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Dickerson JWT. and McGurk H. Brain And Behavioural Development. (1982) Blackie & Son Ltd., Glasgow.

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This historic 1982 book edited by Dickerson and McGurk describes the development of the brain. Modern Notes: neural

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Dickerson JWT. and McGurk H. Brain And Behavioural Development. (1982) Blackie & Son Ltd., Glasgow.

1982 Brain and Behavioural Development

Interdisciplinary perspectives on structure and function

Edited by

John W. T. Dickerson, B.Sc, Ph.D.

Professor of Human Nutrition University of Surrey

and

Harry McGurk, B.A., Ph.D.

Senior Lecturer in Psychology University of Surrey

The LK : Disi&arslty of p*trc-:. Paher^ii'f Bn or

Surrey University Press

Published by Surrey University Press A member of the Blackie Group Bishopbriggs, Glasgow and Furnival House, 14-18 High Holborn, London

Blackie and Son was a publishing house in Glasgow, Scotland and London, England from 1890 to 1991.

British Library Cataloguing in Publication Data

Brain and behavioural development.

1. Developmental psychology

I. Dickerson, John W. T.

II. McGurk, Harry CL \f

155 BF701

ISBN 0-903384-27-2

Printed in Great Britain by

Thomson Litho Ltd., East Kilbride, Scotland

Contributors

Martin Berry John W. T. Dickerson

Miranda Hughes Harry McGurk

A. Merat

Brian L. G. Morgan

Denis M. Parker

Cherry Thompson

Andrew W. Young

H. K. M. Yusuf

Reader in Anatomy, Department of Anatomy, University of Birmingham, Birmingham B15 2XA.

Professor of Human Nutrition, Department of Biochemistry, University of Surrey, Guildford, Surrey GU2 5XH.

Lecturer in Psychology, Department of Psychology, University of Leeds, Leeds LS2 9JT.

Senior Lecturer in Psychology, Department of Psychology, University of Surrey, Guildford, Surrey GU2 5XH.

School of Sciences, Mashad University, Mashad, Iran.

Assistant Professor of Nutrition, Institute of Human Nutrition, Columbia University College of Physicians and Surgeons, New York, NY 10032, U.S.A.

Lecturer in Psychology, Department of

Psychology, King’s College, University of Aberdeen, Old Aberdeen, Aberdeen AB9 1FX, Scotland.

Lecturer in Psychology, Department of

Psychology, University of Surrey, Guildford, Surrey GU2 5XH.

Lecturer in Psychology, Department of

Psychology, University of Lancaster, Bailrigg, Lancaster LAI 4YR.

Associate Professor of Biochemistry, Department of Biochemistry, University of Dacca.

Introduction

The study of structural and functional relationships between brain growth and behavioural development in the human subject is an area of enquiry which cuts across traditional disciplinary boundaries. Biologists, nutritionists, paediatricians, physiologists, psychologists—all have overlapping interests and perspectives on the topic. Yet here, as in so many other areas of research enquiry, the predominant tendency is for investigators to work within the constraints imposed by the concepts and methodologies drawn from a single discipline. Similarly, published material on the topic tends to be written from the viewpoint of a particular disciplinary approach and the field is impoverished thereby.

This volume has been prepared in recognition of the essentially interdisciplinary nature of studies. It is the outcome of collaboration between anatomists, biologists, developmental psychologists, nutritionists and psychophysiologists. Each contributor has made important and original contributions to the research area with which the book is concerned. Moreover, an interdisciplinary perspective has informed these authors’ approaches to their own research and is reflected in the contributions presented here.

The volume is not intended as a comprehensive text on the cross-disciplinary study of processes. Rather, our aim has been to identify a number of active research areas in this general domain within which attempts are being made to integrate our understanding of changes in anatomical and biochemical structure and functions on the one hand with our knowledge of developmental changes in the structure and function of behaviour on the other. Further, each contributor was invited to elaborate his own documented perspective on a topic area rather than to passively review the literature. It has been our intention also that contributors should reflect not only the academic and theoretical significance of particular research problems but also their significance for the development of remediation strategies to counteract the effects of disease, injury and adverse environmental circumstances on the development of brain and behaviour.

The readership to which the book is addressed includes advanced undergraduate and graduate students in biology, clinical and developmental psychology, nutrition and physiology; it will be of interest also to practising paediatricians and nutritionists and to other professionals involved in the child health services. The first four chapters are primarily concerned with aspects of brain structure—anatomical and biochemical—and with the impact of nutritional deficiency, hormone imbalance and toxic agents upon these developing structures; Chapters 5-8 explore relationships between behavioural functions and the structure of the developing brain.

Historically, descriptive anatomy preceded elucidation of physiological processes, and the first chapter sets the scene with a discussion of the development of the human nervous system from an anatomical viewpoint. Distinct but overlapping phases of growth occur, culminating in neuronal and glial differentiation. Development is completed by the growth of the complex dendritic tree, the linking of the dendrites through the development of synapses and the elaboration of the myelin sheath which results in the insulation of nerves and makes possible the efficient passage of nervous impulses. These processes are described in various regions of the central nervous system, including the cerebral and cerebellar cortices, the basal ganglia, the brain stem and the spinal cord. Development is a dynamic process and, as with other aspects of the subject, limitations in the availability of material and in the applicability of certain methods make it necessary to draw upon animal studies in order to make reasonable inferences about the processes in the human brain.

Inferences and extrapolation of this kind are necessary when we try to understand the possible effects of adverse environmental factors on the growth of the human brain. Animal experimentation, then, has necessarily made a considerable contribution to our knowledge. There are, however, considerable differences between experimental animals and man. Not least of these is the time- scale over which developmental changes occur. Moreover, the stage of development of the brain in the newborn differs from one species to another. This is clearly of considerable importance in relation to the timing of the brain growth spurt which we now know is a once-and-for-all process. It is therefore of fundamental importance to consider the comparative aspects of brain growth and development. This theme is developed from a biochemical viewpoint in the second chapter; which includes some discussion of the important concept of ‘critical periods’. These are strictly age-related and species-specific. Moreover, there is not one critical period but many, related to the growth of the different structural entities in the brain which may be expressed in anatomical and biochemical terms, and to these are related, in ways that we do not understand, critical periods of behavioural and psychological development.

The brain grows and develops rapidly early in life and this is when the various processes are most vulnerable to the nutritional environment. Protein-energy malnutrition (PEM) is the most prevalent single factor which might adversely affect brain growth and development and permanently interfere with the achievement of genetic potential. It has been estimated that some 100 million of the world’s children are affected to varying degrees and these are mostly in the developing countries. An understanding of the ways in which malnutrition interacts with other factors in the environment is a necessary basis for the prevention of the permanent stigmata of the condition in the children themselves and also to the future eradication of the condition as a result of better education and opportunities. To provide schools and extensive training programmes without first making sure that children have the capacity to benefit from the facilities makes bad political sense. The importance of an understanding of the effects of malnutrition on brain development is such that an entire chapter has been devoted to its consideration.

Malnutrition of the kind discussed in Chapter 3 is very unlikely to occur in Western societies. However, normal growth and development depends also upon the endogenous regulation of synthetic and metabolic processes in which hormones play a central role. In the neonate, a deficiency of thyroxine in particular results in a distortion of brain growth and development and results in cretinism. Similarly, an excess of corticosteroids during the period of the brain growth spurt produces a distortion of development which is in some ways similar to that produced by protein-energy malnutrition. Growth and development is also affected by the activity of enzymes and these activities are regulated not only by the amounts of enzyme proteins but also by their cofactors, vitamins and trace elements. These biological factors along with a number of pollutants and toxic materials are discussed in Chapter 4.

Technological advances during the past thirty years have greatly facilitated the recording of the brain’s electrical activity, via surface electrodes, from the scalp of human subjects. Recording methods are now relatively simple and safe, and electroencephalographic (EEG) data have greatly informed our understanding of the relationship between bioelectrical events within the cortex on the one hand and change in behavioural state on the other. Similarly, investigations of cortical-evoked potentials consequent upon sensory stimulation have increased our understanding of brain function during perceptual, attentional and other cognitive activities. All this is with respect, primarily, to the mature organism. Chapter 5 is devoted to consideration of the contribution which electrophysiological recording techniques can make to our understanding of brain activity and behaviour in the developing organism. The author relates structural changes in the cortex of the pre-term, full-term and developing infant to changes in electrophysiological activity and in behaviour. The value of EEG developmental milestones for diagnostic and prognostic purposes during early infancy is advocated, though their use as indices of cognitive development during later stages of growth is seriously questioned.

The fact that the brain comes in two more or less symmetrical halves, that these halves are contralaterally organized with respect to their control over body activity, and that humans are predominantly right-handed have led to speculations and controversy over the relative dominance of the right and left hemispheres in the control of specific psychological functions. Traditionally, the left hemisphere has been recognized as dominant in the mediation of speech and language, and the right hemisphere as dominant in visual-spatial tasks. Too often, however, this relative dominance has been interpreted as if man had two brains, one adapted for verbal, the other for perceptual functioning. Such oversimplification of roles distorts what is known about the extent to which duplication and symmetry of function exists and the extent to which the two hemispheres work together as an integrated system. Overelaboration of the functional asymmetry of the two halves of the adult brain has also tended, on one hand, to misinform the kind of question which has been asked about the ontogeny of hemispheric specialization and, on the other to a confounding of questions about equipotentiality with questions about the capacity of the cortex for reorganization following injury. These and related issues are addressed in the sixth chapter of this volume where the author argues that both symmetric and asymmetric organization of hemispheric functions are characteristic of the human brain, at least from the beginning of postnatal life. On this basis, it is argued that the basic developmental problem should be reformulated in terms of how, during their acquisition process, skills that are being newly learned are integrated with functions that are already symmetrically or asymmetrically organized.

Two facts about the developing brain have long been acknowledged. Firstly, as previously indicated, the immature brain is more vulnerable to environmental insult than is the mature brain. Secondly, if injury or damage does occur, its effects on the developing brain are more diffuse and less specific than on the adult brain. The latter, together with the child’s greater potentiality for at least partial recovery of functions disrupted through injury, attests to the functional plasticity of the developing compared with the mature brain. How the diffuse effects of injury are mediated in terms of brain structure and function, and how the potential for recovery is to be interpreted, are issues of considerable controversy. Resolution of the issues involved is of theoretical and practical importance. Discussion and evaluation of the relevant evidence forms the subject matter of Chapter 7; implications for effective remediation regimens are considered.

As in so many other domains, analysis of the relative contributions of nature and nurture to the development of sex differences in behaviour has been the occasion of much polemical discussion. Chapter 8 is devoted to discussion of structural processes and mechanisms which might underlie sex differences, in particular behavioural and cognitive functions. Hormonal influence on brain activity and sex differences in brain differentiation feature large in the discussion. It should be recognized, however, that investigation of potential relationships between sex differences in behaviour implies no commitment to biological determination. Rather, such evaluation is necessary to inform our understanding of the raw material upon which education and culture may operate to influence behavioural expression in a diversity of fashions. As the author argues, brain differences between male and female may well underlie the predilections for the two sexes to act in particular ways, but they cannot be construed as constituting a biological imperative for the development of psychological sex differences.

We should like to thank our contributors for their patient cooperation throughout the various stages of preparation of the volume. Our thanks are due also to Edna Springham, Roslyn Gilbert and Mary Lewis for their assistance in preparation of the typescript.

John W. T. Dickerson Harry McGurk

CHAPTER ONE

THE DEVELOPMENT OF THE HUMAN NERVOUS SYSTEM

MARTIN BERRY

Introduction

A massive escalation in the volume of research effort in developmental neuroscience has occurred over the past ten years. Unfortunately, during this period investigation of the ontogeny of the human nervous system has attracted very little attention and it is difficult to understand the cause. Constraints like a lack of either material or technique no longer apply, since changes in the abortion laws in many countries have made fresh human embryos available to most laboratories in which modern neurobiological staining and tracing techniques are practised. Perhaps the brake applied to a new surge of research is the belief that developmental neuroscience has not matured to the point where it can tackle the apparent complexities of human brain development. Paradoxically, as Sidman and Rakic (1973) have pointed out, the long time-course of the period of human brain development allows temporal resolution of events that in other mammals are compressed often to the extent that sequential stages are indiscernible. Moreover, the large size of the human brain relative to that of most other mammals facilitates the morphological study of individual centres along with their chemical and behavioural correlates. In any event, we need to know more about how our brains develop, not merely for purely academic reasons but also to understand the aetiology and sequelae of congenital brain disease—particularly since this is at present a rapidly expanding area of medicine aided by advances in foetal diagnosis.

Within the brain, a series of distinct but overlapping phases of development characterize regional growth. These may be listed chronologically as neurogenesis, neuroblast migration and neuronal differentiation. Gliogenesis, glio- blast migration and glial differentiation probably take place pari passu with the former but they are less precisely documented. The phases of neurogenesis and neuroblast migration extend into the latter part of the first year of life, and perhaps beyond in certain areas. In most cases neuronal differentiation begins during migration with the elaboration of an axon. Dendritic growth usually commences when migration has ceased. Synaptogenesis occurs as dendrites grow and, indeed, it has been suggested that adhesive interaction between growing axons and dendrites determines all the physical characteristics of the dendritic field (Berry et al ., 1980a). Glial neuronal interaction is apparent from the beginning, since it is glial processes that provide the substrate for migration. Myelination is under way in the second trimester, and the blood brain barrier matures in the last trimester (Pappas and Purpura, 1964). Gliogenesis continues into adult life. The stem cell source is from dormant glioblasts dispersed within the neuropil and the subependymal layer.

Of course, each brain region develops differently, and much regional ontogeny is already documented in existing text books of human embryology. This review concentrates on those areas of the human brain which have received the most attention over the past ten years or so. These regions include the cerebral and cerebellar cortices, the basal ganglia, the brain stem and the spinal cord.

Neurogenesis

All neurones originate from germinal cells located within a layer which cuffs the neural tube and ventricles of the primitive nervous system. Some of the dividing cells become relocated elsewhere within the developing neuropil to form secondary germinal centres, but the major part of the nervous system is formed from matrix cells in the ventricular and subventricular zones (Fig. 1.1). Within this population three species of cell are probably produced—radial glia, neuroblasts and germinal cells. The cell lineage of each type is poorly understood. There is some measure of agreement that activity in the germinal epithelium can be divided into two phases—a proliferative and a migratory phase (Berry, 1974)—and that definitive neuroblasts are formed only throughout the latter. During the proliferative phase the structure of the epithelium is that of a typical pseudostratified columnar type with the basal processes attached to the subpial basement membrane and the apical processes anchored to each other by terminal bars at the lumen. Proliferation within the epithelium is associated with a peculiar interkinetic movement of the germinal cell nucleus (Seymour and Berry, 1975, 1979). Division occurs at the luminal edge, haploid daughter nuclei migrate to the subpial margin where they synthesize DNA, and diploid nuclei then return to the luminal border to complete mitosis. Many of the changes in cell shape associated with interkinetic nuclear migration can be seen in a typical scanning electron micrograph of the neuroepithelium (Fig. 1.2). Although these changes were first described in the neuroepithelium of the cerebral vesicle of the rat (Seymour and Berry, 1975, 1979) and mouse (Meller and Tetzlaff, 1975) parallel studies on the human subventricular zone (Fujita, 1973a, 1975; Fujita et al ., 1975; Hattori and Fujita, 1974, 1976a, b) suggest that the process may be similar in man—see Fig. 1.15. During the proliferative phase, glia and neural germinal cells may be produced but their morphological differentiation is not apparent until the marginal layer appears.

Figure 1.1 Semidiagrammatic drawing of the development of the basic embryonic zones of the cortical plate. Terminology from Boulder Committee (1970): CP, cortical plate; I, intermediate zone; M, marginal zone; S, subventricular zone; V, ventricular zone. Stages A, B and C are common to the primary germinal epithelium in all parts of the CNS. D and E are specific to the cerebral neocortex but the migration of cells to form the cortical plate is a phenomenon not fundamentally different from the establishment of many other neural centres.

As proliferation continues in the subventricular zone, a fundamental change occurs in the organization of the neural epithelium which culminates in the appearance of the marginal zone. One can only speculate about the possible changes in structure of the germinal epithelium which could represent the first signs of differentiation of the constituent cells into radial glia and neuronal matrix cells. Thus, radial glia may maintain their attachment at the inner and outer limiting membranes as mural thickness increases. Presumptive neural matrix cells, however, may detach their basal processes which come to lie within the subventricular zone (Fig. 1.1). Thus, the marginal zone may be occupied only by radial glia process at this early stage. Thereafter, interkinetic nuclear migration is confined to the ventricular and subventricular zones and continued growth separates the outer margin of the subventricular zone from the pial surface widening the marginal zone. The stage is now set for neuroblast production and migration.

During the migratory phase of neurogenesis, germinal cells produce definitive neuroblasts and probably more radial glia. The daughter cells which differentiate into neuroblasts leave the subventricular zone and migrate to other regions in the CNS, whilst daughter cells retaining germinal cell status continue interkinetic nuclear migration within the ventricular/subventricular complex. Throughout the migratory phase of neurogenesis the germinal epithelium undergoes intense mitotic activity. Most neuroblasts leaving the subventricular zone never divide again and differentiate into neurones. Some, however, do establish secondary germinal centres elsewhere in the CNS, such as in the ganglionic eminence in the forebrain (Rakic and Sidman, 1969), in the dentate gyrus (Angevine, 1965; Schlessinger et al, 1978; Stanfield and Cowan, 1979; Kaplan and Hinds, 1977); and the external granular layer of the cerebellum (Rakic and Sidman, 1970; Zecevic and Rakic, 1976) and the olfactory lobe (Kaplan and Hinds, 1977). In general both primary and secondary neurogenesis cease at the end of the migratory period except in the dentate gyrus and olfactory lobe where neurone production may continue for some considerable time beyond birth in rodents. The factors controlling the rate and duration of mitosis in the germinal centres in the CNS are completely unknown.

Figure 1.2 Scanning electron micrograph of the wall of the telencephalic vesicle of a foetal rat aged 14 days post-conception. Note the pseudostratified nature of the epithelium (pial surface is uppermost)— x 1050.

Elgure 1.3 Three-dimensional reconstruction of migrating neurones, based on electron micrographs of semi-serial sections. This reconstruction was made at the level of the intermediate zone indicated by the rectangle and asterisk in Fig. 1.14. The lower portion of the diagram contains uniform, parallel fibres of the optic radiation (OR) and the remainder is occupied by more variable and irregularly disposed fibre systems. The relationships of radial glial fibres (RF, 1-6) with migrating cells (A, B and C) and with other vertical processes is seen. The soma of migrating cell A, with its nucleus (N) and voluminous leading process (LP) are also shown. Cross-sections of cell A in relation to several vertical fibres are drawn at levels a-d. LE, lamellate expansion; PS, pseudopodia (from Rakic, 1972, with permission).

Migration

In most cases, neuroblasts move out from their primary germinal centres in the ventricular and subventricular zone along the radial processes of glia (Sidman and Rakic, 1973). Migrating cells are bipolar, with a leading and trailing process, and use the radially orientated glial fibres as guides. They become detached from the radial glia when they reach their definitive destinations. The morphological characteristics of migrating neuroblasts and their intimate relationship with the radial glia are shown in Fig. 1.3. The way in which the migratory neuroblasts actually move along the glial process, and the mechanisms of obtaining the correct addresses for individual neuroblasts terminating migration at different distances along the process are not known, although analysis of the reeler mouse may help elucidate this problem (Caviness and Sidman, 1972, 1973a,b, 1976). It is likely that the trailing process differentiates into the axon during the course of migration, but the commencement of dendritic growth occurs later, usually after the neuroblast has reached its destination.

In some instances, migration is not guided by radial glia. For example, the establishment of the external granular layer in the cerebellum involves the migration of germinal cells from the subventricular zone in the most caudo- lateral parts of the roof of the fourth ventricle. In this region the neuroblasts accumulate in the presumptive marginal layer and then move tangentially and rostro-medially within this layer to populate the entire surface of the cerebellum (Fig. 1.4) (Rakic and Sidman, 1970; Sidman and Rakic, 1973c). There appear to be no cellular guides to direct this migration and, since all cells over the external surface are replicating, it is possible that cellular movements are achieved as new cells jostle for space within the confines of the marginal layer (Miale and Sidman, 1961). Similar activity is seSn to occur at the secondary rhombic lip of the human embryo as the migratory population of the corpus pontobulbare is established (Fig. 1.4). These cells ultimately form the inferior olivary nuclei and pontine grey matter (Essick, 1907, 1912). Another massive secondary germinal centre, the ganglionic eminence, is established in the forebrain (Rakic and Sidman, 1968, 1969, 1973b) and this provides the neuroblasts destined to form the caudate, putamen, amygdala and other forebrain and diencephalic structures. The mode of migration from the ganglionic eminence is unknown but masses of bipolar neuroblasts streaming into the thalamus, for example, form a continuous cellular band between the two structures called the corpus gangliothalamicus (Fig. 1.5) (Rakic and Sidman, 1969).

Figure 1.4 Model (A) and transverse section (B) of the human rhombencephalon at the end of the third lunar month of gestation. The arrows indicate the migration pathways of the external granular layer (EG) and the corpus pontobulbare (CPB). AO, accessory olive; AR, arcuate nucleus; BIC, brachium of the inferior colliculus; CH, cerebellar hemisphere; CP, choroid plexus; FN, facial nerve’ IC, inferior colliculus, IO, inferior olive; LL, lateral lemniscus, P, pineal gland; RL, rhombic lip; SC, superior colliculus; TN, trigeminal nerve; V, vermis; 4V, fourth ventricle (from Sidman and Rakic, 1973, with permission).

Migratory failure leads to ectopia (Clarke and Cowan, 1975). Movement may be arrested at variable distances along the migratory path or migration may never commence, in which case neuroblasts never leave their germinal centres. Curtailment of migration occurs in many sites in the human nervous system (Rakic, 19756). Granule cell nests may remain in the region of the embryonic external granular layer in the cerebella of normal individuals (Brustowicz and Kernohan, 1952), and subventricular cell ectopia also seems to be common and could constitute potential sites of periventricular neoplasm (Hrabowska, 1978). Ectopia is also a feature of many disease states. In the telencephalon, cells may become arrested anywhere along their path of migration to form radial columns spanning the white matter (Jacob, 1936; Norman, 1966; Volpe and Adams, 1972). In other diseases, cells become arrested to form ectopic laminae (Hanaway et al , 1968; Stewart et al , 1975; Rickman et al , 1973, 1974, 1975). In the cerebellum, arrest of migration of granule cells in cases of neuroblastoma (Kadin et al ., 1970) may occur throughout the depths of the molecular layer. Ectopias associated with migratory failure in the corpus pontobulbare and the ganglionic eminence are relatively common in a variety of brain defects (Rakic, 19756).

Differentiation of neuronal processes

It has already been mentioned that the growth of the axon precedes that of the dendrites. Indeed, in many instances the axon may have contacted its target before migration has terminated. It is through such junctions that trophic and/or inductive chemicals may pass from target cell into afferent terminal and thence by retrograde axonal transport, to the source neurone. In fact, there is good evidence that such a trophic mechanism is operating to control the magnitude of neuronal populations (Hamburger, 1975). Thus, proliferation within primary and secondary germinal centres overproduces neurones. In practice, this redundancy is a safety factor which ensures that adequate numbers of source neurones connect with their targets. Death ensues if the target is not contacted, either because postsynaptic sites are already saturated or because axons are guided to inappropriate destinations. Good examples of this phenomenon are provided by the murine mutants weaver and staggerer (Rakic and Sidman, 1973a, b; Sidman et al , 1965; Sidman, 1968) where, for different reasons, granule cells fail to contact Purkinje cells and die.

Figure 1.5 Migration pathways to the posterior portion of the human thalamus. A and B, semidiagrammatic drawings of the thalamus and adjacent structures sectioned in the horizontal plane. The arrows indicate the main paths of cell migration during formation of the thalamus. Section A is from a 10-week foetus (mag. x 8), section B is from a 24-week foetus (mag. x 4). The arrows near the circle marked 1 indicate that the ventricular zone in the wall of the Illrd ventricle serves as the source of thalamic neurones during early development. The arrows extending from circle 2 indicate the path of migration of cells from their origin in the ganglionic eminence (GE) to the lateral thalamus. The arrows from circle 3 indicate the migratory path through the corpus gangliothalamicus (CGT) into the thalamus. Migrations 2 and 3 occur at a time when the ventricular zone of the Illrd ventricle is spent. C, Golgi impregnated posterior pole of the dorsal thalamus, including the medial portion of the ganglionic eminence (GE). The figure shows the bipolar migratory cells and the gradient of their increasingly more complex shapes as they enter the deeper zones of the thalamus. The 0.1 mm scale at the bottom indicates the magnification of the Golgi preparation. Other abbreviations; C, caudate nucleus; Cl, internal capsule; CM, nucleus centrum medianum; GP, globus pallidus; H, hippocampal formation; LV, lateral ventricle; 3V, the Illrd ventricle (from Rakic and Sidman, 1969, with permission).

It is possible also that trophic cues originating within the target could initiate the dendritic growth of source neurones, and there is some evidence for this in the developing basal lamina of the spinal cord where motor neurones may only develop dendrites when their axons have contacted muscle (Barron, 1943). In the adult, severance of motor nerves results in a collapse of the dendritic tree which regrows when the muscle is reinnervated (Sumner and Watson, 1971). Dendritic growth could also perhaps be initiated by afferent fibres ramifying about the postmigratory neuroblasts. For example, Pinto Lord and Caviness (1979) have suggested that fibres in the plexiform layer of the primitive cerebral cortex could be responsible for initiating apical dendritic growth of neocortical pyramidal cells. Monoaminergic fibres could be major contenders for a role in primary dendritic induction (Berry et al , 1980b,c; Sievers et al ., 1981a) since this neuronal system is one of the first to mature and quickly innervates all areas of the developing CNS (Sievers et al, 1981a).

The pattern established by the initial dendritic outgrowth is often quite different from that of the adult tree. For example, Purkinje cells in the cerebellum (Rakic and Sidman, 1970; Zecevic and Rakic, 1976) at first have multiple perisomatic processes but later they become resorbed as the cell achieves polarity and the typical dendritic tree develops. The factors which bring about such changes are poorly understood but might be mediated by specific groups of afferent fibres (Berry et al, 1978). In all regions of the CNS the period of most active growth of dendritic fields coincides with the arrival of major afferent systems (Morest, 1969a, b). There is now experimental evidence to support the idea that axons and dendrites interact during development to the extent that most of the parameters of dendritic fields appear to be determined by such interactions (Berry et al, 1979a, b; 1980 a,b,c). Selective adhesion between dendritic growth cone filopodia and specific axon groups might be the basis of the interaction for Purkinje cells in the cerebellum, but in many other dendritic systems the attenuated segment lengths and paucity of branch points indicates that modes of interaction differ quantitatively and qualitatively from region to region in the CNS.

Dendritic growth probably continues for some considerable time after neurogenesis is complete; moreover, the potential for growth appears to be prolonged into adulthood and probably accounts for some aspects of plasticity. It is not known how the growth of axonal and dendritic fields is modulated to achieve perfect matching of pre- and postsynaptic elements. There is some evidence that the density of postsynaptic sites may be determined genetically. Certainly, postsynaptic spines form on Purkinje cell dendrites independently of any presynaptic influence (Berry et al ., 1978) and this may be true for other neurones. Axons tend to become segregated topologically before entering a nucleus or cortical area (e.g. Goldman-Rakic, 1980) and such order may simply result from the sequential addition of axons to a projection tract. Segregation also occurs within a centre. The palisading of eye dominance columns in the visual cortex may be achieved by interaction across the geniculo-striate synapse such that appropriately functioning synapses are reinforced, but inappropriate contacts are lost (Stent, 1973). This functional stabilization of connections probably occurs in most central and peripheral sites. Changeux and Danchin (1976) consider that the first formed connections are spatially dispersed and poorly specified. As centres interact, connections are fined down until only those with functional integrity stabilize and survive.

Foliation

The cortices of the cerebral hemispheres and cerebellum tend to fold during growth to form intricate convolutional patterns which are characteristic for each structure (Figs. 1.6,1.7). In the cerebellum, foliation occurs over the period from the 11th foetal week until the 7th postnatal month and reflects the massive increase in volume achieved (Rakic and Sidman, 1970; Zecevic and Rakic, 1976). Thus, the surface area increases by about 2000 times over the period from the 13th foetal week till term. This growth and the accompanying foliation is largely attributable to the proliferative activity of the external granular layer (Altman and Anderson, 1969; Rakic and Sidman, 19736; Lauder et al ., 1974). A mature fissure arrangement is present by the second postnatal month. The pattern is very stereotyped and each lobe can be identified accurately from individual to individual (Loeser et al ., 1972; Larsell, 1947). Inouye and Sen-Ichi (1980) studied the morphological variations in folial pattern in the cerebella of several strains of mice. They found the patterns to be strain specific and concluded that, if regional differences in the rate of proliferation of the external granular layer account for foliation, the former may be under genetic control.

The development of the cerebral hemisphere is also characterized by foliation but the patterns are quite different from those exhibited by the cerebellum. Since there are no secondary germinal centres within the neocortex, the enlargement of the hemisphere surface can only be achieved by an expansion of the neuropil (Dobbing and Sands, 1970, 1973; Dobbing, 1970). By three and a half months (100 days) the major division of the cortex into four lobes has taken place and by five months the first evidence of the lateral fissure is discernible as a V-shaped groove delineating the boundaries of the insular cortex. By seven months central and other primary sulci are formed. At term, all primary sulci are present as well as most secondary convolutions, but the insular cortex is still exposed through a gaping lateral sulcus (Fig. 1.7). Tertiary convolutions begin to appear in the third trimester and only become fully demarcated postnatally (Sidman and Rakic, 1975).

Figure 1.6 Outline of the cerebellar surface in the midsagittal plane in specimens ranging in age from 11 foetal weeks (W) to seven postnatal months (PNM), all at the same magnification as indicated by the 5 mm scale at the bottom of the figure. The asterisks indicate the primary fissure (from Rakic and Sidman,.1970, with permission).

The mechanism of foliation/fissuration is not understood but probably involves the interaction of pial mesenchyme and basal lamina with the glial end- feet (Sievers et al , 1981b; Allen et al ., 1981). The experimental work of Barron (1950) on sheep neocortex focused attention on differential growth within the

Figure 1.7 The developing human brain showing the development of the cerebral hemispheres and their convolutional patterns (from Cowan, 1979, with permission).

cortex as a possible cause of folding. Studies of the human conditions of microgyria and lissencephaly (Rickman et al , 1973, 1974, 1975; Stewart et al , 1975) have been undertaken because these represent the upper and lower limit respectively of the tertiary convolutional spectrum. The lissencephalic brain has no tertiary gyri and supragranular layers are either absent or hypoplastic. The microgyric brain has a large number of small tertiary sulci but the granular and infragranular laminae are either absent or hypoplastic. It was suggested that the differences in cortical folding seen in these two conditions might reflect respective differences in the growth rates of superficial and deep cortical laminae. The results of computer modelling experiments bore out these predictions, strongly indicating that in normal brains random tertiary folding may be brought about by exuberant growth of superficial relative to deep laminae. The problem of how primary and secondary convolutions are formed remains, however. The constancy of the locations of the sulci suggests the mediation of genetic instruction but the nature of the substrate which is encoded remains a mystery.

Development of the cerebellum

The cerebellar anlagen first appear at the 5.7-7.3mm (GL—greatest length) stage and fuse in the mid-line at 24-27 mm (CRL-crown rump length) stage (Bartelmez and Dekaban, 1962). The subventricular zone in the roof of the fourth ventricle forms successively the neurones of the basal nuclei, Purkinje cells and Golgi cells. Matrix cells proliferating in the caudo-lateral margin of the rhombic lip migrate to the surface of the anlage. Their continued mitotic activity causes a sheet of cells, the external granular layer, to populate the entire cerebellar surface (Rakic and Sidman, 1970). During the initial proliferative phase (3-8 foetal weeks) the cerebellum is made up of ventricular, subventricular and marginal layers (see Fig. 1.9). The external granular layer is established over the 10-11th foetal weeks. Mitotic activity declines in the subventricular zone by the 12—13th foetal week and all deep cerebellar nuclei, Purkinje cells and Golgi cells are formed by the 13th foetal week. At this stage the mitotic epithelium is replaced by differentiated ependymal cells (Rakic and Sidman, 1968). An exception to this pattern is the floccular-nodular lobe region of the subventricular/ventricular zone which retains its thickness and continues to proliferate until after birth (Rakic and Sidman, 1970). The external granular layer covers the external surface of the cerebellum by 11-13 foetal weeks (Rakic and Sidman, 1970). Supravital thymidine autoradiography shows that the layer achieves a labelling index of 30 % (Rakic and Sidman, 1968).

Figure 1.8 Composite drawing of the cellular components from a 27-week-old human foetus impregnated according to the Golgi method, a; Bergmann glial cell; b, immature Purkinje cell; c, Golgi cell; d, basket or stellate cell; e, f, granule cells in the horizontal, bipolar stage; g, ‘T’-shaped granule cell; h, immature astrocyte; EG, external granular layer; ML, molecular layer; PL, Purkinje cell layer (from Zecevic and Rakic, 1976, with permission).

The external granular layer increases in thickness over the period of the 19-20th foetal week and at 21 weeks granule cells begin to migrate through the molecular layer to form the granular layer. Granule cell migration occurs along radially directed Bergmann glial processes (Rakic and Sidman, 1970). Their cell bodies lie in the deep cellular layer, and their superficially directed processes course in a quasi-parallel alignment through the molecular layer and the external granular layer, terminating in end-feet which abut against basement membrane forming the glia limitans externa of the cerebellum (Choi and Lapham, 1980; Antanitus et al , 1976; Fig. 1.8).

Granule cells become bipolar in the lower margin of the external granule layer (Zecevic and Rakic, 1976). From each pole a transversely orientated axon grows for some distance before the granule cell commences migration. As migration gets under way the cells transform into a tripolar morphology as the descending leading process glides over the vertically orientated Bergmann glia process. As the cell moves through the molecular layer it leaves the transversely running axon attached, at a ‘T’ junction, to a vertical ascending axon which is paid out behind the migrating granule cell (Fig. 1.8).

A clear lamina appears below the layer of cells which form the lower border of the molecular layer. This is the lamina dissecans (Rakic and Sidman, 1970) which is a transient acellular area present only in the human cerebellum from the 21st-40th foetal week (Fig. 1.9). By 30-32 foetal weeks the cells in the layer above the lamina dissecans are recognizable as definitive Purkinje cells. The granule layer develops below. Electron microscope studies of the lamina dissecans between the 12th and 14th week reveal many randomly organized dendritic and axonal profiles with many presumptive synaptic appositions (Rakic and Sidman, 1970; Zecevic and Rakic, 1976). It is possible that the axons within the middle and deep aspects of this layer are mossy fibres, whilst those in the upper region about Purkinje cell somata are granule and basket cell axons and climbing fibres. The latter first arrive in the cortex between 12 and 14 weeks. No definitive synapses are seen over this period. Within the molecular layer, adjacent to the Purkinje cell layer, a plexus of axons develops at a stage just before granule cells migrate. The origin of these fibres is unknown but they could be monoaminergic and mediate important trophic/inductive cues at about this time.

Figure 1.9 Semidiagrammatic drawing to summarize the main events of histogenesis in the human cerebellar cortex from the ninth foetal week to the seventh postnatal month, at 4, 9, 30 and 40 foetal weeks (wks) and the 7th postnatal month (p.n:m.). The arrows point in the direction of the main stream of cell migrations (E, edendyma; EG, external granular layer; G, granular layer; I, intermediate layer; LD, lamina dissecans; M, molecular layer; P, Purkinje layer; V, ventricular zone; W, white matter (from Rakic and Sidman, 1970, with permission).

Over the period from 12 to 16 weeks, Purkinje cells are bipolar and occupy a lamina in the cortex several rows deep (Fig. 1.10). Between 16 and 24 weeks Purkinje cells become arranged into a single row above the lamina dissecans, and their somata increase dramatically in size, develop spines and synapses appear on the latter (Zecevic and Rakic, 1976). The apical dendritic system develops and invades the molecular layer, but never invades the granular layer. The dendrites ramify randomly within the molecular layer, but over the period from 24 to 28 weeks the system becomes planar, oriented at right angles to the long axes of folia. After 28 weeks, somatic spines disappear and the tree develops secondary and tertiary spiny branchlets.

Figure 1.10 Composite drawings of Purkinje cell images in the human cerebellar cortex at various foetal and postnatal ages (A-J). All cells were selected from sections that were cut in the plane transverse to the folium, close to the midline. Cell profiles in the external granular layer are also outlined. Ages in foetal weeks (W) and postnatal months (PNM) are given on each drawing (Scale 100 ^m, from Zecevic and Rakic, 1976, with permission).

The time-course of development of the Purkinje cell tree is coincident with the period of parallel fibre deposition in the molecular layer (Figs. 1.9, 1.10). It has been suggested that parameters like planar organization, segment lengths, number of branches, direction of growth, etc., are all determined by parallel fibre/Purkinje cell dendritic growth cone filipodial interaction and there is good experimental evidence corroborating this proposition (Berry et al , 1978, 1980a, b, c).

Synapses first appear at 16-18 weeks in the region of the perisomatic plexus in the upper part of the lamina dissecans. Most junctions are asymmetrical and are probably transient contacts of climbing fibres on Purkinje cell somatic spines. At 15 weeks Purkinje cells first develop long finger-like spines on their dendrites without presynaptic attachments or postsynaptic specializations. By 7-8 months spines have become shorter and developed terminal enlargements and synaptic junctions.

The termination of cerebellar development has been nicely documented by Gadsdon and Emery (1976). Postnatally the cell concentration in the external granular layer rapidly decreases over the 6-8 month period. No cells remain after 12-18 months (Fig. 1.11). The number of cells in the internal granular layer is maximal by 22-24 months, at 61 000-62 000 cells/mm 2 . This value is maintained until 6 years, when the number of granule cells begins to decline steadily (Fig. 1.12). The number of cells in the molecular layer reflects the period of granule cell migration which is complete by about 14 months post partum (Fig. 1.13). DNA optical density studies showed that mitotic activity is over by 9 months. Gadsdon and Emery (1976) showed that Purkinje cells were diploid at all stages of development, an observation in agreement with Mann and Yates (1973) and Fujita (1974). These findings refute the work of others who have found Purkinje cells in man to be tetraploid (Lapham, 1968; Lentz and Lapham, 1970).

Several workers have studied the human foetal cerebellum in organ culture. Markesbery and Lapham (1972, 1974) maintained 10-19 week foetal cerebellar cortex in culture for 3-4 months. Cells exhibited migration, differentiated, and retained good organization. Many neurones migrated out from the confines of the tissue over astrocytic processes (Lapham and Markesbery, 1971; Lapham and Williams, 1973). The differentiation of the cerebellar cortex in vitro is remarkably similar to that described in vivo by Rakic and Sidman (1970) (Markesbery and Lapham, 1974).

Figure 1.11 Number of cells per surface millimetre of cortex in the external granular layer of the lateral lobe, related to postnatal age. Each spot represents the mean reading for an individual cerebellum. (Age scale expanded for the first 2 years—from Gadsdon and Emery, 1976, with permission).

Figure 1.12 The cell concentration per mm 2 in the internal granular layer of the lateral lobe related to postnatal age. (Age scale expanded over the first 2 years—from Gadsdon and Emery, 1976, with permission).

Figure 1.13 The cell concentration per mm 2 in the molecular layer of the lateral lobe related to postnatal age. (Age scale is expanded for the first 2 years—from Gadsdon and Emery, 1976, with permission).

Cerebral neocortex

The cerebral vesicle first appears in the embryo at 5.5-7.3 mm (GL) stage (Bartelmez and Dekaban, 1962). Proliferation in the ventricular/subventricular zone leads to migration of neuroblasts along radial glia to establish a lamina, called the cortical plate, below the marginal layer over the 7-10 foetal weeks (see Figs. 1.1, 1.14 and 1.15). The radial glia differentiate early and contain glial fibrillar protein by at least 7 weeks (Choi and Lapham, 1978; Antanitus et al, 1976). The pattern of migration of neuroblasts was first described by Angevine and Sidman (1961) and Berry and Eayrs (1962) as an inside-out progressive establishment of the cortical laminae and it appears that the same sequence occurs in man (Sidman and Rakic, 1973; Rakic, 1975h; Marin-Padilla, 1970a, b).

The work of Poliakov (1961; and cited by Sidman and Rakic, 1973) suggests that the cerebral cortex may be formed by phasic proliferative and migratory activity. The first wave, probably comprising layer Y and VI, commences at about 7-8 weeks and is over by the 10th week when the second wave begins. The duration of this latter wave is long, probably extending into the neonatal period, but most of the cells arrive in the first six weeks. The number of cells migrating in the second is much greater than during the first wave, and this wave establishes layer IV, III and II. Most migratory cells move through the cortical plate to the lower border of the marginal zone where their migration ceases.

Some cells, however, are deposited at all levels of the plate throughout development and this may particularly apply to stellate neurones. Radial glia in the monkey are mitotically active during the initial and later periods of gestation but are mitotically inactive in the midgestational period (Schmechel and Rakic, 1979). This dormant period could allow radial glia to maintain their pial- ventricular attachments as the cortex expands during foliation. This would be important if one function of the radial guides is to accumulate radially orientated columns of cells in the cortex. Thus, the cells in a given column will have originated from the same germinal population, i.e., they are of similar lineage despite changes in the surface area of the cortex relative to that of the ventricle (Rakic, 1978). The exact timing of the sequence of establishment of the different layers of the human cortex is unknown because it is impossible to study this using the 3 H-thymidine labelling technique. Nevertheless, subsequent differentiation of the laminae leaves no doubt that layers VI, V, IV, III and II are sequentially deposited in that order during migration. There are, however, some peculiarities in that some of the first cells to migrate subsequently become trapped in the cortical white matter as interstitial cells (Kostovic and Rakic, 1980) whilst others, probably originating in the lateral wall of the hemisphere, migrate tangentially within the marginal layer to form a lamina of cells, called the subpial granular layer (Brun, 1965). This latter structure first appears at about the 12- 13th foetal week in allocortex and covers the entire cortex by about the 18th week. It is a transitory zone, having disappeared by term, and probably gives rise to glia and neurones. The latter may migrate into the cortical plate or remain in the marginal zone as Cajal-Retzius cells (Rickman et al , 1977). Glioneural heterotopia may arise from persistent cell nests of subpial granular layer origin (Brun, 1965).

Figure 1.14 Camera lucida drawings of a coronal section of the Golgi-impregnated telencephalon of a 97-day monkey foetus. A: coronal section through the parieto-occipital lobe. The area delineated by the white strip between arrowheads is drawn in B at higher magnification. B: enlargement of the portion of cerebral wall indicated by the white strip in A, the middle 2500 ^m of the intermediate zone is omitted (C, cortical plate; D, deep cortical cells; I, intermediate zone; M, marginal layer; MN, migratory cell; RF, radial fibre; S, superficial cortical cells; SV, sub ventricular zone; V, ventricular zone—from Rakic, 1972, with permission).

The period of development of the cortical plate has been divided into five stages (Poliakov, cited by Sidman and Rakic, 1973). Stage I begins at the 7-10th foetal week with the formation of the plate, as the first cellular migration gets under way. The plate divides the wall of the cerebral vesicle into several strata called, sequentially, from the luminal surface outwards, the ventricular zone, the subventricular zone, the intermediate zone, the cortical plate and the marginal zone (Figs. 1.1,1.14). Stage II occupies the period of the 10-llth foetal week in which definitive fibres invade the cortex and form a plexus above and below the plate but never in it (Molliver et al , 1973; Kostovic and Molliver, 1974). Symmetrical axo-dendritic synapses are present above and below the plate with a sharp peak in synaptic density in the plexus deep in the marginal layer. Supra- and infra-plate plexi are probably made up of thalamocortical afferents and monoaminergic fibres (Molliver et al , 1973; Poliakov, 1961; Marin-Padilla, 1970a,h, 1969). During stage III (11—13th foetal week) the. first migratory phase wanes and the first arrivals begin to differentiate and occupy successively deeper positions within the plate as migrating cells take up more superficial positions (Fig. 1.15). The neocortical cells differentiating at this time are probably layer VI and layer V neurones. Stage IV (13—15th foetal week) marks the commencement of the second wave of migration which probably establishes the granular and supragranular layer (Sidman and Rakic, 1973). Stage V marks the decline of the secondary phase of migration in mid-gestation and this last stage includes the entire period of cortical maturation which continues in the neonate and is characterized by a massive expansion in cortical neuropil. Growth during this period mostly takes place in dendritic and axonal systems and is accompanied by maturation of glia.

As post-mitotic neuroblasts migrate out from the subventricular zone, their trailing processes probably develop into definitive axons. Many grow centri- petally to establish connections with sub-cortical targets. Meanwhile, migrating neuroblasts reach the lower border of the marginal zone where their upward movement terminates (see Fig. 1.16). In the case of pyramidal cells the leading

Figure 1.15 The cerebral wall of a 15-week-old human foetus. The four layers which comprise the cerebral wall at this stage of development are the periventricular layer (PV) made up of ventricular and subventricular zones, migratory cells (migr) in the intermediate zone, the cortical plate (CP) made up of closely packed columns of young neurones and the marginal zone (marg) (from Hattori and Fujita, 1974, with permission; x 93).

process, juxtaposed to the marginal layer, develops into the definitive apical dendrite. It was mentioned above that post-migratory neurones occupy successively deeper positions within the cortical plate as cohorts of younger migrating cells attain positions above them. Basal dendrites are elaborated by neurones deep in the cortical plate where axons of the sub-plate plexus ramify (Marin- Padilla, 1970b). Neuroblasts terminating migration in the deep cortical plate may be those which ultimately differentiate into stellate cells. The induction of dendritic growth thus appears to be mediated by fibres residing in the marginal zone and in the sub-plate region. The evidence for these propositions comes from the work of Pinto Lord and Caviness (1979) on the reeler mouse cortex, where apical dendrites bud out from the somal surface of post-migratory neuroblasts apposed to the fibres of the aberrant intermediate plexiform (marginal) layer. Neuroblasts lying above these fibres develop apical dendrites from their deep surface which course centripetally, whilst those below develop apical dendrites from their superficial surface which are directed centrifugally. Thus, the leading process of the migratory neuroblast is not the presumptive apical dendrite. Post-migratory neuroblasts sandwiched between fascicles of fibres develop a bipolar morphology with both principal dendrites having invaded fascicles above and below them. Since the fibres coursing in the cortex at this time are largely, if not entirely monoaminergic (Schlumpf et al , 1980), it is possible that this primary dendritic induction is mediated by this fibre group. Moreover, since in the normal developing cortex, these fibres form a plexus above and below the cortical plate (respectively in the marginal and sub-plate layers) apical dendrites could be induced by fibres in the former and the basal dendrites of pyramidal cells and stellate cell dendrites could be induced by fibres in the latter (Pinto Lord and Caviness, 1979). An additional factor which has largely been ignored, but which may be of importance in dendritic initiation, is the influence of trophic cues passing antidromically from target sites to cortical neurones. Such tropic substances could prime the cells before monoaminergic induction.

The subsequent fate of apical and basal dendritic systems and the dendrites of stellate cells is different. Apical dendrites normally course radially through the cortex and terminate in the marginal layer. The apical shaft thus marks the course and extent of centripetal soma displacement as cortical thickness increases. Elongation would be brought about by interstitial growth. Oblique or lateral branches appear on the apical shaft in regions of cortex where axon strata are concentrated (Kristt, 1978; Wise et al , 1979) and subsequently grow terminally and branch randomly (Hollingworth and Berry, 1975). Inverted pyramidal cells also possess radially directed apical dendrites which terminate in the cortical depths (Van der Loos, 1965; Caviness, 1976). This observation suggests that all apical dendrites might be constrained to grow radially by guidance along similarly orientated elements, like radial glia, but Van der Loos’s (1965) observation on other malorientated pyramidal cells indicates that apical dendrites follow a course orthogonal to the basal axis of the cell with little environmental constraint.

Basal dendrites in contrast grow very slowly through the cortical neuropil (10-80 /rni/day). The distribution of branching angles (Smit and Uylings, 1975) indicates that they are orientated randomly in rat visual cortex but this may not be universal for all areas of cortex (Glaser et al , 1979). Branching has been shown to be random and to occur almost exclusively on terminal segments (Hollingworth and Berry, 1975). Averaged over the period of development in the rat, for example, branching occurs at a frequency of one branch per day but, in reality, is probably non-linear over this period being highest at the time thalamocortical afferents invade the cortex (Kristt, 1978; Wise et al , 1979; Richter, 1980) and zero in later stages when very long, unbranched terminal segments are produced. Basal dendrites possess prominent terminal growth cones and some of the varicosities on their segments may also be growth cones (Morest, 1969a, b; Peters and Feldman, 1973). These sitings probably account for both terminal and intersegmental elongations of dendrites.

It seems doubtful that thalamocortical fibres determine branching patterns according to the filopodial adhesive hypothesis (Berry and Bradley, 1976) since the low frequency of dichotomy is not compatible with the presence of large numbers of axons in the cortex during dendritic growth. Thalamocortical and commissural afferents may trophically support growth (Wise and Jones, 1978) and may constrain dendritic fields within defined domains.

Stellate cell dendrites probably obey rules similar to those for basal dendrites but their domains are probably more tightly controlled by cortical afferents. Like basal and oblique pyramidal cell dendrites their growth spurt coincides with the arrival of afferents (Parnavelas et al, 1978; Mathers, 1979; Wise and Jones, 1978; Kristt, 1978; Richter, 1980; Geisert and Guillery, 1979).

All dendritic systems in the neocortex are modified by either ablating the afferent input or exposing animals to altered environments. In general reducing input causes dendritic fields to either grow less or become retracted (Jones and Thomas, 1962; Coleman and Riesen, 1968; Berry and Hollingworth, 1973), whilst increasing environmental stimulation results in more extensive and more branched fields (Rutledge et al, 1974; Greenough and Volkmar, 1973; Greenough et al, 1973, 1979). In both instances numbers of primary dendrites are not affected and from the results of experiments on the effects of starvation on dendritic development, branching patterns may also be universally unchanged (McConnel and Uylings, in preparation). Plasticity may be attributed to changes in segment lengths and the numbers of branches. Uylings et al (1978) have presented evidence that such plastic changes also occur in mature animals, and this has been confirmed by Greenough et al (1979). Both groups demonstrated that increases in length and branching take place principally over terminal segments. In particular, branching occurred by collateral sprouting some distance from the tip.

If the environment controls the degree of axonal terminal arborization in cortical afferents (possibly by Hebb synaptic modification—Stent, 1973), and if these axons inject quanta of trophic chemical into cortical cells, which mediates dendritic growth, then incrementing numbers of presynaptic elements would mediate an elevated trophic effect. By this means the extent of dendritic fields may be related to the density of ramifying cortical afferents. Preterminal branching of cortical dendrites may occur only when dendrites advance above a threshold rate precipitating microtubule instability in the terminal segment and the production of paraterminal growth cones (Bray et al , 1978). Thus, if branching is related only to the rate of growth, it is easy to see why branching frequency falls off during development (Juraska and Fifkova, 1979) as afferent ingrowth ceases, and how branching might be stimulated as axonal terminal arbors increase in size under the influence of increased traffic of impulses. According to this hypothesis there is no critical period in dendritic development. Thus, dendrites can equate the extent of their postsynaptic membranes with the number of potential presynaptic elements throughout the life of the animal.

Stellate cells exhibit a property, in their response to environmental manipulation, which may be lacking in pyramidal cells in that they can reorientate their fields (Valverde, 1968; Borges and Berry, 1978; Harris and Woolsey, 1979). This response suggests that stellate cells may be trophically influenced by particular afferents occupying defined regions of cortex. Redirection of growth appears to be brought about by suppression of growth of some dendrites and augmentation in others (Borges and Berry, 1978).

Dendritic field growth in the human neocortex (Fig. 1.16) is very well illustrated in the papers by Poliakov (1961, 1966), Rabinowicz (1964), Marin- Padilla (1970a,5, 1969), Purpura (1975a,5, 1977) and Takashima et al (1980). In general primary motor and sensory cortex differentiates before association cortex and in all areas layers Y and VI are always more advanced than the granular and supra-granular layers, except for Cajal-Retzius cells in the marginal layer which develop earlier than any other neurone type in the cortex (Poliakov, 1961; Marin-Padilla, 1970b).

Axon systems develop pari passu with dendrites. Over the mid-gestational period efferent axons develop their collateral systems and prominent afferent projections form horizontal plexi within the cortex. Before mid-term, axon plexi are found in the marginal zone and within the intermediate zone (Marin- Padilla, 19705; Poliakov, 1961). The latter actually consists of an inner and outer plexus of which the outer is the denser. These fibres traverse the internal capsule probably originating in the basal ganglia and thalamus. Some are callosal fibres. This commissure appears in the fourth foetal month and grows very rapidly in the preterm infant (Rakic and Yakovlev, 1968). By 5 months the cells in layers VI and V have achieved their characteristic morphology and by 7 months their dendrites have become studded with spines (Marin-Padilla, 1970; Poliakov, 1966). Layer IV has appeared and the internal and external axonal plexi of Baillarger are present at 7 months, heralding an advanced state of development of intracortical afferent terminal axon arbors (Marin-Padilla, 19705). By 7.5 months miniature stellate cells are recognizable in layer IV and by birth these interneurones have populated all layers. Their axon collaterals terminate in pericellular baskets about pyramidal cells in all layers although deep baskets mature earlier than those placed more superficially. The appearance of pericellular baskets indicates that interneurone inhibitory pathways are established at about birth. In motor cortex layer IV is no longer distinguishable after 2.5 months post partum as pyramidal cells from layers III and V encroach into the layer. Stellate cells establish a slab-shaped vertical axonal field domain extending through the whole depth of the cortex (Marin-Padilla, 1969, 19706, 1972; Marin-Padilla and Stibitz, 1974). Interestingly, their dendritic fields occupy a much smaller area than do their axon fields. The pattern of vertical slab domains adopted by stellate axonal and dendritic fields is mirrored by the afferent fibres engaging them, and probably represents a forerunner of the

1400 - 1400 _

Figure 1.16 Camera lucida representations from rapid Golgi method specimens of brains at different ages, a—14 weeks; b—20 weeks; c—24 weeks; d—28 weeks; e—30 weeks; f — 3 5 weeks; g— 40 weeks; h—6 months (redrawn from Takashima et ai, 1980).

striped distribution of thalamocortical afferents within cortex (Rakic, 1977; Hubei et al, 1977).

Spines are sparse on apical and basal dendrites before the mid-term period. Thereafter spine density increases dramatically (Takashima et al , 1980). At first spines are long and their number is greater over proximal dendrites. Basal dendritic spines appear to mature before apical spines. A common correlate of mental retardation in human infants is spine dysgenesis (Purpura, 1974).

Hippocampus

The anlage of the hippocampus first appears in the medial wall of the cerebral vesicle at about 6 weeks (Humphrey, 1966) when cells migrate from the sub-

ventricular zone into the cell-free marginal zone. Some time after, cells in the germinal epithelium of the vesicle wall laterodorsal to the dentate field develop into the primordium of Ammon’s horn. As already mentioned, cells destined to form the dentate gyrus continue to divide after migration (Cowan et al , 1980). By 10 weeks the pyramidal layer of Ammon’s horn is beginning to differentiate and the fimbria is present. The cells of the dentate gyrus remain undifferentiated and form dense clumps of cells. At 11.5 weeks the double pyramids of Ammon’s horn are distinguishable. By 13.5 weeks all layers of Ammon’s horn and the dentate gyrus are represented (Fig. 1.17) (Humphrey, 1966) and the alveus is present throughout. In the 18-20-week foetus' pyramidal cells are already developing apical dendrites. At 24-28 weeks the apical dendritic systems of pyramidal cells in Ammon’s horn are better developed than the basilar system, and pedunculated knobs and fine spines are present on the former. Infra- and suprapyramidal bundles of the perforant pathway are present but poorly developed (Purpura, 1973a, b, 19746, 1975a,6, 1977). At 28-32 weeks the branching patterns of the basilar dendrites of pyramidal cells are more mature.

Figure 1.17 Stages of development of the hippocampus and hippocampal fissure correlated with CRL and gestational age (from Lemire et al ., 1975).

Apical dendritic growth is extensive and fibre contacts are present. In the immediate postnatal period typical ‘baskets’ develop about pyramidal cell somata. Spine density is mature by about 6 months post partum (Purpura 1973a, b, 1975a, b). Dendritic growth in the dentate gyrus lags behind that in Ammon’s horn and shows a progressive superior-inferior gradient, being most advanced in the suprapyramidal and least in the infrapyramidal limbs (Purpura, 1975a,ft). The period of maximal axonal and dendritic growth in the hippocampus is between 18 'and 33 weeks (Green, 1964; Purpura, 1974b, 1975a, b, 1977). Over this period the branching angles of pyramidal dendrites (Paldino and Purpura, 1979a, b) become reduced, suggesting dynamic compression of the fields. The angle reduction increases at incrementing distances from the soma. Dendritic development is complete by about the 5th-6th month.

Diencephalon

Over the period from the 4-6th week the diencephalic wall is delineated into epithalamus, dorsal thalamus, ventral thalamus and hypothalamus by dorsal, middle and ventral longitudinal sulci (Richter, 1966; Reinoso-Suarez, 1966). In the mouse, neurones formed first in the subventricular zone populate the ventrolateral-caudal parts of the thalamus; those generated successively later form progressively more dorso-medial-rostral regions (Angevine, 1970). In man, the ventricular/subventricular complex produces neurones from the 8th through to the 13th—15th week (Rakic, 1974). By the end of the 3rd month fibre systems demarcate most of the ventral and posteroventral thalamic nuclei (see Fig. 1.5). However, the posterior portion of the thalamus begins to increase in size after the 15th week, as the number of neurones in the pulvinar increases significantly during the mid-trimester when other thalamic nuclei have their full complement of neurones (Rakic and Sidman, 1969). The source of these new neurones is not the subventricular zone in the diencephalic wall, which produces no new neurones after foetal week 18-22 (Rakic and Sidman, 1968,1969). Late-arriving neurones populating the pulvinar originate in the ganglionic eminence in the telencephalon and migrate to the pulvinar through the corpus gangliothala- micus (Fig. 1.5) despite being separated from the thalamus by an ever-deepening sulcus terminalis—Fig. 1.18 (Rakic and Sidman, 1969; Rakic, 1974, 1975b; Sidman and Rakic, 1973). The late development of the pulvinar correlates with

Figure 1.18 Coronal section at approximately the same level of the forebrain in 10 to 14 week human foetuses to illustrate the relationship of the ganglionic eminence (GE) to the basal ganglia and thalamus (T). (MG, medial globus pallidus; FTD, telencephalic-diencephalic fissure; A, amygdala; AC, archicortex; C, caudate nucleus; Cl, internal capsule; CL, claustrum; LG, lateral globus pallidus; P, putamen; RF, rhinal fissure;.SB, subthalamic nucleus (from Sidman and Rakic, 1973, with permission).

the late development of association cortex relative to that of other cortical areas (Poliakov, 1961, 1966). The ganglionic eminence also produces neurones which migrate ventrally to produce the basal ganglia (Fig. 1.18).

Brain stem and spinal cord

Neurones containing catecholamine (CA) and indolamine (IA) first appear at about the 7th foetal week and most systems are present by 13 weeks—Fig. 1.19 (Olson et al ., 1973; Choi et al ., 1975). Proliferation and differentiation over the 7th-23rd weeks establishes a pattern very similar to that laid down in the mammals. By the 3-4th month the system is very well developed (Nobin and Bjorklund, 1973). The nigro-striatal dopaminergic (DA) system is first seen as a condensation of positive CA fluorescent cell bodies in the substantia nigra, from which axons later project to the putamen and later still to the caudate nucleus. CA fluorescent fibres first appear in the hypothalamus during the 10th foetal week and within the median eminence over the 13th week (Hyyppa, 1972). The locus coeruleus and its noradrenergic (NA) axons and the 5-hydroxytryptamine (5-HT) raphe complex are well established by the 13th week.

The remarkable similarity between other mammals and man in the timing, duration and pattern of generation, migration and differentiation of neural systems in the brain stem and spinal cord is also exemplified by the development of the interpeduncular nucleus (Halfron and Lenn, 1976; Lenn et al ., 1978).

The possible role of the monoaminergic (MA) neurone system in development has been emphasized by many workers (Ahmad and Zamenhof, 1978; McMahon, 1974; Bloom, 1975; Sievers et al , 1979, 1980, 1981a) and supported by the findings that MA cell groups are among the first to be generated (Lauder and Bloom, 1974; Nicholson et al , 1973; Taber Pierce, 1973). They quickly metabolize neurotransmitters (Olson and Seiger, 1972; Seiger and Olson, 1973) and connect with their targets, establishing innervation densities similar to those of the adult (Coyle and Molliver, 1977; Schmidt and Bhatnagar, 1979; Zecevic and Molliver, 1978). At the same time ^-adrenergic receptors are elaborated by the target neurones (Walton et al , 1979).

However, the MA inductive/trophic hypothesis has recently been tested (Lauder and Krebs, 1976, 1978; Maeda et al ., 1974; Pettigrew and Kasamatsu, 1978; Wendlandt et al ., 1977) with inconclusive results. Recent experiments by Sievers et al. (1979, 1980, 1981a) have demonstrated that the NA system originating from the locus coeruleus has no effect on the course of postnatal development of the rat cerebellum. Thus, the monoaminergic system may have an important inductive or trophic role in central neural development but probably for early rather than late developmental events (Sievers et al ., 1981a).

In the spinal cord, proliferation in the subventricular/ventricular zones establishes the alar and basal plates (Fujita, 1973b; Wozniak et al ., 1980). Work

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has tended to concentrate on the development of the basal plate because this region offers the opportunity of correlating the acquisition of cutaneous spinal reflexes with the development of the motor neuropil. In general, the first synapses to appear in the embryo are located in the marginal zone of the basal plate (Wozniak et al , 1980; Gamble, 1969). They are always asymmetrical and

Figure 1.19 Schematic drawing of the brain of a 7 cm human foetus. A horizontal projection of major monoamine cell groups as well as of the CA fluorescence of the putamen (large shaded area) and the nucleus accumbens septi area (smaller shaded area) was reconstructed from drawings of about 170 serial sagittal sections. CA—level of anterior retroflexus, P—principal locus coeruleus. The small CA cell groups in the hypothalamus are probably at least partly of the DA type. Similarly, the large CA cell complex of the mesencephalon in all probability represents the developing DA neurones of the substantia nigra. In the pons a large complex of CA cell bodies, probably of the NA type, can be found centred around the dense arrangement of CA cells of the principal locus coeruleus. The projection of CA cell bodies in the medulla oblongata belongs to at least two groups, one ventral and one dorsal. Yellow fluorescent neurones, probably 5-HT-containing, occupy several partly confluent areas along the brain stem from the medulla oblongata to the mesencephalon. (Approx, x 2.5 mag. CA nerve cell groups, □. 5-HT nerve cell groups, 0. Dense diffuse CA innervation gg. Cut surface of the neopallium, ★. From Olson et al., 1973, with permission).

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axodendritic. The presynaptic element contains rounded vesicles. Synapto- genesis proceeds in a cranio-caudal direction from the cervical cord. Axons often have a peculiar relationship with radial glia, in that they become invested in glial cytoplasm (Gamble, 1969). This observation may have an important bearing on the problem of axonal guidance. Myelination of axons begins at about 10-11 weeks (Okado et al, 1980) beginning in the dorsal ventral and peripheral lateral tracts but the cortico-spinal tracts myelinate relatively late (Meier, 1976). Glial production and differentiation continues through the first trimester (Fujita, 1973b; Malinsky et al, 1968; Malinsky, 1972).

Okado et al (1979, 1980) have studied synaptogenesis in the cord in more detail. They find the first synapses at 34-36 days within the motor neuropil and at 40-42 days outside this neuropil. This period is the time of acquisition of reflex activity. The first synapses to appear over the 7-8 week period are axodendritic. Later axosomatic synapses are seen between 10.5 and 13 weeks. All vesicles are round, never flattened.

Synaptogenesis may continue beyond the 19th week. The first appearance of reflex activity at 5.5 weeks is correlated with synapse formation in the neuropil (Okado et al, 1979; Okado, 1980). At 7.5—8.5 weeks the elicitation of definitive local cutaneous reflexes corresponds to a massive increase in density of axodendritic synapses. By 11.5-12.5 weeks the emergence of responses elicited by simultaneously applied double stimuli may correspond to the production of axosomatic synapses which increase the integrative capacity of the neuropil. Thus, in the spinal cord of man, the motoneurone system matures before the afferent input to the cord as it does in other animals (Humphrey, 1964; Vaughan and Grieshaber, 1973) supporting the concept that cutaneous reflexes mature retrogradely with respect to the flow of afferent nerve impulses (Okado et al, 1979; Okado, 1980).

Conclusions

It is clear that the major advances made towards our understanding of human brain development over the past decade are attributable to the revival in the use of the Golgi technique, the application of methods for the visualization of the monoaminergic system, and the use of the electron microscope. The dynamics of developmental events have, however, so far been inferred from animal studies in which experiments have indicated that the same mechanisms may be responsible for similar processes in all mammals. Although, in the past, it seemed impossible to study the dynamics of neural ontogeny in humans because experimentation in vivo is ethically unacceptable, tissue culture in vitro, organ culture and brain slice techniques could be more universally applied to investigate cell kinetics, migration and connectivity using modern labelling methods. Moreover, the greater availability of fresh tissue also means that better

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fixation would enable standard light and electron microscope methods to unfold more qualitative and quantitative details about synaptogenesis, differentiation and the growth of neural processes.

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CHAPTER TWO

COMPARATIVE ASPECTS OF BRAIN GROWTH AND DEVELOPMENT

BRIAN L. G. MORGAN and JOHN W. T. DICKERSON

Introduction

Growth is traditionally measured as the change in weight of the body and its organs with time. Expressed in this way, the growth curve of the brain in all mammalian species is not linear but follows a sigmoidal pattern (Davison and Dobbing, 1968). The transient period of rapid development represented by such curves is known as the brain growth spurt, and this becomes more apparent when the changes with time are expressed in terms of a velocity, or rate, curve. When expressed in this way, species differences become apparent in the timing of the growth spurt of the brain with respect to a physiological milestone such as birth. Davison and Dobbing suggested that the growth spurt of the brain constituted a ‘vulnerable’ or ‘critical’ period when adverse influences would have their greatest effect on brain growth. It is clear, however, that anatomical, physiological, biochemical and psychological functions of the brain all have a critical period of development when they are maturing at their most rapid rate.

There is no single critical period. The critical period of anatomical development is not the same as the critical period of psychological development. Within each aspect of growth, we also have different critical periods; for instance, the period of most rapid cellular division is not the same as that for the most rapid period of myelination or that when dendritic arborization is maximal. Different regions of the brain may be characterized by a different critical period for a similar function. For example, the maturation of a particular enzyme may occur earlier in the cerebrum than in the cerebellum. All critical periods of growth of the brain occur during intra-uterine life or in the early postnatal period. Further, we find that the order of maturational processes is much the same in all mammalian brains. However, the critical periods of growth in each process may occur at different times in relation to birth, which makes interspecies comparisons difficult. A comparison between brain growth in the rhesus monkey and in the human illustrates this point, as the rhesus monkey’s brain is more mature at birth (Cheek, 1975) than the human brain (Dobbing and Sands, 1973). Hence in order to compare the effects of malnutrition just after birth in the human with the situation in the monkey, we would need to study the effects of malnutrition prenatally in the monkey.

Cellular growth

Growth of the brain can occur either by an increase in cell number (hyperplasia), by an increase in cell size (hypertrophy), or by an increase in the amount of extracellular material in the organ. The diploid nuclei of any one species contain a constant amount of DNA which is different from that for any other species (Boivin et al ., 1961; Enesco and Leblond, 1962). In the rat, this is 6.2 picograms and in the human 6.0 picograms. With the exception of a few tetraploid Purkinje cells in the cortices of the cerebrum and cerebellum, all cells in the human brain are diploid (Lapham, 1968). Thus by dividing total brain DNA content by the amount per cell, we can calculate the number of cells. Similarly by estimating total DNA in different anatomical parts of the brain, it is possible to calculate the cell number in each of the different regions. It may be assumed that the proportion of tetraploid cells, particularly in the human brain, is unlikely to be sufficiently large to affect the basic principle.

Neurochemical analyses can provide figures for protein per cell (protein/DNA) and lipid content per cell (lipid/DNA) which with the weight/ DNA ratio give an estimate of cell size. An increase in any of these ratios represents an increase in cell size, whereas an increase in the total amount of DNA in the brain is indicative of an increase in cell numbers.

Thus, whilst total DNA content gives an accurate assessment of cell numbers, it does not differentiate between different cell types in the brain. By using the ratios delineated above, we can also obtain an average figure for cell size. Brain RNA content increases in proportion to the increase in DNA, which maintains an RNA/DNA ratio at a constant level throughout the growing period (Winick and Noble, 1965). The nervous system has many different cell types which can be broadly categorized into glial cells and neurones. The mature rat brain has twice as many glial cells as neurones (Cragg, 1968). Large cerebral neurones differ from small cerebellar neurones. Astrocytes differ from oligodendroglia in size and shape. Those cells associated with the vasculature have yet different dimensions. Furthermore, all of these individual cell types probably have different protein and RNA contents (Winick, 1976).

During gestation in the rat, there is a slow increase in brain weight which at birth is approximately 0.2 g. After birth, the rate of brain growth increases dramatically such that the weight increases several fold during the next 21 days to reach 1.4 g at weaning. We then see a gradual rise in weight to reach a near plateau of 1.8 g at 10 weeks of age. After this time, there is only a small increment in brain growth throughout the life of the animal (Chevallier et al, 1975; Dobbing and Sands, 1971). Brain DNA levels similarly increase rapidly during the first two weeks of life, the rate of accretion reaching its maximum at seven days. Protein accretion mimics brain weight throughout development (Fish and Winick, 1969; Dobbing and Sands, 1971).

Different regions of the brain show different patterns of growth (Fig. 2.1). In the cerebrum of the rat brain, DNA synthesis continues until 21 days postnatally (Fish and Winick, 1969). By this time, the brain has attained about 75 % of its mature weight (Dobbing and Sands, 1971), and the cerebrum accounts for 50% of the total weight (Winick, 1970). After 21 days of life, the cells continue to increase in size by pushing out neuronal processes and so increasing their protein and lipid contents. Total cerebral protein content is achieved at around 65 days of life and brain content at 99 days of age (Fish and Winick, 1969).

Figure 2.1 The total DNA content of the different regions of the brain in rats of different ages (from Winick, 1976, with permission).

The hippocampus has rather unique growth characteristics: on days 14-17 we see an increase in brain cell numbers due to the migration of neurones from under the lateral ventricle into the hippocampus. The hippocampus is also characterized by a postnatal division of its neurones (Altman, 1966; Altman and Das, 1966).

In the cerebellum, DNA synthesis proceeds rapidly for the first 17 days postnatally and then declines rapidly. By 21 days, adult cell numbers are present. At this stage, the cerebellum weighs approximately 15 % of the total brain weight and contains 50 % of the DNA in the whole brain. Thus, the brain’s cellularity is heavily weighted to the cerebellum (Fish and Winick, 1969). A further increase in the DNA content of the cerebellum has been found to occur between 52 and 140 days of age (Dickerson et al , 1972). After day 17, the net protein synthesis also declines for a transient period and the individual cerebellar cell size decreases. This reduction in cell size possibly is an indication of the maturation of larger, more primitive cells into smaller, more mature cells (Winick, 1976).

In the brain stem, cell numbers increase until about 14 days of age (Winick, 1976). After this, there is a great increase in DNA: protein ratios due to the extension of neuronal processes from other brain regions into the brain stem. By day 21, the brain stem accounts for 30% of brain weight (Fish and Winick, 1969).

Neuronal cell division in rat cerebrum ceases before birth (Winick, 1970) whereas in the cerebellum there is a large increase in the microneurone population during the phase of rapid DNA synthesis postnatally. Increases in numbers of granule, basket, stellate and glial cells (Altman, 1966; Altman and Das, 1966) are common to many areas of the brain postnatally.

Less is known of the brain development of other species. In the pig, the most rapid rate of cell division is around birth (Dickerson and Dobbing, 1967). In the miniature swine DNA accumulation is complete by 56 days of age in the cerebrum, 21 days in the cerebellum and 35 days in the brain stem (Badger and Tumbleson, 1975). In the rabbit, the cerebrum and brain stem reach maximum levels by 120 days, and the cerebellum by 75 days (Ftarel et al , 1972). In the guinea pig (Dobbing and Sands, 1970) and monkey (Cheek, 1975), the most rapid rates of division are before birth. Thus both of these animals are more mature at birth than either the rat or man.

In man, brain wet weight increases until about six years of age (Dobbing and Sands, 1973). Patterns of cellular growth have not been delineated as well in the human brain as in the rat brain. Before birth, DNA synthesis is fairly linear. Soon after birth, we see a decline in this rate of accretion but synthesis continues until at least six years of age, and possibly longer. Two peaks of DNA synthesis can be distinguished during the development of the human brain (Fig. 2.2). The first is reached at about 18 weeks of gestation, which corresponds to the maximal rate of neuronal synthesis, and the second peak occurs around birth, which represents the time of most rapid glial cell division (Dobbing and Sands, 1973).

Figure 2.2 (a) Total DNA phosphate, equivalent to total cell number, in the forebrain of human

foetuses and infants; (b) A semi-logarithmic plot of the same data as shown in (a). In (b) regression lines with 95% confidence limits are added (redrawn from Dobbing and Sands, 1973, with permission).

Figure 2.3 Total DNA content in the different regions of the human brain during development (from Winick, 1976, with permission).

In man (Fig. 2.3), the forebrain and brain stem DNA levels reach 70% of mature values by two years of life and gradually increase from that point to reach a maximum at six years of life. In the cerebellum, DNA content proceeds more rapidly and achieves adult levels by two years of age. Cellularity in man is also heavily weighted in favour of cerebellum which weighs only 10% of total brain weight but contains 30 % of total brain DNA. Extensive microneurone proliferation occurs postnatally in the cerebellum (Raaf and Kernohan, 1944) and possibly in other areas too until about 20 months of age, in comparison to 2-3 months of life in the rhesus monkey (Rakic, 1971).

Winick (1976) has proposed a theory (Fig. 2.4) to account for growth in the body. He maintains that for any organ of any species, growth can be divided into three phases. In the first, we see a rapid division of cells with cell size remaining constant. In the second, DNA synthesis continues to increase, albeit at a lower rate than before, and protein synthesis maintains its momentum. Hence, there is

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hypertrophy

Figure 2.4 Changes in brain DNA, protein, and protein/DNA ratios during the periods of cellular growth (from Winick, 1976, with permission).

an increase in cell size and a smaller increase in cell numbers. In the third, there is an increase in cell size as DNA synthesis stops and protein continues to be produced. Growth finally stops when protein synthesis is equal to protein degradation, which is at maturity. Winick emphasizes that there is gradual change from one phase to another in this scheme and a good deal of overlap exists.

Dobbing et al. have criticized this theory in a recent publication (Sands et al , 1979). They show that mean cell size increases at an earlier stage than proposed by Winick and quickly reaches a constant level. Furthermore, their results indicate that cell multiplication continues unabated throughout tissue growth until growth comes to an end. These studies were carried out using kidney, liver and heart and results have not as yet been reported for the brain.

The control of both the rate of DNA synthesis and its period of synthesis are largely unknown. Winick and colleagues (Brasel et al , 1970) have demonstrated a correlation between the activity of the enzyme DNA polymerase and the rate of cell division in the whole rat brain and its regions. Thus, the period of hyperplastic growth is accompanied by high activity of enzymes associated with cellular proliferation. There have also been suggestions that the rate of RNA turnover increases in the growing brain. This is accompanied by an increase in the activity per cell of alkaline RNase, an enzyme involved in RNA degradation (Rosso and Winick, 1975). An interesting finding was the presence of two species

COMPARATIVE ASPECTS

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of cytoplasmic RNA in developing rat brain which disappear at about the time of the cessation of cell division (Lewis and Winick, 1977). Winick and Lewis (1977) have, in fact, implicated a 40 and 34S rRNA in the control of the timing of active cellular proliferation in the rat. These considerations may have important consequences for catch-up growth following a period of nutritional deprivation, a matter which is discussed in Chapter 3.

The polyamines spermidine and spermine, and their precursor, putrescine, participate in many of the processes necessary for nucleic acid and protein synthesis, acting as organic cations by stabilizing the macromolecules and cell organelles involved. In the human brain, the rise in the concentration of spermidine which occurs prior to birth in the cerebellum and brain stem, and perinatally in the forebrain (McAnulty et al ., 1977) corresponds to a period of rapid DNA replication and increase in cell number (Dobbing and Sands, 1973). The concentration of putrescine was also found to reach its peak perinatally. It is of interest that the first phase of the rapid increase in the DNA content of the human brain, corresponding with the period of neuroblast replication, occurred at about the same time as the rapid increase in putrescine concentration. It is postulated that the increase in the concentration of putrescine at the time of extensive neuronal multiplication was due to a rise in the activity of the enzyme ornithine decarboxylase (ODC) which accompanies rapid cell proliferation (Russell, 1970). It is perhaps significant that the concentrations of the ganglioside, G Dla , associated with synaptic growth also increase in the forebrain at this time (Yusuf et al ., 1977).

Brain lipids

The brain contains a large amount of lipid in the form of simple lipids such as cholesterol and complex lipids such as phospholipids, glycolipids and other esters which contain various fatty acids. Cholesterol itself is not esterified in the mature brain. The proportion of the total cholesterol that is esterified in the human brain falls from about 5 % in early foetal life in the forebrain and cerebellum to about 1 % at about 200 days gestation with a small rise and subsequent fall during early postnatal life (Yusuf, 1976; see p. 84). The changes in the proportion of cholesterol esters in the brain stem are rather smaller.

The brain lipid content increases gradually during development. As most of the lipid is contained in myelin it is not surprising that the major increase in lipid concentration occurs in white matter during myelination (Davison and Dobbing, 1968). The rate of myelin synthesis in the postnatal period is greater than DNA synthesis which accounts for increased cholesterol/DNA and phospholipid/DNA ratios (Rosso et al ., 1970).

In the human brain, the lipid content is fairly constant until after seven months of gestation when lipid deposition increases in grey matter to reach adult

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levels by three months of age. Fat deposition continues at a more gradual rate in white matter. By two years of age, 90 % of adult levels have been accumulated and by 10 years, adult levels are achieved. Lipid per cell rises from shortly after birth until at least two years of age (Brante, 1949; Tingey, 1956; Cummings et al , 1958).

In the CNS, myelin is formed from the membranes of oligodendroglial cells and myelination begins after these cells have ceased dividing (Altman, 1969). These glial cells then surround the nerve axons in a spiral fashion and a progressive deposition of lipids occurs within the developing myelin sheath (Bunge, 1968) which results in the transformation of oligodendroglial cell membranes into the specialized adult myelin with its lamellated structure. Pure myelin can be separated from homogenates of nervous tissue by differential centrifugation through sucrose gradients. The adult structure contains 80 % of its dry weight as lipid and myelin does, in fact, account for approximately 50 % of the total lipid of the adult brain. The process of myelination can be studied histologically making use of stains which are specific for the membrane. At present this is the only technique available for the investigation of microscopic areas of the brain. Using this method it has been shown that the myelination of the human brain occurs in cycles with the process starting and proceeding to completion in different areas at different ages from late in gestation through to about 30 years of age (Yakovlev and Lecours, 1967).

Quantitation of the amount of myelin in the brain and descriptions of the process of myelination have been attempted in terms of those lipids that are relatively highly concentrated in the membrane, so-called ‘marker substances’. Cerebroside and cerebroside sulphate are characteristic myelin lipids. Cholesterol is also found in high concentrations in myelin, but it is also present in other cell membranes and whereas cerebroside is not found in the brain before the commencement of myelination, cholesterol is found in the human brain before there is any histological evidence of myelin (Kritchevsky and Holmes, 1962). As already pointed out, the cholesterol found in the mature nervous system, in contrast to that in the plasma, is practically all present in the free state.

It has been estimated that myelin accounts for over 25 % of the weight of the mature brain (Chase, 1976) and evidence from the rate of accumulation of cerebroside sulphatide shows that it accumulates over a relatively short period. Between 34 weeks gestation and term the amount of this lipid in the human brain increases by some 300 to 400 %. The amount rises more rapidly between 12 and 24 weeks of age by which time 50 % of the adult amount is accumulated and the adult amount is probably formed before 4 years of age. Evidence from animal experiments using cholesterol (Dobbing, 1964) or sulphatide (Chase et al , 1967; Ghittoni and Raveglia, 1973) suggests that the early period of myelination may be critical in determining whether the adult amount of myelin is going to be

COMPARATIVE ASPECTS 57

formed. The replication of the oligodendroglial cells whose membranes form myelin is a key factor in the formation of new myelin.

Phospholipids are important constituents of all cell membranes, including myelin. Before birth, the phospholipid pattern of the human forebrain, cerebellum and brainstem is similar with choline phosphoglycerides as the major phospholipids (Yusuf and Dickerson, 1977). After birth the brainstem showed the greatest change in pattern with ethanolamine phosphoglyceride (EPG) becoming dominant. This latter change is probably due to the preponderance of white matter in the brainstem, for EPG accounts for the major proportion of the total phospholipids in white matter (Svennerholm and Vanier, 1972). In myelin isolated from human brain, the ratio of the plasmalogen form of EPG to the diacyl form increases with age (Fishman et al , 1975) with most of the increase occurring in the first year after birth. It could therefore be that the increase in the relative proportion of EPG in the brainstem largely reflects the increase of plasmalogen in myelin.

The lipids of myelin are oriented with respect to the myelin proteins, some of which can be isolated as a complex proteolipid. Proteolipid deposition would appear to follow the same course as cholesterol in rat whole brain (Agrawal et al, 1976). In view of what has been said about the way in which myelin is formed, it is of interest that the amino acid composition of proteolipid protein prepared from the white matter of human foetal or young infant brains contained significantly more aspartic acid, proline, and leucine and significantly less phenylalanine and tyrosine, than that prepared from the brains of patients 18 months of age or older (Prensky and Moser, 1967). The amino acid composition of the younger white matter proteolipid protein was, in fact, similar in composition to that prepared from grey matter at any age. Rat and mouse myelin contain two specific basic proteins which increase during the development of the sheath. The synthesis of these proteins in the mouse appears to reach a peak at about 18 days after birth (Campagnoni et al , 1978).

The principal glycolipids in the brain are cerebrosides and gangliosides. Gangliosides consist of iV-acetylneuraminic acid (NeuNAC), sphingosine and three molecules of either glucose or galactose. A number of different species of gangliosides have been isolated from brain and four of these species constitute the major gangliosides of normal human and rat brain and account together for about 95% of the total ganglioside content (Table 2.1). In the mammalian central nervous system, gangliosides contain 65 % and glycoproteins 32 % of the total NeuNAC, and the rest is free (Brunngraber et al, 1972). The brain has the highest concentration of gangliosides of any tissue in the body with that of grey matter being 15 times as high as that of the liver (Svennerholm, 1970). This represents 5-10% of the total lipid content of some nerve tissue cell membranes (Ledeen, 1978).

Small quantities of glycolipids are found in all cellular and subcellular brain

58

Table 2.1 Major gangliosides of normal human brain (Svennerholm’s nomenclature). From Dickerson (1981).

Name

Symbol

Proposed structure

Monosialoganglioside

Gmi

Gal(l 3)GalNAc(l

-> 4)Gal(l

3

T

2

NeuNAC

4)Glu(l 1 )Cer

Disialoganglioside

^Dla

Gal(l -► 3)GalNAc(l

->4)Gal(l

4)Glu(l -» l)Cer

3

T

t

2

NeuNAC

Disialoganglioside

Goib

Gal(l -> 3)GalNAc(l

-> 4)Gal(l -> 3

t

2

NeuNAC(8

4)Glu(l -> l)Cer

2)NeuNAC

Trisialoganglioside

G T i

Gal(l 3)GalNAc(l

-* 4)Gal(l ->

4)Glu(l -♦ l)Cer

3

t

T

2

NeuNAC

NeuNAC(8

4 - 2)NeuNAC

Key:

Gal = galactose

GalNAc = N-acetylgalactosamine Glu = glucose Cer — ceramide

NeuNAC = iV-acetylneuraminic acid

fractions, but the majority are found in the neurones (Suzuki, 1967; Ledeen, 1978). Similarly, while sialoglycoproteins are present in small amounts in glial cells, the bulk once again is bound to neurones (Dekirmenjian et al , 1969).

The adult human brain is thought to contain 10 11 neurones. Early studies suggested that neuronal cell bodies accounted for only a small fraction of total grey matter gangliosides (Hamberger and Svennerholm, 1971; Norton and Poduslo, 1971). Later studies showed that by far the largest proportion of the gangliosides is located in the dendritic and axonal plexuses (Hess et al ., 1976). On the basis of the results of studies involving the measurement of ganglioside levels in isolated synaptosomes it has been widely postulated that the synaptic plasma membranes are the major loci of gangliosides (Lapetina et a/., 1968; Dekirmenjian et al ., 1969; Morgan and Winick, 1980a). Recent electron microscopy work by Svennerholm and collaborators has demonstrated without doubt that this view is correct (Svennerholm, 1980). However, we have noted

COMPARATIVE ASPECTS

59

(Table 2.1) that there are several different species of gangliosides in the brain, and it has been suggested that in the rat cerebrum, the microsomal disialo- ganglioside, G Dla , may serve as a marker for dendritic arborization.

Several investigators have studied the ganglioside content of the developing rat brain. Pritchard and Cantin (1962) found a linear increase in the concentration of gangliosides in the grey matter up to 25 days of age. James and Fotherby (1963) observed a similar linear increase in ganglioside NeuNAC in the whole brain between three and 16 days of age. Suzuki (1965) found a rapid increase in the amount of gangliosides at about 10 days of age with no increase after approximately 22 days. Merat and Dickerson (1973) found that the concentration of ganglioside NeuNAC in the forebrain rose rapidly during the interval of 1-21 days after birth, was reduced at three months and subsequently rose to mature values by six months. In the cerebellum, the peak concentration was reached by two months of age and the lowest at nine months (the adult value), while in the brain stem, the concentration rose more slowly and had a broad peak from 15 days to two months. Comparison of the pattern of change in these three parts of the rat brain with the changes in the same three parts of the pig brain (Fig. 2.5; Merat and Dickerson, 1973) shows that the major difference is in the timing of the changes and clearly shows that the brain of the pig develops earlier in relation to birth than that of the rat. This is in agreement with what is known about the timing of the growth spurt, cell replication and myelination of the brain in these two species (Davison and Dobbing, 1966,1968; Dickerson and Dobbing, 1967).

There are also definite changes in the patterns of the different gangliosides (G Mi , G Dla , G Dlb and G Tlb being the main types present in mammalian brain) from one area of the brain to another and from one developmental period to another. In the rat brain, it has been shown that some monosialogangliosides (G M1 ) are converted to disialogangliosides (G Dla and G Dlb ) and trisialoganglio- sides (G xlb ) during development, and that the turnover of gangliosides in the immature animal is more than in the adult (Holm and Svennerholm, 1972).

The timing of the developmental pattern of brain gangliosides established by chemical analysis is similar to that found by histological techniques for the development of neuronal processes. The density of axons increases at a maximal rate between the ages of six and 18 days in the rat, while dendritic density increases maximally between 18 and 24 days (Eayrs and Goodhead, 1959).

It has been suggested that gangliosides play an important role in behaviour (Irwin and Samson, 1971; Dunn and Hogen, 1975; Morgan and Winick, 19806,c). Theoretical models have been proposed in which sialo-compounds are viewed as important constituents in the functional units of neuronal membranes in that they exert an ion binding and releasing function. They may also play a role in the storage and release of neurotransmitters.

Synaptogenesis includes the growth of the presynaptic axon, contact with and

days

weeks

months

Age

Figure 2.5 The concentration of ganglioside NeuNAc in the forebrain (FB), cerebellum (CB), and brain stem (BS) of the growing rat (a) and pig (b). Values in the forebrain shown A, in the cerebellum shown #, and in the brain stem shown O (from Merat and Dickerson, 1973).

COMPARATIVE ASPECTS

61

‘recognition’ of the appropriate postsynaptic neurone, replacement of growth cone organelles and assembly at the active zone of pre- and postsynaptic dense material, complete with ion channels and transmitter receptor molecules. There is some evidence to implicate surface glycoproteins incorporated into the synaptic membrane in the recognition process (Rees, 1978). NeuNAC has been shown to be required for the synaptosomal uptake of 5-hydroxytryptamine (serotonin) (Dette and Weseman, 1978). Gangliosides have also been shown to be a key factor in the maintenance of excitability of isolated cerebral tissue (Mcllwain, 1961).

Brain metabolism

Energy metabolism of the brain varies considerably from birth to old age, as does the blood flow. Data from in vitro brain preparations (Himwich and Fazekas, 1941) and blood-flow measurements from intact animals (Kennedy et al, 1972) give substance to the view that cerebral oxygen consumption is low at birth, rises rapidly with cerebral growth and reaches its maximum level when maturation is completed. A number of enzymes of oxidative metabolism in the brain show a similar rise in level of activity (Sokoloff, 1974).

Blood flow reaches peak values at different times in the different regions of the brain according to the speed of maturation of each region (Sokoloff, 1974). Those regions characterized by high levels of white matter show their highest blood flow when myelination is at its peak. From these high values, we see a gradual decline to mature values with increasing age. The changes in blood flow possibly reflect changes in metabolic rate in the brain.

At six years of age, a child has its maximum cerebral blood flow and oxygen consumption. At this time, the brain tissue is consuming 5.2 ml O 2 /100 g per minute, which means that total brain consumption amounts to 60 ml/min or over half the total body basal oxygen consumption. This is much higher than in the adult and possibly accounts for the extra energy needed to sustain the biosynthetic functions of growth and development of the brain (Kennedy and Sokoloff, 1957; Sokoloff, 1966).

As well as cerebral energy metabolism changing with age and brain development, the nutrients used to sustain oxidative metabolism also change. Just after birth, the rat and human are hypoglycaemic and their blood ketone levels low (Krebs et al , 1971). Milk is high in fat (rat milk is 50% fat on a dry weight basis—Dymsza et al , 1964) and therefore ketogenic, and so as the rat pup begins to suckle, its blood ketone levels rise perhaps 10-fold or more (Krebs et al , 1971). Although human milk is not as high in fat content in comparison to the rat a similar ketogenic state exists in the suckling period.

Ketosis in the young rat pup lasts until it is weaned at 21 days on to a rat chow which is high in carbohydrate and fairly low in fat (Krebs et al, 1971). During

62

the first 21 days of life, the ketones form an important cerebral fuel for energy metabolism (Cremer and Heath, 1974). Similar evidence in the dog (Spitzer and Weng, 1972) and human infant (Persson et al , 1972) has substantiated the importance of ketones.. The enzymes involved in ketone utilization are most active during the early postnatal period and least active in adult life and hence the developing brain has a much greater ability to extract and utilize ketones from the blood. After weaning when ketosis subsides, these enzymes become less active and glucose becomes the major substrate for cerebral energy metabolism (Klee and Sokoloff, 1967; Krebs et al, 1971; Middleton, 1973; Carney et al , 1980).

More recent studies in adult rat brain (Hawkins and Biebuyck, 1979) have suggested that 3-hydroxybutyrate metabolism in the brain is limited by permeability. Furthermore, the permeability characteristics vary from region to region throughout the brain depending on the nature of the blood-brain barrier. These workers suggested that ketone bodies should be considered fuel supplements, rather than substitutes, which partially supply specific areas. If utilization is dependent on the blood-brain barrier, it might be expected that utilization would be more even throughout the brain of the neonate because of its higher metabolic requirements associated with an under-developed barrier.

During the first 30 days of life, more than 50 % of the glucose metabolized by the brain is passed through the hexose monophosphate shunt (Winick, 1970). The hexose monophosphate shunt has two advantages for the developing brain —it supplies firstly ribose molecules for nucleic acid synthesis and secondly TPNH, which is used in lipid synthesis.

The newborn mammalian brain, including the human brain, will withstand hypoxia for a longer period of time than the adult brain (Winick, 1976). This possibly reflects the predominance of glycolysis during the early stages of brain development. After birth, respiration becomes more and more important until it assumes the dominant role in glucose metabolism. This change is gradual and proceeds in a caudocephalic direction from spinal cord to cerebral cortex (Porcellati, 1972).

The rate of glucose utilization in the adult brain of most mammalian species is 0.3-1.0 mmol/kg/min and more than 90% of this glucose is metabolized via glycolysis. Some of the pyruvate formed in this way is converted to lactate, but the majority is further metabolized in the mitochondria by the citric acid cycle to give carbon dioxide and water (Winick, 1976).

The brain utilizes carbon skeletons which arise from glucose metabolism to make glutamate and aspartate by metabolic pathways associated with the citric acid cycle as shown in Fig. 2.6. Alanine is synthesized from pyruvate by transamination, glutamine from glutamate by amidation and aminobutyrate from glutamate by decarboxylation. Without exception these amino acids are in dynamic equilibrium with intermediates of carbohydrate metabolism and hence

COMPARATIVE ASPECTS

63

GLUCOSE GLYCOGEN

GLUCOSE 6-PH0SPHATE^=^GLUC0SE l-PHOSPHATE

3-PHOSPHOGLYCERATE—►SERINE

It

2- PHOSPHOGLYCERATE

Figure 2.6 Some important pathways of glucose metabolism in the mammalian brain.

are able to re-enter the carbohydrate pools and can be oxidized to carbon dioxide and water.

Other pathways are present in the brain which bypass certain steps in the Krebs cycle. One such pathway is the y-amino butyrate (GABA) shunt. In this, as shown in the diagram, the succinyl-COA step in the Krebs cycle is bypassed (Lajtha et a/., 1959; McKhann et al , 1960). This pathway may carry a significant share of the flux between a-ketoglutarate and succinate in the citric acid cycle in all species. In the adult guinea pig brain it accounts for 10% of the cortical turnover of glucose (Machiyama et al, 1965). We have no idea at what stage of development this first appears.

Glycogen has a fairly high rate of turnover and is an important part of both neurones and glial cells (Porcellati, 1972), but exactly what role it fulfils in development has yet to be defined.

The unique position of glucose in brain metabolism in the adult brain is partly due to the blood-brain barrier, which impedes entry into the brain of most substrates. Little is known of the development of the blood-brain barrier—we do not know if the barrier develops at the same time for all substrates or whether it develops permeability at different times for different substrates.

64

There is a high rate of influx of amino acids into the neonatal brain (Seta et al, 1972) which is believed to be due to the absence of a blood-brain barrier (Sessa and Perez, 1975). We also find that extracellular markers such as sucrose and insulin are not impeded in their entry into the neonatal brain in the same way as they are in the adult brain until 16-20 days of age (Bradbury, 1975), which is coincident with the development of intracellular levels of amino acids typical of the mature animal. By three weeks after birth, the brain levels of glutamine and the acidic amino acids increase and the basic and neutral amino acids decrease (Machiyama et al , 1965; Agrawal et al, 1966). This differential effect on transportation of amino acids with maturation is probably due to the development of amino acid transport systems within the blood brain barrier, each of which transports a specific group of amino acids to cater for the brain’s needs for that group independent of the other systems.

Three separate, saturable, stereospecific carrier mediated transport systems exist in the adult brain for neutral, basic and acidic amino acids respectively (Oldendorf and Szabo, 1976). Within each group of amino acids, there is competition so that the transport of one member of a specific group is competitively inhibited by the other members of that group. It has been shown that the adult brain can use these transport systems to concentrate amino acids against a tissue gradient. These processes are very susceptible to oxygen and metabolic inhibitors which restrict the flow of amino acids (Guroff et al, 1961; Tsukada et al, 1963; Neame, 1964).

The amino acids essential to the brain, namely L-phenylalanine, L-tyrosine, L- leucine, L-valine, L-methionine and L-threonine, are transported more efficiently than the non-essential amino acids mentioned previously such as L-aspartate and L-glutamate (Oldendorf, 1971; Banos et al, 1973). The brain seemingly takes up all amino acids except taurine; the branched chain amino acids are transported more rapidly than the others (Felig et al, 1973). However, the transport systems have a limited capacity to transport significant quantities of amino acids into the brain. They have low maximal transport capacities and are saturated at quite low concentrations. Arterial blood concentrations of amino acids are also low. In combination these phenomena limit the availability of amino acids for brain metabolic processes (Sokoloff et al, 1977).

Amino acids reaching the brain are utilized for amine neurotransmitter synthesis (the development of the enzymes involved having been well defined— Winick, 1976), protein synthesis and to a limited extent for energy production. Amino acids of the same species as those endogenously synthesized as a byproduct of glucose metabolism may be taken up from the blood and similarly oxidized (Sokoloff et al, 1977). The essential amino acids can also be oxidized by brain tissue.

In vitro brain slices oxidize branched chain amino acids, such as leucine, valine and isoleucine, to carbon dioxide at a similar rate to the kidney, liver and

COMPARATIVE ASPECTS

65

diaphragm (Swaiman and Milstein, 1965; Odessey and Goldberg, 1972). In fact, more than 90 % of the leucine taken up by tissue slices is oxidized and less than 10% goes to protein synthesis (Odessey and Goldberg, 1972; Chaplin et al,. 1976).

The change in amino acid transport capacity demonstrated by the developing brain is one mechanism by which amino acid supply of the maturing brain may be lowered. The similarity in the decrease in protein synthesis and this reduced transport suggests an important role of amino acid supply in controlling protein synthesis in neonatal brain (Winick, 1976).

Proteins are important constituents of all tissues, and are closely involved in metabolism as enzymes, in transport and as structural components. In association with lipids, proteins regulate the properties of membranes and the interchange of ions and molecules both within cells and between cellular and extracellular fluid. Many proteins are being formed continually throughout life and rapid alterations occur even within the diurnal variation of a single day- one theory of memory involves changes in ribonucleic acid (RNA) bases and consequently in protein synthesis (Hyden and Egyhazi, 1964). The complexity of the proteins of the brain therefore makes it impossible to consider a ‘critical’, or ‘vulnerable’ period in brain protein development.

The amount of total protein in the brain continues to increase after the number of cells has reached its mature value. The consequent increase in the protein : DNA ratio is therefore a reflection of the increase in the average size of the cells. The accumulation of protein in the human brain is probably linear from the sixth month of gestation until the second postnatal year and subsequently decreases.

In experimental animals it is possible to study protein synthesis by measuring the rates of incorporation of radioactively labelled amino acids into brain proteins. Studies of this sort have shown that protein synthesis is more active in the immature than in the mature brain (Winick, 1976). Moreover the average half-life of proteins in rat brain increases with age due to the synthesis of more protein with a longer turnover time. Thus, if individual proteins are considered, it has been estimated that some have a half-life of only 3 or 4 days compared with a mean of 17 days. The half-life of in vivo protein synthesis in the human brain is not known but Winick has estimated that if this is assumed to be 14 days there is an overall synthesis of four grams of protein per day.

The decline with age in the in vivo incorporation of amino acids occurs at the same time as a reduction in the in vitro capacity of brain ribosomes to synthesize peptide chains in cell free systems (Yamagami and Mori, 1970; Andrews and Tafa, 1971). Recently it has been shown that polyribosomes prepared from rat brains of different ages have similar activities in w7ro-(Fellous et al , 1974). This suggests that the reduced potential for protein synthesis in adult rat brains may be due to a loss of polyribosome aggregates and an increased inactive

66

monosome population. As yet, the reasons for this are not clearly defined. It could be due to a reduced activity of tRNA, tRNA amino acid synthesis and other elongation factors (the pH 5 fraction of enzymes) in the older brain (Fellous et al , 1974). On the other hand, there may be a reduced quantity of these soluble factors which would lead to a reduced incorporation of the supernatant postmitochondrial fraction obtained from neonatal as opposed to foetal rat brains (Gilbert and Johnson, 1974). Brain tRNA and amino acyl-t- RNA synthetase activity do not seem to change with brain development (Johnson, 1969) but EF1 is rate limiting in brain cell free systems (Girgis and Nicholls, 1972).

Animal models and human brain development

Because of the difficulty in obtaining human tissue, most information relating to human brain development must be extrapolated from studies on other mammals. Different species have different life spans, and we have no way of telling whether a day in the life of a rat is really equivalent to a month in the life of a human (Donaldson, 1908). Furthermore, this may be true at one period of life but not at another. Thus, using time as a gauge of developmental age of the brain is of little value.

Figure 2.7 The rate of increase in weight with age as a percentage of adult weight for various mammalian species. The units of age for the different species are as follows: guinea pig (days); sheep (5 days); rhesus monkey (4 days); man (months); rat (days); rabbit (2 days); pig (weeks) (from Dobbing and Sands, 1979, with permission).

COMPARATIVE ASPECTS

67

Dobbing and colleagues (Dobbing and Sands, 1979) have drawn up growth velocity curves for the brain in a number of species (Fig. 2.7). These curves enable us to divide different mammals into prenatal, perinatal and postnatal brain developers from the positions of their peak velocities or growth spurts relative to the time of birth: birth itself has little or no effect on the developmental processes. The relative size of the area beneath the curve on either side of birth enables one to compare the fraction of the growth spurt that occurred before birth with that occurring postnatally. As stated earlier, this growth spurt constitutes a period when the brain is particularly vulnerable to adverse stimuli (Dobbing, 1974).

When comparing the effects of an adverse stimulus on the brain growth of an animal with that expected in a human, we can apply an equivalent degree of stimulus on the animal for an equivalent portion of the vulnerable period, to that experienced in the human, and in this way we should get an indication of the effect on overall brain growth in the human. Using this approach all animal models are of equal value in elucidating any effect on human brain growth (Dobbing and Sands, 1979). However, as we have stated before, the brain growth spurt is not a homogeneous event. Every region and every developmental process going on in that particular region has a different growth spurt. Hence, to compare the effects of a stimulus on a particular developmental process in a particular anatomical area of the brain and make cross-species extrapolations necessitates knowing the exact timing of the rate of maximal development of the particular process being examined. Winick and co-workers have been responsible for gathering a good deal of basic data on hyperplasia and hypertrophy in different brain regions. But we still lack sufficient knowledge of the development of a large number of such processes and so, although the concept of critical periods of brain growth is a good one, it is not always possible to use it to gain insight to all phases of human brain growth.

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Dobbing, J. (1964) The influence of early nutrition on the development and myelination of the brain. Proc. Roy. Soc. Ser. B, 159 , 503-509.

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Gilbert, B. E. and Johnson, T. C. (1974) Fetal development: the effects of maturation on in vitro protein synthesis by mouse brain tissue. J. Neurochem., 23 , 811-818.

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Irwin, L. N. and Samson, F. E. (1971) Content and turnover of gangliosides in rat brain following behavioural stimulation. J. Neurochem., 18 , 203-211.

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CHAPTER THREE

EFFECTS OF MAFNUTRITION ON BRAIN GROWTH AND DEVEFOPMENT

JOHN W. T. DICKERSON, A. MERAT and H. K. M. YUSUF

Introduction

Intelligence, a manifestation of brain function, is in part genetically determined. The extent to which this genetic potential is achieved is influenced by both the internal and the external environment. Thus, nutrition, hormonal status, infection, sensory stimulation, parental care, and many other factors are so closely intertwined in their effects on the brain that it is often difficult to distinguish the major factor(s) involved in a given situation. This is certainly so when we consider the brain development of children in malnourished communities. So complex is the problem (Cravioto et ai, 1966) that it might be considered to be purely of academic interest to discuss it at all. This is further emphasized by the paucity of our information about man, the species with which this book is mostly concerned. Fortunately, there is now sufficient evidence from animal experiments to make it possible to consider certain basic principles and to make reasonably confident extrapolations to man where the human data itself is inadequate. An understanding of the differences and similarities in the growth and development of the human brain and that of other species is of paramount importance in making any extrapolations (see Chapter 2).

It used to be thought that the brain was in some way ‘spared’ the consequences of malnutrition, and indeed its growth is always affected less by deprivation than that of the body weight. However, it is now clear from studies in experimental animals that the brain is particularly vulnerable to nutritional

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deprivation during the period of its growth spurt. Moreover, in the rat (Dobbing and Sands, 1971), and probably also in the human (Davies and Davis, 1970), the brain only has this single growth spurt which is strictly age-related. Consequently, a deficit in growth which occurs during this time may well not be compensated by subsequent catch-up growth.

Dobbing (1974) has emphasized three important points in connection with the extrapolation from animal studies to man which are often overlooked. The first of these is the actual length of the growth spurts. When considering a graph of these (see Fig. 2.7) it is easy to miss the fact that the spurt in the rat is a matter of days, whereas that in the pig is measured in weeks and that in the human in months. Thus, undernourishing a rat from birth for three weeks eclipses the entire growth spurt whilst the same period of time in the human would eclipse only a small fraction of the spurt. The second fact which Dobbing mentions is the irrelevance of birth, for this occurs at different times in relation to the spurt in different species. As far as we know at present, birth does not affect the growth curve of the brain except insofar as the metabolism of the brain may be affected by hypoglycaemia or hypoxia. Finally, it is of importance to emphasize that the various cellular systems in the brain develop in a definite order and relationship to the growth spurt of the whole brain. In the human foetus the neuroblasts, which develop into neurones, have completed most of their development by the beginning of the growth spurt which is mainly the result of neuroglial proliferation, dendritic arborization and synaptic development and, later, myelination. Thus, the critical period is post-neuronal and during neuroglial proliferation. The early completion of the main neuronal spurt by about 18 weeks (Dobbing and Sands, 1973) means that neuronal proliferation in the human is largely ‘protected’ for it is very difficult to malnourish an embryo. In contrast, the rat with its postnatal growth spurt may be particularly vulnerable to neuronal damage as it is relatively easy to malnourish the animal during the phase of neuronal development. Nutritional deprivation for varying periods of time at different ages will therefore expose different structure-types of cells, dendrites, synapses, and myelin, as well as different functions to the effects of malnutrition in different species.

Valuable as animal experiments are, they cannot replace, only complement, studies in man, even though these have to be much more limited in their scope. Broadly speaking, three kinds of human investigations are possible—measurements of the growth of the brain and its chemical development, and an assessment of some of its functions.

Brain size

Brown (1966) reported the weights of brains taken from autopsies of over 1000 children in Uganda. The mean body weight and mean brain weight were

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significantly lower at various ages in ‘malnourished’ than in ‘non-malnourished’ children and both were lower than a published reference standard. The brain : body weight ratios of the malnourished children were slightly higher than those of the non-malnourished children. The extent to which this may have been

Figure 3.1 The brain weights of malnourished (X) and ‘control’ (#) Jamaican children, plotted (a) against age, and (b) against body weight (from Merat, 1971).

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accounted for by oedema in the brains of children with kwashiorkor could not be ascertained. Oedema of the brain may account for the increased translucency of the head found in acute PEM, which disappeared after 6. months’ rehabilitation (Ergsner et al, 1974). Figure 3.1 shows that the weights of the brains of children dying from PEM in Jamaica tended to be too heavy for their body weight when compared with those for non-malnourished ‘controls’ (Dickerson, Merat and Waterlow, unpublished). The highest ratios tended to be in the more severely malnourished children.

In clinical practice the growth of the brain must be measured indirectly, and head circumference is on the whole accepted to correlate with brain size (Stock and Smythe, 1963; Ergsner, 1974: Cooke et al ., 1977). Ergsner has reported that marasmic infants, possibly because of the earlier occurrence of the malnutrition, have a greater reduction in head circumference than those with kwashiorkor. Catch-up of head circumference occurs during rehabilitation (Ergsner et al ., 1974) and tends to be more rapid and complete in children with kwashiorkor than in those with marasmus (Pearl et al ., 1972).

Malnutrition may also occur in utero resulting in the birth of babies who are underweight for their gestational age, called ‘light-for-dates’ or LFD’s. The head circumference and brain weight of such children have been found to be small for their gestational age (Gruenwald, 1963) though normal for body weight (McLean and Usher, 1970). Head circumference less than the tenth percentile at birth has been found to be associated with poor growth, later microcephaly and neurological deficit in a group of American children whose growth and development were evaluated at 5 years of age and who had weighed 2000 g or less at birth (Gross et al ., 1978). In a longitudinal study (Davies, 1980) it was found that head circumference growth was faster during the first 6 months after birth in LFD than in ‘appropriate-for-dates’ (AFD) babies. Presently available evidence suggests that even severe intra-uterine undernutrition may not necessarily permanently hinder catch-up (Davies, 1980).

Appropriate formulae have been worked out from the limited analytical data available in the human, relating head circumference to brain weight and to protein and DNA content during the first year of life (Winick and Rosso, 1969). Correlations have also been calculated between neonatal body weight and adolescent brain development in rats (Zamenhof et al ., 1979).

Brain composition

Cellular growth

In the whole rat brain, Winick and Noble (1965) produced evidence to show that DNA synthesis, and hence cell replication, stops at about 20 days of age, whereas deposition of protein continues until the brain reaches its adult weight at about

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Figure 3.2 Schematic representation of an earlier view (Winick and Noble, 1966) of tissue growth. Phase I, cell division or ‘hyperplasia’. Phase II, cell division mixed with start of increase in cell size. Phase III, increase in cell size, or ‘hypertrophy’. (Redrawn from Sands et al, 1979, with permission).

90 days of age. It is then possible to distinguish three phases of growth- hyperplasia alone, hyperplasia and hypertrophy, and hypertrophy alone (Fig. 3.2, from Sands et al, 1979). From these results, Winick and Noble (1966) deduced that the control of catch-up growth following a period of growth retardation due, for instance, to malnutrition, depended on the nature of the growth process which was taking place at the time of the insult. Thus, interference with hyperplastic growth would permanently affect cell number and lead to true microcephaly, whereas complete recovery would be possible when only hypertrophic growth was reduced. This suggestion is attractive, seems to fit the findings, and had not been seriously challenged until recently when Dobbing and his colleagues (Sands et al, 1979) showed that a re-examination of the growth events in a number of organs does not show the expected sequence and does not support the previous suggestion that the period of hyperplastic growth constitutes a vulnerable period.

Effects of intra-uterine under nutrition. Intra-uterine undernutrition is usually the result of placental insufficiency and the consequent decrease in the flow of nutrients to the foetus. Intra-uterine growth retardation (IUGR) can also be the result of maternal malnutrition if the mother’s body is depleted due to a poor dietary intake before and during pregnancy, severe illness or frequent close

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Figure 3.3 The effect of protein-energy malnutrition on the DNA content of the human cerebellum, cerebrum, and brain stem. Values for malnourished children shown O and those for ‘normal’ children shown • (Winick et al ., 1970, and redrawn from Winick, 1976, with permission).

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pregnancies. Information about the effects of this kind of malnutrition on the human brain is scanty.

The amount of DNA in the brain depends on the size of the LFD infant (Chase et al , 1972; Sarma and Rao, 1974). Thus in the smaller infant studied by Chase et al the DNA content of the cerebellum was more severely depleted than that of the cerebrum-brain stem. In the latter study differences in depletion between the different parts of the brain were smaller. It is, of course, as pointed out, not known whether such a depletion in cell number could be made up by postnatal rehabilitation nor, indeed, if they are made up, whether the kind of cells formed will be in the same ratio as they would have been had they been formed prenatally (Chase, 1976).

In the human brain it is likely that the number of neurones will only be reduced by undernutrition early in gestation and that even late in gestation it will mainly be glial cell replication which will be reduced. Chase (1976) has suggested that loss of glial cells would not be likely to be as detrimental to intelligence as loss of neurones, and similarly that loss of cells from the cerebellum would not be as detrimental as loss of cells from the cerebrum. Impaired replication of glial cells would be expected to be associated with a decrease in the amount of myelin in the brain since this is formed from the membranes of oligodendroglial cells. Chase pointed out that complete removal of the cerebellum in a number of species results in disorder of movement while no recognizable function relating to intellect, perception or the sensory functions of touch, sight or hearing seemed disturbed by its removal (Dow, 1970).

In the rat, maternal undernutrition during gestation alone has been said to have only a small transient effect on the brain (Barnes and Altman, 1973), and perhaps this is to be expected since the growth spurt of the rat brain is entirely postnatal. However Dobbing (1981) has pointed out that in the rat birth falls between the two consecutive periods of neuronal and glial multiplication, a stage which occurs in mid-gestation in the human. Thus in the rat maternal undernutrition during the last one-third of pregnancy would be expected to reduce neuroblast replication.

Effects of postnatal malnutrition. Our knowledge of the effects of protein-energy malnutrition (PEM) on the number of cells in the human brain is scanty. It seems reasonably certain, however, that the brains of children severely malnourished early in life are small for their chronological age, though they contribute a larger than normal proportion to the body weight (Fig. 3.1). The different parts of the brain of such children contain a smaller amount of DNA than those of more normally nourished children when compared on the basis of chronological age (Fig. 3.3), but probably not when compared on the basis of weight (Fig. 3.4). In the same way the supine length or height of a child is affected by chronic, in contrast to acute, malnutrition, so it would be expected that the

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brain growth of children suffering only a transient period of acute dietary deprivation would be affected less than that of those for whom the deprivation was prolonged.

A problem arises in human populations of identifying with any accuracy the period of malnutrition. Thus it is not unlikely that children who die of PEM were also small at birth due to maternal malnutrition, but it is impossible to get this information in countries like Chile, Uganda or Jamaica from which most of the human material has been taken. However, the effect of malnutrition on brain cellularity has been studied in malnourished infants aged one to two years who were initially breast fed and of whom some were known to have had a normal birth weight (Chase et al , 1974). In these children, the amount of DNA in the cerebrum-brain stem, although lower than control samples for age, was not significantly different. Cerebellum DNA was similar in the malnourished and control children. Chase (1976) suggested that since these children represent the most frequent form of PEM (marasmus and marasmic kwashiorkor) affecting the world’s children, the differences between their study and those of Winick and colleagues may be due to the initial period of breast feeding and thus emphasize the importance of encouraging breast feeding in pre-industrial societies.

The information that is available about the effects of malnutrition on the human brain does not enable us to conclude anything about the permanency of the effects on brain growth or any aspect of its development although, as already pointed out, catch-up of head circumference does occur. In the rat the results of experiments too numerous to review in detail have clearly shown that if the growth of a rat is retarded up to 21 days of age its brain will remain permanently small and contain a smaller than normal amount of DNA. Thus, brain growth and cell replication is determined by chronological age rather than by stage of development. Furthermore, once the process has stopped it cannot be restarted and undernutrition does not alter the timing of its peak velocity, but merely the height of the peak which fails to return to its normal level on rehabilitation (Dobbing and Sands, 1973).

In the rat, relatively mild undernutrition produced by increasing the number of pups in a litter suckled by one mother to weaning (Kennedy, 1957-58; Widdowson and McCance, 1960) can produce a permanent reduction in brain DNA because the nutritional deprivation coincides with the entire growth spurt of the brain. In the pig where the growth spurt is perinatal (Davison and Dobbing, 1966) more severe undernutrition starting towards the end of the spurt is necessary to produce a similar effect (Dickerson et al , 1967). Earlier experiments in the rat (Dickerson and Walmsley, 1967) suggested that the DNA content of the brain of the weanling rat was not affected by undernutrition, and

Figure 3.4 The DNA content of the human brain plotted against the brain weight. Values for malnourished children shown +, and those for ‘controls’ shown #. Age of foetuses in weeks (W), others in months. (From Dickerson, 1981).

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this result would agree with the view that there is a rather clear cut-off point at about 21 days for the cessation of cell replication in rat brain (Winick and Noble, 1966). However, an experiment in which growth was retarded more severely from weaning by feeding a low protein diet (Dickerson et al , 1972) showed that cell number in some areas was permanently reduced. This finding would lend some support to the more recent doubts as to the validity of the idea of a sharp cessation of hyperplastic growth (Sands et al , 1979).

In the rat there are regional differences in the way in which cell multiplication is modified by undernutrition during the nursing period (Fish and Winick, 1969). The cerebellum, where the rate of cell division is most rapid, is affected earliest (that is by 8 days of age) and most markedly. An effect on the cerebrum with its lower rate of cell division appears later (that is by 14 days of age) and is less marked. In the hippocampus, the movement of cells from under the lateral ventricle is delayed and perhaps even partially prevented. Radioautographic studies with labelled precursors have shown that in neonatal rats undernourished for the first 10 days after birth only glial cell multiplication is inhibited in the cerebrum since, as we have seen, neuronal multiplication stops before birth. A reduction in the rate of cell division of neurones under the lateral ventricle accounts, at least in part, for the reduction in the DNA content of the hippocampus at 15 days of age.

Few studies have been carried out in which a biochemical approach to the problem of the effects of malnutrition on the brain have been supported by histological investigation. That histological changes do occur at any rate in animals reared from weaning on low protein diets was shown in rats by Platt (1962) and in pigs and dogs by Platt et al (1964). These workers described degeneration of both neurones and glia in the spinal cord and medulla and found that the changes persisted for as long as 3 months after rehabilitation on a high protein diet. The changes were exacerbated by beginning the malnutrition at an earlier age or by continuing it for a longer period. Neurones in grey matter were reduced in number, appeared swollen and were surrounded by a greater than normal number of ‘satellite cells’. Histochemical changes have been described in the brains of rats malnourished early in life (Zeman and Stanbrough, 1969). By means of special staining techniques it was demonstrated that the enzyme development of the brain was delayed. In some ways the effects of thyroid deficiency and corticosteroid administration are similar to those of undernutrition (Balazs, 1973) and these are discussed in Chapter 4.

Myelin lipids and myelination

Effects of intra-uterine undernutrition. Information is sparse about the effects of intra-uterine growth retardation on the composition of the brain. Such reports as there are usually relate to the analysis of the brains of very few infants.

EFFECTS OF MALNUTRITION

83

The accumulation of the myelin lipids, cerebroside sulphatide (Chase et al , 1972) and galactose cerebroside (Sarma and Rao, 1974) and the activity of the rate-limiting enzyme of sulphatide synthesis, galactolipid sulphotransferase (Chase et a/., 1972) have been found to be low in the brains of LFD babies with respect to their chronological age. As with the DNA content,-we know nothing about the permanency of such changes.

The rat is in some ways not the best model for the human LFD baby. The young animal, and therefore its brain, is small so that the number of analyses that can be performed on a single brain is limited. Moreover, as we have seen, the timing of the growth-spurt of the rat brain is entirely different with respect to birth to that of the human. The newborn piglet, on the other hand, more nearly approximates in weight to that of a newborn baby and the growth spurt of its brain, like that of the human, is perinatal. A litter of piglets may number twelve or more and the body weight of the individual foetuses may vary by a factor of two. A study in which the brains of runt newborn piglets were compared with those of their large littermates and also with normal foetuses of 93-95 days gestation but the same body weight (Dickerson et al , 1971) showed that myelination, as judged by the concentration of cholesterol, was delayed in the growth retarded newborn piglets, but was further advanced than in the normal foetuses of similar body weight. Cellular replication was also retarded in the runts but the mean size of the cells, as judged by the protein/DNA ratio, was similar in each part of the brain to that in the large piglet.

Effects of postnatal malnutrition. There is abundant evidence from biochemical (Dobbing, 1964; Benton et al , 1966; Chase et al , 1967; Dickerson et al , 1967) and histological studies (Benton et al, 1966; Fishman et al, 1969; Stewart et al, 1974) that nutritional deprivation during the period of most rapid growth of the brain retards myelination. More recent studies (Wiggins and Fuller, 1979) using a double isotope technique, have shown that early postnatal undernutrition in the rat depresses myelin synthesis to about the same extent in all major brain regions (cerebral cortex, medulla oblongata, midbrain, hippocampus, striatum and hypothalamus) at 18 and 21 days of age. Furthermore, full recovery in terms of the total amount of myelin in the brain is not possible on subsequent rehabilitation. In the rat, deposition of cholesterol, a commonly used marker for myelin, continues for some time after the normal weaning age of 21 days. In the experiment to which reference has already been made (Dickerson et al, 1972) in which the body weight of weanling rats was held constant for 4 weeks by feeding a low protein diet, deposition of cholesterol in the forebrain and brain stem continued to be below control values after rehabilitation. The period of growth retardation in these animals was after the spurt in myelination is normally considered to be complete. One explanation of this finding is that, as in the human brain (p. 56), myelination occurs in cycles and that there are areas in

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the brain in which it starts and finishes during the early post-weaning period.

We do not know whether myelination will achieve the normally expected levels on rehabilitation of malnourished children, or indeed whether a smaller than normal amount of myelin has any functional significance. Evidence from determinations of cerebroside-sulphatide (Chase et al ., 1974) and cholesterol (Rosso et al, 1970) suggest that the brains of malnourished children contain too

Figure 3.5 Effect of development and malnutrition in early life on the cholesterol ester ratio (cholesterol ester as percentage of total cholesterol) of the human forebrain, cerebellum and brain stem. Forebrain: controls O, malnourished #; cerebellum: controls A, malnourished A; brain stem: controls □, malnourished ■.

EFFECTS OF MALNUTRITION

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little myelin for their chronological age. However, examination of a larger number of brains from children in whom the malnutrition was evidently of differing severity (Dickerson, Merat and Waterlow, unpublished) suggested that myelination may be reduced only when the children have been chronically malnourished. Moreover, the amounts of cholesterol in the forebrains of malnourished children are probably appropriate for the weight of the forebrains even when these are severely reduced for age (Dickerson, 1975).

In the rat, it seems clear that chronic undernutrition delays the maturation of myelin and hence results in a difference, when compared with that of normal animals of the same age, in the qualitative nature of the membrane. Earlier studies (Fishman et al , 1971) in which the composition of the myelin was reported to be normal were not supported by morphometric investigations (Krigman and Hagan, 1976) which showed a 15-fold preponderance relative to control of promyelinating fibres in 30-day-old undernourished rats. Wiggins et al (1976) also found the pattern of myelin-specific proteins in undernourished rats to be characteristic of younger controls. Furthermore, the high preponderance of cholesterol esters in the brain of malnourished children (Fig. 3.5; Yusuf, 1976) and mice (Yusuf and Mozaffar, 1979) has also been interpreted as indicating immaturity of myelin.

Nervous tissue contains a number of species of lipids called gangliosides (Table 2.1) which are primarily located, as the name implies, in neurones and their associated processes. A small amount of ganglioside, accounting for 0.8-1.2% of the total ganglioside of the rat forebrain (Yusuf, 1976), can be recovered from myelin. The total concentration of ganglioside NeuNAC in myelin remains more or less constant, irrespective of age, at about 50 jug per 100 mg (Suzuki et al, 1967). It follows therefore that the increase in the amount of NeuNAC recovered from myelin with increasing age (Table 3.1) represents

Table 3.1 The effect of age on the ganglioside composition of myelin from the rat forebrain

Ganglioside NeuNAC Mole percentage distribution

Age

(days)

in myelin (jig/brain)

Gmi

fjDla

^Dlb

G T i

21-22

7.3

42 (2.8)*

19(1.2)

23 (1.5)

15(1.0)

31

9.5

57(5.5)

19(1.7)

5 (0.5)

51

13

68 (8.8)

15 (2.0)

13(1.6)

4 (0.5)

81

16.4

75(12.4)

10(1.6)

12 (2.0)

3 (0.5)

121

21

85(17.8)

6 (1.3)

6(1.3)

2 (0.5)

Values in parentheses are the total amounts of ganglioside NeuNAC in jig in each fraction

86

the increased deposition of myelin itself. Maturation of the membrane was accompanied by a change in the pattern of the major gangliosides with the mole percentage of the monosialoganglioside, G M1 , increasing with age. These changes are a useful basis for the study of the effects of undernutrition on myelin development.

Pregnant rats were given 50 % of the amount of food consumed by control pregnant animals on the same day of gestation and food restriction was continued through lactation and in the offspring through 121 days of age (Yusuf and Dickerson, 1979). Purified myelin prepared from the forebrains of these animals contained a greater than normal proportion of the multisialo- gangliosides, G Dla , G mb and G T1 (Svennerholm, 1963) from day 31 and a lower than normal proportion of the monosialoganglioside, G M1 , the major ganglioside of mature myelin (Table 3.2). The absolute amount, in /tg, of G M1 did not, however, differ from the control value so the difference in composition brought about by undernutrition was entirely due to retention of the multisialo- gangliosides. The cause of the retention of these compounds is not at presen> known, but one explanation is that immature myelin may be a mixture of ‘mature’ myelin and glial cell membranes and that the immature matrix of ‘premyelin’ is gradually converted to the adult membrane during brain development (Smith, 1967; Cuzner and Davison, 1968).

The ganglioside molecule contains glucosamine and measurements of the incorporation of tritiated glucosamine (d-[1 — 3 H]glucosamine) into myelin G M1 showed that the rate of incorporation in the undernourished animals was higher and so too was the rate of decay (Yusuf and Dickerson, 1979). The differences between these animals and their controls was brought out more clearly when the calculated half-life of G M1 was considered. During the 30-60

Table 3.2 The effect of chronic undernutrition on the ganglioside composition of myelin from the rat forebrain

Age

{days)

Ganglioside NeuNAC in myelin (gg/brain)

Gmi

Mole percentage distribution

t^Dla ^Dlb

G T1

21-22

6.6

45 (2.8)*

22(1.3)

18(1.1)

15(1.0)

31

10

48 (4.7)

26 (2.6)

16(1.6)

10(1.0)

51

17

57 (9.7)

18(2.1)

18 (3.0)

6(1.0)

81

27.3

47(12.8)

26 (7.1)

23 (6.3)

3 (0.8)

121

30.9

49(15.3)

35 (7.9)

21 (6.6)

3(1.0)

Values in parentheses are the total amounts of ganglioside NeuNAC in gg in each fraction

EFFECTS OF MALNUTRITION

87

day interval this was 42 days as compared to 109 days in the controls. Similarly, during the 60-100 day interval the values in the two groups were 37 and 992 days respectively. The long period in the control animals (probably at least equal to the life-span of the animal) is in accord with earlier studies which showed that when 14 C labelled cholesterol or 32 P labelled phosphate were injected into growing animals the label could be recovered from the brain at least 12 months later.

These experiments suggest that chronic undernutrition in the rat, at least, not only retards the deposition of myelin and its maturation, but the membrane formed is metabolically unstable. Destruction of myelin is characteristic of demyelinating diseases, such as multiple sclerosis (MS). White matter from the brain of an individual with MS contains a greater than normal proportion of cholesterol esters and consequently has a high cholesterol ester: cholesterol ratio. A similarly elevated ratio has been found in the brains of children dying of PEM (Fig. 3.5). Could it be that it is the result of the instability of the myelin and consequent demyelination rather than simply myelin immaturity as suggested earlier?

Malnutrition and synaptic development

Each of the 10 11 neurones in the adult human brain consists of a cell body surrounded by a network of delicate tube-like extensions, the dendrites, which provide the main physical surface on which the neurone receives incoming signals. The axon, usually thinner and longer than the dendrites, extends away from the cell body and provides the pathway over which signals can travel from the cell body to other parts of the brain. Information is transferred from one cell to another at specialized points of contact, the synapses (Fig. 3.6). A typical neurone may have from 1000 to 10000 synapses and receive information from something like 1000 more (Stevens, 1979).

The transfer of information across the synapses is accomplished by a chemical transmitter which is synthesized and stored in vesicles within the synaptosome (Fig. 3.6). Passage of an impulse involves the release of the transmitter at the presynaptic membrane into the synaptic cleft and its subsequent inactivation at the postsynaptic membrane. A number of substances have been identified as transmitters. These include acetylcholine (Ach), serotonin (5-HT) and norepinephrine (NE). Histamine and certain amino acids (e.g. glutamic acid and y-aminobutyric acid (GABA)) also function as transmitters. Certain parts of the brain are rich in synapses containing particular transmitters.

It is clear that the development of the information system within the brain involves not only the structural basis for the retention and transfer of information—neurones, dendrites and axons, but also the enzyme systems involved in the synthesis and degradation of the chemical transmitters.

When we consider the growth of the structural components—the dendrites, axons and associated synapses—it must be said that we know very little of a quantitative nature about the timing of these processes. Such information as there is in man has been gained by the use of staining techniques, the Golgi method or a variant of it, which are in themselves fickle and make possible little more than a crude comparison. Probably all that can be said at present is that

EFFECTS OF MALNUTRITION 89

the process of dendritic arborization is predominantly postnatal (Dobbing, 1981).

The best hope presently available, as pointed out by Dobbing, seems to be in the application of the more modern technique of stereology and this is being exploited in studies of the effects of undernutrition in experimental animals (see below). However, application of this technique to the human brain is made difficult by the unavailability of acceptable material and by the sheer bulk of the organ. At present therefore it would seem that a chemical marker would offer certain advantages. Gangliosides seem to have some merit as markers since they are located in high concentration in grey matter; the changes in ganglioside patterns with development in different parts of the brain in different species have been discussed above (p. 59).

Unreliable as the normal staining procedures are, they have suggested that undernutrition from birth in the rat results in substantial reduction in synaptic development (Cragg, 1972; Salas et al ., 1974). By means of stereology, Dobbing and colleagues (Thomas et al ., 1979) have shown that a period of moderate undernutrition from birth results in a deficit of about 37% in the average number of synapses per neurone in the cortex. The important question is, of course, whether this deficit persists on rehabilitation, and adult rehabilitated animals did, in fact, provide no evidence of permanent deficiency (Thomas et al , 1980).

In an attempt to study the effect of the severity and timing of malnutrition on dendritic development using the total ganglioside NeuNAC content as a marker, rat pups were malnourished in three different ways (Merat and Dickerson, 1974). They were (a) undernourished from birth by increasing the litter size, (b) malnourished by feeding future mothers a 12% protein diet from weaning and maintaining them on this diet through pregnancy and lactation, and (c) by giving mothers a 7 % protein diet during gestation and lactation. In view of the fact that many human mothers in poor countries may have a marginally adequate protein intake throughout their lives, it is of interest that the brains of the offspring of rat mothers in group (b) were of normal weight and contained normal amounts of gangliosides. Pups in the other two groups were small for their age at weaning, and had smaller brains which contained smaller than normal amounts of gangliosides. The reduction in gangliosides in the animals whose growth was retarded only from birth was proportional to the reduction in brain weight, but in the brain stem of the more severely retarded animals of group (c) there was evidence of a specific effect of malnutrition on ganglioside deposition so that the amount present was too little for the weight (Fig. 3.7).

Similar results have also been obtained from forebrain tissue of children dying from malnutrition in Jamaica. Fractionation of the gangliosides in these brains showed that the deficit in the total ganglioside NeuNAC in the forebrain was entirely accounted for by the smaller amount of the disialoganglioside, G Dla

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Figure 3.7 The effect of the severity of malnutrition in the rat on the relationship of the amount of A-acetylneuraminic acid (NeuNAC) in the brain stem to brain stem weight. Numerals indicate ages of rats in days reared, • 3 pups to one mother, O 8 pups to one mother, ■ 15 pups to one mother, □ 15 pups to one mother that had been reared on a 12 % protein diet since 24 days of age, A 8 pups to one mother that had been fed a 7 % protein diet from the 5th day of gestation. (From Merat and Dickerson, 1974).

(Fig. 3.8; Merat, 1971; Dickerson, 1980). On the assumption that the distribution of the different gangliosides between the different structural components of the human brain is similar to those in rat brain, it seems that the deficiency in the amount of G Dla might indicate that malnutrition in the human, as in the rat, retards the development of dendritic arborization. Moreover, the retardation in this aspect of brain development would appear to be of a relatively greater magnitude than that which occurred in cell replication or myelination in the same brains, since the amounts of G Dla , but not of DNA or cholesterol, were too small for the weight of the forebrains. It would seem therefore that this feature of developmental retardation might be more serious from a functional viewpoint, for the transmission of information throughout the brain might be less efficient. However, suggestions of this sort, though tempting, are at present a matter only of conjecture.

It may be, however, that gangliosides are related to behaviour and brain function in other ways than simply as structural components of membranes. Theories of learning have been suggested which involve the NeuNAC component of the ganglioside molecule acting as a specific binding site for positively charged neurotransmitters (Schengrund and Nelson, 1975). In support of this

EFFECTS OF MALNUTRITION

91

link between gangliosides and brain function, small changes in ganglioside metabolism have been reported to occur in the whole brain of rats after shortterm environmental stimulation (Dunn and Hogan, 1975; Irwin and Samson, 1971). More recently, increase in the content of certain ganglioside fractions in particular areas of the rat brain after long-term active avoidance conditioning has been shown to be associated with permanent functional connection of the neurones involved (Savaki and Levis, 1977).

These observations are relevant to a possible link between biochemistry and function in the brains of nutritionally deprived animals and children. Further support for such a link has been provided by experiments in which undernourished rat pups were subjected to early stimulation (Morgan and Winick, 1980a). Stimulation of the pups during the first 21 days of life reduced the change

Figure 3.8 The effect of protein-energy malnutrition on the amount of the disialo-ganglioside, G Dla , in the human forebrain. Values for malnourished children shown +, and those for ‘controls’ shown £. Age of children given in months. (From Dickerson, 1980).

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in open-field behaviour induced by the malnutrition. This improvement in behaviour was associated with a significantly higher ganglioside and glycoprotein NeuNAC content in both the cerebrum and cerebellum. Of particular interest was the fact that at age 6 months after the animals had been rehabilitated on a standard laboratory diet, the effects of the early stimulation were shown in an improved ability to learn a Y-maze. The increased levels of gangliosides and glycoprotein NeuNAC also persisted in the adults. The same workers tried another approach to the problem (Morgan and Winick, 1980b). NeuNAC administered intraperitoneally was found to result in raised cerebral and cerebellar ganglioside and glycoprotein NeuNAC. Treatment from 14 to 21 days after birth of rat pups malnourished for the first 21 days of life was found to bring about these changes without affecting brain weight, cell size or number. Changes in behaviour similar to those resulting from early stimulation were described.

The fact that both environmental stimulation and administration of NeuNAC caused the same changes in brain NeuNAC may well suggest that brain NeuNAC plays a role in determining behaviour. An additional link in the biochemical explanation for this role is provided by earlier reports of the close association between NeuNAC and serotonin-containing vesicles (Weseman, 1969). The liberation of NeuNAC from these vesicles by sialidase treatment seems to facilitate the release of serotonin from the vesicles. As we shall see, malnutrition in the growing rat reduces the concentration of serotonin in the brain (Dickerson and Pao, 1975).

The enzyme Na + K + -ATPase plays an important role in the maintenance of sodium and potassium in tissues. Moreover, in nervous tissue the activity of this enzyme is necessary for the polarization of neurones after transmission of the nerve impulses. The activity of the enzyme is extremely low in the brain of the newborn rat and increases rapidly during the brain growth spurt which also coincides with the spurt in myelination (Samson and Quinn, 1967). It is also of interest that the enzyme requires lipids such as cholesterol (Noguchi and Freed, 1971) for its activity.

Undernutrition of rat pups by removing them from the mother for 12 h each day from the 6th 11th day or 6th-17th day resulted in a significant reduction in Na + K + -ATPase activity in cortex homogenates which was partially recovered after 4 weeks’ rehabilitation (Mishra and Shankar, 1980). Again, these changes may have relevance to brain function, for a change in the activity may affect the proliferation ol nerve cells (Samson and Quinn, 1967). The ouabain-sensitive fraction of the enzyme, which was also reduced in this experiment, may also be related to neurotransmitter release (Gilbert et al., 1975). Mishra and Shankar postulated that since inhibition of ATPase may be the physiological mechanism of neurotransmitter release, an analogous situation could occur during undernutrition. Greater release of neurotransmitter in undernourished animals may bring about disturbances in the functioning of nervous tissue.

EFFECTS OF MALNUTRITION

93

In these rats the concentrations of sodium and potassium in the brain were normal. However, the concentration of potassium has been reported to be low in the brains of malnourished children (Alleyne et al , 1969), particularly when the children had gastroenteritis and were presumably losing excessive amounts of potassium in the faeces.

Malnutrition and energy metabolism

For obvious reasons most of our knowledge of brain metabolism has been derived from studies on experimental animals.

Glucose is the main energy substrate utilized by the brain under normal circumstances and is almost completely metabolized to carbon dioxide and lactate. The first convincing evidence that glucose could be replaced in part by other substrates came with the discovery that there was a considerable uptake of acetoacetate and 3-hydroxybutyrate, as measured by arterio-venous differences, by the brains of patients undergoing prolonged therapeutic starvation for obesity (Owen et al , 1967).

In the adult rat the uptake of ketone bodies by the brain is dependent on their circulating concentrations and when these are increased by starvation in the pregnant animal the activities in foetal brain of the enzymes involved in ketone utilization are increased. These enzymes are therefore substrate-induced in foetal brain in contrast to those in adult brain where starvation or fat-feeding has no effect on the activities of the 3 enzymes involved—3-hydroxybutyrate dehydrogenase, acetoacetyl-CoA thiolase and 3-oxoacid CoA transferase (Williamson and Buckley, 1973).

The newborn mammalian brain, including the human brain, is more resistant to anoxia than is the adult organ. However, it is important to note that even short periods of anoxia reduce the rate of cell division in neonatal rat brain as measured both by DNA content and by thymidine incorporation (Baum et al , 1976). As Winick (1976) has pointed out, this difference between the neonatal ability to withstand anoxia and its effect on cell multiplication is important because foetal malnutrition, resulting in intra-uterine growth retardation (IUGR), so often involves vascular insufficiency. Moreover, anoxia at birth in the human full-term baby occurs at a time when brain growth and cell replication is taking place at a rapid rate and it clearly may have an effect on this process.

Fatty acids and brain development

The brain differs from most other organs in that it contains practically no neutral fat, that is triglyceride. Its appreciable content of fatty acids is due to their presence in the various complex phospho-, glyco- and sphingolipids which

94

are important membrane components. Fatty acids can be broadly classified as ‘saturated’ or ‘unsaturated’ and the latter may contain one or more double bonds in different positions along the carbon chain. The unsaturated fatty acids in the brain are derived from two parent short-chain polyunsaturated fatty acids (SCP)—-namely linoleic (18 : 2 co6) and linolenic (18 : 3co3) acids, which are not synthesized de novo in the mammal (Alfin-Slater and Aftergood, 1968; Holman, 1973) although a dietary requirement for linoleic acid only has been shown in man (Collins et al, 1971; Holman, 1973). These parent fatty acids are converted by chain elongation and desaturation into the long-chain polyunsaturated fatty acids (LCP) necessary for brain growth and development. Crawford and his colleagues (Hassam et al ., 1975) have suggested that LCP may not be readily synthesized from SCP because the rate of desaturation is low or because the necessary desaturating enzymes are absent (Cowey et al , 1976).

The overall spectrum of polyunsaturated fatty acids in the human brain changes with age and interest in the LCP is related to the fact that they are associated with the grey matter, growth of which occurs primarily in utero. Since LCP may not be readily synthesized from SCP during the period of rapid brain growth and also since they are not present in vegetable foods, it might appear that animal fat would be necessary in the diet for the normal development of the human brain (Crawford et al ., 1973). This is clearly of considerable importance for those masses of the world population whose diet does, in fact, consist wholly or mostly of vegetable foods.

Presently available evidence suggests that the mother can desaturate and elongate SCP to LCP in her liver, and the foetus obtains its supply of both types of fatty acids from the maternal blood that passes through the placenta (Sanders et al , 1977). Foetal plasma choline phosphoglycerides contain more LCP and less SCP than those of maternal plasma so it seems that the placenta modifies the maternal supply of polyunsaturated fatty acids by preferential absorption or by the desaturation and elongation of SCP. Furthermore, additional modification can be accomplished in the foetal liver and it seems that all these processes are likely to have the result that the supply of fatty acids for the foetal brain is independent of the maternal diet. This conclusion is supported by work in rats (Eddy and Harman, 1975) in which it was shown that varying the degree of unsaturation, or the content of maternal dietary fat, with the exception of lard, did not influence the fatty acid composition of whole brain lipid or of the two major phospholipids, phosphatidyl ethanolamine and phosphatidyl choline in their offspring. The lard used in these experiments contained a small amount of docosahexaenoic acid (22 : 6co3) and the level of this fatty acid was raised in the brains of the offspring of mothers given the lard diet.

It is of interest that the few vegan mothers who have been studied in Britain have produced quite normal infants who have developed into normal children (T. B. Sanders, personal communication).

EFFECTS OF MALNUTRITION

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The developing brain is affected by a dietary deficiency of essential fatty acids (EFA). The results of studies on the offspring of females fed a virtually fat-free diet who were continued on the same diet after weaning showed that the brain is less sensitive than other organs to this deficiency (Galli, 1973). This is also true when the animals are exposed to the effects of a low maternal intake of EFA prenatally (Ailing et al , 1973). In the former study the fatty acids of ethanol- amine phosphoglyceride isolated from the myelin of 180-day-old male rats contained a lower than normal proportion of n-6 acids and a higher than normal proportion of n-9 acids. The triene : tetraene ratio was 1.79 in the EFA deficient animals compared with 0.18 in the controls. These changes were, however, reversible, thus demonstrating that the fatty acids of brain lipids, even those of myelin, undergo continuous replacement. At ages earlier than 180 days it becomes progressively unlikely, the younger the animal, that changes in the fatty acid composition of the brain will be found due to the mobilization of EFA from maternal depots. Changes were, however, pronounced at 18 days of age in the experiments where the maternal organism was depleted prior to mating (Ailing et al , 1973).

Karlsson and Svennerholm (1978) compared the effects of feeding pregnant rats diets low in protein or EFA. Pups were weaned at 30d and continued on the same diet as their mothers. Measurement of DNA, gangliosides and cerebroside led to the conclusion that nutritional deficiencies only delay the development of neuronal membranes but irreversibly reduce the formation of myelin.

Malnutrition and brain protein

Discussion of the mechanisms of mammalian protein synthesis is outside the scope of this book. A brief review of this subject in relation to the brain has been written by Nowak and Munro (1977).

Studies in experimental animals have been aimed at examining the effects of malnutrition on the processes of transcription (RNA synthesis and turnover) and translation (cytoplasmic protein synthesis) in the brain. Underfeeding rats from birth by increasing the litter size has been shown to significantly reduce the synthesis of RNA at lOd of age (Ramirez de Guglielmone et al , 1974). The metabolic transformation of 3 H-orotic acids to nucleotides was also reduced.

Rehabilitation from days 21 to 30 produced an increase towards control values but a reduced incorporation of radioactive label into microsomal RNA still persisted at 30 days. Further studies on a similar animal model by the same group of workers (Duvilanski et al , 1980) has suggested that impaired nucleocytoplasmic transport of both messenger RNA (mRNA) and ribosomal RNA (rRNA) and their effect on protein synthesis could be factors underlying the decreased membrane formation in rats undernourished early in life.

If we consider the process of translation, Patel et al (1975) have shown that

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incorporation of leucine into protein in the forebrain was reduced in 15- and 21- day-old rats whose mothers had been malnourished from the first week of pregnancy. Adequate feeding for 2 weeks restored the incorporation to control levels.

In the inborn error of metabolism, phenylketonuria (PKU), there is a deficiency of the enzyme phenylalanine hydroxylase and the metabolism of phenylalanine (PhAl) is impaired. If the condition is not detected early in life and the child given a low phenylalanine diet, the growth and development of the brain is impaired due to the accumulation in the blood and brain of high levels of PhAl. It is not surprising therefore that this has been one of the most extensively studied examples of how an excess of one amino acid can disturb the levels of other amino acids and protein synthesis in the brain. There is now considerable evidence (Nowak and Munro, 1977) that hyperphenylalaninaemia in infant rats causes a reduction in DNA synthesis, reduces total brain protein and lipid (Davison, 1973), and especially galactolipids and proteolipids. Furthermore there is a reduction in the uptake of 14 C-galactose into brain lipids. Where they have been studied in different parts of the brain the changes are greater in the cerebellum than in the cerebrum.

As Nowak and Munro point out, these changes are comparable to those produced in the suckling rat by malnutrition and are in agreement with the suggestion of a common mechanism dependent on the inadequacy of free amino acid pools in the brain that result from inadequate dietary intake in one case and from competition for entry into the brain in the other.

Amino acids and neurotransmitters

The intracellular free amino acids in the brain, as in other tissues, may be assumed to provide the substrates for protein synthesis. These amino acids are derived from the plasma or, in some cases, produced locally from appropriate precursors. The interpretation of changes in the concentration of individual

Table 3.3 Neurotransmitters in mammalian central nervous systems (Wurtman and Growdon, 1980)

Group

Source

I

Serotonin, acetylcholine,

From a circulating

histamine, dopamine, norepinephrine

precursor

II

Various peptides found in brain neurones

By polyribosomes

III

Glycine, glutamate, aspartate

From glucose or other energy sources

y-aminobutyric acid (GABA)

From glutamate

EFFECTS OF MALNUTRITION

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amino acids in the amino acid pool of any tissue is a complex problem, for they are the result of differences in the relative rates of influx, efflux, incorporation into and release from proteins, degradative metabolism and synthesis. Interpretation is further complicated by the existence of functional compartments within cells so that in an organ as complex as the brain there are different pools in different types of cells. In addition to this fact, and perhaps even responsible for it, it must be considered that certain amino acids are either themselves neurotransmitters or are the precursors of neurotransmitters.

Some 15-20 compounds that probably function as neurotransmitters have been identified in mammalian central nervous systems. A suggested classification is shown in Table 3.3. Wurtman and Growdon (1980) suggest that the rate of synthesis of transmitters in Group I only will normally be coupled to plasma composition and food consumption.

In adult human brain four amino acids are each present at concentrations in excess of 1 pinole per g. These are taurine (1.25 /imole/g), glutamic acid (7.19 /rmole/g), aspartic acid (1.10 /rmole/g), and glutamine (5.55 /an role/g). The other non-essential amino acid thought to function as a transmitter, glycine, is present at a rather lower concentration (0.45) (Hansen et al , 1973). In most species so far studied the concentrations of individual free amino acids are lower in adult than in neonate brain. Exceptions are glutamic and aspartic acids and glutamine, whose concentrations tend to increase with age (Nowak and Munro, 1977). Miller (1969) has identified peaks of free amino acid concentration around the 7th and 20th days, and related them to increased protein synthesis at these times.

It is difficult to find a simple explanation for the fall in concentration of most of the amino acids between birth and maturity. The change in water concentration is inadequate, but increase in lipid concentration could be a contributing factor. However, it seems possible that a major contributing factor is the high level of amino acids in foetal plasma relative to maternal plasma, for these rapidly fall after birth to adult levels (Christensen, 1972).

It is not surprising that there are pronounced regional differences in the concentrations of some amino acids. Thus the concentration of glutamic acid is higher in the cerebral cortex, and GABA in the hypothalamus and midbrain.

For practical reasons, it is difficult to obtain reliable analyses of free amino acids in the human brain because of intervening post-mortem changes. Thus, in the case of these constituents the results obtained on experimental animals, principally the rat, are of considerable importance even though, as with the other aspects considered, results must be extrapolated with caution.

Plasma concentrations of amino acids are influenced by diet and these in turn may affect the passage of amino acids into the brain. It is therefore very important in considering experiments designed to study the effects of malnutrition on brain amino acids to carefully note the nature of the dietary manipula-

98

tion as well as its timing and duration. In rat pups undernourished from birth to 21d by removing them from the mother for different periods of time, Rajalakshmi et al. (1967) reported no change in the cerebrum in the concentrations of aspartic acid, alanine, glutamic acid, glutamine and GABA. Feeding pregnant rats a 7 % casein diet (Pao and Dickerson, 1975), though reducing the body and brain weight at birth, had no significant effect on the concentrations of amino acids or amines (Table 3.4). However, in contrast to the effects of undernutrition, the low protein diet did result in lower levels of glutamic acid. The concentration of aspartic acid was higher in the malnourished pups, as also was that of tyrosine. Higher levels of aspartic acid were also found in the cerebellum but not in the brain stem. In agreement with these observations, incorporation of U- 14 C-glucose into aspartic acid was enhanced in the forebrain and cerebellum. We suggested that these findings could be explained by the effects of the low-protein diet on the activity of the Krebs (tricarboxylic acid) cycle. The activity of this cycle is reduced by a decreased entry of glucose into the brain such as occurred in these animals. This would probably decrease the level of acetyl-CoA and the rate of its condensation with oxaloacetate to form isocitrate. In effect, this would then increase the rate of transamination of glutamate and oxaloacetate, thus resulting in higher concentrations of aspartate and a-oxoglutarate in the brain.

The forebrains of the malnourished pups at 21 days contained normal concentrations of the two neurotransmitters, 5-hydroxytryptamine and norepinephrine (Table 3.4). Since, however, the forebrain weights were lower than in the controls, the absolute amounts of the neurotransmitters were low, a result in agreement with Shoemaker and Wurtman (1971).

Table 3.4 Effect of feeding rats a 7 % protein diet during gestation and lactation on body weight, brain weight, DNA amino acids and amines

Birth

21

days

Control

Malnourished

Control

Malnourished

Body weight (g)

6.2

5.0***

59.7

Brain weight (g)

0.2

0.22***

1.49

1.06***

DNA (^g/brain)

540

501*

2700

1810***

Concentration expressed per g brain tissue

Glutamic acid (/rmole)

5.22

4.59

9.01 1

8.23 1 *

Aspartic acid (gmole)

0.88

0.92

1.50 1

1.90 1 *

GABA (/rniole)

1.19

0.96

2.72 1

2.63 1

5-Hydroxytryptamine {pg)

0.19

0.17

0.32 1

0.35 1

Norepinephrine {pg)

0.20

0.21

0.31 1

0.33 1

1 Values are for forebrain only. Values significantly different

from control

values shown:

when P < 0.05,

and *** when

P < 0.001.

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99

Many pre-school children amongst the world’s poorer nations suffer from malnutrition. It is therefore of considerable interest to know what effect this is likely to have upon the amino acids in the brain since such effects might well be involved in impaired protein and transmitter synthesis in brain function. Giving weanling rats a 3 % casein diet for 56 days (Pao and Dickerson, 1975) produced changes in the plasma levels of some amino acids similar to those found in children with kwashiorkor. Higher concentrations of glycine and histidine were found in both plasma and brain. The concentration of methionine was not

Figure 3.9 Proposed sequence describing diet-induced changes in the concentration of serotonin in the brain. Ratio of tryptophan to tyrosine (T) +phenylalanine (P) +leucine (L) +isoleucine (I) + valine (V) in plasma thought to control tryptophan entry into the brain (adapted from Fernstrom and Wurtman, 1972).

100

changed in the plasma but was raised in the brain. The plasma level of tryptophan was severely reduced by the low protein diet (Dickerson and Pao, 1975) and this was reflected in reduced concentration of tryptophan in forebrain, cerebellum and brain stem and of 5-hydroxytryptamine in the forebrain and brain stem. In agreement with the suggestion by Fernstrom and Wurtman (1971) of a mechanism of control of tryptophan entry into the brain which is affected not only by a supply of protein but also of carbohydrate (Fig. 3.9), it was found that exogenous insulin increased tryptophan intake into the brain of the malnourished animals. Brain and plasma tryptophan levels returned to normal after 7 days on a diet adequate in protein.

Thus, it would appear that these effects were only transient. However, their potential importance may lie in the fact that reduced serotonin synthesis was produced in the brain after the recognized vulnerable period of the growth spurt. Such changes may, in fact, partly explain why behavioural changes in undernourished animals may be less dependent on vulnerable periods of growth (Smart, 1977).

There is evidence that the concentration of ‘free’, in contrast to ‘total’ tryptophan, affects the entry of tryptophan into the brain. The proportion of tryptophan which is bound to albumin depends on the concentrations of albumin and of non-esterified fatty acids (NEFA). The influence of these factors seems not to have been examined in malnourished animals.

A number of experiments on the effects of malnutrition on brain amino acids have been done on other species including miniature swine (Badger and Tumbleson, 1974a, b) and monkeys (Enwonwu and Worthington, 1973, 1974). The results of all these studies as well as those in rats may briefly be summarized (Nowak and Munro, 1977) as showing that in young animals (a) the plasma levels of certain amino acids, particularly the branched chain amino acids and tryptophan are reduced by PEM, and particularly in kwashiorkor or experimental protein deficiency; (b) these changes are reflected in the amino acid pools in the brain; (c) in older animals subjected to PEM the changes in the plasma and brain amino acids are much less severe.

Brain function—behaviour and intelligence

From the preceding discussion it may be concluded that malnutrition in early life distorts the chemical composition of the brain and that effects on certain structural components—cell number and myelination—may not disappear on rehabilitation. It is tempting to ask whether such distortions damage the central nervous system sufficiently to lead to permanent intellectual impairment. On the face of it, this seems unlikely because of the immense functional reserve (Dobbing and Smart, 1974). However, there are numerous studies both in experimental animals and in man which show that undernutrition, which in

EFFECTS OF MALNUTRITION

101

animals can be quite mild, is associated with alterations in behaviour and intelligence. These may not be closely linked with ‘vulnerable periods’ (Smart, 1977) such as we have described (Chapter 2). It is becoming abundantly clear that there are many factors which are inseparably linked with malnutrition so that it is difficult, even in an animal experiment, to isolate malnutrition completely as a single factor. As an example, we may consider the large and small litter experiment in which rats are undernourished from birth by rearing them in large litters, or alternatively that in which pups are undernourished by removing them from their mothers for varying periods of time. They are certainly deprived of food but they are also deprived of mother-infant interactions. In the impoverished circumstances in which so many children in poor countries are raised, there is a complex interreaction of multiple environmental factors which cannot be ignored (Pollitt and Thomson, 1977; Cravioto and Delicardie, 1979).

Some of the difficulties in making and interpreting studies in children have been discussed by Richardson (1976). The problems apparent in animal experiments are compounded and the ‘controls’ on which the whole interpretation of the results are malnourished, or previously malnourished, children depend, may differ in many ways from the ‘experimental’ children. Richardson himself carried out a study on 74 severely malnourished boys who had been treated for malnutrition in a hospital during their first two years of life. They received an average of 8 weeks of in-patient care with good medical care and feeding. Follow-up visits were made by nurses to the boys’ homes for 2 years following discharge. At the time of the study they ranged in age from 6 to 10 years. A classmate or neighbour comparison was selected for each malnourished, or index, child. Aspects of behaviour and intelligence were assessed using the WCSC IQ test, a teacher’s evaluation of school performance, and parents’ reports of behaviour at home. The background histories of the index and comparison boys were determined on the basis of a composite score which was based on three social background variables (Table 3.5; Richardson, 1980). The results of this study suggest that severe malnutrition in the first two years of life has differing consequences for intellectual impairment, depending on the background history and characteristics of the child’s guardian, the economic conditions of the household and the child’s social environment. It was concluded that if severe malnutrition in infancy occurs in a context of a life history which is generally favourable for intellectual development, the early malnutrition appears to have a negligible effect on intellectual functioning. If the general circumstances are unfavourable then severe malnutrition is clearly related to later intellectual impairment.

These conclusions are in agreement with the results of a study of Korean orphans who were examined after being fostered at 2-3 years of age into middle- class American families (Winick et al ., 1975). By 7 years, differences in weight

102

Table 3.5 Background variables used in the measurement of the social background of malnourished children and their comparison children in Jamaica. (Richardson, 1980)

1. Mother’s or caretaker’s capabilities:

(a) Use of spare time.

(b) Level of ability in reading and writing.

(c) Is caretaker a source of help and advice to others?

(d) State of neatness and organization of the house.

(e) Understanding of questions at interview, responses and interviewer’s rating of her intelligence.

2. Socio-economic measure based on home furnishing and appliances:

(a) If electric power, the presence of a refrigerator.

(b) If electric power, the number of other electric appliances.

(c) If no electricity, the presence of a sewing machine.

(d) The type of fuel used for cooking.

(e) The presence of a transistor radio.

(f) Person/bed ratio.

3. Intellectual stimulation derived from:

(a) Whether child had any toys, books or magazines.

(b) Whether child listened to the radio or watched television.

(c) Whether child was taken on trips.

(d) Whether child was told stories or read to.

Table 3.6 Effects of adoption for 6 years or more of female Korean children (Winick et al, 1975). Number of children shown in parentheses

Initial condition

Initial percentiles | for height and weight

Percentiles | at 8+ years height weight

IQ

Malnourished (41)

< 3rd

71.3*

73.9

102*

Moderately nourished (50)

3rd to 24th

76.9

79.9

106

Well-nourished (47)

> 25th

82.8

82.1

112

t Korean standards.

Significantly lower than well-nourished.

Others not significantly different.

and IQ due to malnutrition had disappeared (Table 3.6) and the previously severely and also the marginally malnourished children were achieving exactly the expected standard of American children of the same age and the same grade. These findings in malnourished children from poorer countries are in agreement with those in children in affluent societies who have been malnourished as a result of paediatric disease, where it has been difficult to demonstrate any residual effects on behaviour (Lloyd-Still, 1976). Furthermore, the older the child, the less likely it is that there will be any behavioural deficit.

However, in a recent study in India (Pereira et al, 1979) in which an attempt was made to control for environmental factors by comparing the scholastic performance of survivors of PEM with that of their siblings, the authors

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103

concluded that the poorer performance of the malnourished children argued for a direct effect of PEM on intellectual ability, the supposition being that other factors were controlled in the siblings.

The direct effects of sensory stimulation on brain development have been studied in the rat and other species. These experiments have shown that in young animals an enriched environment with visual and other stimulation results in more advanced brain development (see Dickerson, 1980), including an increase in dendrite arborization (Morgan and Winick, 1980 b).

Lloyd-Still concluded his discussion of the evidence for the effects of malnutrition on behaviour by saying

The evidence suggests that recovery may be related to a combination of adequate nutritional replacement in association with much emotional and psychological support and that this is not only a continuous process but these different parameters also reinforce one another. Thus efforts to alleviate this situation in less fortunate areas of the world require not only nutritional replacement, but more emphasis on improvement in the emotional well-being of the family.

Richardson (1980) concluded his discussion of the problem on a similar note.

As long as it was believed that malnutrition caused mental retardation, it was not unreasonable to try and solve the problem through the single approach of making food available. If our concern is providing children with the best opportunities for the development of their social and intellectual capabilities, then a far more complex net of action is needed.

Only in this way can so many of the world’s children hope to have better prospects than their parents and to stand any chance of breaking out of the vicious circle of the environment in which their lot has been cast.

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Rajalakshmi, R., Ali, S. Z. and Ramakrishnan, C. V. (1967) Effect of inanition during the neonatal period on discrimination learning and brain biochemistry. J. Neurochem., 14, 29-34.

Ramirez de Guglielmone, A. E., Soto, A. M. and Duvilanski, B. H. (1974) Neonatal undernutrition and RNA synthesis in developing rat brain. J. Neurochem., 22, 529-533.

Richardson, S. A. (1976) ‘The influence of severe malnutrition in infancy on the intelligence of children at school age: an ecological perspective’, in Environments as Therapy for Brain Dysfunctions (eds. R. N. Walsh and W. T. Greenough), Plenum, New York, 256-275.

Richardson, S. A. (1980) ‘The long range consequences of malnutrition in infancy: a study of children in Jamaica, West Indies’, in Topics in Paediatrics. 2. Nutrition in Childhood (ed. B. Wharton), Pitman Medical, Tunbridge Wells, 163-176.

Rosso, P., Hormazabal, J. and Winick, M. (1970) Changes in brain weight, cholesterol, phospholipid and DNA content in marasmic children. Amer. J. Clin. Nutr., 23, 1275-1279.

Salas, M., Diaz, S. and Nieto, A. (1974) Effects of neonatal food deprivation on cortical spines and dendritic development of the rat. Brain Res., 73, 139-144.

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Sands, J., Dobbing, J. and Gratrix, C. A. (1979) Cell number and cell size: organ growth and development and the control of catch-up growth in rats. Lancet, ii, 503- 505.

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CHAPTER FOUR

EFFECTS OF HORMONAL AND OTHER FACTORS ON GROWTH AND DEVELOPMENT

BRIAN L. G. MORGAN

Introduction

Various hormones, especially thyroid hormone and growth hormone, are important in the control of normal growth (Zamenhof et al , 1971; Winick, 1976). Optimum growth can occur only when such hormones are at their optimum level. There is some evidence to show that malnutrition impairs brain growth and development via this hormonal system (Monckeberg et al , 1963; Muzzo et al , 1973).

Some infants suffer from inborn errors of metabolism. Such defects involve the enzymes responsible for metabolism of circulating substrates and also the mechanisms for transportation of nutrients into the brain (Pardridge, 1977). If the inability to metabolize a key circulating nutrient lowers its level in the plasma beyond the point when it can satisfy the brain’s needs, or elevates the level to the point of impairing the brain’s uptake of other key nutrients, then the brain’s nutrition will be compromised and continuing growth and development will be impaired. The functional consequences of these inborn errors of metabolism can be extremely debilitating. Inborn errors of metabolism have been discovered concerning phenylalanine (Foiling, 1934), tryptophan (Hsia, 1972), tyrosine (Gentz et al, 1965), valine, isoleucine and leucine (Wiltse and Menkes, 1972), lysine (Fellows and Carson, 1974), proline (Selkoe, 1969), hydroxyproline (Efron et al, 1965), glycine (Hsia et al , 1971), histidine (Wiltse and Menkes, 1972), homocysteine (Gerritsen et al, 1962), cystathionine (Gaitonde, 1970), methionine (Guroff, 1977), arginine (Allan et al, 1958), various carbohydrates (Austin, 1972; Kalckar et al, 1965), and nucleic acid precursors (Nyhan, 1973).

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Much recent evidence has shown that the maternal diet during pregnancy and lactation is critical to normal brain growth and development of the offspring. As shown in an earlier chapter, protein energy malnutrition at this time has devastating effects. However toxic substances such as alcohol (Warren, 1977) and marijuana (Fried, 1976) reaching the foetus via the maternal circulation can also be extremely hazardous to normal brain growth.

This chapter will briefly review the literature in these areas of study.

Thyroid hormones

Neonatal hypothyroidism—animal studies

Animals made hypothyroid in the neonatal period show slow movement, delayed development, low body temperature, thickened skin, abnormal hair and subnormal intelligence (Simpson, 1908,1913,1924a, b).

By 15 days of age a significant reduction in brain growth becomes obvious in hypothyroid rat pups. By contrast, body weights do not become significantly lower until 24 days of age (Eayrs and Taylor, 1951). The reduced brain growth is accompanied by reductions in DNA, RNA and protein in both cerebrum and cerebellum (Faryna et al ., 1972; Gourdon et al ., 1973; Geel and Tamiras, 1967; Balazs et al, 1968). By 21 days postnatally, when normal hyperplasia in the brain ceases, the reduction in cellularity is considerable. However, hypothyroidism, as well as reducing the rate of cell division in brain, extends the time period during which cell division continues to 35 days. Ultimate cell numbers achieved may be even greater than normal (Winick, 1976). However the reductions in protein and RNA are permanent (Gourdon et'cd., 1973).

The neurones in the sensory cortex tend to be smaller and more closely packed than normal (Eayrs and Taylor, 1951). The basal dendritic processes tend to be shorter and show less branching in hypothyroid animals (Horn, 1955). A decrease in the vasculature of the cerebral cortex has also been reported (Eayrs, 1954). However if neonatal ablation of the thyroid gland is followed by treatment with thyroid hormone from day 24 to 60 after birth these organizational changes in the cerebral cortex can be reversed (Horn, 1955).

In the cerebellum there is a delayed migration of the external granular layer, and there is an increase in granule cells over and above normal by day 30. By contrast there is a reduced number of basket cells and an impaired development of astroglial processes. The Purkinje cells show a decreased synaptic content and retarded arborizations. There is also a retarded synaptogenesis in the molecular layer, and the overall pattern of growth in the cerebellum is thus impaired. However, if thyroid hormone is administered to hypothyroid rat pups before the end of the second week of life, many of these changes may be overcome. It is worthy of note that the timetable of cerebellar development may be accelerated

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in mice and rats by administration of thyroid hormone to normal newborn rats (Legrand et al , 1961; Legrand, 1965; Nicholson and Altman, 1972a, b,c; Hajos et al , 1973; Pesetsky, 1973).

Other histological changes in the central nervous system resulting from hypothyroidism are a decrease in the Nissl granules of the cells in the cerebral cortex, cerebellum, medulla and ventral horn of the spinal cord. The spinal cord also shows other characteristic changes. It is lighter and has fewer fibre tracts than normal (Barrnett, 1948).

The effects of hypothyroidism on myelination and on the lipid composition of the brain exceed those induced by malnutrition and are more reversible, i.e. on administration of thyroid hormone (Balazs et al ., 1969; Trojanova and Mourek, 1973). Reductions in the different classes of lipids per cell have been demonstrated in both cerebrum and cerebellum in a number of studies. We see lowered contents of cerebrosides, cholesterol, phospholipids, sphingomyelin and gangli- osides. There is also a reduction in proteolipids in the cerebrum (Balazs et al , 1969; Faryna et al, 1972).

Early studies provided a clue to the biochemical basis of disturbed brain function in hypothyroidism when it was shown that oxygen consumption was as much as 40 % lower in hypothyroid animals (Barrnett, 1948). It has since been- confirmed that thyroidectomy lowers oxygen consumption in both developing and adult brain (Trojanova and Mourek, 1973). Cerebral oxygen consumption in euthyroid rats is low at birth and remains so in the early days of life. The adult level is reached at 45 days of life. If thyroid hormone, T 4 , is given to newborn rat pups it raises oxygen consumption. However after 45 days it has no effect (Fazekas et al, 1951). It has been postulated that T 4 affects protein biosynthesis and so only stimulates oxygen consumption in tissues with a high rate of protein turnover (Sokoloff, 1961). Using liver slices it has been shown that protein biosynthesis is low in hypothyroidism but can be stimulated by addition of T 4 (Du Toit, 1952). Thyroxine administered to normal animals in vivo also increased amino acid incorporation into protein in cell free liver homogenates (Sokoloff and Kaufman, 1961). Other studies have shown that amino acid incorporation into protein is rapid in cell free preparations of infant rat brain in comparison to adult brain (Gelber et al, 1964). However incorporation of amino acids into cerebellar tissue protein during the first three weeks of life has been shown to be slowed considerably by hypothyroidism (Dainat, 1974).

Mitochondria are essential for the incorporation of amino acids into microsomal proteins. Mitochondria from immature rat brains are several times more effective than adult brain tissue in this respect (Klee and Sokoloff, 1964). It seems that the mitochondria interact with T 4 to produce a substance that stimulates the biosynthesis of protein at the step involving the transfer of soluble RNA-bound amino acids to the microsomal protein (Sokoloff et al, 1963; Weiss and Sokoloff, 1963). The mitochondrial fraction can also incorporate amino

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acids into the proteolipid fraction of myelin. Once again this process occurs more readily in young brains than in mature brains (Klee and Sokoloff, 1965).

T 4 also accelerates the incorporation of inorganic 32 P into brain phospholipids. Conversely thyroid deficiency results in a marked decrease in the incorporation of 32 P into this lipid fraction (Myant, 1965). Thus thyroid deficiency inhibits phospholipid synthesis in the brain.

Many enzymes involved in brain metabolism are affected by hypothyroidism. Glutamate decarboxylase, a mitochondrial enzyme in the synaptosomal fraction, has a reduced activity per cell at 17-32 days of life. Lactate dehydrogenase, a supernatant enzyme, is similarly reduced in activity (Balazs et al, 1968). Succinic dehydrogenase activity has been shown to be suppressed in the cerebral cortex, and cholinesterase is also suppressed but to a lesser extent (Van Wynsberghe and Klitgaard, 1973). These enzyme changes do not occur, or are reversed, if thyroid hormone is administered by the tenth day of life.

Enzymes involved in fat synthesis are similarly affected. Fatty acid synthetase, which is involved in the formation of fatty acids such as palmitate from acetyl Co-A, malonyl Co-A and reduced nicotinamide adenine dinucleotide phosphate, is reduced in activity by about 45 % in the young hypothyroid rat (Volpe and Kishimoto, 1972). In control animals this enzyme is most active in the brains of foetuses and young animals as it is concerned with the early appearance and continuous turnover of phospholipids in cell membranes (Volpe et al , 1973). The activity of galactocerebroside sulfatransferase, which is important in the process of myelination, is also reduced in hypothyroidism; this time by about one-third (Walravens and Chase, 1969; Mantzos et al, 1973).

Hypothyroidism and behaviour

Hypothyroidism in the newborn delays the appearance of behavioural characteristics such as eye opening and acquisition of righting and placing reflexes (Van Wynsberghe and Klitgaard, 1973). More complex adaptive behavioural manifestations, for example maze learning and performance in an escape avoidance situation in aversion to an adverse stimulus (Eayrs, 1971) using an auditory conditioning stimulus, are also impaired. Most of these learning deficiencies may be reversed with thyroid replacement therapy even if it is given late. However some deficiencies persist unless replacement therapy is given before the tenth day of life. One such test where this is true is the Hebb-Williams closed field test (Dodge et al, 1975).

Hypothyroidism in primates

A few studies have been conducted on the effects of prenatal hypothyroidism in primates on development of the CNS. They have shown that hypothyroidism

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gives rise to considerable reductions in the non-chloride space, protein and non-protein solids, RNA, cholesterol, NeuNAC, sodium, potassium, ATPase and carbonic anhydrase in both the cerebrum and cerebellum, but no change in DNA content of either area of the brain was found (Kerr et al , 1972; Holt et al, 1973).

Hypothyroidism ( cretinism ) in children

Most studies of hypothyroidism or cretinism in children have used a population suspected of contracting the disorder in very early life or during the foetal period. Unfortunately the early diagnosis of hypothyroidism is often missed in these children because of their rather nondescript symptoms such as lethargy, constipation and feeding problems (Raid and Newas, 1971). Neonatal jaundice, enlarged tongue and umbilical hernias are also found in a large number of cases. If a case is suspected, confirming evidence may be obtained from observations on their osseous development. Bone age of cretins in early postnatal life often approximates osseous development of normal foetuses of 7-9 months of age (Caffey, 1950; Anderson, 1961).

Cretins can show a variety of characteristics, namely low IQ, spasticity, a shuffling gait, uncoordination, awkwardness, jerky movements and a coarse tremor. On the other hand, those with mild cretinism may not show these signs (Money, 1956).

If the abnormalities are to be reversed in the young child they must be recognized at an early age and treated with thyroid hormone. In one carefully conducted study it was shown that when treatment was initiated before the end of the third month of life almost all cretins could be improved to such an extent that their psychometric testing scores exceeded 90. By contrast, when treatment was not started until after three months many children had scores below 90 (Raid and Newas, 1971).

In another study it was shown that if replacement therapy began after one year of age there was little hope of raising the IQ over 90. On the other hand if treatment was begun before six months of age it was shown that as many as 45 % of all children in the study achieved an IQ in excess of 90. As one would expect, children given therapy between the ages of seven months and one year were apt to give results intermediate between the two extremes cited here (Smith et al , 1957).

If the hypothyroidism was contracted at a later age (after six months of age) as many as 41 % achieved IQ’s better than 90. Only a small percentage fell into the uneducable group with IQ’s of less than 50. If the hypothyroidism arose after 13 years the prognosis was even better. By this time the brain has developed and any neurological effects of myxodema exhibited are reversible.

In patients that are deprived of early treatment the prognosis for normal

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brain and neurological development is undoubtedly the poorest. However, even those cases caught immediately after birth and treated at that time show impaired development because of the damage sustained in utero (Wilkins, 1962). In early foetal life thyroxine crosses the placenta. Hence in the event of reduced maternal T 4 production or placental transport of the same the growth of the foetus could be compromised (Man et al ., 1963).

After the first trimester of pregnancy the foetus is able to make thyroid hormone. How important the foetal T 4 is in comparison to that arising in the mother is not clear (Hodges et al , 1955; French and Van Wyk, 1964). In the beagle we know that four times as much T 4 is transported from foetus to mother as vice versa (Beierwaltes and Mato vino vie, 1963). In this case most maternal T 4 is bound to protein and not available for placental transport. On the other hand, foetal T 4 binds less readily to protein and so tends to flow to the mother more easily (French and Van Wyk, 1964). However, the placenta does have the capacity to transport large doses of administered triiodothyronine (Raiti et al ., 1967). The administration of T 4 to mothers who have a history of giving birth to cretins seems to produce children with less severe cretinism which might be indicative of placental transportation (Bacon et al ., 1967) of administered T 4 . Unfortunately the maternal pituitary is unresponsive to foetal needs. Hence if the foetal thyroid secretes little T 4 the maternal thyroid does not respond by secreting more of the same (Dodge et al ., 1975).

Antithyroid agents like propylthiouracil affect both maternal and foetal thyroid glands. Similarly iodine deficiency in the maternal diet also impairs thyroid function in mother and offspring (Lotmar, 1933). Protein-bound iodine in cretins is as low as 0.2 mg/100 ml (Beierwaltes et al, 1959).

The neurological pathology in these children is much the same as that already described for experimental animals. We see a 50% reduction in total brain size. The cerebellum is smaller in size and has small gyri and prominent sulci. The cerebrum has ill-differentiated cortical layers and shows degenerative changes. The pyramidal tracts, basal ganglia and thalamus also appear to be reduced in size. The nerve cell population is greatly reduced and myelination seems somewhat impaired (Lotmar, 1933; Beierwaltes et al ., 1959; Adams and Rosman, 1971).

Hyperthyroidism

There is a danger in administering thyroid hormone to mothers with a history of giving birth to cretins in that hyperthyroidism can be induced (Raiti and Newas, 1971). In animals (Koldros, 1968) excessive doses of T 4 may lead to early maturation of certain developmental processes in the brain (Hamburgh, 1968), but the brain growth and body growth achieved by maturity are stunted (Nicholson and Altman, 1912a,b,c; Pelton and Bass, 1973). Both the cerebrum

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and cerebellum are characterized by having reduced cell numbers, neural processes and myelin. Synaptogenesis is accelerated early on but by 21 days of life we see a reduced synaptic complement (Gourdon et al., 1973). The effect of T 4 and T 3 administration in early life has a similar effect on behaviour. Whereas young animals have an accelerated behavioural and electroencephalographic maturation (Schapiro and Norman, 1967), at maturity their learning ability seems to be significantly impaired (Eayrs, 1964).

Other hormones

Corticosteroids and brain growth

Hormones other than thyroid hormone have a profound influence on brain growth and development. Cortisone given to young mice or rats during the first few days of life impairs somatic and brain growth. In 1965, Howard demonstrated a 35% decrease in forebrain growth in mice treated with cortisone during days 2—7 of life. He reported that during the time when the mice were receiving the treatment DNA production ceased altogether but RNA continued to be produced at a lower rate than normal. He also reported impaired cholesterol synthesis (Howard, 1965).

Other workers (Balazs, 1971; Cotterall et al, 1972) found similar results in the rat. Again administration of corticosteroid during the first four days of life adversely affected the accumulation of DNA in the cerebrum and cerebellum. So profound was the effect that the accumulation of DNA was reduced by 90 % in the cerebrum and 70% in the cerebellum. Following cessation of treatment on the fifth day of life, DNA accretion speeded up to normal rates but at day 35 the cerebrum and cerebellum still had 20 % and 30 % fewer cells respectively than control animals. It was further shown that the incorporation of 14 C thymidine into brain tissue was significantly impaired when the cortisol was given. Later on, when cortisol treatment was stopped, mitotic activity increased; perhaps in an attempt to compensate for any deficiency in cell number. In contrast to Howard’s experiment (Howard, 1965) this study showed that protein /DNA and RNA/DNA ratios were not altered by corticosteroid treatment.

We are still not clear as to how cortisol brings about this impediment to growth. The only clue we have comes from a study in which hydrocortisone was given to ten-day-old mice. This resulted in elevated levels of brain glucose. It was postulated that this might indicate a facilitation of brain glucose uptake or an impaired glucose utilization. Perhaps these high glucose concentrations affect growth in some way as yet poorly understood (Thurston and Pierce, 1969). A reduction in brain growth is also invoked by administration of oestradiol, de- hydroepiandrosterone and testosterone (Howard, 1965).

Rats given cortisol in early life show definite behavioural changes. For

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instance disturbed swimming has been reported (Schapiro et al ., 1970). However, other behaviour seems unaffected such as adaptive behaviour (Howard and Granoff, 1968). Children given corticosteroids early in life show definite behavioural effects (Dodge et al ., 1976).

Growth hormone

Growth hormone deficiency reduces the rate of cell division without altering the time at which the cells divide (Winick, 1976). However, growth hormone only seems to have an effect on growth at certain periods during the animal’s development. Mice genetically devoid of growth hormone show normal organ growth until 10 days of life; at which time the rate of cell division slows down in comparison to that characteristic of control mice and growth stunting occurs (Fig. 4.1). It would thus appear that early hyperplastic growth is independent of the effects of growth hormone (Winick and Grant, 1968).

Rats hypophysectomized at 21 days of age and fed ad libitum were shown to have reduced cerebral weight as well as DNA, RNA and protein contents at both 38 and 49 days of life. When growth hormone was administered during the

Figure 4.1 Growth of hypopituitary dwarf mice and their normal littermates. After 12 days of life the dwarf mice are shown to suffer from growth retardation. Before that time growth, as measured by body weight, was the same in the two groups (from Winick, 1976, with permission).

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experimental period of 21-49 days these defects were partially corrected. But cytoplasm to nucleus ratios remained low as did the RNA levels (Cheek and Graystone, 1969). Hypophysectomy at a later stage in a different experiment did not affect brain weights or protein contents but incorporation of phenylalanine was significantly reduced (Takahashi et al, 1970). This again could not be completely restored by growth hormone therapy. It has been postulated that the effect of growth hormone on DNA synthesis may be explained by the fact that it elevates DNA polymerase activity (Jasper and Brasel, 1973).

Insulin

Insulin given daily to rats hypophysectomized at 21 days of life also had a profound effect on brain growth. At 38 and 49 days of life brain RNA levels were found to be higher than in untreated rats but DNA levels were not affected (Cheek and Graystone, 1969). However, in a further study it was shown that insulin can inhibit growth. Here, when protamine zinc insulin was given to intact rats fed ad libitum from 26-38 days of age, there was an extra whole body weight gain but cerebral weights, water and DNA and RNA contents were all significantly reduced. It was hypothesized that the hypoglycemia induced by the insulin damaged or inhibited cerebral growth in some way (Graystone and Cheek, 1969).

Nerve growth factor ( NGF)

Nerve growth factor was first demonstrated to exist in 1953 when it was shown that a heat labile non-dialyzable nucleoprotein in the microsomal fraction of neoplastic cells caused increased growth of the sympathetic nervous system of experimental animals (Levi-Montalcini and Hamburger, 1953). Winick and Greenberg later demonstrated its presence in the developing human foetus from 9-16 weeks of gestation (Winick and Greenberg, 1965a, b). Whether or not it has a role in the normal growth and development of the brain has yet to be discerned. However, anabolic metabolic processes are enhanced by NGF including RNA, protein and lipid synthesis (Levi-Montalcini and Angoletti, 1968). It causes increased incorporation of glucose into brain gangliosides (Graves et al ., 1969). It has also been shown to stimulate the production of axonal sprouts from injured monamine neurones (Bjerre et al , 1973).

Environment—hormones and behaviour

Behaviour in experimental animals and in children can be modified by environmental stimulation during the period of their brain development and to a lesser extent at a later time. Such effects are accompanied by changes in

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neurochemistry which are possibly mediated by changes in hormonal levels (Winick et al , 1975; My Lien et al ., 1977; Morgan and Winick, 1980).

When infant rats are exposed to the cold the corticosteroid content of their adrenal gland decreases in response to the cold. However, if such animals are regularly handled this depletion is accelerated. The earlier the rats are handled the greater the rate of corticosteroid loss. Handled animals are more responsive to the effects of ACTH leading to the secretion of larger quantities of corticosteroid than in the non-handled rats. Exposure to high steroid levels in early life seems to lead to altered adrenal function in the adult which in turn affects behaviour. Hence here is an example of early stimulation affecting the secretion of a hormone which in turn permanently alters behaviour, perhaps by inhibiting DNA synthesis (Levine et al ., 1958; Levine and Mullins, 1968).

Toxic substances

Foetal alcohol syndrome

In historical documents there are many references to the fact that alcoholic mothers often gave birth to infants with malformations (Warner and Rosett, 1975). In more recent times Lemoine and co-workers (1968) from France and Jones, Smith and co-workers (1973) of the United States have carefully characterized these defects termed “foetal alcohol syndrome” (FAS). The congenital defects usually exhibited by such children include growth retardation, small head size, mental and psychomotor retardation, craniofacial peculiarities and cardiovascular defects. Other defects include anomalies of the joints and genitalia, micrognathia, epicanthic folds, hypoplastic midfacial structures such as a broad nasal ridge, upturned nares, long upper lip, small palpebral fissures, abnormalities of the ears, drooping of the eyelids (ptosis) and crossed- eyedness (strabismus), wide mouth, narrow bifrontal diameter, cleft palate, visceral anomalies and small hemangiomas (Hanson et al ., 1976; Oulette et al ., 1977; Clarren and Smith, 1978). Figure 4.2 shows several children suffering from some of these defects. It seems that if a woman consumes more than 2 grams of alcohol per kilogram body weight per day during gestation then her offspring will suffer from the full FAS and will exhibit most of the above congenital malformations. However, nobody has as yet been able to determine exactly how much alcohol a woman can consume during pregnancy without causing deleterious effects to her unborn child. Further, whether binge drinking or a steady consumption has the more harmful effects is also an unsolved problem.

Infants exposed to alcohol in the prenatal period show growth failure at the time of exposure as well as postnatally. This tends to be disproportionate with body length being affected more than body weight. Many children die in the perinatal period and those that live tend to show profound neurological

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difficulties. This is often characterized by tremulousness, hyperactivity and irritability in the immediate postnatal period. To some extent these symptoms are due to alcohol withdrawal but the tremulousness often persists beyond the usual withdrawal period and often the children are left with a permanent fine motor dysfunction (Hurley, 1980). As we have seen in Chapter 2, brain growth is time dependent and hence the reduced brain growth in these children, where brain development is impaired in litero, is permanent.

As there are many similarities between offspring that have been nutritionally deprived in litero and offspring that have been exposed to alcohol in litero it has been postulated that malnutrition is the underlying cause of FAS (Chernoff, 1977; Randall, 1977; Randall et al ., 1977). This is supported by the fact that alcoholics all suffer from primary undernutrition. However, Jones hotly disputes this scenario and maintains that FAS and malnutrition are unrelated (Jones and Smith, 1976).

Figure 4.2 Facial features of boy with FAS at birth (top left) and at 6 months (top right). Girl with FAS at 16 months (bottom left) and 4 years (bottom right) (from Hanson et al., 1976, with permission).

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Children suffering from FAS have permanent somatic and brain growth stunting as well as alterations in brain function secondary to this impaired growth. There are few long-term follow-up studies of children exposed to early malnutrition which makes comparisons difficult. However, it seems from the results of animal and human studies at our disposal that if a mother is given adequate calories but insufficient protein during gestation, the offspring show similar characteristics to FAS sufferers. Once again, we see long-term growth retardation, behavioural and intellectual abnormalities and neurochemical alterations (Hsueh et al , 1967; Kenney and Burton, 1975). Thus these observations fail to support the view that the retarded growth in FAS and undernutrition have a different etiology.

The specific nutrient deficiencies characteristic of alcoholics are vitamin A (Smith and Lindebaum, 1974), folic acid (Halstead et al , 1967), zinc (McBean et al , 1972) and magnesium (Hurley, 1980). All of these have teratogenic effects which are similar to the effects of prenatal alcohol exposure.

Vitamin A deficiency during pregnancy causes the same kind of defects seen in animal models of FAS. Characteristically we see ocular, cardiovascular, and urethral anomalies (Wilson et al , 1953). Folic acid deficiency at this time also causes the same kind of urogenital abnormalities (Gross et al, 1974).

Zinc deficiency during pregnancy leads to congenital anomalies similar to those seen in FAS. Such deficiencies severely retard cerebellar development in experimental animals (Fosmire et al, 1977). The same kind of cerebellar abnormalities have been described in rats exposed to alcohol during infancy (Bauer-Moffett and Altman, 1975) which supports the concept of nutrient deficiency being the cause of this impaired neural development rather than the effect of alcohol itself. Another way in which this effect on neural development could be mediated is via vitamin A, as zinc is intimately involved in retinol metabolism (Smith et al, 1973).

Finally, magnesium deficiency during pregnancy in the rat leads to decreased maternal weight gain and reduced food intake. If the deficiency occurs during the period 5-12 days of gestation there is a high neonatal mortality and degree of abnormal brain histology. Those offspring that survive have a high incidence of cleft lip, short tongue, hydrocephalus, micrognathia, agnathia, club feet, herniations and heart and lung teratogenital anomalies (Hurley et al, 1976).

All of these observations tend to link the effects of alcohol on foetal growth and development to malnutrition. However, it is possible that there is an alternative explanation. Alcohol could have a direct effect on the foetal tissues. It is readily transported by the placenta and there is a direct correlation between the levels of alcohol in the maternal and foetal circulations (Mann et al, 1975). Alternatively chronic alcoholism could affect maternal metabolism in some way which in turn could have a teratogenic effect (Hurley, 1980).

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Cannabis and development

With the increasing popularity of the use of marijuana amongst young women of child-bearing age, many studies have been designed to investigate the possible effects of cannabis and its constituents on foetal growth and development (Bonnerjee et al., 1975; Joneja, 1976; Wright et al, 1976).

Marijuana and its derivatives have been shown to freely cross the placenta in experimental animals and depending on the dose level and method of administration have various teratogenic effects on the developing foetus (Abel, 1980). It would seem that low doses of cannabinoids have little discernible effect (Haley et al , 1973; Keplinger et al, 1974). Similarly chronic high doses given before and/or throughout gestation have little effect on the growing foetus. This is believed to be due to either altered maternal distribution (Mantilla-Plata et al.,

1975) , masking (Joneja, 1976), or acquisition of a physiological tolerance mechanism (Fried, 1977). Prenatal deaths and congenital abnormalities do, however, occur if high doses of cannabinoids are administered during discrete periods of gestation, Further, the foetus is more susceptible in early gestation (Pessoud and Ellington, 1967; Harbison and Mantilla-Plata, 1972) than in late (Gianutsos and Abbatiello, 1972). Low to moderate doses of cannabinoids given throughout gestation or during critical periods of development, e.g. organogenesis, result in subtle developmental changes but no gross prenatal effects. The usual outward manifestations of moderate exposure are a reduced physical growth and a delayed ontogenetic appearance of such physiological features as incisor eruption, eye opening and visual placing (Borgen et al, 1973; Fried,

1976) , hyperactivity (Borgen et al , 1973), hypoactivity (Fried, 1976) and inferior maze learning (Gianutsos and Abbatiello, 1972).

Certain developmental changes have also been observed in children exposed to cannabis in utero at moderate to heavy doses. Once again, the human foetus seems to be more susceptible in early pregnancy. Such children have an elevated auditory threshold which persists for 6 weeks postnatally (Fried, 1980). Others have reported distal limb teratology (Hecht et al, 1968; Carakushansky et al, 1969). However, in the latter studies, the women were suspected of being multiple drug users which makes it difficult to discern whether the marijuana or some other drug was responsible for the abnormalities.

Many of the developmental consequences associated with prenatal exposure to cannabinoids are shared by offspring from mothers which have been malnourished during gestation (Chow and Lee, 1964; Barnes, 1966; Smart and Dobbing, 1971; Whatson et al, 1978). Malnutrition also potentiates the effects of marijuana on rat pups. When rat dams are exposed to marijuana and fed a low-protein diet during gestation the developmental defects in the offspring are far greater than if dams are fed a high-protein diet at this time. Fried suggests that perhaps the protein content of the diet determines the ability of the dam to

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detoxify the drug (Fried, 1980). This observation could be of great practical importance in the human situation.

Smoking

It is well known that mothers who smoke during pregnancy are significantly more likely to give birth to premature and short-for-dates (SFD) babies (Miller et al , 1978). The effect is thought to be mostly due to hypoxia, but may also be due to reduced maternal supply of amino acids to the foetus. It used to be considered that smoking was not teratogenic, but more recent studies by Himmelberger et al (1978) have suggested that children of smokers are more likely to have all types of congenital abnormalities, including those of the central nervous system. Long-term studies of smokers’ children have shown deficiencies in growth, general intellectual ability, reading age and mathematical ability (Butler and Goldstein, 1973) and in emotional development. It has also been reported that neurological abnormalities, including cerebral dysfunction, abnormal electroencephalograms, impaired auditory tests, squints and hyperactivity, are more common in children of heavy smokers compared with those of non-smokers (Denson et al ., 1975).

Drugs

A number of drugs increase the requirement for specific nutrients and therefore if taken during pregnancy may divert these nutrients away from the foetus. This situation is unlikely to affect the foetus except in circumstances when the intake of the nutrient is already barely adequate. We have already seen that the foetal alcohol syndrome may be due to this mechanism. Anti-convulsant drugs, particularly dilantin and phenobarbitone, induce biochemical evidence of folate deficiency when the diet contains a barely adequate amount of the vitamin, possibly due to induction of drug-metabolizing enzymes (Labadarios et a/., 1978). There is evidence that pregnant women taking anti-convulsant drugs have a greater than normal likelihood of giving birth to a malformed baby. Experiments in rats on a folate-deficient diet resulted in the production of foetuses with neural tube defects and hydrocephalus (Labadarios, 1975).

Congenital malformations of the central nervous systems associated with hormone treatment were first reported by Gal et al (1967) in babies born to mothers who had hormonal pregnancy tests.

Lead

Lead is a neurotoxin and much of the debate about the possible dangers of contemporary lead burdens centres on the possibility that these may produce adverse effects on behaviour and intelligence. It is clearly not possible to debate

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this delicate issue here but it is a matter of potential concern to all those interested in brain development. Lead is trapped in the teeth and skeleton and it might therefore be considered that analysis of dentine and bone would give a better measure of exposure to lead, thus measuring blood levels. Bryce-Smith et al (1977) reported that stillbirth bones contained a higher concentration of lead than those of apparently normal neonates. It was significant that in those stillbirths with malformations of the central nervous system (hydrocephalus, spina bifida, etc.) there was an excess of lead and cadmium with respect to calcium.

Obvious malformations are apparently not the only neural damage associated with a high body burden of lead. More subtle defects may become apparent after birth in those exposed to lead in utero. This is a crucial question on which there is at present no information. It has, however, been reported (Bryce-Smith, 1979) that mentally retarded children tend to have higher blood lead levels than controls, and hyperactivity associated with high blood lead levels improves when the levels are reduced with penicillamine.

Neurologic manifestations of lead intoxication can be produced in suckling rats by feeding lead in the diet of the lactating mother (Pentschew and Garro, 1966). The concentration of lead in the brains of young rats first exposed to the mineral in the mother’s milk and then in the diet are dose-related and significantly higher at each dose level than in the mother (Table 4.1). This difference in brain lead concentration accounts for the fact that rats at 21-35 days of age showed neurological evidence of lead intoxication whereas their mothers did not. It was of interest that the brain lead concentration in these young animals remained high in spite of a fall in the blood lead concentration with increasing age. This suggests that blood lead concentration in young children may be a poor guide to the tissue concentrations. It is also of interest that the young rats showed evidence of abnormal behaviour including a degree of hyperactivity (Mykkanen, 1977).

Table 4.1 Effect of age on the concentration of lead in the brain of rats exposed to diets containing different concentrations of lead acetate (Mykkanen et al, 1979)

Concentration of lead acetate Aqe in the diet (a1100 q )

{days) 0 0.5 1.0 2.0

7

0.15

0.36

_

0.60

21

0.11

1.27

2.55

2.92

35

0.20

1.24

2.55

4.07

49

0.20

•1.22

2.23

3.01

Dam

0.22

0.49

0.91

1.69

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Conclusions

Normal growth and development of the brain depends on the interaction and balance of a large number of factors both endogenous and exogenous. Some of the effects of hormonal deficiencies and excesses are similar to those resulting from malnutrition (Chapter 3) and it may be that the effects of the latter are normally mediated by hormones. In addition, the brain is particularly sensitive to potentially toxic substances, some of which (alcohol, cannabis and tobacco) may be considered ‘social poisons’, whilst others, such as lead, are environmental pollutants. Thus the milieu in which the brain grows must be protected from all these as well as being supplied with adequate nutrients and stimulation if it is to reach its true potential. Failure in respect of the factors reviewed in this chapter may have more dire consequences than protein-energy malnutrition.

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CHAPTER FIVE

CORTICAL ACTIVITY IN BEHAVIOURAL DEVELOPMENT

CHERRY THOMPSON

Introduction

The human electroencephalogram (EEG) can be recorded from scalp electrodes and provides a very easy and safe technique for monitoring brain function. Because of the complexity of the neural events within the brain, and because of the great distance away of the recording electrodes, the precise relation between the EEG and brain activity is not known. It is generally believed that the EEG reflects the summation of the excitatory and inhibitory postsynaptic potentials within the dendritic networks of the superficial layers of the cortex, which in turn reflect the probability of neural activation (Creutzfeldt et al , 1966; Creutzfeldt and Kuhnt, 1967; John and Morgades, 1969). The patterns of EEG activity reflect the ongoing bioelectrical events within the cortex and change consistently with different levels of arousal or gross tonic activation, from coma through varying depths of sleep, drowsiness, alertness and to an excited and agitated state. Predictable changes occur in the EEG when psychoactive drugs, toxic chemical and other agencies affect brain function and behaviour. Although some studies have found specific and localized changes in the background EEG that relate to more selective and focused aspects of behaviour, such as attention and perceptual and cognitive activities (Sutton, 1969; Buchsbaum and Fedio, 1970; Sandler and Schwartz, 1971) in general the EEG is reputed to more consistently reflect general, unspecific behaviour states with similar changes in the patterns of electrical activity occurring over large areas of the head.

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Single spike

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divided into different frequency ranges.

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The most noticeable feature of the human EEG is that it contains well organized rhythmic waves which vary in frequency from less than 1 c/sec up to approximately 30 c/sec. The frequencies present in the EEG and the temporal and spatial patterning depend on the age of the subject and his behaviour, and for descriptive and analytical purposes the range of electrical brain activity recordable from the scalp is divided into various frequency bands which over many years of research have been found to have functional and clinical significance (Fig. 5.1). The slowest frequencies seen in the EEG are termed delta rhythms and vary from less than 1 to 3 c/sec. Slightly faster waves between 4 and 7 c/sec lie within the theta frequency band. The alpha rhythm (8 to 13 c/sec) is the most prominent activity that can be recorded from an alert adult, and the highest amplitudes are seen posteriorly over the occipital lobes when the eyes are closed and the individual relaxed. This rhythm was the first to be recorded through the intact skull of man and recognized as electrical brain activity by Hans Berger in 1929. Also present in an alert individual and particularly prominent over the frontal lobes are the much lower voltage fastest frequencies of the EEG, the beta rhythms, which vary between 14 and about 22 c/sec. Throughout life the healthy brain produces a continuous pattern of rhythmic waves which vary in amplitude between 15 and 150 juV. There is a constant daily cycle of changing EEG frequencies which slow during drowsiness and sleep, when theta and delta activity are predominant, while during wakefulness the faster alpha and beta rhythms are recorded. High voltage (greater than 50/iV) beta waves which are faster than 22 c/sec may be recorded, and these are usually associated with either drug effects or one of several clinical conditions. Paroxysmal, high voltage, slow activity and fast sharp transients or spikes are not recorded from a normal brain (Hill and Parr, 1963; Kooi, 1971).

EEG recordings contain a vast amount of information and there is no doubt that the standard procedures of analysis, dividing the EEG into frequency domains, provide a very crude method for quantification of the data. Subtle moment-to-moment changes in the EEG activity, and patterns of changing relationships between the left and right hemispheres and between the various regions of one hemisphere which may relate to more complex cognitive behaviours are frequently ignored, particularly outside the carefully controlled laboratory environment.

There is one other analytical technique that is now universally used which enables the recording of very small evoked potentials generated in specific cortical areas by sensory and voluntary motor events. These potentials are usually buried in the higher voltage activity of the background EEG and can only rarely be recognized by eye. By repetitively evoking, for example, sensory potentials, and sampling and storing the EEG activity in a computer during the sensory stimulation, the small cortical evoked potentials (which are time locked to the stimuli) add together, while the random appearance of positive and

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negative phases of the background EEG tend to sum to zero. Thus the signal-to-noise ratio of the evoked potentials relative to the EEG is enhanced by a factor which varies in practice from approximately 2 :1 to 4 :1 (Perry and Childers, 1969).

There is one great drawback in this technique of recording evoked potentials— it is necessary to present stimuli or elicit movements a large number of times at random or regular intervals. Evolution has designed a brain which reduces the effectiveness of such repetitive redundant information, and Brazier (1964, 1969) points out that hidden within the recording of an evoked potential is a trend of change, with both central and peripheral habituation. Non-directional variability which may be significant is also lost during a recording. This is of great concern to researchers attempting to build an electrophysiological model which reflects complex perceptual and cognitive behaviours, and careful experimental design can only partly surmount the problem.

Given these broad limitations to the electrophysiological recording of brain activity, nevertheless EEGs and evoked potentials do vary consistently with many changes in brain function that are known to occur, for example, during maturation, ageing and pathological processes. Thus they can provide a useful and reliable sign of certain brain functions. Secondly, information can be obtained about some of the functions of the brain with little or no cooperation on the part of the subject. This means that electrophysiology can provide a unique monitor in young babies and infants where the behavioural repertoire is stereotyped and limited and a lot of the time is spent asleep. The EEG can record maturing patterns of brain activity, emerging cycles of sleep and activity and responsivity to stimulation without interfering with the ongoing processes and thus provide one important view of the changing functions of the cortex in the developing infant.

The EEG in the young premature infant

It is not precisely known when the first signs of electrical activity can be recorded from scalp electrodes, as EEG monitoring of the human foetus is not possible in utero , and records have to be made on very early premature babies before and after they are viable. Reports of the earliest EEGs suggest that very short, disorganized bursts of activity followed by long periods of complete electrical silence can be recorded between 20 and 22 weeks gestational age (Engel, 1964; Robinson and Tizard, 1966; Ellingson et al , 1974). A typical recording from a 27-week gestational age baby is seen in Fig. 5.2. It is not certain whether such activity originates within the cortex (although most researchers imply that it does) since slow ill-defined bursts of electrical activity can also be recorded from hydrancephalic children who have no cortical tissue, and the electrical changes in these cases are presumably emanating from deeper

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iO/v-

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Figure 5.2 The EEG of a 27-week gestational age baby showing a pattern of irregular bursts of brain wave activity interspersed with periods of electrical silence. Redrawn from Lairy (1975).

brain structures. However, the patterns of total electrical suppression followed by brief bursts of activity are characteristic of the immature cortex as well as other brain structures and have been recorded intracortically in animals, where single cells also follow a pattern of very short bursts of firing followed by long periods of silence (Parmelee et al ., 1969). The electrical cellular events including spike generation are very slow and rapidly fatigued. Thus the primitive process of electrogenesis, which appears very different from a fully differentiated neurone, cannot sustain a repetitive response.

These silent periods in the EEG are never seen in the full term infant nor at any other time of life except when the brain is very close to death, and in the case of the early premature infant reflect the enormous immaturity of the neurones and neural connections within the telencephalon. The brain stem structures are already mature and producing continuous electrical activity (Bergstrom, 1969) while in the cortex the neuroblasts are still dividing and do not reach their full number until the conceptual age of 1\ months. Neural connections have hardly begun and any possible neural activity must be extremely limited (Scheibel and Scheibel, 1971).

One of the most significant features in the early stages of the maturing EEG is that the bursts of irregular electrical activity gradually increase in duration

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while the periods of silence shorten, paralleling very closely the electrogenesis and early differentiation of the cortical neurones (Schulte et al ., 1972). Between 24 and 27 weeks no EEG activity may be recorded for periods varying from 5 to 10 seconds up to as long as 2 to 3 minutes, and silences of longer than 20 seconds are the usual pattern (Kooi, 1971; Parmelee and Stern, 1972; Ellingson et al , 1974). At this time the activity of the cortex shows none of the features that are characteristic of a fully functioning brain. The electrical activity is of very high voltage (300 fiV) possibly due to the low electrical impedance of the skull and tissues surrounding the brain as well as the large immature potentials generated within single neurones. There are diffuse spike transients which later disappear and have no pathological significance as they do in a more mature brain. The brain wave patterns are disorganized in time and multifocal in location on the scalp with no synchrony between the hemispheres. The waves being generated are within the delta frequencies and are extremely slow, varying between 0.3 and 1 c/sec. There is no sustained rhythmic activity, neither are there any consistent changes with time to herald the beginnings of physiological periodicity, nor is there any change in the EEG in relation to arousal, movement or behaviour. The electrical activity is random, irregular, unresponsive and dissociated (Nolte and Haas, 1978). At this time movement is almost continuous and localized to the extremities of the arms and legs, and eye movements are sparse and ungrouped. Heart rate and respiration are also highly variable and random showing no consistent patterns from time to time (Parmelee and Stern, 1972).

So at this early stage in gestation the immaturity of electrophysiological parameters is apparent. Electrical activity cannot be sustained in the cortex for more than a few seconds, and at a time before intracortical connections have begun to form, the random activity from the various scalp regions is unrelated. Associations between subcortical activating systems and the cortex are yet to develop and there is no arousal response in the EEG or in any of the other electrophysiological parameters. This is associated with a failure of the young premature to produce a behavioural response to stimulation.

Surprisingly, at this stage in development sensory evoked potentials have been recorded from the cortex. Between 24 and 26 weeks, flashed lights and electrical stimulation of the median nerve of the wrist will evoke very localized responses which are confined to a small region over the primary visual and somatosensory projection areas. Later in development the potentials become far more widespread (Robinson and Tizard, 1966; Hrbek et al ., 1973). Auditory evoked potentials have been recorded a little later (between 25 and 27 weeks after conception) and they show a different pattern of distribution, being widespread throughout the scalp, but again with higher amplitudes over the primary projection areas of the temporal lobes (Weitzman and Graziani, 1968; Lairy, 1975). This distribution pattern gradually changes as the cortical mass increases

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in size and begins to fold, deepening the fissures and overlaying some cortical tissue with more superficial layers. In the temporal lobe the primary auditory areas disappear from view during the first year of life, to become buried deep within the lateral fissure, and the electrical activity from this area becomes inaccessible to scalp electrodes. An auditory evoked potential cannot be recorded from temporal regions once the enfolding process is well advanced and instead a large unspecific vertex response is obtained from the top of the scalp. The vertex potential varies consistently with perceptual changes but the neural connection of this location with the primary auditory pathways is not understood (Gibson, 1976).

A feature seen only in the young premature baby is that no matter what the modality of stimulation the form of the evoked potential is the same. A very large, simple, slow negative potential is evoked some 270 to 300 msec after the receptors have been stimulated. This long delay must in part reflect the immaturity of the peripheral receptors and slow nerve conduction velocities, which at 25 weeks are only 12 metres per second (Thomas and Lambert, 1960), as well as the slow rise times and decay rates of the excitatory and inhibitory postsynaptic potentials of the primitive cortical neurones (Purpura, 1971). The fact that cortical evoked potentials are recordable at all in such an immature brain is remarkable although there is always the problem that the young brain is easily fatigued and cannot respond repetitively. Evoked potentials are frequently not recorded, and the receptors have to be stimulated at a very slow rate compared with children and adults. Stimulation rates have to be longer than once every five seconds (Ellingson, 1960) and Umesaki and Morrell (1970) reported that no response could be obtained unless the interstimulus interval was longer than 10 seconds.

The formation of cortical evoked potentials appears to indicate that there must be some rudimentary connections between specific projection systems and the primary sensory cortical areas by the 24th to 27th week after conception. The shape of the evoked potential and the intracellular results from animals suggest that the connections are probably axodendritic within the limited network of layer 1 of the cortex (Adinolfi, 1971). The simple slow negative potential is the characteristic early response in all developing mammalian brains and closely reflects the cellular behaviour within the primary areas where sensory stimulation produces delayed, large amplitude excitatory postsynaptic potentials with slow rise times and prolonged fall times, and which result in only one axon spike or at the most two spikes (Purpura, 1971).

The middle months of the premature infant

From 32 weeks conceptual age until full term the greatest changes in the EEG occur, and the most noticeable feature is the gradual disappearance of the silent

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Figure 5.3 The EEG of a 30-week gestational age baby. (A) EEG at one day of age. (B) EEG at 8 days of age. Redrawn from Himwich and Himwich (1964).

periods when no electrical activity is recorded. This feature is clearly seen (Fig. 5.3) in the EEGs of a ‘normal’ premature baby at 30 and 31 weeks gestational age. Lairy (1975) suggested that the EEG becomes more or less continuous at 28 weeks conceptual age, and significantly this is associated with the time when the infant first becomes viable. Others place this significant EEG milestone a little later, between 30 and 32 weeks (Robinson and Tizard, 1966; Parmelee et al , 1968; Reisen, 1971; Havlicek et al , 1975). Although the activity of the cortex is continuous after this time, it still retains the primitive pattern of suppression- bursts which remain until approximately two months post-term. During these suppression-burst periods the EEG contains a short run of high voltage slow waves followed by a run of much lower voltage activity (Ellingson et al , 1974). At 33 weeks conceptual age the periods of flattening or suppression (mean duration 11.5 sec) are longer than the high amplitude bursts which have a mean duration of 3.3 secs (Parmelee et al, 1969). At this stage 60 % of the EEG record contains suppression-burst activity and this activity gradually becomes less dominant with increasing age.

From 28 to 30 weeks the EEG also becomes more simple and less random in wave form. It is still primarily delta activity with traces of faster theta waves (4-6 c/sec) which occur in short runs of one to two seconds’ duration. At the

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same time as the EEG becomes continuous the amplitude of the EEG activity drops significantly to within the range seen in children and adults. Maximum amplitudes occur in the occipital regions. There is occasionally the beginning of some synchrony between the two hemispheres but this waxes and wanes and generally there is still very little relationship between cortical areas or hemispheres, and the EEG has the appearance of a few, independent electrical generators containing the same frequencies. This lack of synchrony between areas is an expected finding since the formation of intracortical connections is largely a postnatal process, and topographical differentiation does not develop until this later maturing process.

Superimposed upon the background EEG, and occurring uniquely in the premature brain from about 30 weeks onwards, is a low voltage fast spindling activity which has been reported to vary between 10 and 14 c/sec (Robinson and Tizard, 1966) and 16 and 20 c/sec (Joseph et al , 1976). This activity is unexpectedly fast and rhythmic in such a young brain and is not related to the much later appearance of sleep spindles or to the sensori-motor rhythms which are associated with motor inhibition. The significance and anatomical basis of the spindles is unknown. Non-specific thalamo-cortical projection systems are not functional at this age so the activity may reflect the influence of other brain stem structures on the cortex (Dreyfus-Brisac, 1964). Alternatively the scalp electrodes may be picking up far-field electrical potentials arising directly from the brain stem which may be particularly prominent during this period when the EEG is generating such low voltage waves. Although such an electrical source is a long way from a scalp recording electrode, in recent years it has been proved that far-field sensory evoked potentials can be recorded from the caudal brain stem in adults and children (Gibson, 1976). Whatever the origin, the significance of the unique spindling activity of the premature brain is not understood.

As the background EEG becomes more continuous and stable, begins to drop in voltage, and develops faster frequencies, another significant feature emerges in the process of maturation. It becomes at times possible to recognize different states or behaviours which some authors report as the beginning of the differentiation between sleeping and waking behaviour, although at such an early stage of development when the parameters which define such states are still very unstable and loosely associated or absent, the use of the terms ‘sleeping’ and ‘waking’ is debatable. Concomitant with the emergence of different physiological states is the development of cycles or rhythms of physiological functions. This feature is first seen at 28-30 weeks gestational age. At first the only reliable criterion is body movement, with the development of periods of inactivity accompanied by a significant reduction in muscle tone. No clear differentiation can be detected at this stage in the EEG, nor in other electrophysiological parameters such as eye movements which still remain sparse and fairly continuous (Parmelee and Stern, 1972; Stern et al , 1973; Werner et al, 1977). Heart

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1 sec

Figure 5.4 Different physiological states in a 35 week gestational age baby. (A) Awake. (B) Active sleep. (C) Quiet sleep, trace alternant.

rate and particularly respiration remain very irregular and between 24 and 32 weeks apnoeas are a very common feature with sustained periods of no respiration (Lairy, 1975). This point in maturation marks the beginning of an increasing association between various electrophysiological parameters and the initial steps in the temporal organization of CNS systems.

By 30 to 32 weeks different stages of sleep emerge as seen in Fig. 5.4. One stage is called active sleep , a term applied by Parmelee et ah (1968). It has also been described as irregular sleep (Wolff, 1959), light sleep (Dreyfus-Brisac, 1964) and State 2 (Prechtl, 1968). It appears to correspond to paradoxical or rapid eye movement sleep in children and adults and can be defined as a condition where the eyes are closed and no behavioural responses can be easily elicited to environmental stimuli. There is, however, a considerable amount of phasic motor activity, seen as jerks in the full-term infant and older individuals, and as

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slow writhing movements in the premature. Muscle tone is maintained in premature and young babies but during the rest of life this state is characterized by total spinal inhibition and loss of muscle tone. In prematures active sleep is frequently accompanied by startle response, grimacing, sucking, frowning, smiling and vocalization. In more mature nervous systems heart rate and respiration rate are fast and irregular, with the frequent occurrence of bursts of rapid eye movements. The EEG usually consists of an activated pattern of fast frequencies similar to the waking EEG. In the premature, physiological functions are poorly correlated and perhaps only one or a few of the signs of active sleep are detectable.

The other recognizable sleep state in young babies is quiet sleep as described by Parmelee et al (1968). This state is also called regular sleep (Wolff, 1959), deep sleep (Dreyfus-Brisac, 1964) and State 1 (Prechtl, 1968) and corresponds with slow wave sleep or sleep stages 1 to 4 in children and adults (Rechtschaften and Kales, 1968). During quiet sleep the individual is relaxed with sustained periods when there is little body movement, although muscle tone is maintained even in adults. Similarly other physiological parameters are quiescent with no eye movements and slow regular respiration and heart rates. During this period in children and adults the EEG increases in amplitude and slows to its lowest frequencies within the delta range, while in the late premature and neonate a unique EEG form emerges called trace alternant which maintains the primitive pattern of suppression-bursts with runs of high voltage delta and theta waves alternating with low amplitude slow waves (Prechtl et al , 1969).

Because the immaturity of the neural mechanisms produces unstable periodicities and a loose association between physiological parameters in the premature, it is inevitable that intermediate states are recorded for a significant period of the time which cannot be described as either one of the two sleep states nor as being typical of waking activity, wakefulness being defined as periods when the eyes are open, some movement is present and the EEG shows a low voltage continuous pattern.

The periods of physiological activation which are manifest as rapid eye movement sleep in later life recur at regular intervals both during the sleeping period when they are easily monitored and during waking behaviour as well (Kales, 1969). The period of the cycle (termed the basic rest activity cycle) is one of the most stable events in mature physiological systems and recurs once every 90 minutes in adults (Kales et al ., 1974). When the periodicity is first apparent at 30 to 32 weeks conceptual age the cycle length is very short and extremely unstable, varying between 7 and 17 minutes. From this time there is a significant correlation between the increasing length of the active sleep or basic rest activity cycle and the conceptual age of the infant, which does not appear to be affected by environmental experiences (Clemente et al ., 1972).

Body movements are the first behaviour to display periods of inactivity and

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activity (Werner et al , 1977). A little later eye movements become very much more frequent, reaching a peak in activity around 32 weeks, and they also begin to become temporally organized into quiescent and active periods which makes the identification of active sleep easier and more reliable. Petre-Quadens (1969) reports a maximum in eye movement activity occurring a little later in development around 37 weeks after conception, with this event occurring earlier in females than in males. At this stage the premature will spend a significant amount of time without moving (83 %) which reflects the increasing inhibitory control of higher brain centres on the caudal brain stem and spinal cord reflex activities. This early in development the EEG alone cannot identify any of the different states and the most reliable parameters are body and eye movements.

So by 32 to 34 weeks active sleep is the first behaviour to be reliably recognized and it occupies a significant amount of time varying between 60 % and 80% of the day (Killam and Killam, 1976; Werner et a/., 1977). The dominance of active sleep at this stage of development reflects the neurological basis of this state. Active sleep depends on and is controlled by hind brain structures in the pons, particularly the mass of noradrenalin-containing neurones called the locus coeruleus (Jouvet, 1961; Morgane and Stern, 1974). Although midbrain and forebrain areas participate in active sleep phenomena, they are not important in the maintenance of active sleep. Since the hindbrain is mature long before 34 weeks gestation it is capable of sustaining active sleep significantly earlier than other sleep states and sustained wakefulness which require the control of midbrain and forebrain structures. Because the amount of active sleep is highest in the premature and remains high in the full term infant and neonate, declining steadily until adult values are reached in late childhood, active sleep is frequently regarded as a primitive state equivalent to other caudal reflex functions such as sucking and respiration (McGinty, 1971; Himwich, 1974; McGinty et al., 1974).

As the baby matures and active sleep becomes more organized, this state is increasingly associated with significant physiological and CNS activation. At the onset of active sleep there is a sudden rise in blood pressure and a huge increase in the utilization of oxygen within the brain which is associated with a dramatic increase in neural activity, particularly within the sensory systems where neural firing exceeds that recorded during alert wakefulness (Benoit, 1967; McGinty et al ., 1974; Noda and Adey, 1970; Killam and Killam, 1976). It has been suggested that since active sleep is associated with phasic bursts of intense neural activity, it is a mechanism which is important in the processes of neural maturation, particularly synaptogenesis which occurs primarily in the late premature and neonatal stages but is believed to continue throughout at least the first three decades and probably during the whole of a lifetime. Thus active sleep with its neural storms in some way helps determine the functional connections between neurones which may well encode both the innate and

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experiential components of behaviour. However both active sleep and the functioning of the CNS are quantitatively and qualitatively different in the premature and neonate, and it is by no means certain that the function and effect of active sleep remain constant as other brain areas mature, modify and participate in this early differentiated state.

Several weeks after active sleep is first identified, short, irregular, unstable periods of quiet sleep can be recognized. The best early identification of this behaviour is periods of regular respiration associated with quiescence (Lairy, 1975). The EEG does not begin to correlate with sleep state until 36 to 38 weeks (Lairy, 1975; Werner et al , 1977). Quiet sleep first emerges between 35 and 36 weeks gestation (Parmelee and Stern, 1972; Lombroso, 1979), and at this time active sleep occupies 60 % of the time and quiet sleep 21 %, while the rest of the activity is ill-defined and termed ‘intermediate-stage’. After the first appearance of quiet sleep there is a progressive increase in the amount of time spent in this stage which is concomitant with a gradual decline in the amount of active sleep. This change in dominance is correlated closely with the conceptual age of the premature baby (Parmelee and Stern, 1972). Interestingly, whereas active sleep is maintained by caudal brain structures, the midbrain, limbic, thalamic and particularly basal forebrain areas are essential for maintaining quiet sleep (Morgane and Stern, 1974). Like complex appetitive behaviours, quiet sleep is integrated at many levels of the neuroaxis and its appearance probably signals the beginning of functional connections with the forebrain areas (McGinty et al , 1974). The increasing dominance of quiet sleep and later of course of prolonged wakefulness reflects the developing inhibitory and excitatory control of the cortex over brain stem mechanisms. If anything goes wrong with cortical development, particularly at these early stages but to some extent throughout life, it is reflected in an abnormally low amount of quiet sleep (Magnes et al ., 1961).

So during the eighth month of pregnancy significant electrophysiological events occur. Transient high voltage spikes and periods of electrical silence disappear from the EEG. There are periods of increasing length when the baby lies still with no movement. Eye movements increase and begin to cluster into early embryonic cycles of activity and inactivity. Respiration becomes more regular and rhythmic and is associated with the increasing stability of heart rate which remains throughout prematurity much faster than the heart rate recorded in full-term infants. Quiet sleep and active sleep emerge from the primitive undifferentiated state. It is during this period that the huge expansion of the telencephalon begins with the appearance of secondary sulcation (Lemire et al ., 1975; Yakovlev, 1976). Viability of the premature baby improves significantly although mortality is still some two to ten times greater than that in the full term infant (Behrman et al ., 1971). There is also a sudden maturation in the response to many neurological tests, and sensory evoked potentials change significantly (Graziani et al ., 1968).

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From a time when evoked potentials can first be recorded there is a linear decrease in the latency of the cortical response which is significantly correlated with the conceptual age and does not appear to bear any relationship with birth weight or extra-uterine experience (Graziani et al , 1968; Ganoti et al , 1980). Some sexual differences have been reported, with shorter latencies occurring in females than in males, and shorter latencies have also been recorded in negroes who usually mature earlier in terms of electrophysiological parameters than Caucasian children, although the reason is not known (Engel, 1965). As seen in the visual evoked potentials recorded from five infants in Fig. 5.5, between 35 and 37 weeks gestational age the primitive single negative evoked potential becomes more complex and is preceded by a faster positive component. In animals a similar positive wave is closely confined to the primary sensory areas and is believed to reflect specific basilar axosomatic connections between the sensory pathways and the cortical neurones. The development of the positive component is associated with increasing responsiveness to external stimuli, manifest in visual fixation and pursuit. Visual electrophysiological arousal which coincides with visual classical conditioning and visually guided behaviour occurs much later. Dark-reared cats with abnormal cellular development in the visual areas of the cortex and defective vision have reduced positive compo-

A

B

Figure 5.5 A representation of the typical developmental changes in the visual evoked potential from (A) a premature baby to (E) an adult.

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nents. There is some evidence in man that similar reductions in the positivity of visual evoked potentials are associated with visual defects (Thompson, 1978).

At the same time that the sensory evoked potential begins to develop a more complex morphology, there is a sudden acceleration in the curve of reducing latency. Somatosensory evoked potentials mature earlier than auditory and visual potentials, and by 35 weeks consist of three waves, so that the wave form and the latencies are closer to adult values than the other sensory modalities (Hrbek et al , 1973). At 30 weeks gestational age the latency of the visual evoked potential is 210 to 250msec (Engel and Butler, 1969; Ellingson, 1960; Umezaki and Morrell, 1970). Between 35 and 36 weeks the latency decreases to 200 to 210 msec and by 40 weeks, when the myelination of the optic nerve has begun, the latency of the cortical response to flashing lights is between 155 and 190 msec. The cortical distribution of the evoked potentials remains different from that recorded in adults with a more localized distribution confined to the primary sensory cortices (Ellingson, 1960).

During the last month until full term the eleetrophysiological changes begun earlier continue to become more stable and organized. The periods of active sleep and quiet sleep lengthen and are less likely to be disrupted (Parmelee and Stern, 1972). There is an increasing association between eleetrophysiological parameters (Nolte and Haas, 1978) and an increasing amount of time is spent in quiet sleep (Lombroso, 1979).

Before 38 weeks there is no significant difference in the power of the EEG frequencies during different behaviour states, but in the last weeks the EEG begins to develop different patterns of activity. Between 37 and 40 weeks periods of wakefulness become clearly recognizable and there is a noticeable increase in frequency with more theta activity between 4 and 6 c/sec (Lairy, 1975). The pattern of fast frequencies varying between 16 and 28 c/sec which is unique to the premature baby is still present. By 40 weeks gestational age the EEG has clearly differentiated and become more closely associated with different behaviours and patterns of physiological activity, a significant milestone according to Dreyfus-Brisac (1967) associated with a dramatic improvement in the survival chances of the baby and heralding the imminent birth. In the late premature baby, brief periods of wakefulness are vssociated with a low voltage mixture of theta waves, active sleep is accompanied by a low voltage mixture of delta and theta waves between 0.5 and 6 c/sec, and during quiet sleep either high voltage delta or the pattern of trace alternant is recorded with an alternating pattern of high voltage and low voltage delta waves. The length of the suppression periods has been gradually reducing during the last month and these are by now shorter than the runs of high voltage slow waves—the mean duration of the suppressions is 4.4 sec, the mean duration of the bursts is 5.9 sec (Werner et al , 1977). The density of the eye movements begins to fall by the 40th week and the amount of quiet sleep has increased to 38 % of the time, while active sleep

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has fallen to 52% (Parmelee and Stern, 1972). Because of the increasing improvement in the temporal organization and differentiation of electrophysio- logical parameters only 3 % of the activity is classified as an intermediary stage.

Several authors have reported that it is possible at this stage to record a diffuse general activation response in the EEG to stimulation but that it is extremely inconsistent (Dreyfus-Brisac, 1964; Kooi, 1971). In animals this electrophysiological event is associated with the development of functional connections between tl ? ascending reticular activating system, the diffuse thalamic projection and t ^rtical neurones, and is associated with a recognizable behavioural response to stimuli. It is primarily a postnatal process in animals (Creutzfeldt and Kuhnt, 1967), and is likely to be similar in man since such an inconsistently evoked response may be the result of the misinterpretation of data. Many authors report that no diffuse activation response can be seen in prematures, and EEG arousal is only characteristic of the post-term infant (Havlicek et al., 1975; Lairy, 1975).

It can be seen that during the second half of gestation electrophysiological parameters follow a rapid and precise developmental pattern which can provide a useful index of conceptual age. The majority of authors report that the EEG is correlated with conceptual age but is not as closely associated with birth weight and extrauterine experience (Dreyfus-Brisac, 1962,1964,1966; Ellingson, 1967; Parmelee and Stern, 1972; Dittrichova, 1969). Lairy (1975) claims that between 24 and 41 weeks the EEG changes so rapidly that the conceptual age can be accurately evaluated within two weeks and the addition of other electrophysiological parameters inevitably improves the estimates. It is certainly not possible to be as accurate at any other time of life. The premature EEG contains lower power spectra of theta and delta waves than that of the full-term infant. There are still traces of fast spindling activity and the periods of suppression which occur in quiet sleep are longer than in the full-term baby. However, there is some evidence that the experience of the premature baby may slightly accelerate the developmental processes although the effect seems to be very small and not often reported. There may be longer suppression periods in full-term infants compared with premature babies of the same gestational age (Parmelee and Stern, 1972), and the earlier occurrence of a postnatal milestone, that of the appearance of sleep spindles, by three to four weeks in premature babies (Metcalf, 1969).

Changes after birth—the first year of life

Whatever the gestational age of the baby it appears that CNS maturation progresses in a fixed sequence during the first 40 to 50 weeks after conception, with the programmed unfolding of anatomical and biochemical events altering in a predictable fashion the electrophysiological activity of the brain. It is

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generally believed that at first the neonate is functioning primarily at a subcortical level. The evidence for this is various; for example, motor defects are not apparent until about the second month post term. Primitive reflexes such as the Moro and Babinski reflex are present at birth. An ancephalic child is indistinguishable from a normal child during the first month, and volitional activity is not possible in the neonate (Dreyfus-Brisac and Blanc, 1957; Pritchard, 1964). However the importance of myelinization, which is essentially a postnatal process within the cortex, in controlling the functional capacity of the brain is frequently overemphasized, and electrophysiological evidence clearly suggests that the cortex is having an important modifying effect on brain stem activity before and at full term, since for example an ancephalic child or other babies with cortical damage have different sleep patterns, sleep/wake cycles, muscle tension, etc., and hemiparesis can be recognized from an early age (Robinson and Tizard, 1966).

The brain is still developing very rapidly during the first year of life as seen in the large increase in brain weight. During the first month the rapid expansion and elaboration of the association areas of the frontal, temporal and parietal regions begins, increasing the convexities of these brain areas and deepening the primary and secondary fissures. Myelinization of the cortex begins at term, and synaptogenesis which is also primarily a postnatal process within the cortex reflects environmental influence as well as innate programming (Himwich, 1974).

There is no striking pattern or consistency in the EEG of the newborn during the short periods of waking that they are able to maintain. The activity is diffuse with no apparent differentiation either between the different regions of the cortex or between the hemispheres. The waves are of low voltage (<50/rV), random and arrhythmic, and there is a constantly shifting pattern of asymmetries and asynchronies. The variability of the neonatal EEG is very high with low correlations between repeated EEGs (Ellingson et a/., 1974; Kellaway and Peterson, 1964; Lairy, 1975; Werner et a/., 1977). The dominant frequency during the first three months is within the delta range 3 to 4 c/sec, mixed with diffuse low voltage slow theta waves. Interestingly, some rhythmic activity can be recorded over the central regions of the scalp, and the frequencies arising from this region are also faster. From about the third week post term for the whole of the first year the central regions produce this more mature EEG pattern, followed some three to five months later by similar changes in the occipital lobes, and later still by changes in the temporal, parietal and frontal regions (Hill and Parr, 1963; Hague et al ., 1972). These EEG changes follow closely the maturation sequence of the cortex which involves a huge increase in the arborization of the neural plexus, an increase in the dendritic connections and the myelinization of intracortical and the thalamocortical connections. This occurs first within the sensori-motor cortex, later in the visual and auditory areas and last in the association areas (Yakovlev, 1976).

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During the first three months there is no individualization in the waking EEG, and no sex differences have been detected (Hague et al, 1972). After this time the EEG begins to mature from a slow, random disorganized pattern to one of faster, regular rhythmic activity, greater differentiation between the various cortical regions, an increasing association with different behaviours and a developing responsiveness to stimulation. During the early months it is generally agreed that there is either an inconsistent response or no response at all to increased arousal and attention to stimuli, and no change in the EEG when the eyes are opened or closed. During the third month there emerges more rhythmic activity with the eyes closed and an activation or desynchronized response of faster EEG rhythms when the eyes are opened or when the baby alerts to stimuli, although this reaction is much less consistently evoked than in adults (Kellaway and Peterson, 1964; Havlicek et a/., 1975; Lairy, 1976). This change in EEG reactivity coincides with a noticeable increase in a child’s ability to remain awake. Before 8 weeks the waking periods are usually brief and specifically because of hunger or physical discomfort. By three months activities such as sucking, fussiness and crying decline and the increasing periods of wakefulness are used for other activities; social interaction increases and attentive behaviour to external stimuli is more often present (Weitzman and Graziani, 1968; Sterman et al, 1977).

As well as not being able to jecognize any arousal response in the EEG, it is also impossible in the first few months to identify any change in the EEG as the baby becomes drowsy (Kellaway and Peterson, 1964; Samson-Dolfuss et al, 1964). This suggests that early in development either the EEG is unable to reflect the changing behaviours of the baby, or that at this age more subtle changes in behaviour have not developed and the transition from waking to sleep is extremely rapid (Lairy, 1975). Sleep can occur almost immediately and has more the appearance of reflex response than the characteristics of an appetitive behaviour (McGinty, 1971). Another unique feature is seen as the neonate falls asleep. Instead of slow wave sleep always being at the beginning of a sleep period, which is the case throughout most of life, the mode of onset is variable and the first sleep activity may be that of quiet sleep or more frequently active sleep (Prechtl et al, 1969; Curzi-Dascalova, 1977).

During the first three months of life probably the most dramatic changes occur in sleep behaviour, which over the next few years or so gradually develop into one of the most outstanding biological constants in terms of individual differences in behaviour (Morgane and Stern, 1974). The full term baby sleeps for long periods of time, although individual differences are enormous (mean total sleep time 16.6 hours, range of variation 10.5 to 23 hours). There is a gradual decline in sleep time with maturity so that by three weeks post term the mean sleep time has already declined to 14.5 hours (Sterman and Hoppenbrouwers, 1971; Parmelee and Stern, 1972; Sterman, 1972). In the

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premature baby and during the first two months of life rhythmic patterns of activity occur up to seventeen to twenty times every 24 hours. The duration of the sleep/wake and active sleep/quiet sleep alternation is short, irregular and very sensitive to such disruption as body movements and crying (Lairy, 1975). The baby will initially wake every couple of hours but there is a gradual increase in the duration of the sleep periods. At first these longer sleeping times can occur at any time of the day, but between three and five weeks of age a circadian rhythm begins to emerge with the longest sleep period and more sleep occurring at night (57% total sleep occurring between 8 p.m. and 8 a.m.). By six weeks of age a baby will usually sleep for five to six hours, and after twelve weeks there is a well established diurnal rhythm with a sustained nightly sleep period lasting between eight to nine hours, which is about 70 % of the total sleep time. Day time sleep also becomes consolidated with increasing periods of wakefulness occurring every three to four hours.

The body’s circadian rhythm is fully established by the sixth month and following the sleep/wakefulness cycle the body’s physiology also develops a diurnal periodicity. This is first recognized for body temperature by two to three weeks after birth. Rhythms of urine excretion, heart rate variation and electrolyte metabolism develop between four and twenty weeks post term, while patterns of hormone secretion do not become associated with circadian and sleep periodicities until the rhythms are well established.

Large individual differences in sleep behaviour are apparent from birth and can be seen in the total sleep time, number of rapid eye movements and facial and body movements in active sleep, the frequency of respiration in quiet sleep, vocalization, crying and sucking. These differences persist with considerable stability into later life (Dittrichova et al ., 1976). Some of the differences are probably genetic, others are related to early experience and chronic subclinical states, for example nutrition and hormonal anomalies. Environmental factors may well be important since it has been shown that animals raised in isolated environments sleep far less (sleep is reduced by 40 %) while novel environments can increase the subsequent sleep time by 25% (McGinty, 1971). Stress and psychological function may also relate closely to evolving sleep patterns (Kales, 1969; Sterman, 1972), and since infants spend so much time asleep it is possible that more sleep research could provide a better measure of both individual differences and the progress of development than many waking measures.

One of the most interesting characteristics of sleep behaviour in both the premature and young infant during the first three months is that active sleep is independent of quiet sleep, whereas in the child and adult it is embedded within the long night’s sleep and only occurs after a prolonged period of slow wave sleep. In the young baby active sleep occurs frequently at sleep onset or during waking, particularly when the child is fussing, crying and sucking. At this time

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there is still a loose association of physiological parameters and heart and respiration rate do not yet show a clear acceleration at active sleep onset. The most significant feature of all is that there is no loss of muscle tone and spinal inhibition, which is a cardinal feature of the mature nervous system found in all mammals.

The percentage of active sleep is still high in the full term infant (between 40 % to 50 % of sleep, mean duration 25 minutes) but from birth there is a very rapid decline in active sleep dominance until it occupies about 35 % of the sleep time at three months (Parmelee and Stern, 1972). Other authors suggest a slightly slower fall to between 40% and 42% with a mean duration of 14 minutes (Parmelee et al , 1968; Stern et al , 1969; Dittrichova et a/., 1976). For the rest of the first year the amount of active sleep continues to decline more gradually. The amount of active sleep at the different post term stages is reputed to be reduced in mongol babies, in microcephale and in cases of placental insufficiency (Petre- Quadens, 1969). It has also been reported that active sleep is frequently associated with feeding and sucking behaviour in the early months and occurs for longer periods with breast feeding, possibly because this may involve more handling of the baby, longer periods of rocking and more frequent feeding (Metcalf and Jordan, 1972). At present, the consequences of this suggested relationship can only be guessed at.

The EEG during active sleep consists of a mixture of low voltage (15 to 30 fiV) irregular theta and delta waves, interspersed with higher amplitude delta waves. The dominant frequency is around 4 c/sec (Havlicek et al , 1975). During the first half of the year the frequencies increase to vary between 2 and 6 c/sec and the amplitude decreases slightly so that all the brain activity in active sleep is an irregular low voltage mixture. During the second half of the year the pattern becomes increasingly closer to that of the waking pattern of activity (Ellingson et al ., 1974). The appearance of so-called ‘saw-toothed’ waves during the second to third month post term may reflect the manifestation within the cortex of the ponto-geniculate-occipital spikes recorded during the neural storms in animals (Curzi-Dascalova, 1977).

Beyond a slight shift in frequency there is very little further change in the EEG of active sleep during the first year, which provides a significant contrast to the dramatic EEG changes that occur during quiet sleep corresponding with the early postnatal maturation of the cortex.

As the amount of active sleep becomes less with increasing conceptual age, so there is an increasing amount of time spent in quiet sleep, and this increase is dramatic during the first eight months post term (Dittrichova et al , 1976; Werner et al, 1977). Dittrichova (1969) studying ten full-term babies found that the mean duration of a quiet sleep period was 11 minutes at term and 13.8 minutes at two weeks. This increased to a mean duration of 22 minutes by twelve weeks and was accompanied by a parallel increase in the total percentage of

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quiet sleep experienced which was particularly dramatic during the second to thirty-fourth week. By the eighth month twice as much quiet sleep was recorded as active sleep with 55% of the sleep period being involved in quiet sleep processes. Parmelee et al (1968) reported a close correlation between conceptual age post term and the total amount and duration of quiet sleep periods, and this EEG feature parallels the change in basal forebrain control of limbic and brain stem structures. The increasing amount of quiet sleep is associated with the increasing ability of the cortex to maintain longer and longer periods of wakefulness, accompanied by a reorganization of the temporal patterns of the body’s activity, the processes and significances of which are poorly understood but are certainly related to CNS maturity and not chronological age (Purpura, 1971). Apathetic and unresponsive babies, infants with delayed milestones and hyperactive children have been reported to show a significant slowing in the increase of quiet sleep with age and they also have less active sleep (Kales, 1969; Himwich, 1974; Weitzman, 1974).

The familiar suppression-burst EEG pattern of the premature is manifest as the trace alternant pattern of quiet sleep in the neonate. It is seen as bursts of high voltage delta waves (1 to 3 c/sec) lasting some four to five seconds and interspersed with lower voltage slow waves. The amount of trace alternant declines rapidly during the first weeks of life and it is generally agreed that it disappears some four to five weeks post term (Robinson and Tizard, 1966; Dittrichova, 1969; Metcalf, 1969; Hague, 1972; Ellingson et al , 1974; Werner et al , 1977; Lombroso, 1979). It is replaced by runs of continuous high voltage delta activity (amplitudes greater than 50 fiW) which increases significantly in abundance during the first two months, reflecting the increasing intra-cortical connectivity which begins to synchronize the activity of large populations of neurones (Mizuno et al , 1969). At the beginning of the third month, therefore, slow high voltage delta waves begin to dominate quiet sleep (Gibbs and Knott, 1949; Hague, 1968; Parmelee et al, 1969; Lairy, 1975).

Several weeks after the disappearance of the trace alternant pattern an important sleep activity appears whose significance is not understood. This is the phenomenon of sleep spindles which consist of bursts of medium voltage waves whose frequency varies around 14 to 16 c/sec. The spindles are very distinctive and characteristic of all normal sleep, but they have been reported to be absent in some clinical conditions such as in epileptic and hormone deficient children (Howe et al, 1974; Sterman et al, 1977). Rudimentary spindles may be recognized as early as five to six weeks post term (Robinson and Tizard, 1966; Sterman and Hoppenbrouwers, 1971; Hague, 1972), and are clearly present between the end of the second and third months (Katsurador, 1965; Sterman and Hoppenbrouwers, 1971; Hague, 1972). During the next two months there is a significant increase in the amplitude and duration of the sleep spindles, until they are almost continuous in quiet sleep and far exceed the spindle activity seen

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in adults. There is then a decline in the spindle duration around the age of six to seven months and by eight months this sleep activity begins to cluster into specific quiet sleep periods (Hague, 1972).

The appearance of spindle activity coincides with the beginning of the myelination of the non-specific thalamic projection system and the formation of contacts between its ascending processes and cortical neurones (Himwich, 1974; Yakovlev, 1976). It has been suggested that specific nuclei within the lateral thalamus which are associated with the reticular formation are responsible for the characteristic hypersynchronous runs of rhythmic waves always seen within the cortex (Andersen and Andersen, 1968). This certainly includes spindle activity which may also depend on the integrity of the corpus callosum (Kooi, 1971; Scheibel and Scheibel, 1971), and the appearance of sleep spindles closely coincides with the increasing amount of quiet sleep, sustained sleep periods and maintained wakefulness. Sleep spindles may also be associated with the sensorimotor rhythm and thus be important in inhibitory cortical function particularly in controlling skilled motor behaviour (McGinty et al, 1974). However, the functional significance of this sleep phenomenon must remain speculative until more research is completed.

The arousal response is often most clearly seen in sleep and stimuli can evoke midline phenomena such as the ‘K’ complex, a high amplitude series of waves with an initial sharp negative followed by a slow positive/negative complex, and often succeeded by runs of spindle activity or a reduction of amplitude and an increase in the frequencies of the EEG which heralds a lightening of sleep or perhaps an awakening. It has been suggested that the shape of the ‘K’ complex depends on the significance of the signal (Oswald, 1962). Another similar wave form is the ‘parietal hump’ or ‘vertex sharp wave’ which is again maximal at the vertex but simpler in form. This arousal response consists of repetitive high amplitude sharp negative waves which are particularly abundant early in sleep. These sleep phenomena are absent in the first three months of life which may be due to detection problems in the slow diffuse sleep EEG of the young, yet vertex sharp waves are easy to recognize within the slow activity of adults and children (Metcalf and Jordan, 1972).

So during the first three months of life the sleep of the young infant is different from the child and adult. Unusual behaviour such as sucking and fussing occur frequently, the physiological parameters are as yet not stable, and there are no clear hormonal changes (Sterman and Clemente, 1974). The physiological rest/ activity rhythm, still much shorter than that seen in adults, becomes increasingly regular with a period of about 50 minutes. The periods of activation, which easily become locked on to external cues, frequently coincide with feeding demands (Globus, 1966). This periodicity changes very little during the first year (Weitzman and Graziani, 1968), then gradually lengthens to a period of seventy minutes by the age of ten years or later (Sterman and Clemente, 1974). The

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timing of this maturation pattern is however really a matter of speculation since data is sparse after the first months of life and others report more rapid changes in the basic rest/activity cycle within the first year of life (Sterman and Hoppenbrouwers, 1971).

In the third postnatal month some important milestones are established in sleep behaviour which are closely correlated with increased wakefulness, social interaction and complex responses to stimuli. Firstly, sleep becomes consolidated into a sustained sleep period of six to eight hours at night. At the same time there is an increasing differentiation between the brain activity of quiet and active sleep which in the neonate are very similar (Havlicek et al , 1975). By three months, active sleep activity has reduced in amplitude and increased in frequency, while quiet sleep shows increasing dominance of high voltage delta waves and spindle activity. Also at this time active sleep, which up to this point had been independent of sleep behaviour and frequently occurred at sleep onset and during wakefulness, becomes embedded in quiet sleep and during the rest of life follows a fixed, significant period of quiet sleep before being triggered by quiet sleep mechanisms (Jouvet, 1961). Thus by three months there is no active sleep at the beginning of a sleep period (Graziani, 1974; Werner et a/., 1977). Phasic activity reduces significantly and the physiological parameters are now more closely associated, with heart and respiration rate increasing and becoming irregular in active sleep, while they slow and become regular in quiet sleep. Finally, the last significant change in active sleep at this time is the beginning of the normal pattern of profound spinal inhibition and raised arousal thresholds, whereas before in the more immature system muscle tension is facilitated in active sleep and the infant can be easily aroused (Pompeiano, 1969; Kales, 1969).

During these first three to four months of life the infant is uniquely vulnerable to various forms of mild stress including a disruption of the normal routine. Only a small adaptation response to sleep deprivation has been reported by Anders and Roffwarg (1973) in a group of full-term infants some twenty-four to ninety-six hours old. They lost one sleep period of three to four hours and in their subsequent sleep showed some increase in total sleep time and the percentage of active sleep, but there was no reported change in quiet sleep which is the usual pattern in older individuals. Sterman et al (1977) suggested that sleep adaptation to stress is inadequate in the immature, and in young animals at the equivalent CNS maturity as the first three months in man, there is evidence of an increased number of apnoeas with mild sleep deprivation (Baker and McGinty, 1972).

The age of three months, with the consolidation of sleep into prolonged time periods, decreased muscle tone and arousability and poor adaptation to mild stress, is also the time of the greatest number of reported cases of sudden infant death syndrome. Typically between two and four months young infants die silently in sleep and as yet there is no clearly recognized specific cause. Sudden

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infant death syndromes are often preceded by a disruption in daily routine and interrupted sleep schedules and are typically seen in lower birth weight babies (Weitzman and Graziani, 1974; Kraus et al , 1977). Maintained levels of muscle tension throughout all sleep stages in the very young baby may be protective, to allow easy arousability if an imbalance occurs in the respiratory mechanisms of the brain stem which are still physiologically immature in the first months. Apnoeas are common in the neonate and premature baby and are exacerbated by upper respiratory tract infection, stress and sleep deprivation. With maturity, increasing control and association of physiological parameters should occur at the same time as reduced arousability develops in active sleep. Thus the possibility is raised of a maturational mismatch as sleep is consolidated with a limited response or complete failure to arouse during sleep to correct prolonged apnoeas, which instead results in increasing acidosis and possible respiratory arrest (Sterman and Clemente, 1974).

During the first year of life, and particularly during the first months, the immature cortex cannot sustain high frequency repetitive neuronal discharges and the common pathological EEG pattern of high voltage spikes and slow waves is rare in young babies. Transient spikes in the EEG do not have clinical significance (Ellingson et al , 1974). However, as with premature babies, a good indicator of abnormal development is delayed EEG milestones with an immature EEG within the first year indicating a poor prognosis (Samson- Dollfus et al , 1964). Thus the presence of trace alternant in quiet sleep beyond the first four to five weeks and a delay or failure in appearance of sleep spindles is seen in hypothyroidism, hypoxia and brain damage (Parmelee and Stern, 1972). Malnutrition and hypoglycaemia which are associated with defective myelination and retarded neurocellular growth result in an immature EEG and very disturbed sleep patterns. Quiet sleep is particularly poorly developed. It is reduced in amount, few sleep spindles are recorded and respiration is also less regular. Eye movements may be significantly reduced in active sleep (Dobbing, 1960; Schulte et al, 1972).

Changes into childhood

From three months after birth the EEG begins rapidly to acquire the features which are so characteristic of the adult EEG.

Firstly, the frequencies present in the waking EEG gradually become faster. As can be seen from Table 5.1, delta is the dominant frequency in the early part of the first year. More complex analyses of contemporary data have confirmed the patterns reported by Lindsley (1939) and Smith (1941). By six months theta activity is beginning to predominate, and is clearly established by twelve months. It is mixed with traces of alpha activity, which increases during the second and third year to supersede the slower theta and delta waves during the fourth year.

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Table 5.1 Changes in the EEG average frequency recorded from occipital electrodes: postnatal development from three months to fifteen years

Frequency c/sec

Age Lindsley Smith

(months) (1939) (1941)

3

3.9

3.7

6

4.5

5.0

9

5.8

12

6.3

6.4

18

6.8

6.9

24

7.0

7.2

36

7.5

8.1

42

8.0

8.4

60

8.4

9.0

72

8.6

9.0

84

9.0

8.9

120

9.4

9.7

132

9.8

9.7

144

10.2

9.6

180

10.2

10.0

Data adapted from:

Lindsley, D. B. (1939) Longitudinal study of the occipital alpha rhythm in normal children: frequency and amplitude

standards. J. Genet Psychol. , 55, 197-213. Smith, J. R. (1941) The frequency growth of the human alpha rhythms during normal infancy and childhood. J. Psychol, 11, 177-198.

The rate of change is very rapid in the first two years of life but slows after this until adult values are reached in the mid teens (Robinson and Tizard, 1966; Kooi, 1971). During the second half of the first year differences between the male and female EEG begin to emerge and these persist until puberty with a ‘more mature’, faster pattern of frequencies being produced earlier by females (Hague, 1968; Hague et al , 1972). The young EEG is always typified by the presence of low voltage, slow waves, mixed with the faster dominant rhythms, particularly in posterior regions of the scalp.

Several other changes in the EEG progress with the frequency changes. The brain activity becomes more rhythmic and less random and diffuse with sustained runs of clearly recognizable single frequency waves. This rhythmicity also becomes confined firstly to the central regions and later, during the second half of the first year of life, to the occipital regions reflecting the maturation of the various cortical regions. Thus there is a trend of increasing topographical differentiation of the EEG which begins in the first year and is clearly established

156

by the fourth year, where electrical activity arising over the frontal, temporal, parietal and occipital areas has its own characteristic pattern of amplitude, frequency and rhythmicity. Also late in the first year a relationship begins to develop between the electrical activity of the two hemispheres. The EEG becomes increasingly synchronous while hemispheric differences in amplitude and wave form become apparent, although they are not stable until the seventh to tenth year (Hague et al , 1972; Werner et al , 1977).

Early in the first year the arousal response of the EEG is sometimes recognizable although inconsistently evoked. When the eyes are open, low voltage fast frequencies are recorded, while when the eyes are closed and the individual is relaxed, high voltage, rhythmic runs of slower alpha activity appear, particularly over the posterior regions of the head. This desynchronized pattern with eyes open is also evoked during arousal and attention to stimuli. The response is poor in the second year but is more consistently evoked in the third and fourth years.

This slow progressive maturation of the waking EEG correlates well with changes within the brain. The cortex is still expanding rapidly until the end of the second year and the individual patterns of the tertiary sulcation become well established at this time, continuing more slowly until the end of the first decade (Yakovlev, 1976). Also myelination, synaptogenesis and the elaboration of the cortical dendritic processes proceed at a rapid pace for the first two years then slow to continue into the second and perhaps even into the third decade of life. Hand in hand with this the most rapid changes in the post-term EEG occur within the first two years. Thereafter the maturation rate of the EEG slows, and as there is a greater response to environmental events and more significant changes relating to the behaviour of the individual, so it becomes increasingly difficult to define a normal EEG and specify the timing of EEG milestones. This is further exacerbated by the greater lability of the young EEG, and much larger changes are seen from moment to moment and day to day than is acceptable in the adult. There is therefore a diminishing relationship between the EEG and age, and after the first few years it generally provides a very poor index of maturity except within broad categories.

One of the last dramatic milestones in EEG development occurs between six and eight months with the appearance of a feature unique in the young infant. Drowsiness becomes associated with a specific pattern of high amplitude, very rhythmic theta waves; such activity is termed hyper synchronous. These waves increase in frequency and amplitude during the rest of the first year and become more or less continuous as the child quietens and falls asleep (see Fig. 5.6). Later in the second and third years this activity becomes less marked and decreases in amplitude; it is rarely seen in the fourth year (Kellaway and Petersen, 1964; Samson-Dollfus et al , 1964; Kooi, 1971).

At the same time as the EEG develops several different patterns of activity

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Figure 5.6 Changes in the EEG during drowsiness in a 20-month-old child.

during the states of arousal, quiet wakefulness and drowsiness, quiet sleep becomes differentiated into sleep stages which are similar to those of the adult. Arousal phenomena such as the vertex sharp waves and ‘K’ complex (see p. 152) are clearly recognizable after five or six months, and become increasingly prominent during the first two years, although the final wave form is not complete until much later in life and the response matures into a very individual pattern. Why the ‘K’ complex develops so slowly when evoked potentials can be recorded in prematures and neonates is not clear. Metcalf (1969) suggested that since the ‘K’ complex alters with the type of stimulus evoking it, this sleep phenomenon may well reflect information processing and therefore develops slowly with the increasing capabilities of the child. At the end of the first year sleep spindles have decreased in duration and become clustered into the lighter periods of quiet sleep, and sleep takes on its mature appearance with four recognized sleep stages, Stage 1 with low voltage theta waves and vertex sharp waves, Stage 2 with lower frequencies, 6 K’ complexes and sleep spindles, and Stages 3 and 4 with increasing amounts of high voltage delta activity.

By the end of one year sleep is well consolidated, a circadian rhythm is established and 90 % of infants do not wake habitually during the night (Webb, 1969). Total sleep time falls rapidly during the first year and then follows the pattern of other physiological changes, decreasing more slowly in later years. The mean total amount of sleep is 10.2 hours for three to five year olds and this falls to an average of 9.8 hours in the ninth and tenth years. Webb (1969) reported an enormous variation in the amount of sleep needed in young teenagers but could not relate these differences to school achievement, personality variables or other psychological characteristics. He did not look at younger children. Active sleep does not change very dramatically post term except that its portion of sleep gradually declines over the years to finally reach a stable value of about 20 % in

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the early twenties. Quiet sleep slowly changes as well until it stabilizes in the fourth year. From the age of two to five years the high voltage delta activity of Stage 4 becomes increasingly prominent. It may be partly for this reason that young children are very slow to arouse from sleep, and of course sleep walking, which occurs in Stage 4, is more common in the young (Kales, 1969).

Cortical evoked potentials, established so early in the young brain, are quite well developed at birth. The wave form which becomes more complex in late pregnancy doer not change dramatically and this is particularly so for somatosensory and auditory evoked potentials (Barnet et al , 1975; Desmedt, 1977). The most significant change post term is a decrease in the latency of the response as the nerve conduction velocities, which are only 50 % of adult values at birth, reach their final values by the age of four years (Cracco et al , 1979). Again the change in latency is most rapid during the first year; Ellingson (1960) reported a very sudden, short period of acceleration in the changing latency curve for visual potentials at about seven or eight weeks post term, which he associated with the maturing of macula function and the appearance of focused eye movements together with the beginnings of visual attention. Exact latency changes are reported in the literature (Ellingson, 1964, 1966a, 1967; Desmedt, 1977; Barnet et al, 1975) and it is frequently suggested that the latency of evoked potentials provides a useful and reliable index of age and maturity post term (Barnet et al, 1975). It is generally the early components of the evoked potential which are used in latency measurements and later components are often absent in the early weeks. This has been reported for all sensory modalities, and since it is the late components which reflect changes in attentive behaviour and information processing this finding suggests that although the sensory signals are arriving in the cortex, further elaborate signal processing is not carried out until the fourth to sixth week of life (Ellis and Ellingson, 1973; Desmedt, 1977). This finding correlates with the scarcity and diffuseness of any behavioural response before this age. It has been reported that the late components of the auditory response are poorly developed in Down’s syndrome and may be a measure of abnormal mental function and some forms of brain damage (Barnet, 1971). Harter et al (1977) used a black and white checkerboard pattern of various sizes to evoke visual potentials in ten infants between the ages of six and forty-five days. The smallest pattern subtended a visual angle of eleven minutes of arc and would only evoke a response within the macula region, while the largest patterns provided effective stimuli for peripheral vision. The authors found that all the check sizes produced a significant change in the visual evoked potential even in the youngest babies which would indicate that vision is better than 20/220 in the first week. Behavioural discrimination was not seen however until the twenty-seventh to fortieth day post term, and interestingly it was at this stage that the late components of the cortical response became more prominent and their presence and amplitudes were highly correlated with the percentage

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fixation time. The authors raised the possibility that these late components reflected cortical processing and their appearance marked the transition from passive to active visual discrimination. Krulisova and Figar (1979) could find no change in heart rate when stimuli were presented to young babies until the sixth to eighth week. From this time heart rate was consistently elevated and correlated significantly with attentive behaviour.

The young infant’s evoked potential is of much higher amplitude than the responses recorded in adults. This may be due in part to contamination from the high amplitude waves of the background EEG and because the infant’s thinner skull does not attenuate the activity so much. Less well developed inhibitory processes and more accessible generators, which become remote as the cortex continues to expand and enfold, also play a part (Ellingson, 1964; Thompson, 1978). Infant evoked potentials are also closely confined over the primary sensory projection areas. This distribution is seen during the first three months; then, at about the same time as the late components of the evoked potential develop, the distribution becomes more widespread and can be recorded over association areas of the cortex.

Throughout the first year the sensory systems are easily fatigued and evoked potentials cannot be recorded at high rates of stimulation. This is particularly so in the visual system where cortical potentials are only clearly evoked at flash rates slower than one every second. The rate of response improves to only 4 flashes per second by the end of the first year (Ellingson, 1964).

The wave form of cortical evoked potentials alters predictably with changes in state, for example, changes in attention and distraction. Because of the lability of such behaviours in the infant and young child, evoked potentials are far more variable both from moment to moment and from day to day than in adults. Only very large changes in the shape, latency and amplitude of the evoked potential can be used as indicators of, for example, the age of the child, his behaviour or of the presence of brain pathology.

There is no foolproof method for assessing mental function in children particularly when they are small, and many researchers have turned to the records of brain activity in the hope of finding an objective and reliable index of the ability of a child. Controversy has reigned over the last twenty to twenty- five years as to the usefulness of the EEG and new and better techniques of analysis seem only to have added fuel to the arguments.

Many claim that the patterns of activity in the EEG are related to intellectual development with the dominant EEG frequency and hemispheric associations being the two most significant features. Faster EEG frequencies have been recorded in more intelligent children although very often their controls have been the mentally retarded and brain-damaged individuals. Less regional differentiation and less marked asymmetries in the main frequencies arising from the two hemispheres together with significant slowing of the EEG have

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been cited as signs of limited cerebral processing. Fast, high voltage beta frequencies, focal slow waves and spikes and paroxysmal activity have frequently been associated with cognitive difficulties (Monnier, 1956; Vogel and Broverman, 1964,1966; Vogel et al , 1968; Nelson, 1969).

Evoked potential data is even more controversial. Ertle and his colleagues have argued that the latency of these responses relates to the efficiency of cortical processes. Thus shorter latencies correlated significantly with high IQ scores, whereas slow potentials were recorded in the dull and mentally retarded (Chalke and Ertle, 1965; Ertle, 1968,1971; Nodar and Graham, 1968; Ertle and Schafer, 1969). Rhodes et al (1969) found different features of the visual evoked potential correlated with intelligence. Bright children who scored between 124 and 140 on the WISC had greater asymmetry in the potentials evoked in the right and left hemispheres compared with children who only obtained a WISC score between 70 and 90, and this was most marked in the late components. Conflicting results of hemispheric differences have been reported by other authors (Richlin et al , 1971), while Martineau et al (1980) could only find amplitude differences between the evoked potentials of normal children compared with autistic and mentally retarded children, with greater amplitudes in the late components being found once again to correlate with higher intelligence.

Many investigators have failed to find any consistent feature of brain activity that can provide a valid measure of mental efficiency (Lindsley, 1940; Subirana et al, 1959; Netchine and Lairy, 1960; Netchine, 1967, 1968, 1969; Ellingson, 1966b; Petersen and Eeg-Olofsson, 1971). Netchine (1967) and Ellingson (1966 b) point out that normal individuals are frequently compared with mentally retarded patients manifesting clear evidence of brain damage. Differences in focal and paroxysmal slow and spike activity are then identified to differentiate the groups. This difference is a qualitative not a quantitative one and cannot be used as an index of differences in mental ability amongst clinically normal individuals. Ellingson further points out that the criteria used to judge both normal behaviour and brain activity have varied between authors, controls have been poor and methods deficient, and data are rarely reported on the reliability of the EEG. At best the correlations are low and although statistically significant are not large enough to be useful in identifying single individuals. It is quite possible that inappropriate information is being used in the EEG and techniques of analysis are often very simple. Moreover, investigations of the relationship between brain activity and behaviour have been almost exclusively cross-sectional in nature. Longitudinal studies would provide more informative data on such critical issues as individual differences in maturation and developmental outcomes.

Investigations of evoked potentials have also failed to produce any reliable index of intelligence and psychological function (Schenkenberg, 1970; Schenkenberg and Dustman, 1971; Thompson, 1978; Lowe et al, 1979).

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Individual variability, particularly in children, is so large and the reported differences in latency, amplitude and asymmetry of the waves of the evoked potentials so small, that significant differences can easily be lost and individual findings cannot be identified. Symmes and Eisengart (1971) draw attention to the problems of the huge variation in evoked potentials, not only between children but also during the recording of one child, and argue that extraneous variation due to lapses in attention presents more problems when working with children than with adults. Also eye blinks and eye movements occur frequently in the young and can produce a consistent artifact at the same latency as the late components of the evoked response to visually presented stimuli (Shelburne, 1973).

Conclusions

In spite of the fact that we have been able to record electrical activity through the intact skull for many years, very little is as yet understood about the exact relationship between the EEG and neuronal, biological and psychological function. At best we can record changes or signs within the EEG which are known to occur consistently at the same time as some aspect of behaviour or some change in physiological function. The data on these EEG signs are useful in studies of the premature infant and the neonate. Thus early in development, EEG changes appear to relate to universal innate maturational patterns whereas later in development individual differences become manifest and environmental and psychological factors complicate the findings. The research data on later developmental changes are fragmentary and the suggested significance of the EEG changes can only be tentative. Such psychological milestones as those of sensori-motor development and the emergence of speech have been relatively neglected in EEG and related research. Moreover, in the bulk of EEG and related research to date, data on brain activity in infants and young children have tended, implicitly or explicitly, to be evaluated against criteria derived from studies of adult subjects. Often this has resulted in findings being interpreted as manifesting a lack of, or a reduced level of, function with respect to some adult characteristic. This orientation has identified some fascinating and important associations between electrophysiological activity and maturation patterns in the premature infant and the neonate. On the other hand, it is an orientation which tends to overlook the potential uniqueness of many processes to the infant and young child. Recognition of such uniqueness has been the occasion for significant advances in other areas of developmental psychology. It is perhaps in this direction that the most promising future of developmental psychophysiology lies.

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Noda, H. and Adey, W. R. (1970) Firing variability in cat associated cortex during sleep and wakefulness. Brain Res., 18, 513-526.

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CHAPTER SIX

ASYMMETRY OF CEREBRAL HEMISPHERIC FUNCTION DURING DEVELOPMENT

ANDREW W. YOUNG

Introduction

The cerebral cortex of the human brain is divided into two cerebral hemispheres. The hemispheres are connected to the body by nerve tracts mediating sensation and movement, whose principal organization is contralateral. In other words, the left hemisphere is primarily responsible for sensation and movement of the right side of the body, whilst the right hemisphere is primarily responsible for sensation and movement of the left side of the body. It should be noted that in both cases there are ipsilateral nerve connections between the left hemisphere and the left side of the body, and between the right hemisphere and the right side of the body. The contralateral nerve fibres predominate, however, and the precise role of the ipsilateral fibres is not fully understood.

This ‘crossed’ arrangement of the nervous system is found in many species (Dimond, 1972), though why it evolved is not known. In addition to the ipsilateral and contralateral connections to the body, the cerebral hemispheres are connected to each other by bundles of nerve fibres. In man, the principal interhemispheric connections are mediated through the corpus callosum and the anterior commissure (Seines, 1974; Gazzaniga and Le Doux, 1978).

The fact that most people show a preference for the use of the right hand for a number of activities was noted in ancient times, and has been much discussed ever since. Although individual members of other species may also exhibit lateral preferences, they tend to be less marked than those observed in most humans,

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and when preferences are found they average out across individual animals at about 50 % left preference and 50 % right preference. In contrast, no more than 10% of humans are left-handed (Hardyck and Petrinovich, 1977), though the precise figure obtained depends on the strictness of the criteria used.

During the nineteenth century it was discovered that the majority of adults who suffer serious speech disturbances after unilateral (one-sided) brain injury do so following damage to the left cerebral hemisphere. As well as expressive language (speech and writing), language comprehension was also found to be more likely to be disturbed following left rather than right hemisphere injury. The possibility of a connection between the involvement of the left cerebral hemisphere in both language and right hand preference was quickly seen, and led to the conception of the left hemisphere as being typically the dominant hemisphere and the right hemisphere as minor or non-dominant. This idea held sway in some quarters until quite recently, though not without opposition. Over the last thirty years, however, a convincing body of evidence for right hemisphere superiorities has accumulated (Joynt and Goldstein, 1975), and it would now seem that the cerebral hemispheres each have their own different functions.

Asymmetric organization, then, is typical of certain cerebral hemispheric functions in the adult human brain. The left cerebral hemisphere is specialized for functions of language and speech, and also controls movement of what is for most people the preferred hand, whilst the right hemisphere is superior for a collection of functions that are often rather loosely characterized as non- linguistic and visuo-spatial. These include the perception and memory of nonlinguistic auditory and visual patterns (such as environmental sounds and people’s faces), and spatial ‘reasoning’ (such as when working from an engineering plan). It is not, at present, clear whether functional asymmetries are also typically found in the brains of non-human animals. They have been found in some cases (e.g. Nottebohm, 1970; Dewson, 1976; Trevarthen, 1978), which suggests that the phenomenon may he more widespread than was thought on the basis of studies of lateral motor preferences.

The existence of functional asymmetries between the cerebral hemispheres of the adult human brain raises interesting ontogenetic questions as to how functions are organized in infancy and childhood. For instance, it can be asked whether asymmetry of cerebral hemispheric function is present in infancy, which will be regarded here as the period from birth until two years of age, or whether it develops gradually from an initial bilaterally symmetric organization.

Although such questions are of considerable theoretical and practical importance, they have proved very difficult to answer satisfactorily. The functions being investigated are obviously very complex, and the available methods of investigation are rather indirect. In consequence, conclusions need to be drawn carefully and cautiously. This has not always been done.

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The present chapter is intended to examine our knowledge of asymmetry of cerebral hemispheric function during development. In doing this, no attempt will be made to select only those results that fit a preconceived pattern, or to hide where the gaps in our knowledge lie. In some cases, however, criticisms will be- made of studies that exhibit obvious or characteristic deficiencies. This can create a rather negative impression, but it is necessary in order that the results of unsound studies may be discounted and, it is hoped, in order that such pitfalls are avoided in future investigations.

An excellent review of the development of hemispheric function has been published by Witelson (1977a). The present chapter differs from Witelson not only by including more recent material but also in emphasizing more strongly the importance of studies of the development of normal children and the importance of using methods that are themselves properly researched and understood. The potential value of the application of techniques deriving from experimental psychology to enable a degree of precision in pinpointing the sources of obtained laterality effects will also be stressed.

Organization of function in the adult brain

Before examining the available evidence concerning asymmetry of cerebral hemispheric function during development, it is necessary to clarify certain important features of the organization of cerebral hemispheric functions in the adult brain. It needs to be made clear that some functions are more asymmetrically organized than others and, although this chapter will concentrate on the asymmetrically organized functions, it must not be forgotten that there are many functions that are quite symmetrically arranged (Trevarthen, 1978).

The most marked asymmetry seems to occur for the production of speech, which is almost exclusively under the control of the left hemisphere (Searleman, 1977). The right hemisphere is usually mute or only capable of highly stereotyped utterances. The motor asymmetry involved in the production of speech is much more marked than other motor asymmetries, and left hemisphere control of speech production is found in nearly all right-handed adults, and many left-handers (Goodglass and Quadfasel, 1954; Branch et al , 1964). Hence, left cerebral control of speech production is more common than right- handedness. This point has important implications for developmental theories, since it renders untenable the view that the ontogeny of hemispheric specialization for speech production arises from an increasing and generalized dominance of the left hemisphere consequent on the development of right hand preference.

For the purposes of the present review, the interesting questions raised by the existence of interindividual differences in organization of cerebral function will be ignored, since they have not been studied developmentally, and the pattern of organization of function found in the majority of right-handed adults will be

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regarded as typical. Neither will detailed consideration usually be given to differences between studies in the criteria used for sampling from possible subject populations, since most studies have used subject groups of reasonable size drawn from populations in which the ‘typical’ pattern of organization could be expected to predominate in adulthood.

Despite its being almost completely lacking in the ability to express itself through speech, the right hemisphere does seem to have some capacity to understand language (Searleman, 1977). Zaidel’s (1976, 1978, 1979) studies, especially, have revealed an extensive auditory and a rather more restricted visual comprehension vocabulary, and some syntactic competence as well. It does not, however, appear to be the case that the right hemisphere’s vocabulary is merely an impoverished version of that of the left hemisphere. Instead, the right hemisphere is relatively capable of understanding concrete, imageable words (Searleman, 1977; Marcel and Patterson, 1979) and poor at understanding abstract words.

There is evidence, then, indicating that there are qualitative differences between the language abilities of the left and right hemispheres of the adult brain. The position is much less clear with regard to those abilities for which the right hemisphere shows superiority. These have been comprehensively reviewed by Joynt and Goldstein (1975). For the sake of simplicity, they will be loosely grouped here into ‘perceptual’ and ‘spatial’ abilities.

Although real, these right hemisphere superiorities are often not large, and in many cases would seem to represent quantitative rather than qualitative differences to left hemisphere abilities. In the case of nonlinguistic visual and auditory perceptual superiorities, for instance, both the left and right hemispheres are able to carry out the processes concerned, but the right hemisphere is in some way more efficient. This is one reason why the term ‘superiorities’ is used here with reference to the right hemisphere, rather than ‘specializations’. There is no sense in which the left hemisphere might be regarded as blind or deaf. This point is emphasized by Gazzaniga and Le Doux (1978), who regard the existence of right hemisphere superiorities as a side-effect of the left hemisphere’s language specializations. The only known case in which a claim for a qualitative perceptual superiority of the right hemisphere might be made is that of face recognition, but the evidence indicating that this may be a qualitative rather than a quantitative right hemisphere superiority is far from convincing (Ellis, 1975).

Certain complex spatial tasks, such as finding one’s way about and dressing, are more adversely affected by right than by left hemisphere brain injuries (Joynt and Goldstein, 1975). Similarly, in normal people, although there does not seem to be any difference in basic tactual perceptual abilities between the left and right hands, left hand (and hence presumably right hemisphere) superiorities can be shown for tasks with a degree of ‘spatial’ complexity (Corkin, 1978) such as

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identifying the direction of raised lines felt by touch (Varney and Benton, 1975). Present knowledge of what is involved in such spatial abilities is, however, so rudimentary that it cannot be stated with certainty whether qualitative or quantitative superiorities are involved. Le Doux, Wilson and Gazzaniga (1977) and Gazzaniga and Le Doux (1978) maintain that to the extent that such tasks demand active manipulation of materials (which most do) qualitative interhemisphere differences do arise. They attribute such differences to an involvement of the inferior parietal lobule of the left hemisphere in linguistic at the expense of manipulospatial functions. On this view the right hemisphere is superior for manipulospatial functions only to the extent that the left hemisphere’s language specializations have led to its being deficient in manipulospatial functions.

This brief summary of our knowledge of interhemisphere differences in the adult brain gives some idea of the complexity of the phenomenon of cerebral asymmetry, and how little is understood as to its true nature. Many people have found it convenient to adopt summary dichotomies to describe the functions of each hemisphere, such as left-dominant right-minor, left-verbal right-visuo- spatial, or left-analytic right-holistic. Such descriptions should be treated cautiously. In many cases they distort what is known by ignoring the extent to which duplication and symmetry of function actually does take place, and the extent to which the cerebral hemispheres work together as an integrated system.

The concept of lateralization

Although the investigation of asymmetry of cerebral hemispheric function during development is seriously hampered both by our lack of knowledge of hemisphere function in the adult brain and by the indirect nature of the methods suitable for work with children, quite comprehensive theoretical statements have been attempted. The most well known of these is that of Lenneberg (1967).

Lenneberg’s principal concern was with language functions, but he also discussed the development of hand preference. He did not really offer a new theory of the ontogeny of cerebral asymmetry, but he did give what was already a widely accepted view its most thoroughly documented and complete expression. Although there are slight changes in emphasis at different points in the book, the main point of Lenneberg’s theory is contained in the view that the extent of lateral asymmetry of organization of particular functions in the left and right cerebral hemispheres is not a fixed characteristic of the human brain, but increases during development in a quite regular manner. In other words, some hemispheric functions are claimed to be progressively lateralized. During the first years of life the cerebral hemispheres are seen as perfectly equipotential for language acquisition, in the sense that either could acquire language with equal facility if the other were injured, and there is no asymmetry of function.

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Functional asymmetry begins to emerge toward the end of the second year, but it is not marked, and the right hemisphere is involved as well as the left in language acquisition. The degree of asymmetry increases throughout childhood, reaching the adult level at puberty. As the extent of lateralization of function increases and the right hemisphere’s involvement in language functions falls behind that of the left hemisphere equipotentiality declines, so that the final organization is relatively fixed.

Although directed toward asymmetries of language and hand preference, this type of theory can easily be extended to include the ontogeny of right as well as left hemispheric functional superiorities, though there have been disagreements as to whether the functions of the two hemispheres lateralize concurrently or with one leading the other (e.g. Corballis and Morgan, 1978). There have also been disagreements about the precise age at which lateralization is completed. Krashen (1973) has suggested completion by age five instead of by puberty, whereas Brown and Jaffe (1975) suggest that the process continues into old age. As none of these theories disagrees over the usefulness or the validity of the concept of lateralization they are all regarded here as fundamentally similar to Lenneberg’s position.

Lenneberg’s theory has many attractive features. Many parents feel that it is difficult to tell at first whether a child will be left- or right-handed. The theory brings together a very wide range of observations, and people always seem to have liked theories that postulate general ways in which children and adults differ. None of these, however, is a very good reason for accepting Lenneberg’s position, and during the last ten years it has become clear that his theory is quite wrong. In order to understand why this is the case, it is necessary to look in detail at the available evidence from the developmental studies that have been carried out. These will be grouped into three general types; studies of neuroanatomical asymmetries, studies using noninvasive methods with normal children, and studies of the consequences of cerebral injuries sustained at different ages.

Developmental studies

Neuroanatomical asymmetries

Our understanding of functional cerebral asymmetries may be at present limited, but knowledge of any corresponding neuroanatomical asymmetries is very scant indeed. None the less, neuroanatomical asymmetries do exist. The most thoroughly researched is the asymmetry of the planum temporale in the posterior region of the superior surface of the temporal lobe (Geschwind and Levitsky, 1968). The planum temporale of the left temporal lobe, which forms part of an area of known importance in language functions, is larger than or equal in size to the planum temporale of the right temporal lobe in approximately 90 % of adults.

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Is such an asymmetry present in the brains of babies? It is quite clear that the answer is yes. Studies by Teszner et al (1972), Witelson and Pallie (1973) and Wada et al (1975) have demonstrated differences in the relative sizes of the left and right planum temporale of the foetal, newborn and infant brain. Opinions differ as to whether the degree of this neuroanatomical asymmetry increases between infancy and adulthood. This is hardly surprising, since it is by no means clear which measurements should be used to effect such a comparison. There is no disagreement, however, that the nature of the neuroanatomical asymmetry does not differ between infants and adults.

It is clear, then, that if functional asymmetries are found in the infant brain, this would not conflict with neuroanatomical knowledge. Similarly, the existence of neuroanatomical hemispheric asymmetries in the newborn makes it difficult (though not impossible) to believe in the complete equipotentiality of the cerebral hemispheres for language functions. On the other hand, as Witelson (1977a) points out, the existence of a neuroanatomical asymmetry is not in itself sufficient to imply that the cerebral hemispheres function asymmetrically in infancy. It may only represent the structural bias underlying later developing functional specializations. Because neuroanatomical findings are ambiguous in this way, it is necessary to look at results deriving from other methods.

Noninvasive methods

A number of methods have been devised in an attempt to study functional asymmetries in the normal, intact brain. Following Witelson’s (1977a) terminology, these will be referred to as noninvasive methods.

It is possible, for instance, to study asymmetries of motor control of parts of the body, and lateral preferences. Ontogenetic studies of lateral preference have been carried out for a long time. More recently attention has also been given to asymmetries following auditory, visual or tactile stimulus presentations, and these procedures have been adapted for use with children and, in some cases, infants.

In examining these noninvasive methods, studies of asymmetries in children for processing auditory, visual and tactile stimuli will each be considered in turn. Studies involving the auditory or visual presentation of stimuli to infants will then be discussed, and finally studies of asymmetries of motor control and lateral preferences.

Auditory presentation. The principal auditory nerve connections are contralateral, so that material presented to the right ear is directed to the left cerebral hemisphere and material presented to the left ear is directed to the right cerebral hemisphere. However, substantial ipsilateral auditory nerve connections between the left ear and left hemisphere and between the right ear and right hemisphere also exist.

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When different linguistic stimuli (such as spoken digits) are presented simultaneously, one to each ear, the stimulus presented to the right ear tends to be reported more accurately than that presented to the left ear (Kimura, 1961, 1967). This general method has come to be known as dichotic stimulation, and is readily adapted for use with children. The finding of right ear superiority for linguistic material would seem to reflect its more efficient transmission to the specialized language areas of the left cerebral hemisphere, but it has also been thought that the ascendancy of the contralateral over the ipsilateral auditory nerve connections is particularly marked when both ears are simultaneously stimulated (Kimura, 1967; Cohen, 1977). When material is presented to one ear at a time the differences between ears are small and their demonstration requires the use of sensitive measures (Studdert-Kennedy, 1972; Fry, 1974; Morais and Darwin, 1974) or difficult tasks (Bakker, 1969, 1970; Frankfurter and Honeck, 1973; Van Duyne et al , 1977).

As well as its use in investigating the language specializations of the left hemisphere, the dichotic stimulation technique can also be used to study right hemisphere (and hence left ear) superiorities for the processing of some nonlinguistic auditory stimuli (Gordon, 1970, 1974; Knox and Kimura, 1970). For clarity and convenience the use of dichotic stimulation techniques to study the development of left and right hemispheric abilities will be discussed separately.

The studies of the ontogeny of right hemisphere superiorities for processing nonlinguistic sounds can be quickly dealt with, as few have been carried out. The principal studies are those of Knox and Kimura (1970) and Piazza (1977). Neither of these studies, nor the two unpublished studies referred to by Witelson (1977a), found any change in the left ear advantage across age in the range three years to adult.

The overwhelming majority of dichotic stimulation studies involving children have been addressed to the development of left hemisphere specializations. Witelson (1977a) gives a detailed summary of the methods and findings of over 30 published and unpublished studies carried out up to 1976. These studies differ on many points of methodology. Considering only the published studies reviewed by Witelson, the stimuli used included isolated speech sounds and nonsense syllables (Berlin et a/., 1973; Dorman and Geffner, 1974; Geffner and Dorman, 1976), spoken digits (Kimura, 1963, 1967; Inglis and Sykes, 1967; Bryden, 1970; Knox and Kimura, 1970; Geffner and Hochberg, 1971; Satz et al , 1971; Sommers and Taylor, 1972; Satz et al, 1975; Witelson, 1976a, 19766; Kinsbourne and Hiscock, 1977; Bryden and Allard, 1978), words (Knox and Kimura, 1970; Nagafuchi, 1970; Sommers and Taylor, 1972; Goodglass, 1973; Ingram, 1975a) and animal names (Bever, 1971). In some studies a report was required after each pair of stimuli, whilst in others two, three or even four pairs were presented before report of as many stimuli as possible was required. Both

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vocal and non vocal (such as pointing to a picture of a word’s referent) methods of reporting were used. There were also differences as to whether only right- handed children were used as subjects, and the criteria for establishing handedness when this was done. In addition, a point not taken up by Witelson (1911a) is that various different methods of aligning the left and right ear stimuli for ‘simultaneous’ presentation have been tried (Morton et a/., 1976).

Given that there have been such marked methodological differences between studies, the findings are surprisingly consistent. Almost all of the studies found right ear superiorities for the processing of linguistic stimuli, and almost all found right ear superiorities in the youngest groups of children studied. This has also been true of reports published since Witelson’s review was written (e.g. Mirabile et al, 1975; Borowy and Goebel, 1976; Geffen, 1976; Hynd and Obrzut, 1977; Hiscock and Kinsbourne, 1977; Piazza, 1977; Geffen, 1978; Geffen and Sexton, 1978; Geffen and Wale, 1979; Sextcn and Geffen, 1979). In a number of the published reports (Nagafuchi, 1970; Bever, 1971; Ingram, 1975a; Hiscock and Kinsbourne, 1977; Kinsbourne and Hiscock, 1977; Piazza, 1977) right ear superiorities have been demonstrated in children as young as three years old. Moreover, none of the studies that have investigated such young children has failed to find right ear superiorities.

It is clear, then, that insofar as right ear advantages for reporting dichotic linguistic stimuli are dependent on cerebral asymmetry for language functions, such asymmetries are present from at least three years of age. Supporters of the concept of progressive lateralization have, however, tended to see the most important question as being not so much the ages at which ear asymmetries can be demonstrated, but rather whether the degree of right ear superiority increases across age (Satz et al ., 1975). This is based on the contention that as the degree of cerebral hemispheric functional asymmetry increases, the size of ear advantages for dichotic stimulation should also increase. In other words, dichotic stimulation is regarded as a parametric measure of cerebral asymmetry. This view requires more careful consideration.

The first point that must be made is that even when dichotic stimulation scores are analysed by parametric statistical procedures most studies have not found the degree of right ear superiority for linguistic material to vary across age. In a small minority of studies, however, ear asymmetry was found to increase with increasing age (Bryden, 1970; Satz et al, 1975; Bryden and Allard, 1978). This raises the difficult question of the proper interpretation of findings of this type.

If it were the case that it is appropriate to regard dichotic stimulation as a parametric index of cerebral asymmetry, then the findings of Bryden and of Satz might substantiate the idea that the degree of cerebral asymmetry increases with increasing age. However, there are serious difficulties to be overcome before such a conclusion could be reached. No one has been able to demonstrate satis-

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factorily that the sizes of ear asymmetries are sufficiently closely or uniquely related to the degree of asymmetry of cerebral hemispheric function to serve as an index (Berlin and Cullen, 1977; Witelson, 1977a; Colbourn, 1978). Although it is probable that some modest relationship exists, there are many factors besides cerebral asymmetry which may influence the magnitude of ear advantages. A list of these factors would include the difficulty level of the task to particular subjects (and hence ‘ceiling’ or ‘floor’ effects), individual differences in the relative functional predominance of contralateral and ipsilateral auditory nerve fibres, different strategies for organizing reports of left and right ear stimuli, and attentional biases toward a particular ear. Moreover, the level or levels of stimulus processing at which ear asymmetries due to functional cerebral asymmetries can arise are not properly understood, and few investigations have explicitly controlled for the possibility that the contribution to observed asymmetries arising from different levels of information processing may vary between subjects. All of these potential influences on the size of obtained ear asymmetries are, of course, particularly likely to influence the outcomes of developmental studies which must necessarily sample across wide ranges of ages.

When these several factors are considered it is even more remarkable that the results of the majority of dichotic stimulation studies have been so consistent. The consistency is probably caused by most of the results happening to arise from the same general source of asymmetry, namely the left hemisphere’s superiority for speech decoding, and the few results that do not fit the main pattern of absence of developmental trends in ear asymmetry are best discounted until methods that allow more control over the factors involved are available. This conclusion is strengthened by the failure of Bakker, Hoefkens and Van Der Vlugt (1979) to confirm the developmental trend of Satz et al (1975) using a longitudinal instead of a cross-sectional research design.

From this discussion it is apparent that studies of ear asymmetry to dichotic linguistic stimulation in children must develop better methods for controlling unwanted sources of variance and for identifying the levels of stimulus processing at which cerebral asymmetries arise. Some researchers are beginning to do this. Most notably, an elegant series of studies by Geffen and her colleagues (Geffen, 1976, 1978; Geffen and Sexton, 1978; Geffen and Wale, 1979; Sexton and Geffen, 1979) has demonstrated that when attentional strategies are properly controlled there is no variation across age in the degree of right ear advantage for speech perception. Conversely, Geffen also found that the ability to deploy attentional strategies did vary across age, and that the use of attentional strategies can affect the size of obtained ear asymmetries, so that this factor does need to be controlled.

The identification of the levels of stimulus processing at which cerebral asymmetries arise is more difficult to achieve than the control of attentional strategies, but some progress is also being made. Consider, for instance, what

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aspects of cerebral asymmetry might contribute to the right ear advantage for linguistic stimuli. Two broad classes of effect can be readily distinguished. These are effects attributable to the left hemisphere’s superior abilities for the analysis and temporary storage of speech sounds, which will be called speech decoding asymmetries, and effects attributable to the different types of word that can be recognized by the left and right hemispheres, which will be called lexical asymmetries . Within the class of speech decoding asymmetries a further distinction might be drawn as to whether the asymmetries arise at the level of immediate perceptual analysis, or whether some short-term memory component is involved (as when multiple pairs of stimuli are presented before a report is required).

It is quite clear that a major contribution to obtained ear advantages is made by the general class of speech decoding asymmetries, which are sufficient to account for most of the observed results. This is evident from the fact that many of the ear asymmetries in the studies cited did not depend on the presentation of complete words, but could be obtained when isolated speech sounds or nonsense syllables were used as stimuli. It seems, too, that these speech decoding asymmetries can arise at the level of immediate perceptual analysis, but are heightened when a short-term memory component is introduced into the experimental task (Oscar-Berman et al , 1974; Yeni-Komshian and Gordon, 1974). This has important implications for developmental studies, which have been very free in varying the short-term memory requirements of the tasks used, as Porter and Berlin (1975) point out. It is likely that tasks with a large shortterm memory component will produce developmental trends in ear asymmetry not because cerebral asymmetry changes across age but because of age differences in short-term memory abilities and hence task sensitivity.

Ear asymmetries belonging to the lexical class obviously cannot arise when isolated speech sounds or nonsense syllables are used as stimuli. Although findings of lexical class ear asymmetries have been made in studies of adults using words as stimuli (McFarland et al, 1978; Kelly and Orton, 1979) they are by no means always found (e.g. McFarland et al, 1978; Kelly and Orton, 1979; Young and Ellis, 1980) and probably only arise under conditions that are not typical of most dichotic stimulation studies. The only study to date that has separately considered the possible implications for developmental findings of the distinction between the classes of auditory asymmetries described here as due to speech decoding and lexical factors has been that of Eling et al (1979).

In summary, then, studies of ear asymmetries to dichotic stimulation in children indicate that left hemisphere specializations for speech decoding and right hemisphere superiorities for the analysis of some nonlinguistic sounds are present down to at least three years of age. In most of the studies carried out the magnitude of ear asymmetries did not vary across age. In the few cases where the degree of ear asymmetry did increase with increasing age there is no reason to

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believe that this was a consequence of any process of increasing lateralization of cerebral hemispheric function.

Visual presentation. The optic nerve pathways are organized in such a way that information about visual stimuli falling to the left of the point at which a person is looking (in the left visual hemifield) is projected initially to the right cerebral hemisphere, whilst information about stimuli falling to the right of the point at which a person is looking (in the right visual hemifield) is projected initially to the left cerebral hemisphere. It is not established with certainty whether or not there is some degree of ipsilateral optic projection for stimuli falling close to the visual midline in the foveal and parafoveal regions of the retina, but outside this disputed area the projections are known to be exclusively contralateral (Cohen, 1977; Haun, 1978). This should not be taken as meaning that the left eye sends projections only to the right hemisphere. The fields of vision of each of the eyes overlap to a considerable extent, so that most left or right visual hemifield stimuli are seen by both eyes, and the contralateral optic projections consequently arise from a grouping together at the optic chiasm of the nerve fibres from the corresponding side of the retina of each eye. Because of this anatomical arrangement, the phenomena of eye dominance bear no clear relation to cerebral asymmetry (Porac and Coren, 1976), and will not be discussed.

If we know where a person is looking, then, it is possible to present visual stimuli in such a way that information is initially projected to whichever cerebral hemisphere we choose. Unfortunately, the presentation of a visual stimulus usually leads to an involuntary movement of the eyes to bring it into central vision. It is thus necessary to restrict the presentation time of stimuli to a time less than that needed to make such an eye movement. Estimates of this time vary, but it is usual to regard presentation times of 200 milliseconds (one-fifth of a second) or less as acceptable (Cohen, 1977).

The need to use briefly presented stimuli falling outside central vision obviously places a serious constraint on what can be studied using this technique, but a surprising amount has been achieved despite the limitations. It must be made clear, however, that the method can only permit the initial projection of stimulus information to one cerebral hemisphere or the other. What happens after that is not well understood, though it is probable that information is coordinated by means of the neocortical commissures, and the anterior commissure in particular (Risse et al ., 1978). Most investigators have been sufficiently reassured by the contralateral nature of the optic pathways to use unilateral stimulus presentations (in which stimuli appear only in one visual hemifield), but a case that bilateral presentation (in which different stimuli appear simultaneously in each of the visual hemifields) is a rather better procedure can be made out (McKeever and Huling, 1971; Hines, 1975). Although methods that can allow continuous lateralized input have been

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developed (e.g. Zaidel, 1975) these have not been adapted for use with children.

When words are presented briefly in the left or the right visual hemifield and right-handed adults are asked to name them it is usual to find a right visual hemifield (RYF) superiority (Mishkin and Forgays, 1952; McKeever and Huling, 1971). This RVF superiority is principally due to information about words falling in the RVF being directly projected to the left cerebral hemisphere. However, it has also been claimed to relate to the fact that English is read from left to right. The argument in this case is that the memory trace of the stimulus is initially ‘examined’ by the subject with a left to right scan starting from the point of fixation (Heron, 1957; White, 1969, 1972, 1973). Hence, the RVF superiority would arise from a ‘post-exposural trace-scanning’ mechanism deriving from experience in reading.

This trace-scanning notion no longer needs to be taken very seriously. It can be varied so freely as to become almost unfalsifiable, and even if true it could only be making a minor contribution to the patterns of results found in studies that have used words as stimuli rather than arrays of unrelated letters (McKeever, 1974; Pirozzolo, 1977). It is known, for instance, that the RVF advantage holds for vertically as well as horizontally arranged words and for words in the Hebrew language, which is read from right to left (Barton et al , 1965; Carmon et al , 1976). Furthermore, the size of the RVF superiority is not constant for all types of word, but has been shown to be larger for abstract than concrete words (Ellis and Shepherd, 1974; Hines, 1976, 1977). This pattern of results is most readily interpreted by postulating that both cerebral hemispheres of the adult brain possess at least rudimentary abilities to decode print stimuli, so that the word-class effect derives from the different types of word that can be recognized by the left and right hemispheres.

Another convincing reason for interpreting the results of studies using brief lateral presentations of visual stimuli in terms of functional cerebral asymmetry is that in several studies using nonlinguistic visual stimuli left visual hemifield (LVF), and hence presumably right hemisphere, superiorities have been demonstrated (Kimura and Durnford, 1974). Face recognition has proved to be a particularly useful task in this respect, with many subsequent reports confirming the findings of LVF superiorities by Rizzolatti et al (1971) and Hilliard (1973).

The use of the visual modality of stimulus presentation in studies of asymmetry of cerebral hemispheric function in children is potentially of great interest because of the wide range of skills that can be examined and the considerable range of ages at which the differing skills are learnt. The ability to identify visually represented words, for instance, is achieved at a much older age than is the ability to recognize faces. Unfortunately, a large rumber of theoretical and methodological difficulties are encountered in the case of visual presentation, and progress has been slow in comparison with that made by

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studies using dichotic stimulation. There have not been nearly as many studies carried out, and several of those that have been attempted are seriously flawed.

The most pressing methodological requirement in studies of visual hemifield asymmetries in children is to control fixation. Studies of adults usually rely on a central fixation spot, which subjects are asked to fixate before each stimulus is presented. This procedure is obviously of dubious validity in a developmental investigation. Children may fail to fixate when instructed to do so for a number of reasons. The consequence of a failure by children to fixate when instructed is that stimuli will not fall in the positions in the visual field intended by the experimenter, and will probably be distributed randomly, thus reducing or eliminating ‘visual hemifield’ differences. Since younger children will be more likely to fail to fixate than older children, a bias will be introduced making it probable that findings of differences in asymmetries across age will arise as an artifact of lack of fixation. Moreover, the temptation not to fixate when instructed may be itself related in a complex manner to the difficulty of particular experimental tasks to particular subjects. For these reasons, some form of fixation control is necessary in developmental studies of visual hemifield asymmetries, and all developmental trends found in studies without adequate fixation control (such as Jeeves, 1972; Miller and Turner, 1973; Barosso, 1976; Reynolds and Jeeves, 1978a, 1978b; Tomlinson-Keasey et al ., 1978) must be discounted as irrelevant to any considerations of asymmetry of cerebral hemispheric function.

A difficulty which is partly methodological and partly theoretical is that of ensuring that subjects of different ages are relying on the same cognitive processes or strategies when faced with a given task. It is often assumed that the use of linguistic stimuli will automatically engage specialized left hemisphere mechanisms and lead to a RVF advantage, whilst the use of nonlinguistic stimuli will produce no visual hemifield difference or a small LVF advantage. Cases are known in the adult literature, however, where this generalization breaks down. Matching tasks provide a simple example. Suppose that a pair of words or a pair of letters is presented in one visual hemifield, and subjects are asked to say whether they are the same or different. This can be determined either by comparing the physical appearances of the stimuli (physical match) or by naming them and comparing the names (name match). Studies by Cohen (1972) and Gibson, Dimond and Gazzaniga (1972) have demonstrated that whereas name matches yield RYF advantages, physical matches may be more effectively carried out for LVF stimuli. The implication for developmental studies is that if matching tasks are used they must be arranged in such a way that subjects are forced to adopt only one of the possible strategies. If this is not done, differences across age may simply be attributable to strategy differences. Witelson (19776) first noticed this potential artifact in one of her own studies, but the criticism applies equally to the differences across age found by Tomlinson-Keasey et al.

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(1978) and in Broman’s (1978) experiment involving matching pairs of letters. The general point that it is important to know how subjects actually approach experimental tasks applies, of course, to a lot more than just matching tasks.

Having made these methodological cautions and eliminated some of the more poorly designed studies, the principal studies of visual hemifield asymmetries in children will now be considered, starting with studies of right hemisphere (LVF) superiorities.

The most common task used to investigate LVF superiorities, as in the adult literature, has been face recognition. Young and Ellis (1976) found LVF superiorities for face recognition in five-, seven- and eleven-year-old children, with no differences across age in the degree of visual hemifield asymmetry. Broman (1978) found no developmental differences in LVF superiority for face recognition in the age range seven years to adult. Marcel and Rajan’s (1975) study of seven-year-old children also showed a LVF superiority for face recognition. In contrast, failures to find LVF superiority in seven- and eight-year-old children have been reported by Leehey (1976) and Reynolds and Jeeves (1978b). Reynolds and Jeeves’ study, however, lacks adequate fixation control. Leehey (1976) reports three developmental experiments on visual hemifield asymmetries for face recognition by subjects aged eight to adult that are in most respects carefully designed. When she used bilaterally presented photographs of the faces of people known to her subjects a LVF superiority was found at all ages, but with bilaterally presented unfamiliar faces the eight-year-old children gave no visual hemifield difference in two experiments. Unfortunately, Young and Bion (1980a) were unable to replicate this result, and have suggested that it was probably due to an age difference in directional reporting strategies arising from Leehey’s use of bilateral stimuli without controlled order of report. Studies of visual hemifield asymmetries thus give no grounds at present for claiming any developmental change in the extent of the right hemisphere’s superiority for face recognition.

Studies of right hemisphere superiorities using visual presentation and tasks other than face recognition have also failed to reveal developmental trends. Witelson (1977b) found a LVF superiority for matching pictures of human figures (a task which can only be done by means of a physical match) in boys aged six to thirteen years. Witelson (1977a) described an unpublished experiment finding a tendency to greater LVF accuracy for dot enumeration (p < 0.1) in six- to thirteen-year-old boys. Young and Bion (1979) found greater LVF accuracy for dot enumeration in boys aged five, seven and eleven years, but no visual hemifield accuracy difference in girls. A similar sex difference was found in adult subjects by McGlone and Davidson (1973). The absence of any developmental trend in LVF superiority for dot enumeration is interesting in view of the fact that it is a skill that is present in only a rudimentary form before age three, and even after three years is learnt quite gradually (Klahr and Wallace, 1973;

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Young and McPherson, 1976), whereas recognition of many faces is possible in the first year of life (Schaffer, 1971; Ellis, 1975). It is thus clear that the absence of reliable developmental trends in asymmetry of face recognition by children aged five and above is not simply due to the early age at which the skill is acquired.

Two findings of LVF superiority in children allegedly induced by means of a spatial mental set must also be noted (Kershner et al , 1977; Carter and Kinsbourne, 1979). Only Carter and Kinsbourne tested more than one age group of children, and found no developmental differences in the tendency of spatial priming to produce a LVF superiority for digit naming.

Most studies of visual hemifield asymmetries for linguistic stimuli in children have used printed words. In several cases the principal focus of interest was not so much whether there were differences across age as the possibility of differences between normal and poor readers (Beaumont and Rugg, 1978). These studies will only be referred to when they provide data relating to normal readers under ten years of age.

The general finding has been one of RVF superiorities in normal readers down to as young as six years of age (Olson, 1973; Marcel, Katz and Smith, 1974; Marcel and Rajan, 1975; Carmon, Nachshon and Starinsky, 1976; and one of the experiments of Turner and Miller, 1975). Forgays (1953), however, did find an increase in visual hemifield asymmetry with increasing age. Turner and Miller (1975) and Butler and Miller (1979) reported larger asymmetries when using five- rather than three-letter words. Turner and Miller (1975) also found changes across age when using five-letter words, but not when using three-letter words, though Butler and Miller’s (1979) results did not confirm this observation. It is probable that these somewhat confusing results derive from a failure properly to control the characteristics of the words used. Longer words are more likely than short words to be abstract, and hence to produce larger visual hemifield asymmetries for reasons already mentioned. Conversely, the words recognized by young children under conditions of brief lateral presentation are likely to be mainly concrete, with older children recognizing a more even mixture of concrete and abstract words. Since smaller visual hemifield asymmetries derive from concrete than from abstract words a change in the size of the obtained visual hemifield asymmetry across age will ensue if scores from abstract and concrete words are pooled, but it has nothing to do with any possible difference across age in the organization of cerebral hemispheric functions. Studies which exercise proper control over the characteristics of stimulus words used are clearly needed.

Some developmental studies of left hemisphere specialization have tried using letters instead of words as stimuli. Of these, only the one reported by Carmon et al (1976) meets the minimal methodological requirements specified here. Carmon et al found traces of a developmental trend in visual hemifield asymmetry when using letters as stimuli, but not when using words. The absence

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of a developmental trend in asymmetry with words clearly implies that left hemisphere specialization for at least some of the skills involved in the recognition of visually presented linguistic stimuli was present at all ages. Beyond this, all that can be said is that letter recognition is not a very meaningful task for developmental comparisons, since Bryden and Allard (1976) have shown that even with adults the results obtained are easily affected by the difficulty experienced by subjects in reading the typeface employed. The more difficult typefaces tend to give LVF superiorities, and it is obviously the case that the difficulty of particular typefaces will vary across age.

Taken together, then, the findings of studies of children using visual hemifield stimulus presentations do not support the idea that the degree of asymmetry of organization of cerebral hemispheric functions varies across age. It has only proved possible to date to work with children down to age five, but this disadvantage is offset by the fact that some of the skills that can be studied are being learned at these ages, allowing the possibility of the investigation of initial stages of organization. What is now needed is a more precise analysis of the particular skills used at different ages for word recognition and other tasks, so that these skills can be examined separately. This might throw some interesting light on the role (or absence of any role) played by the right hemisphere in the early stages of learning to read. A related question which has not received the attention it deserves concerns the way in which the right hemisphere acquires the ability to recognize those words it can identify in adulthood. The results of studies by Ellis and Young (1977) and Young and Bion (1980b) suggest that the nature of the difference between the ‘visual vocabularies’ of the left and right hemispheres is semantic, and unrelated to the ages at which different words are first learnt.

Tactile presentation. Although both ipsilateral and contralateral somatosensory nerve connections exist, they are organized into discrete systems that probably serve different purposes (Wall, 1975). It is thought that ‘active’ touch and proprioception (Gibson, 1962) are mediated primarily through the contra- laterally organized pathway passing through the dorsal column and medial lemniscus, whilst passive touch, pain and temperature depend on the spinothalamic system, which has both ipsilateral and contralateral projections (Gazzaniga and Le Doux, 1978).

A useful review of the evidence relating to the role of different cerebral structures in tactile perception is given by Corkin (1978), who points out that there is no evidence for any asymmetry in elementary tactual functions. Tactile asymmetries only occur when the task used engages some higher-order function for which one cerebral hemisphere is superior (Corkin, 1978; Young and A. Ellis, 1979). Most of the findings of tactile asymmetries have derived from studies in which active tactile exploration of stimuli was required.

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It is often the case that left hand superiorities are found for complex tactile perception, but in some cases right hand superiorities are observed. Cioffi and Kandel (1979) found a right hand superiority for identifying two-letter abstract words by touch, which was present down to age six. A right hand superiority for the report of sequentially touched fingers was found down to age seven by Bakker and Van der Kleij (1978).

Left hand superiorities for the identification of tactually perceived nonsense shapes have been found down to age six by Witelson (1974,1976a) and by Cioffi and Kandel (1979). These left hand superiorities did not increase with increasing age, but inconsistent sex differences were observed. Using an accuracy measure, Flanery and Balling (1979) also found a left hand superiority for this type of task which did not vary across age down to age seven. However, when they computed laterality coefficients’, differences across age were observed by Flanery and Balling. Since the computation of such coefficients involves several unjustified theoretical assumptions (Colbourn, 1978), and many different coefficients are available that may all lead to differing outcomes, it is not possible to satisfactorily interpret this particular result.

In some studies, Braille patterns of raised dots have been used as stimuli. Hermelin and O’Connor (1971a, 1971b) found that blind adults and children aged eight to ten years were better at reading Braille with the left than right hand. Rudel et al (1974), however, found that sighted children did not learn Braille letters more accurately using the left hand until they were over ten years of age. Witelson (1977a) objected that the use of a naming task with raised dot stimulus patterns confounds the linguistic and spatial components of the task, but Rudel et al (1977) repeated the finding in a study that required that raised dot configurations only be discriminated, not named.

One curious aspect of Rudel et a/.’s (1977) findings was that not only did children aged over ten years show left hand superiority, but children below ten showed a tendency toward right hand superiority. Attention has been drawn to this because it illustrates the danger inherent in regarding the results of studies of this type as direct measures of asymmetry of cerebral organization. Surely no- one would want to maintain that spatial functions moved from the left to the right hemisphere at age ten? What is evidently happening is that the type of task used by Rudel and her colleagues can be approached using more than one solution strategy, and the younger children rely on a method that involves the left hemisphere to some extent. Their conclusion should thus have been not that cerebral asymmetry varies across age but that more needs to be known about the possible ways in which subjects can approach this type of task. A similar point has been made by Bertelson (1978).

It should by now be clear that the minimum requirement for demonstrating that the extent to which particular cerebral hemispheric functions are asymmetrically organized changes across age is to show that younger children do not

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give a lateral superiority when using the same method of dealing with the given task that produces the lateral superiority observed in older children. This requirement applies generally to studies using auditory, visual or tactile presentation, and it has never been met by any of the studies claiming to find developmental differences in asymmetric cerebral organization. Consequently, the only valid conclusion at present with regard to tactile asymmetries is that left or right hand superiorities for tactile perception can be demonstrated in children down to at least age six under appropriate conditions.

Studies of asymmetries in infants for processing auditorily or visually presented stimuli. The failure of studies of asymmetries during childhood for processing laterally presented stimuli to provide any convincing evidence of changes across age in the asymmetric organization of cerebral hemispheric functions, and the existence of neuroanatomical asymmetries in infants, has led researchers to explore the possibility that functional cerebral asymmetries are present in infancy. A number of techniques have been devised, mostly using electrophysio- logical measures.

Electrophysiological studies have shown cerebral hemisphere differences in early infancy in terms of auditory and visual evoked potentials (Molfese et al, 1975; Molfese et al , 1976; Davis and Wada, 1977; Molfese, 1977; Molfese and Molfese, 1979), EEG power distributions (Davis and Wada, 1977; Gardiner and Walter, 1977), and photic driving (Crowell et al , 1973).

The dichotic stimulation technique has been adapted in order to demonstrate cerebral asymmetries in infants by Glanville et al. (1977), who used a response measure based on heart rate habituation. Entus (1977) also used dichotic stimulation with a sucking response, but a subsequent study (Vargha-Khadem and Corballis, 1979) has not been able to replicate her results.

The findings of these several studies of hemisphere function in infancy convincingly demonstrate that asymmetric organization of function is present, which is incompatible with Lenneberg’s (1967) views. Most investigators have, however, been satisfied to establish the basic point that functional asymmetries can be shown in infancy. Whilst the similarity of the asymmetries found in infants to those found in adults is usually obvious, this tactic avoids questions as to the precise mechanisms involved, and leaves open the possibility that some changes across age might occur. However, since studies of asymmetries for processing perceptually presented stimuli in infants and children have so consistently failed to produce any satisfactory supporting evidence for the notion of progressive lateralization of abilities, it is unreasonable to believe that such changes do occur unless strong supporting evidence can be found elsewhere.

Asymmetries of motor control and lateral preferences. It was mentioned in the introduction to this chapter that the principal innervation of movements of the

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body is mediated through contralateral nerve tracts. Although ipsilateral nerve fibres also exist, their role is not fully understood, but it is thought that their influence is confined to relatively gross movements. An example might be moving a hand by moving the whole arm. Fine motor movements, and especially movements from the level of the wrist of the hands and fingers, are seen as normally involving a relatively high degree of contralateral control (Brinkman and Kuypers, 1972, 1973; Trevarthen, 1974,1978). For this reason, in examining asymmetries of motor control and lateral preferences, particular attention will be paid to the fine control of movements of the hands and fingers.

An important distinction which needs to be made when considering motor asymmetries concerns the difference between lateral preference and relative skill (Annett, 1970; Ingram, 19757?; G. Young, 1977). This is perhaps best illustrated by means of an example. Most right-handed people will always write with their right hand, and nearly always pick up a pen with their right hand. The degree of preference for use of the right hand is similar for both activities. If, however, a right-handed person is asked to carry out these activities using his left hand, he is not likely to experience any difficulty in picking up the pen, but left-handed writing will prove to be much more tricky. The degree of relative skill of the hands for both activities is quite different. It is evident that relative manual skill and hand preference are not the same thing, though they are related (Annett, 1976). Their relation is probably most close for the more difficult and skilled tasks, as Brown (1962) found. Even with difficult tasks, however, the relation of preference and relative skill is not exact, and it is possible to find motor tasks that right-handed people can better execute with the left hand (Kimura and Vanderwolf, 1970). In addition to the contribution of asymmetry of cerebral hemispheric motor functions, hand preference can involve an element of choice, with one hand often being preferred regardless of whether the activities might cause considerable or little difficulty to the other. This means that studies of relative skill of the hands at different ages are of more direct relevance to asymmetry of cerebral hemispheric function than are studies of hand preferences (Denckla, 1974; G. Young, 1977).

The distinction of studies of lateral preference from studies of relative skill makes the results of an otherwise confusing body of studies of motor asymmetries during development fall into a neat pattern. Put simply, studies of relative skill have not found increases in asymmetry across age (one or two have actually found decreases), whereas studies of lateral preference have generated a mixture of results seen as indicating changes in lateral preference and results indicating absence of change in lateral preference across age.

A favourite type of task in studies of relative skill has involved comparisons between the hands for the highest speed or greatest accuracy with which repetitive movements can be carried out. Examples would be moving pegs on a pegboard, or tapping rhythms, and studies of this type which have used children

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down to age five or below include those of Knights and Moule (1967), Annett (1970), Denckla (1973, 1974), Ingram (19755), Finlayson (1976), and Wolff and Hurwitz (1976). The total range of ages covered by these studies is from three to sixteen years. All found right hand superiorities, and none produced evidence of an increase in the degree of right hand superiority with increasing age. In some cases, however, asymmetries were found to decrease in magnitude with increasing age (Denckla, 1974; Wolff and Hurwitz, 1976). These results may be attributable to a decrease in sensitivity of particular tasks across the considerable ranges of ages used in the studies concerned. They do, however, also raise the interesting possibility that there may be changes across age in the extent of asymmetric organization of some skills which do not take the form specified by the concept of lateralization.

Other tests of relative skill which have led to right hand superiorities include hand strength (Ingram, 19755; Finlayson, 1976), speed of writing (Reitan, 1971), and duration of grasp of a rattle (Caplan and Kinsbourne, 1976). Caplan and Kinsbourne’s finding, from a study of two- to four-month-old babies, remains the earliest demonstration of a manual asymmetry.

In two tasks used in Ingram’s (1975 5) study of three- to five-year-old children, which involved imitating hand postures or finger spacings, left hand superiorities were obtained, presumably reflecting the right hemisphere’s superiority for the complex spatial component of the tasks. This finding can thus be seen as both confirming the presence of superior right hemisphere spatial functions at age three and illustrating the importance of distinguishing questions of relative manual skill for different tasks from those of hand preference.

An interesting variation on the basic studies of relative skill on single tasks involves dual-task performance. Studies of adults have demonstrated that requiring them to talk whilst carrying out an independent manual task interferes more with right than with left hand performance (e.g. Kinsbourne and Cook, 1971; Hicks, 1975). Such interference probably occurs when speech and right hand movements demand the use of common left hemisphere functions (Lomas and Kimura, 1976). Studies of interference in dual-task performance in children down to age three have shown that the same types of effect occur (Kinsbourne and McMurray, 1975; Piazza, 1977; Hiscock and Kinsbourne, 1978). The only hint of any change across age arises in the report of McFarland and Ashton (1975), but since their groups contained as few as four subjects, sampling bias cannot be ruled out.

Early studies of motor asymmetries in infants and children were almost exclusively addressed to questions of lateral preference (e.g. Wile, 1934; Giesecke, 1936; Gesell and Ames, 1947; Hildreth, 1949). Although most of these studies would now receive low marks for adequacy of methodology and clarity in reporting what was actually done they were in general agreement that lateral preferences, and especially hand preferences, are established gradually

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throughout childhood, with periods of absence of preference or preferences opposite to those finally adopted. Some more recent studies have also reported results of this type both for infants (Cohen, 1966; Cernacek and Podivinsky, 1971; Seth, 1973; Ramsay, 1979) and for older children (Belmont and Birch, 1963), though there are also studies that have not found changes in hand preference across age in infancy (Ramsay, Campos and Fenson, 1979) or childhood (Annett, 1970).

The explanation of these discrepant findings from studies of hand preference lies in the measures used. Annett (1970) and Ramsay et al (1979) both studied hand preference for quite difficult skills. Hand preference for difficult skills is, for reasons explained previously, likely to be relatively closely related to differential skill, and it is studies of differential skill which do not tend to find changes across age. Most of the studies which did find developmental trends in hand preference used measures based on preference for picking up objects. There is no reason to assume that preference for the same actions is being examined at different ages, since there are a number of different ways of manipulating and picking up objects (Elliott and Connolly, 1973; Kopp, 1974; Bresson et al, 1977).

A type of investigation involving motor asymmetries which does not really fit into the scheme of studies of relative skill or studies of lateral preference also deserves mention. In several studies Turkewitz and his colleagues have shown that very young infants turn their heads more often to the right than to the left (e.g. Turkewitz et al ., 1965; Turkewitz et al, 1969; Turkewitz and Creighton, 1975). Although the demonstration of any motor asymmetry at early ages is of interest, no really satisfactory explanation as to the cause of the bias in head turning has been offered.

Studies of the consequences of cerebral injury at different ages

The findings of studies of infants and children using noninvasive methods have failed to provide evidence indicating that the extent to which particular cerebral hemispheric functions are symmetrically or asymmetrically organized changes across age in the manner implied by the concept of progressive lateralization of abilities. Moreover, they have shown that asymmetry of hemispheric function is present in some form in infancy. Both outcomes are clearly at variance with Lenneberg’s (1967) theoretical position. In fairness, however, it must be pointed out that most of this evidence was not available to Lenneberg, and that his theory was mainly derived from studies of hand preference and from studies of the consequences of cerebral injury at different ages.

It is notoriously difficult to draw valid inferences concerning the organization of cerebral functions from the effects of cerebral injuries, and this difficulty is compounded when it is necessary to draw conclusions about possible organizational differences across age. Several of the problems of methodology and interpretation that can arise have detailed in the reviews of Kinsbourne (1976)

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and Witelson (1977a), which seriously criticized many of the interpretations that have been offered. This is not, of course, to deny the great importance of studies of the developmental sequelae of cerebral injuries, but their relevance to understanding asymmetry of cerebral hemispheric function during development has often been overestimated and misunderstood.

The four main aspects of studies of the consequences of cerebral injury that have received attention will be examined in turn. These are the differences across age in the extent of recovery from unilateral cerebral injuries, the claim of the equipotentiality of the cerebral hemispheres for language acquisition, differences across age in the nature of aphasic symptoms, and the possible involvement of the right hemisphere in the early stages of language acquisition. As it will become clear that many of the studies carried out add little or nothing to our understanding of cerebral asymmetry, a systematic review of all the studies will not be attempted.

Age and the extent of recovery from unilateral cerebral injuries. Many studies of language disturbances in children following left hemisphere injury have shown that the younger the child the more rapid and complete is the recovery. Reviews are provided by Basser (1962), Lenneberg (1967) and Witelson (1977a); see also Parker, this volume. This recovery may be in part due to intrahemispheric reorganization of functions within the damaged left hemisphere (Hecaen, 1976), but it is known from cases where the extent of the injury eventually led to left hemispherectomy that considerable acquisition of language functions by the right hemisphere is possible in the first years of life.

These findings have often been taken to indicate that the lateralization of language abilities proceeds gradually throughout childhood, with the right hemisphere being involved in language functions in the early years. In fact, the findings do not indicate this at all. They simply attest to the remarkable ability of the young brain to recover and reorganize functions in response to injury. This is a complex phenomenon in its own right, widespread throughout the animal kingdom, to which there are a number of different contributory processes (Hecaen and Albert, 1978; Lund, 1978). None the less, the finding that recovery can take place tells us nothing about the organization of function before injury. There is no reason to connect loss of‘plasticity’ with an increase in lateralization.

The claim of the equipotentiality of the cerebral hemispheres for language acquisition. The extent of the recovery of language abilities following early left hemisphere injury is so marked that Lenneberg (1967) was led to the conclusion that the cerebral hemispheres are initially perfectly equipotential for language acquisition. This conclusion was supported by reports of the observations of clinicians, but more systematic and quantitative studies have shown that perfect equipotentiality does not obtain (Dennis and Kohn, 1975; Dennis and

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Whitaker, 1976; Dennis and Whitaker, 1977). Although extensive language functioning can be achieved by the right hemisphere following early injury to the left hemisphere, the left hemisphere is better able than the right to subserve language acquisition even in infancy.

Differences across age in the nature of aphasic symptoms. It has long been known that cerebral lesions causing disturbances of language in children (acquired aphasias) do not produce the same pattern of symptoms as found in adults (Guttman, 1942; Alajouanine and Lhermitte, 1965; Hecaen, 1976). The most common form of acquired aphasia in children involves difficulty with or absence of spontaneous expression (mutism), whilst jargonaphasia and logorrhea occur only in adults. Brown and Jaffe (1975) and Brown (1977) have extended these observations, arguing that the different types of aphasia are systematically related to age not only in childhood but throughout the human lifespan.

Such differences across age in the nature of acquired aphasias are of undoubted intrinsic importance and interest, but what do they tell us about asymmetry of cerebral hemispheric function? They might indicate that, at the 'psychological’ level, the organization of language functions and the relative contribution made by different linguistic skills changes during the lifespan, with some skills being developed to the level of practised fluency at which jargon- aphasia and logorrhea can occur. These changes could, however, be associated with intrahemispheric development and organization of processes principally located in the left hemisphere, and the concept of lateralization is not needed.

The possible involvement of the right hemisphere in the early stages of language acquisition. Although it has been customary to include them in discussions of asymmetry of cerebral hemispheric function during development, it is apparent that the lines of evidence concerning the consequences of cerebral injury at different ages described thus far are not really of central importance to the topic. There is one claim, however, which is potentially crucial, and which has been held apart from the others to show its special role in making the other lines of evidence appear to contribute more to our understanding of the problem than they actually do. The claim falls into two parts, which require separate consideration. Firstly, it is held that childhood aphasias are more likely than adult aphasias to occur as a consequence of injury to the right cerebral hemisphere, and secondly it is held that this implies that the right hemisphere is involved as well as the left hemisphere in the early stages of the acquisition of language functions.

The evidence concerning the first part of the claim is not completely convincing. It is clear that the proportion of children over five years of age experiencing aphasic difficulties following left as opposed to right hemisphere injury is comparable to the proportion found for adults (Krashen, 1973; Hecaen,

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1976). For children aged two to five years, however, aphasia following right hemisphere injury would seem to be relatively frequent from the cases reported in the literature. Witelson (1977 a) gives a rough figure of 30%, but there are several difficulties in taking such a figure at its face value, as Kinsbourne (1976) and Witelson (1977a) have stressed. These difficulties include the possibility that many of the right hemisphere injuries were so extensive as to also involve parts of the left hemisphere, the danger of bias toward referral to specialists and reporting of the more unusual cases (i.e. those where aphasia apparently followed right hemisphere injury) and the poverty of the assessments typically given as to the nature, severity and duration of the aphasic symptoms. These methodological problems are not caused by any lack of competence of investigators, and it is difficult to see how they could all be fully overcome. Kinsbourne (1976) concluded that the existence of such difficulties is sufficient to invalidate the reports indicating greater frequency of aphasias following right hemisphere injuries in young children than in adults; Witelson also advocated that such reports should be treated with caution.

The attention paid to the methodological problems inherent in attempts to calculate the relative frequency of aphasias following right hemisphere injury in young children and adults has tended to draw attention away from the question of what the finding of a greater frequency in young children, if valid, should be taken to mean (a notable exception is the discussion by Moscovitch, 1977). Witelson (1977a) felt that it means that the right hemisphere may participate in the execution of language functions in the early stages of language acquisition, but that its contribution is always less than that of the left hemisphere. What needs to be clarified, though, is whether the right hemisphere’s contribution is of the same type as that made by the left hemisphere, as the concept of progressive lateralization of language abilities would imply, or whether it is important because of functions it can execute which would not normally be viewed as linguistic yet are integral to the early stages of language acquisition. Evidence from psychological studies of language acquisition, for instance, indicates that much of the initial organization involved is closely related to understanding of and interactions with the world of objects, events and other people (R. Brown, 1973; Lock, 1978). It is unfortunate that the level of analytic sophistication attained by psychologists has not been applied to neuropsychological studies of childhood aphasia. If this were done, differences between the types of aphasia following left and right hemisphere injuries sustained in childhood might be found. With mutism being the most common symptom this would obviously be difficult, but detectable differences could arise in the patterns of recovery.

At present, then, firm answers to the important questions that have arisen concerning the possible involvement of the right hemisphere in the early stages of language acquisition have not been provided by studies of childhood aphasias following right hemisphere injuries.

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Overview and conclusions

Having examined the available evidence concerning asymmetry of cerebral hemispheric function during development, it is now possible to consider what general conclusions can be drawn. This will necessarily involve discussion of what type of conceptual and theoretical framework is most useful in describing the existing findings and generating new lines of investigation.

The results of the numerous studies that have been carried out show that asymmetric organization of at least some cerebral hemispheric functions is characteristic of the human brain at all ages during postnatal development. Although considerable recovery and reorganization of function can take place following unilateral cerebral injury sustained early in life, the cerebral hemispheres are not equipotential for language acquisition. Thus the claims of absence of functional asymmetry in infancy and perfect hemispheric equi- potentiality for language put forward by Lenneberg (1967) are simply incorrect.

The question as to whether the degree to which functions are asymmetrically organized increases across age cannot be given such a straightforward answer, and requires some clarification. The total number of asymmetrically organized functions may well increase during the first years of life for the simple reason that many are acquired during this period. In this trivial sense, ‘laterality’ quite probably does increase across age. The concept of lateralization, however, is only of real interest as applied to particular functions, for which it implies that unilateral organization develops progressively from an initial organization that is at least to some extent bilateral. It is this sense that was clearly intended by Lenneberg (1967), Krashen (1973) and Brown and Jaffe (1975).

This hypothesis of progressive lateralization of abilities has not found adequate support in the studies that have been carried out, irrespective of whether it is regarded as valid or as invalid to use parametric statistical analyses. When findings have been claimed to demonstrate progressive lateralization of abilities, it has been shown that enthusiasm for the concept of lateralization has led to lack of attention to more prosaic alternative explanations. Of course, as has been pointed out, the available methods of investigation have not always been adapted for work with all ages of children, so that all of the conceivable lines of enquiry have by no means been exhausted. It thus remains possible for people to believe that substantial positive evidence of genuine progressive changes in lateralization will one day be found. However, this is more a statement of faith than a scientific inference, and a more realistic theoretical framework for research findings needs to be built up.

The research approach dictated by the concept of lateralization has been to look for progressive changes in childhood in the extent of the asymmetric organization of certain functions. This means that studies have often been directed toward the possibility of change in functions that are already

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adequately established. The typical investigative tactic has involved the use of one or two tasks and a wide range of ages of subjects. Such studies have been worthwhile insofar as they have led to the conclusion that progressive lateralization of already acquired functions does not take place. Further studies of this type can still be of value in filling in the many missing details. It may now be more interesting, however, to look for changes in organization whilst functions are actually being acquired. For this purpose, the concept of lateralization should be abandoned, since it arbitrarily predetermines what form such changes would be conceptualized as taking, and they may turn out to be more varied. There is, for instance, no reason to discount the possibility that for some skills the extent of asymmetric organization may actually decrease as they become firmly established and integrated into a child’s repertoire.

A useful approach, then, may be to define the basic problem as one of understanding how newly learned skills are integrated with existing functions that are already symmetrically or asymmetrically organized. This shifts emphasis on to the possibility of relatively rapid changes occurring whilst functions are being acquired rather than long-term changes in already acquired functions, and does not prescribe the form such changes might take. It would require careful studies directed toward quite specific skills at the ages at which they are learned. A few studies of this type have been achieved, and suggestions have already been offered where others are obviously necessary, but they demand precise methods of investigation which have only recently begun to be available. As such methods are developed the studies of isolated tasks across wide ranges of ages deriving from the conceptual framework dictated by the concept of lateralization will probably become of less interest than very detailed studies carried out whilst functions such as prehension, enumeration or reading are being acquired.

Acknowledgements

The assistance provided by SSRC grants HR 5078, HR 6398, and HR 6876 is gratefully acknowledged. I am very grateful to Andrew Ellis for helpful discussion of several points of interpretation.

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CHAPTER SEVEN

DETERMINATE AND PLASTIC PRINCIPLES IN NEUROPSYCHOLOGICAL DEVELOPMENT

DENIS M. PARKER

Introduction

To those interested in the relationship between brain mechanisms and behaviour, study of the outcome of damage to the central nervous system currently provides the most useful information concerning the structural basis of cognition and action. Observation of the pattern of behavioural loss and the extent to which recovery is possible following specific brain injury enables differing models of brain organization to be specifically tested. In fact, this question of the pattern of loss and the extent of recovery lies at the heart of a controversy, between the advocates of functional localization and those who proposed a diffuse physical basis for cognitive functions, which began during the nineteenth century. Some investigators stressed the return of almost complete function following a transient period of loss (Flourens, 1824), or stressed the re- emergence of functions at a reduced level while denying that behavioural effects contingent on the damage were specifically related to the region destroyed (Goltz, 1892). These views were amplified during the present century by the experimental work of Lashley (1929) who argued that, excluding the primary sensory and motor areas of the cortex, the association areas contributed in a unified way to the performance of any complex skill—the well-known principle of Mass Action. The degree of functional loss that could be detected following brain damage was assumed to be determined by the extent, rather than the location, of damaged tissue. The results of Lashley’s experiments, together with his theoretical exposition of them, supported the views of Goldstein (1939) who

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regarded cognitive skills as a function of the entire organism. He saw the symptoms following brain damage as manifestations of a complex adaptive syndrome in which higher intellectual abilities, in particular the ability to abstract, were likely to be depressed. This general intellectual loss was likely to be seen in the patients’ failure on a variety of cognitive tasks, but particularly in linguistic skills since these demanded, more than other capabilities, the integrity of the entire brain. Holding views such as these, there was no problem in accounting for the return of functions after cerebral injury since the intact areas of the brain would continue to function in their usual way following an initial period of shock, although there would of course be a loss of efficiency. Factors such as the age of the subject at the time of injury were seen to play a part, and indeed one of Lashley’s students (Tsang, 1937) had provided evidence that proportionately equivalent lesions in adult and juvenile rats produced less impairment in the younger animals.

In contrast to models of the brain based on assumptions of global processing and diffuse representation, from the middle nineteenth century onwards evidence began to accumulate rapidly that restricted brain lesions often produced highly specific disorders in which the patients’ remaining spectrum of skills were relatively unaffected. Broca (1861) produced two cases in which the patients’ verbal expression was drastically impaired but whose comprehension of language appeared to be relatively good. Wernicke (1874) produced evidence that patients’ ability to comprehend and utter meaningful linguistic statements could be grossly impaired yet their pronunciation and rate of verbal output could remain unimpaired. Other descriptions followed of patients with restricted and often bizarre symptom complexes. Dejerine’s description (1892) of Mr. C is perhaps one of the classic cases. This patient, who had right visual field blindness, could nevertheless recognize objects and continue his everyday life. Despite apparently normal vision in his left visual field and the ability to speak and write normally, he was unable to read by sight even the sentences he had written himself a short while before. He was however able to ‘read’ by feeling the shapes of cut out letters. Other syndromes described included those of disordered motor planning (Leipmann, 1908), the inability to recognize objects (Lissauer, 1890), and the inability to recognize melody (Henschen, 1926). The list could be continued, but the importance of these cases was that they convinced a substantial number of investigators that the brain could not be organized in a diffuse equipotential manner but, on the contrary, must contain relatively specialized processors even for such uniquely human processes as the comprehension and generation of language.

Modern neuropsychology has moved away from the exclusive study of such rare and extraordinary cases to the systematic examination of groups of patients in which the behavioural effects of differences in known cerebral pathology can be investigated. The more extreme forms of cerebral localization have been

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rejected, but the acceptance of specialized processing within and between the two hemispheres of the brain has gained wide acceptance (see Walsh, 1978, and Hecaen and Albert, 1978). This current position regarding the distribution of functional systems within and between the cerebral hemispheres in the adult’s central nervous system is of considerable importance to those interested in neuropsychological development. The relative paucity of information concerning the specific effects of brain damage during development necessitates the use of the effects of adult brain damage as a yardstick against which the outcome of early brain damage may be set. By contrasting the effects of early brain injury with those which occur following damage to the mature brain, it may be possible to ascertain whether the organizational pattern typical of the adult brain is present also in early development or whether it emerges gradually.

It may seem odd that this question should be asked at all, given the fact that, superficially at least, the anatomical structure of the brain is broadly similar in the neonate and the adult, even to the extent of the presence of the adult pattern of anatomical asymmetry (Wada et al, 1975). However, evidence has been presented from time to time which argues that certain crucial functional differences are present. Animal studies have indicated that effects of motor cortex damage in infancy are less deleterious than equivalent damage at maturity since the younger animals escape the flaccid paralysis and spasticity of their elders and retain their postural and locomotor capabilities (Kennard, 1940). Even in humans the claim has been made that children may escape some of the effects of cerebellar injury suffered by adults (Geschwind, 1972). In the area of language it has been known for some time that children who become aphasic following massive left hemisphere injury usually recover speech rapidly (Guttman, 1942), a phenomenon which is not unknown but is certainly rare in the adult (Dejerine and Andre-Thomas, 1912). In such cases it is possible to resort to concepts like plasticity in order to explain the greater resilience of the immature brain, but in some cases the reorganization following injury appears to be so expeditious that it is difficult to believe that other areas of the brain not previously involved have acquired behavioural functions so rapidly (Kennard, 1940; Geschwind, 1972). Even if the idea of greater neural plasticity is accepted, the question may still be asked as to how great this capacity for compensation is? When children become aphasic following unilateral brain damage and language eventually resides in the contralateral hemisphere, does it cope as adequately as the damaged hemisphere would have done? The existence of greater plasticity in the developing brain does not necessarily mean that disparate structures are functionally equivalent. This inference would be valid only if different structures were shown to attain the same degree of functional sophistication.

These two issues concerning the establishment of the adult pattern of neural organization and the extent to which it can be modified following early brain damage will be explored in the following pages.

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The context within which damage occurs during development

It is clear, that, as a child grows from birth, the various indices of maturation (behavioural, neurophysiological and morphological) tend to move together towards levels accepted as indicating greater maturity. The range and complexity of spatial, linguistic and social skills increases. In association with them electrophysiological measures of brain activity move from showing a slow and irregular pattern at birth to faster rhythms and widening of the bandwidth characteristics with increasing age. Neuroanatomical changes are also evident both at a gross level, where changes in surface area and the fissural pattern of the brain are seen (Turner, 1948, 1950), and at the microscopic level, where the size of neurones and the complexity of the dendritic pattern increases (Marshall, 1968). When investigators are concerned exclusively with behavioural development, electrophysiological and anatomical factors may provide an interesting but non-essential background. However, where one is concerned with the outcome of brain injury, which occurs early rather than late in the developmental sequence, then the broad neurobiological context in which the injury occurs assumes increasing prominence. A child who suffers brain injury has not just lived for a shorter time, and consequently experienced less, than an adult. The injury has occurred within a system which has a complex and uncompleted developmental plan which is rapidly unfolding, rather than as in the adult where injury occurs within a system where the developmental sequence may have reached a plateau of several decades’ duration. With this in mind some relevant data which outline the changing status of cerebral structures during development will be examined.

Electrophysiological and neuroanatomical maturation

Electrophysiological measures of cerebral development in man indicate a progressive increase in mean frequency content of the EEG from birth to maturity. Whilst in the neonate this is characterized by a labile pattern with periods of almost total electrical silence and an unclearly differentiated sleep pattern, the adult shows a pattern of continuous activity with a frequency spectrum that is at least superficially related to the subject’s state of alertness and with a well-differentiated pattern during the various stages of sleep (see Marshall, 1968, and Milner, 1976, for reviews, and Thompson, this volume). The adult pattern, with the occipital alpha frequency centred in the region of 10 Hz, and the presence of clear beta activity (14-30 Hz) during arousal, is attained only gradually (Henry, 1944). The most typical frequency band shifts from the delta region (1-3 Hz) at age 1 year and below, through the theta band (4-7 Hz) between 2 and 5 years, to the alpha band (8-13 Hz) between 6 years and adulthood. Beta frequencies become increasingly common in late childhood, and

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are an increasingly common feature of the adult EEG. Measurement of evoked potentials reveals that peak latencies are long in infancy and decrease as maturation proceeds, whilst in general, amplitude tends to decline after an initial rise. This amplitude trend is also characteristic of the development of the gross EEG (Shagass, 1972). Whilst the behavioural significance of the EEG in man is currently an extremely active research area, the status of the research findings is not always unequivocal. The existence during infancy and childhood of a differential density of waveforms in the left and right hemispheres (Walter, 1950) and the presence of lateral differences in auditory evoked potentials (Molfese, 1977) cannot be taken as evidence of functional asymmetry within the cortex at these ages, since they may indicate changes in the thalamus and corpus striatum, which are simply mirrored in an as yet incompletely differentiated and immature cerebral mantle. The EEG data do, however, allow us to see the gradual emergence of intracerebral rhythms whose mean cycle time becomes shorter with age, and whose responsiveness to external stimulation becomes crisper. Furthermore, this developmental trend continues throughout the period from birth to sexual maturity and may actually show reversal in old age (Shagass, 1972).

The impression of a long-term developmental cycle which emerges from examination of human electrophysiological development perhaps finds even stronger support when neuroanatomical development is examined. It is apparent that although the full complement of neurones is probably present in the central nervous system at birth, the brain continues to grow in overall size and the characteristic sulcal and gyral pattern of the adult emerges gradually over the first 6 years, and perhaps even later in the case of the frontal lobe (Turner, 1948, 1950). When the internal differentiation of the brain is considered a complex and protracted pattern of development unfolds (Yakovlev and Lecours, 1967; Lecours, 1975). Using the density of myelin, the lipid sheath surrounding the axons of neurones, as a criterion of maturation these workers have mapped the development of CNS pathways and structures and used the termination of the myelogenetic cycle as an index of when the system reaches final functional maturity.

It is apparent from this research that brain development does not proceed uniformly in all central nervous subsystems. Sensory fibre tracts and associated nuclei myelinate before the cortical intra- and interhemispheric communication systems. Different sensory systems however may show a diversity of time courses. The optic radiations subserving the visual cortex show a short cycle of myelination closely following the myelination of the optic tract, and is virtually complete by 4 months of age. The acoustic radiation subserving the auditory cortex does not show complete development until the 4th year, in marked contrast to the prethalamic auditory system, which is mature by the 4th postnatal month. The intracortical and interhemispheric association fibres,

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which allow communication between different regions and whose disruption leads to many of the bizarre neuropsychological disconnection syndromes (Geschwind, 1965), have prolonged maturational cycles extending into the second decade of life. Examination of the cortex itself indicates that some regions implicated in linguistic competence (inferior parietal lobule) show a slow onset of myelination and that this process may also continue beyond the second decade of life. It should be emphasized that although the study of the myelogenetic cycles of maturation shows a complex extended pattern of development from birth to maturity, a caveat is necessary. Neural conduction can occur in fibres before they become myelinated (Ulett et al , 1944) and indeed myelination may be aided by neural activity (Langworthy, 1933). However, myelin contributes greatly to the efficiency and speed of neural conduction, which underlies the complex analysis and planning characteristics of human cognition and action. The importance of myelin may be appreciated by considering the devastating behavioural effects of demyelination disease in man such as occurs in multiple sclerosis. The myelogenetic analysis emphasizes the manner in which the brain becomes structurally mature. Phylogenetically older structures, in general, mature earlier than those of recent phyletic origin. There are exceptions to this, for example the reticular formation, whose developmental cycle again extends into the second decade of life, partly no doubt because its final operational capability is not required until cortical systems are completely mature.

Both the electrophysiological and neuroanatomical data indicate that the human central nervous system develops over an extended period. Particularly fascinating are the observations that the higher auditory systems (geniculo- temporal pathways) exhibit a developmental cycle that is more than ten times longer than visual structures at the same level of the CNS. It is probable that this reflects the necessity of incorporating into the growing brain the species specific demand of learning the complexities of language via the acoustic mode and allows for the building of the culture-specific phoneme system which is eventually used. However, it is apparent that a considerable part of the developing child’s life is characterized by the presence of cortical structures which are functionally (by electrophysiological and anatomical criteria) immature. The status that these immature structures have in subserving the growing child’s cognitive repertoire is not straightforward. It is possible to envisage the mapping of cognitive growth within the cerebral structures which subserve cognition in the adult in at least two ways. The first view would regard all those structures which are involved in a given functional system in the adult as also being involved in infancy, although the immaturity of the system considered as a whole would limit its capabilities. The limitations seen for instance in perceptual and motor systems in the neonate would be ascribed to the immaturity of the cortical system, which was nevertheless functional, rather

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than to the fact that lower but morphologically more mature structures are controlling the behaviour. The alternative view would regard neurobehavioural development as a process beginning with relatively primitive analysis and response control systems residing in phylogenetically older structures which mature earlier in the developmental sequence. As development proceeds, phylogenetically newer structures, which attain maturity later in the developmental sequence, will capture and modulate the activity of the older systems as well as adding more complex control processes. This process will not have a uniform time course across all systems. In the case of the visual system this transition may occur relatively early in development at two to three months of age since the cortical network in this case has a short developmental cycle. In the case of audition the whole process may be more protracted with cortical control becoming ascendant in the period of 2-4 years, whilst in the complex action systems controlled by the frontal lobe, the processes may take even longer, given the differential growth of the region beyond 6 years of age (Turner, 1948, 1950). Evidence that it is this latter view which is the more reasonable description of neurobehavioural development comes from a number of observations that will be subsequently outlined, but it must be said in advance that the case is by no means proven.

Neuropsychological evidence concerning functional maturation

When damage occurs in the mature brain the effects are usually immediate; the degree of functional loss, whether it be sensory, motor or cognitive, is greatest immediately after the lesion and usually shows some remission over time. In the immature brain in a number of instances the pattern is almost the reverse of this. In the case of hemiplegia, sustained as a consequence of prenatal or perinatal injury, the symptoms of the disorder frequently emerge gradually over a prolonged period. Abnormalities in the use of the hand and arm may emerge at between 4 and 6 months, whilst differences in the behaviour of the legs may not become apparent until 10 months of age or more. Deficits in the use of the lower limbs may only become apparent when the child begins to walk, a milestone that is frequently attained in the normal age range (Lyon, 1961). Finally, athetoid movements do not make their appearance until much later, typically between three and four years of age (Lenneberg, 1968). Thus the developmental pattern is seen to move through a series of stages: for example, the grasp reflex is present initially in both the affected and the normal hand, but it persists on the affected side and usually the hand becomes clenched into a tight fist. Individual finger movements do not appear on the hemiplegic side, although movement of the thumbs may be possible. As the child grows, then, the deficit becomes more severe. However, it is noticeable that these children escape some of the more drastic consequences of hemiplegia resulting from cerebral injury at maturity.

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The severity of paralysis in the upper limb is less and the lower limb is capable of greater use than after comparable damage in adults. That the residual function on the affected side is not attributable to surviving undamaged tissue in the diseased hemisphere is shown by the fact that removing the diseased hemisphere later in development does not cause further impairment and may frequently result in improvement (Cairns and Davidson, 1951).

Two features then are apparent in these cases. The first is the greater capacity of the young brain to compensate and escape some of the consequences of equivalent injury in adulthood—its plastic propensity. The second feature is cogently described by Lenneberg (1968): ‘one may say that the child with a perinatal cerebral injury only gradually grows into his symptoms’. This emergence of deficit with age is compatible with the view that certain systems are pre-programmed to appear at certain stages in development and injury to them will only become apparent when they fail to appear. Similar affects in the motor sphere were observed by Kennard (1940) in macaque monkeys where ablation of the motor cortex in infancy resulted in surprisingly little immediate effect, but precluded the development of fine manipulatory skills, and this, together with signs of dyskenesia, became more apparent as the animals grew older. It appears that the motor cortex only begins to exert its influence gradually and its loss or malfunction may not become apparent until a later stage of development.

Further support for the notion that behaviour early in development may be mediated exclusively by subcortical structures, with cortical processors becoming involved later, has been provided by Goldman (1976). It has been apparent for some time that tasks which require a monkey to remember the location of a stimulus over a brief interval of time are drastically affected by damage to the dorsolateral prefrontal cortex (Chow and Hutt, 1953). These are known as the delayed-response and delayed-alternation tasks. When the dorsolateral frontal cortex is removed within the first 2 months of life however, the operated animals perform as well on this task as unoperated controls as long as testing is carried out within the first year of life (Harlow et al , 1970). If these monkeys are followed into the second year of life they show evidence of increasing impairment of delayed response tasks. Lesions in subcortical structures which are functionally connected with the dorsolateral prefrontal cortex (dorsomedial nucleus of the thalamus and the head of the caudate nucleus), indicate that the monkeys operated on as juveniles show the same pattern of deficit as adults, i.e. failure on delayed alternation tasks (Goldman, 1974). These results emphasize that not only may the effects of brain damage fail to appear early in development and only reveal themselves as the animal grows, they also show that structures which are required for the adequate performance of a task in adulthood (the dorsolateral prefrontal cortex), are not necessary for the performance of the same task when the animal is an infant or a juvenile.

These experiments contribute a salutary warning to those who would assume

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that, because a cortical structure is implicated in a functional system in adulthood it must of necessity be involved in performance of those same functions at an earlier developmental stage. In infant and juvenile macaques subcortical systems are capable of mediating responses which in adults require the participation of the cortex. Furthermore, evidence is available which indicates that the time course over which the effects of cortical lesions become apparent during development differs for different regions. While monkeys aged 2\ months with orbital frontal cortex lesions are equivalent to unoperated controls in the performance of object reversal learning, deficits in performance became apparent by the time the animals are one year old (Goldman, 1974). Thus, while the effects of dorsolateral frontal cortex damage sustained in infancy on delayed alternation tasks do not become apparent until after one year of age, the effects of orbitofrontal damage in infancy on object reversal learning become apparent before one year of age. In the case of both delayed alternation and object reversal learning early in development subcortical structures are capable of mediating the behaviour successfully. With respect to these studies it should be pointed out that macaque monkeys attain sexual maturity between 24 and 30 months of age, so the effects of early brain damage may take a considerable proportion of the developmental cycle before they become apparent.

The evidence cited so far has argued for a model of development in which the complete maturational cycle is prolonged, but within which different systems may attain functional maturity at widely divergent times. Initially, behaviour may be controlled by subcortical systems, and depending on the time-course of the maturational cycle in the higher reaches (cortical) of each system so control will pass to the phylogenetically newer and more adaptive system. Bronson (1974) has argued, on the basis of changes in the pattern of visual behaviour in infants, that in the case of the visual system a transfer of control passes from the superior colliculus to the striate cortex, from the ‘ambient’ to the ‘focal’ system (Trevarthen, 1968), during the 2nd and 3rd postnatal month. Such a view is certainly compatible with the rapid postnatal development of the geniculo- striate system (Yakovlev and Lecours, 1967). In the case of motor function the longer maturational cycle of the medullary pyramids (up to 12 months), which carry the axons of the Betz cells of the motor cortex to the spinal cord and are required for control of individual fingers and skilled sequences (Lawrence and Hopkins, 1972), leads one to expect that transition of control in this case may take place over a more protracted period. The emergence of comparative motor deficit between affected and normal side, in cases in infantile hemiplegia, between 4 and 12 months of age (Lyon, 1961) appears to reflect this longer cycle of development. In man, however, the long-term emergence of a deficit in previously established skills after early brain injury akin to that reported by Goldman (1974, 1976) for the macaque monkey, has not as yet been reported.

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Nevertheless, evidence is available which indicates that, on some perceptual tasks, brain-damaged children may show either a consistent difference from controls over a wide age range (Cobrinik, 1959), or a progressive change, which either diverges from or converges to control values between the ages of 5 and 15 years depending on the particular measure being considered (Teuber and Rudel, 1962). Thus, slowly emerging effects of early brain damage in man are not unknown, but long-term effects, with an intervening ‘silent’ interval, have not, to the present author’s knowledge, been described.

Interactive effects and their interpretation

Generalized effects on intelligence that result from presumed structural incapacity (Hebb, 1942) or following localized injury (Thompson, 1978) have indicated that while early injury may produce generalized depression of full- scale IQ, late injury produces a more specific pattern of deficit, with less depression of full-scale IQ. Research findings of this nature can be seen as support either for a model of brain development in which neural structures only gradually attain their mature state, or alternatively, as support for the view that reorganizational capacities are at work during development which allow savings on specific skills but at the cost of overall depression in intellectual attainment. However, there is no doubt that both views are valid and have independent evidence to support them. The developing brain is more vulnerable than the mature brain and this can be seen in the long term generalized deleterious consequences of nutritional deprivation during the brain-growth spurt, as measured by both neurochemical and anatomical criteria (Dobbing, 1968), and by behavioural criteria (Chase, 1973). However, it is also clear that substantial left hemisphere damage, which usually leads to long-term severe dysphasia in adulthood, results in only transitory dysphasic symptoms when the damage occurs early in childhood (Hecaen, 1976), and there is evidence of savings in visuo-spatial skills following early right hemisphere dysfunction, which is not apparent with equivalent damage at maturity (Kohn and Dennis, 1974).

These findings provide unequivocal evidence of the reorganizational and plastic capacities of the developing brain. However, it is also evident that the usual predetermined pattern of left hemisphere specialization for language and right hemisphere specialization for visuo-spatial skills set limits to this plastic capacity. Where one hemisphere has sustained early injury, the language skills exhibited by a remaining and intact right hemisphere are less proficient than those exhibited by a remaining intact left hemisphere (Dennis and Kohn, 1975). It also appears that visuospatial abilities are better developed in an intact right hemisphere than when the left hemisphere alone remains fully functional (Kohn and Dennis, 1974). Thus, while reorganization is possible following early brain injury, this may be more limited than has been previously thought. Indeed, given

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the anatomical asymmetry present in the neonatal brain (Wada et al, 1975) it would be surprising if this structural specialization were not detectable at some stage in the behavioural effects of unilateral brain injury. The results of unilateral brain injury in early development nicely juxtapose two major tendencies which emerge from neurobehavioural research: on the one hand, the trend towards carrying through the construction of a preprogrammed system over a protracted time period and, on the other, an adaptive plastic capacity which allows the partial redirection of functional systems should damage occur.

The complexity of the processes involved in the analysis of sensory information (Hubei and Wiesel, 1963; Werner and Whitsell, 1973) that has emerged from single neurone recording makes it clear why a great deal of preprogramming must be involved in the construction of complex adaptive neural systems. It is less easy to describe the mechanisms which allow complex brain systems to exhibit the degree of plasticity that they evidently do in early development. The explanation may reside in the fact that younger individuals are less susceptible to transneural degeneration effects and also show higher levels of biosynthetic activity in brain tissue, which may allow damaged networks greater restitutional capacity (see Goldman and Lewis, 1978, for review). It is also evident that behavioural recovery, seen after early injury in some cases, depends on the ability of young animals to profit from experience in a way not available to the adult. Monkeys sustaining brain injury in infancy show greater recovery the earlier training experience is given in development, although the ability to profit from this experience depends on the nature of the task and the site of the lesion in the brain (Goldman and Lewis, 1978). The results of this study gave some indication that it was the nonspecific stimulation effects of the training which were important in recovery, rather than specific carry-over from common features of the task.

The fact that experience per se may be an important factor in promoting recovery is of considerable importance, since there has been suspicion about the value of training programmes in the recovery from brain damage (Byers and McLean, 1962). Given the intricacy of the neurobiological factors involved in early brain injury it may be too easy to forget about the cognitive dimension. During development a child moves from a relatively primitive analysis and interaction with the external world to a stage where his conceptual structures are complex and enable sophisticated analysis and prediction of the environment. The cognitive capacities evident at maturity have been built on simpler ones gathered progressively during childhood. Thus, impairment of systems which gather and utilize information as a consequence of cerebral damage could result in diminished intellectual achievement, not through injury to critical higher-level systems, but because essential ‘feeder’ mechanisms have malfunctioned. An adult with a subcortical lesion which destroys the left auditory radiation and the callosal input from the contralateral hemisphere may show a normal audiogram

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but be incapable of interpreting spoken language (Gloning et al ., 1963). Nevertheless, speech, reading and writing may be normal since their associated cortical circuitry is undamaged and language has been previously established. In a child, bilateral disruption of the auditory radiations by a lesion damaging the lips of the sylvian fissures and the insulae can preclude the normal development of language, despite evidence of hearing in the normal range (Landau et al , 1960). Even children who become peripherally deaf after acquiring speech may not only show arrested language development but lose previously acquired linguistic skills (Bay, 1975). This ‘cognitive starvation’ effect, which is easy to comprehend in the instances cited, may also operate within association areas of the cortex and may underlie the tendency of early brain pathology to produce more global intellectual depression effects than are seen with lesions in adolescence and adulthood.

The data briefly reviewed in this section emphasize that the effects of brain injury in the developing nervous system are particularly complex. When injury occurs, it is within a system whose functional capacities are still unfolding, and the effects of injury are sometimes not immediately apparent. The plastic capacity of the system may also mask the extent of any physical injury and lead to a false assumption that effects have been transitory. There is also the added complication that, whilst injury may not have damaged structures critical for the attainment of certain cognitive skills, because critical ‘feeder’ systems have been impaired, these cognitive mechanisms may not have the experiental basis upon which to build.

The consequences of early brain damage

Global and specific processing

In 1942 Hebb drew attention to the different patterns seen following brain damage in both mature and immature nervous systems. Adults, he found, could be considered to be either aphasic or non-aphasic types (Hebb, 1942). The aphasic type showed obvious evidence of deterioration on verbal tasks and some also showed evidence of impairment on such non-verbal tasks as detecting absurd errors in pictures and block manipulation performance. However, some of the aphasic patients showed evidence of almost normal performance on nonverbal tasks, and Hebb remarked on the wide disparity of abilities seen on particular tests in individual aphasic patients. This conclusion of Hebb’s (that non-verbal skills may be retained to a remarkable extent in some cases of aphasia) is reinforced by more recent research on this topic (Zangwill, 1964; Kertesz and McCabe, 1975). In the non-aphasic type of brain injury on the other hand many verbal tasks could be adequately completed, but there was usually severe impairment on maze learning, block manipulation and picture absurdity tasks, as well as impairment on some verbal tasks, e.g. the defining of abstract

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words, or naming opposites. The two types were, however, sufficiently different for Hebb to state that following adult brain injury a reasonably specific pattern of deficit often emerges—some skills showing deterioration and others being relatively intact. In contrast, a group of children with what he termed ‘exogenous’ brain injury showed no evidence of a dual pattern, that is the ‘aphasic’ and ‘non-aphasic’ types did not occur as a consequence of early brain injury. The group as a whole showed depression of verbal IQ, but since he thought it unlikely that every case of brain injury in infancy involved damage to the language areas it must be that ‘low verbal test scores are produced by early lesions outside the speech areas’ (Hebb, 1942, p. 286). He went on to argue that the more global pattern of intellectual depression seen after early brain injury occurs as a result of the differing demands being made on the adult and the child after cerebral damage. The adult has merely to make use of skills which have already been acquired, whereas the child has still to assimilate a range of skills. Since a greater cognitive demand is made during the acquisition of a skill than by the performance of one already acquired, the growing child is at a greater loss than the adult when an equivalent amount of brain tissue has been lost in both. Hebb went further and argued—following Lashley (1929)—that some degree of equipotentiality must exist in the cortex and that areas outside the classical language areas must be involved in the development, but not the maintenance, of linguistic skills once they have been mastered.

Two major hypotheses then emerge from Hebb’s work (1942). The first is that early, rather than late, brain damage has a more global depressive effect upon intellectual development. The second hypothesis is that the developing nervous system is characterized by a greater degree of equipotentiality than that of the adult, since the attainment of normal adult performance on a range of specific skills seems to depend on the integrity of whole cerebrum. The first hypothesis has, in general, received support from subsequent research. Bryan and Brown (1957) found that there is a strong relation between the age of injury and mean IQ, so that those with an injury present at birth averaged a score of 62, those injured in infancy averaged 66 while those with injuries occurring between 3 and 10 years and between 10 and 20 years averaged 71 and 85 respectively. Thompson (1978) reported that in 282 subjects who sustained localized cerebral injury in childhood, there was a linear relationship between age of injury and full-scale IQ with those injured before 5 scoring 97 and those injured above 15 years scoring 106.5. It should be noted, however, that whilst McFie (1961a) found a rise in mean IQ between those injured in the age bands 1-4 and 5-9 years from 88.8 to 106.0, he found a fall in IQ with those sustaining injury between 10 and 15 years (82.7). However, on balance the findings would seem to support Hebb’s initial contention.

The second hypothesis emerging from Hebb’s (1942) study, that the developing nervous system is characterized by a greater degree of equi-

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potentiality than that of the adult, is rather more contentious since it is more difficult to test than it might appear at first sight. It has already been pointed out that general depression of IQ cannot be used as evidence for a type of mass action operating during development, since it may also argue for an interdependence of separate capabilities being required for the construction of more complex schemata. It is also apparent that brain-damaged children show widely differing patterns of impairment, which would be difficult to comprehend if there were a tendency for the brain to act uniformly in the acquisition of cognitive skills (Strauss and Lehtinen, 1968). There is also the added difficulty that IQ tests may be rather insensitive to specific patterns of disability produced by brain injury, both in children (Boll and Reitan, 1972) and adults (Walsh, 1978), a factor which has resulted in the construction of specialized test batteries.

However, instead of asking whether the general depressive effect of early brain damage on IQ is due to a greater degree of global processing in the immature CNS, it might be more fruitful to consider whether a similar pattern of impairment emerges on specific skills after similar damage in the child and the adult. McFie (1961a), in an investigation of the effects of localized post-infantile cerebral lesions in children, found that there was a tendency for Wechsler verbal scores to be lower following left hemisphere injury and performance scores to be lower following damage to the right hemisphere. He also noted a similarity in the pattern of impairment shown on the Memory for Designs component of the Terman-Merrill scale (1937) between children and adults when comparing the effects of frontal, temporal and parietal injury. He reported that the greatest deficit is to be found in both groups following right parietal damage. Fedio and Mirsky (1969) examined the pattern of impairment exhibited by children with either unilateral temporal lobe or with centrencephalic epilepsy on a test battery designed to measure performance on both verbal and non-verbal tasks, and a task of sustained attention. The children, who had a history of illness dating from early school years, showed similar impairment profiles to those of adults with similar pathology. Those with left temporal epileptiform foci required a greater number of trials to learn lists of ten words and showed greater loss after a 5- minute interval than those with right temporal or centrencephalic pathology. Those with right temporal pathology showed greatest impairment on the recall of the order of random shapes and on production of the Rey-Osterrieth figure. The centrencephalic group showed the greatest deficit on a task requiring sustained attention. Annet et al (1961) also found a similar pattern of verbal and spatial difficulties in children classified on the basis of lateralized EEG abnormalities. These results would suggest that children show impairments of the same type as those found in adults with similar pathology. It may be objected however, that in these cases the damage is characteristic of juvenile rather than infant brain damage, and, if adult cortical specialization appears gradually, then patterns of specific loss will also begin to appear, producing the observed

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similarity to the adult type by middle childhood. However, evidence does exist which would suggest that there is hemisphere specialization, even when damage occurs perinatally or in infancy.

Damage to the left, but not the right, hemisphere before the end of the first year of life results in impairment in the rate at which combinations of words (elementary syntax), but not single words, are learned (Bishop, 1967). Furthermore, children who have had either a left or right hemisphere removed as a consequence of damage sustained during the first year of life show differential effects depending on which hemisphere is involved. Those with left hemisphere removal show greater difficulty in the comprehension of syntax than right hemi- decorticates (Dennis and Kohn, 1975). In particular, difficulties as shown by a greater number of errors are apparent in comprehension of the passive negative, e.g. ‘the girl is not pushed by the boy’, as opposed to the active affirmative, ‘the boy pushes the girl’. In these experiments comprehension was assessed by having the child choose a picture which depicted the sentence. The greater difficulty in the comprehension of passive sentences was also apparent in longer response latencies. Children with early right hemisphere damage followed by hemi- spherectomy show difficulties on spatial tasks (Kohn and Dennis, 1974). The types of spatial task on which they show relative deficit are those which continue to show improvements in normal subjects through the teens, e.g. the WISC and Porteus mazes, and map reading tasks, which require a subject either to state the direction to be taken or to follow a route through markers placed on the floor. Early maturing skills, such as tactile form matching and visual closure, were unaffected in contrast to right hemisphere injury at maturity which severely depresses these abilities. Further analyses of three cases where hemispherectomy antedated the beginnings of speech were presented by Dennis and Whitaker (1976) and two cases where hemispherectomy for unilateral pathology was carried out at ages 3 and 4 years respectively were reported by Day and Ulatowska (1979). In these cases the pattern of deficit is similar to those previously reported and supports the view that the hemispheres are differentially involved in different aspects of cognition. Specialization would appear to be an early-established characteristic of the child’s brain although its potential for reorganization complicates the issue (see p. 225).

Given that differences in the patterning of intelligence subtest scores only really become obvious during adolescence and beyond (Thompson, 1978), whereas specific deficits are detectable by specially devised tests in younger children, IQ tests appear to be insensitive instruments on which to base theories concerning brain development. One obvious factor which will lessen the sensitivity of IQ tests to brain damage early in development is the capacity to transfer the development of linguistic and spatial skills to the contralateral hemisphere should damage occur. This plastic capacity should not however be confused with ideas about mass action or equipotentiality. These latter ideas

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imply the existence of a type of diffuse processing network to which the association cortex within each hemisphere contributes uniformly (Lashley, 1929). The transfer of functional capability from one hemisphere to the other, however, is to be understood in a rather different context. Each cerebral hemisphere contains anatomical structures which are essentially duplicates of those found in the other, with the difference that certain cytoarchitectonic areas may be relatively larger or smaller. In some instances, particularly in the language area, these cytoarchitectonic differences in size may be as great as 700% in favour of the left hemisphere (Galaburda et al ., 1978). However, each specialized cortical area has a pattern of connections to the rest of the brain which, in essence, is a lateral reversal of those found in the other hemisphere. The ability of these ‘duplicates’ to assume some of the functional capacities previously assumed by their cytoarchitectonic counterparts is perhaps not too surprising. Indeed, the puzzling feature is that in a substantial majority of the adult population this ability is lost. The assumption that somehow the areas within each hemisphere act as a kind of equipotential unit, is not supported by the available evidence. If such a diffusely organized system were operative in the left hemisphere during development, then it would be reasonable to assume that unilateral damage, resulting in suboptimal processing capacity, would be sufficient reason to transfer linguistic processing to the remaining intact hemisphere. Milner (1973) has provided evidence, based on language lateralization, tested by the Wada (intracarotid injection of sodium amytal) technique, that only when early injury invades those areas shown to be important for linguistic processing in the adult, will language transfer to the right hemisphere. These results suggest that certain key regions, not the global processing capacity or total operational mode of one hemisphere, promote the establishment of language within that hemisphere.

In considering the question of global or specific processing in development, the evidence on balance suggests a specific processing configuration not dissimilar to that found in the adult brain. It has also been argued that one of the reasons why early brain damage often has a markedly depressive effect on intellectual growth may be that the substrate of complex cognitive processes may require the integrity of fundamental systems in order to attain their full potential. One line of evidence which supports this is the finding that right hemisphere damage, which occurs before one year of age, may have more depressive effects on cognitive growth than damage to the left hemisphere at an equivalent age, or damage to either hemisphere after one year of age (McFie, 1961 b; Woods, 1980). This greater deleterious effect of early right hemisphere pathology on both verbal and performance IQ scores argues for the participation of the right hemisphere in certain fundamental processes that may underlie both linguistic and spatial competence. Given the specialization of the right hemisphere for the acquisition of spatial skills it appears possible that a

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certain elementary sensori-motor coordinate system may normally be established by the right hemisphere, and in some way aid the differentiation of more complex skills which do not, at first sight, appear directly connected to it. The importance of elementary sensori-motor expedience in evolving more complex cognitive operations has been stressed by many theorists, and by Piaget (1979) in particular. However, regardless of whether or not the presence of this correspondence between theories of cognitive development and neuropsychological research finding is accepted, the results obtained by McFie (1971a, b) and Woods (1980) emphasize the importance of the presence of a particular structure at a particular stage during development rather than supporting the view that different structures are functionally equivalent.

Aphasia in children

The study of language disorders in children is important to a number of problems in developmental neuropsychology. It has provided evidence concerning the extent of functional specialization in the cerebral hemispheres during maturation; data concerning the reorganizational or plastic capacity of the developing brain; and a third, equally important, question, evidence as to the manner in which language becomes established in cortical structures. This question is, in fact, separate from those of hemispheric specialization and plasticity. Here we are concerned with the similarity between the aphasic symptoms of the child and the adult. The greater the similarity of the syndromes the more likely it is that the adult structural pattern has become established, even if subsequently the recovery of the child is more complete because duplication of function in the contralateral hemisphere is still possible. In the present section each of these three topics will be examined, but the characteristics of childhood aphasia will be examined first.

The clinical picture found in childhood aphasia was described by Guttman (1942), who noted that despite claims that the syndrome was rare, he had found it not an unusual accompaniment of head injury or intracranial pathology. In contrast to the adult, where complaints with speech difficulties, failures to name objects and paraphrasia are common, the aphasic child is usually apathetic and morose with such extreme poverty of speech that it approaches mutism. Absence of spontaneous speech, lack of willingness to speak, and a hesitant dysarthric telegrammatic-style speech are frequently noted, these symptoms being more common in the younger child. In contrast to the extreme poverty of speech production, comprehension of simple instructions is evident so that parts of the body or objects can be appropriately indicated when a request is made. When prompted to speak difficulties in the manipulation of lips and tongue may be apparent together with failure to produce sound. As recovery progresses, initially the child will speak single words when prompted. It will then move to

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sparse spontaneous utterances before speech moves into a stage when impoverished but spontaneous conversation occurs with persistent dysarthria. This pattern, which bears the imprint of an almost exclusively motor disorder, occurred in all cases below 10 years of age and occurred regardless of the location of the lesion within a hemisphere. Where damage occurred after the tenth year in some cases speech showed a lack of spontaneity but symptoms more characteristic of the adult pattern with impaired auditory comprehension, syntactical and paraphrasic errors, together with difficulties of naming were found. Dysarthria may or may not accompany these symptoms.

This picture of aphasia in childhood has been supported by subsequent research in which the onset of the language loss is sudden following external injury or internal pathology. In Guttman’s cases the five instances of injury which produced aphasia in which the symptom was exclusively one of speech production difficulty were aged 8 years or below, and the two instances in which speech output was not affected but other aphasic symptoms were present were over 10 years of age. The series of cases reported by Hecaen (1976) show that in two instances where the disorder was exclusively one of speech production the children were aged 6, and in the remaining case 3j years. In children aged 7 years and more, comprehension, naming and paraphrasic disorders were more likely to occur. Both Guttman (1942) and Hecaen (1976) stress the fact that recovery may be extremely rapid, marked improvement sometimes being noted in as little as 6 weeks. In children aged over 10 years however, the time course of the disability may sometimes be prolonged. In middle to late childhood the aphasic symptoms begin to mimic the adult pattern, whereas in early childhood the disorder appears to be purely expressive. In adults expressive aphasia is often produced by lesions located in the anterior region of the hemisphere and difficulties in comprehension occur more frequently with temporal and inferior parietal damage (Geschwind, 1970). However, in children below 10 years, disorders of expression appear to occur regardless of the location of the lesion (Guttman, 1942). A second distinctive feature of the aphasic syndrome in young children is the absence of cases of jargon aphasia, where the speech output is rapid with relatively normal articulation but contains many circumlocutions and paraphrasias (Geschwind, 1972). Woods and Teuber (1978) claim to have one documented case of jargon aphasia in a 5-year-old child, but the clinical description is unlike the adult form. The child produced a stream of meaningless sounds, but when recognizable words were uttered they were most often the names of objects. The child also showed evidence of a purely apraxic disturbance, e.g. sticking out his tongue when asked to blow out a light. To the present author, the picture is too dissimilar to the adult form to be classed as an instance of jargon aphasia, the only feature in common being the high rate of vocal, as opposed to verbal, output.

The cases of language loss in childhood so far described were instances where

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loss was abrupt, following external or internal injury, and where injury was usually confined to one cerebral hemisphere. A rather different type of childhood aphasia occurs when the language loss is associated with either the onset or development of bilateral epileptiform abnormalities (Landau and Kleffner, 1957; Worster-Drought, 1971; Gascon et al , 1973). In these cases, the loss of language is associated with difficulties in understanding speech, which, in some cases, may evolve over a matter of days or weeks. The child shows lack of response to speech, which may be mistaken for peripheral deafness. Audiometric testing reveals either mild or moderate hearing loss, but this loss is insufficient to account for the comprehension disorder and, in any case, hearing usually shows progressive improvement after an initial depression. In some cases auditory evoked potentials to pure tones may be normal, but evoked potentials to speech show abnormalities (Gascon et al ., 1973). Loss of language is gradual and persistent, and while in some cases recovery may occur over a period of years (Landau and Kleffner, 1957), in other cases it appears to be permanent (Worster- Drought, 1971). In some cases loss of speech may be almost total and auditory comprehension limited to less than a dozen words. Despite gross impairment in the development of language, frequently these children do not show impairment on non-verbal tasks in intelligence tests. Of the 14 cases described by Worster- Drought (1971), performance IQ ranged from 96 to 140, with only one case falling below 100. This remains true despite the fact that, in many cases, the onset of pathology is at less than 5 years of age. These cases of bilateral abnormality are in contrast to cases where a unilateral lesion produces aphasia, from which the child subsequently recovers yet shows a low overall IQ (Hecaen, 1976).

When damage to a single hemisphere produces aphasia the child usually recovers language, and in the young child this recovery is usually better than when damage occurs above 10 years (Lenneberg, 1967). This has often been seen as evidence that the two cerebral hemispheres are initially equipotential as far as the development of language is concerned. Further, it has sometimes been claimed that both cerebral hemispheres are involved initially in language development with lateralization increasing with age (see Dennis and Whitaker, 1977 for a review). It has already been noted that as far as attainment on certain language tests is concerned the two hemispheres are not equivalent. The view that the right hemisphere is involved in language acquisition in the infant and young child comes from reports of the high incidence of speech disturbances following right hemisphere damage. The incidence of language disorders with lesions of the left and right hemispheres described by different researchers varies widely. In the case of the left hemisphere, damage has been estimated to produce language disorder with an incidence varying from 25% (Ingram, 1964) to over 90% (Dunsdon, 1952). In the case of the right hemisphere the estimated incidence has varied from less than 1 % (Ingram, 1964) to nearly 38 % (Dunsdon, 1952). Only one investigator has claimed an equal frequency of language dis-

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order following either left or right cerebral damage (Basser, 1962). The discrepancies seem too large to attribute to statistical sampling fluctuations. One of the problems encountered in this area is the definition of what constitutes an aphasic language disturbance. Language difficulties are associated with depressed general intelligence (Mein, 1960) so that severe brain damage which produces severe retardation may produce language disturbance indirectly. There is also the problem of whether speech disturbance should be considered an aphasic disturbance (Ingram, 1965). It is already apparent that the syndrome of aphasia • in children may vary from almost total mutism to a clinical picture similar to that of the adult with comprehension disturbance and naming impairment. That the type of impairment can vary not just with age of the child but also be related to the damaged hemisphere can be seen by examining the series of Hecaen (1976). Of 6 cases of right hemisphere damage, only the two youngest (6 and 3^ years) showed any disturbance and this was articulatory. Bishop (1967) has reported that in cases of infantile hemiplegia, articulatory disturbances are equally likely following damage to either hemisphere, but that left hemisphere damage additionally delays the acquisition of word combinations rather than single words.

The possibility of a different pattern of impairment following left and right hemisphere injury is not the only factor which complicates the issue. Woods and Teuber (1978) have pointed out that there is a tendency for investigators since 1940 to report a lower incidence of aphasia following right hemisphere injury than earlier workers. They attribute this to the fact that in older investigations aphasias and hemiplegias were frequently complications of systemic infectious illnesses such as scarlet fever, bacterial pneumonia and diphtheria, which can produce not only focal lesions but also diffuse bilateral encephalopathy. Undoubtedly the frequent reliance on hemiplegia alone as the sign indicating exclusive damage to one hemisphere is likely to result in the inclusion of cases where a less extensive pathology is also present in the hemisphere that is assumed to be intact. Bearing these facts in mind, it would obviously be hazardous to speculate concerning the true incidence of language disturbance following right hemisphere pathology. For the moment it is sufficient to say that the incidence of aphasia following right hemisphere damage may be considerably less than previously thought, perhaps as little as 5 % in those who were previously right-handed (Woods and Teuber, 1978).

A finding that has already been mentioned several times is that concerning the capacity of the right hemisphere to acquire language following early left hemisphere injury. There is little doubt that the capacity to transfer language to the right hemisphere is a real factor in the recovery from aphasia in children. However, it cannot be assumed that in every case of childhood aphasia recovery of language is due to transfer to the contralateral hemisphere. Milner (1974) noted, on the basis of the Wada test, that in adults who were left-handed but had

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sustained early left hemisphere damage, language was present in the left hemisphere in 30 % and bilaterally present in 16 % of cases. Thus, in 46 % of cases who had left hemisphere injury, the left hemisphere was still involved in language to some degree. Whether or not language transferred depended on whether certain critical areas were damaged. In cases where left hemispherectomy is performed, following widespread unilateral damage, it is clear that the presence of linguistic competence is dependent on the remaining hemisphere (Dennis and Whitaker, 1977). When such language transfer does occur, while verbal IQ may not be significantly depressed relative to performance IQ, it should be remembered that such tests do not directly sample knowledge of language structure. Where tests are designed to evaluate grammatical comprehension then deficits appear (Dennis and Kohn, 1975; Teuber, 1975; Dennis and Whitaker, 1976; Day and Ulatowska, 1979). However, with these reservations in mind, children exposed to left hemispherectomy do show an adequate degree of language competence in relation to their overall IQ and it has frequently been remarked that it would be an incredible improvement if each adult aphasic could recover the same level of language competence (Geschwind, 1972).

The duration of such plasticity in the developing brain has been the subject of disagreement. Lenneberg (1967) believed that the period of plasticity in regard to language mechanisms lasted until puberty. Krashen (1973) has challenged this view mainly on the basis that right hemisphere damage above the age of 5 does not often produce aphasia whereas below this age it frequently does. However it should be understood that the issue of the degree to which both hemispheres are involved in language acquisition early in life (and evidence has already been cited that right hemisphere aphasia may be quite different in form from left hemisphere aphasia in young children) is quite a different one from the question of whether interhemispheric transfer is possible. Children between 5 and 10 years do show good recovery from aphasia and it would be surprising indeed if language could have survived in the left hemisphere given the extent and severity of the damage in some instances, e.g. right hemiplegia and hemianopsia (Hecaen, 1976). On the balance the evidence would appear to favour a period of plasticity extending to at least 10 years of age. There is even some indication that a period of reduced plasticity may extend far beyond this age although whether it involves inter-hemispheric transfer or improved within-hemisphere recovery is another question. Teuber (1975) noted that an analysis of 167 cases of brain injury sustained during the Korean campaign showed that the population who were under 22 at the time of injury showed better recovery of language than those who were 23 years and over. It may be premature then to try to set rigid cut-off points for recovery.

The evidence presented here suggests that aphasia in children is not one syndrome but several. In children of 6 years and below mutism and dysarthria appear as the main symptoms with comprehension being relatively well

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preserved. Furthermore this pattern appears to occur regardless of whether the lesion is in the left or right hemisphere and also appears to be insensitive to the precise location of the lesion within a hemisphere (whether it is frontal, temporal or parietal). Above 6 years, symptoms which are regarded by many as truly aphasic (comprehension and naming disorders) appear. The symptoms appear to occur largely following left rather than right hemisphere lesions. Between the ages of 6 and 14, jargon aphasia in its adult form is infrequent although the extended circumlocutions that are one of the characteristics of aphasia do occur (Guttman, 1942). The rapidity of the recovery process in some cases and, in very young children, the preservation of comprehension, makes it extremely unlikely that language has been totally relearned by the right hemisphere (Geschwind, 1972). This factor has suggested to some investigators that the right hemisphere must be involved in linguistic processing at an early developmental stage and in fact retains some capacity for comprehension even in the adult after cerebral differentiation (Kinsbourne, 1975).

It is possible then that during the early stages of language learning both hemispheres acquire comprehension and share control of the speech mechanism. This may be necessary in the initial stages, because fine bilateral control of the speech mechanism is required since suitable motor synergisms for a culture- specific phoneme system are not yet well established in subcortical structures. The consequence of this arrangement is that a lesion to either hemisphere can disrupt speech production but comprehension is relatively unaffected because the structural basis of language as opposed to speech does not require a bilateral component. However, the establishment of subcortical synergisms for the execution of the basic components of speech production together with the presence of structurally more specialized language mechanisms in the temporoparietal region of the left hemisphere normally leads to left hemisphere capture of the speech output mechanism. This process is probably a gradual one, but as it proceeds there is less functional demand for right hemisphere processing of language and there may even be active inhibition of its linguistic processing by the left hemisphere. Eventually this isolation of the right hemisphere may lead to structural changes at the synaptic level so that the re-establishment of control is no longer possible. To the extent that this isolation process is incomplete transfer of control is still possible. Thus in young children (under 5 years) the loss of the left hemisphere will show itself in only transitory speech output disturbances since this process of capture is just beginning and both hemispheres are still involved. Even at this age however the linguistic superiority of the left hemisphere is already apparent (see Young, Chapter 6, this volume, for a review of the psychophysical literature), and it is in fact this superiority that will allow the eventual suppression of the right hemisphere. In children between the ages of six and ten years the speech mechanism is probably under the control of the left hemisphere but right hemisphere control mechanisms have not yet functionally

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atrophied. Left hemisphere damage at this age can produce speech disturbances solely and/or truly aphasic disturbances which are transitory, while damage to the right hemisphere only rarely affects these mechanisms. With the passage of time however, the capability of the right hemisphere wanes through disuse and in the majority of cases only a token linguistic capacity remains. Even if in later life the possibility of direct inhibition by the left hemisphere is removed, by severing the corpus callosum, the right hemisphere has residual linguistic comprehension but remains mute (Gazzaniga and Sperry, 1967). This is probably because the process of gaining control of the speech mechanisms involves the regulation of neuromuscular synergisms at subcortical levels, and these remain under left hemisphere control. It should be noted that the control of the vocal apparatus by the left hemisphere may be specific to its use in the context of spoken language. Where lesions of the left hemisphere produce expressive (Broca’s type) aphasia the ability to use the voice in the context of singing including the fluent production of words may be well preserved (Yamadori et al ., 1977). Evidence for a motor capture account of left hemisphere language dominance can also be found in studies of adult aphasics (cf. Kinsbourne, 1975).

The plasticity of the developing brain

It is usually accepted that the younger the individual when the brain sustains injury, the greater the resilience and the greater the capacity for functional restitution. Against this one must set the view that the developing brain is particularly vulnerable and long-term effects emerge if normal development is impaired. These two views may be partially reconciled by proposing that following early brain damage, specific skills may be spared but at a cost that will be seen in the overall lowered cognitive capacity of the brain (Teuber, 1975). Thus language or visuo-spatial skills may be spared following left or right hemisphere injury respectively, but intellectual achievement as measured by IQ tests or by school performance will show depression. Evidence already cited concerning the specific effects of early brain damage makes it clear that the consequences are not just seen in a uniformly lowered total processing capacity but depend on the site of injury. Language achievement is specifically lowered following left hemisphere injury and spatial skills depressed specifically following right hemisphere injury.

The evidence in favour of a greater degree of plasticity comes from a number of sources. Some animal species show spared sensory capacity following cortical lesions in infancy (Schneider, 1969) while in other species age at time of injury does not appear to affect the magnitude of the deficit (Doty, 1973). Even where pattern vision is spared following early lesions of the striate cortex, the animals may still take longer to pretrain before formal testing can commence (Schneider,

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1970). In man there is evidence of age-related sparing of sensory function. Rudel et al (1974) noted minimal impairment in brain damaged children on somaesthetic thresholds but these children were still impaired on tactile object recognition. Elementary motor function in children may also show greater savings following early massive unilateral injury (Cairns and Davidson, 1951), but such abilities as are preserved, are rudimentary. In man following early unilateral damage that is extensive enough to destroy large areas of the striate cortex, the visual field defects are similar to those produced in adults with similar pathology (Paine, 1960). In this case it might be expected that savings would be possible given the existence of a second, phylogenetically older, visual structure in the midbrain. Where lesions are more restricted, however, savings on visual (in terms of shrinkage of the size of scotoma), somatosensory and motor functions are age-related and show relatively better recovery even when damage occurs early in the third decade of life as compared to later (Teuber, 1975). Without doubt however, the most outstanding examples of functional recovery are those which occur in the areas of language and spatial skills in man following early injury.

The explanation of the functional recovery that does occur following early brain damage is not straightforward. As discussed above, part of the restitu- tional capacity may lie in mechanisms that enable individual neurones to withstand injury so the functional extent of a lesion may be less than in the mature system. It may also lie in neural regeneration per se, although Schneider (1979) has provided evidence that such anomalous regeneration, when it occurs, may actually result in greater behavioural deficit. In the case of the somatosensory and motor systems, while the greater volume of neural circuitry is concerned with analysis and control of the contralateral side of the body, ipsilateral pathways do exist. In the case of the motor system there is even evidence that hypertrophy of ipsilateral pathways occurs after early hemi- spherectomy (Hicks and D’Amato, 1970). These ipsilateral pathways may assume greater functional importance in the case of unilateral brain damage and sustain the limited behavioural savings that occur. The continued development of linguistic and spatial skills after early brain damage are however of a different order. It has been suggested that the survival of these skills in one hemisphere is due to the fact that the necessary processors exist initially in each hemisphere but that during development one hemisphere suppresses the influence of the other. This suppression of the influence of the contralateral hemisphere may be a necessary prerequisite for the development of higher cognitive skills, since processing space may be at a premium. When both language and spatial skills are acquired by only one hemisphere (following early hemispherectomy) neither skill reaches its full potential (Teuber, 1975). Where the corpus callosum is absent during development, and normal interhemispheric communication is consequently impossible, a rather bizarre pattern of cognitive development is

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seen. In such cases of callosal agenesis it appears that either performance IQ or verbal IQ becomes pre-eminent despite the existence of functional capacity in two hemispheres (Dennis, 1977). Extreme discrepancies do not in these cases appear to be predictable from age of the subject at the time of testing, sex, type of agenesis, handedness or specific neurological signs. It appears rather that a mechanism which enables a normal balance of cognitive skills to occur is absent. In the normal individual then the existence of two intact hemispheres may not be sufficient for normal cognitive growth. Some additional mechanism which ensures that unnecessary duplication does not occur and enables an efficient use of available processing capacity seems to be necessary. The consequence of the presence of such a mechanism during development is that usually specific skills become established predominantly in one hemisphere or the other and once they are so established there is little opportunity to recapitulate the process. The failure of the adult brain to fully re-establish linguistic or spatial skills following damage is a consequence of the presence of a mechanism (whose effector path is the corpus callosum) that enables a balanced and complete cognitive growth to occur.

Conclusions

Consideration of the evidence concerning the outcome of brain injury in the developing nervous system leads to the inescapable conclusion that age at the time of injury is a critical factor in determining both the initial syndrome and the pattern of adaptation that follows. Certain abilities such as early maturing spatial skills, language and various elementary sensory and motor functions may show relative recovery, the extent being determined by the location and size of the lesion. Other abilities, particularly those involving fine motor coordination, late maturing spatial skills as well as the overall level of intellectual attainment, may show more profound defects. These latter effects may be partly ascribed to a lower overall processing capacity, but in the case of general intellectual attainment, more profound effects are seen following damage to the right hemisphere before (compared with after) one year of age, a factor which argues that volume of tissue damaged is not the sole consideration. Differing patterns of language disturbances are also seen in children depending on the child’s age at the time pathology develops. These considerations, which emphasize that damage is occurring within a system whose state is continually changing, present particular difficulties for those with interests in the outcome of early brain damage. As Teuber and Rudel (1962) point out: ‘Whether we are working with infrahuman forms or with children, we must define (1) those aspects of behaviour in which the effects of early injury appear only with a delay, as development progresses; (2) those other aspects of performance in which there will be impairment at all ages; and finally, (3) those aspects of performance

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where there is an immediate effect which, however, disappears as development proceeds’. The interpretation of research which finds age-dependent differences is often far from clear. Reports that the patterning of IQ subtests is insensitive to the location of injury in young children may be a genuine indication of an age- dependent difference, despite the fact that such tests were not specifically designed to assess brain damage. However, since it is found that in adults that IQ tests are only indicative of lesion laterality in the acute but not the chronic phase (Fitzhugh et al ., 1962), the failure to find specific indication of lesion location in children with infantile injury may be attributable to the interval between injury and testing rather than an age-related difference in functional organization.

The emergence of specific functional deficit following early brain injury stresses the importance of critical structures for cognitive achievement. Just how extensively the predesignated structures of the nervous system determine the detailed characteristics of cognitive development remains to be seen. It is only relatively recently that explorations of the specific patterns of loss, as measured by specially developed tests, have begun. It is also apparent that much of the research has been concerned with hemispheric asymmetry where the structural similarity of the hemispheres means that the capacity for interhemispheric reorganization may lead to an over-valuation of the plastic capacities of the developing brain. Cases where bilateral loss of a structure is involved give one much less confidence in the restitutional capacity of the young brain. Bilateral frontal lobe damage in childhood appears to have effects at least as serious as equivalent damage in adults (Russell, 1959; Ackerly, 1964) although the paucity of research in this area and the anecdotal nature of some of the findings make conclusions tentative. There is a scarcity of unequivocal evidence that areas of the brain not normally involved in the development or performance of specific functions may assume those functions when other areas are damaged. Goldman and Lewis’s (1978) demonstration that the dorsolateral prefrontal cortex in the macaque may assume some of the functional capability of the orbitofrontal cortex, provided damage occurs early in development, remains one of the few clear demonstrations of such effects in the CNS of primates following bilateral lesions. However, the fact that the normal limits of plasticity and the extent to which they may be influenced by specific experience remain undetermined, gives developmental neuropsychologists particular problems in understanding the precise nature of brain-behaviour interrelations. Nevertheless, the fact that plasticity is a real phenomenon and may be influenced by specific experience (Goldman and Lewis, 1978) gives some hope that understanding of its nature may lead to more effective remediation regimes designed to capitalize on its characteristics.

Acknowledgements

I am grateful to H. D. Ellis and E. A. Salzen for advice and discussion during preparation of this manuscript.

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Milner, E. (1976) ‘CNS maturation and language acquisition’, in Studies in Neurolinguistics, Vol. 2 (eds. H. Whitaker and H. A. Whitaker), Academic Press, London, 31-102.

Molfese, D. L. (1977) ‘Infant cerebral asymmetry’, in Language Development and Neurological Theory (eds. S. J. Segalowitz and F. A. Gruber), Academic Press, London, 21—35.

Paine, R. (1960) Disturbances of sensation in cerebral palsy. Little Club Clin. Dev. Med., 2, 105- 109.

Piaget, J. (1979) ‘Correspondences and transformations’, in The Impact of Piagetian Theory (ed. F. B. Murray), University Park Press, Baltimore, 17-27.

Rudel, R. G., Teuber, H.-L. and Twitched, T. E. (1974) Levels of impairment of sensori-motor functions in children with early brain damage. Neuropsychologia, 12, 95-108.

Russell, W. R. (1959) Brain, Memory and Learning: A Neurologist's View. Clarendon Press, Oxford.

Schneider, G. E. (1969) Two visual systems. Science, 163, 895-902.

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CHAPTER EIGHT

SEX DIFFERENCES IN BRAIN DEVELOPMENT: PROCESS AND EFFECTS

MIRANDA HUGHES

Introduction

Identifying the neural mechanisms which underlie particular behavioural and cognitive functions has become a fundamental aspect of psychological research, and in recent years considerable progress has been made in understanding the way in which both pre- and postnatal hormones can affect brain differentiation. The notion that prenatal hormones which are differentially produced by males and females may have irrevocable effects on the brain as well as on physical morphology is politically provocative; nonetheless, improving our knowledge of the neural substrates of behaviour ought also to facilitate our understanding of how postnatal environment exerts its influence. Thus, to find sex differences in brain differentiation, and to link these to sex differences in cognitive ability and behaviour, does not necessarily imply biological determinism; rather, it enhances our understanding of the raw materials which educational and cultural pressures may mould in a variety of ways.

This chapter discusses the way in which pre- and postnatal hormones affect brain differentiation, and it is argued that the long-term effects of the early hormone environment may predispose any individual to certain ‘masculine’ or ‘feminine’ type behaviours. However, different aspects of our behavioural repertoire are certainly under different degrees of hormonal influence and human behaviour is not clearly sexually differentiated. As Money (1977a) put it so cogently ‘... the only irreducible sex differences are that women menstruate, gestate and lactate, and men impregnate ... most sexually dimorphic behaviour

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as we know it is the product of cultural history and not of some eternal verity programmed by non-cultural biology. 5 (pp. 32, 33).

Following Pfeiffer’s (1936) innovative and now classic work, the precise role of prenatal hormones in the development of the hypothalamic mechanisms which control hormone release at puberty, and which are responsible for the development of sexually differentiated physical characteristics, is well established (Harris, 1964, 1970). The well documented cases of children exposed to abnormal levels of particular steroids in utero (Money and Ehrhardt, 1972), and the work of Dorner (1979) on human homosexuality, have subsequently raised a number of questions concerning the effect of hormones on a wide range of behaviour. The line of reasoning seems to be that if (a) some neural mechanisms (e.g. for gonadotropin release at puberty) are determined by the role of prenatal hormones, and (b) foetuses exposed to abnormal levels of types of particular hormones behave in specific and atypical ways, then it follows that (c) just as the prenatal hormonal environment has ‘wired-up 5 the brain in such a way as to determine the expression of certain endocrine functions, so too can it predispose an organism to specific behaviour patterns. A closer examination of the three stages of this argument should facilitate the development of a conceptual framework within which to extend our understanding of the variety of expression in human abilities and behaviour.

Prenatal sex differences in development

Distinctively male or female development begins at around the seventh week after conception when the initially bi-potential embryonic gonad differentiates to form either a testis (in the case of a male) or an ovary (in the case of a female). This differentiation of the gonads is determined by the genetic sex of the zygote (46XY in the male; 46XX in the female); where there is no second sex chromosome as in Turner’s syndrome (45X) the gonads are undifferentiated at birth, although germinal follicles may have been present in the early foetal stages (Scott, 1978). Jost (1979) tentatively suggests that there may be a specific membrane protein controlled by a locus on the Y chromosome (the H-Y histocompatibility antigen) which is responsible for the differentiation of testes, and whose individuals who do not produce this antigen will form an ovary. Once a testis has been formed the release of a substance (probably a foetal protein) known as Mullerian inhibiting substance (MIS) induces the regression of the Mullerian ducts, and secretion of androgenic hormones enables the development of the male reproductive tracts and genitalia. In the absence of testicular hormones female development occurs; ‘...in mammals and birds body sex shows a basic developmental trend corresponding to that of the homozygous sex. Characteristics of the heterozygous sex have to be actively imposed by the secretions of the corresponding gonads 5 (Jost, 1979, p. 8). Thus, the appearance

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of Turner’s syndrome infants is unequivocally female, and that of Klinefelter’s syndrome infants (47XXY and 48XXXY) is unequivocally male.

Sexual differentiation does not, however, always proceed entirely smoothly, and Scott (1978) has provided a useful classification of some ‘intersex’ conditions. He suggests that there are four basic processes which may distort normal sexual differentiation: (i) chromosomal intersex, in which extra or missing sex chromosomes affect development; (ii) gonadal intersex, in which the gonadal tissue is at variance with the chromosomal constitution of the individual; (iii) partial masculinization of chromosomal and gonadal females, due either to a disorder of adrenal functioning or the exogenous administration of steroid hormones to the mother; and (iv) incomplete masculinization of chromosomal and gonadal males which may occur either because an individual is insensitive to the androgen being produced by the testes or because there is some failure in androgen production. These medical conditions have often been described as ‘nature’s experiments’ because they shed light on the various ways in which hormones affect development.

In Turner’s syndrome, the missing chromosome may be either an X or a Y: evidence for this comes from a report by Leujeune (1964) of monozygotic twins, one of whom was a normal male of 46XY karyotype, the other of whom was born with 45X karyotype (and therefore a female phenotype). Turner’s syndrome females are typically short in stature, and require oestrogen therapy at puberty to effect normal breast development. There may be a range of other physical stigmata present (e.g. shield chest, neck webbing, low-set ears), but general intelligence is not significantly affected (Money and Ehrhardt, 1972). The streak gonads are often entirely non-functional, but they may contain some ova in which case pregnancy is possible.

There are approximately two cases per thousand of males with a 47XXY karyotype, and a similar number with 47XYY karyotype. The former often have small testes and prostates and diminished body and facial hair; they may also show some breast development at puberty, and are frequently infertile. Males with 47XYY karyotype have a tendency to be taller than average, but otherwise display no specific physical abnormalities. It has been estimated that both 47XXY and 47XYY males are over-represented in mental or penal institutions during late adolescence or adulthood. Differences between these groups in deviant behaviour are not significant; however, their crimes are more likely to be sex or property offences than those of their delinquent peers (Meyer-Bahlburg, 1974).

Cases of gonadal intersex (hermaphroditism) show widely varying arrangements of gonadal tissue and genitalia. Scott (1978) suggests that there may be an interchange of genetic material between the X and Y chromosome before the first meiotic division in the primary spermatocyte, which could lead to widely varying sexual differentiation according to the cells in which the Y chromosomal

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material is active. Such cases clearly do not provide a homogeneous subject sample, but are nonetheless interesting individually.

The partial masculinization of females and the incomplete masculinization of males illustrate clearly the role of steroids in the development of sex-related physical characteristics. The former of these conditions is usually due to congenital adrenal hyperplasia (CAH) which occurs as a result of an enzymatic deficiency in the adrenal steroid metabolic pathways. The most common form of CAH is 21-hydroxylase deficiency which results in a build-up of 17-hydroxypro- gesterone, the metabolic derivatives of which have a virilizing influence on the female foetus. Male infants appear normal at birth (although puberty may be accelerated by as much as ten years if the condition is not diagnosed and treated), but female infants have masculinized external genitals. The female internal organs are normal, and with appropriate medical treatment (including surgery to feminize the genitals) these girls may menstruate at puberty and eventually bear children.

Masculinization of females may also arise from the influence of steroid hormones administered to the mother during pregnancy to prevent miscarriage. Ehrhardt and Money (1967) report ten such cases, and Scott (1978) describes an individual case following the administration of norethisterone to the mother. As in the CAH cases, masculinization is apparently restricted to the external genitalia, and can be corrected surgically.

There are three possible defects of the androgenization process which can give rise to the incomplete masculinization of the male: defective androgen production, defective Mullerian regression, and androgen insensitivity. The last of these is the best documented and is often known as ‘testicular feminization’. In this condition infants with a normal male 46XY chromosome complement are born with a female phenotype. Since Mullerian regression has occurred normally, there is a short blind vagina, but the external genitalia are unequivocally female. At puberty, there is spontaneous breast development, although pubic hair tends to be scant. The condition occurs despite normal steroid output from the testes, when the receptor cells fail to respond to the androgens which are present.

Individuals with complete androgen insensitivity may be quite oblivious to their condition until puberty, when they seek medical advice for amenorrhea. However, there are incomplete forms of androgen insensitivity: for example, where there is a failure to convert testosterone to the more potent 5a- dihydrotestosterone there may be incomplete masculinization of the external genitalia. Imperato-McGinley et al (1974) described some such cases in which the affected infants are given a female assignment at birth, but at puberty have to undergo a gender re-assignment because ‘anabolic events at puberty, in particular the increase in muscle mass, the growth of the phallus and scrotum, and the voice change, appear to be mediated by testosterone’ (p. 1214).

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All of these ‘intersex’ conditions have considerable interest for psychology, in that they provide an opportunity to examine the possible behavioural effects of the prenatal hormones. It is certainly true that the prenatal hormonal environment affects cell differentiation in the brain; the speculations which require critical examination are those concerning the behavioural implications of such hormonal effects.

Hormonal action

The role of prenatal hormones in the development of the internal sex organs and genitalia is clearly established. If these hormones exert equally critical influences on brain differentiation, one would expect to find different patterns of neural networks in male and female brains. It is instructive therefore to examine the mechanism whereby hormones exert their influence so that sex differential developmental processes can be appropriately evaluated, and any anomalies of normal development can be interpreted.

The steroid hormones include the male sex hormones (androgens), the female sex hormones (oestrogens and progestins), and the hormones secreted by the adrenal glands (corticosteroids). Structurally, they resemble one another quite closely but differ radically in function. Their common core structure consists of four interconnected carbon rings. The pattern of bonding and the different side groups affect the overall shape of each molecule, and it is these subtle differences in shape which enable the hormones to attach themselves to specific target cells.

Hormones act directly on genetic mechanisms, so that when gene action is blocked (for example, by the action of certain antibiotics) hormones become powerless to exert their characteristic effect. A single hormone can activate an entire set of functionally related but otherwise quite separate genes, and hormonal specificity is dependent on the functional integrity of the target cells as much as on the hormone itself. The cytoplasm of target cells contains specific intracellular receptor proteins which accumulate and retain the hormone (this in contrast to the receptor mechanism of say, amines, for which the receptor site lies in the cell membrane). The steroid hormones then give rise to an increase in RNA synthesis, and can also effect the synthesis of a new variety of messenger RNA; these RNA molecules direct the formation of new protein molecules in the cytoplasm of the cell which enable the target cell to make its functional responses to the hormone.

During development the presence of male hormones will (in general) have a masculinizing effect on a genetic female. However, in experiments on rats it was found that whilst testosterone increased the amount of RNA produced in the liver cells of both males and females, in the female not only was there an increased amount of RNA, but a new type of RNA was being produced; this finding does suggest that even when male and female developing embryos are

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exposed to similar hormonal environments, the consequences need not necessarily be identical (Davidson, 1965). There has been some attempt to discover whether sex differences in brain differentiation are mediated by sex differences in cytoplasmic receptors. Data from Maurer (1973) and from Whalen (1974) show that there was selective cytoplasmic binding of oestrogen in the anterior hypothalamic-preoptic area (of rats), in the median eminence, but not in the cortex; however, the sex differences were not striking \ .. it seems unlikely that the small difference in nuclear retention that we found can account for the large differences existing between males and females in their behavioural responses to oestrogen’ (Whalen, 1974, p. 278).

Sex differences in brain differentiation

Pfeiffer (1936) was the first to establish that sex differences in the reproductive endocrinology of rats were determined by the hormone environment at a specific stage of development. He demonstrated that if a male rat is castrated within 3 days after birth and is subsequently (in adulthood) given ovarian grafts, he will respond to endogenous hormones with a surge of luteinizing hormone (LH) which is sufficient to produce corpora lutea in the ovarian graft. When the ovaries of newborn females were replaced with testes, many of these females failed to show any sign of oestrous cycles when they became adult, but entered a state of constant vaginal oestrus. However, female rats, which were ovari- ectomized at birth and subsequently had received ovarian implants, showed normal oestrous cycles and formation of corpora lutea. Male rats in which the testes were transplanted into the neck region at birth, and which received ovarian implants as adults, showed no capacity to form corpora lutea in the ovarian grafts. Pfeiffer concluded (erroneously) that the pituitary gland becomes sexually differentiated; subsequent experiments (see Harris, 1964, 1970) made it clear that in fact permanent control by the hypothalamus over the pituitary was established by the presence or absence of testosterone in a critical neonatal period. In the absence of testosterone a pattern of cyclic release of follicle stimulating hormone (FSH) and LH by the pituitary was established; when testosterone was present, release of hormones was tonic. Reznikov (1978) states that the critical periods for the sexual differentiation of the brain centres which regulate gonadotropin release \ .. occur in rabbits during the period of 19-23 days, and in guinea pigs at 36-38 days of pre-natal life, in rats, mice and hamsters, in the course of the first five days after birth. In the case of humans, the most probable period of sexual differentiation is considered to be the second trimester of pregnancy. It should be emphasised that experimental influences exerted outside the “critical” period are incapable of moderating the sex- specifying parameters of differentiation of the brain’ (p. 127).

Barraclough and Gorski (1961) demonstrated that cyclic gonadotropin

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release in female rats is regulated from a specific centre in the pre-optic hypothalamic region, whereas tonic gonadotropin response is regulated from the hypothalamic ventromedial arcuate region. Bari Kolata (1979) reviews the recent evidence that (in rats) it is the aromatization of testosterone to oestrogen which is crucial in the sex differences which occur during brain differentiation: when testosterone reaches the brain cells of newborn male rats it is converted to oestrogen and dihydrotestosterone but newborn female rats’ brains are protected from the effects of endogenous oestrogen by a-fetoprotein (a protein made by the fetal liver) which binds oestrogen and thus prevents it from reaching the developing brain. However, animals whose critical period for brain differentiation ends before birth (such as humans) have a-fetoproteins which do not bind oestrogens, and it is not yet clear what mechanisms might protect those animals’ brains from the effects of oestrogen.

Behavioural effects of sex differences in brain differentiation (i) Sexual behaviour

The effects of pre- and perinatal hormones on the sexual behaviour of infrahuman species are reviewed carefully by Hoyenga and Hoyenga (1980), and the interested reader is referred to their text for a detailed list of primary sources. The evidence that early hormones are critical in determining sexual behaviour is unequivocal: neonatal castration of male rats (i.e. deandrogenization) increases all types of female sexual behaviours; and the prenatal androgenization of female rats increases the incidence of mounting and decreases the incidence of lordosis (the female sexual response consisting of concave arching of the back with simultaneous raising of the head and hind-quarters). Comparable evidence is available from primate studies. However, the perinatal administration of androgen to a female rat does not entirely masculinize her complete repertoire of sexual behaviour, any more than the castration of a male entirely suppresses all male-type responses.

Whalen (1974) proposed an orthogonal model of sexual differentiation in which he suggested that ‘during development hormones can defeminize without masculinizing and masculinize without defeminizing, and that hormones can defeminize one behavioural system (e.g. mating) while masculinizing another system’ (p. 469). This conception is not really satisfactory, for if one considers any specific aspect of sexual behaviour (such as lordosis) it is difficult to see how ‘masculinization’ does not also imply ‘defeminization’; however, it does try to deal with the data which indicates that lordosis in the female is not necessarily inhibited by perinatal administration of testosterone, even though she also exhibits increased incidence of mounting. In the same article Whalen raises some important criticisms of the naivety of the behavioural analysis which has often been employed in studies of sexual behaviour, and similar criticism is reiterated

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by Beach (1979). Responses such as lordosis can be only partially completed, and neonatally androgenized females do exhibit weak or partial lordosis responses with moderate frequency. Similarly, mounting is not always accompanied by intromission and ejaculation. A fmer-grained categorization of the behavioural units which comprise ‘sexual behaviour’, and due attention to controlling for the stimulus conditions in which it occurs, might facilitate our understanding of its general structure, and thus enhance our knowledge concerning the differential effects of various hormones. Beach suggests that both male and female brains have the appropriate neural substrates for homotypical and heterotypical sexual behaviour, and that sexual differentiation of the brain serves to alter the probability of a particular response being elicited in a given set of stimulus conditions. Thus, demasculinization does not eradicate the possibility of a male type response, it simply reduces its probability of occurrence. Figure 8.1 shows the critical period during which sexual differentiation of the brain occurs in rats. The degree to which the behaviour of the female rat is masculinized is dependent both on dosage and on timing of testosterone administration.

Figure 8.1 The effects of perinatal testosterone or castration on neonatal rats.

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There is some interesting evidence from Dorner’s laboratories (Dorner, 1977, 1979) that human sexual behaviour may be affected by the prenatal hormonal environment. ‘An androgen deficiency in genetic males during a critical period of brain organization gives rise to predominantly female differentiation of the brain. This androgen deficiency in early life can be largely compensated by increased hypophyseal gonadotropin secretion in later life. Thus, the predominantly female-differentiated brain is post-pubertally activated by an approximately normal androgen level, leading to homosexual behaviour’ (Dorner, 1979, p. 87). The evidence from which this conclusion is derived comes partly from an experiment in which adult males were given an intravenous oestrogen injection: in homosexual males there was a subsequent rise in LH values above initial levels (a response which would be normal in females), whereas in bisexual and heterosexual males no such rise was detected. Goy and McEwen (1980) express some discomfiture with these data, and in particular point to evidence of time- dependent partial dissociation between the differentiation periods of central nervous centres regulating gonadotropin secretion and those responsible for sexual behaviour. However, Dorner (1977, 1979) clearly believes that the evidence of a relationship between prenatal hormones and adult sexual behaviour is now sufficiently strong to contra-indicate the prescribing of any androgenic or anti-androgenic substances to pregnant women, and recent data on females with CAH may tentatively support this view. In contrast to earlier findings which suggested that CAH females were no different from normal controls in their heterosexual interests and behaviour (Ehrhardt et al ., 1968a; Ehrhardt et a/., 19686) a more recent investigation by Money and Schwartz (1977) has suggested that early treated CAH females may be delayed in establishing dating and romantic interests. In addition, they found that in their sexual fantasies CAH females showed an increased rate of awareness of bisexuality relative to controls (although this did not necessarily reflect actual experience). It is plausible that these more recent data reflect a less prescriptive social climate than that which prevailed during the early 1960s when the original data were presumably collected, and one can only conclude that the nature of the biological, cognitive and social factors which regulate human sexual behaviour are by no means well established. This area remains wide open to debate.

(ii) Non-sexual behaviour

The effects of pre- and perinatal hormones on animals are not restricted to endocrinology and sexual behaviour. Levine (1966) cites evidence which demonstrates that female rats who have been injected as neonates with testosterone show male-type behavioural responses in an open field; and that female rhesus monkeys injected with testosterone in utero show levels of rough and tumble play which are approximately equivalent to those of normal male monkeys. Goy (1968, 1970) reports that initiation of play and pursuit play are

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greater in neonatally androgenized female monkeys than in normal females, and a number of workers have reported effects of neonatal hormones on activity (Gray et al ., 1975; Stewart et al ., 1975), exploration (Quadagno et al ., 1972; Gummow, 1975), and learning (Beatty and Beatty, 1970; Dawson, 1972; Dawson et al ., 1973). Quadagno et al. (1977) have reviewed the extensive literature on the effects of perinatal hormones on non-sexual behaviours with particular reference to energy expenditure, maternalism and learning, and they are able to conclude that the effects of early hormones on the behaviour of infrahuman species are well established.

McEwen (1976) and Goy and McEwen (1980) describe the experimental data which have led to the identification of specific neural pathways that are established by the influence of sex hormones and are sexually differentiated, and which underlie sex differences in behaviour. The work of Raisman and Field (1973) represented an important breakthrough in this field: they found that adult female rats have more dendritic spine connections in the preoptic area than males, but that males castrated within 12 hours of birth have spine connections equivalent *o those of the female. They demonstrated that those animals which show frequerd lordosis have different patterns of synaptic connectivity than animals with a limited capacity for lordosis. Various other studies have also shown that the brain of a male rat deprived of androgen and the female exposed to androgen will take on heterotypical characteristics: for example, the size of the cell nuclei in the preoptic area is positively correlated with the degree of lemaleness’ in the rat’s sexual behaviour (Dorner and Staudt, 1968, 1969); both serotonin levels (Ladosky and Gaziri, 1971) and RNA metabolism (Clayton et al ., 1970) are also affected. Litteria and Thorner (1974) and Phillips and Deol (1973) report sex differences in the cerebellum and septum which can be reversed by the presence or absence of androgens. However, even if these differences do indeed underlie the observed differences in behaviour (as seems plausible) and we assume that similar mechanisms of differentiation occur in humans, it is nonetheless unlikely that human behaviour would be so strongly determined by neural networks (particularly in the face of conflicting socialization).

Hormonal anomalies in human development

The data from the above animal studies provide sufficient evidence for the assertion that hormones are critical in determining patterns of brain differentiation, and suggest that pre- and perinatal hormones may also exert long-term effects on behaviour patterns. It is instructive then, to consider the effects of early hormones on human behaviour insofar as this can be achieved within the limitations of ethical considerations (see Reinisch and Gandelman (1978) for an interesting discussion of these issues). It has already been noted that prenatal hormones affect the development of sex-typical physical characteristics, and

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individuals with anomalous genital development at birth, or who present with related problems at puberty (e.g. amenorrhea in patients with testicular feminization), have been studied by psychologists interested in the possible effects on hormones on behaviour.

Two clinical syndromes can be regarded as close counterparts of experimental anti-androgenization (or demasculinization) in animals: Turner’s syndrome and testicular feminization due to androgen insensitivity. In Turner’s syndrome the missing chromosome may be either an X or a Y, and if a few androgen-secreting cells remain in the gonadal streak tissue there may be a mild degree of labial fusion and an enlarged clitoris. Some individuals have a 45X/45XY mosaic karyotype: they have testes, but these are not properly formed and are at high risk for cancer (Money, 1911b). Thus, deandrogenization in Turner’s syndrome is due to a failure of the gonads to manufacture androgens; in contrast, other testicular feminization syndromes are a result of the failure of the target organ cells to take up and utilize the androgens which are secreted from testes in foetuses with the normal 46XY karyotype.

The behaviour of girls and women with either Turner’s syndrome or testicular feminization is unequivocally feminine. In the case of Turner’s syndrome there seems even to be a tendency of extreme conformity to female sex stereotypes: they are known to fight less, to be less athletic and to be more interested in personal adornment than control comparisons (Money and Ehrhardt, 1972); and Theilgaard (1972) reported that women with Turner’s syndrome preferred to wear very feminine-style clothing and jewellery. All but one of the 15 girls in the group studied by Money and Ehrhardt (1972) had played exclusively with dolls, and most of them expressed a very strong interest in maternalistic activities associated with child care. In their anticipation and imagery of romance and motherhood, Turner’s syndrome females were found to be no different from their control comparisons. From these data, one may infer that differentiation of a feminine gender role is not dependent on the presence of prenatal gonadal hormones, nor does it require the presence of a second X chromosome. Indeed, Money and Ehrhardt are prepared to assert that ‘a feminine gender identity can differentiate very effectively without any help from prenatal gonadal hormones that might influence the brain and perhaps, in fact, all the more effectively in their absence’ (p. 108).

Babies born with the testicular feminization syndrome look like absolutely normal females, although these females tend to be of above average height (Money, Ehrhardt and Masica (1968) quote a mean height of 5 feet 1\ inches for their sample of ten patients). Diagnosis of their condition normally follows referral for primary amenorrhea so data regarding behaviour in early childhood are necessarily based on retrospective report (which may be influenced by knowledge of their condition). Even with this caveat in mind the data reported by Money et al (1968) and Money and Ehrhardt (1972) do seem to provide

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strong evidence for the unequivocal differentiation of female gender role in these patients. They reported playing primarily with dolls in early childhood and having dreams and fantasies which reflected the normal sex-role stereotypes of marriage and motherhood. With one exception these women rated themselves as fully content with the female role, and at adolescence they conformed with the normal patterns of heterosexual behaviour. Most of them expressed positive enjoyment in adopting ‘feminine’ styles of dress and personal adornment. ‘Babies with the androgen insensitivity syndrome who are consistently reared as girls have no uncertainties about themselves as girls, women, wives, sexual partners, and mothers by adoption ... they grow to be womanly in their behaviour, in their erotic mental imagery, and in their self-perception, even when they know the medical terminology of their diagnosis’ (Money, 1977a, p. 262).

Reifenstein’s syndrome resembles that of complete androgen insensitivity except that there is partial masculinization of the genitalia during foetal life and the neonate is thus sometimes classified as a male. At puberty the development of secondary sex characteristics nevertheless proceeds as described above. According to Money and Ogunro (1974) those infants assigned as males did not show any preference in childhood for female-type activities (doll play etc.) and made concerted efforts to compensate for their relative inferiority in athletic pursuits. At puberty, their breasts had to be surgically removed; in adulthood their physiognomy is beardless and unvirilized, and because of their extremely small, surgically repaired genitalia they may encounter some difficulty establishing a sex life (none reported homosexual preference). On the whole, gender identity conforms with socialization and there seems to be no evidence from these cases of any biologically based behavioural imperative for feminization. These cases may reflect the experimentally induced ‘demasculinization’ without accompanying ‘feminization’; and as far as we can tell from these few cases the social environment is a paramount factor in influencing preferred activity and gender identity.

The form of male pseudohermaphroditism described by Imperato-McGinley et al (1974) results from a 5a-reductase deficiency which leads to incomplete differentiation of the external genitalia at birth, and thus a female sex assignment is often made. At puberty, however, differentiation of male characteristics occurs and sex re-assignment is necessary. A recent report by Savage et al (1980) confirms the rather surprising finding that this gender-role transition is made relatively easily and they conclude ‘... that exposure of the brain to androgens during foetal life and thereafter appears to have had more effect on determining gender identity than the pre-pubertal sex of rearing’ (p. 404).

In the light of this conclusion it is interesting to consider the effects of the masculinization of a female foetus. These have been documented in two clinical syndromes: progestin-induced hermaphroditism (PIH) and the adrenogenital syndrome (CAH). PIH occurred following the administration of synthetic

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progestins to pregnant mothers with histories of miscarriage; these steroids were devised as substitutes for the pregnancy hormone, progesterone, but because their chemical structure was similar to androgen, they exerted an unexpected masculinizing effect on a female foetus (Walker and Money, 1972). Once this effect was discovered (in the early 1950s) the use of these hormones was discontinued; however, the subsequent development of girls born with PIH has been studied (Ehrhardt and Money, 1967; Money and Ehrhardt, 1972). If the external genitalia were surgically feminized shortly after birth, no further surgical or hormonal treatment was required; this is in contrast to girls born with CAH who require constant maintenance on cortisone to prevent continuing postnatal masculinization and accelerated pubertal development. Table 8.1 summarizes some of the data obtained on the reported behaviour of these cases. Basically, there is little difference between that of the PIH and CAH girls, but both these groups differ significantly from control comparisons on measures of tomboyism, athletic skills and preference for boys’ toys (e.g. cars, guns etc.). Perhaps, as a result of these interests, it is not surprising that these girls also prefer male playmates.

The accuracy of assessment of behaviour in these cases is difficult to evaluate and Ehrhardt and Baker (1974) are clearly aware of this when they discuss, in some detail, exactly how the interviews with patients and their parents were conducted. It is important to be aware'that no observations were made of the

Table 8.1 Behavioural effects of prenatal exposure to androgens*

Childhood behaviour

PIH

CAH

Tomboyism

above average

Athletic interests and skills

above average

Preference for male playmates

above average

Preference for ‘functional’ clothing

above average

Preference for toy cars, guns etc. over dolls

above average

Anticipation of future

Priority of career over marriage

above average

Heterosexual romanticism

normal

Anticipation of pregnancy

normal

Less frequently reported than controls

Dissatisfaction with female role

no

Sexual behaviour

Childhood-shared genital play/copulation play

normal

Adolescent boyfriend and dating

normal

Bisexual/homosexual fantasy

(data not available)

above average

Bisexual/homosexual behaviour

no

within normal range

Data adapted from Ehrhardt (1977); Ehrhardt and Baker (1974); Epstein and Money (1968);

Ehrhardt and Money (1967); Money and Ehrhardt (1972); Money and Schwartz (1977).

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children and that reliability was assessed purely in terms of the concordance between the mother’s and child’s reports. Even so, these data do seem to reflect a tendency for increased activity in females who have been exposed to abnormally high levels of androgen in utero ; and compatible with these tomboyish interests, these girls also seem less interested than control comparisons in personal adornment and maternal behaviours. Their gender identity is nonetheless entirely female (although 35% of them said they would not mind being a boy).

It appears then, that the effect of prenatal androgens on gender identity cannot be as imperative as Imperato-McGinley et al. (1974) and Savage et al (1980) suggest; it is more likely that the activational effects of circulating male hormones at adolescence are crucial to the satisfactory transition to the male gender role for these male pseudo-hermaphrodites. However, the surmise that the behavioural development of CAH and PIH females is in some way analogous to that of prenatally androgenized monkeys (Goy, 1968) is certainly supported by the available data. Furthermore, it is interesting to note that whilst the excess of androgens may be contributing to a masculinizing effect on some behaviours it does not have a global ‘defeminizing’ effect. Indeed, a sample of late-treated CAH patients described by Ehrhardt, Evers and Money (1968) conform strongly to female sex stereotypes in their careers and/or marriages. In fact, the influence of prenatal androgen exposure is probably limited to a specific effect which in some way creates a predilection for physical energy expenditure; associated preferences for functional clothing and male playmates may be no more than a reflection of this basic trait. This conclusion is confirmed to some extent by the finding that males with CAH are no different from a comparison group of unaffected male siblings except that they are more frequently (80 % of CAH males: 20% sibs) reported to engage in intense energy expenditure (Ehrhardt and Baker, 1975).

In two studies (Zussman et al. (1975) cited in Goy and McEwen, 1980; Ehrhardt et al, 1975) which considered the effects of prenatal progesterone on childhood behaviour (not the androgenic progestins which caused PIH), subjects were found to exhibit lower energy levels and a tendency to prefer ‘female type’ clothing styles. They suggest that non-androgenic progestins may actively counteract androgen effects in utero in both males and females.

During childhood, then, the major behavioural effect of prenatal androgenic hormones is on activity level: when the foetus has been exposed to androgen, he/she will subsequently display a predilection for high levels of physical energy expenditure (and these effects appear to be dose-related). These results are consonant with the findings on the effects of androgens in rodents and primates (Quadagno et al , 1977), and they do suggest that these hormones have an organizing effect on brain differentiation which will usually be sexually dimorphic.

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Personality

Reinisch (1977) argues that prenatal exposure to (non-androgenic) progestin also has long-term effects on personality, and her data confirm the earlier suggestions of Ehrhardt and Money (1967) that progestin-exposed subjects show high levels of self-assertive independence and self-reliance. Twenty-six subjects, whose mothers had been administered a minimum dosage of 40 mg progestin for at least four weeks during the first trimester of pregnancy, were tested on age-appropriate Cattell Personality Questionnaires. They exhibited high scores on individualistic, self-assured and self-sufficient factors relative to sibling controls. In contrast, subjects exposed to high oestrogen levels in utero were found to be more group-dependent and group-oriented than a sibling control group.

An investigation by Yalom, Green and Fisk (1973) also attempted to evaluate the long-term effects of prenatal oestrogens on personality. Because diabetic women produce lowered levels of oestrogen and progesterone during pregnancy they are sometimes prescribed supplemental doses of these hormones; Yalom et al. studied the male children of diabetic mothers who had received high oestrogen doses, and compared them to a control group of children with normal mothers and a group of children of untreated diabetic mothers. At the age of 6 the boys who had been exposed to the highest levels of oestrogen were rated by their teachers as being less assertive and less athletic than their male peers. By the age of 16 a whole range of behaviours seemed to be related (albeit weakly) to the level of oestrogen exposure: athletic coordination, competitiveness, assertiveness, aggression, and global measures of ‘masculinity’. The children of diabetic mothers who had not received oestrogen supplements were consistently more masculinized than the control group of sons of normal mothers, and the children of mothers who had received supplemental oestrogen were the least masculine. It is possible that some of these effects may be due to differing levels of activational hormones in these boys since the development of the testes and output of testicular hormones are likely to have been affected (Zondek and Zondek, 1974).

Cognitive ability

In an exhaustive review of psychological sex differences, Maccoby and Jacklin (1974) concluded that males show superior visuo-spatial and mathematical abilities relative to females. Females though, are better at some verbal skills: they are more fluent, they are better readers and spellers, and their speech is more comprehensible than that of males (Harris, 1977). The extent to which these differences reflect underlying differences in neural organization has been a matter of considerable debate (Archer, 1976) since the influence of differential

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socialization in the development of sex-typed abilities is difficult to evaluate. Males and females show similar rates of early babbling (Moss, 1967; Lewis, 1972), but by six months of age girls receive more physical, visual and vocal contact with their mothers (Goldberg and Lewis, 1969; Messer and Lewis, 1972). Infant boys are encouraged more than girls to explore and to be independent of their mothers (Baumrind and Black, 1967; Hoffman, 1972). McGuinness (1976) argues convincingly that sex differences in cognitive abilities may develop from fundamental differences in auditory and visual acuity—from an early age females show lower auditory thresholds and superior pitch discrimination compared to males, and the sex difference increases with higher frequencies and with age (McGuinness, 1972); males have superior foveal vision, greater sensitivity to light and longer photopic persistence.

The aspect of spatial ability in which males most consistently excel is the capacity to rotate mentally three-dimensional images, or to redefine visual images into new planes; males thus perform better on mathematical problems which require spatial visualization (Fennema and Sherman, 1977; Petersen, 1979) and which involve the ability to ‘break set’ and restructure (Garai and Scheinfeld, 1968; Hutt, 1972a, b). Until adolescence, the majority of studies show no sex differences in quantitative skills, but males move ahead after this point and show consistently superior performance (Maccoby and Jacklin, 1974).

If these sex differences in cognitive abilities are subserved by the neural organizing effects of androgens in utero, a sample of females exposed prenatally to androgen would be expected to show a male pattern of abilities. Similarly, if enhanced oestrogen levels affect the neural substrates of verbal behaviour then males exposed to supplemental oestrogen in utero would show a female pattern of abilities. In fact, neither of these hypotheses is substantiated by the available data.

Ehrhardt and Money (1967) report identical mean verbal and performance IQ scores for a PIH sample of ten females (mean verbal IQ = 125, s.d. = 11.4; mean performance IQ = 125, s.d. = 12.5). Although Perlman (1971) (cited in Reinisch et al., 1979, and in Baker and Ehrhardt, 1974) found that CAH girls performed significantly lower than their matched controls on Verbal and Comprehension sub-tests of the Wechsler IQ scale, they also scored lower on Block Design. However, the scores of CAH girls on the Healy Pictorial Completion Test were comparable to those of CAH and normal boys; Perlman suggests that this result may reflect the higher activity levels of the CAH girls which would have made them more familiar with the kinds of situations depicted on the test. Baker and Ehrhardt (1974) report no statistically significant difference on perceptual or verbal factors between AGS patients and sibling control comparisons, although the trends were in the expected direction (i.e. CAH females performed slightly less well on the verbal sub-tests of the WISC than their unaffected female siblings, but slightly better on the perceptual sub-tests).

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Curiously, patients exposed to prenatal androgen do seem to have above average IQ scores, but close examination of the relevant data reveal this finding to be due to factors other than the androgenic influence. Baker and Ehrhardt (1974) tentatively suggest that the recessive genetic trait for CAH may somehow be linked to another trait which favours postnatal intellectual development, and this notion is supported by the finding that the IQ levels of CAH patients do not differ significantly from those of their parents and siblings which are also higher than normal. The elevated IQ of the PIH group (Ehrhardt and Money, 1967) can be ascribed to social class factors among the parents: six of the nine families involved in this study had at least one parent who was a college graduate. Thus, there is no substantial evidence to link prenatal androgens with enhanced IQ scores.

Dalton (1968, 1976) suggested that prenatal progesterone (not of the androgenic type) increased intellectual achievement, but these data were not replicated in a study reported by Reinisch and Karow (1977) and have been discredited on statistical and theoretical grounds (Lynch et al ., 1978; Lynch and Mychalkiw, 1978).

The only study to consider the effects of prenatal oestrogen on cognitive ability is that of Yalom et al. (1973). These (male) subjects were administered the Embedded Figures Test to evaluate their spatial ability: those boys who had been exposed to supplemental oestrogen in utero showed slightly inferior performance relative to the two comparison groups, but this result did not reach statistical significance.

Other hormonally anomalous clinical conditions in no way implicate the role of prenatal hormones in determining the future patterns of intellectual abilities. Patients with testicular feminization show the typical female pattern of lower spatial than verbal ability: in the study reported by Masica et al. (1969) a sample of fifteen cases had a mean Wechsler verbal score of 111.8 and a mean performance score of 102.3. Since their exposure both to hormones and socialization is equivalent to that of genetic females, one can conclude from these data simply that superior male visuo-spatial abilities are not genetically determined from a locus on the Y chromosomes. For some time it was thought that spatial ability was partly determined by a locus on an X-linked gene (O’Connor, 1943; Stafford, 1961), but recent data indicate that the pattern of spatial abilities within familial groups is better explained by a model of an autosomal dominant gene which has reduced penetrance in females (Fain, 1976, cited in Vandenberg and Kuse, 1979). Whether this mechanism might influence brain differentiation must be purely speculative, and there is, as yet, no evidence to this effect.

Turner’s syndrome females have IQ scores within the normal range (Money, 1964; Shaffer, 1962), but also tend to show specific deficiencies in spatial ability. Shaffer (1962) quotes a mean verbal IQ of 106, but a mean performance IQ of 88.

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Alexander, Ehrhardt and Money (1966) showed that Turner’s syndrome females experienced great difficulty on a visual memory test which requires the reproduction of angulated shapes, and Theilgaard (1972) reported that they performed badly on an embedded figures task.

It is reasonable to speculate from these data that androgens play some role in facilitating spatial ability. Since Turner’s syndrome females produce no androgens, and testicular feminized patients are insensitive to their effects, spatial ability is thus slightly impaired. In the oestrogen-exposed patients, the testes may have been producing less androgen than normal (Zondek and Zondek, 1974). The data from the CAH patients indicate that it is not the prenatal hormonal environment which is crucial, so the effect of androgens on spatial ability appears to be activational rather than organizing. This conclusion is supported by data from Petersen (1979) which indicate that females with androgynous somatic characteristics have better spatial ability than their more ‘feminine’ peers.

Similarly, the effect of oestrogens on verbal ability may also be an activational one. Dawson (1972) reports a study of West African males feminized by kwashiorkor-induced endocrine dysfunction. In severe cases of kwashiorkor the liver becomes unable to inactivate the normal amount of oestrogen which the male produces, and Dawson found that males with this condition had ‘significantly lower spatial ability and a more feminine field-dependent cognitive style than controls. In addition these subjects had significantly lower numerical and higher verbal ability compared to normal males’ (p. 24). Presumably though, these males had had equivalent gestational experiences to their controls and so the prenatal hormonal environment is not implicated in these results.

Sex differences in postnatal brain development

The human brain is not fully mature until around sixteen years of age. The main ‘growth spurt’ of the human brain begins during the last trimester of pregnancy and continues into the second year of life. During this period there is an increase in the number of glial cells (from which myelin is derived) and hypertrophy of all cells, specifically in the form of increased axonal terminal and dendritic branching (i.e. interneuronal connections). Most cortical areas are fully myelinated by the child’s third year but myelination of the reticular formation the cerebral commissure, and the intracortical association areas may continue into the second and third decades of life (Marshall, 1968).

Recent evidence suggests that sex differences in brain development are partly reflected in sex differences in hemispheric specialization (Hutt, 1979a; McGlone, 1980). For example, Witelson and Pallie (1973) in a study of infants up to 3 months old, reported that the increased size of the left (relative to the right)

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temporal planum (the posterior surface of the temporal lobe, including part of Wernicke’s area which subserves language) was significant in neonate females but not in males (although a significant difference was found for slightly older (20-90 days) males). Buffery and Gray (1972) cite evidence that in four-year-old girls the degree of myelination in the temporal planum is greater than that for four-year-old boys and they suggest that this may account for the female precocity in language development.

Witelson (1976) describes an experiment which suggests that in boys, the right hemisphere is specialized for spatial processing from as early as six years of age, whereas females show evidence of bilateral representation. She suggested that this specialization might subserve superior spatial skills in males. Levy (1969) postulated that bilateral representation of language in females could interfere with the development of spatial processing abilities in the right hemisphere— thus the cerebral organization which is presumed to give females an advantage in language development and verbal abilities may serve also to impede their development of spatial skills.

Waber (1976) has argued that lateralization is a function of maturation rate rather than sex. On the whole, girls mature faster than boys and generally display a greater tendency towards bilateral representation of skills. However, late-maturing adolescents of either sex are more likely to be strongly lateralized than their early-maturing peers, and are also more likely to show evidence of superior spatial skills.

The evidence for the existence of anatomical substrates which would underlie lateralization processes is both limited and confusing. For example, Wada et al (1975) did not replicate Witelson and Pallie’s (1973) findings on sex differences in cerebral asymmetry in infants: they report that both male and female infants tend to have a larger temporal planum in the left hemisphere than in the right, yet adult females are more likely than males to show the reverse pattern of asymmetry. It is possible that the anatomical asymmetry reported for adult females is a reflection of the greater plasticity of localization of function in females than in males. In a recent report (Hughes et al , 1980), females performed faster on a task which had both a verbal and a visuo-spatial component, whereas both sexes performed at the same speed on the verbal task alone. The authors interpret this finding as reflecting the ability of females to process both aspects of the task in one hemisphere; in males additional time is needed to complete the combined task because information has to be transferred between hemispheres. However, this sort of speculation awaits support or rebuttal from further anatomical evidence.

The ontogeny of hemispheric specialization and lateralization is simply not yet adequately charted. It is not known whether (or how) the environment might modify lateralization and thus we cannot know whether the data of Wada et al. (1975) from adult females are the result of endogenous, hormonally-mediated,

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changes or a reflection of educational experience. Tomlinson-Keasey and Kelly (1979) report that lack of early hemispheric specialization is predictive of better reading skills, and that right hemisphere specialization is positively associated with mathematical skills —data which confirm stereotypic achievements (i.e. females tend to be less lateralized and are better readers, males show a greater tendency towards lateralization of spatial skills in the right hemisphere and are better at mathematics). However, the nature of these relationships needs to be carefully explored.

Witelson (1977) argues that the functional neural substrates for the lateralization of particular abilities may show a plasticity during development which is lost in adulthood, and that this plasticity may reflect a susceptibility to environmental influences. However, experimental support for such an idea is still thin. It may be that lateralization predisposes cognitive strategies and atten- tional biases rather than specific skills. The female precocity in language development leads to a preferential use of language as a processing mode and consequent inferior performance in visuo-spatial skills (McGlone and Kertesz, 1973). Bryden (1979) offers a review of experimental data which serve as a useful reminder that sex differences in cerebral organization are not clearly defined: the degree of overlap between the sexes is often substantial, and seems to vary as a function of the experimental paradigm.

How different are sex differences?

It is easy to fall into the habit of discussing sex differences in ability and behaviour as though these represented absolute differences between two quite distinct populations. A sex difference in mean scores on a particular ability tends to deflect our attention from the within-group variances which indicate how much the groups overlap. Even when there is a statistically significant difference between the mean scores of males and females on a test the majority of both sexes may score within the same range.

The interpretation of a report of sex differences will depend on whether one is concerned with socio-political/practical issues (in which case differences are often trivial and meaningless) or with scientific/theoretic issues (in which case small but consistent differences may yield important insights). Thus, consistent reports of sex differences in verbal and visuo-spatial skills have raised interesting hypotheses both about hemispheric specialization, and the role of prenatal hormones; they do not, of course, provide any justification for boys to do badly when studying modern languages or for girls to abandon mathematics education at the earliest possible opportunity.

It may be that sex differences in certain skills are a result of long-term evolutionary pressures. For example, Hutt (1972 b) argued that athletic and visuo-spatial skills in males maximize hunting success and thus increase the

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probability of survival, whereas the socially communicative abilities and superior manual dexterity of the females have evolved as an adaptive consequence of her predominantly nurturant role in caring for dependent infants. Yet characteristics with a presumed evolutionary adaptive basis are not fixed for every individual: cultural pressures will influence the expression of abilities, and ‘typical’ sex differences are simply not found in some cultures. For example, cross-cultural studies of field-independence (presumed to be related to visuo- spatial skills) reveal no sex differences in Eskimo and Zambian cultures (MacArthur, 1967; Siann, 1972). McGuinness (1976) argues that \ .. the fact that boys do learn to read and write fluently, suggests that though initial processes may be guided by certain sensory differences, there is no reason to assume that these differences must remain. Parents insist that boys learn to speak, read and write but no such insistence induces the females to learn about spatial- mechanical relationships’ (p. 144).

In our own culture then, there is an attempt to educate males in heterotypical skills whereas the converse is not true for females. Even in homes where parents believe that they do not discriminate between male and female children Rheingold and Cook (1975) found that \ .. the rooms of boys contained more animal furnishings, more educational art materials, more spatio-temporal toys, more sports equipment and more toy animals. The rooms of girls contained more dolls, more floral furnishings, and more “ruffles’” (p. 461). The agents of socialization are evidently insidious, and may tend to exaggerate sex differences in proclivities for particular forms of behaviour. Even if we accept that evolutionary pressures have resulted in sex differences in neural organization which may differentially predispose males and females to specific abilities, we must stand this against our knowledge that the plasticity of the human brain will probably enable us to modify the expression of those abilities. This in turn implies a responsibility of educators and caretakers to provide an appropriate range of educational opportunities and role exemplars for their male and female charges.

At present, not only are females less likely to be given the wide range of toys that males have, their role is also under-represented by the literature and television media: \ .. females were under-represented in the titles, central roles, pictures, and stories of every sample of books we examined ... Even when women can be found in books, they often play insignificant roles, remaining both inconspicuous and nameless’ (Weitzman et al ., 1972). Sternglanz and Serbin (1974) made a study of T.Y. programmes with high popularity ratings, and found that half of these programmes did not portray any female roles: of those that did, the authors comment ‘female children are taught that almost the only way to be a successful human being if you are a female is through the use of magic’ (p. 714). Exposed to these kinds of socialization pressures it comes as little surprise that females tend to be diffident about their own ability and are

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particularly unwilling to tackle those skills which they perceive as falling within the male domain (Hutt, 1979b; Byrne, 1978).

Socialization experiences in our culture thus tend to exaggerate a dichotomy of roles and abilities between males and females. Historically, this socialization has acted to repress the female more than the male (her rights to be educated and to vote have, after all, been won only comparatively recently), but there is little doubt that a deliberate educational policy could serve to increase the range of both male and female behaviour. Goy and McEwen (1980, pp. 60-61) present some interesting evidence that female attachment to an infant may be innate (its expression being in part activated by elevated hormonal levels during pregnancy and birth), whereas male attachment is socially learned. This in no way implies that males are unable adequately to perform parenting behaviours, but its expression may be subserved by different neural mechanisms. There is no reason to believe that the expression of sex typical intellectual abilities is any less modifiable.

Towards a model of human sex differences

Waddington’s (1957) notion of‘canalization’ in an epigenetic landscape provides a useful conceptualization for understanding differences in the degree of sexual dimorphism in behaviour. Waddington suggested that, for all members of a species, a set of target physical characteristics (eyes, arms, legs etc.) is defined by the genotype and, despite underlying genetic variability, genetic processes operate together to ensure that these targets are achieved. He depicts the development pathways of the phenotype as a ball rolling through a set of valleys (the epigenetic landscape); the valleys can vary in steepness and thus vary the opportunity of the phenotype to deviate from a given course—-the steepness of the valley reflects the degree of canalization. At certain critical points in development, when the phenotype is undergoing rapid change, it is susceptible to certain environmental or genetically induced stresses. For example, the embryological development of the arms takes place around 38-48 days (postmenstrual); this development is strongly canalized (i.e. all normal humans have arms) but a teratogen, such as thalidomide, taken by the mother during this critical period will inhibit this normal phenotypic development and the foetus will eventually be born either with no arms at all or severe under-development (see Fishbein, 1976, pp. 46-47). The development of some other physical characteristics may also be affected by thalidomide during this period, but in general each character has its own critical period.

As we noted earlier, the basic developmental trend of the body’s sexual characteristics is in a direction corresponding to that of the homozygous sex (i.e. the female). This trend is canalized to develop a female foetus from the zygote which is formed at conception. However, if the embryonic gonad differentiates to

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form a testis, then phenotypic development is deflected from the female pathway when the testis begins to secrete MIS and androgens. Differentiation of neural networks occurs in the same manner: there will be critical periods when the presence or absence of biochemical agents (usually hormones) will affect the development of RNA which is specific to particular structures. Behaviours which depend on these specific neural anlagen for their expression will subsequently be affected. The specificity of hormonal effects is well illustrated by some data presented by Short (1979): certain aspects of male-type sexual behaviour were exhibited by ewes which were androgenized late during gestation (days 50-100, or 70-120) and had essentially female external genitalia; androgenization during early gestation (days 30-80) resulted in complete masculinization of the external genitalia which was not accompanied by male type sexual behaviour. Masculinization of urination behaviour could be effected by androgenization at a relatively late period of gestation after it was no longer possible to masculinize sexual behaviour. The positive feedback effect of oestrogen on LH, which is normally exhibited only as a female characteristic, was sometimes abolished by androgenization but ‘gave no clue whatsoever to the type of sexual behaviour to expect from the animal’ (p. 258). This example illustrates clearly that the degree of masculinization of behaviour cannot be inferred from physical characteristics. The developmental pathways for specific behaviour patterns are also independent of one another, so the masculinization of sexual behaviour does not necessarily imply masculinization of activity levels.

If we return to the image of males and females rolling through their (sometimes overlapping) epigenetic landscapes, it is possible to visualize the way in which different levels of canalization will result in different degrees of sexual dimorphism in the eventual expression of behaviour. If the pathway for a particular neural substrate is very steep, it will be difficult to deflect the phenotype from its developmental path—thus most genetic females will manifest the appropriate ‘female’ behaviour pattern and most males will not. If the pathways are gentle then the phenotypes may be spread more thinly, and a linear male-female dimension may be evident in the subsequent behavioural pattern. The neural mechanism which mediates gonadotropin release is clearly strongly canalized, other neural substrates in humans are less strongly canalized and therefore enable the expression of greater variability in behaviour and skills.

The critical periods for development of the neural networks which underlie particular behaviours may vary in length; they may overlap in time, but they are independent of one another. Thus, in the female rat, by the judicious administration of neonatal testosterone, it is possible to decrease the incidence of lordosis but not to increase the incidence of mounting. Armstrong’s attempt (cited in Jost, 1974) to relate sexual orientation to body type is therefore quite misconceived: there is no reason to believe the homosexuals will have heterotypical body characteristics.

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There are three ways in which hormones can act on the brain to produce sex- differentiated effects. The prenatal hormones organize neural networks in distinctively male and female patterns; they also have a critical role in the development of physical characteristics. Postnatally, the output of gonadotropic hormones can activate these neural networks (for example, in the control of the menstrual cycle). Alternatively, sex-related hormones may have independent effects: an example of this is the yawning behaviour of rhesus monkeys which is normally displayed more frequently by males than by females, but which can be increased in the female by the administration of exogenous testosterone (Goy and McEwen, 1980).

In humans, evolution has operated to permit a high degree of behavioural phenotypic plasticity, which would in turn imply weak canalization of the neural mechanisms which subserve particular behaviours and abilities. (This may account for the conflicting findings in anatomical studies of hemispheric asymmetry, supra). This phenotypic plasticity enables individuals with very different genotypes to exhibit similar or identical behaviour. In the expression of human behaviour and ability then, phenotypic plasticity and not biological canalization may produce conformity of behaviour within a same-sex group. Evidence for sexually differentiated canalization of a particular behaviour requires that its manifestation be virtually universal and not restricted to a single cultural group: the only behaviours which fulfil this stringent requirement are indeed ‘menstruation, gestation and lactation’ in females and ‘impregnation’ by males. The weaker canalization of sex-related brain differentiation in humans relative to infra-human species would also lead us to expect less sexual dimorphism of behaviour in humans; this should always be borne in mind when extrapolating from animal to human studies. Rodent studies have been crucial in extending our knowledge of brain differentiation—they do not necessarily tell us much about human behaviour.

The identification of the brain areas and mechanisms which subserve particular behaviours or the articulation of specific cognitive skills in humans is by no means straightforward. Whilst it has been possible in infra-human species to identify the critical period of development for the expression of certain behaviours (vide Short, 1979) this has not been possible in humans and probably (for ethical reasons) never will be. Nor is it entirely clear how circulating hormones affect human behaviour: studies of the menstrual cycle produce conflicting evidence (Hutt et al ., 1980), and studies of sexual behaviour (e.g. Bancroft and Stakkebaek, 1979) or cognitive ability (Peterson, 1979) have not yielded definitive conclusions. We also lack evidence on the way in which educational experience affects brain development. Thus, information which is vital to a definitive model of the effects of brain differentiation on psychological sex differences is not available. Nonetheless, the existing evidence leaves no doubt that brains of males and females differ as a function both of the prenatal

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environment and subsequent maturational effects. These differences may well underlie the predilection for males and females to act in particular ways, but they cannot be seen as constituting a biological imperative.

Summary

De facto sex differences in ability and behaviour are not as dimorphic as sex differences in physical characteristics. The major influences on sex differential brain development are the sex steroids (androgens, oestrogens and progestins), but their effect on behaviour is attenuated by the weak canalization of the human behavioural repertoire. Sexual differentiation of the brain may create predilections for particular behaviour and specific cognitive strategies, but it does not constitute a biological imperative for psychological sex differences.

Acknowledgements

I would like to thank Dr. J. E. Blundell and Professor J. Scott for their helpful comment and criticism during the preparation of this manuscript. I am also grateful to Derrick Pritchatt who translated the article by Reznikov (1978).

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Index

IV-Acetylneuraminic acid 57, 61, 92 amino acids 96-100 alanine 98

y-amino-butyric acid (GABA) 87, 97, 98 aspartic acid 97, 98 branched chain 64,100 glutamic acid 64, 87, 97 glutamine 97,98 glycine 97,99 histidine 99 methionine 64 taurine 64,97 threonine 64 valine 64 animal models 66 anoxia 93 aphasia 191-192 age differences in 191 in children 219-225 jargon aphasia 220 ATPase, Na + K + 92 axon density 59 axon systems 29

behaviour 59, 92,100 birth 66,74

blood brain barrier 62, 63, 64 brain cells: astrocytes 49 ependymal 18 germinal 7,8 glial 56 glioblast 7 Golgi 18 granule 19

neuroblast 7, 9,11, 23, 25 neurones 49, 51, 55, 58, 74 oligodendroglia 49 Purkinje 14,18,20,21,49 pyramidal 25, 27, 30 radial glia 7 satellite 82 stellate 28, 29, 30 brain composition 76-100 brain differentiation 233, 238-242 and non-sexual behaviour 241-242 and sexual behaviour 239-241 sex differences in 238-239

brain injury 203-228 and behaviour 203-228 and developmental context 206-214, 227 and immature nervous system 214 and intelligence 212, 215-219, 228 and mature nervous system 214 and recovery 212-228 and reorganization 203-227 brain size 74-76 brain stem 36 human 53, 55, 60, 78, 84 neurones: catecholamine 36 caudate nucleus 36 dopaminergic 36 5-hydroxytryptamine 36 indolamine 36 monoaminergic 36 substantia nigra 36 rat 50,51,59,60,89

callosal agenesis 227 canalization 254 cannabis 121 cellular growth 49-55 astrocytes 49

DNA and cell number 49, 50, 51, 52, 53 glial cells 49, 74 human brain 51,53,58 hyperplasia 49,77,110 hypertrophy 49,77 lipid/DNA 49 neurones 49,51,55,58,74 oligodendroglia 49 protein/DNA 49 rat brain 50 RNA/DNA 49 satellite cells 82 theory 53,76 cellular migration 23 cerebellum, development of 18 external granular layer 18, 19, 22 Golgi cells 18 human 53, 55, 60, 78, 81, 84 internal granular layer 21, 22 molecular layer 21 rat 50, o9, 60 synapses 21

263

INDEX

264

cerebral localization of function 204-205, 214, 251

cerebral neocortex 23-31 cerebrum :

human 53,78,81 rat 50,51

circadian rhythm 149,157 CNS maturation 146,156, 206-212 and brain injury 203 cortical plate 25, 26 corticosteroids 82 and brain growth 115 cretinism 113 critical periods 48,49, 74

dendrites 58,59,74,87,88,110 growth of 11,14,26,27,29 diencephalon 35-36 dietary carbohydrate 99 dietary protein 99 DNA polymerase 54 DNA synthesis 53, 54, 55 drugs 122 dysarthria 220

EEG 131-161,206-209 analysis of 133,134,135 as index of mental function 159,160 effects of drugs upon EEG 131 hemispheric differences in 156 hypersynchrony 156 in premature infants 134-146 in sleep 139

pathological patterns 154 rhythmicity of 155,156, 207 silent periods 155 sleep spindles in 151,152 temporal and spatial pattern of 132,133 environment 101, 117 epigenetic landscape 254-255 evoked potentials 136-137, 143-145,156, 158-161

as index of intelligence 161 as index of mental function 160 changes in latency of 158

face recognition 182 foetal alcohol syndrome 118-120 growth failure 118,120 malformation 118 neurological disturbances in 119 nutrient deficiencies in 120 foliation 15-17 lissencephaly 17 mechanism 16 microgyria 17

forebrain:

human 52, 55, 60, 84, 89 rat 59, 60, 85

gangliosides 57, 58-60, 89, 90 disialo- 55,58,59,85,86,89,91 monosialo- 58, 59, 85, 86 trisialo- 58, 59, 85, 86 turnover 59,86 genetic potential 73 glycoproteins 57 growth:

catch-up 74,81 spurt 74

of brain in different species 66 growth hormone 116 guinea pig brain growth 51, 66

hand preference 168 head circumference 76, 81 hemiplegia 209-210

hemispheric asymmetry 156, 168-194, 207, 251

and touch 184-186

contralateral organization of 168-173

development of 173-189

effects of injury and 189-192

hand preference and 170,172

in adults 170

in motor activity 186-189

in reading 180

left hemisphere injury 217, 222 levels of processing and 179 methods of study 174-192 perceptual ability and 171-173 right hemisphere injury 217, 222 sex differences in 250-252 spatial ability and 171-173 hemispheric equipotentiality 190 hemispheric lateralization 172,193, 251 and skill acquisition 194 hermaphroditism 235,244 pseudohermaphroditism 244 higher auditory systems 208 hippocampus 31-34 Ammon’s horn 32 dendritic growth 34 rat 50,51 hormones 233-250

and brain differentiation 233 and personality 247 and cognitive ability 234 postnatal 233 prenatal 233,234-235 and sex differences in behaviour 233 hormonal action 237-238

INDEX

265

hormonal anomalies 242 and behavioural development 242 =246 human brain 51,53,55,56,62,66 brain stem 53, 57, 78 cerebellum 53,57,78,81 cerebrum 53, 78, 81 forebrain 52,55,57,85,91 hyperthyroidism 114 hypothyroidism in children 113-114 hypothyroidism, neonatal 110-114 effects on behaviour 112 dendrites 110 DNA 110 enzymes 112 hyperplasia 110 myelination 111 neurones 110 oxygen consumption 111 phospholipids 112 protein biosynthesis 111 RNA 110 rat cerebellum 110 sensory cortex 110

insulin 117 intelligence 73, 100 intersex conditions 235-236

‘K’ complex 152,157 Korean children 101,102

layer establishment 24 lead 122

light-for-dates (LFD) 76, 79, 83 lipids 55

cerebrosides 56,57 cholesterol 55 cholesterol esters 55, 84, 87 fatty acids 55, 93 essential 95 esterified 100 long chain 95 short chain 94

gangliosides 57, 59, 60, 85, 89, 90

glycolipids 55,57

grey matter 55, 57, 58, 59

human brain 55

phospholipids 55,57

proteolipid 57

white matter 55, 57, 61

malnutrition 73, 77, 85, 87, 93, 97,102 malnutrition, effects on: brain amino acids 98 brain protein 95 brain weight 75

malnutrition, effects on :—continued cholesterol esters 84 dendritic development 89 DNA 78,79,80,81 energy metabolism 93 gangliosides 89, 90, 91 myelin maturation 85, 86 myelination 83,85 Na + K + ATPase 92 potassium 93 satellite cells 82 synaptic development 87 marginal layer 23 Mass Action Principle 203, 214, 216 metabolism 61-66 amino acids 64

y-aminobutyrate (GABA) shunt 63 blood flow 61 energy 61 glucose 62,63

hexose monophosphate shunt 62 3-hydroxybutyrate 62 hypoxia 62 ketones 61,93 migration 11,21,23,25 migration failure 11 milk 61

monkey brain growth 49, 51, 66 myelin 55 cerebrosides 56,57 cerebroside sulphate 56, 83, 84 formation 56, 74, 82-87 lipids 55,82-87 maturation 85 in multiple sclerosis 87 oligodendroglial cells 56,57 proteins 57 quantitation 56 myelinization 56, 147,156, 207

nerve growth factor (NGF) 117

neuroblast migration 25, 26 neurogenesis 7 germinal cells 7 germinal epithelium 7, 8, 9 migratory phase 9 neuroblasts 7, 9,11 proliferative phase 7 radial glia 7, 11,23,24 neuronal processes, differentiation 12-15 neurotransmitters 36, 59, 87, 88 acetylcholine 87,88 amino acids 87, 96 amino acids as precursors 64, 96 epinephrine 87,88 histamine 87

266

INDEX

neurotransmitters —continued 5-hydroxytryptamine (serotonin) 36, 61, 87

synthesis of 64, 87, 88, 99 oedema 76

ornithine decarboxylase 55

parietal hump 152 perceptual ability 171,212 phenylketonuria 96 pig brain 51, 59, 66, 81, 83 brain stem 51, 60 cerebellum 51,60 forebrain 60

placental transfer of fatty acids 94 plasma amino acids 97 plasticity 15,28

protein energy malnutrition (PEM) 76, 81, 87,100,102

protein synthesis 53, 54, 55, 65, 95 Purkinje cells, cerebellum 14,18, 20, 21 putrescine 55

rabbit brain growth 66 brainstem 51 cerebellum 51 cerebrum 51 rat brain growth 66 brain stem 50, 51, 59, 60, 90 cerebellum 50, 51, 59, 60, 82 cerebrum 50, 51, 83 forebrain 59,60 hippocampus 50, 51, 83 reflexes 147 Babinski 147 Moro 147 spinal cord 142 rehabilitation 84,95 Reifenstein’s syndrome 244 RNA:

alkaline RNase 54 rRNA 55 tRNA 66 turnover 54,95

school performance 101 sex differences 233-257 and cognitive ability 247 and evolutionary pressure 252-253, 256 and IQ 248-25C and personality 247 and socialization 253-254 in postnatal brain development 250-252

sex differences —continued of maturation in rat 251 sheep brain growth 66 sialoglycoproteins 58 sleep 139-161 active 142,145, 149-154,157 consolidation of 157 deprivation of 153 quiet 143, 145,149-154, 157 spindles 151,152

time occupied by 145,148-153,157 smoking 122

social background 101, 102 spatial ability 171,212,227 speech and language 169-178,183-184, 190-193,219-225, 227 and hemispheric dominance 169-173, 175-179,186,190-193 and right cerebral hemisphere 191 right ear advantage in 175-177 spermidine 55 spermine 55 spinal cord 36 synaptogenesis in 38 stellate cells 28, 29 stereology 89 stimulation 91, 92,103 sudden infant death syndrome 153 synaptic growth 55, 89 synaptogenesis 38, 59, 74 synaptosomes 58, 87, 88

telencephalon 9,12, 24 thymidine incorporation 93 thyroid deficiency 82 thyroid hormones 109, 110-115 tomboyism 245 toxic substances 118-123 alcohol 118 cannabis 121 drugs 122 lead 122 smoking 122 trace scanning 180 transcription 95 translation 95 Turner’s syndrome 243, 249

undernutrition 74, 86, 92 intrauterine 77, 79, 82, 83, 86, 93 postnatal 81, 82, 83, 86

vertex sharp wave 152 vulnerable period 48, 67,101

@@ Line 156: / Line 156: @@
+==Contents==
-Contents
+Introduction
-Introduction 1
+[[Book - Brain and behavioural development 1|Chapter 1. The development of the human nervous system]] Martin Berry
-[[Book - Brain and behavioural development 1|Chapter 1. The development of the human nervous system]]
-Martin Berry
 Introduction 6
@@ Line 190: / Line 187: @@
 References 39
-[[Book - Brain and behavioural development 2|Chapter 2. Comparative aspects of brain growth and development]]
+[[Book - Brain and behavioural development 2|Chapter 2. Comparative aspects of brain growth and development]] Brian L. G. Morgan and John W. T. Dickerson
-Brian L. G. Morgan and John W. T. Dickerson
 Introduction 48
@@ Line 206: / Line 201: @@
 References 67
-[[Book - Brain and behavioural development 3|Chapter 3. Effects of malnutrition on brain growth and development]]
+[[Book - Brain and behavioural development 3|Chapter 3. Effects of malnutrition on brain growth and development]] J. W. T. Dickerson, A. Merat and H. K. M. Yusuf
-J. W. T. Dickerson, A. Merat and H. K. M. Yusuf
 Introduction 73
@@ Line 235: / Line 228: @@
 References 103
-[[Book - Brain and behavioural development 4|Chapter 4. Effects of hormonal and other factors on growth and development]]
+[[Book - Brain and behavioural development 4|Chapter 4. Effects of hormonal and other factors on growth and development]] Brian L. G. Morgan
-Brian L. G. Morgan
 Introduction
@@ Line 274: / Line 265: @@
 References
-[[Book - Brain and behavioural development 5|Chapter 5. Cortical activity in behavioural development]]
+[[Book - Brain and behavioural development 5|Chapter 5. Cortical activity in behavioural development]] Cherry Thompson
-Cherry Thompson
 Introduction 131
@@ Line 292: / Line 281: @@
 References 162
-[[Book - Brain and behavioural development 6|Chapter 6. Asymmetry of cerebral hemispheric function during development]]
+[[Book - Brain and behavioural development 6|Chapter 6. Asymmetry of cerebral hemispheric function during development]] Andrew W. Young
-Andrew W. Young
 Introduction
@@ Line 329: / Line 316: @@
 References
-[[Book - Brain and behavioural development 7|Chapter 7. Determinate and plastic principles in neuropsychological development]]
+[[Book - Brain and behavioural development 7|Chapter 7. Determinate and plastic principles in neuropsychological development]] Denis M. Parker
-Denis M. Parker
 Introduction 203
@@ Line 350: / Line 335: @@
 References 229
-[[Book - Brain and behavioural development 8|Chapter 8. Sex differences in brain development: process and effects]]
+[[Book - Brain and behavioural development 8|Chapter 8. Sex differences in brain development: process and effects]] Miranda Hughes
-Miranda Hughes
 Introduction 233
 Pre-natal sex differences in development 234
 Hormonal action
@@ Line 387: / Line 369: @@
-INTRODUCTION
+==Introduction==
 The study of structural and functional relationships between brain growth and