Plasticity of central motor pathways in children with ... - Neurology

Plasticity of central motor pathways in children with hemiplegic cerebral palsy Simon F. Farmer, MB, PhD; Linda M. Harrison, PhD; David A. Ingram, MB; and J o h n A. Stephens, DSc

Article abstract-To obtain neurophysiologic evidence for a reorganization of central motor pathways in children who had suffered a cerebral lesion at birth, we performed cross-correlation analyses of multiunit EMG recordings obtained from children with hemiplegic cerebral palsy and marked mirror movements. We found that the motoneuron pools of homologous left and right hand muscles received common synaptic input from abnormally branched presynaptic axons. The results of electromagnetic brain stimulation, cutaneomuscular, and tendon reflex testing suggested that these common inputs are provided by abnormally branched corticospinal tract fibers whose origin is the undamaged motor cortex. NEUROLOGY 1991;41:1505-1510

Considerable evidence from animal experiments suggests that recovery of function following central nervous system damage is dependent upon the time of acquisition of the lesion. For example, hamsters subjected to unilateral section of the pyramidal tract when adults show no recovery of fine manipulatory skills as required during feeding.' However, if the tract is lesioned during early neonatal life, sprouting of a proportion of the severed corticospinal axons occurs, and appropriate connections are made in t h e spinal cord such that fine manipulatory skills are present in t h e a d ~ l t .In ~ .t h~e cat, no new tract develops following neonatal hemispherectomy. However, sprouting of corticospinal terminals can take place; these collaterals cross the cord and terminate ipsilateral to the l e ~ i o nIn . ~the monkey, unilateral pyramidotomy can be associated with remarkable functional r e ~ o v e r ySuch .~ functional recovery in p r i m a t e s m a y result from branching of ipsilateral corticospinal projections from the undamaged motor cortex to motoneurons of t h e distal hand muscles.6 A previous study of a patient with Klippel-Feil syndrome and congenital mirror movements indicated t h a t fast-conducting corticospinal tract axons may branch abnormally to innervate motoneurons on both sides of the spinal cord, t h e consequence of t h i s abnormal branching being marked mirror movements of the distal hand m u ~ c l e s In . ~ t h e present study, we have sought neurophysiologic evidence for similar CNS remodeling in children who had sustained a unilateral cortical lesion at birth causing hemiplegic cerebral palsy a n d marked mirror movements of t h e hand muscles. A preliminary account of these results has been presented t o the Physiological Society.6

Methods. Subjects. All subjects were studied with the permission of the local ethics committee and with informed parental consent. Four children aged between 2 and 5 years were studied; each had developed varying degrees of hemiplegia following cerebral anoxia at birth. Three had right hemiplegia, and one had left hemiplegia. None was receiving medication. These children showed marked mirror movements, predominately affecting the distal hand and forearm muscles. The paretic hand was normally held in a fist. However, voluntary activation was possible and was accompanied by marked mirror movements in the unaffected hand. Two of the four children could walk unaided at the time of testing. In addition, two children aged 4 and 9 years were studied these children had suffered a cerebral lesion at birth but had not developed marked mirror movements. In all the children with CNS lesions, the clinical findings were supported by evidence of cerebral damage on CT. For comparison, 10 healthy children aged 18 months to 12 years were studied; these children showed no more than mild mirroring. Behavioral analysis. Videotape recordings were made of all the children both during the experiments and during the performance of various motor tasks such as repetitive opposition of index finger to thumb and opening a large bulldog clip. Assessment of the mirror movements was based on the criteria of Woods and Teuber? The scoring was on a 0 to 4 scale where 0 = no clear imitative movement, 1 = barely discernable imitative movement, 2 = obvious but unsustained imitative movement, 3 = strong and sustained imitative movement, and 4 = movement equal to that in the intentionally activated hand. The scoring was performed from the videotape recording by a pediatrician with no prior knowledge of either the clinical diagnosis or the results of neurophysiologic testing. Electromyographic recording. Surface EMG recordings were obtained simultaneously from left and right upper limb muscles using a portable Medelec MS7 EMG machine

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From the Department of Physiology (Drs. Farmer, Harrison, and Stephens), University College London, and the Department of Clinical Neurophysiology (Dr. Ingram), The Royal London Hospital, London, UK. Supported by a Wellcome Trust Clinical Fellowship (to Simon F. Farmer). Received October 19.1990. Accepted for publication in final form February 22,1991. Address correspondenceand reprint requests to Dr. Simon F. Farmer, Department of Physiology, University College London, Cower Street, London WClE 6BT. England. September 1 9 9 1 NEUROLOGY 41 1 6 0 6

taneously from left and right intrinsic hand muscles. Single (Medelec, Old Woking, Surrey, England). Multiunit EMG was sweeps of EMG from both sides, triggered by the magnetic recorded using neonatal ECG electrodes (Arbo H82V), modistimulus, were displayed on the Medelec EMG machine and fied to produce a recording area of 1 cm2. Electrodes were recorded on magnetic tape. placed 2 cm apart, center to center, on the dorsal surface of the Cutaneomuscular reflex testing. Cutaneomuscular reflexes forearm when recording from the forearm extensor muscles were recorded from one child with right hemiplegia and (FA EXT); for the intrinsic hand muscles, predominantly the marked mirror movements and from three healthy, agefirst dorsal interosseous muscle (lDIM), one was placed over matched controls. Each child gripped a plastic toy with both the muscle and the other adjacent medially over the dorsal hands so as to produce bilateral background EMG activity, surface of the hand. EMG was amplified (X2,000), filtered which was recorded simultaneously with surface electrodes (-3 dl3 at 20 Hz and 10 kHz), and stored on magnetic tape over the left and right FA EXT. Electrical stimuli were deliv(Racal Store 4) for future analysis. In all the children, simulered, using ring electrodes (Medelec), to the digital nerves of taneous EMG recordings were obtained from left and right either the left or right index finger at a strength of twice lDIM, and from left and right FA EXT, while they played threshold for perception at three per second. Rectified EMG using both left and right hands. from both left and right sides was then averaged, time-locked Cross-correlation analysis. Only those portions of the reto each stimulus, for 500 to 1,000 sweeps (CED Sigavg softcording during which simultaneous EMG was present were ware). analyzed. Periods of marked phasic activity were excluded because inclusion would result in marked background slow Results. Mirror mouements. The four children with periodicities in the subsequent cross-correlation analysis. hemiplegia all displayed marked mirror movements Analysis was performed using medium- to large-amplitude (grades 3 to 4; median, grade 4). The movementsparticspikes. These were selected by passing the multiunit EMG ularly affected the distal hand muscles and were present signals from left and right sides through a level detection during all types of movement. However, they were most circuit (Neurolog NL 200). The resulting transistor-transistor logic (TTL) pulses of 200 psec duration were passed into a marked when the child attempted to open the hemimicrocomputer (Sperry 50) via a laboratory interface (CED plegic hand. The two other children with cerebral palsy 1401, Cambridge Electronic Design, Cambridge, England), primarily exhibited dystonic movements affecting both and the times of occurrence of the motor unit spikes deterlimbs. In the older child (aged 9), no mirroring was mined. Cross-correlation histograms (1-msec bin width) were present; in the younger child (aged 4), only mild (grade constructed between the times of motor-unit spike occurrence 1) mirroring could be detected. In four normal children, recorded from the left and right muscles (minimum 2,000 no mirror movements were observed the remainder spikes per multiunit EMG recording). The cumulative sum showed mild mirroring (grades 1to 2; median, grade 1). was calculated as described by Ellawaylo; the duration of the In the normal children, the mirroring was symmetric cross-correlation peak was taken as the time between the and, in general, was most apparent during forceful points of inflection. The significance of any cross-correlogram movements (for example, when the child attempted to peaks detected was assessed according to the criteria of Davey et a1.I' The size of the peaks was measured in terms of k , the open a bulldog clip with thumb and index finger). peak bin count divided by the mean bin count.I2 Cross-correlation analysis. Figure 1A shows a crossIn previous studies, cross-correlation analysis has been correlogram constructed between motor unit spikes reperformed using single or multiunit spike trains obtained corded simultaneously from the left and right intrinsic using nerve filaments or intramuscular recording~.'~J~ In the hand muscles (1DIM) of a normal child aged 2 years who present study using young children, intramuscular electrodes did not display mirror movements. The cross-corcould not be used, and multiunit recordings were obtained relogram and the associated cumulative sum are both during play using small surface electrodes. The time course of flat, indicating that the two multiunit recordings, ala correlogram peak obtained from such recordings is similar to though recorded simultaneously, are independent of that found previously (mean, 23.2 msec; range, 21 to 28 msec, n = 5 ) when cross-correlating multiunit spikes recorded bilatone another. Figure 1B shows a cross-correlogram conerally using needle electrodes in a patient with Klippel-Feil structed between motor unit spikes selected from simulsyndrome and is not dissimilar to that described for cortaneous multiunit recordings from left and right relogram peaks obtained from single-unitdata in this ~ a t i e n t . ~ intrinsic hand muscles in a child aged 2 with right Tendon-jerk testing. In all the children, the tendon-jerk hemiplegia and marked mirror movements (grade 4/4). response was tested. A tendon hammer was used to percuss In contrast to figure lA, it can be seen in figure 1B that manually, in turn, the left or right extensor tendons at the there is a central peak in the cross-correlogram and an wrist. Closure of a microswitch a t the time of impact indicated inflection in the associated cumulative sum. The durathe time of stimulation. Surface EMG was recorded simultion of this symmetric peak was 18 msec, indicating an taneously from the left and right FA E X T in the manner increased probability of motor unit discharge in the left previously described. The left and right EMGs were rectified hand muscle 9 msec before and after the motor unit and averaged (20 sweeps) time-locked to the stimulus tap using an averaging program (CED Sigavg software). discharges in the right hand muscle. In this child, signifMagnetic brain stimulation. Percutaneous focal magnetic icant central cross-correlogram peaks were also obbrain stimulation was performed on two children with hemitained between EMG activity recorded from left and plegia and mirror movements, and three healthy, age-matched right F A EXT. controls using a Novametrix Magstim 200 stimulator (maxAll four children with hemiplegia and marked mirror imum output, 2.0 T) a t a stimulus strength of 90% of the movements displayed central peaks in the cross-cormaximum, via a figure-of-eight coil (cf Amassian et all4)siturelograms constructed from motor units recorded from ated over either the left or the right cortical hand area. The left and right lDIM and left and right F A EXT. In total, stimuli were given while the child gripped a plastic toy with 31 correlograms were constructed from such data, and both hands so as to produce bilateral EMG activity. Surface EMG was recorded in the manner previously described, simuleach revealed a central peak in the cross-correlogram. 1606 NEUROLOGY 41 September 1991

CROSS-CORELOGRAM: LEIT ID1M:RIGHl IDlM

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Normal child: Focal magnetic stimulation to lefi motor cortex A Right hand

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Hrmiplegic child: Focal magnetic stlmuiation to undamaged (right) motor cortex C Lefthana

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Figure 1. Cross-correlograms between simultaneous EMGs from left and right hand muscles, minimum 2,000 referenct spikes. T h e cumulative s u m is plotted above each correlogram and scaled as cumulative conditional probability I s ] . (A) T h e cross-correlogram and cumulatioe s u m from a normal child, aged 2, are flat; (B) in contrast, those from a child with a right hemiplegia and mirror movements, aged 2, contain a central peak and a n inflection.

The mean degree of synchrony, expressed as k,was 1.43 (SD, 0.15), and the mean duration of the central peak was 23 msec (SD, 5 msec). In contrast, cross-correlograms (n = 34) constructed between motor units from left and right lDlM and left and right FA EXT in the 10 normal children did not reveal evidence of significant cross-correlogram peaks. In addition, cross-correlograms between motor unit spikes of left and right hand muscles of the two children with cerebral palsy who had not developed marked nlir ror movements failed to show a central peak (11 = 12). Focal magnetic brain stimulation and reflex testing. Focal magnetic stimulation of the hand area of the motor cortex in normal children elicited a short-latency (approximately 15 msec) response in the contralateral

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Figure 2. Focal magnetic brain stimulation of the motor cortex. Stimuli were given to the motor cortex via a figureof-eight coil. Simultaneous EMGs f r o m the left and right hand muscles (1DIM) are shown as single sweeps triggered by the scalp stimulus. (A and B) Stimulation of left motor cortex in a normal child, aged 2. (A) A short-latency (approximately 15 msec) response is present i n EMG from the hand contralateral to the stimulated cortex; (B) no corresponding response is present in EMG from the hand ipsilateral to the stimulus. (C and D)Stimulation of the undamaged (right) motor cortex i n a child with right hemiplegia and marked mirror movements. Short latency responses (at about 15 msec) are seen i n both the contralateral (C) and ipsilateral l D I M (0).

lDIM (figure 2A); there was no evidence of an ipsilateral response (figure 2B). The results of focal magnetic brain stimulation of the right motor cortex in a child with damage to the left cortex are also shown in figure 2, C and D. In contrast to figure 2, A and B, it can be seen that stimulation of the undamaged motor cortex of the herniplegic child produces a response at a short and similar latency in both the contralateral (figure 2C) and ipsilateral (figure 2D) hand muscles. The mean latenSeptember 1991 NEUROLOGY 41 1607

Hemiplegic chi1d:Cutaneomuscuiar reflexes recorded from forearm extensor muscles

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Figure 3. Cutaneomuscular reflex responses recorded from a child aged 2 with right hemiplegia and mirror movements during voluntary contraction of the forearm extensor muscles. Electrical stimulation of the digital nerves of the index finger at three stimuli per second, twice threshold for perception. Following stimulation of the left index finger, the reflex response from the unaffected(left) side (A) displays the typical E l , 11, and E2 pattern; that from the affected (right) side (B) shows abnormal crossing of the E2 component. The crossed and uncrossed E2 components are labeled with arrows. Following stimulation of the right index finger, the reflex response from the hemiplegic (right) side (C) consists only of an E l component and an I1 component; no crossed components are present in the average from the unaffected (left) side (0). The vertical calibration bars represent a 20% modulation of mean background EMG. (A and B) One-thousand sweeps of EMG averaged. (C and 0)Five-hundred sweeps of EMG averaged.

cies of these bilateral responses followingrepeated stimulation of the right motor cortex in this child were 16.2 msec for the contralateral (left) hand muscles and 16.3 msec for the ipsilateral (right) hand muscles. Similar results were obtained in a second 2-year-old child with left hemiplegia and mirror movements. In this case, the mean latencies of the responses obtained from stimulation of the undamaged (left) motor cortex were 18.4 msec for the right hand and 18.5 msec for the left hand. All these responses were seen in single sweeps of EMG. Focal stimulation over the damaged motor cortex in these children did not produce either a contralateral or ipsilateral muscle response. Following a tap to the back of the wrist, the rectified averaged FA EXT EMG recorded from the stimulated side showed a large reflex response at a latency consistent with motoneuron excitation via spinal proprioceptiveand cutaneous afferent pathways (approximately20 msec). In all the healthy and cerebral palsy children studied, spinal reflex responses were only seen on the stimulated side; they were not observed in the averaged rectified EMG recorded from the FA EXT of the nonstimulated side. In normal children, stimulation of the digital nerves of the index finger produces a triphasic modulation of ongoing voluntary muscle activity recorded from FA EXT, comprising an increase in EMG (El), followed by a decrease (Il), followed by a second increase in EMG (E2). In children aged 2 years, the E l component pred o m i n a t e ~ Stimulation .~~ of the digital nerves of the index finger in the normal children produced a typical cutaneomuscular reflex recorded from the ipsilateral FA EXT with El, 11, and E2 components. No crossed reflex responses were present in the average constructed 1608 NEUROLOGY 41 September 1991

from EMG of the contralateral, nonstimulated hand. The cutaneomuscular reflexes of a 2-year-old child with damage to the left motor cortex and mirror movements are shown in figure 3. In this child, El, 11,and E2 responses were present on the unaffected (left) side when the digital nerves of the left index finger were stimulated (figure 3A). However, in contrast to the normal children, simultaneous averages from the affected (right) side revealed a reflex response at a similar latency to the E2 component recorded from the unaffected side (figure 3B). In addition, the I1 component is also present on the nonstimulated side (figure 3B). When the digital nerves of the index finger of the affected (right) hand were stimulated (figure 3C), the reflex on this side consisted of E l and I1 components only, the E2 component being absent. In contrast to stimulation of the unaffected hand, no crossed reflex response was present following stimulation of the hemiplegic hand (figure 3D).

Discussion. Cross-correlation analysis. The finding of a sharp peak a t time 0 in a cross-correlogram constructed between motor unit discharges from two different muscles indicates the presence of presynaptic axons that branch to provide common innervation to both motoneuron pools.12J6Bremner et all7 reported a modal value of 13 msec for the central peak of their correlograms constructed from single units recorded within one muscle or from two different muscles involved in finger movements in humans. The time course of these peaks was well matched by equations developed by Kirkwood and SearsI6on the basis that such peaks are produced by the joint occurrence of excitatory

postsynaptic potentials evoked in motoneurons by branches of common stem presynaptic fibers. For multiunit recordings, wider cross-correlogram peaks are produced. This can be accounted for by differences in conduction time in both the pre- and postsynaptic elements.l2In their study of first dorsal interosseous motor units, Datta and Stephens13reported that the position of the central point of the correlogram peak between different motor unit pairs was not always at time 0 but could be offset by as much as 5 to 6 msec either side of zero. Thus, compared with single-unit recordings, the width of the central peak constructed from multiunit data could be increased by about 10 to 12 msec. In the present study, the mean duration of the multiunit correlogram peak was 23 msec. This is 10 msec longer than the modal value for single-unit data reported by Bremner et all7 and therefore of a time course consistent with the hypothesis that such peaks could be produced by the simultaneous arrival of activity in branches of common stem presynaptic fibers. The presence of such peaks in the cross-correlograms constructed between motor units of the right and left hand and forearm muscles in the four children with cerebral palsy and pronounced mirror movements indicates that the right and left motoneuron pools of these children share common synaptic inputs. Evidence for such functional bilateral common inputs was not found in normal children of a similar age. Reflex testing and focal magnetic brain stimulation. In all the children tested, the short-latency spinal response of the tendon jerk reflex remained confined to the stimulated side. Thus, the abnormally branched presynaptic inputs, responsible for the cross-correlated activity between motor unit activity from the left and right sides in the children with cerebral palsy, are unlikely to have originated from spinal reflex pathways. This conclusion is strengthened by the observation that the E l component of the cutaneomuscular reflex was also confined to the muscles of the stimulated side in the hemiplegic child from whom the cutaneomuscular reflex was recorded. In this child, there is a suggestion that an I1 component may be recorded from the hemiplegic hand following stimulation of the digital nerves of the unaffected hand. This component is probably of spinal origin15;however, it is unlikely that this pathway is responsible for the bilateral cross-correlogram peaks since the latency of this component suggests the involvement of a number of interneurons. The short latency of the responses recorded from the distal hand muscles following magnetic brain stimulation is consistent with transmission via fast-conducting corticospinal tract axons.18-zo The presence of bilateral short-latency responses following focal magnetic stimulation of the undamaged motor cortex in the children with cerebral palsy indicates that the undamaged corticospinal tract has innervated ipsilateral as well as contralateral hand motoneurons. The results of crosscorrelation analysis suggest that this abnormal innervation has been achieved by axonal branching. The above inferences are supported by the finding that the long-latency cutaneomuscular reflex circuitry is excited bilaterally following stimulation of the digital

nerves of the index finger of the unaffected hand. The E2 component of the cutaneomuscular reflex is dependent upon the integrity of the dorsal columns, motor cortex, and corticospinal tractz1; its bilateral distribution following stimulation of the digital nerves of the index finger unaffected by the CNS lesion is further evidence of the abnormal distribution of corticospinal pathways. However, stimulation of the hemiplegic hand produced a short-latency E l component only, with no E2 component. This result is consistent with previous studies indicating that damage to the motor cortex acquired a t birth or during adult life can result in the diminution or loss of the E2 component of the cutaneomuscular reflex.21.22 General considerations. The neurophysiologic data presented here suggest that in children with hemiplegia and marked mirror movements, branched corticospinal axons from the undamaged cerebral hemisphere innervate ipsilateral as well as contralateral lower motoneuron pools. This branching may take place during postnatal development in response to the lesion. Alternatively, during fetal life, bilaterally projecting corticospinal axons may exist, but normally, the ipsilateral branch is withdrawn before making contact with motoneurons. Thus, pre-existing ipsilateral branches might be envisaged to remain if unilateral motor cortical damage occurs during fetal or early neonatal life. While we cannot exclude this latter possibility,we believe the former is more likely since there is a substantial amount of evidence in the literature to suggest that axonal branching can occur following a CNS l e s i ~ n , ' *whereas ~ , ~ we can find no evidence in the literature to support the latter. The accurate mirroring of entire hand and finger movements exhibited by these children suggests that the abnormal bilateral branching is not random, but may rather be directed to the equivalent motoneuron pools on the two sides of the spinal cord. The presence of abnormal branching of corticospinal axons from the undamaged motor cortex to ipsilateral motoneurons provides a novel pathway whereby motor commands may access motoneurons whose descending connections have been lost as a result of a unilateral cerebral lesion. Moreover, this novel pathway may improve the prognosis for motor development in these children.

Addendum. Merline and Kalil ( J Comp Neurol 1990;296:506-516),using new techniques to label corticospinal cells of the hamster, have recently reported that no regrowth of severed axons occurs following unilateral pyramidotomy. However, they demonstrated that corticospinal fibers originating from the intact cortex may respond to the lesion by branching and innervating those areas of the spinal cord where the descending connections have been lost. These new findings clearly support the hypothesis proposed in the present paper. Acknowledgments We would like to thank the many parents and children who took part in this study. Special thanks to the staff a t the Bobath Centre for the September 1991 NEUROLOGY 41 1509

Treatment of Children with Cerebral Palsy, London, for providing recording facilities, and for their expert help and encouragement.

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