodipine to L-type Ca2+ channels. These physiological variables were considered to be indicators of neuronal and synaptic activity. In general, structures in the cerebellum, thalamus and the somatosensory cortices which increased their rCBF in response to somatosensory stimulation also showed high binding of [ "C]nimodipine. Voluntary movements carried out largely independently of sensory feedback, natural somatosensory stimulation and passive stimulation of the somatosensory system all activate the somatosensory system. However, it is possible by subtraction techniques to show that differences in activations between these conditions exist in the cerebellum and the somatosensory cortices in the anterior part of the parietal lobe. 1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 113-124

The somatosensory system in man comprises the dorsal column system or the lemniscal system, the spino-cerebellar system and the spino-thalamic system. Centrally, the lemniscal system ends in the primary somatosensory cortex (SI). From here, somatosensory information is distributed to somatosensory association areas of which we now know six (Roland 1987). Only the upper parts of the somatosensory system are visible with positron emission tomography (PET). The analysis is therefore restricted to the cerebellum, the cerebellar nuclei, the region of the red nucleus, the ventral lateral-ventral posterolateral (VL-VPL) nuclei of the thalamus, and the somatosensory areas depicted in Fig. 1. The somatosensory system can be studied by passive stimulation of an immobile part of the skin, for example by vibrating the hand of subjects. In addition one can study the system under natural conditions when subjects sample the somatosensory information by actively exploring objects, such as during tactile discrimination of the shape of objects. Finally, all voluntary somatomotor activity inevitably causes an afferent information flow in the somatosensory system because of the movements and excitation of receptors in the skin, muscles, tendons and joints. We have studied the activity of the somatosensory system 113

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FIG. 1 . Preliminary delimitation of somatosensory cortical areas in man in Talairach coordinateson the basis of the present study and Roland (1987). The broken lines indicate that SII and the RI-PO are localized beneath the hemispherical surface in the parietal operculum. SPA,superior parietal lobule; IPA, intraparietal sulcus; SPC, postcentral sulcus.

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by these three approaches. The regional cerebral blood flow (rCBF) was used as an indicator of neuronal activity.

Methods

In all studies the regional cerebral blood flow was measured as an indicator of regional synaptic activity in normal volunteers who inhaled 50 mCi of the freely diffusible tracer, "CH3F, in a single breath. The arterial concentration of tracer was determined continuously. From the arterial concentration of the rCBF tracers and the PET measurements of the concentrations of tracer in the brain, the rCBF was determined pixel by pixel during the first 80 s by the dynamic method described by Roland et a1 (1987). The rCBF images were corrected for differences in arterial partial pressure of COz between control measurements and test rCBF measurements by 4% per mmHg. For determination of the brain anatomy of each subject and the final standardization of the PET images, each subject was equipped with a fixation helmet and had a high resolution magnetic resonance tomograph taken (Seitz et a1 1990a). The computerized adjustable atlas of Bohm and Greitz (Bohm et a1 1986, Seitz et al1990a) was then adapted to the individual magnetic tomographic image of the brain by linear and non-linear elastic transformations, as described by Seitz et a1 (1990a). Thereafter, all images were transformed into a standard brain anatomy as described by Seitz et a1 (1990a). The main feature of this atlas is that one can construct pictures of the change in rCBF between rest and activated conditions in which the brains all appear with the same shape and size, irrespective of the actual different shapes and sizes of the individual brains. This allows the construction of pictures of the mean changes in rCBF between rest and the test measurements, or between different test measurements. The accuracy and precision of these procedures were evaluated (Seitz et a1 1990a). The mean rCBF changes during the different tests were localized to anatomical structures from the database of the atlas. With this technique, active synaptic regions can be localized with a precision beyond the spatial resolution of the PET camera (Seitz et a1 1990a). Each subject was measured in one control state, a rest state defined by Roland & Larsen (1976). During all measurements, arterial pCO,, EEG, eye movement recordings and video monitoring were performed, as is standard in our laboratory. The rCBF from the control state was subtracted from that of the test state to give individual subtraction images. These were re-formatted by the adjustable computerized atlas into standard size and shape and subsequently averaged to give mean ArCBF images. The pixel ArCBF was tested for conformity to a Gaussian distribution. Paired descriptive t-values were then calculated pixel by pixel, corresponding to the mean ArCBF images (Seitz et a1 1990a). According to preliminary investigations the spatial correlation between pixel values of ArCBF extends for 8 mm, after

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which it becomes negligible, Pixels 8 mm apart were therefore regarded as in practice uncorrelated. An apriori arbitrarily set numerical level of 2.3 was used to dichotomize the pixels of the t-images. This value was chosen on the basis of an examination of the distribution of noise and signal in rest and test images in the study of Seitz et al (1990a). If all changes in rCBF between the test and control state are due to random fluctuations, one can estimate the probability of getting 2 , 3 and 4 uncorrelated pixels exceeding a numerical value of 2.3 in a sample of 9 uncorrelated pixels from an upper limit to the hypergeometrical distribution to be less than 0.05, 0.005 and 0.0005, respectively. In the study of Seitz et al (1990a) it was shown that the background noise in the mean ArCBF images did not exceed a numerical value of 3.0 m1/100 g per min. For this reason, all mean ArCBF values exceeding a numerical value of 5.0 m1/100 g per min were examined in a re-sampled population of the subjects participating in the test. In addition, the group of subjects was randomly assigned into two groups of five subjects each. We then analysed whether all spots having a mean ArCBF exceeding 5.0m1/100g per min appearing in the first group were also present in the second group. Only spots having ArCBF values consistently exceeding 5.0 m1/100 g per min in all re-sampled populations were considered in the further analysis. Post hoc it was examined which of the spots that were consistently activated in all re-sampled populations coincided with areas having t > 2.3, and all such spots were localized to the anatomical structures by the computerized atlas. By analysing the number of clustered uncorrelated pixels in noise pictures generated by subtracting pictures of rCBF obtained during one test condition, we saw that clusters of three independent pixels or more having t > 2 . 3 were rare (Pc0.05).For these reasons we regarded activation as having taken place in an area encompassing at least three uncorrelated pixels and having a spot for which ArCBF was consistently larger than 5.0ml in all re-sampled populations. When the pictures of the mean rCBF during somatosensory discrimination were compared statistically to pictures of the rCBF from vibratory stimulation and motor performance, a t-value was calculated as:

in which the horizontal line signifies the mean value of a pixel. In these cases the regions to be compared were known apriori and a significance limit of 0.05 was used (two-tailed test).

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Results and discussion

We first examined the parts of the somatosensory system which showed altered rCBF in nine normal blindfolded volunteers who discriminated the shape of objects with their right hand (Roland 8i Larsen 1976, Seitz et a1 1991). This increased the rCBF in both posterior lobes and in the right anterior lobe of cerebellum. In addition, the right deep cerebellar nuclei (dentate?) were activated. Further rostrally, the left VL and VPL region of thalamus increased its rCBF. Finally, the hand area of the postcentral gyrus (SI) and all somatosensory association areas, with the exception of the SII and the areas in the parietal operculum, were activated. It could also be shown that these stations of the somatosensory system have a high binding of the L-type Ca2+ channel antagonist, [ llC]nimodipine, when subjects do the same test (Roland & Seitz 1991). This indicates that the neurons in the regions showing changes in rCBF are depolarized during the task (Roland & Seitz 1991). The activations of the posterior lobe of cerebellum, the anterior part of the superior parietal lobule (SPA) and the cortex lining the intraparietal sulcus (IPA) were bilateral (Fig. 2A) (see colour plate). The spatial resolution was not sufficient for us to determine whether the cortex lining the posterior and anterior bank of the postcentral sulcus (SPC) was activated bilaterally, or only the posterior bank. In any case, the bilateral activation of SPA and IPA indicates that the perceptual reconstruction of shape, subsequent to the analysis in SI and perhaps the anterior part of SPC, is distributed to both hemispheres. In the vibration task, the fingers of the right hand were strongly vibrated. Undoubtedly, this stimulus excites the muscle spindles of the hand and some forearm muscles as well (Goodwin et a1 1972). The subjects were asked to pay attention to the vibration in order to discover small changes in frequency which, however, did not occur during the PET measurement of rCBF. The vibration is a simple sinusoidal signal which carries no information on shape. This activated the left SI, the retroinsular cortex-parietal operculum (RI-PO) and the SII bilaterally (Fig. 2B) (see colour plate). The rCBF in the two SPAS and the left SS decreased. No significant changes in rCBF could be measured in the cerebellum or the thalamus. The rCBF in the left tegmentum decreased, but not sufficiently to reach statistical significance. We could not find any significant changes in the cerebellum or the thalamus. This is in contrast to the findings of Fox et a1 (1985), who described a 4% increase in rCBF in the anterior lobe of the cerebellum ipsilaterally to the stimulated hand. The frequency of the movements of the fingers needed t o carry out the explorations of objects in the shape discrimination task was 3.5 Hz. In another task of sequentially opposing the thumb and the four ulnar fingers of the right hand, the movements were to be carried out as a realization of a definite movement programme without emphasis on sensory feedback. After training, the nine subjects participating could achieve an overall finger movement

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frequency of 3.2 Hz (Seitz et a1 1990b). This task increased the rCBF in the right anterior lobe of cerebellum, the left VL-VPL region of thalamus, the left SI and SS (Seitz et a1 1990b) (Fig. 2C) (see colour plate). Because all mean rCBF pictures conformed to the computerized atlas of Bohm and Greitz (Bohm et a1 1986, Greitz et a1 1991) it was possible to subtract the mean rCBF during vibration and motor performance from the mean picture of rCBF in somatosensory discrimination. This enables one to see to what extent the anatomical sites of activation in the three tests coincided. If a field cancels out by this subtraction, it does not necessarily imply that the neurons in this field d o the same computation in the two tests. Because the rCBF is monotonically related to the regional metabolism, cancellation means that the regional cerebral metabolism in the field is of the same size in the two tests during the period when rCBF was measured and that the fields in both tests had an identical localization. Subtraction of mean rCBF during vibration from the mean rCBF during somatosensory discrimination showed cancellation of the SI activation, indicating that it was not possible to distinguish the somatotopical area activated and the local SI energy expenditure in the two tests. The right and left posterior lobe of cerebellum, the right central nuclei of cerebellum, the left red nucleus region, the left SPA and SS were significantly more activated during shape discrimination (Seitz et a1 1991). When the mean rCBF obtained during the motor performance was subtracted from the mean rCBF obtained during somatosensory discrimination, the SI and right anterior lobe of cerebellum cancelled out. The posterior part of the left SPC, the left SPA, left SS and left and right IPA were significantly more activated during shape discrimination. Subcortically the posterior lobes of the cerebellum, the right central nuclei of cerebellum and the left VL-VPL were more activated in shape discrimination than in motor performance (Seitz et a1 1991).

The connections of the primate posterior lobe of cerebellum are not known in detail. The posterior lobes are also activated when subjects learn and recognize the shapes of objects tactually (Roland et a1 1989). We assume that this neocerebellar part is activated as a part of cortico-cerebellar circuits. The finger movements during somatosensory discrimination and motor performance activated an identical part of the anterior lobe of cerebellum. Somatosensory stimulation alone does not seem to give any detectable activation of this site. The deep cerebellar nuclei receive inhibitory afferents from the Purkinje cells. Since the cortical cerebellar activity was increased in both the anterior and posterior lobe, one would expect the rCBF of the deep cerebellar nuclei to decrease. Apparently this was not so, and this could mean that regulation of the activity in the deep cerebellar nuclei is more complicated. That the left tegmentum mesencephali had a higher rCBF in somatosensory discrimination than when the fingers were vibrated might be due to the decrease

FIG. 2 (Roland & Seifz) Descriptive f-images of the changes in rCBF in the cortical somatosensory areas at the centre of the somatosensory hand area. The precentral sulcus, the central sulcus, the postcentral sulcus, the intraparietal sulcus and the cingular sulcus are called in from the atlas database. Left in the pictures corresponds to the right side of the brain. (A) Somatosensory discrimination of shape with the right hand (eight subjects). (B) Vibration of the fingers of the right hand (six subjects). (C) Motor performance of a complicated sequence with the fingers of the right hand (Seitz et a1 1990) (nine subjects).

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of rCBF in this region that was provoked by the vibratory stimulus. That the left VL-VPL was more active in somatosensory discrimination than in motor performance either could be due to a larger synaptic metabolism in both the VL and VPL nuclei, or could mean that one of these nuclei is more activated during somatosensory shape discrimination. That these nuclei were not activated in vibration could mean that the vibratory signals are transferred to the cortex by other and smaller nuclei. It has been proposed that the VPI nucleus was engaged in the transmission of such signals to SII (Friedman et a1 1986). The SI activity was of approximately similar magnitude and location in all three tasks. Presumably the afferent signals which reached SI were quite different in the three tasks. Nevertheless, the synapses in SI seemed to be activated to approximately the same degree. In all three tasks the initial analysis of the afferent signals was carried out over the whole anterior-posterior extent, from the bottom of the central sulcus to the rim of the postcentral sulcus. The SII was activated selectively by vibration. This of course does not imply that vibration is the only type of somatosensory signal that can excite SII neurons. The adjacent region (RI-PO) was activated only during vibration. The differences in rCBF during vibration, shape, discrimination and motor performance were, however, not significant. The RI-PO region seems to be of particular importance for detecting microgeometric surface deviations (i.e. roughness) (Roland 1987). The SS was active only in the two conditions (shape discrimination and motor performance) where movements of the fingers in intrapersonal space occurred. It was more active when the movements were carried out in order to sample relevant somatosensory information about objects than when it participated in analysing the feedback from the moving fingers in the motor task. Lesions of this area cause clumsiness in the handling of objects under tactual guidance (Roland 1987). The anterior part of SPC-that is, the cortex in the anterior bank of the postcentral sulcus-seemed to be active contralaterally in all three types of stimulation, whereas the posterior part was active only during shape discrimination. This part is continuous with the IPA, which is a remote somatosensory association area. This area and the SPA were selectively activated in the shape discrimination task. This could suggest that the final analysis of the signals leading to the tactual perception of shape and the representation of shape was performed by these remote somatosensory association areas. Probably none of these somatosensory association areas performs only a single function, such as the recovery of tactual shape from afferent somatosensory signals, but, as documented in this chapter, there is most likely to be a functional specialization of these areas.

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Acknowledgements These investigations were supported by The Soderstrom-Konig Foundation and The Soderberg Foundation by grants from the Karolinska Institute, and by a grant from the Deutsche Forschungsgemeinschaft to R. J. S.

References Bohm C, Greitz T, Blomqvist G, Farde L, Forsgren PO, Kingsley D 1986 Applications of a computerized adjustable brain atlas in positron emission tomography. Acta Radio1 Suppl 369:449-452 Fox PT, Raichle ME, Thach T 1985 Functional mapping of the human cerebellum with positron emission tomography. Proc Natl Acad Sci USA 82:462-467 Friedman DP, Murray EA, O’Neill JB, Mishkin M 1986 Cortical connections of the somatosensory fields of the lateral sulcus of macaques: evidence for a corticolimbic pathway of touch. J Comp Neurol 252:323-347 Greitz T, Bohm C, Holte S, Eriksson L 1991 A computerized brain atlas: construction, anatomical content, and some applications. J Comput Assisted Tomogr 15:26-38 Goodwin GM, McCloskey DI, Matthews PBC 1972 The contributions of muscle afferents to kinesthesia shown by vibration induced illusions of movements and by the effect of paralysing joint afferents. Brain 95:705-748 Roland PE, Larsen B 1976 Focal increase of cerebral blood flow during stereognostic testing in man. Arch Neurol 33:551-558 Roland PE 1987 Somatosensory detection of microgeometry, macrogeometry and kinesthesia after localized lesions of the cerebral hemispheres in man. Brain Res Rev I2:43-94 Roland PE, Seitz RJ 1991 The functional anatomy of a single brain function: somatosensory discrimination of shape. In: Franztn 0, Westman J (eds) Information processing in the somatosensory system. Macmillan Stockton Press, London, p 275-286 Roland PE, Eriksson L, Stone-Elander S . Widen L 1987 Does mental activity change the oxidative metabolism of the brain? J Neurosci 7:2373-2389 Roland PE, Eriksson L, Widen L, Stone-Elander S 1989 Changes in regional cerebral oxidative metabolism induced by tactile learning and recognition in man. Eur J Neurosci 1~3-18 Seitz RJ, Bohm C, Greitz T et a1 1990a Accuracy and precision of the computerized brain atlas programme for localization and quantification in positron emission tomography. J Cerebr Blood Flow Metab 10443-457 Seitz RJ, Roland PE, Bohm C, Greitz T, Stone-Elander S 1990b Motor learning in man: a positron emission tomographic study. NeuroReport 1 :57-60 Seitz RJ, Roland PE, Bohm C, Greitz T, Stone-Elander S 1991 Somatosensory discrimination of shape: tactile exploration and cerebral activation. Eur J Neurosci 3 :48 1-492

DISCUSSION

Frith: Can you give more details of the shape discrimination task?

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Roland: This is a two-alternative, forced-choice discrimination of shape. In the first two seconds, the blindfolded subject receives the first object in the right hand; in the next two seconds he receives a second object. So he has only one object in his hand at a time. He is then forced to choose the object which he judges is the most oblong. If he judges that the second object is the most oblong, he briefly extends his right thumb. Frith: Is the subject entirely free to explore the objects? Roland: Yes. He is completely unrestricted in the way he explores the surfaces. However, as we showed in 1987, the subjects explore the objects in an elaborate but stereotyped fashion (Roland & Mortensen 1987). The movements seem to be made so as to convey the maximum information to the somatosensory system. That is, they concentrate on edges and surfaces which are optimal to explore. Frith: And in this free task, do you also observe frontal activation? Roland: Yes. You could see, when you subtracted, for instance, the motor performance task from the somatosensory discrimination task, a large band of prefrontal activation. Of course one can question whether this has to do with the comparison of stimuli and the working memory involved in the discrimination, but the subtractions showed that it was not involved in the mere execution of the motor task. Jeannerod: I wondered about your vibration stimuli. Did you try to apply pure vibration on the tendons, and eventually to induce illusions of limb motion? Would you not expect to see more anterior activation, in the region of area 3 in the central sulcus, for instance? Roland: We tried to induce illusions of movement by vibrating the biceps tendon with a very strong stimulus, close to 2 mm in amplitude. We are sure it excites a lot of muscle spindles, but we didn’t do that during the PET measurement. I think one has to take the PET images to mean that even the deep part of the cortex lining the central sulcus was activated. This means that although we cannot talk about cytoarchitectural areas, nevertheless, this is where area 3A is supposed to be, in the depth of the sulcus. Porter: Were all the fingers vibrated? Roland: Yes. Cappa: All your experiments with the somatosensory discrimination were performed with the right hand (left hemisphere). Have you also tried the other hand? This is the sort of task where you could expect to find some hemispheric difference in the extent or degree of activation. Roland: We haven’t looked into that. The subjects are blindfolded, and they discriminated with the right hand. I wouldn’t care to speculate about the possible activation patterns, but in lesion studies, it doesn’t seem to make any difference, whether the lesions are contralateral to the right hand or to the left hand (Roland 1987). However, one should be cautious in comparing the effects of lesions with the activation patterns because, clearly, if you damage the anterior part of the cortex lining the intraparietal sulcus, you see no contralateral deficit in the

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somatosensory discrimination of shape. This could be because information is transferred to the homologous area in the other hemisphere in subjects with lesions, but that’s speculation. Fruckowiak: It seems to me that your somatosensory discrimination task is quite complex. You were suggesting that by subtracting away the confounding components, including motor performance (which would control for the motor aspect of somatosensory discrimination) and vibration (which might control in some way for the purely sensory aspects), you are left with those areas of the brain that are specifically associated with the discrimination of shape. Have you analysed your results in that way, and can you say which parts of the brain you think are associated purely with the discrimination of shape? Roland: There is a little bit more evidence on that. When you subtract the motor activity, such as during the motor performance test, you are left with the activation that you see. Also, if you don’t have the subjects move their fingers, but just passively press objects against their skin, you see no activation of the motor cortices, but activation of the somatosensory cortices (Roland & Larsen 1976). I don’t think the present subtraction experiment is a very elegant way of ruling out the motor component, but it is difficult to find a good control for movements which mimic exploratory movements of objects. Fruckowiak: I agree that it is difficult finding controls in all these PET experiments, but if one accepts that those are reasonable controls, do you feel you have been able to map on to the brain those areas where computation of the vectors of the shape, so to speak, may be occurring? Roland: I think that would be to overinterpret the data, because there is surface information in the objects as well which is not shape information, and you would have to do more subtractions, especially of surface components, to be sure that what you really see is activation due to the reconstruction of shapes. Baron: It is an excellent idea t o look at activation of the calcium channels during a sensorimotor task, using [ “C] nimodipine, but I wasn’t clear whether the study you reported was a study of subtraction of rest from a sensorimotor task-that is, activation minus rest-and whether the changes you described represented changes in specifically bound radioligand. Porter: This is a rather important issue to clarify, because it’s the first time that we have had an opportunity to address something that may be a real indicator of what is happening at a synaptic location. Roland: The study that I referred to was not activation minus rest; it was a study of the maximal binding capacity, Bmm, in pmol/ml, during the sensorimotor task, namely the tactile discrimination of shape. The idea of the study was that nimodipine binds to one particular state of the three main states of the Ca2+ L-type channel. Nimodipine is supposed to bind to the inactivated state of the channel and keep the channel inactivated for some time. Nimodipine is also metabolized, so we had to subtract from the arterial input function the proportion of metabolites in the arterial blood to obtain the proper input

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function to the brain. The metabolites do not cross the blood-brain barrier to any significant degree, nor do they bind to binding sites in the brain, according to experiments in animals (F. Traber, personal communication). We used a two-step procedure to determine the maximal number of binding sites (B,,,) during a tactile two-alternative forced-choice discrimination of shape. The assumption was that a three-compartment model adequately described the kinetics of [ 'C] nimodipine. By injecting a large amount of nonradioactive nimodipine, we could occupy the receptors and subsequently inject a tracer amount of labelled nimodipine (protection experiment) to get an estimate of the concentration of free ligand in the tissue and the rate constants kl and k2 for the passage of the ligand across the blood-brain barrier. The study demonstrated that the B,, of [ "C] (-)nimodipine is spatially correlated with the locations in the brain where blood flow increases during the same test of somatosensory discrimination. The B,, is not correlated to the absolute values of rCBF during somatosensory shape discrimination. The B,,, images thus are not subtraction images. Frackowiak: When you determine kl or k2, d o you determine them both for the rest state and for the activated state, or d o you use just one value which you use for both? Roland: We examined the B,,, of [ "C] ( -)nimodipine only during the activated state, so we determined kl and k2 during this state. We looked at the spatial distribution of kl and k2 and couldn't find any difference in the ratio k l / k 2 . Frackowiak: If you are looking for evidence to suggest that there is a specific uptake of the nimodipine that reflects calcium channel activity at a focus, you will need to make a comparison between a state where the channels are less and then more activated. If there is an underlying blood flow change as well, you will have to correct for this in your k l estimation at least. Roland: You determine kl by fitting the initial part of the curve describing the tissue concentration. B,,, is determined in the interval 20-50 min and thus is not influenced by rCBF and rCBF changes. MacKenzie: Dr Roland, I don't quite understand the displacement experiment. You say that you displace labelled nimodipine from the vessels using cold nifedipine, but my understanding was that the L-type calcium binding sites are in the tunica media, and are therefore protected by the blood-brain barrier. Roland: You may have a good point there. It is said that the musculature of brain vessels contains L-type channels, and if nifedipine doesn't cross the blood-brain barrier, then it is not very well suited to displacing the binding of nimodipine on the vasculature. MacKenzie: Have you figures for the difference in density of L-type calcium channels, comparing vascular tissues with the neuropil? Roland: I don't know the density of the L-type channels in the vasculature. In skeletal muscle the density is much higher than it is in neurons. The eye

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muscles for example show high binding of the ligand compared to the average binding in brain. MacKenzie: Are you labelling neurons or vascular elements with nimodipine? Roland: I don’t think I’m labelling the vascular elements! How would you explain that the labelling of nimodipine does not follow the blood flow pattern? This is one argument that we are not labelling vascular elements. I don’t think there is a density of vascular elements to that extent in the brain. In the thalamus, for instance, you cannot get such a high binding with a vascular tracer. This of course has to be verified and compared with the animal experiments of van den Kerckhoff (1986), who in ex vivo autoradiographic studies showed that nifedipine binds to the vasculature, but only insignificantly to brain tissue, and therefore can be used to displace nimodipine from the vasculature. References Roland PE 1987 Somatosensory detection of microgeometry, macrogeometry and kinesthesia after localized lesions of the hemispheres in man. Brain Res Rev 12:43-94 Roland PE, Larsen B 1976 Focal increase of cerebral blood flow during stereognostic testing in man. Arch Neurol 33551-558 Roland PE, Mortensen E 1987 Somatosensory detection of microgeometry, macrogeometry and kinesthesia in man. Brain Res Rev 12:l-42 van den Kerckhoff W 1986 Crossing the blood brain barrier-nimodipine and nifedipine. In: Smith T (ed) Nimodipine report from 4th European Workshop on Clinical Neuropharmacology Calcium antagonists and cerebral ischemia: new pharmacological results. (Facultad de Medicina, Universidad de Navarra, Pamplona) Bayer, Germany, p 22-23

.

Does inter-subject variability in cortical functional organization increase with neural ‘distance’ from the periphery? Peter T. Fox* and Jose V. Pardo**

*Research Imaging Center, University of Texas, Health Science Center, San Antonio, TX 78284-7800, USA and **Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA

Abstract. In mapping the functional anatomy of the human brain, anatomical variability is a recurring concern. The degree to which the functional organization of any one subject or group of subjects is more generally predictive is largely unknown. We have previously reported that the inter-subject variability of primary visual, somatosensory and motor cortices is small (4-8 mm). Many have suggested, however, that higher-order brain areas will be considerably more variable. For this reason we assessed the anatomical variability of several brain areas participating in language perception and production. In 10 anatomically normal subjects undergoing evaluation for partial complex epilepsy we applied a previously described battery of lexical tasks; intra-subject image averaging was used to minimize the effects of variations in response magnitude. We found inter-subject anatomical variability to be uniformly consistent, with no appreciable effect of distance from the neural periphery. I991 Exploring brain functional anatomy with positron tomography. Wiiey, Chichester (Ciba Foundation Symposium I63) p I2.5- I44

The development of positron emission tomography (PET) techniques for mapping the functional organization of the human brain has led to a rapid increase in our knowledge of the brain locations of many cognitive, affective, motoric and perceptual processes. Image averaging (Fox et al 1988a) and related techniques (Friston et a1 1991), in particular, have permitted cortical areas supporting higher-order neural processes to be located and mapped. This conference is a timely response to and an important index of the scientific impact of the rapidly emerging field of non-invasive functional brain mapping. Despite the quickened pace with which we are learning about the mean locations of many cognitive processes, little is known about inter-subject variability in the locations of these processes. We have previously reported that the inter-subject variability of the location and internal order (mapping) of the primary visual, somatosensory, and motor cortices is small, with typical inter-subject standard deviations of 4-8 mm. 125

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Despite this, it has generally been assumed that higher-order processes (such as those supporting language and attention) will be considerably more variable. This belief has been based principally on the variability of behavioural deficits following acquired brain lesions and on electrical stimulation mapping of cerebral cortex (see Ojemann et a1 1989). In the present study we assessed the inter-subject variability of several functional zones activated by two linguistic tasks. The tasks were drawn from a previous study of single-word processing in healthy, right-handed volunteers (Petersen et a1 1989). Whereas that study used inter-subject image averaging, the present study employed intra-subject averaging, to allow responses to these tasks to be reliably detected in individual subjects. Functional zones were selected to represent a variety of levels in the hierarchy of neural process. Areas closest to the periphery included peristriate visual areas (input processing) and primary motor areas (output processing). Premotor areas, involved in movement programming, were further removed from the neural periphery. Prefrontal areas, involved in semantics and attention, represented a still higher-order level of neural processing. Methods

Subject population Ten persons between the ages of 13 and 52 years, with medically intractable, partial complex epilepsy, were studied. All subjects were recruited in the course of evaluation for surgical therapy. Criteria for inclusion in this study included: no focal lesions or atrophy by anatomical imaging studies (X-ray computed tomography or magnetic resonance imaging); normal inter-ictal neurological examination; and no lateralizing ictal or post-ictal symptomatology . All subjects underwent assessment of the hemispheric lateralization of language functions by intracarotid injections of sodium amytal (Wada & Rasmussen 1960). By this test, seven subjects were left-hemisphere dominant for language, one subject was right-hemisphere dominant, and two subjects were of mixed or indeterminate dominance. The use of positron emission tomography as a test for hemispheric dominance for language will be the subject of a separate report (J. V. Pardo & P. T. Fox, unpublished). Image acquisition

Each subject underwent a series of measurements of brain blood flow (CBF). Subjects over the age of 18 (n = 9) had between six and nine CBF scans. A single under-age subject had three CBF scans. The behavioural conditions defining the scanning protocol are described below.

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Brain blood flow was measured using bolus intravenous injections of H2150, as previously described (Herscovitch et a1 1983, Raichle et a1 1983, Fox & Raichle 1984, Fox et a1 1985a). A PETT VI system was employed (Yamamoto et al1982). Informed consent was obtained from each subject, using forms and procedures approved for this study by the Human Studies and Radioactive Drug Research Committees of Washington University.

Behavioural protocol The behavioural protocol was an abbreviated version of that reported on by Petersen et a1 (1989). Three behavioural conditions were used: (1) eyes-closed rest (Rest), (2) repeating aloud visually presented nouns (Repeat nouns), and (3) generating a single verb (a use) for each visually presented noun (Generate verbs). Words were presented beneath a small fixation cross for lSOms, with an inter-stimulus interval of 850 ms (one wordls). Repetition of each behavioural condition was used to allow intra-subject image averaging. Each subject was imaged in each condition one, two, or three times, depending on the subject’s tolerance for the procedure and radiation exposure limitations.

Image analysis All images were normalized both anatomically and physiologically. Anatomical normalization consisted of converting each data set into a proportional, bicommissural coordinate-space format (Talairach et a1 1967, Fox et a1 1985b, 1988a). Physiological normalization consisted of correcting for inter- and intrasubject variability in whole-brain blood flow (Fox & Raichle 1984). After normalization, all images from each behavioural condition of each subject were averaged, creating composite images for each state of each subject. Image analysis was based upon subtractive comparisons of the three composites. Two subtractions employed were: (1) Repeat nouns minus Rest, and (2) Generate verbs minus Repeat nouns. After image-pair subtraction, localmaximum searching for both increases and decreases in blood flow was performed. Output from the local-maximum search routine (Mintun et a1 1989) was subjected to a modified change-distribution analysis procedure (Fox et a1 1988, Fox 1991), as follows. The greatest focus of change lying within a fixed radius (2cm) of each previously reported mean location (Tables la,b) was identified. If no response could be discriminated from background noise, the response was considered absent. Thus, while not creating fixed regions-ofinterest, a directed local-maximum search strategy was performed. On the basis of numerous previous studies, neural processes can be associated with the above-described areas with a good degree of confidence. In the Repeat nouns minus Rest subtraction, responses were sought in lateral occipital cortex,

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lateral rolandic cortex, medial prerolandic cortex, and the frontal operculum (Table la, Fig. 1). The lateral occipital area sampled is peristriate, extraprimary visual cortex (Brodmann area 18, or V2). This area supports early, non-linguistic aspects of visual processing and is distinct from the inferomedial areas implicated

TABLE l a Functional areas searched: repeat nouns minus rest Lobar location

Putative process

Hemisphere

X

Y

Lateral occipital

Extrastriate, visual

Operculum

Primary motor mouth Premotor, Broca

Medial prerolandic

Premotor, SMA

24 26 46 54 50 62 0

-58

Lateral rolandic

Left Right Left Right Left Right Midline

Z

__

-66 0 4 8 -5

02 06 40 36 22 10

12

50

Locations searched were taken from Petersen et al (1989). All coordinates are expressed in m m in a proportional, bicommissural coordinate space based upon Talairach et al(l967). X , right-left axis. Y, anterior-posterior axis. Z, superior-inferior axis.

FIG. 1. Searched areas, Repeat nouns minus Rest. Locations used as starting points for searches of foci of neural activation elicited by the Repeat nouns - Rest subtraction are shown. These locations were drawn from earlier studies of healthy, right-handed volunteers (Petersen et al 1989). See Table la.

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in visual word-form processing (Petersen et a1 1989, 1990). For word stimuli, however, this area responds more robustly than primary visual cortex (Petersen et al 1989). The lateral rolandic cortex activation is best attributed to the primary motor (Brodmann area 4, or MI) representation of the vocal apparatus, lying immediately anterior to the reported coordinates for the primary sensory mouth representation (Fox et a1 1987a). Medial prerolandic activation is the supplementary motor area (Brodmann area 6a, or SMA), corresponding closely to previously reported coordinates (Fox et al 1985b). The activation in the frontal operculum is in inferior premotor cortex (Brodmann area 44/6), an area loosely designated as ‘Broca’s area’. In our population of right-handed normal volunteers, this area was bilaterally activated by speech (Petersen et a1 1989). Note that both SMA and Broca’s area can be activated by imagined movement and movement preparation, indicating their role as motor programming areas, at earlier (higher) stages in movement execution than primary motor cortex (Fox et a1 1988b; P. T. Fox et al, unpublished data). In the Generate verbs minus Repeat nouns subtraction, responses were sought in superior, middle and inferior lateral prefrontal cortex, and superior anterior cingulate cortex (Table 1b, Fig. 2). The lateral prefrontal activations (superior, middle and inferior), thus far, have proved to be specific to semantic manipulations, whether requiring active production of a word (as in the Generate verbs task) or performed as a monitoring task without overt speech production (Petersen et a1 1989, Posner et a1 1988). This response cluster is not produced either by visual perceptual processes, or by non-linguistic motor tasks. It is, then, among the highest-level, cognitive-processingareas reported by PET activation studies. The anterior cingulate activations seem best attributed to a ‘late selection’ or ‘selection for action’ process (Posner et a1 1988, Corbetta et a1 1990) that is not specific to linguistic tasks and cannot be attributed to lower-order perceptual or motoric processes. Cingulate activation, then, represents a highorder, attentional process. Several brain areas implicated in these tasks by our previous work in normal volunteers were not specifically searched. Primary visual cortex was not sampled, because CBF responses to single-word stimuli are stronger and more reproducible in lateral extrastriate cortex than in medial striate cortex (Petersen et a1 1989). Moreover, the Repeat nouns minus Rest subtraction did not lend itself to resolving the closely clustered activations of primary visual cortex, medial extrastriate visual cortex, anterior cerebellum and lateral cerebellum. Putamen and superior colliculus were deemed not germane to the issue of cortical process variability. Results

Frequency of observation The frequency with which focal responses could be identified in the areas predicted (from our work in normal subjects) was high, between 70% and 100%

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TABLE l b Functional areas searched: Generate verbs minus Repeat nouns ~

~~

Lobar location

Putative process

Hemisphere

X

Y

Superior prefrontal Middle prefrontal Inferior prefrontal Superior anterior cingulate Inferior anterior cingulate

Semantic Semantic Semantic Selection for action

Left Left Left Midline

42 38 30 00

36 36 46 26

Selection for action

Midline

04

33

Z 20 08 -6

38 28

Locations searched were taken from Petersen et a1 (1989). All coordinates are expressed in rnrn in a proportional, bicommissural coordinate space based upon Talairach et al(1967). X,right-left axis. Y, anterior-posterior axis. 2, superior-inferior axis.

FIG.2. Searched areas, Generate verbs minus Repeat nouns. Locations used as starting points for searches of foci of neural activation elicited by the Repeat nouns - Rest subtraction are shown. These locations were drawn from earlier studies of healthy, righthanded volunteers (Petersen et al 1989). See Table lb. (Tables 2a,b). As might be expected, primary motor (MI) and periprimary visual (V2) cortical responses were highly consistent. Primary motor responses were detectable in all of the left hemispheres and in 80% of the right hemispheres. Extrastriate visual responses were present in all of the left hemispheres and in

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TABLE 2a Response magnitude and frequency of detection: Repeat nouns minus Rest

Functional area

Hemisphere

Magnitude

% detection

Lateral occipital (extrastriate visual) Lateral rolandic (primary motor mouth) Operculum (premotor, Broca)

Left Right Left Right Left Right Midline

3.7 (1.27)

100 89 100 80 80 70 86

Medial prerolandic (premotor, SMA)

3.3 (0.73) 2.5 (0.53) 2.3 (0.53)

2.1 (0.54)

1.9 (0.73)

2.4 (0.64)

Response magnitude expressed in blood flow in units of ml 1OOg-’ min-’ (?one standard deviation).

TABLE 2b Response magnitude and frequency of detection: Generate verbs minus Repeat nouns

Functional area

Hemisphere

Superior prefrontal* (semantic) Left Right Middle prefrontaI* (semantic) Left Right Inferior prefrontaI* (semantic) Left Superior anterior cingulate Midline (selection for action) Inferior anterior cingulate Midline (selection for action)

Magnitude

% detection

2.6 (1.03)

100

2.3 (0.49)

80

1 .o (1.01) 2.3 (0.83)

67 88

2.2 (1.04)

80

Response magnitude is expressed in blood flow in units of ml 1OOg-’ min-’ ( t o n e standard deviation). *Responses were searched for in both hemispheres and when present in the right hemisphere (one subject) were projected onto the left hemisphere.

90% of the right hemispheres. Less readily predicted, however, was the consistency of responses seen even in areas supporting higher-order motoric and cognitive processes. Supplementary motor area responses were observed in 90% of the subjects in whom the area was sampled. Inferior premotor (Broca’s) responses were present in 80% of the left hemispheres and 70% of the right hemispheres. Lateral prefrontal (‘semantic’) responses showed similar consistency, being present in 70% (inferior), 80% (middle), and 100% (superior) of subjects. Anterior cingulate (‘selection for action’) responses were detected in 80% (inferior) and 90% (superior) of subjects.

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TABLE 3a Response location and location variance: Repeat nouns minus Rest Functional area

Hemisphere

Lateral occipital (extrastriate visual)

Left Right Left Right Left Right Midline

Lateral rolandic (primary motor mouth) Operculum (premotor, Broca) Medial prerolandic (premotor, SMA)

Anatomical variability

...-..

5.9 6.6 5.9

5.4

6.4 9.6

4.2

Anatomical variability is expressed as one standard deviation (in mm), averaged for the three coordinate axes. For variability in each axis, see Fig. 4.

TABLE 3b Response location and location variance: Generate verbs minus Repeat nouns Functional area

. - - ~

Superior prefrontal* (semantic) Middle prefrontal* (semantic) Inferior prefrontal* (semantic) Superior anterior cingulate (selection for action) Inferior anterior cingulate (selection for action)

Hemisphere

Anatomical variability

Left Left Left Midline

9.9 7.4 6.9 3.4

Midline

7.0

Anatomical variability is expressed as one standard deviation (in mm), averaged for the three coordinate axes. For variability in each axis, see Fig. 5. *Kesponses were searched for in both hemispheres and when present in the right hemisphere (one subject) were projected onto the left hemisphere.

Response magnitude Responses varied in magnitude from a high of 3.7ml 1OOg-’ min-I in peristriate visual cortex to a low of 1.O ml 100 g- I min- I in inferior lateral prefrontal cortex (Tables 3a,b). While primary and periprimary areas tended to have the more intense responses, this was not universally true. For example, superior lateral prefrontal (‘semantic’) responses were very robust, at a mean of 2.6ml 1OOg- min- l , Response magnitude was highly correlated with frequency of observation (Fig. 3). This suggests that in some subjects, responses reported as absent were present but lost in the background noise of the subtraction images. Computation of anatomical variability was necessarily limited to responses reported as present. Further averaging is one means by which detection frequency could be improved.

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110

100 T3 al

>

L

f 90

n

0

L

LL

70

60

2

4

6 Mean response

8

10

FIG. 3. The frequency (percentage) with which functional areas were detected in individual subjects was strongly correlated (r = 0.79) with mean response magnitude (CBF, ml 100 g - I min- I). Areas showing weaker activation were less readily discriminated from background noise.

Location variance In the Repeat nouns minus Rest subtraction, anatomical variability was quite low (Table 3a). Periprimary visual cortex showed a mean variability of 6 mm (expressed as the mean of the inter-subject standard deviations for each coordinate axis). Primary motor cortex (mouth) had a mean variability of 5 mm. Opercular premotor cortex varied less on the left (6mm) than on the right (10 mm). Supplementary motor cortex showed extremely high location consistency (4 mm). In the Generate verbs minus Repeat nouns subtraction, anatomical variability was somewhat higher, on average, but was remarkably low in some areas (Table 3b). The variability in location of the three ‘semantic’ prefrontal areas ranged from 7 mm to 9 mm. The superior anterior cingulate was extremely consistent in location, with a standard deviation of only 3mm. The inferior anterior cingulate was more variable, at 7 mm. Two of the three functional areas abutting the midsagittal plane had extremely low anatomical variability, namely SMA (4 mm) and superior anterior cingulate (3 mm). Note that this was not due to lesser variability in the X (lateral-medial) axis; rather, anatomical variability was distributed essentially equally across all three axes (Figures 4 and 5 ) .

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Discussion The cerebral cortex, the brain’s largest structure, performs its highest-order processes. From microanatomical studies it is well established that cerebral cortex is composed of a complex mosaic of discrete zones distinguished by neuron type, by laminar structure, and by local and remote connectivity. Similarly, the functional processes of cerebral cortex occupy highly discrete zones. Taskinduced neural activations form constellations of discrete foci of change. Presumably, this discrete localization of process is based upon the local specificity of neural architecture and connectivity, with each area supporting a computational component of the entire behaviour . Our knowledge of the forces whereby cortex develops from a homogeneous, equipotential sheet (O’Leary 1989) into a complex mosaic of discrete processing zones is remarkably scant. The study of pathological alterations in cortical reorganization is a route to understanding of the origins of cortical organization. For example, developmental cognitive disorders such as dyslexia or attentiondeficit disorder almost certainly entail alterations in the spatial distribution of linguistic and attentional neural processes. Similarly, early deafferentation (e.g. congenital auditory or visual impairment) or amputation must cause permanent 20

E

-E g

10

.-5 c

0 0 V

J

0

R

L

v2

R

MI

R

L

SMA

L

Broca

FIG. 4. Response variability, Repeat nouns minus Rest. Anatomical variability (expressed as the mean of the inter-subject standard deviation in each axis in mm) was slightly greater in the frontal operculum (‘Broca’) than in primary motor (Ml), supplementary motor (SMA), and extrastriate visual (V2) areas. Anatomical variability was distributed roughly equally across anatomical axes.

135

Anatomical variability of functional areas

Pref rontal

( left)

Ant. cingulate

FIG. 5 . Response variability, Generate verbs minus Repeat nouns. Anatomical variability (expressed as the mean of the inter-subject standard deviation in each axis in mm) in these high-order linguistic areas was not consistently greater than in primary motor or sensory areas. (Also see Fig. 4 and Tables 3a, 3b.) Anatomical variability was distributed roughly equally across anatomical axes. alterations in cortical organization. Even the functional recovery following brain lesions in adults is a potential example of cortical reorganization. The rules of cortical self-organization can only be fully understood by the study of its aberrations. Abnormal development, in turn, can only be understood in the context of a thorough knowledge of normal functional organization and its normal variability. PET is an important new tool for the investigation of cortical process distribution. Electrical stimulation mapping

Prior studies of inter-subject variability of the higher-order functions of the human brain are few. Prior to the recent advent of physiological imaging, direct electrical stimulation of the cortical surface during neurosurgery was the sole source of such observations. Ojemann has recently reviewed his extensive experience using this technique to identify the cortical zones supporting the overt naming of visually presented objects (Ojemann et a1 1989). On the basis of 117 patients with left-hemisphere dominance for language, it was concluded that there was ‘discrete localization in individual patients but substantial variability between patients’. This seems reasonably representative

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of the experience of the stimulation-mapping literature and is at odds with our observations. Electrical stimulation mapping has several acknowledged (Ojemann et a1 1989) limitations that hamper direct comparisons with PET functional brain mapping. Stimulation mappings identify only areas essential for a specific language task; PET subtraction mapping indicates areas participating in the task, but not whether they are essential. Stimulation mapping influences neural populations both locally and remotely, through fibres of passage; PET mapping can safely be presumed to show only neural populations actively engaged in the behaviour. PET imaging allows for progressive analysis of behaviours, through the use of converging experiments. In stimulation mapping there has been little progress made in ‘parsing’ the individual components of complex behaviours (such as picture naming). Indeed, in contrast to reports of deficit analyses in chronic lesions, Ojemann et al (1989) observe that ‘attempts at analyzing localization of different types of naming errors have generally proved to be nonproductive’. Thus the differential functions of the areas implicated by stimulation mapping are unknown. Finally, stimulation mapping can access only exposed cortex; PET mapping is not limited by sulcal unfolding, detecting with equal efficiency neural activations in exposed cortex, buried cortex, and subcortex.

Previous PET studies Prior PET studies of inter-subject variability in functional organization using quantitative anatomical methods have been limited. We have reported on the inter-subject variability of the primary visual cortex (1985a, 1987b), primary somatosensory cortex (1987a), primary motor cortex (1985a), the supplementary motor area (1985a), and the frontal eye fields (1985a). When an automated response-localization algorithm was used (Mintun et a1 1989) for rather robust activations, the inter-subject variability for specific retinotopic/somatotopic locations ranged from 1 mm to 4 mm and from 2 mm to 10 mm (expressed as one standard deviation) in primary visual and somatosensory cortices, respectively, with mean variabilities of 2 mm (visual) and 4 mm (somatosensory). When manual response localization and less robust stimuli were used (Fox et a1 1985a), response variability, predictably (Mintun et a1 1989; Fig. 6 ) , was somewhat greater: 5 mm for primary motor cortex, 6 mm for primary visual cortex, 9mm for supplementary motor cortex, and 9 m m for the frontal eye fields. The studies just described reported inter-subject variability of relatively loworder brain areas. Activation responses in primary and periprimary areas tend to be quite robust, because large groups of neurons can be entrained in unison by rapidly repetitive stimuli (Fox & Raichle 1984). Higher-order areas are not so readily entrained and may demonstrate learning effects (Raichle et a1 1991). Inter-subject averaging (Fox et a1 1988a) and related strategies (Friston et a1

137

Anatomical variability of functional areas

E

-E

n v,

5

.-

+ 0

v

0 J

.l 6.

4-

I

1

2 1 2

4

I

I

6

8

10

Meon response

FIG. 6. Variability (mean inter-subject standard deviation, in mm) in the anatomical location of functional areas showed a weak negative correlation (r = - 0.14) with response magnitude (CBF, ml 1OOg-I min-I). This effect is of the order predicted by the performance characteristics of the local-maximum search algorithm (Mintun et a1 1989), and does not support the inference that areas showing more robust activations were less anatomically variable.

1991) have overcome some of the barriers to the mapping of brain areas supporting language, attention, and other complex behaviours. Inter-subject averaging, however, precludes the assessment of inter-subject variability in functional organization.

This study: strengths, limitations and new directions Expression of anatomical location and its variability in terms of proportional, three-dimensional coordinates relative to the bicommissural plane is an important feature of the present study. The strengths of this approach are several. It is fully quantitative, allowing for parametric statistical manipulation. It is a precise, unambiguous means of indicating the locations studied and their variability. It does not require the use of ancillary anatomical images (such as magnetic resonance images). For all of these reasons, it is rapidly becoming the standard anatomical nomenclature in the field of functional activation imaging. The major weakness of this approach (and of this study) is that it does not allow for comparison with the traditional nomenclature of cortical anatomythat is, sulcal boundaries. Stimulation mapping data have, for the most part, been reported with reference to surface anatomy. New techniques for the threedimensional rendering of magnetic resonance images and for the registration

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of PET and MR images are making it possible to precisely relate foci of neural activation to surface markings. This raises the question of the most appropriate ‘anatomical space’ within which to work. Although the presence and location (relative to the bicommissural space) of major sulci are rather consistent (Talairach et al 1967, Steinmetz et a1 1989), configurations of the lesser sulci show a high degree of individual variability (On0 et a1 1990). Thus, other than at the major fissures bounding the primary sensory and motor zones, surface markings are not strongly predictive of functional zones. Variations in the cortical location of specific functional areas, then, may or may not correspond to variation in the locations of surface features. If not, Cartesian coordinates form a more appropriate ‘anatomical space’ for the systematic assessment of cortical organization than do surface markings. It is also possible that yet another ‘anatomical space’ may prove more useful than either surface markings or bicommissural coordinates. For example, surface-flattened mappings have gained wide acceptance in primate neurophysiology (Van Essen 1985) and have recently been introduced for quantitative analysis of human cortex (Jouandet et a1 1989). Although still in development, the surface-flattened rendering of co-registered PET and MR images (Carman et a1 1989) undoubtedly will prove a powerful tool for future mappings of human cortical organization. Conclusions In the present study, functional zones were selected to represent a variety of levels in the hierarchy of neural process. Areas closest to the periphery included peristriate visual areas (input processing) and primary motor areas (output processing). Premotor areas, involved in movement programming, were areas at a further remove from the immediate input/output processing at the neural periphery. Prefrontal areas, involved in semantics and attention, represented a still higher-order level of neural processing. While different areas did show differences in inter-subject variability, these differences were not obviously related t o the ‘order’ of the areas (i.e. their distance from the periphery). That is, higher-order areas were no more variable than the lower-order sensory and motor areas. Functional areas lying near the midsagittal plane tended to be the least variable. This consistency of location was present in all three anatomical axes, not simply in the lateral-medial (X) axis. Note that while our subjects had no gross brain abnormalities detectable by structural imaging, they were not physiologically normal; all had medically intractable partial complex epilepsy. While chronic epilepsy might a priori have been considered likely to induce cortical reorganization, this seems not to be the case. The cortical areas engaged in this clinical population were the same as those previously described in normal volunteers. Although no similar measure of variability of functional anatomy exists for high-order areas in normal

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subjects, it is safe t o assume that it will be no greater than that observed in this patient group. Overall, then, our findings indicate that: (1) cortical organization shows good inter-subject consistency, even for high-order processes, and (2) there is no obvious negative effect on anatomical consistency of distance from t h e neural periphery.

Acknowledgements We thank Dr Marcus Raichle and Dr Michel Ter-Pogossian for providing the environment in which this work was performed. We thank Dr Sidney Goldring for referring subjects for this study.

References Carman GJ, Mora BN 1989 Noninvasive computational cartography of human visual cortex based on magnetic resonance imaging (MBI) and positron emission tomography (PET). SOCNeurosci Abstr 15:1106 Corbetta M, Miezin FM, Dobmeyer S , Shulman GL, Petersen SE 1990 Attentional modulation of neural processing of shape, color, and velocity in humans. Science (Wash) 248: 1556- 1559 Fox PT 1991 Physiological ROI definition by image-pair subtraction. J Cereb Blood Flow Metab 11:A79-A82 Fox PT, Raichle ME 1984 Stimulus rate dependence of regional cerebral blood flow in human striate cortex, demonstrated by positron emission tomography. J Neurophysiol 51:1109-1121 Fox PT, Fox JM, Raichle ME, Burde RM 1985a The role of cerebral cortex in the generation of saccadic eye movements: a positron emission tomographic study. J Neurophysiol 52:348-368 Fox PT, Perlmutter JS, Raichle ME 1985b A stereotactic method of anatomical localization for positron emission tomography. J Comput Assisted Tomogr 9: 141- 153 Fox PT, Burton H, Raichle ME 1987a Mapping human somatic sensory cortex with positron emission tomography. J Neurosurg 63:34-43 Fox PT, Miezin FM, Allman JM, Van Essen DC, Raichle ME 1987b Retinotopic organization of human visual cortex mapped with positron-emission tomography. J Neurosci 7:913-922 Fox PT, Mintun MA, Reiman EM, Raichle ME 1988 Enhanced detection of focal brain responses using intersubject averaging and change-distribution analysis of subtracted PET images. J Cereb Blood Flow Metab 85:642-653 Friston KJ, Frith CD, Liddle PF, Frackowiak RSJ 1991 Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab 11:690-699 Herscovitch P, Markham J , Raichle ME 1983 Brain blood flow measured with intravenous H,I5O. I. Theory and error analysis. J Nucl Med 14:782-789 Jouandet ML, Tramo MJ, Herron DM et a1 1989 Brainprints: computer-generated twodimensional maps of the human cerebral cortex in vivo. J Cognit Neurosci 1:88- 117 Mintun MA, Fox PT, Raichle ME 1989 A highly accurate method of localizing regions of neuronal activation in the human brain with positron-emission tomography and ISO-water. J Cereb Blood Flow Metab 9:96-103 Ojemann G, Ojemann J , Lettich E, Berger M 1989 Cortical language localization in left, dominant hemisphere. J Neurosurg 71:316-326 O’Leary DDM 1989 Do cortical areas emerge from a protocortex? Trends Neurosci 12:400-407

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Ono M, Kubik S, Abernathy CD 1990 Atlas of the cerebral sulci. Thieme, New York Petersen SE, Fox PT, Posner MI, Raichle ME, Mintun MA 1989 Positron emission tomographic studies of the processing of single words. J Cognit Neurosci 1:153-170 Petersen SE, Fox PT, Snyder AZ, Raichle ME 1990 Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science (Wash DC) 249:1041-1044 Posner MI, Petersen SE, Fox PT, Raichle ME 1988 Localization of cognitive functions in the human brain. Science (Wash DC) 240:1627-1631 Raichle ME, Martin WRW, Herscovitch P, Mintun MA, Markham J 1983 Brain blood flow measured with intravenous H2ISO.11. Implementation and validation. J Nucl Med 24:790-798 Raichle ME, Fiez J , Videen TO, Fox PT, Pardo JV, Petersen SE 1991 Practice-related changes in human brain functional anatomy. SOCNeurosci Abstr, in press Steinmetz H , Furst G, Freund H-J 1989 Cerebral cortical localization: application and validation of the proportion grid system in MR imaging. J Comput Assisted Tomogr 13: 10- 19

Talairach J, Szikla G , Tournoux P et a1 1967 Atlas d’anatomie stCrCotaxique du tklenckphale. Masson, Paris Van Essen DC 1985 Functional organization of primate visual cortex. In: Peters A, Jones EG (eds) Cerebral cortex, vol 3: Visual cortex. Plenum, New York, p 259-329 Wada J, Rasmussen T 1960 lntracarotid injection of sodium amytal for the lateralization of cerebral speech dominance. J Neurosurg 17:266-282 Yarnarnoto M, Ficke D, Ter-Pogossian MM 1982 Performance study of PETT V I , a positron computed tomograph with 288 cesium fluoride detectors. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 29529-533

DISCUSSION

Mazziofta: When one looks at patients with complex partial epilepsy, one in three o r one in four have some structural change, usually in terms of the size of the temporal lobe o r horn on the side where the epileptic focus is ultimately proved t o be. Is that an issue here, in terms of structural distortions that wouldn’t fit appropriately into Talairach space? Fox: The patients who entered into this study were fairly heavily selected. There were n o other indications (such as focal atrophy) that could have guided surgical resection. P E T was not being used as frequently as it has been in the UCLA experience, where it is a n integral part of the evaluation of all epileptic subjects. Rather, medically intractable subjects in whom the seizure focus couldn’t be lateralized electrically, or by magnetic resonance imaging, or lateralized by associated motor o r sensory seizures, underwent PET. So we had a n anatomically very normal group of epileptic subjects. We could not detect anatomical distortions o r atrophy in a n y o f them. Frith: In your ‘Generate verbs’ task, did the subjects know in advance what words they were going t o get? Fox: No; it was a different word on every trial, a n d we used different word lists on successive trials.

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Frith: And presumably there are many possible answers that one can give, so it’s not just a semantic component, but also some sort of free generation component, which may be relevant-as we shall see! (Frith 1991: this volume). Fox: This has been explored a fair amount. The left frontal areas are active during semantic monitoring experiments, whereas the cingulate is not (Petersen et a1 1990). But the cingulate is active during non-linguistic decision tasks (Pardo et a1 1990, Corbetta et a1 1990) and the left frontal is not. We have made some progress in identifying the cognitive processes of the different areas. Friston: Do you now feel that the stereotactic reference system is best, or can one improve on localization with reference t o principal gyral features? You have presented a convincing demonstration that the Talairach coordinates are probably good enough for most of us. Have you had a chance to assess any reduction in the scatter of landmarks when you refer, not to the intercommissural line, but to some cortical reference such as the central sulcus? Fox: No. Clearly the next step is to identify sulcal and gyral anatomy and assess which anatomical system is most consistent. One reason for choosing this data set to work with was that it contained activations in areas of both major sulci and in areas of high sulcal variability. The central sulcus is one of the most consistent sulci, while the operculum is varied in its sulcal patterns. Yet we see very comparable stereotactic coordinates in both MI and Broca’s responses. My conclusion is that variability of the gyral pattern does not predict variability in the functional location. Primary sensory and motor processes are typically localized on the banks of a major sulcus; higher-order processes tend not to be bound to such deep markings. This does not imply that they are more variable in location. Think of a partially deflated beach ball with a pattern on it. The ball can be indented in any number of ways, yet the surface pattern stays more or less the same in a three-dimensional space. Similarly, the distributions of functions on the cortex may be more constant than the sulcations. That is something that needs to be pursued: exactly what are these dimples and ripples in the cortex good for? Are they the best markers of functional location? Friston: Could you pursue the beach ball analogy by completely ignoring any reference to structural anatomy and using only functional anatomy? For example, could you transform your positional information with reference to the centroids of functional activation in the primary sensorimotor cortices? If you could demonstrate a significant reduction in positional variance of your secondary and tertiary functional foci, but using functional landmarks as opposed to structural landmarks, you would have demonstrated that functional anatomy has primacy in terms of brain organization, over and above structural anatomy. Fox: A good challenge! Porter: This depends on the definition of structure. You may talk about structure in terms of the folding of a surface and the relationship of a zone

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Discussion

of interest to that fold. 1 think the definition that is relevant for function is a connectionist one, in which the particular connected cells of a region, which make up the structure of interest, may not reside in a constant fold. Jeannerod: Dr Fox, your superior frontal area seems to correspond to the area in man shown to be involved in the sequencing of motor actions. Could activation in this area be related to the sequential aspects of speech during the production of words? Fox: If a subject is reading aloud from a word list, we don’t ‘see’ that area, so 1 couldn’t accept the hypothesis that this area might be involved simply in motor programming. The frontal ‘semantic’ areas are very near to areas in which one can invoke a response with other motor tasks. For example, this area is active during movement preparation, or imagining a movement; but not during silent word reading. I think that agrees with Professor Roland’s experience as well? Roland: Yes, I agree with that. Baron: How you interpret your findings in terms of individual subjects is unclear to me. Thus, when you use your method in single subjects and you list the presence or absence of focal activation, does this mean that when activation is absent, the method is not adequate for finding the activated area, or is it that the individual subject did not use that area to perform the task? Fox: That’s a hard one! There are certainly cortical areas, like the inferior prefrontal area, with low response magnitude. In areas of weak response, our detection frequency was lower. This would suggest that when a response was judged absent, it might have been weakly present, but not above background noise. On the other hand, some responses, like right MI, could be absent even in the presence of a very robust left MI response. There are major differences between subjects in response patterns, not so much in location, but in presence or absence. One area may be robustly activated on one side and completely missing on the other. I think it’s not simply that we are always working near the threshold of the method. There is something scientifically worthwhile involved in those variations in the magnitude. Baron: Is the inter-subject variability that you observe related in some way to the sampling of your PET camera, which has undetected gaps between the detector rings? Fox: No. As we move off centre, we lose some response magnitude, but we did not leave areas unsampled. Zeki: I would like to understand exactly what you mean by this problem of the gyri and the sulci. I could give you examples of areas in the prestriate visual cortex where the areas lie inside the suIcus, or spill over into a gyrus, or where the boundary between areas is on the crown of the gyrus. I don’t think there is any correlation between the gyri and the boundaries of visual areas.

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Fox: Yet for certain areas, it’s clear that there is; if you wanted to find area 3, you would look at the posterior bank of the central sulcus. Zeki: Yes. But as a general rule of cortical organization the sulci are there to increase the surface area of the brain, and the boundaries can fall anywhere. Fox: Would you care t o speculate as t o why, in the primary sulci, in primary somatosensory, primary motor, in primary visual or primary auditory cortex, the gyral anatomy and the microanatomy are very closely bound to one another, but in other areas they are not? Zeki: I would have thought that in V2 they are very closely bound too. Fox: Why is it so closely bound sometimes and not other times? Why is it closely bound at all? Zeki: I don’t see it as a problem. Plum: Dr Fox, what is the test reproducibility within the individual, as compared to between individuals? In other words, are we talking about an area of cortex which shows several degrees of metabolic freedom in achieving its function? Fox: It is hard to do the same test repeatedly in one subject for the higherorder areas, because you can’t detect these responses well on a single trial; therefore one must average either between subjects or within subjects. The answer isn’t yet to be had, unfortunately. For areas of greater response magnitude, we’ve shown test-retest reproducibility of one pixel (2-3 mm) (Fox et a1 1987). Plum: In areas MI or SI, I would predict that one would find consistency. My question had to do with whether, during transactions involving the association areas, one observed a variety of strategies for generating a response, or whether any given task required similar changes in brain metabolism, independently of how the mind or any particular groups of muscles carried it out. Fox: If the subject did the task differently on each trial, we would get no benefit from averaging. Porter: Dr Fox, your subjects ranged in age from 11 to 56 years. Have observations been made on younger subjects which would give us some indication about the development, during childhood, of language processing, and of language information, that would illuminate the meaningfulness of the various areas which you see to be activated during the utilization of language? Mazziotta: Dr Harry Chugani at UCLA has looked at a spectrum of ages and I could present some results from that (see p212). Porter: This would be very useful, because we are reaching the mid-point of the meeting, and it would be important to find areas where there could be some agreement about the future activities which might be pursued using these methods.

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References Corbetta M, Miezin FM, Dobmeyer S, Shulman GL, Petersen SE 1990 Attentional modulation of neural processing of shape, color, and velocity in humans. Science (Wash DC) 248~1556-1559 Fox PT, Burton H, Raichle ME 1987 Mapping human somatic sensory cortex with positron emission tomography. J Neurosurg 63:34-43 Frith CD 1991 Positron emission tomography studies of frontal lobe function: relevance to psychiatric disease. In: Exploring brain function with positron tomography. Wiley, Chichester (Ciba Found Symp 163) p 181-197 Pardo JV, Pardo PJ, Janer KW, Raichle ME 1990 The anterior cingulate cortex mediates processing selection in the Stroop attentional conflict paradigm. Proc Natl Acad Sci USA 87:256-259

Petersen SE, Fox PT, Snyder AZ, Raichle ME 1990 Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science (Wash DC) 249: 1041- 1044

A thought experiment with positron emission tomography S. Zeki Department of Anatomy, University College, Gower Street, London WClE SBT, UK

Abstract. This paper describes a thought experiment. The experiment supposes that the technique of positron emission tomography (PET), as we know it today, was available in 1920 and had been applied then to a study of the visual cortex of man. The ‘results’ of the experiment show that such an approach would have generated new concepts about the functioning of the visual cortex, and that PET can therefore be considered to be an hypothesis-generating technique. 1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 145-164

Is positron emission tomography (PET)an hypothesis-led or an hypothesisgenerating technique? This was the question that was raised earlier in the symposium. It is an interesting one, which I thought I might address today. The paper that I shall give will therefore be different from the one that I had intended. I want to use my time instead to perform a ‘thought experiment’ about PET before you. There is nothing wrong with this. Physicists and mathematicians do it all the time and usually make quite a good living out of it, or at least a far better one than experimental neurobiologists. If PET technology had been available in 1920 The experiment that I have in mind is as follows. Let us suppose that, as a technique, PET was available in 1920and let us ask whether it would have given us any new hypotheses about the organization of the visual cortex. 1920 is a good date to take. It represents, roughly, a halfway point between the beginnings of the scientific study of neurology and the emergence of modern concepts of the organization of the cerebral visual cortex. It is a time when concepts of the organization of the visual cortex had been sorted out, or so neurologists of the day imagined, after many years of infighting, particularly between Henschen and von Monakow, those two implacable enemies. And it is close enough to the time when scientists were beginning to think of using regional cerebral blood flow as an index of cortical activity and had indeed performed some experiments using this approach. 145

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As a scientific discipline, neurology began in earnest on the afternoon of 18 April 1861, when Broca declared to the Socittt d’Anthropologie in Paris that the integrity of the third left frontal convolution was necessary for the production of articulate speech. This discovery ushered in the concept of the cortical localization of function, much strengthened in 1870 when Fritsch and Hitzig localized movement to another, architecturally distinct, part of the cerebral cortex. Not many years after Broca’s discoveries, it became obvious that vision was another function that has a special seat in the cerebral cortex and by the turn of the century this seat had been localized to the striate cortex, at least by Henschen. Just over a century later, the 1970s saw a major revision of the concept of visual representation in the cortex which the early clinical neurologists had bequeathed to us (see Zeki 1990 and 1991 for reviews). First came the demonstration, in both the macaque and the owl monkey, of the presence of multiple visualareas in the cortex outside the striate area (area V1) (Zeki 1969, 1971, Allman & Kaas 1971a.b). These studies suggested that vision is a much more complex process than the early neurologists had imagined it t o be. Next came the demonstration, from the macaque monkey alone, of a functional specializafionamong the visual areas of the prestriate (Zeki 1974a, 1978a). The foundation stone of the concept of functional specialization in the visual cortex lay in the demonstration that one of the visual areas, area V5, is specialized for visual motion while another, V4, is specialized for colour and form in association with colour, and a third, V3 (and probably the contiguous V3A) for form (Zeki 1973, 1974b, 1978b). It would naturally be naive to suppose that these are the only functions of these areas, or their only specializations. But the properties of the cells in each are sufficiently different from those in the others to make it virtually certain that they undertake different tasks, not the same task at an ever-increasing level of complexity, as had been supposed by Hubel & Wiesel (1965) from their work in the cat. The demonstration of functional specialization was made hand in hand with the demonstration (again based on studies in the macaque monkey alone) that the striate cortex sends parallel and independent outputs to these specialized visual areas, thus ushering in the notion of parallelism into the organization of the cerebral cortex in general and the visual cortex in particular (Zeki 1975). In brief, by the 1970s the principle of localization had been extended very substantially as far as vision is concerned and we began to realize that the cortical processes involved in vision are substantially more complicated and sophisticated than early neurologists had believed. In particular, we began to understand that, far from being the ‘visual perceptive centre’ (Holmes 1945), the striate cortex was only the initial stage in an elaborate cortical apparatus which deals with vision. The recent demonstration of parallel outputs from the striate cortex and of a specialization for colour and motion in human visual cortex (Zeki et al 1991) might therefore seem to be nothing more than a confirmation that, in man too, the visual cortex is organized along similar principles. This might tempt one

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to ask what new concepts PET, as a technique, is introducing. The purpose of my ‘thought experiment’ is t o convince you that the new concept that we have of the organization of the visual cortex could have come from PET studies, rather than from anatomical and physiological studies. From which it follows that PET is now poised to provide us with important insights on the organization of uncharted cortical areas and in domains such as thought and language which are not accessible to experimental study in animals. There are other good reasons for choosing the year 1920. Even though a Gedunken experiment does not have to be constrained by such vulgarities as techniques and instrumentation, it nevertheless should be technically plausible (although the clever physicists dispense even with this requirement). And 1920 was only a few years before experiments identical in principle to the PET experiments were performed. In 1927, Cobb and Talbot had undertaken a tedious study to determine the relative extents of the capillary bed in animals exposed to olfactory stimuli. They had found that the bed was much richer in stimulated animals than in normal controls. Moreover, the effects were confined to the olfactory cortex. Soon thereafter, Fulton (1928) had studied changes in the vascularization of the occipital cortex by noting the conditions in which an increase in the vascular bruit occurred in a patient with a defect over that region. He had found that the bruit increased whenever the patient attempted to read. Olfactory and auditory stimuli did not increase the bruit and, most interestingly, the presence of light per se did not increase it either. The latter finding, had it been taken seriously by visual physiologists, might have made them think a little more carefully about using diffuse light when trying to stimulate cells of the visual cortex, as Jung was to do later when studying the physiology of the visual cortex in the cat. Conceptually, these were the precursors of the modern PET experiments, although the technology has of course changed beyond all recognition. Another good reason for choosing 1920 is that Karl Lashley had started by then to create an atmosphere that was distinctly hostile to the concept of localization. He was to become especially hostile to the notion that the ‘visual association’ cortex could be subdivided, either on cytoarchitectonic or on any other criteria, considering it to constitute instead a single ‘functional unit’ together with the parietal cortex (Lashley & Clark 1946), though he was careful not to define what this ‘functional unit’ might be. Many years later, Lashley (1948) was to join others before him and deny specifically the possibility of a localization for colour vision in the human brain, a topic of some interest for our thought experiment. He was not the first to deny this. Other scientists of equal eminence had done much the same. Concepts of the visual cortex in 1920

There is, finally, one other important reason for choosing 1920, indeed the very reason for conducting this thought experiment at all. If PET had been available

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at that time, could it have changed the then prevalent concepts of how the visual cortex is organized and could it have introduced new concepts? By the 1920s a consensus had emerged among neurologists who had speculated about the organization of the visual cortex. They had supposed that the striate cortex (area V1)-which Holmes (1945) was to describe as a ‘merely perceptive’ centre-was the sole cortical area responsible for ‘seeing’, while the cortex surrounding it was vaguely considered to be the visual ‘association’ cortex. What the precise function of this ‘association’ cortex might be, no one knew. Or, if they did, they were very careful not to reveal it to others. In his summary, Monbrun (1939) had stated that ‘A I’heure actuelle tous les auteurs sont rallies a la theorie du centre [visuel] corticale unique’. Through his anatomicopathological studies, Henschen had worked out in great and correct detail the connections between retina and striate cortex and had shown the former to be mapped on the latter in a very precise manner, leading him to think of the striate cortex as the ‘cortical retina’, a formulation which the disciples of von Monakow had described as ‘une localisation ri outrance’ (Vialet 1894). This cortical retina had to ‘receive’ all the visual ‘impressions’ formed on the retina. Henschen was especially insistent that ‘the cortical retina is also a retina for colour impressions’ (Henschen 1894), thus dismissing the views of others like Verrey (1888), who had proposed that there is a colour centre outside the striate cortex, though they had imagined that this was part of the primary visual receptive cortex-in other words, that the latter was not co-extensive with the striate cortex. The only element of the organization which Henschen had got wrong was the representation of the macula, considering it to be localized anteriorly in the calcarine sulcus whereas it is actually located posteriorly in the occipital pole. Von Monakow had a powerful aversion to the views of Henschen. The ‘famous brain scientist’, as Henschen (1930) was to call him, had decided that not much was known about the visual cortex ‘in spite of the work of Henschen’ (von Monakow 1911). He objected strongly to Henschen’s conclusion that the primary visual cortex, the ‘cortical retina’, was co-extensive with the striate cortex. He had developed a somewhat inflated theory of a mobile retinal centre, based on what he imagined to be the great equipotentiality of the cortex, a view which Henschen thought was ‘disastrous for the development of the theory of visual function’ (Henschen 1930), though one of which Lashley (1948) strongly approved because it corresponded rather closely with his own similar views about the equipotentiality of cortical areas in the execution of complex tasks. Von Monakow’s theory supposed that the primary visual cortex was widely represented throughout the occipital lobe, and included the cuneus and the fusiform and lingual gyri. This was particularly so for the representation of the macula (or central vision) and would account, he believed, for the phenomenon of macular sparing, in which central vision is spared following an hemianopia produced by a cortical lesion. But, like Henschen, he was strongly opposed to the idea of a separate colour centre in the fusiform gyrus.

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Acceptance of so specific a centre, of such a high degree of localization, would after all have compromised his theory of a mobile macular centre, particularly since colour vision is more than anything else macular vision. He therefore joined forces with Henschen in dismissing the notion of a colour centre in the occipital lobe. Not much had been left of von Monakow’s theory by 1920, with most scientists adhering to Henschen’s views and with Monbrun (1939) writing mockingly that ‘Cetteconception de la ‘projectionfke”de la rktinesur I’kcorce ckrkbrale . . . ci ktk longtemps combattue . . . et surtout par von Monakow’, but ‘Les reform& de guerre avec hemianopsiespartielles n ’ont pas encore vu reparaitre la restitution si chbre a Monakow’. But von Monakow was still alive in 1920 and would no doubt have been keenly interested in the results of PET experiments on the visual system, especially if they shed some doubts on the ideas of Henschen, who was also alive then. Among the most eminent neurologists concerned with the visual cortex had been Gordon Holmes, a man still greatly revered and admired today. He was a man ‘. . . with strong likes and dislikes and no pretence of diplomacy and compromise’ (Duke-Elder 1970). One of the ideas which he much disliked and showed little inclination to compromise with, just like Henschen and von Monakow, was the idea of a separate representation of different visual functions in the cerebral cortex. He had successfully dismissed the somewhat feeble evidence of Riddoch (1917) which had led the latter to the notion that there might be a separate representation of visual motion in the striate cortex, arguing that ‘. . . the condition described by Riddoch should not be spoken of as a dissociation of the elements of visual sensation’, since ‘. . . occipital lesions do not produce true dissociations of function with intact retinal sensibility’ (Holmes 1918) (see Zeki 1991 for a review). Together with Henschen, von Monakow and others, he had also dismissed the notion that there might be a separate visual area, outside the striate cortex, specialized for colour, writing that ‘My observations . . . tend to show that an isolated loss or dissociation of colour vision is not produced by cerebral lesions’ (Holmes 1918). By 1945, he had gained more confidence. He wrote that ‘there is no evidence that [ colour vision] is subserved by any other area [besides the striate cortex] ’ (Holmes 1945). Finally, no one had taken the slightest notice of Poppelreuter’s (1923) speculations, based on altogether indifferent evidence, that there might be a separate representation of the different attributes of vision within the striate cortex. Why was it possible to dismiss the notion that there is a submodality segregation within the visual cortex? The answer is not straightforward. It can be ascribed in part to the fact that the evidence was either weak or incomplete. But it was almost certainly due as well to the fact that accepting such evidence would have meant overturning deeply held beliefs about the organization of the visual cortex in particular and the functions of the cerebral cortex in general (see Zeki 1990). It is in this latter context that we shall perform the thought experiment.

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The localization of the colour and motion centres with PET I shall begin by supposing that the experiment that I have performed in collaboration with Richard Frackowiak and his colleagues at the Hammersmith Hospital (Zeki et a1 1991) had been performed by us in 1920. The first experiment can be considered to have been one designed to reveal the cortical areas that are active when subjects view a coloured display. The display that we chose was a Land colour Mondrian (a collage of different coloured matt papers of arbitrary shape, forming an abstract scene with no recognizable objects and bearing a certain resemblance to the paintings of Piet Mondrian). We compared the regional cerebral blood flow (rCBF) in the brains of subjects when they had viewed such displays and when they had viewed an identical pattern, though this time composed of equiluminous shades of grey. The comparison revealed that area V1, and the adjoining area V2 (which it is difficult to separate from in the low resolution scans), are equally active in both conditions. In the cortex outside areas V1 and V2, however, comparison of the scans showed that it was in the territory of the lingual and fusiform gyri that the most significant change in rCBF had occurred when subjects had viewed the coloured Mondrian. No other part of the cortex surrounding V1/V2 reached significance. (The activity was in fact slightly higher in the fusiform gyrus. For reasons discussed elsewhere [ Zeki et a1 19911, we consider that the colour centre [human area V4] is in the fusiform gyrus and that the active zone in the lingual gyrus corresponds to human V2.) At first, such an experiment might lead us to conclude that Verrey (1888) and MacKay & Dunlop (1899) had been right when, some several decades before, they had considered that there is, within the territory of the lingual and fusiform gyri, a ‘centre for the chromatic sense’ (Verrey 1888). But perhaps a more careful examination would have convinced us that this was an unjustified conclusion. We could equally well have demonstrated that visual impulses are funnelled to this part of the association cortex surrounding the striate area, regardless of what attribute of vision they represent. This certainly would have been the conclusion that von Monakow would have liked to reach. Our demonstration would have greatly pleased him, therefore, and would probably have irritated Henschen in equal measure. Since the spatial resolution of PET is relatively low and since we cannot therefore distinguish area V1 from area V2, von Monakow would probably have been delighted that the limits of the primary visual cortex, as he would have interpreted it, were much greater than what Henschen had proposed. His obvious delight at the discomfiture of Henschen would have been abated somewhat if we had drawn his attention to the PET study of Fox et a1 (1986), which has shown that the primary visual cortex is co-extensive with the striate cortex and that there is a point-to-point retinal map in it. Henschen would probably have been especially irritated (and von Monakow delighted in equal measure) by the PET demonstration of Fox et a1 (1986) that

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the macula is represented posteriorly in the occipital pole and the periphery anteriorly in the calcarine sulcus. But von Monakow would have had to account for why it is that the activity outside the striate cortex is restricted to the lingual and fusiform gyri only, the very area which had already been implicated in cases of achromatopsia by Verrey and by MacKay and Dunlop, and did not include the entire occipital lobe, in all of which he believed the macula to be represented, at least potentially. And Henschen, like von Monakow, would have had to reconsider his contemptuous dismissal of the syndrome of achromatopsia as resulting from a lesion outside the striate cortex (he had written that if achromatopsia could result from a lesion outside the striate cortex, then a patient with an intact fusiform and lingual gyrus but with a damaged striate cortex ‘would have to be absolutely blind and yet be able to see colours, which makes no sense’ [Henschen 19101 ). In the context of the time, we might also have concluded that the cortical processes involved in vision were essentially hierarchical, with one visual centre ‘analysing’ all the elements of the visual scene and feeding those signals to the next area in the hierarchy, though we would have restricted the area to the fusiform and lingual gyrus. This latter area would undertake the same task but at a more complex level. Indeed, we might even have supposed that this was an associational level, since the area involved is in territory which was regarded as ‘associational’ at the time (i.e. in 1920). At the very least, we would have been led to the conclusion that not the entire visual ‘association’ cortex was active during this visual task, a conclusion that might have led us to question whether the visual association cortex was a single cortical area, as neurologists of the time had supposed. To determine that this cortical zone was not merely visual association cortex, but a specialized visual area, we would naturally have had to perform another experiment, one in which colour is replaced as the critical attribute by another visual submodality, say motion. This is precisely what we did. When subjects were asked to view a stationary pattern made of small blackand-white squares, and view the identical pattern when it was moving coherently in different directions, the change in rCBF was in some respects similar to the one that we observed with the colour experiment, and in others different from it. Both the similarity and the difference are highly significant. The similarity lies in the fact that in this experiment, just as in the first one, areas V1 and V2 were similarly active in both conditions. By contrast, comparison of the ‘stationary’ and the ‘moving’ scans revealed that the only region of significant rCBF change in the cortex outside V1/V2 had occurred when subjects had been viewing the moving pattern. Moreover, the region of maximum change was geographically quite distinct from the region showing the maximal change during colour stimulation, Today we refer to it as human area V5.

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Conclusions from the experiments with PET

With these two experiments, we would have been justified in reaching the following conclusions: 1 . That the cortex outside the striate area is visual in function. 2. That this cortex is not made of one single area, as its uniform cytoarchitecture had implied to so many, but that it must consist of at least two areas, and probably more (since only a small portion of what was regarded as visual association cortex was activated in both studies combined). This would have led us to the further conclusion that cytoarchitectural uniformity may not be a good guide to functional uniformity, thus giving Lashley something further to think about. 3. That the two visual areas outside the striate cortex must be specialized to deal with different attributes of vision, one area (VS)being concerned with motion, and the other (V4) with colour, and that there must, therefore, be a functional specialization in the visual cortex of man. We would no doubt have added, as indeed we did on numerous occasions, that it would be naive to suppose that these are the only functions of these two areas, but only that these are among their chief functions (see, for example, Zeki 1978a,b and Zeki et a1 1991). Without doubt the latter statements would have made not the slightest impression on those who, without reading our papers in detail, would nevertheless have insisted that we had assumed that each area has a single function only, in order to be the better placed to attack us. 4. That because the striate cortex is active in all conditions, it must feed the specialized areas. We could have also surmised that there must be parallel connections from the striate cortex to these areas, and that the striate cortex must act as a segregator, parcelling out different signals to different prestriate areas for further, and independent, processing.

Powerful new concepts would have been introduced, displacing the earlier simplistic ones. Holmes would have been less, not more, confident and assertive in 1945 than he had been in 1918; Lashley and others may have found it more difficult to dismiss the notion of specialization in the visual ‘association’ cortex, and the evidence for a colour centre outside the striate cortex would have been re-instated, instead of ‘vanishing’ from the clinical literature (Damasio 1985). Much more significantly, the evidence obtained using PET would have led to important new questions. Why are colour and visual motion separately mapped in the cortex? Why are they represented both in the striate cortex and in cortex outside? Can the representation of these two attributes in the striate cortex itself be separate? It might even have led to a more careful study of the pronouncements of scientists like Helmholtz who had stated that ‘colour vision is not due to an act of sensation but to an act of judgement’. From that it would have been but one step to asking the fundamental question of whether colour

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is a primary visual ‘impression’ to be passively received by the cortex, or whether the cortex has to undertake some considerable amount of work to assign constant colours to surfaces. It would, in brief, have helped immeasurably in the development of new concepts of how the visual image is constructed by the brain. As it happened, it was anatomical and physiological studies that were to introduce these new concepts and usher in the new questions which preoccupy us today. But the thought experiment convinces me that PET may generate important new hypotheses and questions about the visual cortex in particular and, more generally, about the cerebral cortex at large.

Ackno wledgernent 1 am grateful to the Wellcome Trust for supporting my work.

References Allman JM, Kaas J H 1971a A representation of the visual field in the caudal third of the middle temporal gyrus of the owl monkey (Aotus trivirgatus). Brain Res 35:85-105 Allman JM, Kaas JH 1971b Representation of the visual field in striate and adjoining cortex of the owl monkey (Aotus trivirgatus). Brain Res 35:90-106 Broca P P 1861 Perte de la parole, ramollisement chronique et destruction partielle du lobe antkrieure gauche du cerveau. Bull SOCd’Anthropol (Paris) 2:235-238 Cobb S, Talbot JH 1927 Studies in cerebral capillaries. 11. A quantitative study of cerebral capillaries. Trans Assoc Am Physicians 45:255-262 Damasio A 1985 Disorders of complex visual processing: agnosias, achromatopsia, Baht’s syndrome, and related difficulties of orientation and construction. In: Mesulam MM (ed) Principles of behavioral neurology. Davis, Philadelphia, p 259-288 Duke-Elder S 1970 System of ophthalmology, vol 12. Churchill, London Fritsch G, Hitzig E 1870 Uber die electrische Erregbakeit des Grosshirns. Arch Anat Physiol Wissenchaft Med 37:300-332 Fox PT, Miezin FM, Allman JM, Van Essen DC, Raichle ME 1987 Retinotopic organization of human visual cortex mapped with positron-emission tomography. J Neurosci 7:913-922 Fulton J F 1928 Observations upon the vascularity of the human occipital lobe during visual activity. Brain 51:310-320 Henschen SE 1894 Sur les centres optiques ckrtbraux. Rev Gen Ophtalmol 13:337-352 Henschen SE 1910 Zentrale Sehstorungen. In: Lewandowsky M (ed) Handbuch der Neurologie. Springer, Berlin, vol 2:891-918 Henschen SE 1930 Pathologie des Gehirns, vol 8. Stockholm [privately published] Holmes G 1918 Disturbances of vision by cerebral lesions. Br J Ophthalmol2:353-384 Holmes G 1945 The Ferrier Lecture: The organisation of the visual cortex in man. Proc R SOCLond B Biol Sci 132:348-361 Hubel DH, Wiesel TN 1965 Receptive fields and functional architecture in two nonstriate visual areas (18 and 19) of the cat. J Neurophysiol 28:229-289 Lashley KS 1948 The mechanism of vision. XVIII. Effects of destroying the visual ‘associative areas’ of the monkey. Genet Psycho1 Monogr 37: 107-166 Lashley KS, Clark G 1946 The cytoarchitecture of the cerebral cortex of Afeles:a critical examination of architectonic studies. J Comp Neurol 85:223-305

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MacKay, G ,Dunlop JC 1899 The cerebral lesions in a case of complete acquired colourblindness. Scott Med Surg J 5503-512 Monbrun A 1939 Les affections des voies optiques ritrochiasmatiques et de I’icorce visuelle. Trait6 d’Ophtalmologie (SociCte Franqaise d’Ophtalmologie) Masson, Paris, p 903-905 Poppelreuter W 1923 Zur Psychologie und Pathologie der optischen Wahrnehmung. Z Gesamte Neurol Psychiatr 83:26-152 Riddoch G 1917 Dissociation of visual perceptions due to occipital lesions, with especial reference to appreciation of movement. Brain 40: 15-57 Verrey [ L] 1888 Himiachromatopsie droite absolue. Arch Ophtalmol (Paris) 8:289-301 Vialet M 1894 Considerations sur le centre visual cortical a propos de deux nouveaux cas d’hkmianopsie corticale suivis d’autopsie. Arch Ophtalmol (Paris) 14:422-426 von Monakow C 1911 Lokalisation der Hirnfunktionen. J Psycho1 Neurol 17:185-200 (Translated by G von Bonin (1960) in Some papers on the cerebral cortex. Springfield, IL) Zeki SM 1969 Representation of central visual fields in prestriate cortex of monkey. Brain Res 14:271-291 Zeki SM 1971 Cortical projections from two prestriate areas in the monkey. Brain Res 34: 19-35 Zeki SM 1973 Colour coding in rhesus monkey prestriate cortex. Brain Res 53:422-427 Zeki SM 1974a The mosaic organization of the visual cortex in the monkey. In: Bellairs R, Gray EG (eds) Essays on the nervous system: a festschrift for Professor J. Z. Young. Clarendon Press, Oxford, p 327-343 Zeki SM 1974b Functional organization of a visual area in the posterior bank of the superior temporal sulcus of the rhesus monkey. J Physiol (Lond) 236:549-573 Zeki SM 1975 The functional organization of projections from striate to prestriate visual cortex in the rhesus monkey. Cold Spring Harbor Symp Quant Biol 40:591-600 Zeki SM 1978a Functional specialization in the visual cortex of the rhesus monkey. Nature (Lond) 274:423-428 Zeki SM 1978b The third visual complex of rhesus monkey prestriate cortex. J Physiol (Lond) 277:245-272 Zeki S 1990 A century of cerebral achromatopsia. Brain 113:1721-1777 Zeki S 1991 Cerebral akinetopsia (visual motion blindness). Brain I14:811-824 Zeki S, Watson JDG, Lueck CJ, Friston KJ. Kennard C. Frackowiak RSJ 1991 A direct demonstration of functional specialization in human visual cortex. J Neurosci 1 1 :641-649

DISCUSSION

Corbettu: You observed two cortical areas in your experiment, one for looking at colour stimuli and one f o r looking at motion stimuli. In monkeys, multiple areas process each attribute, and it is very likely that the human visual system is organized in the same way. I wonder whether you might have been able t o detect more regions by showing the same stimuli but asking subjects to make colour or motion discriminations on those stimuli. Zeki: We were guided in PET experiments by the results of physiology, and these results show that you can activate a cell of V5 very specifically with the kind of stimuli that we use. It turns out that V5 is surrounded by satellite

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areas, as is V4 and all other areas of the prestriate cortex. And the satellite areas of V5, such as V5A, have more complicated properties than V5 and are more involved with attentional problems, with problems of the direction of gaze, and so on. If one were to modify the paradigm respecting the physiological evidence, one would find that one is recruiting more and more of the areas. We have been guided by the simplest and most effective type of stimulus that drives the cells in this area. Lassen: There is no task? The subject should not react to the stimulus? Zeki: No, he is just looking. If you do have an attentional task, or if you combine the stimulus with a motor task, I agree that you will activate more and more areas. Porter: What instructions were given to your subjects? Zeki: Their instructions were to open their eyes and fixate a cross in the centre of the screen. Jeannerod: Concerning the connections between V1 and other areas like V4, you mentioned that the distribution of the fibres occurs after the main cortical retina which you locate in V1. From there, fibres are distributed to V4, V5, and so on. How would you then explain the observations made by Stoerig & Cowey (1989) in patients with posterior lesions including V l ? These patients are hemianopic, in the sense that they report no visual experience from the part of the visual field corresponding to the lesion. Yet, by the use of the forcedchoice paradigm, where they are forced to react to stimuli presented within their scotoma, they can be shown to detect colours. Zeki: There is evidence from monkey studies for a direct projection from the lateral geniculate nucleus to V4. It is dangerous to say that this is how it occurs in man, but if we do have such a system, it is possible that these patients can just about distinguish that the stimuli are different, without being conscious of that. This is the best interpretation I can give. There is also the problem of hemispherectomized subjects being able to distinguish motion. In that case, you might say that the colliculus is involved. I would be hesitant to say this for colour, because collicular cells in the monkey have no colour specificities. Jeannerod: We studied several hemispherectomized subjects, in whom we demonstrated blindsight (Perenin & Jeannerod 1978, 1979). As these patients had undergone a complete corticectomy, they had no V1, and no V4 either. Unfortunately, we did not test them for colour vision. Zeki: Are they still alive? It would be very interesting to do this. Jeannerod: Yes, they are still alive. Porter: Were their cerebral hemispheres removed when they were children? Jeannerod: Yes, for the treatment of intractable epilepsy. Mazziotta: In your original study, Dr Zeki, where you had eyes closed versus the black-and-white pattern, you didn’t see midbrain or thalamic centres in the PET image; but with fluorodeoxyglucose, we see those anatomical sites with

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PET. Is this an issue of the resolution with oxygen-15, or an analysis question, or a physiological one? Zeki: I think we just did not concentrate on these regions of the brain. Muzziottu: Wouldn’t that come out of that global analysis, to see collicular or geniculate sites? Fruckowiak: The geniculate areas were probably not within the field of view in every PET study. The analysis is such that you sample only those planes that have been studied in every member of the group of subjects being looked at, so I would be hesitant to talk about the colliculi at this time. Zeki: There was good activity in the lateral geniculate nucleus. Frackowiak: The geniculate certainly came up; you see that in the midsagittal sections. Jeannerod; You chose 1920 as the date for your gedanken experiment. This seems to me a questionable date, because at that time people were reacting against the exaggerations of the previous century, where there had been so much parcellation of cortical function. In the 1920s, anatomists and physiologists were exploring another topic, namely the associations between cortical areas. In that sense, they were our precursors, because we are now using this concept of networks and connections. Zeki: I think that 1920 is a perfectly good year. The concepts of the early neurologists had solidified by then in the thinking of neurologists as well as in the popular mind. After all, Holmes said nothing in his Ferrier Lecture of 1945 which he had not said earlier, in 1918. These views were not to change until the 1970s. If PET had been available in 1920, it might have hastened the process along. Fox: I am less convinced by your thought experiment that I hoped I would be! Being engaged in PET studies as my primary work, it disturbs me to think I have to go back to 1920 to be convinced that PET could add to the body of neuroscience. How do you see PET contributing to neuroscience as it stands now? You have shown us that brain areas that you and others have identified and determined the functions of, using electrophysiological techniques in nonhuman primates, also exist in man, but the functions had already been elaborated and, as you pointed out earlier, the circuitry has been elaborated in a way that PET will not reveal to us in any more detail. So I am not sure that I see, particularly at this level of research, in the visual system, where PET is adding anything. Zeki: The point I was trying to make is that one wouldn’t have to give the glory for the recent concepts about the organization of the visual cortex to the anatomists and physiologists, if these PET experiments had been available in 1920. To determine the specializations of an area, you wouldn’t need to know the details of the responses of the single cells in it, but you would be able to say that when you have a colour stimulus and a moving stimulus, then two different parts of the prestriate cortex are activated. That is a considerable

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achievement in terms of showing parallelism and separation of function in the brain. Vast parts of the cortex are still unexplored, and using the same technology you could make predictions about other parts of the cerebral cortex. The separation between 1920s and 1990s in terms of studying the cerebral cortex is not quite as great as one might want to believe. Frackowiak: I could develop that argument further and bring it into the 1990s, perhaps. Whereas one can agree with everything you said, there are also areas where the electrophysiologist may be unable t o approach certain questions experimentally. For example, you demonstrate functional specialization for two of the attributes of the visual scene. But how is all this reintegrated back into the full visual image, which is so beautifully correlated, spatially and temporally? Those things can only be looked at when you have a report from the perceiver, who is the human, and the only one able to report to you, in order to guide your experiments. Zeki: Yes; electrophysiology is not necessarily the best method to tell us anything about that; you need to look at entire areas of the cortex and at the interaction of areas, to be able to answer that question. Porter: Surely that must involve an extension beyond the sorts of observations that you have now demonstrated, to go beyond reception to perception, and to interpretation, for all the things that PET can contribute to, but where neither the anatomist nor the physiologist who works on monkeys will be able to make any comment. Frackowiak: That is taking the argument a bit far, I think. Professor Zeki tells me that when trying to investigate the precise, detailed connections between different cortical areas, to understand questions of reintegration, the electrophysiologist has a fundamental problem which relates to the difficulty of knowing which parts of the brain to sample. He has very fine temporal resolution, a very fine needle, and can pick out little clusters of cells. But he cannot be guided where to go unless there is some way of looking at the brain as an interconnected system, at the level of the interaction of larger cortical areas. By being able to look in the human at which areas interact in the performance of a higher function, we may be able to return to the non-human primate and guide electrodes into groups of cells whch are spatially separate but may have some temporal relationship in terms of firing patterns. There may be a two-way interchange here, especially in studying some of the higher-order functions that we shall be discussing later. Corbettu: May I add a further point on the importance of being able to monitor spatially separated areas at the same time in order to understand vision. Theories of visual recognition suggest that the basic visual features of an object (e.g. luminance, colour, motion) are first analysed in a spatially segregated parallel fashion, and then recombined in some higher-order object representation before memory systems are accessed. For example, the percept of a simple twodimensional object like an oriented bar can be obtained by using very different

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visual cues, such as luminance, colour, or motion. In all cases one perceives an oriented bar, but the basic information feeding that object representation can be very different and is most probably represented in different brain regions. When you do an experiment in the monkey, you can record from one or the other level, but really you need to record in both simultaneously to understand that perceptual process. A more general and theoretical point, 1 think, is the importance of conceptualizing vision (or cognition) as a set of operations (or computations) that have evolved to resolve a variety of perceptual (or cognitive) problems (Marr 1982). Our approach is to try to think of any task in terms of the underlying operations needed to solve it, and then to use PET as a way to localize these different operations in the brain (Posner et a1 1988). Porter: Professor Zeki, are we constrained by the fact that we have to look for a location at which whatever it is we are trying to understand is situated? Could we not consider the possibility, demonstrated by the connectivities which you illustrated, that beyond the first receptive point, these functions become distributed in a whole series of brain regions? Zeki: Yes, our theory of multistage integration (Zeki & Shipp 1988, Zeki 1990) takes into account the fact that all these areas are interconnected with each other, either directly or through higher areas, or through diffuse back projections from the specialized areas to the distributor areas such as V1 and V2. One would have supposed that, because of all these interconnections, all cells in every area would respond to a very wide variety of visual attributes. Yet the remarkable fact has been the demonstration of specialization. I mean to say that if you were to record from a wavelength-selective cell in V1 or V2 or V4, you would find it extremely difficult, if not impossible, to change its selective properties after many hours of recording. These are therefore very robust systems. So the critical question is to know under what conditions the operations that allow interactions come into play, and what physiological mechanism is used. Roland: You and the Hammersmith group have shown very beautifully that you can, with a rather simple paradigm, dissect out areas which have high synaptic activity during motion vision and during colour vision. However, if PET is a concept-generating tool as well, what does your finding tell you conceptually? You have found an area which processes colour to some extent; but is this the area which, when you close your eyes, will re-evoke all the coloured images stored in your brain? Or is it the area that participates if you try to re-evoke coloured images in any such operation within the brain? Or does this finding indicate that V4 is just a station of specialization before you reach a higher degree of integration, maybe in one brain area, or in multiple areas? This is where the new concepts have to be generated. So far, we have been working with a concept called the ‘functional specialization’ of pattern vision. The next step is to ask: what does the experiment tell you?

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Zeki: One step at a time! I was performing a ‘thought’ experiment to tell you that if PET had been available in 1920, it would have had a profound effect on our concepts of how the brain processes visual information and more generally on our concepts of brain function. Colour vision has been instrumental in showing subdivisions of the visual cortex. It is an epistemological problem of considerable significance: is the knowledge ‘out there’, or is it a construction of the brain? These issues could have been addressed by PET, had it been there in the 1920s. As to the next step, this is a real opportunity for PET, to be able to ask questions about the interactions of the visual input with memory, language, attentional systems, and other systems, and to develop new concepts. I don’t know what they are. Gulyris: In two series of PET experiments on the human visual cortex we investigated those cortical areas involved in the processing and analysis of different visual submodalities, including colour, form, disparity, pattern, spatial frequency, and orientation discrimination. Ten subjects participated in each experimental series. Two-alternative forced-choice discrimination tasks were used as stimulus paradigm. In the reference task of the first series, the subjects were asked to discriminate between black and white random dot patterns with equal (50-5OOro) or unequal (e.g. 40-60%) amounts of black and white dots. In the colour task the discrimination was made between coloured random dot patterns of different spatial frequencies with or without ‘red dominance’ (e.g. a 40% red, 20% green, yellow, blue pattern, versus a 25% red, green, blue, yellow pattern). In the form discrimination task they had to discriminate between a circular and a rectangular pattern made up by random noise. In the disparity task the patterns were random dot stereograms with a central figure seen either in front of or behind the fixation plan. In the pattern discrimination task the discrimination was made between random dot patterns and gratings of various spatial frequency and orientation. This task also served as reference task for the second experimental series with an orientation and a spatial frequency task. In the orientation task the subjects had to discriminate between gratings of identical spatial frequency but with different orientations, whereas in the spatial frequency task the orientation of the gratings were identical, the spatial frequencies differed. The performance levels and response latencies were controlled in the experiments. When the functional images had been standardized, with the help of Bohm and Greitz’s computerized brain atlas (CBA) (Bohm et al 1983, 1986, 1991, Seitz et al 1990, Greitz et al 1991a,b), averaged subtraction (specific task minus reference task) regional cerebral blood flow images (ArCBF; n = 10 subjects), variance images, and per pixel descriptive t maps were created in the CBA. Changes were quantified, statistically evaluated, and localized with the use of the CBA’s anatomical database. Those fields specifically activated by the different visual tasks in the visual cortex or its close neighbourhood are listed in Table 1. The anatomical terms used there follow the CBA database (Greitz 1991a).

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TABLE 1 (Gulyus) Fields activated by a range of visual tasks in the human visual cortex and neighbouring areas

Cortical area

Spatial Colour Disparity Orientation frequency Form Pattern

Occipital medial gyri Occipital lateral gyri Occipital superior gyrus

+ +

medial gyrus Occipito-temporal

+

Occipito-temporal lateral gyrus

Parahippocampal gyrus

Inferior temporal gyrus Superior temporal gyrus Precuneus Superior parietal gyrus Angular gyrus

Cingular gyrus

(posterior part)

+ + +

+

+

+ + +

+ +

+

+

+

+

+

+ +

+

+ +

+

+

Frackowiak: We have to be particularly careful about ascribing areas to functions before we are very clear about the function that we are studying. The function in the test where the frontal eye fields and also various other areas are activated might encompass several cognitive processes, rather than a single one. Gulyusis:1completely agree with you. Our conceptual hypothesis is that a ‘pure perceptual task’ is an ill-defined stimulation paradigm. Because the brain may use various and rather versatile strategies to tackle a given perceptual task, in our experiments we felt the need to engage the brain with tasks (i) that are simple and straightforward enough to involve one visual submodality, (ii) that, notwithstanding, require intensive, concerted and focused brain activity, in that way reducing the possibility of letting the brain operate simultaneously in different domains, and (iii) that have as perfect as possible stimulus and response controls. In contrast, we feel that a ‘pure perceptual task’ (e.g. asking the subjects to look at a coloured pattern and just to look at it) leaves several questions open. Do the subjects only use their brains to look at the pattern, or, at the same time, are they engaging their brains with other activities, as well-e.g. are they thinking of their wives, or sailing boats, or, say, next weekend’s television programmes? Do the subjects perceive the colours after several seconds, or do the perceived colours fade away as a result of well-known psychophysical phenomena? For these reasons, we believe that a well-defined discrimination task may reveal more about task-specific areas in the brain than a ‘pure’ perceptual paradigm. Frackowiak: From Professor Zeki’s paper, it is clear that we have the ability to be more analytical than purely descriptive, but in order to do that we must

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describe precisely what we are doing when we get a result, and what that result pertains to. Cu&ds.- I agree. We cannot fully exclude the possibility that there are other mental operations, independent of the given task, during a visual discrimination task which are not present during a simple ‘pure’ perceptual task, or vice versa. Nevertheless, we think that a discrimination task includes less mental activity not pertinent to the given task, than does a less-well defined perceptual paradigm. Zeki: How do you know that they are not present? I may be thinking about my work when I am looking at a moving stimulus. Roland: There may be a point of clarification needed here. Two-alternative forced-choice tasks were used; this is a very rigid paradigm. The stimuli were presented quickly (800 ms interval), so the subject would have little chance to think about anything else. The control tasks were the discrimination of randomnoise dot patterns, for tasks involving form, disparity and the colour; this was one set of studies where all subjects went through all four discriminations with that control. It was all the same paradigm; the only thing that was varied was either the form, the disparity, or the colour. Zeki: It seems to me you have set up a false situation in which you are attacking what you call ‘pure perception’ and setting up another kind of paradigm, which is a perfectly legitimate thing to do, but you are making assumptions about it which you don’t know. I don’t know what you mean by ‘pure perceptions’. Gulyas: As for our experiments, we are not talking of ‘pure perception’; we clearly talk about a well-defined discrimination task. In contrast, we believe that in your experiments (Lueck et a1 1989, Zeki et a1 1991) you used a ‘pure perceptual’ paradigm, for you asked your subjects just to look at the Mondrian. In that case, as I explained earlier, we do not really know what operationstask-related or not-take place in the brain. This is why we tried to avoid such a perceptual task and use a two-alternative forced-choice discrimination task. Jeannerod: Dr Gulyas, you said that the duration of stimulation was 120 ms, so how can you say that there were no eye movements in this condition? Gulyas: We continuously monitored the eye movements with EOG. Jeannerod: There were no exploratory eye movements? Gulyas: Not really. Since the stimulus presentation period was 120 ms, the subjects had no time to scrutinize the images. Mazziotta: A question for Professor Zeki. Have you tried moving the colour panel? Have you, in other words, put the two processes simultaneously in the same stimulus, and, if so, is it the result the sum of the two individual variables, or something different? Zeki: We haven’t done that experiment yet. Mazziotta: What would you predict, if the colour stimulus were moving? Zeki: I make no predictions.

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Fox: On a more philosophical point, of how I look at these experiments, and what I consider as a successful and an unsuccessful experiment: it’s very easy, given the cooperativity of human subjects, and the complexity of the behaviour of which they are capable, to activate many brain areas. If I ask someone to remember something and talk about it freely, there is activation in 20, 30, 40 areas. The challenge is more along the lines that Dr Corbetta discussed, trying to associate an area with a process. The experiments that I would consider most successful are those where you activate one area. When we see a behaviour like colour perception isolated, and conclusively identified as substantially involved in a process, 1 learn a lot from that. When I see a behaviour that activates many areas and we cannot ascribe a given process to any of those with any certainty, I am much less satisfied. Zeki: I agree. Corbetta: I would like to make a comment about this distinction between ‘passive’ and ‘active’ states; that is, the difference between simply looking at a visual stimulus (e.g. a colour ‘Mondrian’) and undertaking a task on the same stimulus (e.g. a colour discrimination). I agree that the passive presentation of a stimulus is the first study one wants to do. However, one has to be aware of possible confounding factors in this kind of experiment. For instance, the experimenter does not have any control on the subject’s behaviour: he does not now how much the subject is engaged on the task (i.e. the arousal level), or whether he is selectively processing some aspects of that stimulus, or whether he is thinking about something completely extraneous to the experiment. The presence of some selective processing might activate regions not related to the stimulus per se, and differences in arousal might affect the level of activation in a specific region. We commonly observe more regions that are activated during selective processing than during the passive presentation of the same stimuli, and activation of primary visual cortex and surrounding cortex is much stronger when subjects are discriminating than when they are simply looking at the stimulus (this volume: Corbetta et a1 1991). Similar observations on V1 activity (Mountcastle et a1 1987) as a function of working (active processing) and non-working (passive presentation) states have been also made in animals at the single-unit level. So, in conclusion, the simple presentation of a visual stimulus is fine, but it is just a first step. Zeki: We may have a basic disagreement on what we mean by ‘passive perception’. I agree that there is a difference between looking at something and undertaking a task in response to what one sees, but the notion that colour is a passive thing, that the brain undertakes no operation to go ‘beyond the information given’, is the wrong idea which has led everyone astray. Whereas Helmholtz and Maxwell and Young got it right-at least in recognizing that you cannot account for colour vision purely in terms of the activation of the receptors-most physiologists and psychophysicists have not understood the

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problem or, if they have, have chosen to ignore it. To assign a colour to a surface, the cerebral cortex has to undertake a considerable amount of work. There is no simple and obvious relationship between the wavelength composition of the light reflected from a surface and the colour that the brain assigns to that surface. Instead, the brain must compare the wavelength composition of the light coming from the surface with the wavelength composition of the light coming from surrounding surfaces. That comparison, which leads to what Helmholtz called ‘discounting the illuminant’, is a property of the brain, not the world outside, even if all the information needed to undertake it is present out there. Put more simply, the brain has to undertake some work; it does not passively register the coiour of a surface. This is where I disagree with Dr Corbetta when he speaks about a ‘pure passive stimulus’. The same applies to motion vision. We know from the elegant work of Tony Movshon that the cells of V1 are not able to see coherent motion; you have got to go to V5 for that (Movshon et a1 1984). This involves work in the cortex; it is not a purely passive thing. References Bohm C, Greitz T, Kingsley D, Berggren BM, Olsson L 1983 Adjustable computerized stereotaxic brain atlas for transmission and emission tomography. Am J Neuroradiol 4~31-733 Bohm C, Greitz T, Blomqvist G et a1 1986 Applications of a computerized adjustable brain atlas in positron emission tomography. Acta Neuroradiol Suppl 369:449-452 Bohm C, Greitz T, Seitz R, Eriksson L 1991 Specification and selection of regions of interest (ROIs) in a computerized brain atlas. J Cereb Blood Flow Metab 11:A64-68 Corbetta M, Miezin FM, Shulman GL, Petersen SE 1991 Selective attention modulates extrastriate visual regions in humans during visual feature discrimination and recognition. In: Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Found Symp 163) p 165-180 Greitz T, Hoke S, Bohm C et a1 1991a A data base library as a diagnostic aid in neuroimaging. Neuroradiol Suppl 33:2-4 Greitz T, Bohm C, Hoke S, Eriksson L 1991b A computerized brain atlas: construction, anatomical content, and some applications. J Comput Assisted Tomogr 15:26-38 Lueck CJ, Zeki S, Friston KJ et a1 1989 The colour centre in the cerebral cortex of man. Nature (Lond) 340:386-389 Marr D 1982 Vision. WH Freeman, New York Mountcastle VB, Motter BC, Steinmetz MA, Sestokas AK 1987 Common and different effects of attentive fixation on the excitability of parietal and prestriate (V4) cortical visual neurons in the macaque monkey. J Neurosci 7:2239-2255 Movshon JA, Adelson EH, Gizzi MS, Newsome WT 1984 The analysis of moving visual patterns. In: Chagas C, Gattass R,Gross CG (eds) Pattern recognition mechanisms, Pontifical Academy, Citta del Vaticano, p 117- 151 Perenin MT, Jeannerod M 1978 Visual function within the hemianopic field following early cerebral hemidecortication in man. I . Spatial localization. Neuropsychologia 16~1-13 Perenin MT, Jeannerod M 1979 Subcortical vision in man. Trends Neurosci 2:204-207

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Posner MI, Petersen SE, Fox PT, Raichle ME 1988 Localization of cognitive functions in the human brain. Science (Wash DC) 240:1627- 1631 Seitz RJ, Bohm C, Greitz T et al 1990 Accuracy and precision of the computerized brain atlas programme (CBA) for localization and quantification in positron emission tomography. J Cereb Blood Flow Metab 10:443-357 Stoerig P, Cowey A 1989 Wavelength sensitivity in blindsight. Nature (Lond) 342:916-918 Zeki S 1990 A theory of multistage integration in the visual cortex. In: Eccles J C , Creuzfeldt 0 (eds) Principles of design and operation of the brain. Pontifical Academy, Citta del Vaticano, p 137-154 Zeki S, Shipp S 1988 The functional logic of cortical connections. Nature (Lond) 335:311-317

Zeki S, Watson JDG, Lueck CJ, Friston KJ, Kennard C, Frackowiak RSJ 1991 A direct demonstration of functional specialization in human visual cortex. J Neurosci 11 ~641-649

Selective attention modulates ext rastriate visual regions in humans during visual feature discrimination and recognition Maurizio Corbetta, Fran M. Miezin, Gordon L. Shulman and Steven E. Petersen Department of Neurology and Neurological Surgery, McDonnell Center for Studies of Higher Brain Function, Washington University School of Medicine, St Louis, MO 631 10, USA

Abstract. Positron emission tomography (PET) was used to identify regions of the human visual system which were selectively modulated by attention during feature discrimination and recognition tasks. In a first experiment, subjects were cued to the shape, colour or speed of visual stimulus arrays during a same-different match-to-sample paradigm. The psychophysical sensitivity for discriminating subtle attribute variations was enhanced by selective attention. Correspondingly, the neural activity (as measured by blood flow changes) in different visual associative regions was enhanced when subjects attended to different attributes of the same stimulus (intraparietal sulcus for speed; collateral sulcus and dorsolateral occipital cortex for colour; collateral sulcus, fusiform and parahippocampal gyri, superior temporal sulcus for shape). These regions appeared to be specialized for processing the selected attribute. Attention to a visual feature, therefore, enhances the psychophysical sensitivity as well as the neural activity of specialized processing regions of the human visual system. In a second experiment the effect of target probability (which biases attentional selection) was studied during visual search tasks involving the recognition of a single-feature (i.e. colour) or a featureconjunction (i.e. colour x orientation) target. Target probability positively modulated neural activity of extrastriate visual regions, which were related to the single-feature or feature-conjunction processing level. These results suggest that selective attention can influence different processing levels in the visual system, possibly reflecting a facilitatory effect on different visual computations or task components.

1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 16.5-180

The problem of attention is central t o studies of human cognition because it relates to the focal nature of our behaviour-that is, the limitation in the amount of information that can be processed, and/or the number of actions that can be planned and conducted. Selection systems might have developed t o protect t h e brain from computational overloading (Kahneman 1973), and/or orchestrate coherently the various operations activated by a given task (Allport 1980, Ullman

1984). 165

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A major development in this field has been the recognition of the distributed organization of brain attentional systems (Mesulam 198 1). Various deficits in attentional behaviours are evident after focal damage to different brain loci (Heilman et al 1987), and selective modulations of neuronal responses at singleunit level are demonstrated in sensory, ‘association’, and premotor regions under different task conditions (see Wurtz et a1 1984, Wise & Desimone 1988). The variety of effects of attention on task performance, therefore, cannot be easily explained by a single mechanism acting early or late in the processing (Broadbent 1958, Deutsch & Deutsch 1963). Instead, it is more likely that distinct attentional mechanisms (Posner & Petersen 1990) may influence different processing stages. These selection mechanisms can be studied by assessing the contribution of attention to the components of a given task, and then localizing the related processing modulations in the brain. Here, we discuss the influence of selective attention during visual feature discrimination and recognition tasks. In a first experiment, it is demonstrated that selective attention enhances psychophysical sensitivity and neural activity in specialized processing of human extrastriate visual cortex during single-feature discriminations. In a second experiment, it is demonstrated that effects related to target probability manipulations are evident at different processing stages in visual extrastriate cortex during single-feature and feature-conjunction recognition tasks. PET experimental strategy The positron emission tomography (PET) activation methodology developed at Washington University, St Louis (Fox & Mintun 1989, Mintun et al 1989) for the purpose of identifying regions of the brain related to specific information-processing operations was adopted in both experiments. This strategy includes the use of ( I ) normal volunteers; (2) lSO-labelled water as blood flow tracer, with a short half-life (123 s) and scan time (40 s) that allow several scans in a single session; (3) image subtraction, between an activation and a control scan, to isolate areas of change between conditions; (4) inter-subject image averaging to enhance the signal of activated regions compared to a noise background; and ( 5 ) a computer algorithm to determine the location and magnitude of changes in the image, and to assess their statistical significance. For the purpose of analysing the distribution of change in PET subtraction images, distributions of radiation are virtually identical to those of blood flow. We routinely use the radiation images to avoid an arterial line, which is necessary for estimating true blood flow values. Selective attention to shape, speed, colour

Psychophysical procedure and scan sequence A psychophysical task was developed in a first group of subjects with which to study the influence of visual attention on the discrimination of subtle

Selective attention in the visual system

Frame 1

Frame 2

I

I

167

Key-press interval

I I

400 600

0

n 0

I

I

2500

1060

t i m e (ms)

u 0 .

0

0

n

u

Frame 1

Frame 2

FIG. 1. Visual feature discrimination task. The size of each element was either 0.8" x 0.8"of visual angle or the just noticeable difference (shape). Colours were either red o r green, or the just noticeable difference in hue. Speed was either 18 degrees per second or the just noticeable difference.

stimulus changes of the shape, colour or velocity of a multidimensional visual stimulus. A same-different task was used. On each trial subjects fixated a small spot, and were presented with two 400 ms stimulus frames, separated by a 200 ms blank display interval (Fig. 1). The stimulus frame was a spatially random distribution of identically coloured small bars, moving horizontally as a coherent sheet either to the left or to the right. The direction of motion was constant within a trial, and was randomly shifted across trials. The shape, colour and velocity of all elements might independently change between the first and the second frame. Stimulus changes were close to threshold (about 1.6 d ' unit), as assessed for each subject in a separate psychophysical session. The subject's task was to compare the first stimulus frame with the second, and report (by a key-press) if the two frames were same or different for a particular dimension, specified at the beginning of each experimental block. In three blocks, subjects discriminated a stimulus change of either shape, colour or velocity (Selective attention). Half the trials were 'different', and contained a change in the specified dimension, and half the trials were 'same'. Same and different trials also contained in equal proportions stimulus changes in zero, one, or both of the unspecified or irrelevant dimensions. For instance, during same or different trials in a colour block, velocity and shape might stay

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constant in both frames, velocity might change, shape might change, or both velocity and shape might change. In a fourth block, subjects detected changes in any attribute, dividing attention across dimensions (Divided attention). In this case, none of the stimulus dimensions varied on half of the trials (same trials), and changes in only one dimension (i.e. in colour, shape or velocity) occurred on the other half (different trials). Psychophysical sensitivity in both selective and divided conditions was assessed by recording ‘hits’ (different response to a different trial) and ‘false alarms’ (different response to a same trial), and calculating a criterion-free sensitivity index (d ’), The functional anatomy of these two attentional conditions was studied in a separate group of subjects who were scanned during the three selective (colour, shape, speed) and the divided attention conditions. In addition, a passive scan condition, in which the same set of stimuli was shown and subjects alternated key-presses without discrimination, and a fixation point-only scan condition, in which subjects fixated a small central spot on the screen with no other stimuli being presented, were also run.

Results and discussion In the psychophysical experiment, subjects were generally more accurate in the selective than in the divided attention condition ( P c 0.001)’ and the sensitivity advantage (on average, 0.9 d ‘ unit) was similar for all three tested dimensions. In the PET experiment, similar results were obtained, although a smaller number of trials was run in the 40 s scan time. The effects of selective attention on feature discrimination may be explained by ‘early’ modulations of visual processing regions or by ‘late’ effects at some decision or response selection mechanism. Furthermore, in the visual system the mechanism of selection might be represented by an enhancement operation in the selected channel (colour during colour discriminations), or by a firtering operation in the unattended channels (shape and speed during colour discriminations). Here, only blood flow activations localized in extrastriate visual cortex after subtracting the divided attention scan from each of the selective attention scans will be discussed. In this subtraction, factors such as sensory stimulation, arousal, and motor output were matched, so that differences in the attentional set are the most likely factor in explaining the obtained activations. The main result was that different regions of extrastriate visual cortex were activated by attending to different features of the same stimulus (Fig. 2) (see colour plate). Attention to colour activated regions in the collateral sulcus, between lingual and fusiform gyrus, and in dorsolateral occipital cortex. Attention to shape activated regions in the collateral sulcus (commonly to colour), fusiform and parahippocampal gyri, intersection calcarine fissure/ parieto-occipital sulcus, and a region of temporal cortex in the superior temporal

FIG. 2 (Corbetta et al) Top left: PET activation in the collateral sulcus for attention to colour and shape, and not for attention to speed (average coordinates in Talairach space (Talairach et al1967): Superior/Inferior (S/I)= -3; Left/Right (L/R)=+25; Anterior/Posterior (A/P)= -63). Top right: PET activation in dorsolateral occipital cortex for attention to colour only (S/I=12; L/R=+26; A/P= -65). Bottom left: PET activation in superior temporal sulcus for attention to shape only (S/I=2; L/R=254; A/P= -2). Bottom right: PET activation in intraparietal sulcus for attention to velocity only (S/I=16; L/R=43; A/P= -56).

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sulcus. Finally, attention to speed activated a region in the inferior parietal lobule in or near the intraparietal sulcus. These activations most likely represent an enhancement of neural activity in regions specialized for processing the selected attribute. For instance, the response in the collateral sulcus for attention t o colour matched an activation described by the London group during the passive presentation of coloured stimuli taking the form of an abstract, Mondrian type of painting (Lueck et a1 1989). The response in the intraparietal sulcus for attention to velocity was adjacent to activations obtained in our laboratory and the London laboratory (Miezin et a1 1987, 1988a,b, Zeki et a1 1991) during various tasks involving motion analysis and pursuit eye movement. Possible homologies between some of these regions in human visual cortex and some monkey visual areas have been proposed elsewhere (Corbetta et a1 1990; see also Zeki et a1 1991). These regions probably represent the ‘locus’ at which a selective signal from higher-order centres (top-down) modulates visual analysis. The enhancement of blood flow corresponds to neuronal signals that facilitate the processing of relevant information. Recent data from single-unit recording experiments in monkey suggest that both ‘set-related’ (the encoding of a task instruction) and ‘matching’ (the actual coincidence between the attended to and the actual visual input) signals might account for the selective blood flow modulations reported in this study. Haenny et a1 (1988) found that the activity of over 50% of neurons in area V4 (a visual area specialized in form and colour analysis) to oriented stimuli was different when the monkey was cued to look for different orientations. The modulation was observed when the monkey was instructed with visual or tactile cues. The independence of the modulation from the modality of cue presentation suggests that it was the instructional meaning of the cue, rather than its sensory content, that influenced V4 neurons. In our task, instruction-related signals, such as attention to colour, delivered by higher-order centres, might ‘prime’ the appropriate visual pathways. Another neuronal signal which may produce such blood flow modulations is the sensory enhancement related to the ‘matching’ operation between an internal, set-related signal (priming) and the appropriate visual input. About 70% of V4 neurons show an enhancement of the visual response and a sharpening of the tuning function (an index of the sensitivity and specificity of the response), when the monkey detects a target stimulus in a match-to-sample feature discrimination task (Haenny & Schiller 1988), particularly in conditions of low discriminability (Spitzer et a1 1988). Sensory enhancement and the sharpening of tuning functions may account for the higher psychophysical sensitivity observed in the selective conditions over the divided condition. Set-related signals may ‘prime’ the selected processing pathways, where stimulus variations of the feature being attended to trigger stronger and more selective neuronal visual responses than in unprimed pathways

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(higher signal-to-noise ratio). The resultant higher quality transmission of relevant information from the visual system in turn might determine lower psychophysical thresholds. Visual selection by the enhancement of relevant information (rather than by the filtering of irrelevant information) may be limited to shape, colour or speed, or may be a more general solution in the visual system. We have observed blood flow enhancement during visual activity in other tasks involving visual selection. Petersen et a1 (1988) have demonstrated a spatially specific enhancement in occipito-parietal cortex during attending to the location of a visual stimulus. Furthermore, a left ventro-medial extrastriate region, that appears to be related specifically to the analysis of visually presented words (Petersen et a1 1990), is enhanced when people monitor the meaning of a word in a semantic task (S. E. Petersen, personal communication). Recent single-unit data have demonstrated, however, the existence of both mechanisms of selection in extrastriate visual cortex. As already mentioned, neurons in areas V4 and infero-temporal cortex (IT), which are specialized for object processing (Van Essen 1985), are selectivelyenhanced during colour and orientation discrimination tasks. Similarly, neurons in posterior parietal cortex and lateral pulvinar, which are specialized for visuo-spatial processing (Andersen 1987), are selectively enhanced during location detection tasks. In addition, Moran & Desimone (1985) have showed a spatially selective filtering of ‘unattended’information in areas V4 and IT during orientation discriminations. The apparent incongruence between PET and some of the single-unit data on filtering might reflect the existence of a different kind of selectivity. On computational grounds, Ullman (1984) has proposed that the visual computations (or routines) needed to process efficiently a particular display might be recruited, as a function of task demands, by selecting the location in space of a stimulus, its intrinsic features, or its intrinsic features at a particular location. The filtering of neuronal activity in V4 for stimuli flashed at ‘unattended’ locations is present in a task which encourages location-by-task dependent selection, whereas the enhancement obtained in other single-unit and PET experiments encourage either location-only, or feature-only dependent selection. The successful discrimination of the shape, colour or speed of an array of visual stimuli can be achieved by monitoring activity in a single relevant channel. The recognition of most objects in real life, however, is based on the analysis of multiple cues-for example, colour, orientation, motion and depth. Cognitive and computational results (Treisman & Gelade 1980, Marr 1982) suggest that recognition is at least a two-stage process. In a first stage, the basic visual cues about an object are analysed by the visual system in parallel; that is, multiple visual areas or subdivisions of the same area appear to process different features of the same object. In a second stage, the result of these spatially segregated analyses must be recombined according to some rule (spatial, temporal, or both)

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in order to recreate the perceptual unity of that object before the accessing of memory or recognition systems. In the second experiment, we studied the influence of selection on these two theoretical processing stages, by asking subjects to search among distractors for a particular two-dimensional object which was defined either by a singlefeature value (i.e. a particular colour) or by a conjunction of feature values (i.e. a particular colour and orientation). The probability of target recognition was also manipulated (many vs few targets) in the two tasks, possibly allowing us to disentangle selective effects at the feature and conjunction level.

Colour or colour x orientation target recognition

Psychophysical procedure and scan sequence Subjects were presented with a set of visual stimuli consisting of four objects, that were simultaneously and briefly flashed in a ‘diamond’ configuration around the fixation point (Fig. 3). Subjects were instructed to indicate by a

Stlmulus

_-

SAMPLE

time

900 ms

TARGET

NO TARGET

COLOR task

COLOR x OR I ENTAT I ON task

TARGET PROBABILITY= 5% o r 45% t r i a l s FIG. 3. Visual feature recognition task. The size of each square was 2" X 2" of visual angle. The size of each rectangle was 1" x 4" of visual angle. The distance from the centre of each element to the fixation point was 4".The colours were red, green, blue, yellow, and pink. The target colour was either red or blue (in different scans). The orientations were 0", 45", 90" and 135" of visual angle. The target orientation was either 0" or 90" (in different scans).

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key-press (yes, no) whether a target object, previously shown for about 15 seconds at the beginning of the task (sample), was present in the display or not. In one condition (Colour task) the target was defined by a single feature, namely a particular colour. On target trials the target (e.g. the red square) was randomly presented at one of four locations. Squares of other colours (‘distractors’) were presented at the other three locations. In different scans the target was presented on either 45% or 5% of the trials. On non-target trials, only the distractors’ were presented at all four locations. In a second condition (Colour x orientation task) the target was defined by a conjunction of features, namely a particular colour and orientation. On target trials, the target (e.g. the red vertical bar) was randomly presented at one of four locations. Bar distractors of different colour and orientation were presented at the other three locations. The target was presented on either 45% or 5% of the trials in different scans. On non-target trials, two distractors always assumed the relevant colour (e.g. red) and the relevant orientation (e.g. vertical), respectively; the other two distractors always assumed irrelevant colour and orientation values. Both colour and orientation values, therefore, had to be analysed on each trial to recognize conjunction targets. In both colour and colour x orientation conditions, the target colour ‘popped out’ in the display, presumably orienting subjects to search first upon colour information. As control scan, a passive condition was also run, in which the same set of stimuli was shown and subjects alternated key-presses without discriminating.

Results and discussion Primary visual cortex and surrounding regions were powerfully activated by all recognition tasks in comparison to the passive baseline. This early response was not modulated by the target probability manipulation, and most likely represents changes in visual activation due to the behavioural transition between active and passive states, and/or to differences in task complexity or difficulty (e.g. responses were stronger for the conjunction than for the single-feature task). An extrastriate visual region in dorsolateral occipital cortex was activated when many, rather than few, colour targets were presented-i.e. 45% colour, 5% and 45% colour x orientation conditions (Fig. 4) (see colour plate). This response was probably dependent on the number of positive colour matches, because it was still significant when the low probability condition was subtracted from the high probability condition in the colour task. In this subtraction visual, motor and arousal factors are closely matched, and the target probability manipulation is the most likely explanation for the obtained activations. No dorsolateral occipital response was localized in the high-low probability subtraction for the conjunction task, because the same number of coloured targets was presented in the two conditions.

FIG. 4 (Corbettu el ul)PET activations in dorsolateral occipital cortex, related to colour matching (average location S/I=16; L/R= k26; A/P= -63). The passive task as a subtraction scan in all four active conditions. Notice absence of a response in the low probability colour task (5% colour targets), and presence of a response in the high colour, and low and high probability colour x orientation tasks (respectively 45%, 100% and 100% colour targets).

FIG. 5 (Corbetta et a0 PET activations in posterior infero-temporal cortex, related to object target matching (average location S/I= -8; L/R= -48; A/P= -39). The passive task as subtraction scan in all four active conditions. Notice responses only in the high probability target colour, and colour x orientation conditions (in both conditions 45% object targets).

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The dorsolateral occipital response overlapped a region modulated by attention to colour in the previous experiment. Accordingly, this activation represents a selective enhancement of neural activity in a colour-related processing region. This experiment further suggests that a ‘matching’ rather than a ‘set-related’ signal is contributing to the observed blood flow response in this experiment. The magnitude of the response was bigger when the selected colour value (e.g. red) corresponded many times t o the actual visual input (45% colour, 5 % and 45% colour x orientation), although in all tasks subjects were actively searching for the same colour value-that is, they were presumably selecting it. The enhancement of activity in colour-related processing regions, which appears to signal the presence of a colour target (positive match), may allow this information to be passed to second-level representations. Finally, a region in the posterior portion of the right inferior temporal gyrus was significantly more active when many, rather than a few, targets were presented in both the colour and the colour x orientation task (Fig. 5) (see colour plate). This region was significantly active across both the passive and low probability subtractions, suggesting again a dependence on target probability manipulation. The posterior right temporal region, which is more active in the high versus low probability conditions, is a candidate for a second-level visual representation. Either of two explanations seems equally plausible. The temporal activation could represent a region in which a colour-matching signal is added to a shapematching signal. For both single-feature and conjunction conditions, there would be differential activation when the signals were added at the second-level representation. Alternatively, the temporal region could be a region where feature signals are compared to a final target template. The temporal region, on this hypothesis, does not represent a general conjunction area, but is activated by a positive match between an internal template of the target object, and a correct combination of single-feature values. General conclusions

Activity in specialized processing regions of human extrastriate visual cortex is enhanced by selective attention during tasks in which attention is directed to the intrinsic features of an object-its shape, colour, or speed. The enhancement of visual activity correlates with more accurate psychophysical performance, probably due to a higher signal-to-noise ratio in the transmission of relevant visual information. During single-feature and feature-conjunction recognition tasks, some enhancements appear to encode the positive match between a selected feature value and an appropriate visual input. These positive matching signals might be functionally important for signalling the presence of the selected feature to a second-level representation, which also appear to encode preferentially the occurrence of positive conjunctions.

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A ckno wledgenzents We thank Sue Dobmeyer for help in data collection, and Marcus Raichle for his enthusiastic support. This research was supported by N I H grants 50172 and 54449, and the McDonnell Center for Studies of Higher Brain Function, grant 26239P.

References

Allport DA 1980 Attention and performance. In:Claxton G (ed) Cognitive psychology: new directions. Routledge & Kegan Paul, London, p 112-153 Andersen RA 1987 The role of the inferior parietal lobule in spatial perception and visualmotor integration. In: Plum F (ed) Handbook of physiology, section 1 : The nervous system, vol 5 : Higher functions of the brain (part 2) Oxford University Press, New York (American Physiological Society, Bethesda) p 483-518 Broadbent DE 1958 Perception and communication. Pergamon Press, London Corbetta M, Miezin FM, Dobmeyer S, Shulman GL, Petersen SE 1990 Attentional modulation of neural processing of shape, color, and velocity in humans. Science (Wash DC) 248: 1556- 1 559 Deutsch J , Deutsch D 1963 Attention: some theoretical considerations. Psycho1 Rev 70~80-90 Fox PT, Mintun MA 1989 Noninvasive functional brain mapping by change-distribution analysis of averaged PET images of H2I5O.J Nucl Med 30:141-149 Haenny PE, Schiller P H 1988 State dependent activity in visual cortex. 1. Single cell activity in V , and V, on visual tasks. Exp Brain Res 69:225-244 Haenny PE, Maunsell JHR, Schiller PH 1988 State dependent activity in monkey visual cortex. 11. Retinal and extraretinal factors in V4. Exp Brain Res 69:245-259 Heilrnan KM, Watson RT, Valenstein E, Goldberg ME 1987 Attention: behavior and neural mechanisms. In: Plum F (ed) Handbook of physiology, section 1: The nervous system, vol 5 : Higher functions of the brain (part 2). Oxford University Press, New York (American Physiological Society, Bethesda) p 461 -481 Kahneman D 1973 Attention and effort. Prentice Hall, Englewood Cliffs, NJ Lueck CJ, Zeki S, Friston KJ et a1 1989 The colour centre in the cerebral cortex of man. Nature (Lond) 340:386-388 Marr D 1982 Vision. WH Freeman, New York Mesulam MM 1981 A cortical network for directed attention and unilateral neglect. Ann Neurol 10:309-315 Miezin FM, Fox PT, Raichle ME, Allman JM 1987 Localized response to low contrast moving random dot patterns in human visual cortex monitored with positron emission tomography. SOCNeurosci Abstr 13:625 Miezin FM, Fox PT, Raichle ME, Allman JM 1988a An extrastriate region in human visual cortex sensitive to low contrast dots and high temporal frequencies. Invest Ophthalmol 8t Visual Sci (ARVO suppl) 29:326 (abstr) Miezin FM, Applegate C, Petersen SE, Fox PT 1988b Brain regions in humans activated during smooth pursuit visual tracking. SOCNeurosci Abstr 14:795 Mintun MA, FOXPT, Raichle ME 1989 A highly accurate method of localizing regions of neuronal activation in the human brain with positron emission tomography. J Cereb Blood Flow Metab 9:96-103 Moran J , Desimone R 1985 Selective attention gates visual processing in extrastriate cortex. Science (Wash DC) 229:782-784 Petersen SE, Fox PT, Miezin FM, Raichle ME 1988 Modulation of cortical visual responses by direction of spatial attention measured by PET. Invest Ophthalmol & Visual Sci (ARVO suppl) 29:22 (abstr)

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Petersen SE, Fox PT, Snyder AZ, Raichle ME 1990 Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science (Wash DC) 249:1041-1044 Posner MI, Petersen SE 1990 The attention system of the human brain. Annu Rev Neurosci 13:25-42 Spitzer H, Desimone R, Moran J 1988 Increased attention enhances both behavioral and neuronal performance. Science (Wash DC) 240:338-340 Talairach J , Szikla G, Tournoux P et a1 1967 Atlas d’anatomie stereotaxique du tklencephale. Masson, Paris Treisman AM, Gelade G 1980 A feature-integration of theory of attention. Cognit Psycho1 12:97-136 Ullman S 1984 Visual routines. Cognition 18:97-159 Van Essen DC 1985 Functional organization of primate visual cortex. In: Peters A, Jones E G (eds) Cerebral cortex. Plenum Press, New York, p259-329 Wise SP, Desimone R 1988 Behavioral neurophysiology: insights into seeing and grasping. Science (Wash DC) 242:736-741 Wurtz RH, Richmond BJ, Newsome WT 1984 Modulation of cortical visual processing by attention, perception, and movement. In: Edelman GM, Gall WE, Cowan WM (eds) Dynamic aspects of neocortical functions. Wiley, New York, p 195-217 Zeki S, Watson JDG, Lueck CJ, Friston KJ, Kennard C , Frackowiak RSJ 1991 A direct demonstration of functional specialization in human visual cortex. J Neurosci 11:641-649

DISCUSSION Plum: What is the latency when the stimulus drives the response in a naive subject compared to when the subject is primed for attention? For example, is the latency less in primed subjects performing tasks in which one must both direct attention and recognize the stimulus in order t o respond properly? Corbetta: We did not actually measure the reaction time of the subject’s response in these experiments, but the accuracy. Subjects were more sensitive in discriminating a stimulus variation when they directed their attention to the proper visual feature, and this advantage in accuracy should also yield a shorter latency of response. The cognitive literature indicates that processing efficiency is enhanced when attention can be directed before stimulus presentation. Plum: You made reference to the comparator, and the additional step of the comparator being unknown. I was curious whether the same anatomical pathways would be involved when one knew in advance the point to which attention was to be directed compared to trials where such warning was omitted. The question relates to possible changes induced by intentionality as well as attention alone. Corbetta: We have not carried out that comparison. In both tasks (selective attention to colour, speed, shape, and the two-dimensional recognition task) the subject is voluntarily selecting one attribute of the stimulus; if you like, the subject’s will is looking for something in that display. Given the limited temporal resolution, we cannot distinguish this ‘set-related’ signal from the effect of that

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signal on the analysis of the incoming input. Probably we see activations that reflect a combination of both. To see the ‘set-related’signal in isolation we should try to design an experiment in which a subject is attending to a feature (e.g. colour) for a 40-second period (the time needed for a PET measurement), and the actual visual stimulus is never presented. If our hypothesis is correct, we should be able to see activation in colour-related areas. Haenny and co-workers (Haenny & Schiller 1988, J . Maunsell, personal communication) have obtained some evidence for a ‘set-related’ signal in isolation, recording in monkey V4. Instructing a monkey to attend to a particular orientation, either visually or tactilely, they observed that neuronal firing during a discrimination task was modulated by the orientation value the animal was looking for. The modulation was independent of the modality of the instructing stimulus, suggesting that the symbolic, rather than sensory, content of the instruction was modulating visual activity. Zeki: This has now been found everywhere in the visual cortex; it has been extended to V1, for example. Corhetta: No-not to V1. These ‘top-down’ effects were found only in V4 in this particular task. In general, attentional modulations of visual responses are commonly found in several other extrastriate visual areas such as posterior parietal cortex (Bushnell et a1 1981), middle superior temporal area (MST) (Komatzu & Wurtz 1988), or infero-temporal cortex (IT) (Moran & Desimone 1985, Richmond & Sat0 1987), but not in V l . Jeannerod: Several people, including Wurtz and his group, did experiments on the enhancement of cell activity in several cortical areas during attentional tasks in the monkey. They found very little enhancement in V1 (Wurtz & Mohler 1976). Corbetta: I think it is very important to distinguish between non-selective and selective (or attentional) enhancement of visual activity. A non-selective enhancement may reflect variations in the level of arousal, that may be as large as between sleep and wakefulness (Livingstone & Hubel 1981) or as subtle as between working and non-working states. Mountcastle and co-workers have shown that the same visual stimulus yields a stronger neuronal response when the animal is waiting for a stimulus (working) than when he is idle (non-working) between trials. This effect has been observed in both V1 and extrastriate visual cortex (posterior parietal and V4) (Mountcastle et a1 1987). These modulations, however, are non-selective because they globally affect the responsiveness to a stimulus, independently of the kind of stimulus or the task context. In contrast, a selective enhancement reflects a specific change in activity related to the choice of a particular feature among other features (e.g. colour vs speed and shape), or a particular stimulus value within the same feature (e.g. a particular location in space among other locations). The modulations I have described are selective in this regard, and we try to control as best we can for non-selective variation in activity.

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Lassen: Dr Roland did a study of selective attention in three modalities, and it would be nice to know whether your studies, Dr Corbetta, add to what he found, or if they disagree. It was the point about whether the primary somatosensory area or the secondary area was enhanced, I think? Roland: Ours was a differently designed experiment (Roland 1982). We weren’t looking at within-channel selective attention, as you are, Dr Corbetta. We were comparing visual, auditory and somatosensory channel attention, giving the same stimuli in all three conditions, and then having the subjects attending to one particular issue, using the same stimuli three times. We could not of course monitor the primary auditory or primary visual area with the 133Xcintracarotid technique, but we found that the biggest enhancement in blood flow was in the sensory association areas. That was our conclusion. Dr Corbetta, you said that within one channel, say the visual channel, you can have selective attention to a particular aspect of the stimulus. There is another dimension to consider, that has been called scrutinizing. If the subject is pre-set to detect a specific feature of, say, a visual stimulus (that is, he is informed about which feature to detect), he can do this very quickly. If he is not pre-set he has to scrutinize the stimulus for a longer time in order to detect a feature. These processes are not exactly the same as ‘attending’ to different aspects of a rather simple stimulus. Would your paradigm, especially the one where you compare the high probability to the low probability conditions, tell us anything about scrutinizing, and did you look at the eye movements of the subjects? Corbetta: I’m not sure what you mean by ‘scrutinizing’. The selective versus divided attention conditions in the first experiment can, I think, be compared to what you call a pre-set versus a non-pre-set condition. When the subject does not know what feature he is looking for (divided or non-pre-set), we have observed relatively less activity (compared to selective or pre-set) in specialized visual areas and more activity in frontal regions (prefrontal cortex). This result might reflect the activation of representations that deal with a more complete description of the visual stimulus (prefrontal cortex), in a situation in which the subject has not been cued for a specific visual attribute. Alternatively, this frontal activity might represent short-term memory operations, related to the different number of features that the subject has to remember between the first and the second stimulus frame in the divided attention task. The eye movement problem is not an issue. Subjects were instructed to maintain fixation, and eye movements were monitored with EOG.Moreover, the stimulus display time was looms, shorter than the latency of a saccade. Frackowiak: May I go back to your first experiment, the enhancement at the primary specialized cortical site? You see an increase in cerebral blood flow, and therefore increased firing at that site, when the subject is attending to one of the multiple channels in this modality (e.g. V4 for colour). How do you interpret that result, in terms of the mechanism of that increase? If this activation

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is due to a top-down mechanism, why are you not seeing other areas which are associated with that activation? But if this is a mechanism coming from bottom up and dependent on the input, how is that happening, and what is the mechanism likely to be at the activated site? Corbetta: It is very important to make a theoretical distinction between the source of a top-down signal (what I have been referring to previously as a ‘setrelated’ signal) and the locus where that signal is acting (the visual regions in which we observed these feature-selective modulations). Indeed we have observed several regions outside the visual system that are commonly active during the selective attention conditions (to colour, shape, or speed). These areas include pulvinar, basal ganglia, and sylvian-inferior premotor cortex, and some are candidates for the source of a selective signal acting on visual regions. The pulvinar in particular has been proposed to have an attentional role in modulating visual activity (LaBerge & Buchsbaum 1990, Desimone et al 1989). Interestingly, we have also observed that an entirely different set of extravisual regions, such as anterior cingulate and right prefrontal cortex, were active in the divided attention task in which attention was divided across features. In the two tasks, therefore, the same perceptual judgement (a single-feature discrimination) was implemented through distinct neural systems. We can speculate that the decision in the selective condition was reached by monitoring activity only within the channel being attended to, in which the signal-to-noise ratio was higher thanks to the selective enhancement. The response was then implemented through a sylvian-premotor route. On the other hand, in the divided attention condition the decision was probably obtained by monitoring activity within all three channels, possibly in prefrontal cortex, and then selecting a response through an anterior cingulate route. Friston: You say that in the condition of divided attention there was activation of the anterior cingulate (compared to non-divided attention tasks). That is a splendid result. Now, the conjunction task (in the second experiment) is also a divided attention task. Did you replicate the anterior cingulate activation? Corbetta: This task (two-dimensional object recognition) was also set up to activate the cingulate in the conjunction condition, but we did not get that result. One possibility is that the discriminability between the two dimensions (colour and orientation) was unbalanced-namely, differences in colour were larger than differences in orientation. So in the conjunction task the subject always searches upon colour information first, and then checks for the right orientation. In other words, he does not have to monitor both channels to make the right judgement, and he can base his decision on a temporally spaced single-channel analysis. This might explain the lack of engagement of the frontal systems. It would be interesting to do the same experiment by matching the discriminability for colour and orientation. Friston: So, if I understand correctly, it was the difference in discriminability that led you to adopt a serial model wherein colour is detected first and then

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the second attribute. The colour centre (V4) has been identified in the experiments of Professor Zeki and colleagues. Why has V4 not been activated in your conjunction task? Corbetta: I cannot say whether V4 was active or not in the colour task. Unfortunately in this experiment we recorded in all conditions a very strong aspecific enhancement in medial occipital cortex (V1 /V2), going from passive to active conditions. The same visual stimulus produced a 10-15070 stronger response (against the usual 5-6%) when subjects were discriminating (active) than when they were simply looking at it (passive). This aspecific enhancement masked most of the interesting responses in lingual and fusiform gyrus. Zeki: Are you sure that it was striate cortex and not V2? Corbetta: We cannot distinguish between V1 and V2 in this task. Frith: One of the very interesting things about Anne Treisman’s original experiments (Treisman 1988) was that she made the distinction between focused attention, which was needed for the conjunction condition (searching for a green ‘T’ among green ‘X’s and brown ‘T’s), whereas for the non-conjunction condition (searching for an ‘S’ among green ‘X’s and brown ‘T’s), you did not need to focus your attention. The demonstration of this was that in the conjunction condition you necessarily know where the target is but in the nonconjunction condition you can be aware of the presence of a target without knowing where the target is. I would have thought that this result would imply that components of the visual system concerned with spatial position should be enhanced in the conjunction condition. Corbetta: We saw some parietal activation in the recognition task (which may be related to spatial covert orienting), but we did not explicitly manipulate spatial position. We should do an experiment in which one location is first cued, and then at that location either a single-feature or a conjunction task must be performed. By manipulating the location (e.g. left or right hemifield) one should be able to define better the role of spatial attention in these conditions. Cappa: Have you studied the effects on the activation pattern of inducing a bias in the spatial allocation of attention? This could be done by providing to the subject advance information as to the likely locus of stimulus presentation, which could be either valid or misleading, as in the paradigm originally proposed by Posner et a1 (1982). Corbetta: Petersen and his colleagues (1988) have studied the effects of attending to a visual location on the visual responses induced by the lateralized presentation (say, in the right visual hemifield) of a flashing checkerboard. This stimulus activates the primary visual area (Fox et a1 1987) and various extrastriate visual regions. They compared these activations in two conditions, respectively when the subject was attending to the stimulus location (stimulus attended) and when he was attending to a symmetrical point in the opposite visual hemifield (stimulus unattended). By subtracting activity obtained in the ‘unattended’ condition from activity obtained in the ‘attended’ condition, one

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should be able to isolate regions whose activity is related to the selection of the stimulus location independent of its sensory content. They localized a region at the occipito-parietal junction, that changed hemisphere with t h e side o f attention (right occipito-parietal for left field attention), and that might represent an analogy o f the spatial selective enhancement reported in posterior parietal cortex by Wurtz et a1 (1980).

References Bushnell MC, Goldberg ME, Robinson DL 1981 Behavioral enhancement of visual responses in monkey cerebral cortex. I. Modulation in posterior parietal cortex related to selective attention. J Neurophysiol 46:755-772 Desimone R, Wessinger M, Thomas L, Schneider W 1989 Effects of deactivation of lateral pulvinar or superior colliculus on the ability to selectively attend to a visual stimulus. SOCNeurosci Abstr 15:162 Fox PT, Miezin FM, Allman JM, Van Essen DC, Raichle ME 1987 Retinotopic organization of human visual cortex mapped with positron-emission tomography. J Neurosci 7:913-922 Haenny PE, Schiller PH 1988 State dependent activity in visual cortex. I. Single cell activity in V, and V, on visual tasks. Exp Brain Res 69:225-244 Komatzu H, Wurtz RH 1988 Relation of cortical areas MT and MST to pursuit eye movements. I. Localization and visual properties of neurons. J Neurophysiol 60:580-603 LaBerge D, Buchsbaum MS 1990 Positron emission tomography measurements of pulvinar activity during an attention task. J Neurosci 10:603-619 Livingstone MS, Hubel DH 1981 Effects of sleep and arousal on the processing of visual information in the cat. Nature (Lond) 291:554-561 Moran J , Desimone R 1985 Selective attention gates visual processing in extrastriate cortex. Science (Wash DC) 229:782-784 Mountcastle VB, Motter BC, Steinmetz MA, Sestokas AK 1987 Common and differential effects of attentive fixation on the excitability of parietal and prestriate (V4) cortical visual neurons in the macaque monkey. J Neurosci 7:2239-2255 Petersen SE, Fox PT, Miezin FM, Raichle ME 1988 Modulation of cortical visual responses by direction of spatial attention measured by PET. Invest Ophthalmol & Visual Sci (ARVO suppl) 29:22 (abstr) Posner MI, Cohen Y, Rafal RD 1982 Neural systems control of spatial orienting. Philos Trans R SOC Lond B Biol Sci 298:187-198 Richmond BJ, Sat0 T 1987 Enhancement of inferior temporal neurons during visual discrimination. J Neurophysiol 58: 1292-1306 Roland PE 1982 Cortical regulation of selective attention in man. A regional cerebral blood flow study. J Neurophysiol 48:1059-1078 Treisman A 1988 Features and objects. The Fourteenth Bartlett Memorial Lecture. Q J EXP Psycho1 40A;201-237 Wurtz RH, Mohler CW 1976 Enhancement of visual responses in monkey striate cortex and frontal eye fields. J Neurophysiol 39:766-772 Wurtz RH, Goldberg ME, Robinson DL 1980 Behavioral modulation of visual responses in monkeys. Psychobiol & Physiol Psycho1 9:42-83

Positron emission tomog raphy studies of frontal lobe function: relevance to psychiatric disease Chris Frith CRC Division of Psychiatry, Waiford Road, Harrow, Middiesex HA1 3UJ and MRC Cyclotron Unit, Harnrnersmith Hospital, Ducane Road, London W12 O M , UK

Abstract. The frontal lobes in man include about one-third of the total cortical area of the cerebrum, a considerably greater proportion than in other primates. It is likely that the frontal lobes subserve the most complex of cognitive functions including will and consciousness. During the performance of willed actions (spontaneous selection of actions without help from external cues) an increase of activity can be observed in dorsolateral prefrontal cortex. Critically, there is no increased activity in this location when the same actions are performed routinely. Such observations, which systematicallyuse positron emission tomography (PET) in conjunction with specific cognitive activations, should make it possible (a) to specify more precisely the cognitive components comprising ‘frontal’ attributes such as willed behaviour and planning, (b) to relate these components to particular frontal lobe areas, and (c) to show how these frontal lobe areas interact with other parts of the brain. Psychotic patients typically show abnormalities of willed behaviour (e.g. poverty of speech and action) and consciousness (e.g. hallucinations, delusions of control). PET studies of frontal lobe function in patients with these signs and symptoms should not only provide information about the pathophysiology of these disorders, but also increase our knowledge of the brain systems underlying the most complex human faculties. 1991 Exploring brain functional anatomy with positron tomography. Wiley. Chichester (Ciba Foundation Symposium 163) p 181-197

The prefrontal cortex regulates complex behaviour The prefrontal association cortex is far larger in man than in other primates. In the adult human brain it accounts for nearly one-third of the cerebral cortical surface (Brodmann 1925). The frontal cortex is required for the regulation of complex behaviour. Damage to the frontal lobes impairs the highest human faculties (Lezak 1983, chapter 16; Blumer & Benson 1975, Eslinger & Damasio 1985): will (e.g. impairments of executive control), affect (e.g. flattening and blunting of affect) and social interaction (e.g. indifference and social withdrawal). A particular feature of the regulation of behaviour exerted by the frontal cortex is that it is conscious (Goldstein & Scheerer 1941). Tasks that 181

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can be carried out without conscious attention are largely unimpaired by frontal damage. Thus, frontal cortex also has an important role in regulating conscious experience. Psychotic symptoms involve ‘frontal’ functions The main symptoms of psychosis reflect abnormalities in precisely those faculties which depend upon the frontal cortex. For example, schizophrenic patients often show avolitional behaviour (a defect of will), auditory hallucinations (a defect of consciousness), flattening and incongruity of affect (defects of affect), and social withdrawal and paranoid delusions (defects of social interaction) (Wing & Wing 1982). Even if the brain abnormalities that underlie psychosis turn out not to originate in the frontal cortex, the pathophysiology of the psychoses would be illuminated by an increased understanding of the role of the frontal cortex in these higher human faculties. Clues to the precise role of the frontal cortex Our knowledge of the psychological processes subserved by the frontal cortex comes from three sources: clinical observations of patients with frontal lobe damage, psychological test performance of these patients, and experimental studies of animals with lesions of the frontal cortex. It has proved difficult to combine and interpret results from these different sources. Patients with frontal lesions associated with a catastrophic change in life style may perform well on ‘frontal’ tests. For example, Eslinger & Damasio (1985) describe a patient who had a large orbito-frontal meningioma removed. This patient performed well on a wide variety of tests. Yet he went bankrupt, was fired from a number of jobs, and was divorced twice within a two-year period. In animal studies the effects of precisely localized lesions can be investigated, but it is difficult to study defects of will, consciousness and affect in non-speaking, nonhuman primates. Comparisons of deficits across species are also problematic, since a human performing the same task as a monkey may engage different cognitive processes (e.g. by using verbal mediation). The potential for PET in elucidating ‘frontal’ function Positron emission tomography (PET) activation studies have the potential to eliminate this confusion. In these studies the brain is ‘activated’ by requiring the volunteer to engage in some task, such as moving a finger or thinking, while he is being scanned. Using PET in this way it is possible to study the highest of human faculties and to include introspective data. For example, in many of Roland’s studies (e.g. Roland & Friberg 1985) the volunteers did not engage in any overt behaviour, but indulged in purely introspective activities, such as

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imagining themselves leaving their house and then turning alternately right or left at every corner. At the same time, it is possible to localize activity within the frontal cortex with a precision similar to that achieved in studies of experimentally induced lesions (e.g. the effects of lesions in area 46 on the delayed response task; Goldman-Rakic 1987). In addition it will be possible to observe interactions between frontal cortex and other, remote brain regions. We hope that such studies will answer three main questions: 1. Are there several discrete areas within the frontal cortex which subserve different cognitive functions? 2. It is possible to characterize these cognitive functions? 3 . How do these postulated frontal ‘modules’ interact with other parts of the brain?

Psychological processes subserved by different areas of frontal cortex Studies of patients with frontal lesions have had only slight success in demonstrating that different parts of the frontal cortex have different cognitive functions. This is because the lesions involved are usually large, often extending even beyond frontal cortex proper. For the same reason, the characterization of the various cognitive processes associated with the frontal lobes has not been very successful either. The function of the frontal cortex tends to be described in everyday-language terms, such as planning, integration of behaviour, and so on (Duncan 1986). Such ideas are not appropriate if we are to define ‘frontal’ function in terms of a number of independent and precisely specified cognitive components. The delayed response task Formulations of the role of frontal cortex derived from studies of lesions in experimental animals can be much more precise. For example, an enormous amount of work has been devoted to establishing the role of area 46 in the performance of delayed response tasks (Goldman-Rakic 1987). In a task of this type, the monkey is shown two food wells, one of which contains food. Both wells are then covered with opaque plaques. The apparatus is then hidden for a short time. After the delay the monkey is shown the apparatus again and is allowed to uncover one of the wells in order to obtain food. When he makes his response, there is nothing in the immediate situation to help him make the right choice. For example, great care is taken to eliminate smell cues. In the past, the well on the left has contained food as often as the well on the right. He can only make the right response by remembering where the food was hidden just before the delay. Goldman-Rakic has proposed that there are two critical features of this task that require the special functions of prefrontal cortex: (1) there is n o

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immediately available stimulus indicating which response to select; (2) response selection is guided by information held in memory, an ‘inner representation’ of what happened in the past. We should note that once the information carried across the delay has been used to select the response, it is no longer of value. Indeed, remembering that food had been, say, under the left plaque on previous trials would interfere with current performance. This type of memory, in which material is held for a short time and then discarded, is called ‘working’ memory and is clearly distinct from ‘long-term’ memory (Baddeley 1986). On the basis of this analysis, Goldman-Rakic proposes that the function of frontal cortex is to enable behaviour to be controlled by ‘inner representations’ rather than external cues. Does this analysis also apply to tests of ‘frontal’ function in humans? The Wisconsin Card Sorting Test is considered particularly sensitive to frontal damage (Milner 1963). In this task the subject has to sort cards on which there are designs varying in colour, shape and number. On first being presented with a card, the subject does not know on which of these dimensions t o base his responses. He has to proceed by trial and error, because after each selection the experimenter will tell him whether he was right or wrong. After some trials, the subject will discover the correct dimension and from then on his responses can be determined by the stimulus on the card. However, at this point, the experimenter changes the rule and the process begins all over again. This task clearly has the two critical features proposed by Goldman-Rakic: (1) the response is not sufficiently specified by the stimuli on the card; (2) ‘working memory’ is needed to record what happened on the immediately preceding trials in order to select the correct response. Many other ‘frontal’ tasks can also be shown to involve these two components. For example, in the fluency tasks, patients are asked to name as many words as they can think of beginning with the letter F in one minute, or to draw as many different abstract designs as they can. In these tasks the precise response required is not specified (‘name any animal’) and the subject must keep track of what he has just done in order to avoid repeats (Miller 1984, Jones-Gotman & Milner 1977). ‘Inner representation’ and social behaviour Prefrontal lesions, particularly of orbital cortex, can cause impairments in social behaviour For example, after prefrontal lesions, monkeys became socially incompetent, losing their place in the social hierarchy and becoming isolated (Myers et a1 1973, Butter & Snyder 1972). Why should ‘inner representation’ in working memory be relevant to social behaviour? Surely, in social interactions, all the relevant stimuli of voice and face are immediately present? Over the last few years, it has become apparent that ‘inner representations’ are more important

.

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for the regulation of social interactions than almost any other cognitive activity (Astington et a1 1988). When my wife says, ‘Do you want a cup of tea?’, the ‘correct’ response is to go and make the tea, not to say ‘yes’. In this case my behaviour is not regulated by the immediate stimulus (what she says), but by my knowledge of her wishes. My wife’s behaviour is determined by an inner representation (her wish for tea), and my behaviour is determined by an inner representation of her inner representation (my inference of her wish). This kind of representation is often called a ‘metarepresentation’ and is clearly fundamental to successful social interactions. The supervisory attentional system Shallice (1988, chapter 14) has outlined the sort of computational mechanisms that would be needed for the frontal cortex to regulate behaviour. He proposes that the frontal cortex subserves a ‘supervisory attentional system’ (SAS). In describing the functions of this system, Shallice makes a major distinction between routine acts and novel acts (where an act is a response directed towards a goal). The responses required in a routine act are completely specified by the immediately available stimuli. The various stimuli in the environment have the potential to elicit various acts. By competitive interaction, the act most appropriate to the pattern of stimulation will become dominant and its associated responses will occur. In this situation, the pattern of activation ‘represents’ the external stimuli. In a novel situation there is no appropriate act to become dominant. In this case, control is taken over by the SAS. The SAS imposes a pattern of activations on the various possible acts, based not on the current pattern of external stimulation, but on current goals and memories of how to achieve them. This imposed pattern of activation permits one act to become dominant and responses appropriate to the novel situation can occur. Shallice’s SAS is clearly designed to deal with situations in which the appropriate response is not sufficiently specified by the immediately available external stimuli. If Shallice’s formulation is correct, it has very important implications for the use of ‘frontal tests’. A task will only be a ‘frontal test’ for so long as it is novel. Thus, with practice, most tasks will cease to be frontal tests. There is evidence for this in a study by Risberg et a1 (1977), who showed that frontal cortex ‘habituated’ when a complex problem-solving task was performed more than once. Interactions between prefrontal cortex and other brain areas An important feature of both Goldman-Rakic’sneuroanatomical and Shallice’s computational considerationsis that frontal cortex does not function on its own. It is not that frontal cortex solves difficult problems, while temporal cortex solves easy ones. The frontal cortex solves difficult problems by interacting with other

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parts of the brain. Thus Goldman-Rakic proposes that visuo-spatial problems involve parietal-prefrontal connections, while problems that entail use of memory involve limbic-prefrontal connections. Shallice proposes that the SAS (frontal cortex) modulates lower-level systems (other parts of the brain) by activating or inhibiting particular schemata. PET scanning techniques are particularly suitable for studying interactions between prefrontal cortex and other parts of the brain. Descriptive PET studies of prefrontal cortex

In a great many pioneering Scandinavian studies (mostly using the conventional 33Xeinhalation method) it has been shown that many different tasks activate prefrontal cortex. The principal features of these tasks are that they are fairly complex and/or require the manipulation of mental images. For example, Lassen et a1 (1978) and Larsen et a1 (1978) have shown that both silent and normal speech activate the supplementary motor area (SMA). However, silent speech additionally activates areas of prefrontal cortex. Unlike normal speech, silent speech requires that we construct an image of the speech in our minds. Furthermore, there are no external cues which regulate silent speech. Roland & Friberg (1985) studied a series of purely mental tasks all of which activated prefrontal cortex. They report that, of all the tasks they studied, the one which generated the most prefrontal activity required subjects to imagine their living room and describe all the furniture in it. This is a clear example of behaviour being determined by a complex ‘inner representation’. More recent PET studies have looked at the effects of traditional ‘frontal’ tasks on brain activity indexed by changes in regional blood flow (rCBF). Weinberger et al (1986) have shown that performance of the Wisconsin Card Sorting Test activates prefrontal cortex. This was not the case with another task (number matching) in which responses were completely specified by the stimuli. Warkentin et a1 (1989) have shown that a verbal fluency task also activates prefrontal cortex. In both these studies it was found that the prefrontal cortex of schizophrenic patients was significantly less activated during the performance of these ‘frontal’ tasks. Experimental PET studies of prefrontal cortex

The subtraction technique developed by the St Louis group has revolutionized the study of cognitive activations using PET and is particularly suitable for identifying the precise role of various regions of prefrontal cortex. Such studies measure regional blood flow (rCBF) using I5O as tracer. rCBF gives an indirect measure of neuronal activity-facilitatory as well as inhibitory. The essence of the subtraction technique is to decompose a complex task into simple cognitive components that can be studied separately. If the essence of ‘frontal’ function

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is to take over routine activities for novel purposes, then it should be possible to study rCBF associated with the ‘routine’ component of the task and subtract this from the rCBF associated with the novel task. The difference should reveal prefrontal activity. Such a comparison was made in the study by Petersen and his colleagues (1988). The routine task was to read aloud words presented once a second. The novel task was to give a use for the words that were presented (e.g. cake-eat). The novel task activated a number of areas of prefrontal cortex on the left, including area 46. The novel task in this experiment differs from the routine task in two ways. First, the meaning of the stimulus word must be analysed. This is not necessary in the routine task, where it is sufficient simply to convert the print into sound. Second, the response to be given is not completely specified. Many correct responses are possible and the volunteer must choose one of these (e.g. cake-eat, cake-cut, cake-bake, etc.). Obviously, from the analysis of frontal tasks I have presented, I believe it is this latter component of the task that was associated with the prefrontal activation. The experimenters considered it was the analysis of word meaning. My colleagues at the MRC Cyclotron Unit and I have used the same technique to study ‘frontal’ tasks which we have previously used in the study of schizophrenic patients. Many such patients show ‘poverty of speech’. Not surprisingly, this type of patient produces an abnormally small number of words in a verbal fluency task (Allen & Frith 1983). In contrast, schizophrenic patients with incoherence of speech produce unusual or even inappropriate words. For example, when asked to name animals, they might say ‘aardvark’ or ‘chips’. In a PET study of normal volunteers, we used a verbal fluency task, a lexical decision task and ‘counting aloud’ to elicit changes in rCBF (Frith et a1 1991a). As far as possible, the rate of production in the three tasks was equated. In the verbal fluency task the subjects said as many words as they could beginning with the letter A. In the lexical decision task they heard a series of phoneme strings beginning with the letter L and indicated whether they were words or not by saying ‘correct’ (e.g. ‘lesson’) or ‘incorrect’ (e.g. ‘larrot’). In the counting task the volunteers counted aloud slowly (one number per two seconds) from one upwards. In contrast to counting and lexical decision, verbal fluency activated an area of dorsolateral prefrontal cortex on the left, largely coincident with area 46 (see Table 1). In contrast to counting, lexical decision activated an area of superior temporal cortex bilaterally. These areas are observed to be activated in other studies in which subjects had to listen to words. Of particular interest was the observation of reduced activation of superior temporal cortex in the verbal fluency task relative to counting. We have proposed that this reduction in activity reflects an interaction between prefrontal cortex and superior temporal cortex, by which the area of the brain associated with the routine analysis of words is taken over for the novel task of word production (Friston et a1 1991).

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TABLE 1 Talairach coordinates (mm)of most significanlly activated pixels in left dorsolateral prefrontal cortex

Coordinates Study ~.

-_____~

Petersen et a1 1988 Frith et a1 1991a Frith et a1 1991b, expt 1 Deiber et a1 1991 Frith et al 1991b,

expt 2

Task

X

Y

Z

Word generation (visual

-42

24

20

-34

22

-43

29

24 20

Four-choice random

-34

32

28

Two-choice random finger movement

-35

39

21

presentation) Free verbal fluency Paced verbal fluency joystick movement

In a second study of verbal fluency we followed up the observation of Petersen et a1 (1988), and contrasted semantic analysis with response production in the absence of sufficient specification (Frith et al 1991b). In each of the three tasks the subject heard a sequence of words. In the control (‘shadowing’) task, the subject simply repeated the words out loud as he heard them. In one experimental task, the subject said the opposite word (e.g. ‘hot’-‘cold’). This task requires semantic analysis, but the response is entirely specified by the stimulus, since the 20 words chosen all had a single, unambiguous opposite and the subjects had practised the task beforehand. No prefrontal activation was found in this task relative to the shadowing task. In the fluency task, subjects heard only the word ‘next’, at the same rate as the words in the other tasks, and had to respond with any word beginning with F. This task requires no semantic analysis of the stimulus word, but the response is very inadequately specified. With this task we observed activation in dorsolateral prefrontal cortex on the left (see Table 1) and reduction of rCBF in superior temporal areas, We conclude that this area of dorsolateral prefrontal cortex is activated when responses have to be generated that are not sufficiently specified by the stimuli. I have proposed that the features of the ‘negative’ type of schizophrenia which can all be described as ‘poverty of action’ (poverty of speech, flattening of affect, lack of volition), arise because these patients can no longer generate actions spontaneously (Frith 1987). In other words, while they can act in response to clear-cut environmental stimuli, they cannot act when the appropriate response is not sufficiently specified by the stimulus. This is the case, not just for the production of words, but for all kinds of actions. A consequence of a lack of spontaneity is that these patients often show stereotyped behaviour. In situations in which a series of random responses is required (e.g. specifically generating a random sequence, or guessing whether the next toss of a coin will be heads

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or tails), schizophrenic patients with negative features produced stereotyped response sequences (Frith & Done 1983). We have examined such tasks in another PET study of normal volunteers (Frith et a1 1991b). This experiment was modelled closely on the second verbal fluency study described above. In all conditions the experimenter touched the first or second finger of the subject’s right hand in a random sequence at the rate of one stimulus per two seconds. In the control condition the subject simply raised the finger that was touched. In the experimental condition the subject had to raise one of the two fingers ‘at random’, each time that one of the fingers was touched. In order to achieve ‘random’ responding, the volunteer had to choose each response independently of what had gone before. Sometimes he would move the finger that had been touched, but sometimes he would move the other. Sometimes he would move the finger he had moved on the previous trial, but sometimes the other. In the task in which responses had to be generated at random in this way there was bilateral activation of dorsolateral prefrontal cortex in an area showing considerable overlap with that observed in the verbal fluency studies (see Table 1). There were also areas of decreased activity associated with the random generation task. These were not in the superior temporal cortex, as in the verbal fluency studies, but in area 39 at the end of the angular gyrus. Lesions in this area are often associated with finger agnosia (e.g. Mazzoni et a1 1990). Such patients are unable to identify which of their fingers has been touched. Here again, we may be seeing an interaction between prefrontal cortex and a brain area associated with the routine performance of a particular task. In an independent study on motor control carried out at the MRC Cyclotron Unit by Deiber and her colleagues (Deiber et a1 1991)’ it was observed that having to make a sequence of random movements of a joystick into four different positions also activated area 46 bilaterally (see Table 1). In Table 1 are listed the coordinates in Talairach space of the areas of most significant activation in the five experiments I have just reviewed. The differences between these coordinates are within the limits of resolution of the technique, suggesting that these various tasks are activating a common area of prefrontal cortex. In every case, also, the critical feature of the task is that responses have to be generated which are not adequately specified by the immediate situation. Conclusions The experimental PET studies I have briefly described in this chapter suggest that a particular area of prefrontal cortex (area 46) is associated with a particular psychological process (generating responses when these are not sufficiently specified by the immediate situation). In addition, there is preliminary evidence that these studies can reveal some of the interactions between prefrontal cortex and more posterior parts of the brain. A defect in this psychological process

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is associated with avolitional behaviour in psychotic patients. In terms of ability t o function in society, this is probably t h e most incapacitating of the many features of schizophrenia. PET activation studies provide a means for elucidating the pathophysiological basis of this disorder.

Acknowledgements I am grateful to Richard Frackowiak, Karl Friston and Peter Liddle who were my collaborators in the studies described in this chapter. I am also grateful to all the members of the MRC Cyclotron Unit, especially the PET Methods Section, without whom this work would not have been possible,

References Allen HA, Frith CD 1983 Selective retrieval and free emission of category exemplars in schizophrenia. Br J Psychol 74:481-490 Astington JW, Harris PL, Olson DR 1988 Developing theories of mind. Cambridge University Press, Cambridge Baddeley AD 1986 Working memory, Clarendon Press, Oxford Blumer D, Benson DF 1975 Personality changes with frontal and temporal lesions. In: Benson DF, Blurner D (eds) Psychiatric aspects of neurological disease. Grune & Stratton, New York, p 151-170 Brodmann K 1925 Vergleichende Lokalisationslehre der Grosshirnrinde, 2nd edn. JA Barth, Leipzig Butter CM, Snyder DR 1972 Alterations in aversive and aggressive behaviors following orbital frontal lesions in rhesus monkeys. Acta Neurobiol Exp (Warsaw) 32525-565 Deiber M-P, Passingham RE, Colebatch JG, Friston K J , Nixon PD, Frackowiak RSJ 1991 Cortical areas and the selection of movement: a study with positron emission tomography. Exp Brain Res 84:393-402 Duncan J 1986 Disorganisation of behaviour after frontal lobe damage. Cognit Neuropsychol 3:271-290 Eslinger PJ, Damasio AR 1985 Severe disturbance of higher cognition after bilateral frontal ablation: patient EVR. Neurology 35: 1731- 1741 Friston KJ, Frith CD, Liddle PF, Frackowiak RSJ 1991 lnvestigating a network model of word generation with positron tomography. Proc R SOCLond B Biol Sci 244:lOI-lM Frith CD 1987 The positive and negative symptoms of schizophrenia reflect impairments in the perception and initiation of action. Psychol Med 17:631-648 Frith CD, Done DJ 1983 Stereotyped responding by schizophrenic patients on a twochoice guessing task. Psychol Med 13:779-786 Frith CD, Friston K J , Liddle PF, Frackowiak RSJ 1991a A PET study of word finding. Neuropsychologia, in press Frith CD, Friston KJ, Liddle PF, Frackowiak RSJ 1991b Willed action and the prefrontal cortex in man: a study with PET. Proc R Soc Lond B Biol Sci 244:241-246 Goldman-Rakic PS 1987 Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In: Plum F (ed) Handbook of physiology, section 1: The nervous system, vol 5 : Higher functions of the brain. Oxford University Press, New York (American Physiological Society, Bethesda) p 373-417 Goldstein K, Scheerer M 1941 Abstract and concrete behaviour: an experimental study with special tests. Psychol Monogr 43: 1- I5 I

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Jones-Gotman M, Milner B 1977 Design fluency: the invention of nonsense drawings after focal cortical lesions. Neuropsychologia 15:653-674 Larsen B, Skinhoj E, Lassen NA 1978 Variations in regional cortical blood flow in right and left hemispheres during automatic speech. Brain 101:193-209 Lassen NA, Ingvar DH, Skinhoj E 1978 Brain function and blood flow. Sci Am 239: October, p 62-7 1 Lezak MD 1983 Neuropsychological assessment. Oxford University Press, Oxford Mazzoni M, Pardossi L, Cantini R, Giorgetti V, Arena R 1990 Gerstmann syndrome: a case report. Cortex 26:459-467 Miller E 1984 Verbal fluency as a function of a measure of verbal intelligence and in relation to different types of cerebral pathology. Br J Clin Psycho1 2353-57 Milner B 1953 Effects of different brain lesions on card sorting. Arch Neurol9:90-100 Myers RE, Swett C, Miller M 1973 Loss of social group affinity following prefrontal lesions in free-ranging macaques. Brain Res 64:257-269 Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME 1988 Positron emission tomographic studies of the cortical anatomy of single-word processing. Nature (Lond) 331 585-589 Risberg J, Maximilian VA, Prohovnik I 1977 Changes to cortical activity patterns during habituation to a reasoning task. Neuropsychologia 15:793-798 Roland PE, Friberg L 1985 Localisation of cortical areas activated by thinking. J Neurophysiol 53: 1219-1243 Shallice T 1988 From neuropsychology to mental structure. Cambridge University Press, Cambridge Warkentin S, Nilsson A, Risberg J, Carlson S 1989 Absence of frontal lobe activation in schizophrenia. J Cereb Blood Flow Metab (suppl 1) 95354 Weinberger DR, Berman KF, Zec RF 1986 Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow (rCBF) evidence. Arch Gen Psychiatry 43:114-125 Wing JK, Wing L 1982 Psychoses of uncertain aetiology. Handbook of psychiatry, vol3. Cambridge University Press, Cambridge.

DISCUSSION

Porter: Would you or others here care to speculate about the relationship between increases in blood flow in one area and decreases in another area which you have identified, which may well be anatomically connected? Frith: I believe that these findings reflect a functional relationship between brain areas, and that the relationship is one of reciprocal inhibition. However, before this belief can be justified, there are many methodological problems t o be considered. Lassen: We need to know more about the method of data generation if we are t o interpret these studies. In many studies, arterial blood is not sampled. One then looks at the PET images generated using a standard arterial input curve and compares patterns, usually after normalizing the images to their mean value. In this case, for every increase relative to a control state there must by definition also be a decrease, which may not mean anything. But, so calculated, you must find some areas going down. Therefore, information on how you calculate your data is appropriate.

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Evans: It is certainly true that you must have a total density of positive and negative being equal but it’s a surprise if you get a negative change which is very focal. You can get positive peaks which are very focal and those can be counteracted by broad-based negative components. But if you get a focal negative change, it has to mean something specific to the task being tested or possibly to vascular artifacts. Friston: It is important to respond to the problem you bring up, Dr Lassen. The point is that if one normalizes the global activity, then one has (by definition) a5 many inhibitions (focal or not) as activations. However, this does not explain the observed negative correlations in activity between remote (but connected) brain areas when activity is repeatedly measured over time. We have observed these correlations in our longitudinal studies, which suggest that as one brain region increases its activity a functionally connected region shows evidence of decreased activity. This is further evidence in support of the notion that focal inhibitions or de-activations have a biological validity. Let me give you a concrete example. If postsynaptic receptors in the prefrontal cortex (e.g. D1 dopamine receptors) are inhibitory, decreased transsynaptic activity in that region would result in disinhibition of excitatory (glutaminergic) afferentation to remote areas-for example, the temporal cortices. In short, decreased prefrontal activity will be associated with increased temporal activity and the two will be negatively correlated. We have seen this fronto-temporal coupling many times. This sort of explanation depends on the simplifying assumption (which Dr Sokoloff sketched out for us earlier, p 43) that measured regional cerebral blood flow reflects transsynaptic activity. Zeki: When you obtain these selective attention mechanisms, can one account for them by saying that one area is actually inhibiting another one and that this entails an increase in blood flow? Porter: This was one of the issues that we were attempting to get people to address earlier. Fox: There may be simpler ways of looking at some of these results. The postulate has been made that global normalization in the presence of focal activation (increased CBF) will necessarily cause significant negative change, as well. That is clearly not the case, for the reason that Dr Evans has pointed out. Global normalization distributes the effect of the discrete activation(s) over the entire data set. This will not reach significance. When you find a statistically significant negative peak, that means something. Negative peaks are not a common finding when one compares activation to the simple, control state. Thus if you compare ‘eyes-closed rest’ to a robust stimulus, such as hand vibration, one does not find negative peaks (Fox et a1 1988). If one compares more complex behavioural states, particularly when they are not well matched, ‘negative changes’ are easily produced.

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Imagine the subtractive comparison of (1) visual stimulus, auditory deprivation, with (2) visual deprivation, auditory stimulus. Using either condition as the ‘control’ state, we will see both ‘positive’ and ‘negative’ activation. This in no way implies that these areas are mutually inhibitory, or that any inhibition has taken place. Frith: In the second verbal fluency study we were aware of this problem and we deliberately had words presented in both the fluency condition and the shadowing (control) condition; so it wasn’t simply that there was nothing to hear. If there was less of a response to the words that were being presented, this would have to reflect some sort of active habituation, or some process of non-attention. Fox: I wouldn’t argue against inhibition of mutually connected areas. A complex neural system may well inhibit some components t o amplify others. We have raised three different levels of possible explanation of ‘negative’ activation. Firstly, it could be due to global normalization, which I don’t believe. Secondly, it could be due to imperfect control of the behaviours. I think that can happen, although I wouldn’t say that it explains all that you have shown us, Dr Frith. Thirdly, it could imply inhibition and relate to system connectivity. This is the most interesting possibility. Your data give us indications that this may occur. Cholfet:Dr Frith, I have a question about your fluency task. I understand that you showed an increase of activity in the prefrontal cortex and a decrease in the posterior part of superior temporal gyrus. Richard Wise and I have found the opposite to this. I wonder if the explanation is that you compare the verbal task not to a rest state, but to a previous lexical task. So d o you think there is a real, active decrease of activity in Wernicke’s area during your verbal fluency task? Frith: In the first study we compared verbal fluency with counting, so there was no stimulus coming in; the subjects were generating words in both cases. That comparison shows a reduction in temporal cortex, particularly on the left. Jeannerod: Lesions of the dorsolateral prefrontal cortex, at least in the domain of language, produce very little effect. It would be interesting to look at remote metabolic effects in patients with such lesions, to see what areas are de-activated by the lesion. Fox: But a lesion restricted to Broca’s area produces very little lasting language disturbance, too. Cuppa: If you remove the entire left prefrontal cortex, sparing Broca’s area, the only language defect which is usually found is an impaired performance in controlled association or verbal fluency tests: Milner (1964), for example, reported a decrease in the number of words beginning with a given letter that the patient could provide in five minutes. These neuropsychological data, which have been replicated several times, are in total agreement with Dr Frith’s

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findings. On the other hand, patients with severe lexical-semantic defects, as indicated by impairment of word comprehension and word retrieval, usually have lesions which involve the left temporal lobe (Coughlan & Warrington 1978). Fox: Perhaps we are using the term ‘semantic’ in different ways. To ascribe to an area a role in semantic processes, or to describe a task as a semantic task, refers to the fact that subjects needed to access the meaning of the word, not more than that. Cuppu: I would call that a timed word retrieval task, then. Passinghum: The point, surely, of what Dr Frith was saying was that he didn’t believe that the lateral prefrontal cortex was involved in semantic processing. He would predict that a lesion would not produce a semantic impairment. Frith: Yes, that was precisely my point. Fruckowiuk: If we now put together the study described by Dr Friston, where we saw an interaction between a cognitive component and a pharmacological manipulation, and this rather concrete proposal, suggesting that there are changes in activity at the level of the dorsolateral prefrontal cortex which are dopaminergically mediated, and which then affect neuronal firing in the superior temporal gyrus, one can also conceive of a PET experiment for testing that specific hypothesis, by putting these two designs together. Cappu: Yes; because there is evidence that manipulation of the dopaminergic system has some effect on verbal fluency, at least in selected aphasic patients (Albert et a1 1988). Roland: We have to be very careful in speculating about the anatomical connections in man, which are basically unknown. We must be particularly cautious about speculating whether, in the macaque, prefrontal cortex connections correspond to those in the human. We shall not be able to solve the problem of whether one area is homologous to that of a monkey in the general sense. Dr Frith’s finding that there is a decrease in the auditory cortex during self-generation of words at a quite high level, but not at a more primitive level when subjects simply speak, amplifies some earlier findings by Bo Larsen with a similar technique (Larsen et a1 1978). He found a slight increase in the primary auditory area during counting. However, if you let the subjects report from their visual memory in order to produce fluent descriptive speech, you don’t see any increase in the auditory association areas (Roland et a1 1985). There might be an explanation for this. In monkeys, auditory association cortical neurons inhibit their firing activity during self-generated sounds. Dr Frith, in the finger movement task, was the frequency of finger movement when the fingers were touched comparable to the frequency of finger movement when subjects were free to move their fingers? I ask this because you found a decrease in the primary motor area. Frith: Their fingers were touched in both conditions. In the fixed condition they simply lifted the finger up when it was touched; in the ‘choice’ condition

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they lifted when a finger was touched, but they had to choose which finger to lift. So the rates were absolutely identical. Passingham: This was also true of the experiment by Deiber et al(l991) in which tones paced movements of the joystick; in that experiment we also found that the dorsal prefrontal cortex was activated when the subject generated the direction in which to move the joystick. Plum: Does it take as much energy to inhibit a response as it does to facilitate one? Porter: Or more? Plum: In other words, cannot the result be looked at as a passive functional failure rather than an active inhibition in the language area? Sokoloff: If it takes neuronal firing to release an inhibitory neurotransmitter, then it takes as much energy to release an inhibitory transmitter as it does to release an excitatory one. Porter: We clearly have some difficulty in making a simple translation between what a nerve cell generates in terms of impulses, whether this cell then produces inhibitory or excitatory connections, and anything about the energetics of the function subserved. But what we have to assume is that there will be a metabolic cost that is created both by inhibition and by excitation at the synaptic junctions where those actions occur. The question is whether or not the relative values of those metabolic changes in one whole zone of cortex, compared with another entire zone, will give the sorts of results which have been shown. Roland: There is a point which ought to be clarified here. People speak about presynaptic release, and the energy costs of that release. But there is another part of the story, namely the energy costs of postsynaptic depolarization. The two might not be the same. What we see with PET is both the presynaptic and the postsynaptic metabolic costs, plus the effect of the presynaptic activity on the astrocytes. Porter: Nerve cells are engaged in reconstituting their internal ionic environment, and metabolic activity occurs in glial cells to restore the extracellular medium. All of this exchange occurs in a time span which is probably consistent with measurement over the long periods of time for which many PET measurements are made, whether they be of metabolic activity or of the subsequent blood flow changes. MacKenzie: There is every reason to suspect that the blood flow and the metabolic response to the manipulation of a given neurotransmitter system will differ between systems. This is because, firstly, brain blood vessels respond to almost all neurotransmitters and, secondly, the cerebrovascular bed is probably the most richly innervated vascular bed in the body, in terms of multiple neuronal populations. There are already experiments that show that the quantitative metabolic costs of specific neurotransmitter manipulations are a function of that manipulation.

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Zeki: Dr Frith, the finger agnosia is the Gerstmann syndrome. Is that a specific defect? I thought it was associated with other defects. Can you get finger agnosia as a pure syndrome without aphasia? Frith: The current feeling is that the Gerstmann syndrome does not really exist as a special complex. You can certainly get parts of it on their own. I don’t know the answer to your question of the relationship between finger agnosia and aphasia, but finger agnosia is a well-documented problem. Cappa: There are two recent case reports of ‘pure’ Gerstmann syndrome due to focal left parietal lesions without any associated language defect (Roeltgen et al1983, Mazzoni et a1 1990); furthermore, the ‘syndrome’ has been transiently produced with cortical stimulation (Morris et al 1984). These ‘pure’ cases indicate that the co-occurrence of the four symptoms has some localizing value; this however does not necessarily support any unitary functional interpretation of the syndrome, as being due to a common physiopathological mechanism. Plum: If the Gerstmann complex occurs at all as a disorder, it is almost always accompanied by other manifestations of cerebral dysfunction. Several investigators doubt that it exists as a specific psychological manifestation of focal cerebral disease. Passingham: May I make a further comment on Dr Frith’s study? We can do studies with monkeys in which they act on the basis of information in working memory; but we can’t ask them to do what they like. The PET scanner allows us to look at something that only people can do-true voluntary action. Porter: That is an important point and is, of course, the reason we are holding this meeting!

References Albert ML, Bachman D, Morgan A, Helm-Estabrooks N 1988 Pharmacotherapy of aphasia. Neurology 38:877-879 Coughlan AD, Warrington EK 1978 Word comprehension and word retrieval in patients with localised cerebral lesions. Brain 101:163-185 Deiber M-P, Passingham RE, Colebatch JG, Friston KJ, Nixon PD, Frackowiak RSJ 1991 Cortical areas and the selection of movement: a study with positron emission tomography. Exp Brain Res 84:393-402 Fox PT, Mintun MA, Reiman EM, Raichle ME 1988 Enhanced detection of focal brain

responses using intersubject averaging and change-distribution analysis of subtracted PET images. J Cereb Blood Flow Metab 85542-653 Larsen B, Skinhoj E, Lassen NA 1978 Variations of regional cortical blood flow in the right and left hemispheres during automatic speech. Brain 101:193-209 Mazzoni M, Pardossi L, Cantini R, Giorgetti V, Arena R 1990 Gerstrnann syndrome: a case report. Cortex 26:459-467 Milner B 1964 Some effects of frontal lobectomy in man. In: Warren JM, Akert K (eds) The frontal granular cortex and behavior. McGraw-Hill, New York, p 313-331 Morris H H , Lueders H , Lesser RP, Dinner DS. Hahn J 1984 Transient neuropsychological abnormalities (including Gerstrnann’s syndrome) during cortical stimulation. Neurology 34:877-883

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Roeltgen DP, Sevush S, Heilman KM 1983 Pure Gerstmann’s syndrome from a focal lesion. Arch Neurol 40:46-47 Roland PE, Lassen NA, Friberg L 1985 Regional cortical blood flow changes during fluent speech in subjects with verified hemispheric dominance. J Cereb Blood Flow Metab 5 (suppl 1):205-206

Memory mechanisms in the processing of words and word-like symbols M. E. Raichle Mallinckrodt Institute of Radiology, Department of Neurology and Neurosurgery and McDonnell Center for Studies of Higher Brain Function, Washington University School of Medicine, St Louis, MO 631 10, USA

Abstract. Modern functional imaging techniques such as positron emission tomography (PET) provide the opportunity to examine in some detail the implementation of mental activities in the human brain. Using measurements of changes in local brain blood flow obtained with PET as a marker of changes in local neuronal activity we have examined the processing of single words and wordlike symbols. These studies reveal the very distributed, modular nature of this implementation and provide some preliminary insights into the role of memory

mechanisms in the process.

1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundalion Symposium 163) p 198-217

Changes in neuronal activity are accompanied by rapid ( < 1 second) changes in local blood flow and metabolism in the brain (Raichle 1987). Positron emission tomography (PET) accurately and rapidly measures changes in local blood flow (Raichle 1983, 1986). If we assume that all mental activity is accompanied by changes in local blood flow, PET is ideally suited to accomplish the task of relating changes in local neuronal activity to mental activity. Such studies reveal the distributed, modular and very flexible nature of the implementation of mental activity in the human brain (Petersen et a1 1988, 1990). The PET technique is especially important because it permits an examination of these distributed modular relationships in the normal human brain. In this paper I shall briefly outline a strategy employing PET measurements of changes in local brain blood flow. These measurements are obtained by subtracting measurements made in a control state from those made in a functionally activated state in the same subject. The measurements are then averaged across subjects (and occasionally within a subject) to improve the signal-to-noise properties of the resulting image. From such data emerges a map of the distributed modular brain organization underlying normal human cognition. Using PET measurements of local blood flow and strategies for accurately localizing these changes, the general topography of systems concerned with the analysis of words and word-like symbols is presented, along with some 198

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preliminary insights into the possible role of memory mechanisms in the process. The technique Emission tomography is a technique that produces an image of the distribution of a previously administered radionuclide in any desired section of the body. Positron emission tomography uses the unique properties of the annihilation radiation that is generated when positrons are absorbed in matter (Raichle 1983) to provide an image that is a highly faithful representation of the spatial distribution of the radionuclide at a selected plane through the tissue. Such an image is effectively equivalent to a quantitative tissue autoradiogram obtained with laboratory animals, but PET has the added advantage that it is relatively noninvasive and safe; hence, studies are possible in living animals, including humans. PET has been used in humans to measure brain blood flow, blood volume, the metabolism of glucose and oxygen, acid-base balance, receptor pharmacology and transmitter metabolism (for an introduction to this literature see Raichle 1986). In this paper I shall focus on the measurement of brain blood flow and its use in mapping the local functional activity within the normal human brain. Our strategy for the functional mapping of neuronal activity in the human brain with PET is composed of a number of important elements. These include the deliberate selection of blood flow measured with the PET adaptation of the Kety autoradiographic technique (Herscovitch et a1 1983, 1987, Raichle et a1 1983), or estimated from the radioactive counts accumulating in brain tissue during 40 seconds following the intravenous bolus administration of H2I5O (Fox et a1 1985), as the most accurate and flexible signal of changes in local neural activity that can be detected with PET (Fox et al 1988a). Linearly scaled images of blood flow or radioactive counts in a control state are subtracted from images obtained during functional activation in each subject (i.e. paired image subtraction). The control state and the stimulated state are carefully chosen so as to isolate, as far as possible, a single mental operation (e.g. Petersen et a1 1988). By subtracting blood flow measurements made in the control state from each task state we can identify those areas of the brain concerned with the mental operations unique t o the task state. This extends to our work a strategy first introduced to psychology by Donders in 1868, in which reaction time was used to dissect out the components of mental operations (Donders 1969). In our work we can now d o so in terms of specific regions of the brain. These subtraction images form the basis of a data set that is composed of averaged responses across many individual subjects or across many runs in the same individual. Image averaging dramatically enhances the signal-to-noise properties of such data. This enables us to detect even low level responses associated with mental activity (Mintun et a1 1989, Fox et a1 1988b).

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Functional mapping studies

For several years now we have been examining the cortical anatomy of single-word processing (Petersen et a1 1988, 1989, 1990) as an initial step in the study of language. Because of the great complexity of language, restriction of our efforts to an understanding of the processing of individual words seemed warranted. Furthermore, the design of tasks appropriate for such studies with PET was greatly aided by existing knowledge in cognitive psychology, linguistics and clinical neurology (e.g. LaBerge & Samuels 1974, Coltheart 1985, Damasio 1984). In our initial sfudies (Petersen et a1 1988, 1989) we used four behavioural conditions in each subject to form a three-level subtractive hierarchy in which each task state was intended to add a small number of mental operations to those of its subordinate (control) state. In the first-level comparison, the visual presentation of single words without a lexical task was compared to visual fixation on small cross-hairs on a television monitor without word presentation. Words were presented for 150 ms at the rate of once per second on a television screen during the 40 second measurement of blood flow. No motor output or volitional lexical processing was required in this task; rather, simple sensory input and involuntary word-form processing were targeted by this subtraction. The areas of brain identified as active during the passive viewing of words appear to support two different computational levels, one of passive sensory processing in primary visual cortex and a second level of modality-specificwordform processing in extrastriate areas. The main regions activated were in striate cortex bilaterally and extrastriate areas medially and laterally on the left and the right extending to the temporo-occipital boundary laterally. The primary striate responses were similar to those produced by simple sensory stimuli such as the checkerboard annuli used in our earlier experiments (Fox et a1 1986, 1987). The regions in extrastriate cortex became candidates for a network of cortical modules that code for visual word form. Experiments were then undertaken to determine the possible role of extrastriate areas in the processing of seen words (Petersen et a1 1990). Four stimuli were chosen: false fonts (letter-like symbols grouped into units of word length); consonant letter strings; pseudo-words; and words. Four hypotheses emerged from this study: (1) If the extrastriate areas observed with words are concerned with the processing of the simple visual features of the stimulus, then all of these stimuli should produce the same response. (2) If some of the extrastriate areas are concerned with a letter level of analysis, then only the latter three stimuli would activate them. (3) If some of the areas are concerned with the orthographic regularity (i.e. word form) of the stimuli, then only the latter two stimuli would activate them. Finally, (4) if some of the extrastriate areas are concerned with the analysis of words themselves, then only seen words should produce a response.

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The results of this experiment (Petersen et a1 1990) dramatically demonstrated that a probable group of closely clustered areas located anterior to V1 medially on the left was activated by words and non-words, both of which obeyed the rules of the English language, and not by consonant letter strings or false fonts. Common to all stimuli were bilateral responses extending inferiorly from occipital cortex into temporal. Taken together the several regions of striate and extrastriate cortex activated by passively viewed words appear to combine, functionally, to analyse visual symbols according to their features, which includes the fact that they behave according to rules of the English language. This latter observation demonstrates the degree to which brain organization is affected by learning. Words presented auditorily, with subjects passively fixating visually on the cross-hairs, activated an entirely separate set of areas in temporal cortex bilaterally (Petersen et a1 1988, 1989). Areas in left posterior temporal cortex (appropriate candidates for Wernicke’s area) were clearly seen with auditory presentation but were conspicuous by their absence during the passive presentation of words visually. Only when subjects were asked to judge whether pairs of visually presented words rhymed were responses seen in these areas (Petersen et a1 1988, 1989), emphasizing the functionally flexible nature of these modular relationships. In the second-level comparison, subjects were asked to repeat the words presented auditorily or visually. The control state for the PET blood flow subtraction was the passive presentation of auditory or visual words. Areas related to motor output and articulatory coding were activated. In general, similar regions were activated for visual and auditory presentation. Responses occurred in primary sensorimotor mouth cortex bilaterally, the supplementary motor area (SMA), and in insular cortex bilaterally. The left insular response is near Broca’s area, a region often viewed as specifically serving language output. But similar insular activation was also found when subjects were instructed simply to move their mouths and tongues (unpublished), arguing against specialization of this region for speech output. In the third and final level of comparison, subjects were asked to speak a verb for a seen or heard noun (i.e. a conditional associative task), again while monitoring a fixation point. The control state for this task was speaking the seen or heard noun. Responses were identified in four areas of the cerebral cortex for both auditory and visual word presentation: (1) the left lateral inferior prefrontal cortex; (2) the anterior cingulate cortex; (3) the left posterior temporal cortex in the area of the middle temporal gyrus, which was active only when we increased the inter-stimulus interval to 1500 ms from lo00 ms (unpublished); and (4) the insular cortex bilaterally which, in contrast to the other cortical areas just mentioned and the cerebellum (below), showed a decrease in activity when compared to simply speaking the seen or heard noun.

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One of the surprising features of this task was the responses observed in the right lateral cerebellar hemisphere. Because our control state for this task was speaking the seen or heard noun, we are confident that we subtracted the motoric aspects of simply saying words which would clearly be expected to activate the cerebellum. Furthermore, we had already shown that to simply speak a seen or heard noun activates more medial areas in cerebellum bilaterally and not the areas in the right lateral cerebellum revealed in this task. This result strongly suggested t o us that the cerebellum plays an important role in high level information processing involving a task that engages the left prefrontal cortex. This is the first direct evidence in support of the hypothesis that the cerebellum has an important part to play in high level information processing in normal humans, as hypothesized by others (Leiner et a1 1989, Berntson & Torello 1984, Bracke-Tolkmitt et a1 1989). Further studies in our laboratory (M. E. Raichle, J. A. Fiez, S. E. Petersen & T . 0. Videen, in preparation) of this interesting conditional associative task (‘say a verb’ for a seen noun) reveal significant improvement in performance (i.e. in reaction times and errors) with practice over as few as six trials. This effect of practice is accompanied by striking changes in the cortical organization just described (above). Practice results in a significant reduction in the activity in left prefrontal cortex, anterior cingulate cortex, left posterior temporal cortex and the right cerebellar hemisphere. Accompanying these reductions was an increase in activity in the insular cortex bilaterally. These very dramatic and statistically significant changes in brain functional organization with practice cause the brain organization of the behaviour in the learned state to resemble that of simply repeating a seen noun, a highly overlearned and automatic task for most fluent readers. We believe these results provide us with the first glimpse of the functional circuitry underlying procedural memory or so-called habit learning in the normal human brain (Mishkin & Appenzeller 1987, Squire & Zola-Morgan 1988). Noteworthy is the fact that the famous amnesic patient H. M. can learn this task quite normally (J. A. Fiez, S. E. Petersen & M. E, Raichle, unpublished). One final study (L. R. Squire, J. G. Ojemann, F. M. Miezin, T. 0. Videen, S. E. Petersen & M. E. Raichle, in preparation) deserves mention as we consider the role of memory mechanisms in the processing of words. In this study we wished to determine whether the explicit recall of recently seen words would activate classical areas of the limbic system associated with declarative memory (i.e. the hippocampus, amygdala and related structures: Squire & Zola-Morgan 1988). In this PET study, normal subjects were asked to recall words from a previously presented visual list in response to the visual presentation of word stems (i.e. the first three letters of a word). The striking feature of our results was the fact that only the right hippocampus was activated by the memory features of this experiment, suggesting that the task was processed as a visual recognition task rather than a linguistic task involving visual word form and

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meaning. Conspicuous by their absence were the left hippocampus and the right and left amygdala. These results are entirely consistent with the very interesting work of Levy & Trevarthen (1977) on patients with corpus callosum section in relation to hemisphere specialization for visual analysis. Additionally, the results demonstrate the feasibility of studying classical aspects of memory processes in normal human subjects with PET. Conclusions

This brief review is intended to demonstrate that a combination of cognitive and neurobiological approaches to the study of normal human subjects, aided by modern imaging techniques, can give us important new information about the flexible, distributed, modular organization of cognition in the normal human brain. Progress in our evolving understanding of the implementation of mental activities in the human brain will be dependent upon an appreciation of the distributed nature of the processing. Inferences drawn about the role of specific local neuronal ensembles in particular mental activities must be guided by the knowledge that an ensemble may be only a part of a very distributed network in which local areas of the brain contribute highly specialized component functions. Continued progress in this type of work should serve to enlighten us about the solution to the problem of mind-brain interaction that has intrigued us for so long. Finally, one must hope that the insights gained will provide a more rational basis for the understanding and treatment of some of man’s most devastating diseases.

Acknowledgements This work was supported by grants NS 06833 and HL 13851, and by the MacArthur Foundation.

References Berntson, GG, Torello MW 1984 The paleocerebellum and the integration of behavioral function. Physiol Psycho1 10:2- 12 Bracke-Tolkmitt R, Linden A, Canavan AGM et a1 1989 The cerebellum contributes to mental skills. Behav Neurosci 103:442-446 Coltheart M 1985 Cognitive neuropsychology and the study of reading. In: Posner MI, Marlin OSM (eds) Attention and performance XI. Lawrence Erlbaum Associates, Hillsdale, NJ, p 3-37 Damasio AR 1984 The neural basis of language. Annu Rev Neurosci 7:127-147 Donders FC 1969 On the speed of mental processes. Reprinted in Acta Psychologica 30:412-431

Fox PT, Perlmutter JS, Raichle ME 1985 A stereotactic method of anatomical localization for positron emission tomography. J Comput Assisted Tomogr 9:141-153 Fox PT, Mintun MA, Raichle ME et a1 1986 Mapping human visual cortex with positron emission tomography. Nature (Lond) 323:806-809

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Fox PT, Miezin FM, Allman JM, Van Essen DC, Raichle ME 1987 Retinotopic

organization of human visual cortex mapped with positron-emission tomography. J Neurosci 7:913-922 Fox PT, Raichle ME, Mintun MA, Dence C 1988a Nonoxidative glucose consumption during focal physiologic neural activity. Science (Wash DC) 241 :462-464 Fox PT, Mintun MA, Reiman EM, Raichle ME 1988b Enhanced detection of focal brain responses using intersubject averaging and distribution analysis of subtracted PET images. J Cereb Blood Flow Metab 8542-653 Herscovitch P, Markham J , Raichle ME 1983 Brain blood flow measured with intravenous H,ISO. I. Theory and error analysis. J Nucl Med 24:782-789 Herscovitch P, Raichle ME, Kilbourn MR, Welch MJ 1987 Positron emission tomographic measurement of cerebral blood flow and permeability surface area product of water using "0-water and "C-butanol. J Cereb Blood Flow Metab 7527-542 LaBerge D, Samuels SJ 1974 Toward a theory of automatic information processing in reading. Cognit Psycho1 6:293-323 Leiner HC, Leiner AL, Dow RS 1989 Reappraising the cerebellum: what does the hindbrain contribute to the forebrain? Behav Neurosci 103:998-1008 Levy J, Trevarthen C 1977 Perceptual, semantic and phonetic aspects of elementary language processes in split brain patients. Brain 100:105-1 18 Mishkin M, Appenzeller T 1987 The anatomy of memory. Sci Am 256:80-89 Mintun MA, Fox PT, Raichle ME 1989 A highly accurate method of localizing regions of neuronal activation in the human brain with positron emission tomography. J Cereb Blood Flow Metab 9:96-103 Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME 1988 Positron emission tomographic studies of the cortical anatomy of single-word processing. Nature (Lond) 331:585-589

Petersen SE, Fox PT, Posner MI, Raichle ME, Mintun MA 1989 Positron emission tomographic studies of the processing of single words. J Cognit Neurosci 1:153-170 Petersen SE, Fox PT, Snyder AZ, Raichle ME 1990 Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science (Wash DC) 249: 1041 - 1044 Raichle ME 1987 Circulatory and metabolic correlates of brain function in normal humans. In: Plum F (ed) Handbook of physiology, section 1: The nervous system, vol5: Higher functions of the brain. Oxford University Press, New York (American Physiological Society, Bethesda) p 643-674 Raichle ME 1983 Positron emission tomography. Annu Rev Neurosci 6:249-268 Raichle ME 1986 Neuroimaging. Trends Neurosci 9525-529 Raichle ME, Martin WRW. Herscovitch P, Mintun MA, Markham J 1983 Brain blood flow measured with H2I50. 11. Implementation and validation. J Nucl Med 24~790-798 Squire LR, Zola-Morgan S 1988 Memory: brain systems and behavior. Trends Neurosci 11: 170-175

DISCUSSION Wise: How many trials did the patients have, to get practised in t h e tests? Raichle: In the experiment I presented it was six repetitions. You get a plateau in response time at that point. The question has arisen whether, if you practised over long times, you would achieve anything like the speed of just repeating

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the word. The only person with that kind of exposure is Julie Fiez, the graduate student directly involved in these experiments, and she claimed she’s coming close. Lassen: When one sees that training attenuates the ‘red islands’ so markedly, it seems that the better you are at a task, the less you use of your cortex! Handwriting experiments by Dr Mazziotta (involving writing your signature with the ‘wrong’ hand) tell a similar story. What are we using the cortex for? Mainly for coping with the difficulty or novelty of the task, and not so much for actually performing it? Mazziotta: In that experiment, when a normal person wrote his or her name, which is a very overlearned task, the largest PET response was in the striata; a minimal response occurred in the frontal cortex. When subjects wrote their name with their non-dominant hand, it was the reverse; there was no response in the striata and a large response in the contralateral frontal cortex. When patients with early Huntington’s disease did this task, there was little or no glucose metabolism in their striata; their primary response was all cortical, although they were very practised at the task. So the system may be reciprocal in a protective way. Our conclusion was that learning a task could cause a transfer of the running of the task from one site of the brain to the other, and at that time we predicted it would also occur when the person viewed the task as automatic (they could do something else at the same time). This was speculative, but seemed reasonable. But then, when the striatal system was taken away, as in the Huntington’s disease patients, again through post-experiment interrogation, we found that their performance was maintained in the cortex at the expense of automaticity. Those patients said that they had to focus on doing the task, whereas normal subjects didn’t have to focus with the dominant hand but did with their non-dominant hand. So a reciprocal system involving automatic subcortical structures and ‘manual’, non-automatic cortical sites seemed plausible. Lassen: Was there any subcortical activity in your subjects when they were highly trained, Dr Raichle? Mazziotta: Or was there any area that went up? You showed areas that went down in activity. Raichle: The changes were highly reciprocal. Left frontal, cingulate and temporal cortices and the right cerebellum were reduced, whereas sylvian-insular cortex was increased bilaterally with practice. Our interpretation is that we are dealing with two parallel pathways, an automatic pathway (sylvian-insular) that deals with highly overlearned activities such as repeating words, and a nonautomatic pathway. We believe that the cerebellum plays a key role in guiding the learning process. Mazziotta: In our earlier experiments we didn’t have a big enough axial view to look at the cerebellum as well as the cerebrum, so we had no data there.

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Another comment is that we have done visual tracking of finger movement. As we slowed the rate of a stimulus, the magnitude of the blood flow response in the SMA progressively went up. We reduced the rate to the point where the moving target went from almost continuous movement to a pause-so there was a time when there was no action, no output, but there was preparation for the movement. Is that like your paradigm? Raichle: We increased the interval between stimuli from 850 ms to 1350 ms (i.e., words were presented every 1500 ms for 150 ms) in the latest experiments as compared to our original language work (Petersen et a1 1988). This apparently modest change resulted in the dramatic increase in activity in the left posterior temporal cortex observed in the present experiments (p 201). Two camps have formed in the lab: one view is that this region in temporal cortex is a verbal memory buffer; the other is that subjects can now do better semantic processing because of the slower rate and this area is concerned with semantic processing. We are now starting experiments that will allow us to decide between those two hypotheses. Fox: You described a decrease in activity in the posterior frontal area, in the insular cortex, which I take it is in Broca’s area or close to that-an area clearly involved in speech production. I would like to offer a speculation on that. When people do the ‘repeat’ task, they never miss; they respond very quickly every time the word is presented. When subjects do a verb generation task, particularly on a new word list, they generate words only about 40% of the time; the other times they freeze and don’t generate a response. Thus, as people practise, they will be speaking more and more. So, in a comparison between repeating words and generating verbs from a novel list, one would predict that Broca’s area would be less active in the latter because the subjects are talking less often. As they learn the word list and their production goes up to loo%, it will appear that you are getting a negative activation. Raichfe: We anticipated this point. That was why, in the behavioural studies that led up to the final set of experiments, we looked at this. We wanted to study a task in which the confounding variable is not the voice envelope. We actually find, at the slower rate of word presentation used in these experiments, that the voice output-the motor output-is identical in the learned and nonlearned condition. The reaction time, however, is less. You would also anticipate, at least in MI and SMA, that if there was less output, activity (i.e,, blood flow) in primary motor cortex and SMA would be less. But in these experiments that was not found. So we have excluded that interpretation. Friston: A conceptual point that we have had to deal with in studies of procedural learning (of sequences of finger movements) is the nature of the plastic changes underlying learning. It seemed to us that the activation effect could only be attenuated as learning took place. The alternative, namely an augmentation of the activation effect over trials, would produce an enhanced activation at the end state of a skill being learnt. Considering all the skills one

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has to learn, this would leave one with a fairly busy brain! Are you saying, therefore, that the insula show increases in activity as the performance becomes automatic, or that a decrease is attenuated? Raichle: The latter is the better way of putting it. The activity in sylvian-insular cortex was less in the naive condition, and then it came back up to levels at which you would be normally producing speech. It was re-engaged. Warrington: Dr Raichle, you use the concept ‘repeat’ as if repeating a word was a simple task that can be used as a control for more complex operations, the activity of the one to be ‘subtracted’ from the other. One of4he main problems with this methodology is the necessity for the subtraction manipulation. I am not convinced that having t o speak aloud a word that starts with three given letters maps onto the repetition condition. These two tasks are completely orthogonal and a simple subtraction may not be appropriate. On a more general point about word repetition, in neurology we know that the repetition task itself can be successful with some task demands and not in others (McCarthy & Warrington 1984). In other words, task-specific repetition deficits are observed. The ‘transcortical motor aphasic’ is the patient who can repeat words and cliches but, if the repetition task requires attention (such as repeating a novel word or sentence), he fails. Conversely, the ‘conduction aphasic’ is the patient who makes phonological errors on the passive repetition task but if he is forced to think about what he is repeating before responding, it comes out fairly accurately. Thus selective deficits occur, depending on the conditions of testing, in tasks where the requirement is merely to repeat one word. The crucial difference appears to be where the word to be repeated is actively attended to or merely passively repeated. Raichle: I would certainly agree. I would also say that the way in which you describe it causes me to reflect on the differences in functional anatomy we observe during repeating a seen noun, or the well-rehearsed saying of a verb for a seen noun (identical functional anatomy by PET), as compared to the functional anatomy observed when naively saying a verb for a seen noun. Could it be that the conduction aphasic has a lesion in the sylvian-insular pathway which we assign to more routine responses, and the transcortical motor aphasic has a lesion affecting one or more components of our left frontal, left temporal, cingulate, cerebellar circuitry? Warrington: Yes, this is a very plausible hypothesis. However, the critical lesion for transcortical motor aphasia is likely to be more posterior in the superior parietal lobe of the left hemisphere. Porter: I wonder if you, Dr Raichle, or any of the others here who are interested in language, have thought of dealing with the situation by delaying or distorting the auditory component of the words produced? For example, what if the word were delayed in time? Has that sort of experiment been used in these situations?

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Wise: We have thought about this. We got on to the question of how you monitor your own speech, and whether it’s pre-articulatory, which is the current psychological view, and you check your output before you make a sound; or do you monitor your speech after you have spoken and heard it? Frith: This is relevant to my interest in schizophrenia, because I believe that auditory hallucinations reflect some sort of abnormality of this selfmonitoring process. We haven’t yet designed an experiment in which to study speech, but we have recently completed an experiment on the monitoring of eye movements. We looked at exactly this problem, of contrasting the situation where the world ‘out there’ moves, while your eyes stay still, and the situation where the world stays still but you move your eyes. The movement on the retina in the two conditions is more or less the same. Preliminary results suggest that V5 only lights up on PET when there is actual movement out there, and not when you are simply moving your eyes. This suggests that responses to movement are switched off when the movement is self-generated. Zeki: This must be seen against the background of physiological results which show that the cells in V3 and V3A are often sensitive to the animal’s direction of gaze. Porter: And this is related to something which may be akin to saccadic suppression? Frith; Yes, 1 am sure that is a similar phenomenon. Chollet: How do you explain the cerebellar activation, Dr Raichle? Is it a purely motor activation, and why is it so lateralized? Ruichle: We do not think it is motoric, because the motor activity in the control state and in the state we were testing was the same, as far as we could measure it. And, furthermore, the motor activity generated in the control state (repeating words) in the cerebellum was different from the activity in the cerebellum during the verb-generating task, which involves at least two areas in the right lateral cerebellar hemisphere. So I think that the cerebellar activity we observe during verb generation is not due to motor activity as such. Illustrative of the possible role of the cerebellum in naive verb generation was a patient whom we studied (Fiez et al 1990) with infarction of his entire right cerebellar hemisphere. Although he recovered almost completely from his initial ataxia and limb and hand incoordination, he was unable to learn the verb generation task. He made many errors which he did not notice and showed no improvement in the speed of his performance. All of this difficulty occurred despite above-average intelligence and otherwise completely normal language function. Lussen: Could I ask a little more about the cerebellum? The activation of the cerebellum that Per Roland showed us was near the midline, and Bob Collins’ data in animals also show that the motor component of the cerebellum is close to the midline, and that the lateral hemisphere is not engaged.

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Roland: That is basically correct, if you look at the anterior lobe of the cerebellum with PET in sensory-motor tasks. However, in some sensory-motor tasks, we also find activation of the posterior lobe of the cerebellum. We have also shown that during learning, regional oxidative metabolism increases in the lateral cerebellum. But we do not understand the connections of the cerebellum very well in man, not even in higher primates. They are known for the macaque, but even with different monkey species there are such big differences in the construction of the dentate nucleus, receiving especially from the lateral part of the cerebellar hemisphere, that it would be difficult to transfer data from monkey to man. I agree that there is probably a lot of ‘cognitive activity’ going on in the cerebellum, that we are not able to explain on an anatomical basis yet. Porter: In sub-primate animals, such as the rat, evidence has been obtained for a role of olivo-cerebellar connections in learning, in particular the learning of motor skills (Llinas et a1 1975, Ito & Mijishita 1975). Cappa: Your finding of right hippocampal activation is unexpected for a verbal memory task, Dr Raichle. The word-stem paradigm is however very complex; preserved lexical priming has been observed not only in amnesic subjects, but also in aphasic patients with left hemisphere lesions (Blumstein et a1 1982). It would be extremely interesting to see whether you get the same laterality effect using PET to study some simpler verbal memory tasks, such as word list learning, and to compare this with visual memory activation. Raichle: Had we known the complexity of this experiment, we might have started off on a simpler one! Nevertheless, it has provided us with very useful information. I think the laterality of the hippocampus is incontrovertible, and will be reproducible. Corbetta: More on the role of the cerebellum in cognitive processes. Ivry & Keele (1 989) have reported an interesting timing deficit in cerebellar patients. These patients had problems in producing and maintaining a simple finger rhythm, but also in judging interval durations between two lights without any motor output. The deficit in timing function, therefore, extends beyond a motor domain into a purely perceptual task. Raichle: Dr Larry Squire, in conjunction with Steve Kosslyn (personal communication), looked at the priming aspects of the word-stem, memory experiment, in parallel with what we are doing. They presented word-stems to normal individuals. They get priming only when word-stems are in the left visual hemifield-that is, are presented to the right hemisphere. The difference again is dramatic. Gulylfs: It is! In a series of experiments we investigated the cortical areas involved in the discrimination processes of a ‘feature uncertainty’ type of paradigm. In preliminary single-feature tasks the subjects were cued before stimulus presentation with respect to those stimulus features which were to be discriminated (either orientation or spatial frequency of pairs of gratings with identical spatial frequencies or orientations, respectively), whereas in a ‘feature

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uncertainty’ type of paradigm, the subjects were only cued after stimulus presentation with respect to the stimulus feature which had to be discriminated (the gratings differed both in orientation and in spatial frequency, and one of the two was indicated by the colour of a light-emitting diode [LED] after the pair of gratings had already been presented). This latter task imposes an extra work load on working memory as well as on attentional processes. In the feature uncertainty task, in addition to the activation of those areas involved in the single-feature orientation and spatial frequency discrimination processes, there were strong activations bilaterally in the superior frontal gyri, as well as unilaterally in the right hippocampus. It is also worth mentioning that in another series of experiments, in a form discrimination task we also found unilateral activation in the right hippocampus, whereas in colour or disparity discrimination tasks we did not find marked activation in the hippocampi. Friston: I was intrigued by the right laterality of the hippocampal activation and I am trying to find a reconciling explanation, given the parahippocampal activation we presented earlier, with strong left lateralization when remembering words. The task we used was explicitly lexical in nature, whereas yours was more along the lines of visual pattern recognition, with part words and graphemic cues. I am wondering whether the fact that the patterns were words is something of a ‘red herring’. If there is left lateralization for lexical processing and right for visual recognition memory, then there is a nice double dissociation in our data sets. Raichle: I agree with that! Jeannerod: It is known that animals with a unilateral vestibular lesion (e.g., hemilabyrinthectomy) will compensate for their defects within days or weeks, according to the size of the animal. In cats, most of the recovery is achieved within about two weeks. If, however, the vestibular cerebellum has been removed before the vestibular lesion, compensation of the vestibular deficit will never occur (Courjon et a1 1982).This is good evidence that the cerebellum is important for compensatory processes during recovery. Mazziotta: Dr Harry Chugani at UCLA has studied children who have had hemidecorticectomies (for epilepsy), which leave basal ganglia and thalamus intact. Using PET one sees a contralateral pancerebellar hypometabolism for glucose, in dentate nuclei and cortex. The cerebellum recovers over a period of about 10 years; we have seen in one subject a reverse situation, where the contralateral cerebellum actually has a higher metabolic rate than the side of the corticectomy. This is different from adult patients with focal cerebral lesions, as Dr Baron has described, where only cortical changes in cerebellar glucose metabolism are found contralateral to the injured cerebrum, sparing the dentate nucleus. These patterns might be of interest in terms of the site-specific lesionorientated components of the process. Baron: Dr Raichle, you now report, in the modified word generation

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paradigm, significant activation in Wernicke’s area and surrounding posterior temporal cortex. But in your original paper (Petersen et a1 1988), one of the main points was that your data suggested that you could generate semantic tasks without going to the lexicon area. How do you reconcile these discrepant findings? Raichle: All I can do is say how the results differed in terms of experimental design. In the most recent study (p 201), the inter-stimulus interval was increased by 500 ms. If you go back to the original experiment (Petersen et a1 1988), you can see a hint of this response in the posterior left temporal lobe in the original data, but, because it was below our statistical level of cut-off, it was not discussed or even mentioned. Baron: So what is your interpretation, in terms of neural networks and distributed systems? Raichle; One interpretation is that it’s in the verbal memory buffer; the other is that it is concerned with some aspect of semantic processing that was made more difficult by the shorter inter-stimulus interval in the original experiment. Wise: That’s an interesting idea, that you are seeing activation in the verbal short-term memory system. In your later study (Petersen et a1 1990) you presented strings of pseudo-letters or letters (nonsense fonts, consonant letter strings, non-words and real words). You found for the non-words and real words a left-lateralized medial extrastriate blob on PET. You suggest, plausibly, that this is the site of the visual word-form system. It could equally be some kind of short-term trace of visually presented words. Rapid presentation of pseudoletter strings or unpronounceable consonant strings may not result in a shortterm memory trace, but words which obey normal orthographic rules, even if they are meaningless words, may be remembered, at least for a few seconds. This brief memorization may be automatic, even if the subjects have not been explicitly asked to remember the stimuli, because that’s the way this system is organized. Could left medial extrastriate cortex be the site of the visual verbal short-term memory store? Raichle: It’s certainly an interesting idea. Evans: In relation to Dr Baron’s question, we have investigated the question of semantic processing. We first used a typical single-word recognition study (animal names). We found the extrastriate and inferior frontal activation that the St Louis group observed, as well as an inferior temporal focus. We then asked subjects to tell us whether the animals have horns, tusks or antlers-we were asking for attributes of the animals. We see what could be a semantic, interpretive response in the posterior superior temporal area. The inferior frontal response seems to have been reduced. There’s no component of that in the second study. Porter: At this stage we might take up the issue of what may happen during brain development, as revealed by PET, and ask what happens to changes in regional metabolism as brain functions are acquired in childhood.

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Muzziottu: Dr Harry Chugani at UCLA has studied glucose metabolism using PET and fluorodeoxyglucose in patients, to illustrate the metabolic maturation of the human brain, in terms of the qualitative pattern from the first few days of life until one year, at three different anatomical levels, compared to that of a normal 28-year-old adult. These children had had one or two seizures and it was for that reason they were scanned. Dr Chugani continued to follow them, and verified that they developed normally with no subsequent seizure activity. Later, he has been doing such studies on children who are presumed to have normal brains and nervous systems but are having fluorodeoxyglucose PET evaluations for cardiac reasons. Hc sees a stereotyped pattern of glucose metabolism which is highest in the brainstem and central part of the cerebellum, in the thalami, and then in the sensory motor cortex, particularly in somatosensory and motor cortices, initially more so than in visual and auditory cortex. The next thing to appear is a more complete activity in the cerebellar hemispheres and the striatum, which appears equal to the thalamic activity by about the third month of life. At that time also, areas adjacent to primary sensory-motor cortical zones become more metabolically active, leaving, by the second half of the first year of life, the neocortical zones as the most underdeveloped metabolically. The last area to achieve the qualitative pattern of the adult is prefrontd cortex, which reaches adult levels of metabolic activity between 7-8 months and one year. So there is a stereotyped pattern which has been verified with a high resolution PET scanner and is beginning to be confirmed in children with presumably normal nervous systems. There’s also a distinct quantitative pattern for each site in the brain, with a curve of metabolic activity that is lower than the adult value at first, but reaches a value 2-3 times greater, and then, during the second decade, declines to the adult level. The curve is different for each part of the brain, and the sequence is roughly shifted in the order that I mentioned the structures. This is being looked at now in other species, in rodents, cat and monkey. It may be that this family of curves is the same in different species, but the time of birth has moved on this spectrum of curves, depending on the maturation of the animal, whether in utero or postnatally. In a few patients with cortical dysplasia and epilepsy subsequent to it, Dr Chugani observed a combination of different factors. A minority of these children have glucose hypermetabolism combined with increased inter-ictal spikes, but not clinically overt seizures. Most of the children have hypometabolism. The dysplasia and heterotopias have been verified neuropathologically after surgery. The patterns in the newborn child and in the normal elderly adult have been compared with individuals with early, moderate and late Alzheimer’s disease. There is, in some parts of the brain, particularly in neocortex, a reverse running

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of the pattern of maturation that I described during cortical degeneration in Alzheimer’s, ultimately leaving sensory and motor cortex, no neocortical areas, and cingulate activity, on PET scan. Roland: To go back to our discussion of Dr Corbetta’s paper, there seems to be fairly good agreement about where to place V4-if it’s not in the lingual gyrus it is in the fusiform gyrus and probably very close to the lingual gyrus. However, from images obtained by the Hammersmith Hospital and St Louis groups, V5 was not located in the same place. The Hammersmith group located V5 slightly below the AC-PC line, but the St Louis group appear to locate it far above that line. Is that so? Frackowiak: V5 is present 4 mm and 8 mm above the AC-PC line over the convexity, in the Hammersmith results. Corbetta: We find that the focus for attention to speed is 16mm above the AC-PC line. There are other experiments on motion perception in the lab. Fox: Yes. In addition to the attention and motion experiments, we have looked at coherent motion versus random motion and versus static stimuli. The coordinates fall below what we are considering the middle superior temporal area (MST). Roland: So is the message to take home that there is another area which actually enhances its activity during attention to motion, and that it is not the same as VS? Zeki: There are several other motor-related areas in the visual cortex. Fox: Pursuit eye movements activate the higher area, referred to as MST. If you fixate and watch coherent motion, you don’t activate that area, but you activate a lower area. Corbetta: Neuronal activity in MT (or V5) is not modulated by attention (Wurtz et a1 1984). However, attentional modulations have been found in area MST, which receives the bulk of MT output. This is an enhancement of a visual response when a visual stimulus is the target of a pursuit eye movement. Passingham: Professor Roland has suggested that our brains may be wired up differently from that of a monkey. Let us hope not! Let’s assume that we are just big monkeys, until we are forced to recant. The advantage of assuming similarity is that we have a discipline to guide us; we can use what we know of the anatomy and physiology of monkeys. Zeki: I think it’s safe to assume that there are substantial similarities in the organization of the motor pathways between monkey and man. Passingham: Consider the cerebellum. We could say that language has access to the cerebellum by some novel pathway. But in the macaque we know that the temporal lobe (other than V5) has no projection to the cerebellum. I think it’s better t o assume for the present that the wiring is the same, and find some other way of explaining the contribution of the cerebellum to verbal learning.

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Lassen: Can we continue this line of thought and say that the right hemisphere of the cerebellum is connected to the left frontal lobe and that any time that the left hemisphere works harder, then the right cerebellum must inhibit it, because it is an inhibitory circuit? This suggests that the cerebellum may play a less distinct role than, say, the cortex, in the production of language. Porter: It is fair to say that, in all those situations in which the anatomical results that have been described with some precision in the monkey have been able to be checked in human material, the pathways that have been demonstrated in the monkey are shown to exist in man. They have been well conserved in the primate brain, and monkey studies provide good guides to human connectivity. Certainly, in relation to the connections between the cerebral cortex and the cerebellar hemispheres, throughout phylogeny, those connections are preserved. The human cerebellum has increased in size and in connectivity via the transsynaptic pathways through the pons and deep cerebellar nuclei in precise relationship to the increase in development of the frontal and parietal lobes. No one would deny that. Roland: When it comes to the cerebellum, Dick Passingham may have a point. However, this is supported not by anatomical data but by electrophysiological data, such as those from Dr K. Sasaki’s group and others. When it comes to, say, visual cortex, I am not sure I can subscribe to what was said, because I haven’t seen any of these visual studies showing activations extending far into the temporal lobe. Actually, it can be questioned whether vision at all involves the temporal lobe, except for the most posterior part. This is definitely not the same in the monkey, where in the inferior temporal lobe there are neurons responding heavily to visual stimulation in visual recognition experiments, where we cannot find any such responses in man. So we should not generalize here; we must be cautious where caution is needed. Evans: I described data earlier (p 21 1) with responses to single-word recognition in inferior temporal cortex. Roland: Words, yes, but it can be asked whether it is the visual process or the language process you see. Zekk The inferior temporal cortex is very inadequately charted physiologically, at the present time. Mazziotta: Another comment on cerebellar relationships. We have studied over 200 patients with temporal lobe epilepsy having complex partial seizures. About 70% of those patients have profound hypometabolism of the temporal lobe. Only one had crossed-cerebellar changes, and that patient has had changes involving the thalamus as well as temporal lobe structures. So, from a functional point of view (and this of course is a chronic lesion which has all these temporal features), epileptic lesions or other lesions elsewhere in the cerebral hemisphere do produce consistent transtentorial effects, but temporal lobe metabolism alone, at least in our experience of glucose metabolism, doesn’t seem to.

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Raichle: I would like to second Dr Passingham’s position but also point out that the patient whom I mentioned was deficient on other tasks as well as those involving language, some of which have been classically studied in monkeys, but with little or no attention paid to the cerebellum. So it’s entirely appropriate to address questions to cerebellar function, and I suspect there is a lot of correspondence there between monkey and man. Jones: Dr Raichle, you showed that people can learn how to carry out a task; in fact the activation gets weaker and weaker. Earlier we have talked about how we are planning to do many small studies in individuals and then add them up. Will we run into trouble, and can we avoid it? Raichle: Yes! You have to keep this in mind; task performance becomes a more and more important variable here. One could easily be fooled on a task by simply doing repeated studies in the same person. The entire cortical organization may change in the course of your experiment. Wise: But have you found the threshold? How many times do you have to repeat a task before you start seeing changes in activation patterns on a PET scan? Raichle: The learning curve comes down very rapidly over the first 3-4 practice trials. On the other hand, if you keep changing the lists, and you can assure yourself that there is no correspondence between any of the words on your several lists (which could be a tricky issue), you might be able to keep the response up over several repeat scans. Wise: Does it really matter if lists of words in language activation tasks are changed? Not much will be remembered from long lists over the 15 minutes between PET scans. Raichle: There are many forms of the Generate word test that we now use and all show this learning phenomenon. Wise: It is disappointing, because if we wish to do single-case studies on patients, it would be helpful to be able to repeat tasks and then average them. Raichle: It might be disappointing from an experimental point of view, but it may be exciting in terms of the way the brain behaves! Friston: Some of the best animal models of neural plasticity and learning rely on adaptation and habituation. The ability to study habituation in man is a tremendous opportunity to look at plasticity in v i v a I look forward to the day when we can study plasticity and habituation using single-subject designs. Jones: We may need to develop even more sensitive tomographs to realize the required counting statistics necessary to register habituation in a single subject. Lassen: We have seen many red or white islands activated in the cortex (in the sense of a blood flow increase). With the tomographic method that I use, we can compare right and left hemispheres. In a normal man we see that at rest the right hemisphere often has a slightly higher blood flow (1-2%) than the left. In many test situations, this is accentuated where the subject is engaged

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in mental activity, just as, perhaps, even in the cingulate gyrus. Are there any more global effects, or is ‘everything’ focal? Frackowiak: Who doesn’t normalize it away? Evans: If there is a hemispheric change, you don’t normalize that away. If it was symmetrical in the baseline, and the whole right hemisphere went up in the activation condition, you would see that even after normalization. Roland: There are global effects on flow in some tasks. It could be difficult to say how big, but they can reach 4-5 ml distributed over the hemisphere; but of course we must not normalize the global changes away, or we will not see them. Such global changes are not found in every task. In many tasks the absolute blood flow does not change, neither over one hemisphere, nor globally in the brain. In those conditions you see regions with decreases, some of them significant but not all of them, Fox: In exploring alternative analyses of the data that 1 showed on language activation in epileptics we simply compared all the activity in the two hemispheres. That is, we identified the more activated hemisphere, with no region specification. This discriminates language dominance as well as did the Wada test. Of course, regional analysis shows that the entire hemisphere is not being activated. Rather, a constellation of discrete areas of change can give a significant hemispheric change. Dr Roland might be seeing something similar. Friston: It is not a question of constructs. To me, the distinction between global flow and flow at a particular pixel is completely arbitrary, because global flow is the sum of all pixel flows. We make an arbitrary distinction between global and focal, and we are justified in doing so if the two measurements are independent. This independence is of course never total but is approximated in a pixel-based approach. In truth, global and focal flows are just different views of the same data from different perspectives. Anybody still using region-of-interest based analyses will be subject to a confounding of global and regional changes. This is less the case for pixel-based approaches. As a partial answer to the question about global changes, let me say that I was always suspicious of the assertion by Peter Fox that we would be unable to produce a reliable change in global flow under physiological conditions in normal subjects. I now think he is probably right. We routinely analyse global changes in all our activation studies and have yet to demonstrate a significant effect, despite finding intriguing trends. References Blurnstein S, Milberg W , Shrier R 1982 Semantic processing in aphasia: evidence from an auditory lexical decision task. Brain and Language 17:301-316 Courjon JH, Flandrin JM, Jeannerod M, Schmid R 1982 The role of flocculus in vestibular compensation after hemilabyrinthectomy. Brain Res 239:251-257 Fiez J , Petersen SE, Raichle ME 1990 Impaired habit learning following cerebellar hemorrhage: a single case study. SOCNeurosci Abstr 16:287

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Ito M, Mijishita Y 1975 The effects of chronic destruction of the inferior olive upon visual modification of the horizontal vestibulo-ocular reflex of rabbits. Proc Jap Acad 5 1 :716-720

Ivry RB, Keele SW 1989 Timing functions of the cerebellum. J Cognit Neurosci 1:136-152 Llinas R, Walton K, Hillman DE, Sotelo C 1975 Inferior olive: its role in motor learning. Science (Wash DC) 190:1230-1231 McCarthy RA, Warrington EK 1984 A two-route model of speech production: evidence from aphasia. Brain 107:463-485 Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME 1988 Positron emission tomographic studies of the cortical anatomy of single-word processing. Nature (Lond) 331~585-589

Petersen SE, Fox PT, Snyder AZ, Raichle ME 1990Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science (Wash DC) 249:1041- 1044 Wurtz RH, Richmond BJ, Newsorne WT 1984 Modulation of cortical visual processing by attention, perception, and movement. In: Edelman GM, Gall WE, Cowan WM (eds) Dynamic aspects of neocortical functions. Wiley, New York, p 195-197

Language activation studies with positron emission tomography Richard Wise*, Uri Hadar**, David Howard? and Karalyn Patterson$

*MRC Cyclotron Unit, Hammersmith Hospital, London W12 OHS, UK, **Department of Psychology, Tel A viv University, Ramat A viv 69978, Israel, ?Department of Psychology, Birkbeck College, Malet Street, London WClA 7HX, UK and $Applied Psychology Unit, 15 Chaucer Road, Cambridge CB2 2EE UK

Abstract. Behavioural tasks produce changes in regional cerebral blood flow (rCBF), the result of increased local neural activity. These changes can be measured with positron emission tomography (PET). Language activation studies by means of PET are being used to relate regional patterns of cerebral activation to information-processing models of speech and reading. Significant activation confined to both superior temporal gyri has been observed when normal subjects hear words played backwards, listen to non-words, and perform category judgements on pairs of heard real words. Prestriate cortex is activated by seeing strings of letter-like symbols, consonant strings, pronounceable non-words and real words, with additional activation in left medial prestriate cortex in response to the non-words and real words. Left posterior superior temporal gyrus (PSTG), left dorsolateral prefrontal cortex (DLPFC) and supplementary motor area (SMA) are engaged when subjects retrieve verbs from memory to match nouns. Finally, primary sensorimotor cortex is activated during articulation. There is particular interest at present in the precise roles of left PSTG and DLPFC in single-word comprehension and generation, and interpretation of the results depends critically on the design of the single-word tasks used for behavioural activation. 1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 218-234

Over the same period that has seen the development of techniques designed to produce both anatomical and functional images of the brain there has been a major change in neuropsychological research, with the rise of cognitive neuropsychology and the attendant use of information-processing models to understand and explain normal and abnormal cognitive functions (Shallice 1988). The cognitive neuropsychology of language has been a major area of interest, but often discussions about the functional organization of language have paid little attention t o where particular processes occur in the brain. Cognitive neuropsychology is largely based on the study of single patients in the search for selective losses of specific behavioural abilities as a result of brain injury or disease; the dissociation of symptoms revealed by the detailed study of a number of patients with a range of language impairments is used to infer 218

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the presence of specific processing subcomponents in the normal brain. It might appear that by performing an anatomical scan (X-ray computerized tomography [ CT] scanning or magnetic resonance imaging) on each patient, it would then be a simple matter to relate the site of a focal cerebral injury to the processor(s) shown to be impaired in the behavioural studies. However, this approach has had only limited success, because often lesions are very extensive, or a disorder of particular interest is observed in a patient with a degenerative disease and the CT scan simply shows diffuse atrophy. Furthermore, the processing elements of the brain are arrayed in parallel distributed networks (Goldman-Rakic 1988), and a lesion at the site of a particular cortical processor or a remote one disrupting the processor’s input o r output connections may produce a similar clinical picture. Functional brain imaging offers a more direct approach t o the correlation of mental processes with specific cerebral regions, and one that can be applied to normal subjects. It has been known for several decades that language tasks are associated with focal increases of rCBF (for example, Ingvar 8z Schwartz 1974, Lassen et a1 1978). The initial attempts to relate structure to language function had to contend with problems of spatial resolution, tracer limitations and relatively unsophisticated data analysis, and the activation tasks were not selected with reference to models of normal language processing. The development of rapid oxygen- 15-labelled tracer techniques to measure rCBF (Raichle et a1 1983, Lammertsma et a1 1990) and the design of sensitive, multi-slice, PET cameras (for example, Spinks et a1 1988) have added greater sophistication to rCBF activation studies of language processing. To increase the signal-to-noise ratio, a number of normal subjects are studied with subsequent inter-subject averaging. This requires anatomical standardization of all images (Fox et a1 1985, Friston et al 1989), normalization for global flow differences (Fox et a1 1988, Friston et a1 1990), and statistical analysis of the changes in rCBF across activation tasks (Fox et a1 1988, Friston et a1 1991). As oxygen-15 has a half-life of only 2.1 minutes, repeat studies of a subject during one scanning session are possible, and typically six to eight measurements of rCBF are made on each subject while a variety of language tasks are performed. A number of limitations to the technique are immediately apparent. Intersubject averaging may improve the detection of signal, but the assumption has to be made that all the normals in the study are ‘wired up’ the same way (as an obvious example, potential subjects for language studies are all assessed for right-handedness t o ensure that there is a very high probability that language is predominantly localized in their left cerebral hemispheres). Six or eight activation states will only allow a very small part of language function to be studied at one time, and to build up a comprehensive picture will require a large number of studies on many subjects.

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The study of patients, to investigate the recovery of language functions, raises further problems, in particular whether it is appropriate to average patient data. The answer in many cases is likely to be that it is inappropriate, for much the same reasons that many neuropsychologists have moved away from grouped data and towards single-case studies (Shallice 1988): mixing the results from patients reveals only common features, and individual differences of great potential interest are obscured. However, the comparison of an individual patient’s results with grouped normal data, to look for significant regional differences, is a relatively insensitive technique, and one that is open to problems of interpretation-for example, does the patient show a regional difference from normal subjects because of an adaptive change in the neural networks processing the task, or because of an irrelevant stimulus such as discomfort from a full bladder of which the investigator was unaware at the time the patient was studied? Irrelevant stimuli are likely to be randomly distributed amongst a group of normal subjects, and therefore conveniently ‘lost’ during inter-subject averaging. Finally, there is a particular problem with anatomical standardization in patients who have large cerebral lesions distorting the normal anatomy. A number of studies on single-word processing in normal subjects have been published. Studies on single patients have not yet appeared in the literature, although, despite the potential pitfalls, a number of groups, including our own, are currently working with aphasic and alexic patients. Single-word processing in normal subjects

The St Louis group initiated the style of language study that is now being emulated by others. The first published results (Petersen et al 1988, 1989) demonstrated a number of distinctive features in the design of the study. Firstly, each activation task was designed to probe a defined part of single-word processing. The selection of simple single-word tasks permitted a much higher standard of interpretation, because the most detailed information-processing models of language processing have been developed from single-word tests on subjects and patients. Secondly, each task was chosen to add only one or a very few processing operations, by comparison with the preceding stimulus. The complete set then formed a subtractive hierarchy, and comparison between tasks was intended to isolate individual processing elements. Much of what appeared in the initial publications was uncontroversial. Thus, early visual processing was localized in both left and right prestriate cortex, early auditory processing was observed in both superior temporal gyri (STG),and articulation was observed to involve the supplementary motor area (SMA) and primary sensorimotor cortex serving the articulatory muscles. It was demonstrated that reading aloud single words did not appear to involve the left temporo-parietal region, which was interpreted as evidence that reading does not require a preliminary phonological encodement of the written material and

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access to semantics, prior to articulation. However, one unexpected result was that the generation of verbs, excluding hearing or seeing the stimuli and articulating the response, only activated left DLPFC. This region was considered by Petersen et a1 to be the centre for processing semantic associations. Support for this hypothesis came from a parallel experiment, in which subjects were asked to monitor lists of words for a particular semantic category: again, there was activation of left DLPFC. Many of our preliminary results have supported the findings of the St Louis group, but there have been a number of differences which raise important issues about the design of language activation tasks and the interpretation of the results. At the level of early auditory and visual processing we have seen strong signal in both STG and both prestriate regions, respectively (Fig. 1) (see colour plate). The auditory stimuli were words played backwards on tape-sounds with the complex frequency transitions of ordinary language but without recognizable phonemes; the visual stimuli were a computer-generated nonsense font-letterlike symbols without the form of recognizable letters. We compared the two states with each other in order to demonstrate the sites of early auditory and visual processing. In a separate group of subjects we employed a rest state, and four different single-word language tasks (Wise et a1 1991). The first was to ask the subjects simply to listen to a list of non-words (words with no meaning but with normal English phonological structure). The second involved monitoring noun-noun pairs (a superordinate followed by a basic level noun, e.g. ‘furniture-table’) and deciding which were correct pairings (half were incorrect, e.g. ‘vegetableshirt’). The third task was similar to the second, but required monitoring of verb-noun pairs. All three tasks were performed without the subjects speaking. In all three tasks there was activation of bilateral STG. There was no recognizable difference in the distribution of activation between the three tasks, and although a direct comparison was not possible because the studies were done on different groups of subjects, there appeared to be no difference from listening to reversed words. There must be a much greater level of processing involved in category judgements on noun-noun and verb-noun pairs than in listening to reversed words, and the failure to see an obvious difference in terms of the distribution of activation suggests two possiblities: either the neural networks involved in early auditory processing overlap those required to make category judgements (which must involve access to the networks encoding the meanings of the nouns and verbs, the semantic system); or activation of the semantic system produced a signal that was below the sensitivity of the technique to distinguish signal from background noise, possibly because the semantic system occupies widely distributed regions. The fourth activation task, which required the subjects to listen to a list of nouns presented at a slow rate (15 words per minute) and to generate appropriate verbs as fast as possible (the subjects reported achieving 2-4 verbs per noun),

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produced a very different distribution of activation. As with the other three tasks, the subjects were asked to remain silent; the verbs were generated ‘inside the head’. The slow rate of presentation of words was below the threshold for the production of significant activation in right or left primary auditory cortex, or in right auditory association cortex. However, there was still significant activation of association cortex in the left posterior superior temporal gyrus (PSTG). Furthermore, there was activation observed in left DLPFC (in two regions, in the inferior frontal gyrus and the posterior part of the middle frontal gyrus), and in the SMA. This result raised a number of issues. Activation of the SMA suggested the recruitment of networks involved in the production of speech, even though the subjects were silent during the task; we may have intended to avoid activation of speech output networks with our task, but the brain appears to be organized such that the internal generation of words automatically recruits at least some output networks. This automatic distribution of processing means that a subtractive hierarchy of activation tasks may only be subtractive in terms of the observable behaviour required of the subjects, and not in terms of activated brain regions. We confirmed the involvement of left DLPFC in the retrieval of verbs from memory, but we also demonstrated that left PSTG was recruited by this task. This was not due to early processing of the heard nouns, evidenced by failure to show activation in other superior temporal regions (a conclusion supported by correlating percentage increase of rCBF in superior temporal regions with the rate of presentation of words across the non-words, noun-noun and verb-noun category judgement, and verb generation tasks; there was a significant linear correlation except in left PSTG). Our verb generation task differed in four respects from the similar task employed by the St Louis group: the rate of presentation of stimuli, the output (the subjects in the St Louis study spoke their responses), the control state against which the activation task was compared, and the number of responses to each stimulus. We suspect that the first three differences have been largely responsible for the disagreement about the involvement of left PSTG between the two studies. The subjects in the St Louis study heard words at 60 per minute, and if the networks for processing heard words, up to the level of comprehension, overlap or at least lie in close proximity to one another in the left PSTG, then the signal from early processing may dominate the rCBF increase in this region. Thus, in a comparison of verb generation against repeating a list of heard words delivered at a rate of 60 words per minute, as was done in the St Louis study, any additional activation of left PSTG by verb generation over and above the early acoustic processing of words may have been lost in the comparison. Additionally, our verb generation task was compared with a rest state. The control state in the St Louis study was repetition of real words which, it was assumed, would not activate the semantic system. However, it is very likely that simply hearing a familiar word automatically involves comprehension, as the

FIG. 1 (Wise et al) Comparison of hearing reversed words against ‘reading’ nonsense font (above), and the reverse comparison (below). To the left, the results have been summarized as statistical parametric maps (SPM) in three whole-brain projections: sagittal, coronal and transaxial. VPC and VAC refer to the vertical projections through the posterior and anterior commissure, respectively. On the sagittal and coronal projections, the intercommissural line has been set on zero. The auditory task activated primary and association auditory cortex bilaterally; the visual task activated prestriate cortex, also in both hemispheres (level of significance set at < 0.001: any pixel > 0.001 has been excluded). To the right of the SPM projections the results have also been displayed on drawings of the medial (upper two of four) and lateral (lower two of four) aspects of each hemisphere.

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St Louis group acknowledge in a later publication (Petersen et al 1990), and therefore if left PSTG is part of the semantic system it may not be revealed in a comparison of two tasks that both involve the semantic system. There is also the question of what influence articulation has on the subject’s own auditory cortex. The St Louis study gives some intriguing information on this point. In one comparison, silent inspection of a list of words was compared with reading the list aloud. Reading aloud activated output structures, such as SMA and primary sensorimotor cortex, but apparently there was no significant increase of rCBF in auditory cortex-despite the fact that when reading aloud the subjects were hearing their own voices at the brisk rate of 60 words per minute. This suggests an attentional mechanism whereby the response of the auditory cortex, at least in terms of increased rCBF, is present when the speech input is ‘other’ and absent when the voice is ‘own’. The signal from a PET study is the net change in rCBF in response to a task. An interaction in a region whereby one aspect of the task, such as comprehending a spoken word, increases rCBF while another, such as turning the attention of the auditory cortex away from one’s own voice, suppresses rCBF in a closely related region may result in an apparent lack of activation, although in reality there is a complex interplay of different neural influences. We have observed selective activation of left PSTG in other tasks. Reading aloud lists of concrete and abstract words was compared with the control state of seeing nonsense font and saying the same word in response to each stimulus. Although the subjects were reading different words in the active state and simply saying the same word over and over again in the control state, the neural networks responsible for articulation were similarly activated, and there were no significant differences between task and control in anterior structures. The only significant difference in posterior structures was activation of left PSTG in response to reading aloud real words. A very similar result was seen when the subjects repeated aloud concrete and abstract words that they heard, compared to hearing reversed words. Our results suggest a central role for left PSTG in single-word tasks. If we refer to a simple model of single-word comprehension and production (Fig. 2), is it possible to identify this process? In doing so, we shall have to explain why the St Louis group did not activate the left PSTG in many of their single-word tasks. Both groups have used reading and repeating words aloud as activation tasks, but with different ends in mind, and this is reflected in the difference in the control states. Neural networks associated with articulation were identified in the St Louis design; reading and repeating aloud real words were compared to seeing and hearing real words without the subjects speaking. However, the obvious difference between task and control in our study was that the stimuli were meaningful in the activation tasks compared to the controls (reading and repeating real words compared with seeing nonsense font and hearing reversed words, with vocalization during the control states). If we combine these results

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FIG. 2. A simple model of single-word processing adapted from Ellis & Young (1988). After early acoustic analysis of a heard word the appropriate information is passed to the auditory input lexicon, the site of encoded entries for familiar words (the visual input lexicon performs the same function for read words). Subsequent activation of the appropriate entry in the semantic system makes the meaning of the word apparent to the subject. The speech output lexicon is the word-form store for familiar spoken words, and it may not be separable from the auditory input lexicon (indicated by the enclosing box). Although there are three routes by which either a heard or read word can be spoken (a route for direct grapheme-to-phoneme conversion is not depicted in the diagram), we consider that the evidence in the neuropsychological literature supports the notion that hearing or reading a familiar word will normally automatically activate its entry in the semantic system. The study of Petersen et a1 (1988) suggests that monitoring of one's own speech after articulation (dashed line) does not normally occur.

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with the involvement of left PSTG during silent verb retrieval, and the lack of involvement of regions outside the STG in the category judgement tasks, can we assume that left PSTG is part of the neural network which makes up the semantic system? There are a number of reasons for thinking that this has not been established on the data available. This region could be acting as the speech output lexicon (the word-form system for speech output) in a number of the tasks (including silent verb generation, because, as previously discussed, networks involved in speech output are activated by this task). In Fig. 2, the auditory input and speech output lexicons are depicted as separate processors, but some consider that these are a single entity (Allport & Funnel1 1981), and therefore one possibility is that left PSTG acts as the input lexicon when hearing words and as the output lexicon during preparation for articulation. One argument against this is that because left PSTG was not activated in the comparison of reading aloud versus reading silently in the St Louis study, the speech output lexicon must be in one of the anterior regions that were activated in this comparison (although we have already alluded to the possible masking influence that ‘own’ voice may have on rCBF in the PSTG, and such an effect will have to be excluded in a future study before we can rule out left PSTG as the site of the speech output lexicon). A further explanation for the number of tasks that have elicited a left PSTG response in our series of studies is the activation of verbal short-term memory. Paying attention to any single-word task will automatically involve short-term memory. Patients with impairment of auditory verbal short-term memory have lesions involving the left superior temporal region (Warrington et a1 1971). Although the memory trace may only last a few seconds, there is the implication that this trace represents continuous neural activity over this time period, with renewal of activity each time a new stimulus is presented. Whether the neural pathways responsible for verbal short-term memory are separable from those involved with auditory or visual encodement of phonemes or graphemes is another issue, one that cannot be revealed by a PET study because the memory trace is dependent on the subject perceiving a spoken or written word. Studies on single patients We have only very limited information from patient studies to date, although we are hopeful that these will give insight into the functional recovery of language after focal cerebral injury, such as infarction. Ideally, each range of activation tasks should be tailored to a particular patient’s deficits, but this raises a major practical problem. If we are to see which regions, outside the site of injury, are being activated abnormally, the patient has to be compared to a group of normals: after anatomical standardization and normalization of global CBF across patient and subjects, each pixel of patient data is compared with the scatter of values from the same pixel in normals, and the results are displayed as the

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regions where rCBF in the patient is significantly different from the normal range. The power of such a test clearly increases with the number of normal subjects studied, which raises the spectre of gathering data on about one dozen normal subjects for each patient studied. Currently, we are pursuing two possible solutions. The first is to study a number of aphasic patients, with a range of deficits that have recovered to a variable degree with time after the onset of symptoms, with ‘off-the-peg’ activation tasks on which we already have normal data. This approach is based on the knowledge that our range of tasks covers a large number of anterior and posterior regions that are known to be the common sites of lesions in aphasic patients. So, for instance, we can look at verb generation in a patient with a left posterior frontal infarct; we know that left DLPFC is normally used in the task, therefore we can investigate when abnormal activation patterns, possibly compensatory, occur in the patient. This might be termed the neurological approach. The alternative has been to identify a particular group of patients with a well-defined aphasic or alexic syndrome and collect normal data for that group. We still do not group the patient data in analysis, because no two patients are exactly alike in terms of the details of their behavioural deficits, and we have no apriori evidence for thinking that the attempts by the patients to overcome their deficits rely on the same neural networks. This is a more neuropsychological approach. We are beginning to see results. As an example, we have studied one patient with deep dyslexia in whom the whole of the left middle cerebral artery territory had become infarcted (flow 410 m1/100 ml per min). Deep dyslexia is an acquired disorder, with a number of features which include semantic errors during reading, e.g. reading ‘street’ as ‘avenue’, a wrong word with similar meaning, and a relatively preserved ability to read concrete words, e.g. ‘comb’ or ‘train’, compared to abstract words, e.g. ‘faith or charity’ (see Shallice 1988). Our activation tasks were designed to investigate the dissociation between this patient’s reading of concrete and abstract words. In the three tasks of seeing nonsense font, reading abstract words and reading concrete words, the patient showed increased blood rCBF in right extrastriate cortex and right inferior temporal gyrus compared to twelve normal subjects. This presumably reflects the greater degree of early visual processing of the letter or letter-like strings in the right hemisphere as a result of the devastation of most of the left hemisphere. There were no additional right hemisphere regions activated by reading abstract words compared to ‘reading’ nonsense font, but reading concrete words produced additional activation in right thalamus and right frontal cortex. Analysis on the data from further patients with deep dyslexia is currently being undertaken to see whether this result is found in other patients. Concluding remarks

It is apparent that language tasks readily produce measurable changes in rCBF

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on PET images of the brain, but it is a different matter to relate these regional changes to specific subcomponents of sophisticated information-processing models of language. The design of activation and control tasks is a matter of very fine judgement, and even then the investigator may be defeated by neural networks that overlap, and by conflicting influences on rCBF within one resolvable region. There is also the considerable problem of conservative statistics. The analysis of PET activation images can be likened to looking at a range of mountains beyond a forest. The high peaks are easily seen, and the observer might suppose that these are the only mountains in the region. However, if the observer is aware that mountain peaks are frequently topped by clouds, he may guess that distant clouds visible above the tree-tops may indicate the presence of other peaks too low to be visible-trends of increase in rCBF that fail to reach statistical significance, especially when the number of subjects studied is small, may indicate other cortical regions involved in the language task under investigation. Of course, the observer will remain completely unaware of many of the lower peaks uncapped by clouds while he stays on the wrong side of the forest, but, as the forest in this analogy is the noise inherent in the technique of PET, we shall always stand behind a forest that partially obscures our view. We can only hope for new techniques that will lop some of the height off the trees, but inevitably any PET activation study is going to underestimate the distribution of neural networks engaged by a task. It is only right that we should view with scepticism any attempt, on the basis of a significant blob on a PET scan, to constrain a complex mental process to one small brain region. There is one further important caveat in relation to studies when there is cerebral pathology present. We are using an indirect marker (rCBF) of neural activity, and the ability of the resistance blood vessels to respond normally to physiological stimuli such as increased neural activity may be attenuated after brain injury. Therefore, an absence of signal, particularly in the hemisphere ipsilateral to a large, recent focal injury, does not mean that there is not increased neural activity in partially damaged or undamaged regions of that hemisphere.

Acknowledgements We wish to thank the members of the PET Methods and Radiochemistry Sections of the MRC Cyclotron Unit, without whom our studies would not have been possible.

References Allport DA, Funnel1 E 1981 Speech production and comprehension: one lexicon or two? Philos Trans R SOCLond B Biol Sci 295:397-410 Ellis AW, Young AW 1988 Human cognitive neuropsychology. Lawrence Erlbaum Associates, Hove, UK Fox PT, Perlmutter JS, Raichle ME 1985 A stereotactic method of anatomical localization for positron emission tomography. J Comput Assisted Tomogr 9:141-153 Fox PT, Mintun MA, Reiman EM, Raichle ME 1988 Enhanced detection of focal brain responses using intersubject averaging and change-distribution analysis of subtracted PET images. J Cereb Blood Flow Metab 8:642-653

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Friston KJ, Passingham RE, Nutt JC, Heather JD, Sawle GV, Frackowiak RSJ 1989 Localization in PET images: direct fitting of the intercommissural line (AC-PC) line. J Cereb Blood Flow Metab 9:690-696 Friston KJ, Frith CD, Liddle PF, Lammertsma AA, Dolan RD, Frackowiak RSJ 19YO The relationship between global and local changes in PET scans. J Cereb Blood Flow Metab 10:458-466 Friston KJ, Frith CD, Liddle PF, Frackowiak RSJ 1991 Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab 11:690-699 Goldman-Rakic PS 1988 Topography of cognition: parallel distributed networks in primate association cortex. Annu Rev Neurosci 1 I : 137- 156 Ingvar DH, Schwartz MS 1974 Bloodflow patterns induced in the dominant hemisphere by speech and reading. Brain 97:273-288 Lammertsma AA, Cunningham VJ, Deiber M-P et a1 1990 Combination of dynamic and integral methods for generating reproducible functional CBF images. J Cereb Blood Flow Metab 10:675-686 Lassen NA, Ingvar DH, Skinhoj E 1978 Brain function and blood flow. Sci Am 239 (4):50-59

Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME 1988 Positron emission tomographic studies of the cortical anatomy of a single-word processing. Nature (Lond) 331:585-589

Petersen SE, Fox PT, Posner MI, Raichle ME, Mintun MA 1989 Positron emission tomographic studies of the processing of single words. J Cognit Neurosci 1: 153-170 Petersen SE, Fox PT, Snyder AZ, Raichle ME 1990 Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science (Wash DC) 249:1041-1044 Raichle ME, Martin WRW,Herscovitch P, Mintun MA, Markham J 1983 Brain blood flow measured with intravenous H,I5O. 11. lmplementation and validation. J Nucl Med 24:790-798 Shallice T 1988 From neuropsychology to mental structure. Cambridge University Press, Cambridge Spinks TJ, Jones T, Gilardi MC, Heather JD 1988 Physical performance of the latest generation of commercial positron scanner. IEEE (Inst Electr Electron Eng) Trans Nucl Sci 35:721-725 Warrington EK, Logue V, Pratt RT 1971 The anatomical localisation of selective impairment of auditory verbal short-term memory. Neuropsychologia 9:377-387 Wise R, Chollet F, Hadar U, Friston K, Hoffner E, Frackowiak R 1991 Distribution of cortical neural networks involved in word comprehension and word retrieval. Brain 1 14: 1803- I8 17

DISCUSSION

Zeki: In t h e prestriate cortex, are the areas that light up always on the left? Wise: You are referring to the nonsense font response. We get bilateral extrastriate activation in response t o letter-like symbols. T h e St Louis group see a differential activation, with increased activation coming up in the left medial extrastriate when the word seen is either real, or at least obeys normal English orthographic rules. A consonant string or nonsense font won’t activate that area so strongly.

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Zeki: And the activation that appears selectively on the left is in addition to the other areas? Raichle: Yes! Zeki: Secondly, I want to know what you really mean by networking in parallel, and processing in parallel. This distinction seems to be rather subtle, but may blur interesting things, actually. Wise: By processing in parallel I mean that a number of different processes are happening at the same time; in other words, there are a number of processors that are independent but are being activated simultaneously. For example, our category judgement and verb generation tasks must have engaged short-term memory systems, particularly during the verb generation task, when the subject was holding a noun in memory and thinking of a number of different verbs to match the noun. Furthermore, the subject had to remember the verb he had just generated to avoid perseveration. Therefore, I don’t know for certain whether some of the activated regions in this task are related to short-term verbal memory or to verb retrieval. As to anatomical parallelism, the neural network that is dealing with the meaning of words may physically lie very close to the networks that deal with acoustic analysis of speech sounds. If they lie near one another, then one signal may dominate over the other. So, if we give a subject a word with meaning, and one with no meaning at all, or even a funny sound with speech-like frequency transitions but no phonemic content, they could all produce a blob in very much the some region on a PET scan. Zeki: You are implying that a single area, on the classical definition, could be subdivided into subareas, much as you might be able to divide the striate cortex into subregions, which are in fact undertaking processing in parallel. Their extensions are also undertaking parallel processing. Wise: Yes; for example, you are getting all visual information into primary visual cortex, all mixed in together, but then it separates out into different anatomical regions that process the subcomponents of complex visual information simultaneously. Zeki: No; that’s the whole point! The inputs and the outputs are not mixed together . Wise: It is mixed macroscopically, though not, I agree, at the microscopic level. You can’t pick out a specific colour signal in the primary striate cortex with a PET scan. Baron: With respect to the activation you saw in the supplementary motor area, could this be due to some kind of internal articulatory rehearsal as part of a working memory process? Wise: I think so. I suspect that when a subject was given a word like ‘apple’, the first verb he thought of may have been ‘eat’, and it was almost coming out, but not quite; he was getting ready to speak it. There’s no reason why processing should just stop at selecting the verb with the right

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meaning; processing would continue up to the point of articulation. This is how I visualize it. Cuppa: I am not convinced that the best control group for the deep dyslexic patient consists of normal readers. Deep dyslexics usually have very large lesions, and therefore perhaps this patient was simply using what brain remained to him for reading. A better control situation might be another dyslexic patient with a large left hemispheric lesion, but with a different dyslexic pattern, without any effect of word concreteness. Wise: You are probably right! It is difficult to sort out which control group to use. We were trying initially to see how the right cerebral hemisphere of the deep dyslexic patient differed from the right hemisphere of normal readers. But I agree that a large hole in the left cerebral hemisphere must have all sorts of profound effects, whatever the resulting neurological deficit. We do think, though, that the right hemisphere was involved, to explain the dissociation between concrete and abstract reading. Cuppa: Yes, because there is evidence from other fields, such as auditory evoked potential studies (Papanicolaou et a1 1984), that some linguistic processes in chronically aphasic patients are carried out by the right hemisphere. Perhaps the participation of this hemisphere in reading is not specific for deep dyslexia, but can be found in any patient with an extensive left hemisphere lesion, who by definition cannot use the normal left hemisphere pathways for reading. Wise: Yes. We are planning to scan more patients with more common forms of alexia. Corbetta: I’m not convinced by the kind of subtraction that you are using, Dr Wise. You use a lot of what we call ‘complex subtractions’-that is, a subtraction between two activation tasks (for example, hearing words played backwards minus reading false fonts, or reading words minus reading false fonts). These complex subtractions may be problematic when there are functional interactions betweem the activated brain systems. For example, we have data suggesting that visual and auditory systems work in a cross-inhibitory fashion. When the visual system is engaged by a visual task, the auditory system shows blood flow reductions, and vice versa (S. E. Petersen & M.E. Raichle, personal communication). In order to assess the relative role of each task in explaining activations obtained in a complex subtraction between the two, you should compare each task with a simpler control state (e.g. a visual fixation point control). So I’m not against complex subtractions in general, but I really think they should be used along with simple subtractions. Wise: There are two schools of thought on this. I am sympathetic to your preferred approach. In fact, in our reading tasks, we had no fixation point control; they all involved seeing nonsense font or words. In our earlier work on hearing words (Wise et a1 1991), there was a rest state, better called the freewheeling brain state, when there was no activation task used. However, even if one looks at concrete reading versus fixation point control, or abstract reading

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versus fixation point control, and compares the difference, a statistician will tell you that what is important is the direct comparison between concrete and abstract reading. Frackowiak: The best control state is the ‘constrained state’, which differs from the active state only by the feature you are trying to map. To call a ‘free-wheeling’ state, or even a state where you are fixating on a cross and dreaming about anything you like, a ‘control’ state, is to my mind quite wrong. Raichle: We seem to be polarizing this issue of control states when it doesn’t need to be polarized. We in St Louis do as many complex subtractions as you do, but we have also found it useful, in evaluating the data at the outset, to compare these various states against, say, a fixation point, because it gives you the entire picture. It’s a means of gaining a perspective as you look at the data. Dr Wise, we have struggled, as you have, with the auditory system, and we seem to be thinking along the same lines. It has been very difficult to separate these things out. We think it’s possible that much of the complex anatomy of the auditory system is packaged more closely together than that of the visual system. Therefore, we have greater difficulty, given the resolution available, with the anatomical relationships of the auditory system and with pulling things apart that are so close together. We once looked for simple functional responses (induced by hand vibration) in individuals who had compromised cerebral vasculature (occluded carotid artery on one side) but no infarction of tissue (Powers et a1 1988). Their vasculature didn’t respond normally to such stimulation (Powers et a1 1988). This has always worried us in relation to studying patients with vascular lesions. I was delighted to see that you are doing this and are getting good responses. Have you thought about the fact that once the brain has been injured, the relationship between the vasculature and the neuronal elements could be distorted, and could mislead you? Wise: Yes. We know that we use an indirect marker of neural activity when we measure regional blood flow. You will see some results from Richard Frackowiak where motor activation tasks elicited local blood flow increases in stroke patients. However, if a lesion alters the reactivity of resistance blood vessels, changes in flow may not occur in response to variations in neural activity. It is a pity that regional oxygen metabolism doesn’t seem t o be a better way of looking at changes in brain activity, but, according to you, oxygen metabolism is uncoupled from blood flow during activation. Obviously, a metabolic tracer would be better than a blood flow tracer for following changes in electrical activity. Raichle: Or, possibly, if one could think of ways to couple electrical recording to your PET study, guided by where you think the response might be, to see if you get an electrical response.

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Wise: We are hoping that although the right hemisphere may have a degree of vasoparalysis after a left hemisphere stroke, the vascular reactivity returns fairly soon after the insult. So, we hope to see changes in the right hemisphere, if there are any interesting changes to see. But 1 agree that we are constrained by this problem, and it probably means that the most interesting studies, serial ones starting very early after the ictus, are going to encounter this difficulty. Frith: It seems to me that many of the questions that are raised by these interesting results could be answered with purely psychological experiments, rather than having to go into PET. Maybe for each PET experiment you should be doing ten psychological experiments first, to ensure that you have the right paradigms. For example, your finding of SMA activation is very interesting, and suggests that you should look at the effects of articulatory suppression on some of these tasks. We have done this in relation to verbal fluency. We asked people to write down as many words as they could think of in a category, while saying ‘la la la’ all the time. This interferes with the task when you are asked to give all the words you can think of beginning with, say, the letter A, but not when you have to give all the words that are, say, animals, suggesting that there is an articulation component in the phonological task but not in the semantic task. Thus we might expect the SMA to light up in phonological verbal fluency, but not in semantic verbal fluency. There are similar ways in which you could ask questions such as: is there a store for real words which is not involved in processing consonant strings? You can demonstrate the distinction psychologically, and then ask PET whether such a store can be localized. Warrington: Dr Wise, 1 think the flow diagram that you showed (Fig.2, p 224) is too simple and needs to be expanded to incorporate all the data now available. I also find the use of the word ‘semantic’ too simplistic. I liked your point that there is a lot of information available, not only in the neurological literature, but also in the cognitive neuropsychological literature; but I do not think this is sufficiently well known. The idea that ‘semantics’ are ‘in’ the frontal lobes is not secure. First, equating ‘word retrieval’-that is, pronouncing a word aloud-with semantic knowledge of that word is inappropriate. There are patients with full semantic knowledge of a word who may have grave difficulty in word retrieval tasks. Second, there is likely to be more than one procedure for retrieving a word-for example, when you are naming an object, when you are answering a question, and when you are trying to fill in the ‘slots’ in a sentence frame. You also retrieve words when you are doing a word-generating task. 1 suggest that the last is least like normal language, although this is a task that is very useful to the clinician. The question: ‘how many words can you think of beginning with the letter A?’ is, in my view, a problem-solving task and probably not a core component of spoken language. Perhaps because it is such an unfamiliar problem-solving task, we do, in fact, find frontal lobe deficits. Similarly with monitoring tasks: monitoring the events going on in the

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outside world is known to be impaired in patients with ‘frontal’ lobe lesions rather than in those with semantic deficits. Semantic deficits are more appropriately examined using quite different testing procedures. These two kinds of task, both purporting to access semantic knowledge, may be impaired in patients in whom semantic knowledge may be demonstrated to be entirely intact. Wise: I depicted only one ‘black box’ for the semantic system, and this is clearly inadequate. We have to start somewhere, however. I am sure there will be considerablerefinement of the type of activation tasks we use in future studies. We are really dependent on advice from cognitive neuropsychologists. Roland: Dr Wise, you showed us very beautiful dissections of language processing by your activations; you also showed this block diagram, to which Professor Warrington referred. But how do you commit your block diagram to the activations you see, and how do those activations modify your block diagram of the processing? You may say that this diagram is just an aid to thinking about these processes, but I don’t think that’s sufficient as an answer. If you believe that processing is going on, as is indicated in this diagram, you must be able to identify the stations in the diagram by looking at the activations. If a block diagram is to be useful, then you have to be able to define, within that diagram, what you are talking about, anatomically and physiologically. If not, you could just move your boxes around so that they fit whatever hypothesis you might like to test. Wise: I see your point; we have a major conflict of interest here. The Ellis & Young (1988) ‘black box and arrow’ diagram is simple, but I used it because the PET scanner is a simple machine compared to the brain, and if you include say 40 black boxes, you will never match then with the results from PET studies. One must remember that all these ‘black boxes’ were derived from behavioural studies on normal subjects or patients, with no reference to anatomy at all. Many cognitive neuropsychologists do not mind where those ‘black boxes’ are, but are concerned that they can be demonstrated to exist as processing subcomponents of language, using observations on symptom dissociations in patients. I am trying to put the ‘black boxes’ on the brain; and you are also saying that we should do this, because the processors of a neuropsychological model must exist as neural networks. However, a particular network may be localized to one small region or be widely distributed, either diffusely or as a number of discrete subcomponents. We may not be able to identify distributed networks on a PET scan, if there is only a small, diffuse increase in flow in response to an activation task.

References Ellis AW, Young AW 1988 Human cognitive neuropsychology. Lawrence Erlbaum Associates, Hove, UK

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Papanicolaou AC, Levin HS, Eisenberg HM 1984 Evoked potential correlates of recovery from aphasia after focal left hemisphere injury in adults. Neurosurgery 14:412-415 Powers WJ, Fox PT, Raichle ME 1988 The effect of carotid artery disease on the cerebrovascular response to physiologic stimulation. Neurology 38: 1475- 1478 Wise R , Chollet F, Hadar U , Friston K , Hoffner E, Frackowiak R 1991 Distribution of cortical neural networks involved in word comprehension and word retrieval. Brain 1 14:1803- 1817

The functional anatomy of recovery from brain injury R. S. J. Frackowiak, C.Weiller and F. Chollet

MRC Cyclotron Unit, Hammersmith Hospital, Ducane Road, London W12 OHS, UK

Abstract. The functional neuroanatomical basis for recovery from ischaemic brain injury is not known. We have used positron emission tomography (PET) to study changes in the functional organization of the brain in patients recovering from striatocapsular motor strokes. Significant changes in regional cerebral blood flow (rCBF) were found during repetitive sequential opposition movements of the fingers in normal subjects and in patients with recovery from motor deficits. There was a difference in the pattern of cerebral activation when patients performed the motor task with the unaffected hand (when the activation was lateralized to contralateral sensorimotor and premotor cortex and ipsilateral cerebellum) and when the task was performed with the recovered, previously plegic hand (when the activation was bilateral and involved novel areas of cortex, especially area 40). Comparisons of rCBF maps at rest in the patient group and in normal subjects showed areas with significantly decreased rCBF in the patients (contralateral to the plegic hand in the basal ganglia, thalamus, insular cortex, brainstem and ipsilateral cerebellum), which reflected the distribution of dysfunction caused by the ischaemic lesions. A significantly increased activation over and above that in normal subjects was found in patients during movement of the recovered fingers in ipsilateral premotor cortex and bilateral frontal operculadinsular regions and area 40, the ipsilateral basal ganglia (the ischaemic lesion lying contralaterally) and the contralateral cerebellum. We postulate that these findings may be explained by the generation of movements by pathways that are different from those that normal subjects use to perform what are ordinarily fairly simple, automated tasks. We suggest that this is a direct demonstration of cerebral plasticity resulting in the resolution of acquired motor deficits. 1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 235-249

Clinical recovery of neurological function is often observed after acute ischaemic brain injury (Twitchell 1951). A number of mechanisms have been proposed t o account for such recovery. Among these are redundancy i n the neural representation of function, sprouting and reinforcement of existing, though normally secondary or alternative neuronal circuits, a n d the formation of new polysynaptic connections (Merill & Wall 1978, Wall 1977). Clinical observations further indicate that a degree of bilateral cerebral control of motor function may persist into adulthood. Hence there may be a role f o r ipsilateral cortical

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efferent pathways in subserving movement after contralateral cerebral injury. This hypothesis is most dramatically supported by the motor recovery observed in children after surgical hemispherectomy (Gardner 1933). Conversely, it is also clear that unilateral hemispheric lesions can induce bilateral motor deficits (Jones et a1 1989, Colebatch & Gandevia 1989). Positron emission tomography (PET) can be used to detect significant regional changes in cerebral blood flow (rCBF) which are an indirect measure of local neuronal activity (Raichle 1987). Focal rCBF changes can be elicited by behavioural, physiological or other stimuli and can be detected, in vivo, from the whole brain simultaneously. The site of focal CBF change gives information on the cerebral structures associated with, or underlying, the activity under study. We have chosen ischaemic stroke in man as a natural model of brain injury. Lesions are produced which can be clearly defined anatomically by appropriate computed tomography (CT) or magnetic resonance imaging (MRI). The model is inconvenient in that the site and extent of the lesion are not controllable, because every human stroke is different and significant distortions of normal anatomy may be induced. There may also be remote functional effects that are reflected in rCBF changes that are not necessarily predictable from the site of the infarct and which may themselves have an influence on recovery (Feeney & Baron 1986). We have developed methods that allow comparison of patterns of change in local neural activity (reflected by significant changes in rCBF) in both patients and normal subjects. In this way we have sought to find evidence for plastic changes of functional neural connectivity in man. This chapter describes work on the functional anatomy of recovery in the motor system. To this end we have used a finger opposition task which we know from previous studies gives a large, reproducible lateralized increase of rCBF (Colebatch et a1 1991). We chose to investigate recovery of motor function because it can be measured relatively simply by clinical observation and there is considerable knowledge of the normal anatomy of finger movements. Clinical material

Patients were selected with first-time ischaemic events, clearly characterized by a single, appropriately sited lesion on structural imaging, with no other antecedent neurological or significant general medical history. The primary criterion for inclusion was the presence of a hemiparesis of acute onset affecting one upper limb (at least), followed by substantial recovery of power and dexterity, sufficient to allow the performance of a rapid (three movements per two seconds), sequential finger-to-thumb opposition task. The 10 selected patients had a variety of anatomically sited lesions but all involved at least the striatocapsular region and spared the primary motor cortex. For analytical purposes, the ‘normal’ hand was always located to the left (indeed, all but two infarcts were on the left) and the recovered hand to the right, by flipping

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the images of the two patients with right hemisphere infarcts about the vertical axis. Mapping cerebral blood flow changes Regional cerebral blood flow (rCBF) was measured with a dynamichtegral technique with P O z as the flow tracer (Lammertsma et a1 1990), which was administered by inhalation for two minutes. Twenty-one successive PET images were collected for 0.5 min before tracer delivery (background scan) and for 3 min after the beginning of tracer administration. Patients and normal subjects performed the motor task repetitively in a controlled manner throughout the scanning period. The task consisted of sequential finger-to-thumb opposition movements which were not forceful but brisk, precise and of large amplitude, with the tip of the thumb touching each of the four fingers in turn at a rate of three oppositions in two seconds. Six blood flow scans were performed in each session, with two at rest, two while moving the fingers of the left, unaffected hand, and two while moving the fingers of the right, recovered hand. The ordering of tasks was balanced to avoid habituation effects. The PET brain images of individuals were transformed to conform to a standard anatomical space by identification and reference to the intercommissural line (AC-PC line), as described previously (Friston et a1 1989). Each image was smoothed to account for variation in normal functional anatomy. The confounding effect of global differences in CBF between subjects was removed using an analysis of covariance (Friston et a1 1990). All image analysis was then performed on a pixel-by-pixel basis to generate mean CBF maps for each activated state across all subjects. This averaging procedure resulted in improvement of signal-to-noise ratios and an estimate of error variance for each pixel in the maps. The comparisons between brain states were then performed in a planned manner using standard statistical techniques from which were generated statistical parametric maps (SPM) of significant stateassociated changes in rCBF. Comparisons were made between (a) the resting distribution of blood flow in patients and normal subjects; (b) the pattern of activation elicited by movements of each hand in patients; and (c) the magnitude of the activation elicited in patients on movement of each hand and that obtained in normal subjects. Functional disconnections We analysed the functional disconnections caused by the infarct by comparing cortical and subcortical distributions of rCBF in the group of ten patients at rest with the distribution of blood flow in a group of ten age-matched normal subjects. The 10 patients were aged 21-62 years (mean: 41 years) and all had ischaemic striatocapsular infarcts. No other focal abnormality was seen on

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structural imaging. The extracranial and intracranial large vessels were normal on Doppler examination. The 10 healthy volunteers were aged 28-69 years (mean: 47 years), had no significant antecedent neurological history, and were neurologically normal and functioning at work and socially without detectable impairment, Some generalizations can be made from the results of this study because of the relatively homogeneous siting of the lesions in the striatocapsular region. At rest, there was significantly decreased rCBF in the brains of patients in the left striatum and internal capsule, corresponding to the site of the lesion. In addition, there were significant decreases in the left insular, primary sensorimotor and lateral prefrontal cortices, thalamus, midbrainlcerebral peduncle and in the contralateral cerebellum (Fig. 1) (see colour plate). None of these areas was infarcted on structural imaging. These areas of significant hypometabolism at rest can be considered as direct, functional remote consequences of the focal infarcts. It is however, possible that parts of the areas of hypoperfusion immediately surrounding the infarcts are caused by partial neuronal attrition, short of frank infarction; but this cannot be true for the more distant areas and those lying outside the territory of the feeding artery. These areas also constitute components of the motor system-in particular the primary motor and prefrontal cortices, and the striatum, thalamus and cerebellum. On the other hand, other components, such as the premotor cortex on the side of the lesion, are conspicuous in their lack of any change in rCBF, while the insular cortex has a much less clearly defined relationship to this system. The striatocapsular lesions result in a complex pattern of chronic deactivation which includes motor and neighbouring association areas. The hypoperfusion in the midbrain/ peduncular region can be interpreted as a result of degeneration of the pyramidal tract, a major constituent of this anatomical region. There were other areas in which rCBF at rest was higher in patients than in normal subjects, namely the right striatum (putamen and caudate nucleus) and premotor cortex, and left posterior cingulate. The findings in contralateral premotor cortex and its subcortical projection area, the striatum, are of particular interest, given the changes in activity in the supplementary motor areas (SMA) and in both premotor cortices with repetitive tasks of the upper limb that we have observed in normal subjects (Colebatch et al 1991). The chronic increase in rCBF due to a remote ischaemic lesion may therefore constitute the result of functional disinhibition of motor areas in a single network by a contralateral lesion in a constituent part of the same system. The disinhibition of the contralateral ‘motor hemisphere’ may form an integral part of the recovery process. The recovered hand

The pattern of rCBF changes seen in response to movement of the ‘normal’ hand was compared to that elicited by the same movement carried out by the

FIG. 1 (Fruckowiuk et ul) Comparison of rCBF at rest between 10 patients with striatocapsular infarcts and 10 normal subjects. Areas with decreased rCBF in patients are shown. The upper row represents features averaged from the 10 patients into Talairach space. Below, coronal, sagittal and transverse projections of the statistical parametric maps (SPMs) obtained by a comparison between patients and normal controls are displayed. All areas with significant decreases in rCBF in the patients are shown. The grid is the standard, proportional, stereotactic grid of Talairach & Tournoux (1988) which defines the three-dimensional space into which all the brains have been normalized. The line drawings are of the horizontal brain contours at the level of the AC-PC line (intercommissural line) (below), in the midsagittal plane (upper lefr), and at the midpoint of the AC-PC line in the coronal plane (upper right). The display permits rapid inspection and localization of all the data. The ‘hot’ end of the rainbow scale (distributed over 255 levels) shows areas of maximally significant rCBF difference and the ‘cold’ end the threshold of P
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previously paretic, recovered hand in the same patients (Chollet et a1 1991). Hence the patient acted as his or her own control and the assumption inherent in this design was that a hemispheric lesion leading to motor dysfunction would not result in secondary consequences for the organization and functional relationships of the normal hemisphere on activation. This assumption, given the results reported above, is clearly a simplification. We studied six patients two or more months after a first hemiplegic stroke. Again all had a single, demonstrable and appropriate ischaemic lesion on CT or MRI in middle cerebral artery territory (five subcortical strokes and one cortico-subcortical stroke, all sparing the primary sensorimotor area). Major recovery of motor function had occurred in all patients such that they were able to perform the finger opposition task as well as normal volunteers. Comparisons were made of the rCBF map at rest with that recorded when the fingers of the recovered hand were being moved, and then with the map obtained when the unaffected hand was active. When the fingers of the unaffected side were moved, the pattern of activation was highly lateralized. The rCBF increased significantly in contralateral primary sensorimotor cortex ( + 24.4%; 48 to 60 mm above the AC-PC line) and in the ipsilateral cerebellar hemisphere ( + 14%; - 20 to - 12 mm below the AC-PC line). The increase in the ipsilateral sensorimotor cortex was not significant (+ 3.5%). rCBF increased to some degree bilaterally in the insular and premotor cortices, the SMA, the supramarginal gyms (area 40) and the putamen. The changes were significant only on the contralateral side except for the SMA and area 40, in which they were bilateral. When the recovered hand was being moved the pattern of cerebral activation was bilateral. rCBF increased significantly in both contralateral (+ 23%) and ipsilateral ( + 10%) sensorimotor cortex and in both cerebellar hemispheres. There was now a significant bilateral increase in rCBF insular and premotor cortices in addition to area 40 and SMA. The magnitude of the rCBF changes in area 40 and SMA was similar to that during movement of the ‘normal’ fingers. There was no significant increase in either putamen. This result demonstrates a role for ipsilateral motor pathways in the recovery from motor disability and implies an increase of synaptic input to ipsilateral motor cortex. This latter deduction follows because the increase in rCBF occurs at the sites of projection of neurons; therefore increased activity in motor cortex suggests increased synaptic firing in the area. The increased activation of the inferior parietal cortex (area 40) during movement of the recovered hand is also of interest, because this area is thought to be a somatosensory association area (Roland et a1 1980) which has known connections to inferior area 6 (premotor cortex) (Strick 1985). This latter area connects with motor cortex and therefore constitutes an alternative pathway by which activation of efferent motor pathways occurs. A further observation of interest is that of Fries et a1 (1991), who examined a patient with degeneration of the pyramidal tract demonstrated

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on MRI with suprathreshold transcranial electrical stimulation of the cortex. The patient showed a remarkable degree of recovery of motor function; bilateral motor responses were elicited with stimulation of the damaged hemisphere, while strictly unilateral responses followed stimulation of the ‘normal’ hemisphere. The authors’ interpretation of these findings also focuses on the suggestion that the bilaterality of the response in the face of corticospinal degeneration implies that alternative, bilateral, polysynaptic cortico-reticulo-spinal connections mediate motor function. Activation in patients compared to normal subjects Finally, we have investigated the pattern of cerebral activations in patients with striatocapsular infarctions and compared them to the mean changes in rCBF elicited by the same motor task in a group of 10 normal subjects. The patterns of rCBF change elicited by the ‘normal’ as well as the recovered hand were compared separately. This study addressed the issue of whether the pattern of cerebral reorganization affected one or both hemispheres and avoided the assumption that the unaffected hemisphere was normal in the patients. When patients moved the recovered hand they activated the usual motor areas to the same extent as normal subjects, namely ipsilateral cerebellum and contralateral sensorimotor and premotor cortex. An area comprising anterior insula, premotor cortex and frontal operculum (0 to + 12 mm above the AC-PC line) was activated bilaterally with a significantlyhigher rCBF increase in patients compared to subjects. There was also significantly greater activation of bilateral area 40, ipsilateral striatum and lateral area 6 and contralateral cerebellum in the patients. We conclude from this result that patients with motor stroke due to striatocapsular infarction use the ordinary lateralized motor pathways to the same extent as normal subjects. Additional bilaterally distributed pathways are also used to bypass the interruption of efferent traffic from the motor cortex. In this context, area 40 is considered to be a sensory association cortex with projections to the premotor area which is specialized in its most inferior parts (area F5) for distal limb movements. There was also significant activation in patients compared to normals in the anterior cingulate (area 32) in the midline (20 mm above the AC-PC plane) and bilateral prefrontal cortex. The pattern of cerebral activation was found to differ from normal when the unaffected hand was moved by patients. Patients activated the striatum, the insular, low prefrontal and high premotor cortices and the supramarginal gyrus more than normal subjects. All these areas were on the appropriate side and contralateral to the lesion. There were no areas which normal subjects activated more than patients. However, there was a clear tendency in patients to a decreased rCBF in the posterior cingulate and lateral parietal cortex (area 39).

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Activation patterns in individual patients

So far we have studied the individual alterations in activation patterns in five patients compared to our group of 10 normal subjects and have correlated the findings with the anatomical lesions. The findings are presented here as illustrative case reports to demonstrate that it may be possible to analyse the functional anatomy of recovery in individual patients. 1. A patient made a slow and incomplete recovery from a right hemiplegia caused by a pallidal and posterior limb of internal capsule infarct. He activated the left sensorimotor and right insular cortex more than normal subjects when moving the recovered hand. 2. A patient with an infarct of the left putamen, caudate and anterior limb of the internal capsule and a rapid, complete recovery showed additional activation in the right striatum, insular cortex and low premotor cortex, bilateral supramarginal gyri and anterior cingulate. 3. A patient with an infarct of the left pallidum and posterior limb of the internal capsule with slow but complete recovery showed additional activation, above that in normal subjects, in the left sensorimotor cortex and right striatum, low premotor cortex and supramarginal gyrus. 4. A patient with an infarct in the left caudate and the anterior limb of the internal capsule made a slow and incomplete recovery, with synkinetic movements of the unaffected hand. He showed widespread additional activation above that in normal subjects on the right side in the striatum, low prefrontal and premotor cortices, the supramarginal gyrus and the left cerebellum. 5 . A patient with a lacuna in the posterior limb of the left internal capsule showed complete recovery and synkinetic movements of the unaffected hand. He had supranormal activation in the left sensorimotor cortex and right premotor cortex. This patient is interesting in that his lesion was small and probably affected only part of the pyramidal tract. It is clear that different activation patterns may be associated with recovery; one hypothesis is that the site of the lesion plays a dominant role in determining the precise plastic changes that the brain may undergo when damaged. Summary and conclusions Our studies suggest that one mechanism underlying recovery from stroke may involve activation of the normal established cortical pathways and the bilateral recruitment of additional motor areas. In patients recovering from motor stroke the supramarginal gyrus and an area of cortex comprising insular, ventral premotor and frontal opercular cortices appear to constitute an additional motor system that is recruited over and above its normal contribution to the execution of a sequential motor task. This pattern of activation is more diffuse than under

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normal physiological conditions; this may account for the fact that movements cannot be made with the same facility as is possible for the normal specialized pyramidal tract, thus explaining the clumsiness associated with incomplete recovery. The motor system contralateral to the lesion appears relatively disinhibited, as shown by the results of the studies made at rest. This may be responsible in some way for the activation of the ipsilateral cortex that is associated with recovery. Though it mediates the recovery process, the ipsilateral cortex also influences the function of the unaffected hand. This may have two further effects, both of which are clinically recognized. Firstly. the bilateral nature of the recruited areas may be responsible for the production of associated movements of the opposite hand when the recovered hand is performing a motor task. A number of our patients exhibited synkinetic movements of the unaffected hand though none showed mirror fractionated movements. Secondly and more speculatively, the contralateral ‘unaffected’ hand will receive a modified input that differs from normal. This may be partly responsible for the mild involvement of the primarily unaffected contralateral hand (Colebatch & Gandevia 1990). Such a mechanism might interact with the more commonly suggested one involving uncrossed corticomotoneuronal fibres. The anterior and posterior cingulate cortices form an extensively interconnected system dealing with selective attention or vigilance (Posner & Petersen 1990). These areas are reciprocally activated in normal subjects when they perform finger movements to a random cue, but not when performing simple, regular, automated tasks such as the one we used (Frith 1991). Precisely this pattern of activation, with increased rCBF in anterior cingulate and decreased rCBF in posterior cingulate, was found in our patients, suggesting that the task is no longer processed as a simple, automated movement, but requires increased attention for its execution. The same argument accounts for the activity of the left prefrontal cortex, which plays a role in the internal generation of movements (Frith 1991) and may be the cortical substrate for an intentional system. Interestingly, both systems, anterior and posterior cingulate and prefrontal cortex, already show abnormal activity in our patients at rest. It appears that more precise individual studies are now possible in patients by comparison with large groups of age-matched normal subjects. Our group of normal subjects against which individual comparisons have been made comprises only 10 individuals. The reliability of such comparisons will be improved by increasing the size of the reference group. Comparison of rest states provides information on functional de-activations and compensatory activations as well as delimiting functionally the full extent of ischaemic damage. Comparison of the activations provides information on the changed pattern of neuronal firing associated with recovery. Advances in technology with improved sensitivity due to increased sampling of tissue by modern PET cameras raise the possibility of comparing a rest with an activated state in one individual

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in the future. These techniques are providing unique information on the plasticity of the brain, and even in a single system there is a richness of compensatory mechanisms which deserves further study.

A ckno wledgemen is Dr C. Weiller is a Feodor Lynen Research Fellow of the Alexander von Humboldt Foundation, Bonn-Bad Godesberg, Germany. Dr F. Chollet is a member of the Department of Neurology of the HBpital Purpan in Toulouse and was partly funded by INSERM.

References

Chollet F, Di Piero V, Wise RJS, Brooks DJ, Dolan RJ, Frackowiak RSJ 1991 The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol 29:63-71 Colebatch JG, Gandevia SC 1989 The distribution of muscular weakness in upper motor neuron lesions affecting the arm. Brain 112:749-763 Colebatch JG, Deiber M-P, Passingham RE, Friston K, Frackowiak RSJ 1991 Regional cerebral blood flow during voluntary arm and hand movements in human subjects. J Neurophysiol 65: 1392-1401 Feeney DM, Baron J C 1986 Diaschisis. Stroke 172317-830 Fries W, Danek A, Witt TN 1991 Motor responses after transcranial electrical stimulation of cerebral hemispheres with a degenerated pyramidal tract. Ann Neurol29:646-650 Friston KJ, Passingham RE, Nutt JG, Heather JD, Sawle GV, Frackowiak RSJ 1989 Localisation in PET images: direct fitting of the intercommissural (AC-PC) line. J Cereb Blood Flow Metabol 9:690-695 Friston KJ, Frith CD, Liddle PF, Dolan RJ, Lammertsma AA, Frackowiak RSJ 1990 The relationship between global and local changes in PET scans. J Cereb Blood Flow Metabol 10:458-466 Frith CD 1991 PET studies of frontal lobe function: relevance to psychiatric disease. In: Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Found Symp 163) p 181-191 Gardner WJ 1933 Removal of the right hemisphere for infiltrating glioma. JAMA (J Am Med Assoc) 101:823-826 Jones RD, Donaldson IM, Parkin PJ 1989 Impairment and recovery of ipsilateral sensorymotor function following unilateral cerebral infarction. Brain 112:113-132 Lammertsma AA, Cunningham VJ, Deiber M-P et a1 1990 Combination of dynamic and integral methods for generating reproducible functional CBF images. J Cereb Blood Flow Metab 10:675-686 Merill EG, Wall PD 1978 Plasticity of connections in the adult nervous system. In: Cotman CW (ed) Neuronal plasticity. Raven Press, New York, p97-111 Posner MI, Petersen SE 1990 The attention system of the human brain. Annu Rev Neurosci 13:25-42 Raichle ME 1987 Circulatory and metabolic correlations of brain function in normal humans. In: Plum F (ed) Handbook of physiology. Section 1: The nervous system, vol. 5 : Higher functions of the brain. Oxford University Press, New York (American Physiological Society, Bethesda) p 643-674 Roland PE, Larsen B, Lassen NA, Skinhoj E 1980 Supplementary motor area and other areas in organization of voluntary movements in man. J Neurophysiol 43:118-136

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Strick P 1985 How do the basal ganglia and cerebellum gain access to the cortical motor areas? Behav Brain Res 18:107-124 Talairach J , Tournoux P 1988 Co-planar stereotactic atlas of the human brain, 2nd edn.

Thieme Verlag, Stuttgart

Twitchell TE 1951 The restoration of motor function following hemiplegia in man. Brain 74~443-480 Wall PD I977 The presence of ineffective synapses and the circumstances which unmask them. Philos Trans R SOCLond B Biol Sci 278:361-372

DISCUSSION

Baron: Should we gather from your presentation that you have altered your recently published conclusions (Chollet et a1 1991) relating to the role of the right hemisphere in the recovery of motor function after stroke? Fruckowiak: No. There were significant changes in the right hemisphere. In that paper, where we presented the data from the second (recovery) experiment that I described here, in which the control was the patient using his normal hand (see p 238), we were making the assumption that the normal hand is associated with a normal hemisphere-making it function, so to speak. Where the modification comes in is that we have now tested that hypothesis and found it to be wanting (p 240). In other words, the unlesioned hemisphere has in fact changed its pattern of connectivity and firing in comparison to entirely normal subjects. So the conclusion of the paper (Chollet et al 1991) stands, that both hemispheres contribute to recovery; but we may be getting closer to the mechanism by which the hemisphere ipsilateral to the affected hand is contributing, in the sense that both striatum and areas of the insula, even at rest, appear t o have an increased metabolism, which may have something to do with altered connections with the other hemisphere. We haven’t worked out the anatomy of this and are finding it difficult to d o so, and to assess the significance of what is going on in the insula, for example, where electrophysiological data are more sparse than from other, more accessible areas of cortex. Corbettu: You showed an increase in blood flow in the contralateral cerebellum of patients compared to normals in the activation state. What happened in the supposedly diaschitic ipsilateral cerebellum? Frackowiak: The resting activity of the group of patients compared to the group of normals at rest showed a small area of de-activation in the appropriate (contralateral) cerebellar hemisphere, covering the period when we did the scans-from two weeks to a couple of months after the infarct. Corbetta: What about the rate of finger movements? Presumably there must be a difference in performance between normal subjects and patients? Fruckowiak: No. The execution was controlled by a tone; they had t o perform three finger-thumb oppositions in two seconds. A criterion for inclusion into

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the study was that patients were able to perform this task with the recovered hand. Our aim was to delineate the functional anatomy of recovery; therefore the principal criterion for inclusion was effective recovery. Raichle: I am interested to see that you are doing what we would call ‘unpaired comparisons’. That is, you are not now subtracting scans for an individual person in two different states, but two different groups of people in different states. This presents very interesting challenges about re-registering their brains. I am interested in how you have solved some of the technical problems involved. Frackowiak: These techniques are due largely to the work of Karl Friston in the laboratory. However, in the data discussed here, we specifically excluded patients with large ‘holes’ in the brain. The primary reason was the problem you have just referred to. Richard Wise, in contrast, by the nature of the deficits he is studying, had to include patients with large cortical lesions. There are a number of ways of registering images, from linear scaling, t o scaling around large structures on which you have a good fix, such as subcortical nuclei, or the plastic re-sampling transformations described by Dr Friston. With a large lesion in one hemisphere it is possible to flip the normal hemisphere about the vertical axis to obtain a good estimate of the cortical rim on the abnormal side. In short, there are a number of possible strategies, the choice being determined by the particular problem in hand. Raichle: With the smaller lesions you have done a very effective job; we have noticed that in areas around the base of the brain, which are more difficult to fit, we encounter a substantial number of artifacts; but you apparently do not. Frackowiak: These areas have indeed caused us a lot of trouble also, but now we feel confident that we have resolved them, though perhaps not perfectly yet. Jeannerod: Were you able to correlate the level of metabolic activity in the normal hemisphere with the rate of recovery? In other words, did you have, or could you have, groups of patients who exhibited good recovery and groups with no recovery? Frackowiak: That’s a crucial question and we hope to design an experimental paradigm to investigate it. We should like to study similar groups of patients with lesions in similar places but who have not experienced recovery, or only a degree of recovery. If we do a simple comparison of those who have recovered and those who have not, the first question to ask is whether the effort being put into the task is the same. There are ways of addressing that question. Also, one could assess the degree of recovery, and then begin to do a correlative analysis against recovery, for each region. This is what we shall be doing. Lassen: What is the opposite cerebral hemisphere really doing during recovery from stroke? You have a lesion on the left side of the brain, and you move the right hand, and you see that the right insula, the anterior cingulate g y m on the right side, and a few other right-sided areas increase their blood flow. What are they doing? Is it simply a ‘diffuse’ sign of the extreme effort of doing

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the task at the same rate as it could normally be done, which is a much harder task for the patient? Or is the opposite (right) hemisphere really aiding in a more task-related fashion? If the patient were to recover completely, would this ancillary ipsilateral function die out? Or be enhanced? And what is the insula doing anyhow in hand movements? We know very little about that. Fruckowiuk: I can only speculate, using observations from the clinic. Our interpretation of the activation of the anterior cingulate was roughly along the lines you suggest, that a task that is relatively automatic demands much more attention when done with the recovered hand. We have increasing evidence that the anterior cingulate and associated regions of the brain have something to do with attending to motor tasks, as I discussed. The first way that we have interpreted the bilateral hemispheric input to the recovered hand relates to the anatomical facts about uncrossed pyramidal fibres. But many of those fibres do indeed cross at spinal cord level, so it is unclear whether this is a sufficient explanation. It also begs questions about the interrelationships of the two hemispheres. We have also gone to the literature. Colebatch & Gandevia (1989) have noted that when patients have strokes in one hemisphere, there are deficits in the ipsilateral limb as well as the contralateral one. We have also made, as have others, clinical observations of associated movements of the unaffected hand that would be compatible with ipsilateral hemispheric activation. When the patient is performing the motor task with the recovered hand, the other hand may be showing gross or mass movements which are tonic and limited in extent. These are not invariably present, but motor efferents to that limb are clearly activated. We shall need to do simultaneous electrophysiological records from both limbs, to describe these phenomena more carefully in relation to the activation. Be that as it may, these phenomena are still all components of the recovery process; as to how they interact, I do not know yet. Our observations of compensatory changes in activity in the undamaged hemisphere, even at rest, when no motor function is being performed, are the most difficult to interpret. They seem to be priming areas which subsequently will have a much higher increase in activity than in the normal subject, when the appropriate movement is made. Whether this is cross-hemispheric disinhibition, or whether it represents compensation through subcortical loops, is not known. Muzziottu: Have you considered studying brain glucose metabolism in the same patients? From a practical viewpoint this is not so attractive, but with the 3D imaging and the possibility of giving much lower doses of fluorodeoxyglucose, you might be able to explore whether there’s a difference between the flow response and the metabolic response, given patients with lacunar infarcts and probably generalized small vessel vascular disease. Since you would have to spread the studies out over many days, and have a cooperative control group as well, it would be a formidable task, but you could evaluate the studies over the recovery period.

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Frackowiak: I can see the reasons why you suggest this, particularly in relation to the uncoupling of glucose and oxygen metabolism, but I haven’t considered doing it. Fox: As I understand it, you tested patients of different handedness, and some lesions were in the right hemisphere and some on the left, but you flipped the images so that they all appeared as if they were in the right hemisphere, for the purposes of analysis. You have therefore masked any information about hemisphere dominance; if the patient had a right hemispheric lesion but was right-handed, the activation pattern in his left hemisphere might be quite different than for the reverse. Frackowiak: This is true. We controlled for that to some extent aposteriori, by taking out the one right-hemisphere lesion in the group of six patients in which recovery was studied and reanalysing the remaining five; the results were the same, so we felt we could include the sixth subject. Fox: Are you finding any correlates during these tasks with handedness, and hemispheric dominance? When the right hand is used you record left-hemispheric activity and vice versa; so the phenomenon of handedness has escaped this paradigm. Frackowiak: I think it has. We can’t derive any sensible conclusions about handedness from this paradigm. The analysis of studies of individuals within the group experiments is uninformative; the averaging implicit in group studies is necessary to tease out the signals from the underlying noise. What we have found exciting is that you can compare the flow distribution of one patient against a group of normals and still produce signals which seem to make sense. We have done this in a preliminary fashion with the results in this series, and there seems to be a very satisfying internal coherence to the results. Fox: An additional comment on the role of insula: in our speech-production tasks we have seen opercular activation, both superficially and deep. Tongue movement causes a similar pattern of activity (Petersen et a1 1990). Actual and imagined hand movements show a similar pattern of activity in the insula (Fox et a1 1988). This seems to be reproducible, and I wouldn’t regard it as being unexplained or unpredictable. Frackowiak: I am very interested to hear that. The diagram of the insula in Peters & Jones (1985) fails to explicitly implicate motor functions of the upper limb in the roles that that structure plays. Of course, there are other cortical regions, like the low premotor regions, which are just adjacent. Rizzolatti, for example, suggests that they have to do with goal-directed fine finger exploratory movements (Gentilucci et a1 1989); so, if you are also finding activation in the insula, with other movements, that becomes an interesting site to study further. Lassen: Dr Fox,can you tell us if moving one hand in a specific fashion will produce a blood flow increase in the insula on both sides, on the contralateral side, or what?

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Fox: In the first group of experiments, our impression was that regardless of the hand used, right or left, there was a bilateral insular blood flow increase with movement. When we compared imagined movements, the bilaterality was less impressive; the right hand would induce left insular activity and the left would induce right activation. In right-handers, it was easier to activate the left insula than the right, and there was some bilaterality; so it wasn’t as consistently simply bilateral activity. Mazziotta: Dr Frackowiak, have you seen any mouth or tongue movements during the finger task? We have examined visual tracking with the tongue; and we see bilateral inferior homunculus premotor or motor area activations. If you simply watch a child learning a new fine motor manual task, the mouth and tongue are moving a lot. I wonder whether that might contribute to the results. Frackowiak: Activation is indeed bilateral, with use of the recovered hand. However, we were using the inhalation method, so the face was masked, and we have not looked for associated tongue movements. Fox: The concept of sympathetic apraxia and Broca’s aphasia should be invoked here. It’s a common observation that in a patient with a left frontal lesion, a non-fluent aphasia and a right-hand paresis, one often finds apraxia of the left hand. Cuppu: There is another piece of evidence for the role of the insula. If you collect a group of patients with orofacial apraxia, and you overlap the CT lesions, the crucial area of damage is in the left frontal operculum and probably involves the insula (Tognola & Vignolo 1980). I would expect some of your patients with subcortical left hemisphere stroke to have also transient aphasia. Have you studied language activation in your recovered stroke patients? Frackowiak: Not in the groups I discussed, but Richard Wise and I have a programme which is addressing that question. We have gone faster with the motor studies for two reasons. One is that the basic anatomical pathways are better known. Secondly, the lesions in the motor stroke are often very small, if the selection bias is for major recovery; whereas in the aphasic patients the lesions involve quite large areas which may be superficial in the cortex. This presented us with technical difficulties which we are only now resolving. Cappa: The subcortical aphasia group could be a suitable one in which to study language recovery. One can find patients with small subcortical lesions and aphasia lasting for one month or so (Cappa et a1 1983). Corbettu: You raised the possibility of studying functional connectivity by using cross-correlation analysis between regions that may not necessarily be significantly activated. Can you expand on this issue? Frackowiak: We can do correlational analyses to look at functional connectivity, because our comparisons are not done on a paired basis, patient by patient, but on a group basis, across patients, for the different brain states. Therefore for each such brain state, consider each voxel in the image. A value

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can be derived for the mean blood flow, as can an estimate of the variance among the patients making up the group. This is an analytical process that is based on a simple analysis of covariance, as Karl Friston has described (Friston et a1 1990). If you look at a number of brain states which represent differential activation in one system, for example the visual system, you can perform a simple covariance analysis across the brain states in the mean images and look at the variation of the blood flow, in the brain as a whole, with that at some reference site of interest. The result is to pick out only those areas which are functionally coupled to a key area often known to be of crucial importance to that particular system, such as area V1 in visual experiments. In our visual experiments, there is covariation of blood flow in areas V4 and V5 with blood flow in V1 and V2. Covariation may be positive or negative, but nowhere else have we seen a coherent functional (CBF) coupling when the visual stimuli have related to colour and visual motion. This blood flow covariance means that there is a necessary functional relationship between the areas. We want to explore this further, and are hoping to demonstrate networks as covarying structures which will need anchoring in anatomical and electrophysiological fact. The thalamus is a potent example of this idea. In motor paradigms such as I have described, there is no significant activation of this crucial sensorimotor structure. Nevertheless, rCBF covaries coherently with rCBF changes in the thalamus only in regions known to be intimately associated with motor function-for example, primary and supplementarymotor areas, supramarginal gyri, parietal area 5 , and cerebellum.

References Cappa SF, Cavallotti G, Guidotti M, Papagno C, Vignolo LA 1983 Subcortical aphasia: two clinical-CT scan correlation studies. Cortex 19:227-242 Chollet F, Di Piero V, Wise RJS, Brooks DJ, Dolan RJ, Frackowiak RSJ 1991 The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol 29:63-71 Colebatch JG, Gandevia SC 1989 The distribution of muscular weakness in upper motor neuron lesions affecting the arm. Brain 112:749-763 Fox PT, Petersen SE, Posner M, Raichle ME 1988 Is Broca’s area language specific? Neurology 38 (suppl 1):172 Friston KJ, Frith CD, Liddle PF, Dolan RJ, Larnmertsrna AA, Frackowiak RSJ 1990 The relationship between local and global changes in PET scans. J Cereb Blood Flow Metab 10:458-466 Peters A, Jones EG (eds) 1985 The insula (chapter X). Cerebral cortex, vol 3: Visual cortex. Plenum Publishing, New York Petersen SE, Fox PT, Snyder AZ, Raichle ME 1990 Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science (Wash DC) 249:1041-1044 Gentilucci M, Fogassi 1, Luppino G, Matelli M, Camarda R, Rizzolatti G 1989 Somatotopic representation in inferior area 6 of the macaque monkey. Brain Behav EVOI33~118-121 Tognola G, Vignolo LA 1980 Brain lesions associated with oral apraxia in stroke patients: a clinico-neuroradiological investigation with the CT scan. Neuropsychologia 18:257-281

Testing cerebral function: will it help the understanding or diagnosis of central nervous system disease? J. C. Baron INSERM U. 320 and Centre Cyceron, €Id Henri Becquerel, 14021 Caen, France

Abstract. The recent introduction of non-invasive tools for the quantitative mapping of cerebral function in humans (e.g. cerebral blood flow measurement and positron emission tomography) in conjunction with detailed in vivo tomographic morphology (computed tomography and magnetic resonance imaging) has led to a fruitful interaction between clinicians and fundamental neuroscientists. This has led to the development of a productive, scientifically sound human neuroscience whose aim is to explore brain function directly in the human subject. With respect to the physiological state, this research has resulted in major findings especially in the fields of visual function, attention, anticipatory anxiety, language, motion and somaesthesia. The study of disease states has resulted in less impressive findings. The investigation of patients with focal brain lesions has revealed time-dependent alterations of cerebral blood flow and energy metabolism in widespread grey matter structures, as a result of disconnection; however, these functional alterations apparently reflect a variety of processes, from Wallerian or retrograde degeneration to reversible or irreversible transsynaptic or transneuronal effects, which makes their interpretation uncertain. Likewise the cellular and neurochemical basis for the recovery of energy metabolism in deafferented brain areas remains speculative. Although several types of metabolic effects due to disconnection are correlated to well-defined neuropsychologicaVbehavioura1impairment (and recovery therefrom) unexplained discrepancies exist and their role in individual patients remains obscure. The study of the brain’s ‘functional reserve’ by activation paradigms would presumably shed more light on the clinicaVfunctiona1brain relationships in disease but such investigations are hampered by unresolved methodological issues such as the choice criteria for the control population (?healthy controls, ?asymptomatic brain-lesioned patients) and task (?pseudo-impaired). There are also complex statistical issues because of the requirement to study single cases as a result of the inter-subject variability in lesion topography, size or duration, as well as in the pattern and degree of behavioural impairment. The design of controlled experimental paradigms in non-human primates, involving controlled lesions and sequential behavioural and PET assessment, may help to resolve some of these issues. 1991 Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Foundation Symposium 163) p 250-264

In the last 15 years there have been tremendous developments in techniques for imaging the living human brain, in the form of two-dimensional or 250

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three-dimensional imaging of the brain’s morphology (X-ray computed tomography, magnetic resonance imaging) and function (single photon emission tomography, positron emission tomography, quantitative EEG mapping, magnetic resonance spectroscopy and magnetoencephalography). The clinician now has routine access to high resolution morphological images of his patient’s brain, that can be compared to quantitative maps of important neurobiological markers such as perfusion, oxygen consumption, glucose utilization, specific receptor or re-uptake site density, or enzyme activity. Interestingly, these developments in human neuroimaging have been paralleled by homologous breakthroughs in autoradiographic techniques that now allow the neuroscientist to map pharmacological as well as physiological variables (such as cerebral blood flow, pH, glucose utilization) in the brain of the monkey, the cat or the rat. These convergent developments have led to strong and fruitful interactions between clinicians and fundamental neuroscientists. In addition, because neuroimaging techniques also require multidisciplinary teams, the interfacing of clinicians with physicists and mathematicians is now commonplace. One side effect of this recent momentum has been the emergence of clinicians who are actively engaged in the neuroscience of the human brain, and whose aim is to better understand brain function directly in the human. In the field of positron emission tomography (PET), major findings have appeared regarding neuronal network operations in the physiological state, thanks to the pioneering methodological developments (the so-called ‘activation’ paradigm) by the group in St Louis, Missouri (Fox et a1 1985, 1988, Fox 1989, Fox 8z Mintun 1989, Mintun et al 1989). Particularly impressive and provocative has been the demonstration of focal neuronal cluster activation during cognitive operations such as semantic processing and the output of words, or selective or sustained attention (Petersen et a1 1988, 1990, Corbetta et a1 1990, Pardo et a1 1991), as well as during emotional reactions such as anxiety in anticipation of pain (Reiman et a1 1989). The clinician, however, is naturally attracted by disease conditions. The question arises as to whether functional brain imaging with PET has led to correspondingly major breakthroughs in the clinical sciences-that is, in the diagnosis and understanding of disease. The issue of the role of PET in neurological practice has recently been comprehensively covered by Brooks (1991). He reviewed the clinical applications of PET with respect to the measurement of cerebral haemodynamics, energy metabolism (i.e. oxygen consumption or glucose utilization) and neurotransmission parameters, and concluded that ‘PET can demonstrate characteristic patterns of disruption of regional cerebral metabolism and neurotransmitter systems associated with the cortical and sub-cortical degeneration, and so help to characterize the type of dementia or akinetic-rigid syndrome affecting patients when this remains unclear after clinical assessment and structural imaging. Sub-clinical involvement in subjects at-risk for degenerative conditions such as Alzheimers, Parkinson’s,

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and Huntington’s diseases can also be demonstrated. In cases where extracranial artery stenosis is causing impaired cerebral perfusion, PET can assess the degree of haemodynamic compromise present, and provide a rationale for revascularisation. Functional imaging is valuable for lateralising epileptic foci in patients with focal seizures who have a normal surface EEG and are under consideration for temporal lobectomy, enabling avoidance of the use of depth electrode studies in certain instances. Finally, PET can give insight into the adaptive mechanisms the brain uses to overcome focal injury, and can directly monitor the effects of therapy on regional cerebral metabolism’. Brooks also indicated that the successful implementation of PET methods has led t o rapid developments in single photon emission computerized tomography (SPECT) imaging, a much less expensive and hence clinically widely available method. Despite these positive results in the field of diagnostic applications, progress in the understanding of the mechanisms of brain disease made possible by PET has been less impressive. As one especially illustrative example of in vivo studies of functional neuroanatomy, let us consider the issue of the widespread metabolic effects of focal brain lesions (e.g. a circumscribed infarction, tumour or haemorrhage) (Baron et a1 1984, Feeney & Baron 1986, Baron 1987). Although quite impressive in extent and magnitude, these effects on brain energy metabolism remain poorly understood in terms of both neuronal mechanisms and clinical implications, despite more than 10 years of active investigation since the original reports of Kuhl et a1 and Baron et al in 1980. This is not the place to enter into a detailed account of present knowledge on these effects, and the reader in referred to a recent review on the subject (Baron 1989). We shall here only highlight some of the controversial points in relation to the issue addressed in the title of this chapter. Focal brain lesions may, in the acute stage, induce hypometabolism of both the ipsilateral and the contralateral cortical mantle, the ipsilateral basal ganglia and thalamus, and the contralateral cerebellar cortex, the distribution and magnitude of the hypometabolism being dependent on the structures that are actually damaged. In addition, some of these distant metabolic effects are subject to recovery according to a variable time course. Basing themselves on von Monakow’s controversial concept of ‘diaschisis’ (1914)’ many clinicians found it convenient to lump all these distant effects into an ill-defined mechanism of ‘deactivation’, and to hold them responsible for causing most of the clinical expression of lesions, and functional recovery therefrom (Table 1). In our review on diaschisis (Feeney & Baron 1986), we warned against the uncontrolled use of this term, which should be restricted only to those distant metabolic effects for which a transsynaptic mechanism is likely and that fulfil the following criteria: (1) identification of the fibre tract involved; (2) demonstration of a reversible process; and (3) correlation with a behavioural symptom, including parallel improvement with time, and response to pharmacological manipulations. It is only if this strict definition is adhered to that this modern view of diaschisis

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TABLE 1 Remote metabolic effects of brain lesions

Remote hypometabolic area

Ipsilateral cerebral cortex Contralateral cerebral cortex Ipsilateral basal ganglia, thalamus Contralateral cerebellum

Lesion (example)

Clinical correlates

Thalamic lesion (‘thalamo-cortical diaschisis’) MCA territory infarction, thalamic lesion Cortical lesion

Aphasia Neglect Amnesia

Capsular infarction (‘crossed cerebellar diaschisis’)

Coma?

Delirium? Aphasia? Motor neglect? Ipsilateral ataxia?

MCA, middle cerebral artery. Neglect: ‘inattention’ to the hemi-space contralateral to the brain lesion. Motor neglect: hemi-hypokinesia contralateral to the brain lesion.

may ultimately prove useful (Table 2). At present, however, only a single distant effect, thalamo-cortical diaschisis, has been shown to fulfil most of these criteria (Baron et a1 1989), although proportional improvement with time of cortical hypometabolism and neuropsychological impairment is still uncertain, while parallel response to pharmacological manipulations has not been demonstrated at all. Less specifically, significant positive correlations between the severity of aphasia measures and left temporo-parietal hypometabolism have been repeatedly demonstrated in patients with subcortical stroke (Metter et a1 1988, Karbe et a1 1989). However, at the individual level, unexplained discrepancies sometimes exist between the patient’s behavioural status and brain metabolic images (Baron et a1 1989, Pappata et a1 1990). The cellular basis of the various types of remote metabolic effect of lesions, and in turn their behavioural significance, would certainly be clarified, at least to some extent, by parallel histological and neurochemical investigations. However, the opportunity to obtain pathological tissue in humans is limited. TABLE 2 Criteria for diaschisis 1.

2. 3. 4. 5.

6. 7.

Circumscribed lesion Functional effect at a distance Identification of the fibre tract involved A transsynaptic or transneuronal effect A reversible process Correlation with behavioural impairment Response to pharmacological manipulation with parallel behavioural change

(Modified from Feeney & Baron 1986.)

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In a single patient with fluctuating behavioural impairment, left frontal-lateral hypometabolism and a large lacuna in the anterior limb of the left internal capsule, Metter et a1 (1985) reported a lack of significant neuronal loss in the left frontal cortex, suggesting that the hypometabolism that existed before death reflected a functional effect of frontal-thalamic disconnection. Studying patients with thalamo-cortical or crossed cerebellar diachisis by means of high resolution magnetic resonance imaging (MRI), Pappata et a1 (1987) reported that these metabolic effects were not accompanied by morphologically detectable tissue atrophy: long-standing hemispheric lesions, however, are known to at times induce crossed cerebellar atrophy, although almost exclusively in the developing human brain. With respect to the ipsilateral thalamic hypometabolism frequently seen in patients with cortico-subcortical lesions, Pappata et a1 (1987) reported a patient with long-standing hemispheric infarction who displayed associated thalamic atrophy detected by MRI. Our understanding of the cellular basis of remote metabolic effects of brain lesions has recently benefited from histological studies of anterograde, retrograde and transsynaptic-transneuronaldegeneration after experimental brain infarction (Kataoka et a1 1989, Fujie et a1 1990, Iizuka et a1 1990, Tamura et a1 1990), and from combined histological and 2-deoxy [ 14C]glucose autoradiographic studies in macaque monkeys subjected to ablation of cortical areas 4 and 6 of Brodmann (Gilman et a1 1987, Shimoyama et a1 1988). These studies all indicate that, after cortical damage, the thalamus displays massive retrograde degeneration of the corresponding thalamo-cortical neurons, with macrophagic infiltration (a cellular process that may enhance local glucose utilization and thus tend to mask the reductions in CMRglu [cerebral metabolic rate for glucose] resulting from decreased synaptic activity) and gliosis, and subsequent gross atrophy. In monkeys with ablation of areas 4-6 of cortex, however, Shimoyama et a1 (1988) noted the presence of metabolic depression in several thalamic nuclei, without histological changes, indicating that thalamic hypometabolism is probably not entirely due to retrograde degeneration but is perhaps also due to a transsynaptic retrograde effect. With respect to the striatum, Gilman et a1 (1987) noted in the cortex-ablated monkey the presence of infiltrates of microglial cells and astrocytes in this structure, suggesting anterograde degeneration of the cortico-striatal fibres, accounting for at least part of the sustained decrease in CMRglu measured in these structures. These authors, however, noted no histological changes at all in the globus pallidus, a structure nevertheless demonstrating metabolic depression, and concluded that this metabolic effect must have been indirect, i.e. occurring transneuronally along the cortico-striato-pallidal pathway. With respect to the contralateral cerebellum in the monkeys in which areas 4-6 were ablated, Shimoyama et a1 (1988) reported reduced metabolic rates of glucose unaccompanied by histological changes, arguing in favour of a transneuronal functional effect; this agrees with the fact that in humans, crossed

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cerebellar diaschisis can occur on a purely functional basis, namely as a result of functional depression of the cerebral cortex without actual damage (e.g. during Wada’s test or transient ischaemic attacks, and as a result of thalamocortical diaschisis) (Biersack et a1 1987, Pappata et a1 1990). After cortical damage, callosal fibres are known to degenerate (Kataoka et a1 1989), and degeneration of callosal terminals in the contralateral cortex presumably accounts for part of the observed contralateral metabolic depression (so-called ‘transhemispheric diaschisis’). With respect to ipsilateral cortical hypometabolism after thalamic lesions, degeneration of the thalamo-cortical axon terminals after experimentalthalamic injury has been described (Van Ferreira 1952); however, the metabolic depression observed at the cortex seems out of proportion to the density of thalamo-cortical endings within the cortex (Peters 1979). Moreover, Girault et a1 (1985), in rats, showed that the cortical hypometabolism induced by a lesion in the ventromedial nucleus was not confined to the neuron layers where the thalamocortical axons end, and hence rejected this interpretation. Retrograde degeneration of the cortico-thalamic neurons has only been observed in children with long-standing lesions of the thalamus (Kwak et a1 1978); experimentally, retrograde cortical degeneration has only been demonstrated in the cortico-spinal neurons several weeks after transection of the axons (Cowan 1970, Feringa et a1 1984). Finally, transsynaptic neuronal death does occur in subcortical structures but has no real equivalent in the cerebral cortex (Cowan 1970). Thus, thalamo-cortical hypometabolism presumably reflects, at least in part, a functional transsynaptic effect. Overall, therefore, it appears that the depression in integrated metabolic activity seen with PET in distant structures does not have a unique cellular basis but actually reflects mechanisms that differ according to each case considered (Table 3). In directly disconnected thalamic nuclei, massive retrograde somatic degeneration occurs; in the cortico-striatal, thalamo-cortical and transcallosal TABLE 3 Cellular basis of diaschisis

Remote metabolic effect

Putative cellular mechanism

Thalamic hypometabolism Striatal hypometabolism

Retrograde cell body degeneration Terminal degeneration + transsynaptic

Pallidal hypermetabolism

Functional transsynaptic disinhibition Terminal degeneration+ transsynaptic

Transhemispheric hypometabolism

Thalamo-cortical hypometabolism Crossed cerebellar hypometabolism

effect

effect

Terminal degeneration+ transsynaptic effect Transneuronal effect-long-term degeneration

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projection areas, terminal degeneration would explain only a part of the metabolic effects measured, while transsynaptic mechanisms would explain the rest. In the ipsilateral globus pallidus and contralateral cerebellum, on the other hand, transneuronal effects would be exclusively involved. Even in the latter instances of distant hypometabolism mainly caused by transsynaptic-transneuronaleffects, it is likely that morphological changes in dendritic spine arrangement parallel the metabolic depression observed (Fifkova & Hassler 1969, Matthews et a1 1976). The case of crossed cerebellar diaschisis is of special interest in this respect, because it is known to span the whole continuum of transneuronal effects from a purely functional, transient hypometabolism (see above), to a permanent metabolic depression (Pantano et al 1986), possibly evolving towards irreversibledegeneration (crossed cerebellar atrophy). Such a transition from purely functional effects to irreversible degeneration presumably depends on: (1) the final extent of the causal lesion and subsequent deafferentation; (2) the number of neuronal relays interposed between the lesion and the deafferented structure; (3) the uniqueness or multiplicity of afferent systems to the structure of interest; and (4) the plasticity of the brain, stage of brain maturation and age of the subject at time of lesion. In addition to the variety of mechanisms described above that underlie distant metabolic effects, recovery from these distant effects must also reflect various processes, but here relevant morphological and neurochemical data are even less available. Presynaptic events may occur, such as increased activity of nondamaged afferents, restored activity of damaged but surviving afferents, or sprouting of afferents from contralateral homologous nuclei or from different nuclei. Postsynaptic events could also play a role, such as postsynaptic hypersensitivity, or reorganization of the interconnected, parallel-distributed neuronal networks (see Kiyosawa et al 1989 for general discussion). After unilateral lesion of the nucleus basalis of Meynert in baboons, almost full recovery of the initially depressed cortical glucose utilization occurred, despite sustained reductions in choline acetyltransferase activity (ChAT), perhaps indicating that measurement of the ‘resting’ (unchallenged) metabolic rate was not able to reveal the underlying neurochemical impairment. Alternatively, metabolic recovery in this case could reflect the restoration of efficient synaptic activity by mechanisms such as the enhanced activity of undamaged presynaptic terminals, or postsynaptic network reorganization. Similar processes may underlie the parallel recovery of cortical hypometabolism and neuropsychological impairment after thalamic stroke (Baron et a1 1986, 1989), but we lack relevant supporting neurochemical data. In addition to reduced metabolism, diaschisis may also, in specific instances, take the form of enhanced energy metabolism. Thus, increased CMRglu develops in the ipsilateral substantia nigra after experimental striatal lesion in rats, presumably as a result of reduced inhibitory GABAergic input; this metabolic enhancement precedes neuronal death and atrophy (also seen in humans after

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massive basal ganglia infarction) (Tamura et a1 1990). Similarly, increased CMRglu affects the globus pallidus in both experimental parkinsonism and Parkinson’s disease, presumably also as a result of loss of striatal GABA input. Despite this appearance of increased metabolism, ‘disinhibition diaschisis’ does not reflect ‘better’ neuronal function, but rather reflects an imbalance between inhibitory and excitatory inputs with threatening neurotoxicity; neuronal death, in this case, may serve to restore a disabling functional imbalance, and its prevention by neuroprotective drugs such as GABA agonists actually tends to impede functional recovery (Schallert et a1 1990). Conversely, the hypometabolism of classic diaschisis may reflect a beneficial compensatory process that tends to restore the balance, initially disrupted by the lesion, among interconnected neuronal networks. These considerations may be important in designing strategies for the pharmacological manipulation of functional recovery (Schallert et a1 1990). All the above considerations indicate that PET studies of the remote metabolic effects of lesions in the ‘resting’ state are not easily interpretable in neurobiological terms, and do not provide a comprehensive test of either prevailing cerebral function or the existing potential for functional recovery. It is therefore tempting to use activation paradigms to test the brain’s functional state, because this could help to predict its capacity for functional recovery and possibly shed new light on the mechanisms of the latter (Fox 1989). This would also be consistent with the original concept of diaschisis as a loss of neuronal response to physiological stimulation (von Monakow 1914, Feeney & Baron 1986, Ginsberg et a1 1989). Finally, this approach could lead to a better understanding of the neuronal basis of abnormal behaviour, and perhaps to an accurate diagnosis in stages of the disease where ‘resting’ metabolism may be entirely normal. Unfortunately, there are several methodological problems that need to be considered before this paradigm can be used in brain-lesioned patients. Firstly, averaging of the brain’s CBF response across several patients, as would be neccessary if one applied the methodology generally employed in healthy subjects, may not be valid because of variability between subjects in: (1) lesion characteristics, in terms of exact topography, size and duration; (2) clinical expression (e.g. severity of aphasia) despite similar lesions, with possible interference from the age at onset; (3) actual activation performance; and (4) the behavioural strategy for task performance (e.g. motivation, use of intact capabilities). A second problem, and a more technical one, may result from distortion of the brain stereotaxic coordinates due to the lesion itself, which could induce artifacts both in the inter-subject averaging process and in the determination of the anatomical sites of activation. These problems presumably explain why so few studies using state-of-the-art activation methodology in patient series have been reported (Chollet et a1 1991), and why they have focused only on motor activation, which, compared with cognitive paradigms, induces

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considerable and consistent CBF activation. A different approach is the singlecase approach (Powers et a1 1988, Leblanc & Meyer 1990, Di Piero et a1 1990) where problems related to inter-subject averaging disappear. However, this advantage is exchanged for a worse signal-to-noise ratio, which becomes a serious problem when individual subjects are analysed. Nevertheless, assuming that habituation effects are not present, repeated activation scans can be obtained in a single session, which will improve the signal-to-noiseratio (see Fox & Pardo 1991: this volume). Because of these problems, single-case investigations have so far dealt with somatosensory or motor activations only. In addition, Powers et a1 (1988) warned against the possibility that, in patients with cerebrovascular occlusive disease, activation paradigms may not induce full CBF responses, because of impaired haemodynamic reserve; metabolic (CMRglu) activation in response to somatosensory stimulation, on the other hand, appears to be intact in carotid artery occlusive disease (Chang et al 1989). In rats, however, Ginsberg et a1 (1989) demonstrated that even the CMRglu response to somaesthesic activation could be considerably blunted in the parietal cortex after frontal cortex infarction, indicating that areas of diaschisis may lose their normal metabolic response to physiological stimulation. Whatever the approach used-either the group-approach or the singlecase approach-major problems relate to the nature of the control data to which the results obtained in the patient(s) under investigation will have to be statistically compared. If independent controls are used, it is unclear whether they should be healthy subjects, or patients with similar lesions but no (or recovered) clinical impairment. Also, the control subjects should presumably carry out the activation task with similar performance characteristics (e.g. motor rate and excursion) to those of the patients, but this creates serious challenges with cognitive tasks (?‘pseudo-impaired’ performance). An alternative is to use each patient as his or her own control (Chollet et a1 1991), either by using a ‘control’ hemisphere (assuming the neuronal network strategy is the same in both hemispheres, an assumption that obviously does not apply to cognitive tasks, or perhaps also during the recovery phase) or by means of a longitudinal (follow-up) PET sequence obtained throughout the recovery process. A final issue relates to interpretation of the results of PET activation paradigms in brain-lesioned subjects, because lesions never affect a single behavioural capacity, and can alter not only a given behaviour by itself, but the attentional, planning, emotional, affective or ‘drive’ operations that underlie (or prepare for) the execution of this behaviour (as in the case of unilateral hypokinesia following a contralateral brain lesion-so called ‘motor neglect ’). The design of experimental paradigms in non-human, awake primates, entailing controlled lesions and sequential behavioural and PET assessment, may help resolve some of the issues raised above (Baron & Miyazawa 1991). However, the results obtained in monkeys might sometimes prove difficult to

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interpret in terms of human brain-behaviour relationships, while specifically human activities, such a s language, will escape this experimental approach. References Baron JC 1987 Remote metabolic effects of stroke. In: Wade J, KrCzevil: S, Maximilian VA, Mubrin Z, Prohovnik I (eds) Impact of functional imaging in neurology and psychiatry. J Libbey, Paris, p 91-100 Baron JC 1989 Depression of energy metabolism in distant brain structures: studies with PET in stroke patients. Semin Neurol 9:281-285 Baron JC, Bousser MG, Comar D, Castaigne P 1980 ‘Crossed cerebellar diaschisis’ in human supratentorial brain infarction. Trans Am Neurol Assoc 105:459-461 Baron JC, Rougemont D, Soussaline F et a1 1984 Local interrelationship of cerebral oxygen consumption and glucose utilization in normal subjects and in ischemic stroke patients: a positron tomography study. J Cereb Blood Flow Metab 4:140-149 Baron JC, D’Antona R, Pantano P , Serdaru M, Samson Y, Bousser MG 1986 Effects of thalamic stroke on energy metabolism of the cerebral cortex. Brain 109: 1243- 1259 Baron JC, Levasseur M, Mazoyer B et al 1989 The link between cortical hypometabolism and neuropsychological deficit after thalamic lesions: a PET study. J Cereb Blood Flow Metab 9 (suppl):740 (abstr) Baron JC, Miyazawa H 1991 The use of positron emission tomography to assess effects of brain lesions in experimental subhuman primates. Methods in neurosciences. CRC Press, New York, vol 7, in press Biersack HJ, Linke D, Brassel F et a1 1987 Technetium-99m HM-PA0 brain SPECT in epileptic patients before and during unilateral hemispheric anesthesia (Wada test): report of three cases. J Nucl Med 28:1763-1767 Brooks DJ 1991 PET: its clinical role in neurology. J Neurol Neurosurg Psychiatr 54: 1-5 Chang JY, Kelley RE, Ginsberg MD et a1 1989 Assessment of ‘cerebral reserve’ in patients with occlusive cerebrovascular disease by a somatosensory activation strategy and positron emission tomography. J Cereb Blood Flow Metab 9 (suppl 1):S358 (abstr) Chollet F, Di Piero V, Wise RJS, Brooks DJ, Dolan RJ, Frackowiak RSJ 1991 The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol 29:63-71 Corbetta M, Miezin FM, Dobmeyer S, Shulman GL, Petersen SE 1990 Attentional modulation of neural processing of shape, color, and velocity in humans. Science (Wash DC) 248~1556-1559 Cowan WM 1970 Anterograde and retrograde transneuronal degeneration in the central and peripheral nervous system. In: Nauta WJH, Ebbesson SOE (eds) Contemporary research methods in neuroanatomy. Berlin, Springer, p 217-251 Di Piero V, Chollet F, Dolan RJ, Thomas DJ, Frackowiak R 1990 The functional nature of cerebellar diaschisis. Stroke 21: 1365-1369 Feeney D, Baron JC 1986 Diaschisis. Stroke 17:817-830 Feringa ER, Gilbertie WJ, Vahsling HL 1984 Histologic evidence for death of cortical neurons after spinal cord transection. Neurology 34: 1002- 1006 Fifkova E, Hassler R 1969 Quantitative morphological changes in visual centers in rats after unilateral deprivation. J Comp Neurol 135:167- 178 Fox PT 1989 Functional brain mapping with positron emission tomography. Semin Neurol 9: 323-329 Fox PT, Mintun MA 1989 Noninvasive functional brain mapping by change-distribution analysis of averaged PET images of H2I5Otissue activity. J Nucl Med 30:141-149

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Fox PT, Perlmutter JS, Raichle ME 1985 A stereotactic method of anatomical localization for positron emission tomography. J Comput Assisted Tomogr 9: 141- 153 Fox PT, Mintun MA, Reiman EM, Raichle M E 1988 Enhanced detection of focal brain response using intersubject averaging and change-distribution analysis of subtracted PET images. J Cereb Blood Flow Metab 8:642-653 Fox PT. Pardo JV 1991 Does inter-subject variability in cortical functional organization increase with neural distance from the periphery? In: Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Found Symp 163) p 125-144 Fujie W , Kirino T, Tomukai N, Iwasawa T , Tamura A 1990 Progressive shrinkage of the thalamus following middle cerebral artery occlusion in rats. Stroke 21: 1485- 1488 Gilman S, Dauth GW, Frey KA, Penney JB 1987 Experimental hemiplegia in the monkey: basal ganglia glucose activity during recovery. Ann Neurol 22:370-376 Ginsberg MD, Castella Y, Dietrich D, Watson BD, Busto R 1989 Acute thrombotic infarction suppresses metabolic activation of ipsilateral somatosensory cortex: evidence for functional diaschisis. J Cereb Blood Flow Metab 9:329-341 Girault JA, Savaki HE, Desban M, Glowinski J , Besson M J H 1985 Bilateral cerebral metabolic alterations following lesion of the ventromedial thalamic nucleus: mapping by the ''C-deoxyglucose method in rats. J Comp Neurol 231:137-149 Iizuka H , Kaoru S, Young W 1990 Neural damage in the rat thalamus after cortical infarcts. Stroke 21 :790-794 Karbe H , Herholz K, Szelies B, Pawlik G, Wienhard K, Heiss W D 1989 Regional metabolic correlates of Token test results in cortical and subcortical left hemispheric infarction. Neurology 39: 1087- 1088 Kataoka K, Hayakawa T , Yamada K, Mushiroi T , Kurada R, Mogami H 1989 Neuronal network disturbance after focal ischemia in rats. Stroke 20:1226- 1235 Kiyosawa M, Baron JC, Hamel E et a1 1989 Time course of effects of unilateral lesions of the nucleus basalis of Meynert on glucose utilization of the cerebral cortex: positron tomography in baboons. Brain 112:435-455 Kwak R, Saso SI, Suzuki J 1978 Ipsilateral cerebral atrophy with thalamic tumor in childhood. J Neurosurg 48:443-449 Kuhl DE, Phelps ME, Kowwell A P , Metter EJ,Selin C , Winter J 1980 Effects of stroke on local cerebral metabolism and perfusion. Mapping by emission computed tomography of '*FDCi and I3NH3. Ann Neurol 8:47-60 Leblanc R , Meyer E 1990 Functional PET scanning in the assessment of cerebral arteriovenous malformations. J Neurosurg 73:615-619 Matthews DA, Cotman C, Lynch G 1976 An electron microscopic study of lesion-induced synaptogenesis in the dentate gyrus of the adult rat. I. Magnitude and time course of degeneration. Brain Res 115:l-21 Metter EJ, Mazziotta JC, Itabaschi HA, Mankesvich NJ, Phelps ME, Kuhl D E 1985 Comparison of glucose metabolism, X-ray CT and postmortem data in a patient with multiple cerebral infarcts. Neurology 35: 1695-1701 Metter EJ, Riege WH. Hanson WR et al 1988 Subcortical structures in aphasia. Arch Neurol 45: 1229- 1234 Mintun MA, Fox PT, Raichle M E 1989 A highly accurate method of localizing regions of neuronal activation in the human brain with positron emission tomography. J Cereb Blood Flow Metab 9:96-103 Pantano P , Baron JC, Samson Y, Bousser MG, Derouesne C, Comar D 1986 Crossed cerebellar diaschisis: further studies. Brain 109:677-694 Pappata S, Tran-Dinh JC, Samson Y, Baron JC, Carnbon H, Syrota A 1987 Remote metabolic effects of cerebrovascular lesions: magnetic resonance and positron tomography imaging. Neuroradiology 29: 1-6

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Pappata S, Mazoyer B, Tran-Dinh S, Cambon H, Levasseur M, Baron J C 1990 Cortical and cerebellar hypometabolic effects of capsular, thalamo-capsular, and thalamic stroke: a positron tomography study. Stroke 21: 519-524 Pardo JV, Fox PT, Raichle ME 1991 Localization of a human system for sustained attention by positron emission tomography. Nature (Lond) 349:61-64 Peters A 1979 Thalamic input to the cerebral cortex. Trends Neurosci 2:183-185 Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME 1988 Positron emission tomographic studies of the cortical anatomy of single-word processing. Nature (Lond) 331 585-589 Petersen SE, Fox PT, Snyder AZ, Raichle ME 1990 Activation of extrastriate and frontal cortical areas by visual words and word-like stimuli. Science (Wash DC) 249:1041-1044 Powers WJ, Fox PT, Raichle ME 1988 The effect of carotid artery disease on the cerebrovascular response to physiologic stimulation. Neurology 38:1475- 1478 Reiman EM, Fusselman MJ, Fox PT, Raichle ME 1989 Neuroanatomical correlates of anticipatory anxiety. Science (Wash DC) 243:1071-1074 Schallert T, Jones TA, Lindner MD 1990 Multilevel transneuronal degeneration after brain damage. Behavioral events and effects of anticonvulsant-aminobutyricacidrelated drugs. Stroke 21 (suppl III):III-143-I1I-146 Shimoyama 1, Dauth GW, Gilman D, Frey KA, Penney JB 1988 Thalamic, brainstem, and cerebellar glucose metabolism in the hemiplegic monkey. Ann Neurol24:718-726 Tamura A, Kirino T, Sano K, Takagi K,Oka H 1990 Atrophy of the ipsilateral substantia nigra following middle cerebral artery occlusion in the rat. Brain Res 510:154-157 Vaz Ferreira A 1952 Silver studies of degenerating thalamo-cortical connections. J Neuropathol Exp Neurol 1 1 :44-52 von Monakow C 1914 Die Lokalisation im Grosshirn und der Abbau der Funktion durch Kortikale Herde. J F Bergmann, Wiesbaden

DISCUSSION Plum: Dr Baron has very beautifully summarized this area, but I remain troubled by the non-physiological term, diaschisis, which is commonly used to describe the phenomenon. I suggest that a description such as ‘functional disconnection’ would convey more meaning and be more in keeping with contemporary physiological thought. You yourself, Dr Baron, have described very well an interpretation of the possible mechanisms that may go on during functional disconnection, leading in some cases to transsynaptic changes in the more remote neurons. However, we have no way of judging at the present time what, if any, morphological/biochemical changes may take place on the distal side of the synapse, for example when neurotrophic factors are cut off from the initiating axon. Why, for example, does it take such a long time before secondary degeneration occurs in the second neuron, in human beings? The delay that occurs in morphological transsynaptic degeneration was well illustrated in a case report by Ingvar and Sourander in 1970. A man aged 51 had a rupture of an aneurysm at the apex of the basilar artery. The haemorrhage destroyed a large part of the paramedian posterior thalamus and produced an initial coma, followed by a chronic vegetative state attributed to failure of

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physiological activation of the cerebral hemispheres. A year after the injury, a biopsy of the left frontal cortex revealed normal morphology, but when the man died, two years later, the cortex contralateral to the initial biopsy and in ail other areas showed diffuse, severe degeneration. The changes included severe destruction of the intralaminar and, to a lesser degree, specific paramedian nuclear regions of the posterior thalamus and the mesencephalic reticular formations. No evidence of asphyxia1 or direct neuronal injury could be found. Similar delayed transneuronal degeneration in the cerebellum following several years after contralateral cerebral infarction was also described by Baudrimont et a1 (1983). The aetiology of either the functional disconnection or the eventual transsynaptic neuronal changes in these cases has not, to my knowledge, been well examined at the cell biological level. Nevertheless, it appears that enough biological facts are known to rescue the occurrences of functional metabolic disconnection and transsynaptic degeneration from being relegated to an arcane, non-biological ‘syndrome’. Baron: Neurologists have been arguing for so many years about diaschisis and degeneration! In m y opinion, the main point to keep in mind is that even though atrophy or degeneration can be demonstrated by morphological measures, if it takes so long to happen, it means that it may well be prevented; it is not inescapable. And this is the whole purpose of the concept of diaschisis. Plum: I don’t disagree with that. It is simply that I dislike putting a name to something that we don’t fully understand but deserves neurobiological classification. Baron: This is a general fact of medicine! But I did make the points that one has to be very careful when using terms and that we must understand as much as possible what we are talking about. However, it is equally dangerous to equate diaschisis with irreversible degeneration, because if there are ways to prevent transneuroiial degeneration before it develops, this could help the brain and improve recovery-although in some instances it may not, as I indicated (Schallert et a1 1990); we simply don’t know yet. Muzziottu: Huntington’s disease is another example of hypermetabolism in a damaged system, this time in the human. In the early stages, early symptomatic or presymptomatic patients who have striatal hypometabolism tend also to have thalamic hypermetabolism. Then, as the disease progresses, with probable spread of pathology into the pallidum, thalamic hypometabolism occurs, the former coming from the disinhibition of the thalamus with increased firing there, through the pallidum or through pallido-subthalamo-pallidal tracts; there’s an even number of neurons in those pathways, presumably. Another example would be the transcerebellar changes in children, which may be very different from those in the adult. The hypometabolic features seen after decorticectomy in children apparently recover for many years, and, at least by MRI, the volume of the tissue in the cerebellum doesn’t seem to shrink.

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The question may be whether patients with cerebellar lesions have either thalamic hypometabolism through dentato-rubro-thalamic tracts, or some other pattern of transtentorial change in the other direction. Do you know of any examples of that, Dr Baron? Baron: There are reports of patients with unilateral cerebellar lesions exhibiting a slight reduction of blood flow in the contralateral cerebral cortex. However, it’s apparently a very small effect, a less than 10% reduction of perfusion (Broich et a1 1987, Attig et a1 1991). Zeki: May I just support Fred Plum on the use of the term diaschisis? This word should be expunged from the civilized medical literature! Let me give you two examples at random. In 1890, von Monakow tried to explain the phenomenon of ‘mind blindness’ by recourse to ‘diaschisis’. Then Lenz, with a patient who was achromatopsic after a lesion in the fusiform gyrus, dismissed that lesion in favour of diaschisis as an explanation. (Later, H.-L. Teuber wrote a spirited defence of diaschisis.) The use of the term made them believe that they had understood and classified interesting issues. Instead, they managed to bury these issues. I fully agree that using this term seems to imply that one has an understanding of something; actually it confuses the issue. Baron: I myself have no reason to promote this word, but it so happens that for physicians and neurologists t o communicate with neurophysiologists and other neuroscientists, there needs to be some common language. Sometimes jargon helps people from different areas of science to get into contact and start to think about and discuss what they see. For example, when clinical neurologists see PET images showing small brain lesions with major remote metabolic effects they are amazed, and they use the word ‘diaschisis’ because that’s the only word they know to describe what they see! But this word will lead them to address more fundamental issues, and this is quite positive. Zeki: It is just a ‘word’; that is the problem. If you say that a syndrome is due to partial or complete deafferentation of an area, people understand that, whereas diaschisis . . . . ! Baron: You are right, but unfortunately ‘deafferentation’ may not mean much to many young neurologists! Jeannerod: And physiologists equally would not care to use the term ‘diaschisis’, which is a poorly defined term. Why not just use ‘remote effects’? Passingham: I thought that the word ‘diaschisis’ was used for temporary effects. Thus it wouldn’t cover remote effects that were not temporary, such as degeneration. Plum: Unfortunately, there is no way of predicting which aspects of metabolic disconnection will remain permanent and which will recover. I would much rather have physicians ask why this temporary disconnection develops than to invoke ‘diaschisis’ and, by finding a ‘diagnosis’, close their minds on the subject!

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References Attig E, Botez MI, Hublet C, Vervonck C, Jacquy J, Capon A 1991 Diaschisis ctrkbral croist par ltsion drkbelleuse. Rev Neurol (Paris) 147:200-207 Baudrimont M, Gray F, Meininger V, Escourolle R, Castaigne P 1983 Atrophic cerCbelleuse croiste aprks ltsion hkmisphtrique survenue A I’age adulte. Rev Neurol (Paris) 139:485-495 Broich K, Hartmann A, Biersack HJ, Horn R 1987 Crossed cerebellar-cerebral diaschisis in a patient with cerebellar infarction. Neurosci Lett 83:7-12 Ingvar DH, Sourander P 1970 Destruction of the reticular core of the brahstem. A patho-anatomic follow-up of a case of coma of three years duration. Arch Neurol

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Schallert T, Jones TA,Lindner MD 1990 Multilevel transneuronal degeneration after brain damage. Behavioral events and effects of anticonvulsant-aminobutyric acidrelated drugs. Stroke 21 (suppl III):III-143-111-146

Final general discussion Porter: Part of the objective of the symposium has been to have the views of people who are, in effect, cellular neurobiologists and biochemists, coupled together with comments from those who are technologists and use complicated machinery to apply biochemical tests to the nervous system, in the context of the neurology of normal brain function or of the disturbances produced in patients with disease. It would seem to me that there has been considerable concordance in the presentations that have been made, whether they have related to the technology, or to its applications to patients. We have spent a lot of time looking at the margins, the areas of disagreement, and that’s one of the important outcomes of an assembly such as this. We should now identify some of the territories that need further thought. I have therefore invited identified people to make comments in each of several areas. It seems to me that we should consider issues of the theory that underlies the analysis with which PET is concerned, and then move to the technology itself and ask what are the new technical approaches which are just around the corner. The importance of these could derive from the contributions they make to better temporal or spatial resolution or to the analysis of mechanisms of brain function. I think we do not need to spend time on validation (that is, on the observations that demonstrate that we have found out what we already knew); but it is important that we consider the advances in knowledge that have been revealed by the applications of those technologies- the neuroanatomical, or functional anatomical, significance of those blobs, and bright and dark patches that are illustrated in tomograms. Finally we should consider their clinical significance. May I ask Dr Friston to tell us his view about the potential for technological innovation which is based on a theoretical consideration of the background to the analysis of function which PET allows us to pursue. Friston: There are a number of experimental variables over which we have control in PET. These variables include the subject’s intentional state, which we change with instruction, with the objective of eliciting different cognitive processes (as with Dr Corbetta’s work on attentional processes). We can also change the sensorimotor field (as in Professor Zeki’s work in the extrastriate cortex), Other variables include neurotransmitter function with the use of selective centrally active drugs. We have also heard about another important manipulation, namely time or trial number, which Dr Raichle introduced in terms of learning and memory. Rather than considering habituation a confounding experimental artifact, we should regard it as being, very usefully, under experimental control. 265

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We now have increasingly sophisticated ways of analysing large amounts of data and the ability to manipulate not just one variable, but a number of these variables in the same study. This allows an exploration of the interaction between, say, psychological process and neurotransmitter function, or learning and drug effects. Information about these interactions cannot be obtained by studying each level in isolation. In terms of innovation based on theoretical considerations, I think this will depend o n input from experts in each field (neuropsychological, neuropharmacological and neuroanatomical). It is clear from Elizabeth Warrington’s perception of the level of our psychological sophistication that there is a place for such input. Her observation is well taken, if somewhat deflating. At a more speculative level, I hope to see a move towards PET studies of neuroplasticity and the habituation effects of mechanisms underlying real-time changes in the wiring of the brain. I would like to make a specific point in relation to pharmacology in PET studies of functional antomy. The use of ‘hot’ versus ‘cold’ ligands is worth mentioning. People will be aware of the use of radiolabelled (hot) ligands to assay receptor number (e.g. radiolabelled raclopride). Such approaches give static unidimensional part measures of a neurotransmitter system. The alternative approach is to use blood flow (or oxygen metabolism) as an index of neurotransmission and to perturb a neurotransmitter system dynamically with ‘cold’ drugs. (There is an interesting interface where one tries, through a nonpharmacological manipulation, to displace ‘hot’ ligand by provoking release of endogenous neurotransmitters.) I would like to adopt the dogmatic stance that from the view of functional anatomy, the way forward is the use of ‘cold’ ligands in conjunction with non-pharmacological (functional) activation of brain systems. Zeki: Dr Friston and Professor Frackowiak have developed the technique of covariance, which is a huge step forward, because of the difficulties of studying anatomy in the human brain. The DiI tracer technique is not so successful because it traces fibres over small distances only. So we have here an indirect method which gives us confidence that the areas which we show to light up in PET scans in the different conditions are anatomically connected. In a sense, that’s a validation of known anatomical connections in the human brain, and once this has been taken to other systems it is a powerful way of showing anatomical connections in the cortex without actually seeing them. Baron; 1would like to warn against manipulating pharmacological variables and then trying to correlate one neurotransmitter with patterns of changes in blood flow. The latter would be very difficult to interpret, because changes can be widespread along several neuronal relays, and hence one would lose specificity.

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MucKenzie: I agree. It is a very exciting prospect to correlate specific transmitter changes with blood flow, but it is also likely to be rather difficult. Can anyone name a single neurotransmitter that is not also a vasoactivator? Frackowiak: That confounding variable can be accounted for in the framework of the analysis, as long as the transmitter is reasonably uniformly distributed throughout the brain, and the vasodilator effect is uniform in all blood vessels. MacKenzie: The evidence all suggests that there is no vasoactive agent which has the same regional effects in the brain; even when agents are acting on isolated vessels taken from different brain arterial systems, the vasomotor effects are different in terms of maximal response and efficacy. There is also another problem for the experimental design; once you start simultaneously manipulating blood flow and metabolism, you are also re-setting cerebrovascular resistance. Nobody has yet looked at whether blood flow responses at different resistances are the same. It’s exciting, but there’s a lot of work to be done here. Raichle: I would make a plea for a more neurobiological approach to an understanding of the regulation of the brain vasculature. For too long we have looked at the brain blood vessels as if they were in petri dishes. In fact, these blood vessels are part of the brain, which consists of glial cells, neurons, and blood vessels. A neurobiological approach to that unit (i.e., glia, neurons and blood vessels) is essential. It is a very manageable problem. Porter: Unfortunately, that unit in the brain is not organized in quite the same way as the vascular supply of the glomerulus in the kidney, that can be approached with micropuncture techniques! Hence we will have to develop a better understanding of the precise relationships between the elements that make up the unit before we can make progress on that front. I am afraid we shall not end up with satisfactory answers to each of the questions I posed at the start of this discussion. However, I hope that this process of review may reveal some of the issues that will prompt further thought and further investigation. As we now move on to the technical approaches to the usages of this theoretical background that may be just around the corner, I would like Dr Iida and Dr Townsend to make comments. Zidu: I want to return to the issue of the uncoupling of blood flow and oxygen metabolism. We have completed simulation studies on this, trying to explain it in terms of methodological errors, in relation to tissue heterogeneity, blood volume correction, and errors in the input function such as delay and dispersion. Of these factors, delay and dispersion did not explain the uncoupling, although systematic errors were induced in both CBF and CMR02. Errors due to the blood volume determination were found to be small. There may be concern about using the same blood volume data for resting and activated studies, but this caused only a small error, and this is not the explanation of the uncoupling. The greatest effects on the magnitude of increases in CMR02 were due to tissue heterogeneity. The heterogeneity problem was linked t o the choice of Vd

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value. We could correct for the heterogeneity by using an empirically calculated V , value, to get an accurate and constant (scan time independent) CMR02 value. We’ve found that a large Vd and short scan length tend to yield small increases in CMR02, and a small Vd and prolonged scan length tend to yield larger increases in CMR02. We analysed the data of a motor activation study collected at Hammersmith Hospital. We observed that a Vd of l.Oml/ml with very short scan length provided only a 2% increase in CMROl (for this stimulation, CBF increased 20% for the same subjects), while a Vd of 0.8 with a longer scan time provided an 8% increase in CMR02. Thus, an increase in CMROz is dependent on the assumed Vd vlaue and scan length. However, this does not explain the uncoupling issue completely. There are two points to consider; firstly, we didn’t find any sources of error in the methodology to explain the uncoupling, although there is an argument against the previous report. As long as we don’t see any reason, I think we should accept this observation, and consider a physiological explanation. Secondly, we have a significant signal in the 1502 oxygen method, although the amplitude is smaller than CBF by a factor of about three. I think it is possible to do a CMR02 activation study, and I am very keen to measure CMR02 in activated conditions, in absolute terms, to investigate the relationship between CBF and CMR02. Townsend: What I tried to show in my paper was that 3D reconstruction for PET is now a reality, not just for specially constructed prototypes, but with commercially available, septa-retractable scanners. In our work with the 953B we have observed, in clinical imaging situations, overall NEC gains of 3 to 5 , which represents a signal-to-noise improvement of over a factor of three in the centre of the field of view. The improvement in image quality is considerable. During this year, we should see a further countrate increase with the delivery of the first scanner with three rings of blocks giving an axial field of view of 15 cm. These sensitivity improvements will not necessarily clear away Richard Wise’s forest, but they will help reduce the tree height so we can have a better view of the mountain tops! With these new scanners with retractable septa and l5cm axial field, the operating parameters will need to be carefully optimized. The optimal settings for energy threshold, time resolution, and so on will have to be studied in detail in situations as close as possible to the clinical situation. The optimal values are not necessarily the ones we use in 2D imaging with septa extended. There are still clearly a number of issues to be addressed in reconstruction. Iterative approaches are still under study, and some first attempts are being made to apply these algorithms to 3D reconstruction. The use of magnetic resonance images to guide the PET reconstruction by suggesting the locations of edges and so on seems a promising approach. Work on reducing the currently long 3D reconstruction times is obviously of paramount importance.

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With respect to spatial resolution, we have seen substantial improvements in 3D image quality as a result of the improved sampling in the axial direction. There is currently work under way to construct block detector designs with 3 mm detectors. However, the sensitivity of the block will be unchanged and we will, of course, need good statistics to take advantage of this improved spatial resolution. Scatter, which has been the so-called enemy for many years, is now being confronted, and we and other groups are working on scatter correction algorithms in 3D. The latest scanners are able to acquire data from two energy windows (the photopeak and a lower, scatter window), so perhaps we shall be able to measure scatter in a way similar to that already used for random coincidences. We may then end up with a scatter correction procedure which does not introduce systematic errors into the reconstruction. This is important, because there is no point in reducing the statistical error (increasing sensitivity) below the level at which you have systematic errors from other sources. Finally, a work of caution about the data-handling problem. Current scanners obviously have the potential to generate more data than we can easily handle and the problems that will arise should not be underestimated. The new threering scanner will be able to acquire data for 47 slices of 3 mm thickness, which represents about 35 Mbytes of data per frame. A typical dynamic study will thus acquire 0.5 gigabytes of data. Solutions to handling such large amounts of data exist (compression, etc.), but they must be foreseen and planned. However, such problems will pale into insignificance beside the data-handling problems which will arise should Terry Jones ever get funding for his spherical PET machine: that scanner will present us all with a lot more challenges for the future! Jones: May I make a point about quantitation? Many people have gone away from this, because they are trying to avoid arterial blood sampling, and they are satisfied with identifying regional increases in activation. They mainly focus on where it is occurring, rather than its magnitude in ml/g per minute. Also, arterial blood sampling has been resisted by many people. Dr Iida briefly described the possibility of monitoring the arterial input function non-invasively. He left us with the impression that to do this, one has to obtain funding from two grant-giving bodies, for heart and brain, because you need both a cardiac scanner and a brain scanner! We should not forget the possibility of monitoring a peripheral artery. Dr Iida pointed out that the delay and dispersion imposed when you monitor blood withdrawn through a radial artery, which is your input function, are very prolonged. Here we could consider lowering peripheral resistance by warming the hand. In fact, we are collaborating with a company that is making for us a PET scanner for the wrist (also to be used for small animals), to explore the possibility of monitoring the arterial input function by scanning the radial artery.

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Baron: I am not totally satisfied with all that discussion, because what we really want to know is whether or not we have to measure CBF in absolute terms to do so-called ‘activation’ research, or can we get along with only I5O water images? Evans: There is a ‘dirty little secret’ in PET where we have machines with intrinsic resolutions of about 5 mm but we reconstruct images to about 20 mm, in order to overcome the problems inherent in inter-subject averaging, so we are throwing away a tremendous amount of information. Something that 1 take from this meeting that is very gratifying is that a number of people have shown that there is an anatomical variability left undealt with, on the order of 0.5 cm. Peter Fox then showed us that there’s also a functional variability which incorporates that anatomical variability, of about the same order. So there is a considerable potential, if we can remove that anatomical variability, perhaps by non-linear image averaging, to reconstruct to resolutions more closely approaching the intrinsic resolution of the system and really to separate out those peaks. Fox: The topics of global variability and of quantifying in units of rn1/100mg per minute deserve further comment. Absolute quantification, at least in our hands, is very susceptible to errors that produces uniform effects over the whole brain. A slight shift in the timing of the arterial curve, or misestimation of the degree of delay and dispersion, will effect changes over the entire brain-that is, global variations. Such errors cannot be looked at as the sum of the regional changes. They are errors that are introduced in the mathematical transformation between tissue counts and blood flow; these truly are global changes. They are a noise that we introduce in attempting to quantify in absolute units and could equally well be looked at as a degradation of the data. If we are attempting to identify regional changes in the brain, the global variability is of less interest. Many of us have looked repeatedly for global effects, quantifying as carefully as we can in units of ml per lOOg per min, and even with very robust stimuli we have found minimal effects. Only if you use over-complicated tasks, to recruit many different lobes simultaneously, can you produce physiological global effects. I find that not overwhelmingly interesting. It has been our strategy to avoid arterial sampling unless we are dealing with a disease state, in which absolute quantification is important. For the sorts of studies discussed here, I am hard pressed to see the advantage. Porter: I guess that this topic will have to wait for its resolution until the next meeting on the advances in PET technology! May we now turn to the question of what are the advances in neurological knowledge that have been illustrated by this technique, and what are the changes in the way we are required to think about the nervous system and its functional anatomy as a result of those observations. I have invited Dr Raichle to introduce the discussion of the new knowledge obtained.

Final general discussion

271

Raichle: Something that has impressed me a great deal is the fact that with autoradiographic techniques in animals, and with metabolism and blood flow in humans, as one begins to define very specific mental operations you realize that these are implemented in a very distributed, modular fashion in the nervous system. Having seen that, and reflecting on the very detailed studies being done in animals with single-unit recordings of neural networks, looking at sophisticated functions to which one attributes a role for these isolated modules, one must conclude that the neuronal ensembles under investigation are probably only one component of very distributed systems. One has to keep that in mind; with the techniques we have been discussing, we can begin to define the ‘macroanatomy’ in which these distributed ensembles perform. We have to understand these relationships before we can begin to understand the local microanatomy and what the individual modules or ensembles of neurons are doing. The data gained so far with functional imaging technology suggest that it will contribute substantially to this process in both humans and animals. For so long we have relied on damage to the human nervous system to understand much of its functional anatomy. We can now begin to appreciate its normal functional anatomy. As this process proceeds, we shall realize that areas of the nervous system had other functions that we had not attributed to them before. A major example is the cerebellum. We have given it credit for guiding our motoric behaviour but now realize that it may have functions extending well beyond that, into the cognitive domain. In addition to greatly enhancing our understanding of normal function, this new information will substantially guide the types of questions that we then address in patients with lesions. So I think that functional imaging studies have the great potential to affect our understanding of human disease, by readdressing old questions and introducing new ones. All of this will broaden our understanding of the general physiology of the normal human brain, and eventually lead us to a better understanding of the relation between the brain and the mind. Corbettu: We have not discussed the possibility of linking electrophysiological recording (EEG, ERPs, or MEG) and PET information. This approach can be advantageous for both approaches. Electrophysiologists could use PET information to constrain their model for localizing a dipole generator within the brain. Investigators using PET could use electrophysiological information to improve the temporal resolution of their measurements or to track the sequence of activations during a given task. For instance, it would be of great theoretical importance to know whether in a ‘verb generation’ task, left prefrontal cortex is engaged before or after anterior cingulate cortex (Petersen et a1 1989), or whether in a selective attention task the modulation in visual cortex is preceded by an instructive signal from higher-order regions (this volume: Corbetta et a1 1991).

272

Final general discussion

Porter: Such an attempt t o link real-time electrical events in brain structures both to behavioural events and to regional metabolic changes that accompany those behaviours, in order t o understand the sequential or in-parallel activities of nervous elements, may require that the electrical registration of neuronal activity be generated as a result of magnetoencephalography, rather than conventional EEG studies. In fact the EEG has not been very informative about the sort of complicated behavioural tasks to which you refer. Raichle: I would totally concur with what Maurizio says. If one could provide an estimate of the location of the so-called electrical dipole using functional imaging techniques, and of course we have been looking at that in this symposium, one would drastically simplify the problem of assigning some anatomical specificity to observed electrical phenomena recorded externally. The question of whether magnetoencephalography or dense-field surfaceelectrode recording is superior is still an open discussion. Plum: I think nobody would have dreamed that epilepsy produced focal hypometabolism in the brain until the results obtained by PET became available. Perhaps most important, PET has reunited the scientific interests of neurophysiologists and research-level neurologists. Essentially, neurophysiological research in epilepsy had moved to a degree of elegance with microelectrode studies and micropharmacological work that excluded the participation of all but a very few clinical neurologists, PET studies have enabled a much larger group to reach the forefront of epilepsy research. PET has also opened major new doors in behavioural and psychiatric research. We are beginnning to see hitherto altogether unknown changes in brain metabolism accompanying the major psychoses. We are also starting t o understand transactional changes which take place in the forebrain, in association with disease or injury to the cerebellum. I believe that this is no less than the dawn of a new era in experimental, mechanistic human neurophysiology and neuropathology. Advances in PET gain credit for stimulating neuropsychologists to formulate new ways of more explicitly identifying limitations in human brain functions. Previously there were no satisfactory tests for determining the functional effect of severe frontal lobe deficits, other than observing the actual behaviour of psychopaths, or of those with badly damaged frontal lobes. PET provides a window which takes us beyond anecdote and reunifies the scientific study of bedside disease, and the way the brain works. Porter: It has become clear that in many of the behavioural situations that are being examined using these methods, which reveal blobs or hot spots, and which may indicate increases or decreases in metabolic function or in blood flow, multiple regions of changed activity tend to be revealed in relation to complex functions. It has been suggested that this tells us something about the networks of interconnected regions of the nervous system which must be covarying in activity in some way in relation to that function. 1 am going to

Final general discussion

273

ask Dr Passingham to comment on the functional anatomy that is revealed by these sorts of observations. Passingham: We are faced with a pattern of spots, as on a Rorschach test. The key to the interpretation is the anatomy, physiology and pharmacology of the brains of other primates. Let me comment on four features. (1) The spots are widely distributed. This is because the anatomical systems are distributed. If you put an anterograde tracer into inferior parietal or dorsal prefrontal cortex, you find terminations that are widely dispersed, in the neocortex, cingulate cortex, caudate, superior colliculus and so on (Selemon & Goldman-Rakic 1988). We have shown that many of the cortical components of this particular system are activated when subjects voluntarily decide in which direction to move a joystick (Deiber et a1 1991). (2) There are areas in which there are no spots. This is because there are parallel systems; one system does not project to the same areas as the other. For example, in studies in which subjects read words, there is activation in prestriate and infero-temporal cortex, but not in parietal cortex. (3) There is also overlap between spots. In studies on voluntary movement or on the generation of verbs, there is activation in lateral prefrontal cortex at sites with similar coordinates. The overlap indicates the use of either common memory mechanisms or common outputs. (4) Finally, there aren’t enough spots. Richard Wise and others have commented on this. If you look at the maps that we all produce, they won’t work. There must be other stepping stones on the way. Here the covariance techniques can help to reveal these hidden stages. Porter: May I ask Richard Frackowiak to conclude with a comment on the clinical significance of PET, as it has been revealed in this meeting. Frackowiak: At the trite level, it is said that the clinician is interested only in diagnosis and prognosis and, in neurology, rarely in treatment. PET has very little to offer us here. We have a wealth of clinical experience over 150 years; we have instruments which tell us about the structure of the brain; we have ways of investigating the brain electrically, and so on, all of which give us much information about how disease affects the individual patient. My belief is that in man, well-characterized diseases will serve as models of specific types of disturbances of brain function (which can be monitored and measured by classical clinical techniques) and that the resulting syndromes will be related to the behavioural mechanisms that underlie them, which in turn PET will relate to specific cerebral networks and structures. The investigation of normal people and those in whom normal brain function is disturbed by disease is where PET will have its greatest impact in the understanding of how the brain is organized functionally. I think this will be particularly true and fruitful for the behavioural diseases, and perhaps the psychiatric diseases-diseases where we note in the symptomatology disorders of higher representations unique to man. So this is an area where I see the future.

274

Final general discussion

Starting from this philosophical consideration, there are already areas where one can see this programme of research developing in the immediate future. Some of these have been alluded to in the statements we have just heard. These include the ability t o monitor functional interactions at a regional level in the brain considered as a system, which is unique to the way in which we sample the activity of the whole brain with PET. The interaction of function with pharmacology has been alluded to by Karl Friston, but one could also conceive, perhaps, of a study of interactions of recovery processes after motor stroke with various therapies. How can one modify synapses and connectivity in the brain, so that one obtains longer-term changes in behaviour? The ability to demonstrate plastic changes in brain areas associated with functional or behavioural change is already being explored with PET. The ability to demonstrate that a particular behaviour is associated with activity in a given neural system is only the first step towards then attempting modification of the behaviour by pharmacological or psychological means. The distribution of activity in a brain system, and its modulation in relation to alterations in behaviour that can be clinically monitored, provide a possible way forward to the determination of the neurotransmitter bases of these behavioural changes. These are some of the areas in which I believe we shall see a major impact of PET in human neurobiology. A more general effect of PET will be (perhaps echoing Professor Plum here) to give us new insights into the functional anatomy of the symptoms our patients exhibit when we examine them at the bedside, which in turn will help us to understand the principles underlying the functional anatomy of the normal human brain.

References Corbetta M, Miezin FM, Shulman GL. Petersen SE 1991 Selective attention modulates extrastriate visual regions in humans during visual feature discrimination and recognition. In: Exploring brain functional anatomy with positron tomography. Wiley, Chichester (Ciba Found Symp 163) p 165-180 Deiber M-P, Passingham RE, Colebatch JG, Friston KJ, Nixon PD, Frackowiak RSJ 1991 Cortical reas and the selection of movement: a study with positron emission tomography. Exp Brain Res 84:393-402 Petersen SE, Fox PT, Posner MI, Raichle ME, Mintun MA 1989 Positron emission tomographic studies of the processing of single words. J Cognit Neurosci 1:153-170 Selemon LD, Goldman-Rakic PS 1988 Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior. J Neurosci 8:4049-4068

Summi Robert Porter Faculty of Medicine, Monash University, Dayton, Melbourne, Victoria 3 168, Australia

I would like to conclude with one or two comments on points which have not come out in the final general discussion. In my introductory comments I said something about temporal relationships. The major deficiency that I detect in our understanding, as obtained with these methodologies, is still the failure of positron emission tomography to give us information about the temporal relationships between events in one area of the brain and another. When multiple regions of metabolic activation are revealed, is their activation simultaneous (or closely correlated in time), or sequential? This becomes an important matter in understanding the functional significance of the presumed connections between these multiple activated regions. Perhaps PET needs to be combined with other methods of direct registration of real-time neuronal events by electrical or magnetic recording techniques. It has also become clear that some of the functional changes, which we might have ascribed to an increase in synaptic activity, or even to an increase in sprouting and the development of terminal branches and synaptic connections, along with an increase in the capillary supply of those regions, are in fact accompanied by a decrease in metabolism and in blood flow. Here, perhaps, is a paradox. If we wish to use PET to begin to understand plasticity in the nervous system, as it is demonstrated in its earliest stages, from the generation of learned behaviour during childhood development, and in the modification of behaviour in disease states, we shall need to explore the mechanism of such plastic modifications. It will require the involvement of cellular neurobiologists and biochemists to understand whether or not, depending upon the situation that is under investigation, there is a direct relationship between synaptic density, capillarity, glial metabolism, and the sort of measures that can be obtained by the techniques we have been hearing about. Surely the opportunity must be taken to study those things with the PET technique that can be studied only in man. That must mean that our concentration must be on things like language, memory, thinking, and knowing. Here is an enormous challenge: how are those functions to be broken up into the separable elements that can be analysed using the PET technique? Do we have sufficient understanding of mental processes, and have we bridged the gap between the psychologist’s approaches to the study of the mind and that of the clinical neurologist or biochemical neuroscientist? 275

276

Summing-up

Importantly, and in the longer term, what about the grand concept of the need to generate, not a spherical instrument, but perhaps a spherical consortium of minds-the association and interaction of those people who can bring a variety of creative talents and attitudes to address a major unsolved problem? It is still necessary to define what it is that needs to be solved which would justify the effort and the expenditure. Certainly it will be necessary to associate neuropsychologists and cellular biochemists with neurologists and psychiatrists and technologists, to address any major problem of functional brain anatomy. What I have understood from this meeting is that a question or questions about mental functions must be identified. The grand objective surely must be to know the mind, and, if that is our objective, PET may be one of the tools that will have to be used in addressing that question. Perhaps that is a sufficient justification for us to determine that the consortium of interests justifies the level of cooperation and expenditure that would be required. We have, during this meeting, attended to a number of very important ‘here and now’ questions. It is possible to conclude that the potential exists, already, to measure synaptic changes directly with markers of transmitter or ionic exchange and to correlate these with increases or decreases in metabolic activity and blood flow. We still need to understand the precise control of these measurable events and the stimuli which produce them. An understanding of the links between synaptic and neuronal activity on the one hand, and these measurable changes, on the other, can be obtained from manipulation of brain function and behaviours. Through such studies we shall gain knowledge about the control of functional anatomy. Using existing techniques, we can ask questions which will allow an extension of our knowledge beyond the known facts of physiology and of structure and connections in the human brain. We have the capacity to explore how connected networks in the human brain behave in relation to natural function. As we have seen, it is possible to reveal cooperation between separate parts of the brain in association with identified functions, and this cooperation is detected by covariation in the metabolic changes in several regions. Not only are temporal relationships between one structure and another or between metabolic change and behavioural event important, but the association of these changes with only some aspects of a complex task may have temporal features which need our consideration. Hence, in the repetitive tasks which may be used to approximate a functional ‘steady state’ during PET measurement periods, the influence of novelty, of early learning and of habituation may all impinge on the observations that are made. Measures of metabolic change in a given brain region may depend on the frequency with which a stimulus is presented or the rate of repetition of a task. While it will be important for these variations to be understood, they may also provide clues about the regional functional anatomy of the ‘mental’ processes that are coincident with the different metabolic responses which occur in these different temporal domains.

Summing-up

277

The unique contributions of PET will depend on the intelligent definition of the brain function to be examined, on the experimental control of the separable elements of function, and on exploitation of those special opportunities for functional analysis that require that the studies be performed in sentient human beings. Hence new knowledge is most likely to come from the applications of PET to the study of language, or memory, or thinking or knowing. Neuropsychological theories of cognition can be tested. Moreover, the investigations can be extended to study those functional states in which, as in schizophrenia, a well-documented disturbance of thought processing may exist. Development of brain function during early life, learning and plastic changes in brain function may be studied directly in man. We have heard, in this symposium, of studies of patients with disorders of cerebral function which interfere with their human abilities and decrease their capacities in vision, in learning, in memory, in language, in motor performance, in emotional reactions or in cultural development. We have not heard of contributions from PET which hold promise of cures or remedies for these disabilities. Nevertheless, the intelligent use of findings from PET and other investigative methods may reveal facts which will usher in the development of new concepts, which may contribute eventually to the illumination of the full functional anatomy of the human brain. We may be able to explore the mechanisms by which this functional anatomy is established and delineate the capacity for flexibility in these complex functions. I thank everyone for their contributions to this symposium. We are all particularly indebted to Professor Frackowiak, who proposed this meeting, and who, together with Dr Peter Fox and with the Ciba Foundation, is responsible for its structure and has made it possible for us to enjoy participation in a most interesting discussion of matters which are of immediate and direct concern to us all. I know that we all wish the Foundation to be thanked very sincerely for this opportunity to pursue an interest with which all of us have had some involvement, and which we shall continue to pursue.

Index of contributors Non-participating co-authors are indicated by asterisks. Entries in bold type indicate papers; other entries refer to discussion contributions. Indexes compiled by Liza Weinkove Baron, J. C., 122. 142, 210, 211, 229, 244, 250, 262, 263, 266, 270 *Bench, C. J., 76 *Bookstein, F., 93 Cappa, S. F., 87, 121, 179, 193, 194, 196, 209, 230, 248 *Chen, G., 93 Chollet, F., 193, 208, 235 Collins, R. C., 6, 21 Corbetta, M., 91, 154, 157, 162, 165, 175, 176, 177, 178, 179,209,213,230, 244, 248, 271 *Cowen, P.J., 76

*Dolan, R. J.,

76

Evans, A. C., 41, 42, 69, 70, 71, 73, 104, 106, 111, 192,211,214,216,270 Fox, P. T., 20,38,40,51,90, 102, 103, 108, 109, 110,125, 140, 141, 142, 143, 156, 162, 192, 193, 194,206,213,216, 247, 248, 270 Frackowiak, R. S. J., 19,20, 21,37,52, 54, 70, 71, 73, 75, 76, 107, 110, 111, 122, 123, 156, 157, 160, 177, 194,213, 216,231,235,244,245,246,247,248, 267, 273 Friston, K. .I.,76, 87, 88, 89, 90, 91, 141,178, 192,206,210,215,216,265 Frith, C. D., 76, 120, 121, 140, 141, 179, 181, 191, 193, 194, 196, 232 *Grafton, S.,

93

*Grasby, P. M., 76 GulyBs, B., 102, 159, 160, 161, 209 *Hadar, U., 218 *Howard, D., 218 Iida, H.,

23, 37, 38,39,40,41,42,267

Jeannerod, M., 121, 142, 155, 156, 161, 176, 193, 210, 245, 263 Jones, T., 37,39,41,52, 71,72,73,74, 75, 105, 110, 215, 269 *Kanno, I . ,

23

Lassen, N. A., 54, 74, 106, 155, 177, 191, 205, 208, 214, 215, 245, 247 *Liddle, P. F., 76 MacKenzie, E. T., 123, 124, 195, 267 Mazziotta, J. C., 16, 17, 18, 19,40,72, 88, 93, 101, 102, 103, 104, 105, 106, 108, 140, 143, 155. 156, 161, 205,210, 212, 214, 246, 248, 262 *Miezin, F. M., 165 *Miura, S., 23 *Pardo, J. V., 125 Passingham, R. E., 88, 101, 104, 194, 195, 196, 213, 263, 273 *Patterson, K., 218 'Pelizzari, C., 93 *Petersen, S. E., 165 Plum, F., 17,18, 19,20,54,74,90, 110, 111, 143, 175, 195, 196,261, 262,263, 272

278

Index of contributors

Porter, R.,

1, 16, 17, 18, 19, 38, 39,47, 51,75,87,90, 101, 107, 108, 121, 122, 141, 143, 155, 157, 158, 191, 192, 195, 1%,207,208,209,211,214,265,267, 270, 272, 273, 215

Raichle, M. E.,

17, 18, 20, 21, 38, 39, 52, 53, 54,73,74, 75, 88, 89, 105, 106, 198,204,205,206,207,208,209,210, 211,215,229,231,245,267,271,272 Roland, P. E., 21, 39, 41, 47. 72, 108, 113, 121, 122, 123, 124, 142, 158, 161, 177, 194, 195,209,213,214,216,233

*Seitz, R. J., 113 *Shulman, G. L., 165 Sokoloff, L., 18, 19,20, 43,45,47,49, 50, 51, 52, 53, 54, 195

279

*Toga, A. W., 93 Townsend, D. W., 57, 70, 71, 72, 73, 268

*Valentine, D.,

93

Warrington, E. K., 207, 232 *Weiller, C., 235 Wise, R. J., 20,50,204,208,211.215, 218, 228, 229, 230, 231, 232, 233

Zeki, S.,

16, 17, 89, 101, 102, 104, 105, 106, 109, 142, 143,145, 154, 155, 156, 157, 158, 159, 161, 162, 176, 179, 192, 196, 213, 214, 228, 229, 263, 266

Subject index Acceptance angle, increased, 58,59,67, 68 Achromatopsia, 15I , 263 Activation studies, 9- 13 brain-damaged patients, 225-226, 238-240, 257-259 H2150infusion rates and, 34 psychopharmacological, 76-92 simultaneous CBF and CMRO, measurement, 27, 35 somatosensory system, 113-124 word processing, 126-139, 186-189, 200-203, 220-226 Adenosine, 12 a,-adrenoceptors, buspirone and, 85 Age effects, 4, 143, 212 Agnosia, finger, 189, 196 Alexia, 226, 230 Alzheimer’s disease, 83, 213, 251-252 Amygdala, 202-203 Anatomical normalization See Stereotactic normalization Aphasia, 1, 194, 230 activation patterns after recovery, 226 Broca’s, 248 conduction, 207 subcortical, 248, 253 transcortical motor, 207 Apraxia, 248 Arterial insufficiency, colour vision and, 16 Arterial sampling, 269-270 Arterioles, cerebral organization, 7-8 response to functional brain activation, 12-13 Attention, 165-180 motor function after stroke and, 242, 246 selective vs. divided, visual discrimination and, 166-171, 173, 175-179 spatial allocation, 179- 180

Attentional system@) distributed nature, 166 supervisory (SAS), 185 Auditory cortex, response to one’s own speech, 194, 223 Auditory system, 231 Avolitional behaviour, 182, 190 Barbiturate anaesthesia, 20 Bismuth germanate (BGO) detectors, 58, 59 Blindsight, 155 Brain functional anatomy See Functional brain anatomy functional architecture, 7-9, 10, 11 plasticity of functional architecture, 13-14, 19 structural anatomy See Neuroanatomy surface topography, 1-2, 111, 137138, 141, 142-143 Brain atlas, computerized (CBA), 102103, 115, 159 Brain development, functional changes, 4, 143, 212 Brain infarction experimental, 254-255 in humans See Stroke Brain injury, focal, 218-219, 252 anatomical standardization, 220, 245, 257 cortical reorganization, 134- 135 design of PET studies, 257-259 distant metabolic effects, 238,252-257 functional anatomy of recovery, 225-226, 230, 235-249 transsynaptic effects, 255-256, 261262 vascular function after, 227,23 1-232, 237-238 Brain vasculature, 267 function after brain injury, 227,231232, 237-238

280

Subject index organization, 7-9, 10, 11, 17 Broca’s area See Premotor cortex, inferior Buspirone, 77-78 blood flow effects, 78, 81, 82 effects on memory and CBF, 81-85, 89, 90-92 memory effects, 78, 80, 81, 87 Calcium (Ca2+)channels, L-type, 117, 122- 124 Capillaries density in relation to blood flow changes, 18-19 organization, 7-8, 9, 10, 11, 17 Carbon dioxide, oxygen-15-labelled (C150,), 79, 237 Carbon monoxide, oxygen-15-labelled (CI5O), 26-27 Carbon monoxide poisoning, 16, 17 Cerebellum, 209, 271 in high level word processing, 202, 205, 208, 213-214, 215 metabolic effects of remote lesions, 210-211, 238, 253, 254-255, 256, 262-263 recovered stroke patients, 239, 244 recovery processes and, 210-21 1 in somatosensoryprocessing, 117, 118, 209 Cerebral blood flow (CBF) arterial sampling and, 269-270 and CMRO, measured simultaneously, 26-27, 29-31, 32-33, 34-35, 41-42 global changes, 216, 270 H,lSO autoradiography and PET, 24-26, 27-29, 30, 31-34, 35, 37 hemispheric differences, 2 15-2 16 optical imaging studies, 12 optimum scan length, 24-25, 27-29, 33-35, 37, 38, 39-41 rapid measurement, 23-42 regional (rCBF), 2, 3 brain-injured patients, 227, 231 -232, 237-238 capillary density and, 18-19 covariance analysis, 79-80, 249 early studies, 2. 147 ‘frontal’ function and, 186-189 potential errors, 191-193, 270 psychopharmacological studies, 7692, 266-267

281 recovered stroke patients, 236-242, 244-248 somatosensory system, 115-1 19 stimulus rate dependency, 9-12,20, 21 visual cortex, 150-151. 168173 word processing and, 126-139, 198203, 219-227 uncoupling from oxidative metabolism, 20-21, 51-55, 231, 267-268 Cerebral cortex 1, electrical stimulation mapping, 135-136 landmarks, 98, 99, 104-105, 106, 108 metabolic effects of remote lesions, 253, 255 pathological reorganization, 134- 135 Cerebral metabolic rate for glucose (CMRglu), 254, 258 See also Glucose metabolism, cerebral Cerebral metabolic rate for oxygen (CMR02), 23-24, 54 and CBF measured simultaneously, 26-21,29-31,32-33,34-35,41-42 uncoupling from CBF, 55. 267-268 See also Oxygen consumption, cerebral Cingulate cortex recovered stroke patients, 238, 240, 242, 246 verb generation task and, 129, 131133, 141, 201, 202 visual processing and, 178 Cognition, psychopharmacological activation studies, 76-92 Coincidences, 60 random, 58, 60-62, 67-68 scattered, 58, 269 true, 58 Colour vision, 162-163 arterial insufficiency and, 16 attention and, 166-173, 175-176 carbon monoxide poisoning, 16, 17 cortical centre, 146, 147, 148- 149, 150-153, 154, 158 object recognition and, 171-173, 178-179 V1 lesions and, 155 Computed tomography (CT) correlation with PET images, 94, 95, 107

282

Subject index

Computed tomography (confd) focal brain lesions, 219 Cortical dysplasia, 212 Counting rates, 57, 64, 69-70, 72 Covariance analysis, 79-80, 249, 266 Cytoarchitecture, 89-90, 101-102, 152 Cytochrome oxidase plasticity of zonal distribution, 13 zonal distribution, 8-9, 10, 11, 18 Deadtime, electronic, 72, 74 Delayed response task, 183- 184 Dentate gyrus, energy metabolizing enzymes, 13 Dentate nucleus, 117, 209 Developmental changes, 4, 143, 212 Diaschisis cellular basis, 255-256, 261-262 criteria for, 252-253 crossed cerebellar, 253, 254-255, 256 disinhibition, 257 thalamo-cortical, 253, 254 transhemispheric, 255 use of term, 261, 262, 263 Dominance, hemispheric, motor recovery after stroke and, 247 Dopamine agonists, local glucose metabolism and, 47-50 Dyslexia, deep, 226, 230 Electroencephalography (EEG), image correlation, 96, 272 Electrophysiology, 157 cerebral cortex mapping, 1, 135-136 combined with PET, 109, 271-272 Energy metabolism, brain cell body vs. synapse, 19, 43-51 optical imaging studies, 12 See also Glucose metabolism, cerebral Energy metabolizing enzymes, zonal distribution, 8-9, 10, 11, 18 Epilepsy, 1 cerebral glucose metabolism, 212, 214 functional imaging, 252, 272 language activation studies, 126-139, 140, 216 uncoupling of blood flow and oxidative metabolism, 54-55 Eye movements, 161, 177, 208 Finger agnosia,

189, 196

Finger movements random, prefrontal activations, 188, 189, 194-195 recovered stroke patients, 236, 238240, 244-245 somatosensory activations, 117-1 18, 119 visual tracking, 206 ['XF]Fluorodopa, 65, 66, 70, 71, 99 Frontal cortex, 181-197 delayed response task, 183- 184 PET studies, 182-183, 186-190, 205 schizophrenic (psychotic) symptoms and, 182 supervisory attentional system, 185 See also Prefrontal cortex Frontal eye fields, 136, 160 Frontal lobe lesions, 182, 183, 272 Functional brain anatomy, 1-2, 271 correlation with structural anatomy, 93-97, 98-99, 101-111 experimental approaches, 7 inter-subject variability, 125-144 intra-subject reproducibility, 143 recovered stroke patients, 235-249 word processing, 199, 200-203 See also Activation studies

GABA (y-aminobutyric acid), local glucose metabolism and, 47 155, 156 Geniculate nucleus, lateral, Gerstmann syndrome (finger agnosia), 189, 196 Glucose metabolism, cerebral, 2, 3, 246-247 activation studies, 9- 12 Alzheimer's disease, 213 barbiturate anaesthesia and, 20 cell body vs. synapse, 43-51 developmental changes, 212 epilepsy, 212, 214 remote effects of focal lesions, 254, 256-257 uncoupling from blood flow/oxygen consumption, 20-21, 51-55, 267-268 zonal variation, 8-9, 10, 11 Glycolysis, brain, 18, 19, 51-52, 55 Gyral anatomy, variability, 109, 141, 142-143

283

Subject index

Habituation, 71-72, 215 Hand movements, synkinetic, 241,242, 246 Hippocampus, 43, 47 capillary density, 8 memory and buspirone interactions, 78-85, 87, 90 visual word recognition and, 202-203, 209, 210 Huntington’s disease, 205, 252, 262 Hypotension, hypothalamic-hypophysial effects, 43-44, 46 Hypothalamic-hypophysial system, local glucose utilization, 43-44, 46 Hypoxia lactate dehydrogenase distribution and, 18, 19 striate cortex susceptibility, 16, 17 Image averaging inter-subject, 136-137, 166, 199, 219-220, 237 intra-subject, 126, 127 patient data, 220, 257-258 Image correlation, 93-1 12 inter-subject (single modality), 94, 97-98 intra-subject (cross-modality), 94, 95-97, 107 Image registration brain-damaged patients, 245 different image modalities, 95 three-dimensional reconstructions, 7 1 Image subtraction techniques See Subtraction techniques Imaging techniques, 250-251 See also Computed tomography; Magnetic resonance imaging; Positron emksion tomography; Single photon emission computed tomography Inferior temporal cortex (IT), 170, 173, 176, 213, 214 Inner representations, 184, 186 social behaviour and, 184-185 Insular cortex recovered stroke patients, 238, 239, 240, 241, 244, 246, 247-248 word processing and, 201, 202, 206207 Ipsapirone, 77 Joystick movement, random,

188,189,195

Lactate, brain levels, 5 1, 55 Lactate dehydrogenase (LDH), 5 1 plasticity of zonal distribution, 13 zonal distribution, 8, 10, 11, 18, 19 Language, 4, 216 electrical stimulation mapping, 135136 inter-subject variability in functional zones, 126-144 recovery after brain injury, 225-226, 227, 248 See also Word processing Lateral geniculate nucleus, 155, 156 Laterality, hemispheric blood flow changes, 215-216 word analysis, 202-203, 209, 210 Learning, 4 brain functional architecture and, 13-14 cerebellar function in, 208-209 functional brain organization and, 201, 202, 205, 206-207, 215 habit (procedural memory), 202 Lexical decision task, 187-188 Lexical processing See Word processing Magnetic resonance imaging (MRI) composite images, 98, 99, 102-103 correlation with PET images, 94, 95-97, 105-106, 107, 108-109, 138 focal brain lesions, 219, 254 PET image standardization, 115 Magnetoencephalography, 272 Median nerve, electrical stimulation, 9 Memory, 4 auditory verbal short-term, 225, 229 hippocampal activity and buspirone interactions, 78-85,87,89,90-92 procedural (habit learning), 202 visual verbal short-term, 21 1 word processing and, 199, 202-203, 209, 211 working, 184 Middle superior temporal area (MST), 176, 213 Middle temporal area (MT) See V5 Morphometrics, image correlation, 98 Motion vision attention and, 166-171, 173, 175-176 cortical centre, 146, 151, 152, 154155, 158, 163, 213

284

Subject index

Motor cortex functional activation, 9 primary (MI), inter-subject variability, 129, 130-131, 133, 134, 136, 142

recovered stroke patients, 239-240 See also Sensorimotor cortex Motor function, recovery after brain injury, 235-249 Motor neglect (unilateral hypokinesia), 253, 258

Na+/K -ATPase, 45 Neuroanatom y composite image-derived, 97-98 correlation with functional anatomy,

bolus injection vs. slow infusion,

25-26, 27, 28-29, 30, 31-34, 35. 37-39 CBF measurement, 24-26,27-29, 30, 31-34,35,37 Oxygen consumption, cerebral, 2. 3

measurement in tissues, 52 uncoupling from glucose utilization, 20-21, 51-55, 231, 267-268

See also Cerebral metabolic rate for oxygen Oxygen deficiency See Hypoxia

+

93-97, 98-99, 101-111

inter-subject variability, 106-107, 109

99, 103-104.

monkeys vs. humans, 194, 213-214 See also Stereotactic normalization Neuromodulation, 77, 83 Neuronal cell bodies, glucose utilization, 43-51

Neurotransmitters, 77, 266-267 and brain vasculature, 12, 87, 195 ["CjNimodipine, 117, 122-123. 124 Nitrous oxide, 12 Noise equivalent count rate (NEC), 61, 62, 64, 66-67, 69-70, 72

Noise propagation, 63-64 Nuclear magnetic resonance (NMR) imaging See Magnetic resonance imaging (MRI) Nuclear magnetic resonance (NMR) spectroscopy, proton, 5 1 Object recognition. visual,

157-158, 170-173, 175-176, 178-179 Olfactory bulb, 8, 10 Olfactory cortex, 11, 147 Optical imaging, 12 Orientation discrimination, visual, 169, 170 Oxygen-15 (IsO), 23-24, 186, 219 Oxygen-15-labelled oxygen (lSO,), 23-24, 41, 268

simultaneous CBF and CMRO, measurement, 26-27,32-33,34-35, 41-42

Oxygen-15-water (H2150), 127, 166, 199

23, 26-27,

Parahippocampal gyrus, buspirone and memory challenge interactions, 8 183, 84

Parallelism, visual cortex organization, 146, 152

Parietal association cortex, buspirone and memory challenge interactions, 81, 87

Parietal cortex, inferior (area 40), recovered stroke patients, 239,240, 24 1

Parkinson's disease, 251-252, 257 Plasticity, 215, 275 functional architecture, 13-14, 19 See also Recovery Positron emission tomography (PET), 2-4

brain-lesioned patients, 257-259 CBF and CMROz measured simultaneously, 26-27,29-31, 32-33, 34-35

clinical applications, 274

4, 251-252,273-

concepts of visual cortex functioning and, 145-164 correlation with structural images, 93-97, 98-99, 102-111, 173

electrophysiology combined with,

109,

frontaVprefronta1 cortex studies,

182-

27 1-272

183, 186-190

future prospects, 275-277

265-266, 270-271,

hypothesis generation,

89-90, 145, 153, 158-159 interpretation, 2-3, 191-193, 273 potential errors, 52-55, 270 psychopharmacologicalstudies, 76-92 rapid CBF measurement, 23-42

Subject index

285

recovered stroke patients, 235-249 Salt-loading, hypothalamic-hypophysial somatosensory system, 113-124 effects, 43-44, 46 three-dimensional reconstruction, 58, Scan length, optimum, 24-25,27-29,30, 63-64, 70, 268-269 33-35, 37, 38, 39-41 word processing, 198-217, 218-234 Scatter correction, 67-68, 70,73-74, 269 Positron emission tomography (PET) Scatter fraction, 60-62,64,67-68,73-74 scanners, 57-75 Schizophrenia future improvements, 73-75,268-269 auditory hallucinations, 208 sensitivity, 58, 59, 73 frontal cortex function, 182 septa retraction, 58, 59-68, 69-72 PET studies of prefrontal cortex Prefrontal cortex (PFC), 181-182 function, 186, 187-189, 190 area 46 function, 183-184, 187, 189 Sciatic nerve, electrical stimulation, 12, buspirone and memory challenge inter38, 44-45, 48-49, 50 actions, 81-83, 84-85 Semantic analysis, 232-233 interactions with other brain areas, functional mapping, 21 1-212, 221, 185- 186 225 recovered stroke patients, 238, 240, 242 prefrontal cortex function and, 129, social behaviour and, 184- 185 141, 188, 194, 221 somatosensory processing and, 121 Sensorimotor cortex, primary visual processing and, 177 recovered stroke patients, 239 word processing and, 129, 186-190, remote effects of focal infarction, 238 193-194, 201, 221, 222, 273 speech production, 201,206,220,223 effects of practice, 202 Septa retraction, 58, 59-68, 69-72 inter-subject variability, 131-133, Serotonin (5-HT), hippocampal memory 142 system and, 83 See also Frontal cortex Serotonin (5-HT,A)receptors, 77-78, 83 Premotor cortex Shape discrimination inferior (Broca’s area), 129, 201, 206 somatosensory, 117-1 18, 120-122, inter-subject variability in response, 123 131, 132, 133, 134 visual, 166-171, 173, 175-176 lesions, 193, 248 Signal-to-noiseratio (SNR), septa retraction recovered stroke patients, 239, 240, and, 58, 62, 64-67, 72 24 1 Single photon emission computed tomoremote effects of focal infarction, 238 graphy (SPECT), 252 Prolactin, 79, 80 correlation with PET images, 94, 95 Psychopharmacological studies, 76-92, Social behaviour, 182, 184-185 266-261 Somatosensory association areas, 113, Psychotic symptoms, frontal cortex 117, 119, 177, 239 function and, 182 Somatosensory cortex, 114 Pulvinar, 178 activation studies, 117, 118, 119 attentional modulation of activity, 177 Radial artery sampling, 269 primary (SI), 113, 114, 117, 118, 119, Radiation dose, 69, 70, 72, 73 136 Receptors See under Neurotransmitters secondary (SII), 114, 117, 119 Recovery Somatosensory system, 113- 124 cerebellar functions, 210-21 1 Spatial resolution from remote effects of focal brain cross-modality image correlation, 96, lesions, 256 105 functional anatomical basis, 235-249 PET, 4, 99, 269 language functions, 225-226 Speech Regional cerebral blood flow See Cerebral areas activated by, 129, 142, 186,201, blood flow (CBF), regional 206, 220-221, 223-225

286

Subject index

Speech (contd) auditory cortex response, 194, 223 schizophrenic patients, 187 self-monitoring, 208 silent, 186, 201, 222, 229-230 Speed discrimination, visual, 166-171, 173, 175-176 Spherical geometry, PET scanners, 7374 Spinal cord, local glucose utilization, 45-46, 48-49, 50 Statistical parametric mapping (SPM), 79-80, 88 Stereotactic normalization, 79, 102-104, 106-107, 127, 141-142 brain-lesioned patients, 220, 245, 257 image correlation and, 98 Stimulus frequency, 9-12, 20, 21 Stimulus quality, 9 Striate cortex See Visual cortex, primury Striatocapsular infarction activation studies, 240 rCBF changes at rest, 237-238 Striatum Huntington’s disease, 205, 262 recovered stroke patients, 238,240,244 Stroke functional anatomy of recovery, 226, 235-249 rCBF changes at rest, 237-238 subcortical, 248, 253 Subtraction techniques, 6, 34 prefrontal cortex function, 186-188 somatosensory activations, 115-1 16, 118, 122 stroke patients, 245 visual activations, 159, 166 word processing, 127-129, 199, 207, 230-23 1 Siiccinate dehydrogenase, 18-19 Sulcal anatomy, 103, 137, 138, 141, 142-143 Superior temporal gyrus (STG) early auditory word processing, 220, 22 1 single-word processing, 193, 223-225 cerb generation task and, 222-223 Supervisory attentional system (SAS), 185

Supplementary motor area (SMA) intcr-subject variability in response, 129, 131, 133, 134, 136

recovered stroke patients, 239 speech production and, 186,201,206, 220, 223 word processing and, 222, 229-230, 232 Supplementary somatosensory area (SS), 114, 117, 118, 119 Synaptic terminals, energy consumption at, 19, 21, 43-51, 195 Synkinetic hand movements, 241, 242, 246 Temporal cortex visual functions, 173, 214 word processing and, 187, 188, 201, 202, 206, 211-212, 214 See also Inferior temporal cortex; VS Temporal gyrus, superior See Superior temporal gyrus Temporal resolution, 4, 6, 271, 275 Thalamus, 249 effects of remote lesions, 253, 262-263 lesions, cerebral cortical effects, 253. 255 somatosensory activations, 117, 118, 119 Three-dimensional (volume) reconstruction algorithm, 58, 63-64, 70, 268-269 Training brain functional architecture and, 13-14 word processing and, 202, 204-205

V1 See Visual cortex, primary

V2, 8 , 150, 151, 249 word processing, 128-129, 130-131, 132-133, 134 V3, 146, 208 V3A, 146, 208 V4, 155, 176. 179, 249 functional specialization, 146, 150, 152, 158, 169, 170 localization, 213 V5 (middle temporal area, MT), 208,249 functional specialization, 146, 151, 152, 154-155, 163 localization, 213 VSA, 155 Vasodilatation, afferent stimulation inducing, 12 Verb generation See Word generation

Subject index Verbal fluency task, 184, 186 prefrontal cortex function, 187-188, 193 supplementary motor area function, 232 Vibration stimulation, 117, 118-119, 121 Visual cortex concepts of functional organization, 145-164 extrastriate (prestriate) attentional modulation of responses, 165-180 functional specialization, 146, 150153, 154-163 visual word processing, 200-202, 220, 221, 228-229 See also V2; V3; V4; V5 functional activation, 9-12 primary (striate cortex, V l ) , 146, 148, 149, 155, 249 attentional modulation of activity, 176 effects of hypoxia, 16, 17 functional mapping, 136, 150-151, 172 local glucose utilization, 43, 44 simultaneous measurement of CBF and CMRO,, 27, 33, 35 visual word processing, 200 zonal organization, 8

287

Visual discrimination attentional modulation, 165- 180 feature uncertainty paradigm, 209210 fields activated, 159-161 Visual system, 4 functional activation, 9-12 ‘passive’ vs. ‘active’ stimulation, 160161, 162-163 selective attention in, 165-180 Water, oxygen- 15-labelled See Oxygen-15water Whisker barrels, mouse, 13, 17 Willed behaviour, 188-189, 196 Wisconsin Card Sorting Test, 184, 186 Word generation, 127. 140-141,232-233 auditory cortex function, 194 functional mapping, 129-133, 201202, 206, 208, 211, 221-223 prefrontal cortex function, 187- 188, 221, 222 Word processing diagrammatic model, 224, 232, 233 inter-subject variability of functional zones, 126-144 memory mechanisms, 198-217 prefrontal cortex function See Prefrontal cortex, word processing and See also Language