Neurological Assessment in the First Two Years of Life

1

INTRODUCTION

Giovanni Cioni and Eugenio Mercuri

The advent of neonatal intensive care units in the 1950s dramatically changed the spectrum of survival and outcome of high-risk newborns, and raised the need to identify appropriate instruments for the assessment of these infants.

Several methods for the neurological examination of the newborn have been developed, including assessments of tone and reactions (Saint-Anne Dargassies 1977), behaviour (Brazelton 1973), movements (Prechtl 1990), and methods integrating the different approaches (Dubowitz et al 1999). In contrast, less attention has been devoted to the assessment of neurological function after the neonatal period and, more generally, in the first years after birth. Some neurological examinations suitable for infants have been developed and used in clinical and research studies (Touwen 1976, Amiel-Tison and Grenier 1986, Haataja et al 1999).

More attention has been devoted to developmental scales. Over the years it has become obvious that the development of the infant’s brain is not just related to motor function and that different aspects of development, such as perceptual and cognitive function, should be systematically investigated. From the pioneering work of Gesell in the 1940s a number of scales have been developed over the years. This has made it possible to obtain not only a global measure of development but also subscores for the main domains. Moreover, neuropsychological tests are also available, mainly in the research setting, for the assessment of specific aspects of behaviour.

The advent of sophisticated neurophysiological and neuroimaging techniques has provided further evidence of the complexity of the developing brain and of the onset and maturation of different neural functions. Until recently, however, some of these techniques, although widely used in older children and adults, had not been used in infants because of the lack of age-appropriate normative data. Using an integrated approach, recent studies in high-risk infants have described the maturation of specific aspects of function and their correlation with the maturation of brain structures on imaging.

This book is the result of collaborative work among three groups (in Pisa, London and Rome), and their collaboration with other European and American centres.

The aim of the book is to provide a review of the state of the art of the clinical application of various techniques for the neurological assessment in the first two years of life. After a brief description of the neurophysiological basis of development in the first years, and of brain reorganization after early lesions, we critically review various methods used for neurological assessment in young infants, providing details of our own experience using two different approaches (classical neurological examination and assessment of general movements) in normal infants, and assess their value in identifying infants at risk of neurological sequelae and predicting outcome.

Chapters 2–7 describe the value of neuroimaging and neurophysiological techniques, reporting the changes observed on brain MRI in normal preterm and full-term infants in the first two years, the main types of abnormal MRI findings and their prognostic value, and the predictive value of neurophysiological findings (EEG and evoked potentials) in relation to brain lesions.

Chapters 8–12 describe neuropsychological and perceptual/communication assessment techniques for use in the follow-up, with a systematic review of the methods of multi-domain assessment (developmental scales) and other techniques assessing specific aspects of cognitive, perceptual and sensory abilities. Special attention is given to hearing, language and communication and to development of vision and visual attention both in normal infants and in those with neonatal brain lesions.

The final two chapters are devoted to intervention, describing how the identification of specific profiles of impairment can lead to the development of appropriate plans for early intervention, and to the potential contribution of data from multicentre longitudinal follow-up studies to the identification of major risk factors, and the validation of new diagnostic and treatment protocols.

REFERENCES

Amiel-Tison C, Grenier A (1986) Neurological Assessment during the First Years of Life. New York: Oxford University Press.

Brazelton TB (1973) Neonatal Behavioral Assessment Scale. Clinics in Developmental Medicine 50. Philadelphia, PA: JB Lippincott.

Dubowitz L, Dubowitz V, Mercuri E (1999) The Neurological Assessment of the Preterm and Full Term Newborn Infant, 2nd edn. Clinics in Developmental Medicine 148. London: Mac Keith Press.

Haataja L, Mercuri E, Regev R, Cowan F, Rutherford M, Dubowitz V, Dubowitz L (1999) Optimality score for the neurologic examination of the infant at 12 and 18 months of age. J Pediatr 135: 153–161.

Prechtl HFR (1990) Qualitative changes of spontaneous movements in fetus and preterm infants are a marker of neurological dysfunction. Early Hum Dev 23: 151–158.

Saint-Anne Dargassies S (1977) Neurological Development in the Full-Term and Premature Neonate. Amsterdam: Elsevier.

Touwen B (1976) Neurological Development in Infancy. Clinics in Developmental Medicine 58. London: Heinemann

2

NEUROPHYSIOLOGICAL BASIS OF DEVELOPMENT

Janet Eyre

Introduction

Older views of developmental plasticity focused on the protective effect of a young age at the time of the brain damage. A younger rather than an older age at onset was thought to produce fewer and/or less severe symptoms and a more rapid recovery. It is now clear that quite specific effects of early brain damage persist and produce complex and often severe patterns of impairment which are different from those observed following lesions in the adult brain.

Although an understanding of the nature of neural plasticity in response to damage is critical to those attempting to augment recovery from neurological insults, it is misleading to treat the underlying mechanisms as self-reparative. An appreciation that these mechanisms evolved as an expedient for fine-tuning neurological circuitry during normal development by taking advantage of contextual information, and that they may only be available for response to damage as an incidental side effect, can help us to focus on how best to augment desirable, and avoid any undesirable, effects.

Seminal studies in the early 1960s by Wiesel and Hubel on the organization of ocular dominance columns signified the starting point of extensive basic research on developmental brain plasticity (Wiesel and Hubel 1965). Investigation of neuroplasticity has expanded rapidly over the past ten years and has uncovered the remarkable capacity of the developing brain to be shaped by activity and environmental input. Reorganization of developmental systems occurs not only within modalities but can even extend across different modalities (Rauschecker and Korte 1993) and lead to transfer of functions between cerebral hemispheres (Eyre 2003b 2004, 2005).

Knowledge of the time course and processes of normal development is essential both for a better understanding of current rehabilitation treatments and for the design of new strategies for the treatment of children who sustain brain damage early in life.

Development of the cortex

NEUROGENESIS AND THE DEVELOPMENT OF CORTICAL LAYERS

Cortical neurons are generated in the ventricular zone of the cortical wall and in the subcortical ganglionic eminence and reach their destination by both radial and tangential migration (Rakic 1972, Anderson et al 2002). The first postmitotic neurons accumulate superficial to the neuroepithelium immediately beneath the pial surface at five weeks postconceptional age (PCA), forming the preplate (Rickmann and Wolff 1981). The largest of the preplate neurons already have dendritic processes and also axons which course into the intermediate zone and give rise to the first efferent connections of the cortex by 7 weeks PCA.

Although preplate cells are also neurons, they are distinct from those that will populate the definitive cellular layers 2–6 of the mature adult cortex. Layers 2–6 emerge from the neurons of the cortical plate. The cortical plate first emerges within the preplate at 8 weeks PCA (Meyer et al 2000). As the cortical neurons become postmitotic, they migrate to split the preplate into two zones: a superficial marginal zone, which will later become layer 1, and a deeper subplate, a transient structure present only during development. At this time subplate neurons have already assumed a pyramidal shape, and have complex dendritic trees and axons which form a clearly visible fibre tract within the intermediate zone (Meyer et al 2000). The subplate neurons therefore have a high degree of maturity in comparison to the immature morphology and tight compaction of the cortical plate neurons at this early stage of development. An intermediate zone also develops above the ventricular zone but below the subplate, comprising migrating neurons and efferent and afferent fibres (Fig. 2.1) (Marin-Padilla 1971, 1972).

After the arrival of the first cortical plate neurons, formation of the layers within the cortical plate proceeds by progressive adjunction of new immigrant neurons in an inside-out gradient; thus layers 6 and 5 are generated early and layers 2 and 3 are generated last (Rakic 1974). The marginal zone will eventually form layer 1 of the cortex.

The peak of cell proliferation in the germinal epithelium occurs at the end of the first trimester in humans. The neuronal migration period occurs between 8 and 16 weeks PCA. Cell proliferation in the ventricular zone is evident until 16 weeks. From this time the volume and thickness of the ventricular zone decreases until 22–24 weeks, when only a few rows of sparse cells can be recognized in the germinal epithelium (Zecevic et al 1999). There is a 50 per cent increase in the volume of the cortical grey matter between 28 weeks PCA and term (Hüppi et al 1998). This is associated with growth and differentiation of cortical neurons, the arrival of a massive contingent of afferent fibres relocating from the subplate into the cortical plate, and the growth of callosal and long associative corticocortical fibre systems (Kostovic and Judas 2002).

The subplate

The subplate comprises a heterogeneous population of neurons located directly under the cortical plate, which is only present during development. There is structural, immunocytochemical and electrophysiological evidence that subplate neurons are integrated in a functioning synaptic circuit with extensive axonal projections within the developing cortical plate (Kanold 2004). Thalamocortical axons initially form temporary synapses on subplate neurons (Kostovic and Judas 2002). Deletion of the subplate (Ghosh and Shatz 1992) or its improper differentiation (Zhou et al 1999) causes inappropriate thalamocortical innervation and prevents the accurate formation of layer 4. These data indicate that molecular markers as well as electrical activity patterns in the subplate may influence the in-growing thalamocortical axons.

Fig. 2.1 Diagrammatic representation of the developmental events proposed by Meyers and her colleagues for the early development of the human neocortex. All figures were drawn at the same magnitude with the aid of a camera lucida. The first Reln immunoreactive neurons appear at Carnegie stage 16 (5 weeks PCA) and increase in number from Carnegie stages 17 to 19 (6 to 6.5 weeks PCA). The first CR immunoreactive neurons appear at Carnegie stage 19 (6.5 weeks PCA) in what could now be called the preplate. GAD immunoreactive neurons first appear at stage 20 (7 weeks PCA). Concurrently, Reln immunoreactive neurons settle in the subpial compartment. At stage 21 (7 weeks PCA), the pioneer cells send the first corticofugal fibres. The preplate is split apart into a minor superficial component and a large deep component, the subplate, through the first cohorts of the cortical plate, at stages 21 and 22 (8 weeks PCA). (IZ, intermediate zone; MZ, marginal zone; PP, preplate; VZ, ventricular zone.)

Source: Meyer et al 2000.

Finally subplate neurons also extend the first corticofugal axons from the neocortex into the internal capsule, before many of the neurons of layer 5 and 6 have become post-mitotic and begun migration from the ventricular zone (Fig. 2.1) (Meyer et al 2000). The observation that subplate neurons send the first axons into the internal capsule led to the intriguing suggestion that these axons may play a pioneering role in establishing the corticofugal projections of layer 5 and 6 neurons (McConnell 1988, Shatz et al 1990). In rats, however, the subcortical distribution of subplate axons is restricted to the internal capsule and thalamus; subplate neurons do not project to the superior colliculus nor extend from the internal capsule into the cerebral peduncle (De Carlos and O’Leary 1992), suggesting that the axons of the subplate do not have a central role in pioneering deep subcortical projections such as the corticospinal tract.

The generalization of these observations to other species, especially man, must be made with caution since the population of subplate neurons in rodents, and in rats in particular, is relatively small. The subplate structure is very much larger and more highly developed in phylogenetically more advanced species. The maximum subplate to cortical plate ratio during development in the mouse and rat is only 1:2; in the cat, 1:1; in the monkey, 3:1; and in humans it reaches a ratio of 4:1 at approximately 25 weeks PCA. Not only is the subplate larger in extent in human and subhuman primates than in cats and rats, but it also persists for a much longer period during development. In man the subplate is discernible but progressively decreasing in size up until soon after birth (Mrzljak et al 1988, Meyer et al 2000, Kostovic and Judas 2002).

It has been proposed that subplate neurons are required for the development of a complex cortical organization, since the size of subplate and the extent of its synaptic linkages are more prominent in species with increased radial and tangential cortical connectivity, such as cats, monkeys and humans (Kostovic and Rakic 1990, Mrzljak et al 1992). The relevance of this proposal to human development lies in the observation that in a neonatal rat model of hypoxic-ischaemic injury which produces the characteristic pattern of subcortical injury associated with human periventricular leucomalacia, selectivesubplate neuron death is seen. This may provide an explanation for the high frequency of cognitive, motor and sensory deficits observed in babies with periventricular leucomalacia, and for the fact that, with decreasing gestational age, periventricular leucomalacia is associated with more pervasive abnormalities of cortical development (Inder et al 1999).

Differentiation of the neocortex

The adult neocortex is composed of six major layers, which are distinguished by differences in the morphology and density of neurons that constitute them (Brodmann 1909). The developing cortical plate lacks many features that distinguish neocortical areas in the adult, even after all the neurons have been generated and layers begin to differentiate within it. During corticogenesis the laminar destination of cortical neurons appears to be determined early in the life of the neuron, potentially prior to the final mitosis in the ventricular zone (McConnell 1995). Although neurons in different layers have unique dendritic configurations and axonal projections, most, if not all, types of cortical pyramidal neuron initially develop with a common morphology and only later develop the dendritic shape characteristic of their class and layer, by developmental sculpting (Koester and O’Leary 1992).

Different regions of the developing cortex may initially be interchangeable in terms of the axonal connections they develop and maintain, and even in their capacity to form complex and highly organized neuronal assemblies (O’Leary et al 1992). Thus, the neocortical neuroepithelium generates populations of neurons which rely on interactions with intrinsic and extrinsic patterning information, acting both separately and synergistically at different stages of neocortical development, to generate their characteristic area-specific features. Intrinsic and extrinsic cortical patterning information includes: molecular factors intrinsic to the ventricular zone, to the subplate and to the maturing neocortex; spontaneous activity patterns in the subplate or neocortex; later arriving molecular factors extrinsic to the cortex, such as derived anterogradely from afferent pathways or retrogradely from efferent pathways; and extrinsically driven activity patterns, either sensory inputs or spontaneous activity extrinsic to the cortex (O’Leary and Nakagawa 2002).

The timing and pattern of development of efferent projections from and afferent projections to the cortex is important in understanding this activity-dependent phase of cortical development.

Development of afferent somatosensory projections

The arrival and entry of the first complement of dorsal root fibres occurs by 2.5 weeks PCA and these axons bificate into ascending and descending projections by 3 weeks PCA. According to Okado the first synapses appear in the primordial dorsal horn at 4.5 weeks PCA and at this time a few axons also project into the ventral motor pools (Okado 1981). The growth of the long ascending branches of the dorsal root axons to form the cuneate and gracile fasciculi occurs between 6.5 and 8 weeks PCA. Myelination of dorsal root fibres and some ascending fibres begins by 24 weeks PCA and by 31 weeks the entire cuneate and gracile fasciculi are well myelinated (Konstantinidou et al 1995).

The structural and functional development of cutaneous sensory synaptic connections within the spinal cord has been shown to be activity-dependent in rodents (Beggs et al 2002). This may mean that alterations in the pattern of sensory inputs, arising from sensory stimulation, tissue injury and pain during neonatal intensive care for example, will disrupt normal synaptic organization in the sensory system (Walker et al 2003). If so, abnormal or excessive activity related to skin inflammation or injury in the fetus or neonate may have the potential to cause long-term changes in sensory processing. This is supported by clinical studies suggesting that early pain related to surgical and procedural interventions during intensive care management of preterm neonates has long-term consequences for pain behaviour and perception in later life (Porter et al 1999).

Surprisingly there is no literature on the development of the projections from the dorsal column nuclei to the ventrolateral nucleus of the thalamus in man. The first thalamocortical afferents are observed at 5–7 weeks PCA (Kultas-Ilinsky et al 2004). As discussed previously, these afferents make temporary synapses with subplate neurons before invasion of the cortex occurs between 22 and 25 weeks PCA (Kostovic and Judas 2002). The mechanisms by which the thalamocortical connections in the developing cortex become topographically ordered are not completely understood. During the initial stage, in-growing thalamic axons are guided to their appropriate cortical targets by molecular cues intrinsic to the cortex. In the second phase, the topographical organization has been shown to be an activity-dependent process for several developing sensory systems, such as visual and somatosensory thalamocortical projections (for reviews see O’Leary et al 1995, Penn and Shatz 1999, Levitt 2003). If the source of activity is altered during this critical period then the normal patterns of connectivity are disrupted.

SOMATOSENSORY EVOKED POTENTIALS

An indication of the degree of maturation of somatosensory pathways can be obtained from somatosensory evoked potentials. Following electrical stimulation of the median the somatosensory pathways of a newborn can be assessed reliably over the Erb’s point and over the spinal cord. For the first six months of postnatal age these subcortical responses are more constantly recordable than the cortical responses. The first cortical response to median nerve stimulation, termed N20 in mature adults, is called N1 in newborns. The early N1 deflection is measurable in most normal preterm infants from at least the seventh gestational month. However, although the overall waveform morphology of the N1 response is similar to that of the N20, the latencies of the responses are markedly longer and the responses smaller and wider in preterm babies than in adults. In longitudinal studies of preterm infants, the response latencies shorten and the responses become shorter in duration and more prominent with increasing age until adult-type responses are obtained between 2 and 3 years of age (Taylor et al 1996).

Corticospinal axonal projection and withdrawal

Studies within our laboratory of embryonic human brain development confirm the observations of Meyer and her colleagues that between 6 and 7 weeks PCA the cortical plate has not yet formed (Meyer et al 2000). It is surprising, therefore, that axons, which follow the course of the corticospinal tract, reach the medulla by 8 weeks PCA and are observed to decussate (Humphrey 1960, O’Rahily and Müller 1994) (Fig. 2.2). This must raise the question of whether these early axons arise in man from subplate neurons.

In adults, layer 5 of the neocortex is the exclusive source of cortical projection neurons to the spinal cord and cortical targets in the midbrain and hindbrain. In adulthood the distribution of layer 5 neurons projecting to each subcortical target is restricted to particular areas along the tangential extent of the neocortex. Corticotectal neurons which project to the superior colliculus are, for example, found primarily in the visual cortex, whereas corticospinal neurons are largely limited to the primary motor and somatosensory cortex. In rats, however, at birth, layer 5 neurons that project to the spinal cord or to the superior colliculus are present in a continuous distribution across the entire neocortex (Fig. 2.3). Using retrograde fluorescent tracers, it has been possible to demonstrate that the mature restricted distribution of layer 5 neurons is achieved not by cell death but by selective axonal elimination (Schreyer and Jones 1982, Stanfield et al 1982, Bates and Killackey 1984).

Subsequent studies using high resolution anterograde tracing with DiI have revealed that, during development, layer 5 neurons innervate their targets in the midbrain and hindbrain via collateral branches of corticospinal axons, and that, as a population, layer 5 neurons across the neocortex initially develop a similar set of collateral projections. Thus layer 5 projection neurons can best be regarded as a single class which initially share a developmental program directing them to project towards the caudal pole of the nervous system. To generate the mature pattern of layer 5 projections, functionally appropriate for each specialized area of the cortex, different combinations of branches are later selectively eliminated. Thus development of the mature patterning of cortical projections is a late event in corticogenesis (O’Leary and Koester 1993).

Fig. 2.2 Horizontal sections from 8-week PCA fetus. These three sections from the caudal medulla (A, B) and rostral cervical spinal cord (C) from the same fetus demonstrate immunoperoxidase reactivity for GAP43 (a marker for growing axons) in nerve fibres following the course of the corticospinal tract. The arrows in A and B point to the location of the pyramids on the ventromedial surface of the medulla, which are very small at this stage of development. Small, GAP43 positive fibres can be seen leaving the pyramids and crossing over in a dorsolateral direction, indicating that axons have already entered the corticospinal decussation. This is shown more clearly in the higher-power figure (D, an enlargement of part of B). In the spinal cord, the dorsolateral funiculus (arrow) is small and contains some GAP43 immunoreactive fibres, which may be continuations of the axons observed at the decussation.

Recent studies provide new insights into the molecular events that underlie such axonal pruning (Ehlers 2003, Kantor and Kolodkin 2003). The mechanisms that control the final pattern of cortical projections, however, are not well understood, although the available evidence indicates a modulatory role for sensory input. For example, if somatosensory information is aberrantly routed to the visual cortex in developing rats prior to axonal withdrawal, layer 5 neurons in the visual cortex permanently retain their normally transient corticospinal axonal projections. Similarly, layer 5 neurons transplanted from visual cortex to motor cortex will permanently retain their projection to the spinal cord (Stanfield and O’Leary 1985, O’Leary and Stanfield 1989, O’Leary et al 1992).

In man there are no data to confirm or refute whether the initial axonal projection from layer 5 cortical neurons arises from the whole of the cortex. In the Macaque monkey a halving of the area of the cerebral cortex from which corticospinal axons originate has been demonstrated during the first eight postnatal months, when brain volume overall increases by more than 30 per cent. These changes are associated with a threefold reduction in the number of retrogradely labelled cortical neurons, providing convincing evidence for an exuberant corticospinal projection and significant corticospinal axonal withdrawal in subhuman primates (Galea and Darian-Smith 1995).

Fig. 2.3 On the left: sagittal sections through the cortex of a rat aged 3 postnatal days, 15 postnatal days and in adulthood, showing labelled cells following an injection of Fast Blue at the high cervical level (adapted from Schreyer and Jones 1982). On the right: coronal sections through the anterior parietal cortex in rats aged from 4 to 11 postnatal days (P4–P11), showing labelled cortical cells following injection of horseradish peroxidase into the high cervical spinal cord.

Source: Adapted from Bates and Killackey 1984, Schreyer and Jones 1988.

Several studies in the rat indicate that a staggered outgrowth of corticospinal axons occurs, with many days elapsing between the appearance of the first projecting axons and the attainment of the peak number of corticospinal axons (Schreyer and Jones 1982, Gribnau et al 1986, Gorgels et al 1989, Gorgels 1990). Axonal collateral projection withdrawal also occurs over a protracted period and correlates with a dramatic reduction in corticospinal axonal numbers (Schreyer and Jones 1982, Gorgels et al 1989).

Staggered outgrowth of corticospinal axons also occurs in man. At 8 weeks PCA the pyramids are very small and they remain relatively small until there is a sudden and very large increase in size between 15 and 17 weeks PCA. There is a further large, but less rapid, increase in the size of the pyramid between 17 and 26 weeks, where it more than trebles in cross-sectional area (Humphrey 1960). Corticospinal axons reach as far as the lumbar enlargement by 18 weeks PCA (Humphrey 1960). By 40 weeks PCA corticospinal axons have begun to express neurofilaments and undergo myelination.

Corticospinal projections in several mammalian species develop transient ipsilateral projections early in development which are predominantly withdrawn by the time maturity is reached (Stanfield 1992). In the kitten, it has been demonstrated that unilateral inhibition of the motor cortex leads exuberant ipsilateral corticospinal projections from the uninhibited cortex to be maintained, at the expense of contralateral projections from the inhibited cortex, which become much reduced (Fig. 2.4) (Martin and Lee 1999, Martin et al 1999). The reduction in corticospinal projections from the inhibited cortex is due to interhemispheric competition between the corticospinal projections, and not due to activity blockade per se, since in a subsequent study bilateral inhibition of the motor cortices, which eliminated interhemispheric competition, led to qualitatively normal projections from both hemispheres (Martin and Lee 1999, Martin et al 1999).

Fig. 2.4 The percentage of spinal grey matter labelled in the cervical spinal cord by anterograde transport of label placed on the forelimb area of the sensorimotor cortex in three groups of animals: four normal cats (CONTROL); four cats who had unilateral infusion of muscimol (UNILATERAL INHIBITION); and four cats who had bilateral muscimol infusions (BILATERAL INHIBITION). All infusions were made 3 mm below the pial surface at the centre of the forelimb area of the motor cortex. The infusions were continuous between postnatal weeks 3 and 7, which is the period of postnatal refinements of corticospinal terminations in cats. The left-hand hashed and solid bars represent cervical spinal cord contralateral to the cortex labelled, and the right-hand bars, the ipsilateral cervical spinal cord. Inactive (solid bars): data obtained from labelling projections from motor cortices infused with muscimol. Active (hashed bars): data obtained from labelling projections from normal motor cortices. Stars mark data significantly different from control values p<0.05.

Source: Data derived from Martin and Lee 1999, Martin et al 1999.

Focal transcranial magnetic stimulation (TMS) of the motor cortex in babies at the time of birth evokes responses in ipsilateral and contralateral muscles, demonstrating significant ipsilateral and contralateral corticospinal projections during development in man (Eyre et al 2001) (Fig. 2.5). In longitudinal and cross-sectional studies of normal babies and children, neurophysiological findings are consistent with the withdrawal of corticospinal axons over the first 24 postnatal months (Eyre et al 2001), as has been observed in sub-human primates (Galea and Darian-Smith 1995) (Fig. 2.6). Furthermore, rapid differential development of the ipsilateral and contralateral projections occurs over this time, so that responses at 2 years postnatal age in ipsilateral muscles are less frequent, significantly smaller, and have longer onset latencies and had higher thresholds than responses in contralateral muscles. The differential development of the ipsilateral responses is consistent with a greater withdrawal of ipsilateral corticomotoneuronal projections than contralateral, as has been observed during development of the corticospinal tract in animals. The small and late ipsilateral responses observed in older children and adults are consistent with the persistence of a small ipsilateral corticomotoneuronal projection, with slower conducting axons than contralateral projections (Eyre et al 2001, Eyre 2005).

Spinal innervation

Studies in animals reveal that early in development corticospinal axons initially occupy a larger terminal field within spinal grey matter and contact more spinal neurons than in the adult (Curfs et al 1994, Martin et al 1999). The elimination of supernumerary synapses and refinement of the area of termination during the process of axonal withdrawal occur in conjunction with the proliferation of synapses from the subset of axons that are maintained (Li and Martin 2001, 2002). In this way specificity in corticospinal connectivity is a dynamic process involving withdrawal of inappropriate connections and reinforcement and extension of appropriate connections, occurring at both the motor cortex and its sub-cortical projection sites including the spinal cord.

In man there is extensive innervation of spinal neurons prior to birth, including monosynaptic projections to alphamotoneurons of the ventral horn and inhibitory interneurons (Eyre et al 2000a, 2002, Eyre 2003a, 2003b) (Fig. 2.7). These observations in preterm and term babies should not be taken to mean that the corticospinal system is at that time capable of delivering control to the spinal cord for movement. It is proposed that the early corticospinal innervation, rather than furthering motor control per se, occurs to allow activity in the corticospinal system, together with sensory feedback, to shape development of the motor cortex and spinal motor centres (Eyre et al 2000a, 2001).

There is evidence from studies in the cat that the corticospinal system is incapable of exciting spinal motor circuits to a sufficient degree for controlling limb movements until their axon terminals are refined topographically. Given the importance of activity-dependent shaping of neuronal connectivity, such a mechanism would allow activity in the corticospinal system early in development to play a significant role in the development of circuit connectivity, without influencing movement (Meng and Martin 2003). There is indirect evidence to support the relevance of these observations in the cat to man. Generally in the first 12 to 24 months after birth, when axonal withdrawal and corticospinal connectivity refinement are likely to be still occurring (Eyre et al 2001), the thresholds for evoking muscle action potentials to TMS are high and the responses are inconsistent. This is followed by a drop in TMS threshold, the onset of consistent responses to TMS, and correlated improvement in hand skills, including the ability to perform relatively independent finger movements (Nezu et al 1997, Eyre et al 2000c).

Corticospinal activity during development is also involved in the shaping of spinal reflex development. Lesions in sensory motor cortex and/or infusion of muscimol over the motor cortex during development disturb the development of segmental afferent input in rats (Gibson et al 2000, Clowry et al 2004). Similar observations have been made in children who suffered lesions to the corticospinal system in the perinatal period (O’Sullivan et al 1998).

Activity-dependent development of the corticospinal tract

Substantial lesions of the sensorimotor cortex or corticospinal tract in subprimate mammals early in postnatal life lead to hypertrophy of the undamaged motor cortex and corticospinal projection (Hicks and D’Amato 1970, Huttenlocher and Raichelson 1989, Rouiller et al 1991, Jansen and Low 1996, Uematsu et al 1996). These changes are associated with maintenance of an increased ipsilateral corticospinal projection from the undamaged hemisphere. The cells of origin of the induced aberrant ipsilateral axons are more widely distributed than and distinct from the cells of origin of the crossed or contralateral corticospinal projection (Huttenlocher and Raichelson 1989, Reinoso and Castro 1989, Stanfield 1992, Jansen and Low 1996). There is no evidence for double labelling of corticospinal neurons in neonatally hemispherectomized animals that in adulthood had spinal cord injection of fluorescent tracers (Reinoso and Castro 1989). Thus induced ipsilaterally projecting corticospinal axons from the undamaged cortex do not arise as branches of the contralateral corticospinal projection, but arise from neurons which extend axons into the ipsilateral spinal cord during development, and whose axons would normally be withdrawn.

There are now repeated observations in man which demonstrate substantial plastic reorganization of the motor cortex and corticospinal projections following pre- or perinatal lesions to the corticospinal system (Benecke et al 1991, Carr et al 1993, Cao et al 1994, Lewine et al 1994, Maegaki et al 1995, Muller et al 1997, Nirkko et al 1997, Graveline et al 1998, Muller et al 1998, Hertz-Pannier 1999, Holloway et al 1999, Balbi et al 2000, Eyre et al 2000b, 2001, Thickbroom et al 2001). The findings of these studies are remarkably consistent with those made in animals following perinatal lesions to the corticospinal system.

HYPERTROPHY OF THE CONTRALESIONAL CORTICOSPINAL TRACT FOLLOWING UNILATERAL LESIONS

In children and adults who have suffered extensive damage to one motor cortex early in development, significant bilateral corticospinal innervation of spinal motoneuronal pools persists from the undamaged hemisphere. Thus focal TMS of the intact motor cortex evokes large responses in ipsilateral and contralateral muscles, which have similar latencies and thresholds (Fig. 2.8). These observations have been made following perinatal unilateral brain damage arising from a variety of pathologies including infarction, dysplasia, and arteriovenous malformations (Benecke et al 1991, Maegaki et al 1995, Eyre et al 2000b, 2001). Short latency ipsilateral responses do not occur in normal individuals outside the perinatal period. Nor do they occur in individuals who acquired unilateral cortical lesions in adulthood, establishing that fast ipsilateral responses are not simply unmasked by unilateral lesions. Furthermore, the responses in contralateral muscles evoked by stimulation of the intact motor cortex, although within the normal range for age, are abnormally clustered towards short onset latencies and low thresholds (Eyre et al 2001).

Fig. 2.5 Mapping of the origin of responses evoked in right biceps brachii using TMS and a focal figureof-eight coil. The coil was positioned using a latex 1 cm × 1 cm latex grid placed on the scalp. The individual was 5 weeks old. The filled circle marks the vertex. The traces are EMG recorded in right biceps brachii. TMS was applied at the beginning of each trace. Responses were obtained in right biceps brachii following stimulation of both the ipsilateral