COGNITIVE NEUROSCIENCE

Reorganization of cortical hand representation in congenitalhemiplegia

Yves Vandermeeren,* Marco Davare, Julie Duque and Etienne OlivierLaboratory of Neurophysiology, Institute of Neuroscience (INES), Universite catholique de Louvain, Brussels, Belgium

Keywords: cerebral palsy, corticospinal tract, motor cortex, plasticity, primary motor cortex

Abstract

When damaged perinatally, as in congenital hemiplegia (CH), the corticospinal tract usually undergoes an extensive reorganization,such as the stabilization of normally transient projections to the ipsilateral spinal cord. Whether the reorganization of the corticospinalprojections occurring in CH patients is also accompanied by a topographical rearrangement of the hand representations in theprimary motor cortex (M1) remains unclear. To address this issue, we mapped, for both hands, the representation of the first dorsalinterosseous muscle (1DI) in 12 CH patients by using transcranial magnetic stimulation co-registered onto individual three-dimensional magnetic resonance imaging; these maps were compared with those gathered in age-matched controls (n = 11). In thedamaged hemisphere of CH patients, the representation of the paretic 1DI was either found in the hand knob of M1 (n = 5), shiftedcaudally (n = 5), or missing (n = 2). In the intact hemisphere of six CH patients, an additional, ipsilateral, representation of the paretic1DI was found in the hand knob, where it overlapped exactly the representation of the non-paretic 1DI. In the other six CH patients,the ipsilateral representation of the paretic 1DI was either shifted caudally (n = 2) or was lacking (n = 4). Surprisingly, in these twosubgroups of patients, the representation of the contralateral non-paretic 1DI was found in a more medio-dorsal position than incontrols. The present study demonstrates that, besides the well-known reorganization of the corticospinal projections, early braininjuries may also lead to a topographical rearrangement of the representations of both the paretic and non-paretic hands in M1.

Introduction

A large body of evidence suggests that the motor system of patientswith congenital hemiplegia (CH) undergoes extensive reorganization.On the one hand, functional magnetic resonance imaging (MRI)studies have consistently demonstrated that, in CH patients, paretichand movements lead to a widespread bilateral activation of motor-related areas, suggesting a redistribution across both hemispheres ofthe neural resources controlling the paretic hand (Thickbroom et al.,2001; Staudt et al., 2002; Vandermeeren et al., 2002a, b; Staudt et al.,2004). On the other hand, in some CH patients, it has been shown thattranscranial magnetic stimulation (TMS) applied over the intact motorcortex elicits ipsilateral motor evoked potentials (iMEPs) in the paretichand muscles, suggesting the existence of a contingent of corticospinal(CS) neurones establishing some connections between the intacthemisphere and ipsilateral paretic hand motoneurones (Maegaki et al.,1997; Staudt et al., 2002; Vandermeeren et al., 2003a). Theseipsilateral CS projections may represent aberrant projections arisingfrom the damaged hemisphere that were stabilized during thedevelopment because of a lack or a diminution of descending outputs

normally carried out by crossed CS projections (Eyre et al., 2001;Staudt et al., 2004). Recent studies using magnetoencephalographyhave corroborated this view by demonstrating, in CH patients, theexistence of coherent oscillations between the primary motor cortex(M1) and ipsilateral hand muscles, providing further evidence that,after an early CS lesion, the control of paretic upper limb movementsmay at least partly shift into the intact hemisphere (Gerloff et al.,2006; Belardinelli et al., 2007).However, so far, little attention has been paid to the topographical

reorganization of the cortical hand representations in CH patients(Maegaki et al., 1997; Thickbroom et al., 2001), and most of ourknowledge about the reorganization of cortical motor maps followingCS lesions comes from studies in adult monkeys and adult strokepatients. In non-human primates, anatomical studies have shown thatM1 and non-primary motor areas are heavily interconnected and sendparallel projections to the spinal cord through the CS tract; the largeredundancy of these connections may underlie the reorganization ofthe motor system that sometimes takes place after an injury (Liu &Rouiller, 1999; Dancause et al., 2005). Indeed, in adult stroke patients,it has been suggested that several cortical areas could be adaptivelyrecruited after a unilateral CS tract injury: (i) in the damagedhemisphere, the face or arm representation in M1 bordering the paretichand representation (Weiller et al., 1993; Thickbroom et al., 2004;Platz et al., 2005; Cramer & Crafton, 2006); (ii) in the damagedhemisphere, the premotor or postcentral areas (Calautti et al., 2003;

Correspondence: Dr Y. Vandermeeren, *Present address below.E-mail: yves.vandermeeren@uclouvain.be

*Present address: Service de Neurologie, Cliniques Universitaires UCL de Mont-Godinne,Universite catholique de Louvain, Avenue G. Therasse, 1, B-5530 Yvoir, Belgium.

Received 17 April 2008, revised 9 December 2008, accepted 10 December 2008

European Journal of Neuroscience, Vol. 29, pp. 845–854, 2009 doi:10.1111/j.1460-9568.2009.06619.x

ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd

European Journal of Neuroscience

Fridman et al., 2004; Thickbroom et al., 2004) and ⁄ or (iii) in theintact hemisphere, the motor ⁄ premotor areas (Johansen-Berg et al.,2002; Lotze et al., 2006). Because both the hand representations in M1and CS projections undergo a profound experience-dependent adap-tation postnatally (Martin & Lee, 1999; Chakrabarty & Martin, 2000,2005; Eyre et al., 2001), the reorganization of the motor systemsubsequent to an early brain injury, as in CH patients, may differdramatically from that observed after a comparable CS lesion inadults.The aim of the present study was therefore to investigate, in CH

patients, the topography of the paretic and non-paretic handrepresentations in both hemispheres. To do so, we mapped the firstdorsal interosseous muscle (1DI) representation of both hands in bothhemispheres of CH patients by means of TMS co-registered ontoindividual three-dimensional (3D) MRI images; these results werecompared to maps gathered in age-matched healthy children.

Materials and methods

Experimental subjects

All participants, and their parents for those under 18 years of age,gave written informed consent. The experimental protocol conforms tothe Declaration of Helsinki and has been approved by the EthicalCommittee of the Universite catholique de Louvain.

Twelve CH patients (13.3 ± 3.7 years old; see Table 1 and Fig. 1)and 12 age-matched right-handed control subjects (12.9 ± 3.5 yearsold) participated in this study; for technical reasons, only the data from11 control participants were analysed. Data from these patients andfrom controls have already been partially incorporated in previousstudies (Vandermeeren et al., 2002a,b, 2003a,b; Duque et al., 2003).CH patients were selected on the basis of a hemiplegia documented inthe first postnatal year; none of them was born prematurely. Allpatients had a nearly normal school level, excluding major cognitivedeficits. They underwent a comprehensive examination, including anevaluation of spasticity (Ashworth, 1964), a global functionalevaluation of the paretic upper limb [Melbourne Assessment test(Randall et al., 2001)], and an assessment of digital (Purdue pegboardtest) (Mathiowetz et al., 1986) and manual (box and block test)(Mathiowetz et al., 1985) dexterity of both hands. Mirror movements(MMs), i.e. involuntary mirroring movements in the passive hand,were scored from 0 (absent) to 4 (identical) during index-to-thumbopposition, wrist prono-supination, and sequential finger opposition(Woods & Teuber, 1978). Structural magnetic resonance images wereacquired on a 1.5-T MRI system (Signa Horizon Echospeed, GE,USA) using a three-dimensional gradient echo T1-weighted sequence:repetition time, 23 ms; echo time, 3 ms; flip angle, 30 �; 124contiguous axial slices (1.5 mm thick), field of view, 24 cm;256 · 256 matrix. The cerebral lesions of the CH patients are shownin Fig. 1 and described in Table 1.

Table 1. Clinical, functional and imaging data of congenital hemiplegia (CH) patients

CHpatient(sex)

Age(years) Clinical description Anatomical MRI

1 (M) 8 Right hemiparesis with equinus and tiptoe walking, righthand disuse, spasticity (1)

Left white matter ASI (centrum semiovale and periventricular), leftventriculomegaly, left internal capsule atrophy (both anteriorand posterior limbs)

2 (F) 13 Left mild equinus, no evident impairment of the upperlimb, spasticity (0)

No visible lesion

3 (F) 17 Right hemiparesis with equinus, spasticity (1) Left postcentral cortical ASI, small left (posterior) parietal cyst withspared precentral gyrus, right ventriculomegaly

4 (F) 17 Mild left hemiparesis with hand dyspraxia, mild left handdystonia, partial seizures (well controlled bycarbamazepine), spasticity (0)

Right cortical cyst involving the lateral premotor cortex in front of theinferior precentral gyrus and rolandic opercule, mild hemisphericasymmetry (right > left), left white matter ASI (parietal andcorticospinal tract in pons)

5 (M) 11 Right hemiparesis with equinus, right hand disuse,spasticity (1)

Left white matter ASI (corona radiata) consistent with remote cerebralinfarction, left ventriculomegaly, right parietal microlesions(dilated Virschow–Robin spaces)

6 (M) 13 Right hemiparesis with equinus, right hand disuse,spasticity (2)

Left white matter ASI (corona radiata), left ventriculomegaly, small leftparaventricular cavity

7 (F) 16 Right hemiparesis with equinus, right hand disuse,spasticity (3)

Left cortico-subcortical ASI (rolandic opercule and premotor cortex infront of the lower part of the prefrontal gyrus), left hemisphericatrophy, periventricular dilatation

8 (F) 19 Left hemiparesis with equinus, left hand disuse,spasticity (3)

Right white matter ASI (deep corona radiata and central sulcus)

9 (M) 12 Left hemiparesis with equinus, left hand disuse,spasticity (2)

Large right white matter ASI with right hemispheric hypotrophy

10 (F) 16 Right hemiparesis with equinus, right hand disuse,spasticity (1)

Left precentral cortico-subcortical ASI (hand knob), left paraventricularASI (deep parietal)

11 (F) 8 Right hemiparesis with equinus, right hand disuse,spasticity (2)

Left central macrocystic encephalomalacia, left hemispherichypotrophy, bilateral ventriculomegaly, right parietal microlesions(dilated Virschow–Robin spaces)

12 (M) 10 Right hemiparesis with equinus, right hand disuse,spasticity (2)

Left schizencephaly, left cerebral and cerebellar hemispherichypotrophy, mild left ventriculomegaly, pachygyria

M, male; F, female; ASI, abnormal signal intensity.

846 Y. Vandermeeren et al.

ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 29, 845–854

TMS

Subjects were comfortably seated in an armchair and wore anelectroencephalography cap with a grid (1 · 1 cm). Focal TMS wasdelivered using a Magstim 200 (Magstim Company, UK) through a90-mm figure-of-eight coil. The electromyograph (EMG) wasrecorded simultaneously from the left and right 1DIs via surfaceelectrodes, amplified (·500–2000), bandpass filtered (5–2.500 Hz;Neurolog, Digitimer, UK), and digitized at 5 kHz using a personalcomputer with a CED-1401 interface (Cambridge ElectronicDesign, UK).

The coil was held tangential to the scalp with the handle pointingbackwards 45� away from the sagittal plane; its position was adjustedto elicit the largest motor evoked potentials (MEPs) in the target 1DI.Once this optimal coil position, the ‘hot spot’, was found, the resting

motor threshold (MTh) was defined as the lowest intensity eliciting100-lV peak-to-peak amplitude MEPs with a 0.5 probability (Rossiniet al., 1999). Then, during the mapping procedure, the stimulationintensity was set at 110% of MTh. Six TMS pulses (inter-pulseinterval >5 s) were delivered at each stimulation site, starting at the‘hot spot’ and then centrifugally at the surrounding positions in stepsof 1 cm, until no more MEPs were elicited. On average, 37 ± 9stimulation sites (n = 52) were investigated in order to construct a fullmap. We first mapped the non-paretic hand representation in the intacthemisphere and then the contralateral paretic hand representation inthe damaged hemisphere. When ipsilateral MEPs (iMEPs) were foundin the paretic hand following intact hemisphere stimulations, thewhole mapping procedure was repeated to map the ipsilateral 1DIrepresentation. Muscle relaxation was monitored by audio electro-myographic feedback throughout the experiment.

Fig. 1. Cerebral lesions in the congenital hemiplegia (CH) patients. Magnetic resonance imaging scans of the 12 CH patients. Arrowhead, main lesion; R, right sideof the brain. See Table 1 for description.

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ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 29, 845–854

TMS–MRI co-registration

The 3D contours of the scalp surface were digitized with anIsotrack II (Polhemus) and co-registered with the 3D scalp surfacesegmented from the MRI image (Noirhomme et al., 2004; Davareet al., 2006). For each stimulation site, the coordinates of threepoints located onto the coil were digitized and co-registered into the3D MRI space using the transformation matrix derived from thescalp co-registration. A line perpendicular to the coil plane wasprojected from the coil center onto the brain surface (impact point).A continuous cortical map was generated by interpolation betweenthe impact points, using the rectified MEP area averaged separatelyfor each site as a scalar value. Then, the 3D coordinates of thecentre of gravity (CoG) of the MEP map were computed(Noirhomme et al., 2004). The anatomical location of the CoGon the cortical surface was determined on native individual 3Dmagnetic resonance images, based on established anatomical criteria(Yousry et al., 1997). As the aim of the study was to seek fortopographical rearrangements of the cortical hand representations inCH, the patients were grouped according to the location of theirCoG with respect to the ‘canonical’ location of the CoGs foundin controls [i.e. the precentral gyrus hand knob (Yousry et al.,1997)].For inter-subject comparison, the individual magnetic resonance

images were then spatially normalized using SPM99 (WellcomeDepartment of Imaging Neurosciences, London, UK), and theindividual transformation matrices were applied to the CoG of eachTMS map. The lesion and adjacent damaged structures were excludedfrom the normalization process using a cost-function maskingprocedure (Brett et al., 2001), in order to avoid excessive normali-zation of lesioned brain regions (e.g. a cyst, a scar or nearby tissueerroneously stretched and mapped as normal cerebral tissue in acanonical topography) (Vandermeeren et al., 2002b, 2003b). In eachsubject, we computed the Euclidean (vectorial) distance between theCoGs gathered for the different 1DI representations; this calculationwas performed by using the absolute value of the X-coordinates toallow comparison across hemispheres. To perform inter-group com-parisons, we calculated the Euclidean distance between the mean CoG

coordinates gathered in different subgroups for distinct musclerepresentations.

Statistics

The CoG coordinates from controls and different CH subgroups werecompared using multivariate anovas (manovas). anovas were thenused to compare separately the X-, Y- and Z-coordinates. The MEPcharacteristics and functional scores were compared with paired(within-subject) or unpaired (between-subjects) t-tests. Data areexpressed as mean ± standard deviation.

Results

Control subjects

The M1 representations of the right and left 1DI were strictlycontralateral (Table 2; Fig. 2), and the CoGs of these 22 1DIrepresentations gathered in control subjects were exclusively found inthe precentral gyrus hand knob, as reported in the literature (Yousryet al., 1997). The CoG coordinates of the dominant and non-dominant1DI representations were not significantly different (manova:F3,18 = 2.212, P = 0.122). In controls, the Euclidean distance betweenthe mean CoG coordinates of the right and left 1DIs was 6.5 mm (seeTable 2 for individual values). The contralateral MEP (cMEP)latencies and MTh were identical in both hands (paired t-tests: allP = 0.37).The digital dexterity was higher in the dominant than in the non-

dominant hand (Purdue pegboard, P = 0.012), whereas the manualdexterity was not significantly different (box and block, P = 0.352).Four control subjects exhibited some MMs (Table 2), which did notdiffer significantly between hands (P > 0.9).

Hand representation(s) in the intact hemisphere of CH patients

In all CH patients, the representation of the contralateral, non-paretic,1DI was strictly localized in the contralateral intact hemisphere

Table 2. Representations of the dominant and non-dominant first dorsal interosseous muscle (1DI) in controls

Control(sex)

Age(years)

Dominant 1DI

EU

Non-dominant 1DI

CoG coordinates cMEPs CoG coordinates cMEPsFunctional scores, dominant(non-dominant)

X Y ZLatency(ms)

MTh(%) X Y Z

Latency(ms)

MTh(%)

Purduepegboard

Box andblocks

MM(0–12)

1 (M) 8 48 )19 60 20.8 50 11.6 41 )10 58 21.1 52 16 (15.7) 65 (59) 3 (3)2 (F) 13 41 )15 64 20.5 34 8.1 45 )15 57 21.1 43 15.7 (16.3) 61 (72) 0 (0)3 (M) 10 49 )7 53 21.3 55 15.1 34 )8 54 21.1 50 13.3 (15.3) 62 (59) 2 (2)4 (F) 17 52 )27 55 21.2 34 28.4 32 )9 64 21 36 15.7 (17.7) 68 (78) 3 (3)5 (M) 12 47 )16 58 20.8 52 6.4 47 )12 53 20.5 54 14.7 (16.7) 63 (69) 0 (0)6 (F) 13 41 )15 62 20.6 36 12.8 33 )7 56 20.1 39 14.3 (15.7) 65 (69) 0 (0)7 (F) 19 43 )13 61 22.2 39 5.5 38 )11 62 22.2 29 14 (15.7) 66 (67) 0 (0)8 (M) 13 35 )12 57 22.8 34 9.6 43 )14 62 22 33 17 (16) 80 (76) 0 (0)9 (M) 16 48 )15 58 21.5 39 8.2 40 )17 58 21.3 45 15 (18) 76 (85) 0 (0)10 (F) 8 54 )20 54 19.9 62 13.5 44 )19 63 20.2 72 11.7 (13) 62 (65) 5 (4)11 (M) 10 44 )12 58 19.5 75 9.4 40 )20 61 19.6 75 15 (14.7) 68 (59) 2 (1)Mean 12.9 46 )16 58 21 46.4 – 40 )13 59 20.9 48 15.9 (14.8) 68.9 (66.9) 1.4 (1.4)SD 3.5 6 5 3 1 13.6 – 5 4 4 0.8 14.9 1.4 (1.4) 8.5 (6) 1.5 (1.7)

CoG, center of gravity; cMEP, contralateral motor evoked potential; MTh, motor threshold; MM, mirror movement (non-paretic ⁄ paretic hand) (Woods & Teuber,1978); EU Euclidean distances (mm); SD, standard deviation. In all controls (n = 11), the CoGs of both 1DI representations were located on the hand knob of theprecentral gyrus (Randall et al., 2001). X, Y and Z are in reference to the stereotactic space (Talairach & Tournoux, 1988) and Montreal Neurological Institutetemplates. X-coordinates are in absolute values to facilitate comparison between right (+X) and left (–X).

848 Y. Vandermeeren et al.

ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 29, 845–854

(Table 3; Fig. 2). In 11 patients, the CoG of the non-paretic 1DI wasfound in the precentral gyrus; in only one patient (patient no. 11), itwas found slightly shifted in the middle frontal gyrus, just anterior tothe hand knob (Table 3). Surprisingly, we found that the CoGcoordinates of the non-paretic 1DI representation differed significantlyfrom those of the control dominant 1DI (manova: F3,19 = 3.275,P = 0.044). Therefore, in all subsequent analyses, the representationof the non-paretic 1DI in CH patients was not used as a reference, andcomparisons were systematically made with respect to the dominantand non-dominant hand representations gathered in controls.

On the basis of their paretic hand representations in the intactipsilateral hemisphere, CH patients were categorized into threedifferent subgroups. The first subgroup (n = 6; Table 3) wascharacterized by a representation of the ipsilateral, paretic, 1DIlocated exactly in the hand knob of the intact M1 (Fig. 2). The CoGcoordinates of this representation did not differ from those of thedominant 1DI representation found in controls (manova:F3,13 = 1.068, P = 0.397; Euclidean distance between mean CoGcoordinates, 4.1 mm). In these patients, the CoG coordinates of the

contralateral non-paretic and ipsilateral paretic 1DI representationswere indistinguishable (manova: F1,11 = 0.077, P = 0.971; Euclideandistance between the mean CoG coordinates, 0.8 mm; see Table 3 forindividual Euclidean distances).The second subgroup (n = 2) was also characterized by a cortical

representation of the ipsilateral paretic 1DI in the intact hemispherebut it was shifted caudally (Y) and ventrally (Z) when compared withthat of the control dominant 1DI representation (Euclidean distancebetween the mean CoG coordinates, 7.5 mm). In these patients, theCoG of the non-paretic 1DI representation was found to be shiftedtowards the medial (X) and dorsal (Z) directions when compared withthe control dominant 1DI representation (Euclidean distance betweenthe mean CoG coordinates, 12.4 mm). In the intact hemisphere ofthese patients, the Euclidean distances between the CoGs of the non-paretic and ipsilateral paretic 1DI representations were 23.5 and13.4 mm, respectively.Finally, in a third subgroup (n = 4), the representation of the paretic

1DI was lacking in the intact hemisphere, as indicated by an absence ofiMEPs in the paretic hand when TMS was applied over M1. However,

Fig. 2. Anatomical projection of the mean centers of gravity in controls and congenital hemiplegia patients onto the statistical parametric mapping (SPM)normalized brain. In the damaged hemisphere, the paretic hand representation was shifted posteriorly in five of 10 patients (lower left). The non-paretic handrepresentation was shifted medio-dorsally in six of 12 patients (lower middle). The ipsilateral paretic hand representation was shifted posteriorly in two of eightpatients (lower right). HK, hand knob.

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ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 29, 845–854

even in these patients, the CoG coordinates of the non-paretic 1DIrepresentation differed from those of the dominant 1DI representationfound in controls (manova: F3,11 = 4.207, P = 0.032; Euclideandistance between the mean CoG coordinates, 12.5 mm): the CoG of thenon-paretic 1DI was shifted towards a more medial (X) and dorsal (Z)position (anovas: for X, F1,13 = 10.61, P = 0.006; for Y,F1,13 = 2.334, P = 0.151; and for Z, F1,13 = 12.021, P = 0.004).In these three subgroups of patients, the cMEP latency and MTh

recorded from the non-paretic 1DI were similar and indistinguishablefrom those found in the dominant 1DI in controls (t-tests: allP = 0.104). In the six patients with overlapping non-paretic andipsilateral paretic 1DI representations in the intact hemisphere, thecMEP and iMEP latencies were not significantly different (pairedt-test: P = 0.060), although the MTh was higher for the iMEPs (pairedt-test: P = 0.03). In the two patients with a caudal shift of theipsilateral paretic 1DI representation in the intact hemisphere, iMEPlatencies seemed to be longer and the MTh lower.

Paretic hand representation in the damaged hemisphereof CH patients

The representation of the paretic 1DI in the damaged hemisphere wasonly compared with that of the control non-dominant 1DI, because, asalready mentioned, the non-paretic 1DI representation cannot beconsidered as a valid reference.In two CH patients, TMS applied over M1 in the damaged

hemisphere failed to elicit cMEPs in the paretic 1DI. In five of the tenpatients in whom TMS elicited cMEPs in the paretic 1DI, the CoGwas located in the hand knob (Table 4; Fig. 2), at a location that did

not differ from that of the control non-dominant 1DI (manova:F3,12 = 0.634, P = 0.607; Euclidean distance between the mean CoGcoordinates, 4.5 mm). In the other five patients, the CoG of the paretic1DI was found in the postcentral gyrus of the damaged hemisphere(Table 3), shifted laterally, caudally and ventrally (anovas: for X,F1,14 = 14.16, P = 0.002; for Y, F1,14 = 20.25, P = 0.0005; and for Z,F1,14 = 9.32, P = 0.009). In these patients, the coordinates of theparetic 1DI CoG were significantly different from those of the controlnon-dominant 1DI (manova: F3,12 = 9.284, P = 0.002; Euclideandistance between the mean CoG coordinates, 15.8 mm).When compared with the cMEPs recorded from the non-dominant

1DI of controls, the latency of cMEPs from the paretic 1DI whoserepresentation was found within the precentral gyrus (n = 5) wassignificantly longer (t-test, P = 0.029), whereas those from CHpatients with postcentral CoGs (n = 5) were similar (t-test, P = 0.144).

Functional evaluation of CH patients

As far as the non-paretic hand is concerned, in the four CH patientswithout an ipsilateral paretic 1DI representation in the intact hemisphere,the dexterity scores and MMs were not statistically different from thosefor the control dominant hand (t-tests: P = 0.122). In contrast, in the sixCH patients with a overlap of the non-paretic and paretic 1DIrepresentations in intact M1, dexterity and MMs for the non-paretichand were worse than in controls (t-tests: P = 0.013). The two patientswith a postcentral paretic 1DI representation had well-preserveddexterity in their non-paretic hand and intermediate MM intensity.As expected, the dexterity of the paretic hand was worse than that of

the control non-dominant hand (t-tests: P = 0.009). When the different

Table 3. Intact hemisphere of congenital hemiplegia patients: representations of the contralateral non-paretic and ipsilateral paretic first dorsal interosseous muscle(1DI)

Anatomical locationof the ipsilateralparetic 1DI CoG andpatient number

Non-paretic 1DI*

EU

Ipsilateral paretic 1DI

CoG coordi-nates

cMEPs CoG coordinates iMEPs Functional scores, non-paretic (paretic)

X Y ZLatency(ms)

MTh(%) X Y Z

Latency(ms)

MTh(%)

Melb(%)

Purduepegboard

Box andblocks

MM(0–12)

Absent (n = 4)1 35 )15 62 18.6 60 – – – – – 99 12 (7.3) 41 (37) 4 (6)2 36 )13 66 21.7 50 – – – – – 98 16 (14) 64 (70) 0 (2)3 31 )9 66 20.3 50 – – – – – 100 17.3 (11) 72 (53) 0 (2)4 41 )8 64 21.8 48 – – – – – 100 16.7 (14.3) 61 (66) 0 (0)Mean 36 )11 65 20.6 52 – – – – – 99.3 15.5 (11.7) 59.5 (56.5) 1 (2.5)SD 4 3 2 1.5 5.4 – – – – – 1 2.4 (3.3) 13.2 (14.9) 2 (2.5)

Precentral gyrus (HK) (n = 6)5 46 )12 53 21 57 8.5 54 )9 53 20.9 86 96 13 (4) 56 (34) 3 (7)6 37 )25 66 21.1 45 10.5 36 )15 63 23.2 64 93 15.3 (6) 64 (42) 6 (7)9 35 )15 70 18.1 44 17.5 39 )31 64 20.8 56 51 13.3 (0) 64 (14) 1 (5)10 49 )19 53 20 33 5.1 46 )15 54 20.7 40 98 13.7 (5) 57 (42) 5 (6)11* 39 )5 56 17.8 60 13.4 38 )18 59 19.1 68 73 13 (1) 37 (13) 8 (4)12 42 )12 58 21.2 59 9.9 37 )4 61 21.2 59 71 1.3 (14.7) 59 (37) 7 (10)Mean 41 )15 59 19.9 49.7 – 42 )15 59 21 62.2 80.3 13.8 (2.9) 56.2 (30.3) 5 (6.5)SD 5 7 7 1.5 10.8 – 7 9 5 1.3 15.1 18.5 1 (2.4) 10 (13.4) 2.6 (2.1)

Postcentral gyrus (n = 2)7 35 )15 66 19.9 52 23.5 51 )18 49 34.6 52 84 15.3 (2.3) 65 (40) 4 (5)8 35 )15 63 20.9 43 13.4 44 )22 56 22.9 43 89 16 (3.7) 63 (33) 2 (2)Mean 35 )15 65 20.4 47.5 – 48 )20 53 28.8 47.5 86.5 15.7 (3) 64 (36.5) 3 (3.5)SD 0 0 2 0.7 6.4 – 5 3 5 8.3 6.4 3.5 0.5 (0.9) 1.4 (4.9) 1.4 (2.1)

CoG, center of gravity; HK, hand knob45; cMEP, contralateral motor evoked potential; iMEP, ipsilateral motor evoked potential; MTh, motor threshold; EU,Euclidean distances (mm); SD, standard deviation; Melb, Melbourne Assessment score37; MM, mirror movement (range 0–1236) in the non-paretic ⁄ paretic hand.*For the non-paretic hand, all CoGs were onto the HK, except for CH no. 11 (CoG located over the medial frontal gyrus, just in front of the HK).

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ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 29, 845–854

subgroups of CH patients were compared, it appeared that theanatomical location of the paretic 1DI representation in the damagedhemisphere did not influence the residual hand function and MMintensity (all t-tests: P = 0.133). However, the paretic handimpairment was less severe and MMs were less pronounced inpatients without an ipsilateral paretic 1DI representation in the intacthemisphere (n = 4) than in those with an overlap of the non-pareticand paretic 1DI representations in intact M1 (n = 6) (t-tests:P = 0.024). A similar trend was observed when comparing CHpatients without an ipsilateral paretic 1DI representation (n = 4) andthose with a postcentral paretic 1DI representation in the intacthemisphere (n = 2). The two CH patients without a representation ofthe contralateral paretic hand in the damaged hemisphere had a poorfunctional outcome and prominent MMs.

Discussion

The aim of the present study was to map, in CH patients, the corticalrepresentation(s) of their paretic hand in both the damaged and intacthemispheres and, indeed, we found some differences in the location ofthe paretic hand representation when compared with that of age-matched controls. However, surprisingly, we also found that, in CHpatients, the cortical representation of the non-paretic hand in theintact hemisphere differs from that of controls, suggesting that an earlyunilateral lesion of the CS tract led not only to a rearrangement of itsspinal projections but also to a topographical reorganization of thecortical representations of both hands.

Non-paretic hand representation in the intact hemisphere

In the intact hemisphere, we found that the location of thecontralateral non-paretic hand representation varies according to that

of the ipsilateral paretic hand in the same hemisphere. Unexpectedly,in the intact hemisphere of 50% of CH patients, we found that theCoG of the non-paretic hand representation was shifted to a moremedial and dorsal position when compared with controls, in whom itwas reliably found in the hand knob (Yousry et al., 1997). On thebasis of data published in the literature, the coordinates of therepresentation of the non-paretic hand representation in the intacthemisphere of CH patients correspond to the dorsal premotor cortex(PMd) (Table 5). This finding may reflect an increased excitability ofCS neurones originating from the PMd and projecting to thecontralateral non-paretic hand motoneurones in order to compensatefor a lack of CS projection from M1. Alternatively, this may indicatea shift of the non-paretic hand representation towards a portion ofM1 normally devoted to the representation of the proximal upperlimb and located in the depth of the central sulcus (Thickbroom &Mastaglia, 2002; Rathelot & Strick, 2006), and the use, in the presentstudy, of an algorithm projecting the CoG onto the cortical surfacemay have led to an apparent shift of the hand representation towardsthe PMd.This topographical reorganization of the non-paretic hand repre-

sentation in 50% of the CH patients included in the present study mayreflect a use-dependent plasticity related to the recruitment ofalternative CS projections. After an early brain injury, a lifelongincrease in reliance on the non-paretic hand in daily activities mayhave abnormally shaped the representation of this hand and modifiedits topographical distribution in the motor and premotor cortex.Indeed, animal studies have shown that the emergence and refinementof the cortical motor representations and CS projections during theperinatal period is experience-dependent (Martin & Lee, 1999;Chakrabarty & Martin, 2000, 2005; Eyre et al., 2001). Moreover, animbalance of transcallosal interactions between the damaged and intacthemispheres, known to occur in CH (Muller et al., 1997; Heinen et al.,1999; Shimizu et al., 2002; Murase et al., 2004), may have played a

Table 4. Damaged hemisphere of congenital hemiplegia (CH) patients: representation of the contralateral paretic first dorsal interosseous muscle (1DI)

Anatomical location ofthe contralateral paretic1DI CoG and patient number

CoG coordinates cMEPs Functional scores (paretic hand)

X Y ZLatency(ms)

MTh(%)

Melb(%)

Purduepegboard

Box andblocks

MM( ⁄ 12)

Precentral gyrus (HK) (n = 5)2 35 )9 62 21.1 55 98 14 70 2–04 52 )6 48 21.7 45 100 14.3 66 0–08 44 )16 54 20.5 55 89 3.67 33 2–29 48 )18 69 32.3 66 51 0 14 5–010 41 )22 61 28.9 64 98 5 42 6–5Mean 44 )14 59 24.9 57 87.2 7.4 45 3–1.6SD 7 7 8 5.4 8.4 20.7 6.4 23.3 2.4–2.1

Postcentral gyrus (n = 5)1 50 )22 56 18.5 66 99 7.33 37 6–43 47 )26 58 19.4 51 100 11 53 2–05 46 )19 52 22.4 78 96 4 34 7–36 48 )21 48 20 56 93 6 42 7–67 54 )28 41 20.1 53 84 2.33 40 5–4Mean 49 )23 51 20.1 60.8 94.4 6.1 41.2 5.4–3.4SD 3 4 7 1.4 11.2 6.4 3.3 7.3 2.1–2.2

Absent (n = 2)11 – – – – – 73 1 13 4–812 – – – – – 71 1.33 37 10–7Mean – – – – – 72 1.2 25 7–7.5SD – – – – – 1.4 0.2 17 4.2–07

CoG, center of gravity; HK, hand knob45; cMEP, contralateral motor evoked potential; MTh, motor threshold; Melb, Melbourne Assessment score37; MM, mirrormovement (range: 0–1236); SD, standard deviation.

Cortical hand maps in congenital hemiplegia 851

ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 29, 845–854

permissive role in the topographical reorganization of the non-paretichand representation within the intact hemisphere.It is worth noting that the subtle but consistent impairments

reported in the non-paretic hand of CH patients (Forssberg, 1999;Duque et al., 2003) may well be related to this concurrentreorganization of the non-paretic and paretic hand representations.We have previously shown that the regional glucose consumption isabnormally high in both M1s of CH patients (Vandermeeren et al.,2002b), suggesting that long-term changes may occur in the intacthemisphere as well. Moreover, the functional MRI activation patternfound during the performance of voluntary movements with thenon-paretic hand reveals an excessive lateralization towards theintact hemisphere in CH (Vandermeeren et al., 2003b). Therefore,these results suggest that neither the function nor the corticalrepresentations of the non-paretic hand in the intact hemisphere maybe considered to be normal in CH patients.At first glance, it may seem counterintuitive that the non-paretic

hand representation was found to be shifted only in CH patientslacking an ipsilateral paretic hand representation in the intacthemisphere. However, this result supports the hypothesis that, inCH patients with an ipsilateral representation of the paretic hand inthe intact hemisphere, the plastic reorganization favored the stabil-ization of a unique neuronal population projecting bilaterally to thespinal cord or spatially co-localized projections, consistent with theprominent MMs found in these patients (Carr et al., 1993; Staudtet al., 2002; Vandermeeren et al., 2002a). This may have constrainedthe reorganization within the canonical hand representation corticalzone.

Paretic hand representation in the damaged hemisphere

In 50% of our CH patients with a contralateral representation of theparetic hand in the damaged hemisphere, the paretic hand representationwas shifted over the postcentral gyrus. This topographical reorganiza-tion may reflect a recruitment of the CS projections originating from theprimary somatosensory cortex (S1). As 15–16% of the corticomoto-neuronal projections originate from S1 in adult primates (Rathelot &Strick, 2006), and as the developing CS projections undergo a dramatic

activity-dependent reconfiguration during the perinatal period (Martin& Lee, 1999; Eyre et al., 2001), it is sensible to assume that spared CSprojections originating from S1 could sprout and innervate themotoneurones lacking normal CS inputs from M1.

Ipsilateral paretic hand representation in the intact hemisphere

In sharp contrast to controls, in eight of 12 CH patients, an ipsilateralrepresentation of the paretic hand was also found in the intacthemisphere. When both ipsilateral paretic and contralateral non-paretichand representations overlapped (n = 6), prominent MMs were found,suggesting that their ipsilateral and contralateral CS projections wereeither intermingled or arose from a unique neuronal populationprojecting bilaterally to the spinal cord (Carr et al., 1993; Staudt et al.,2002; Vandermeeren et al., 2002a). In the two remaining patients, theipsilateral representation of the paretic hand was shifted caudally,possibly reflecting an activity-dependent reorganization of the CSprojections originating from S1.

Conclusion

Mapping intrinsic hand muscle representations in CH patients andcontrols by means of TMS co-registered onto 3D MRI revealed atopographical reorganization of the cortical hand representations inboth the intact and damaged hemispheres of CH patients whencompared to controls. Importantly, this topographical reorganizationinvolved not only the contralateral and ipsilateral representations ofthe paretic hand but also the representation of the non-paretic handwithin the intact hemisphere. Whether these topographical reorgani-zations form the long-term substrates for a beneficial adaptation (or atleast the best possible recovery) or reflect maladaptive processesremains to be explored. Future work combining TMS with functionalimaging or magnetoencephalography and electroencephalography(Gerloff et al., 2006; Belardinelli et al., 2007), at rest or duringmovement (Fridman et al., 2004), should give us further insights intothe functional relevance of the different patterns of motor systemreorganization after early brain injury.

Table 5. Normalized center of gravity (CoG) coordinates of controls as compared to published coordinates from transcranial magnetic stimulation (TMS) mappingand functional imaging data in normal subjects

Body part Area Reference Side (n) Task, method X* Y Z

Hand M1 Present study R (11) ⁄ L (11) 1DI, TMS mapping 46 ⁄ 40 )16 ⁄ )13 58 ⁄ 59Classen et al. (1998) R (14) ⁄ L (11) 1DI, TMS mapping 37 ⁄ 37 )13 ⁄ )12 53 ⁄ 53Picard & Strick (2001) Meta-analysis, fMRI and PET 38.2 )22.2 56.9Ehrsson et al. (2000, 2001) R (5) Precision grip, fMRI 40 ⁄ 36 )16 ⁄ )20 44 ⁄ 48Alkadhi et al. (2002) R (24) Hand opening, fMRI

Sequential finger opposition, fMRI3637

)22)20

5858

Huang et al. (2004) R (8) ⁄ L (8) Index finger lifting, MEG 34 ⁄ 34 )20 ⁄ )20 59 ⁄ 56Fink et al. (1997) R (3) Whole-hand opening, PET 37 ⁄ 38 )22 ⁄ )31 50 ⁄ 66

Hand PMd Picard & Strick (2001) Meta-analysis, fMRI and PET 37.3 )14.4 60.3Ehrsson et al. (2000, 2001) R (5) Precision grip, fMRI 36 )12 60Huang et al. (2004) R (8) ⁄ L (8) Index finger lifting, MEG 38 ⁄ 40 )9 ⁄ )6 52 ⁄ 50Fink et al. (1997) R (3) Whole-hand opening, PET 28 ⁄ 37 )1 ⁄ )14 46 ⁄ 68

Shoulder M1 Fink et al. (1997) R (3) Shoulder abduction ⁄ adduction, PET 27 ⁄ 35 )24 ⁄ )35 64 ⁄ 67Shoulder PMd Fink et al. (1997) R (3) Shoulder abduction ⁄ adduction, PET 21 ⁄ 44 )2 ⁄ )20 53 ⁄ 67

R, right; L, left; 1DI, first dorsal interosseous muscle; PET, positron emission tomography; fMRI, functional magnetic resonance imaging; MEG, magnetoen-cephalography; M1, primary motor cortex; PMd, dorsal premotor cortex. Data were gathered from right-handed healthy subjects. X, Y and Z are in reference to thestereotactic space (Montreal Neurological Institute template). *X-coordinates are in absolute values to facilitate comparison between right and left. In each column,coordinates are given for the right ⁄ left side, respectively.

852 Y. Vandermeeren et al.

ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 29, 845–854

Acknowledgements

This work was supported by grants from the Communaute Francaise deBelgique – Actions de Recherche Concertees (ARC grant 07 ⁄ 12-007), theFonds Speciaux de Recherche (FSR) of the Universite catholique de Louvain,the Fonds de la Recherche Scientifique Medicale (FRSM) and the FondationMedicale Reine Elisabeth (FMRE). J. Duque and M. Davare are research fellowat the Belgian National Funds for Scientific Research (FNRS).

Abbreviations

CH, congenital hemiplegia; cMEP, contralateral motor evoked potential; CoG,center of gravity; CS, corticospinal; 1DI, first dorsal interosseous muscle; 3D,three-dimensional; iMEP, ipsilateral motor evoked potential; M1, primarymotor cortex; MEP, motor evoked potential; MM, mirror movement; MRI,magnetic resonance imaging; MTh, motor threshold; PMd, dorsal premotorcortex; S1, primary somatosensory cortex; TMS, transcranial magneticstimulation.

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