Reorganization in congenital hemiparesis acquired at different gestational ages

It is well established that the reorganizational potential of the developing human brain is superior to that of the adult brain, but whether age-dependent differences exist already in the prenatal and perinatal period is not known. We have studied sensorimotor reorganization in 34 patients with congenital hemiparesis (age range, 5-27 years), using transcranial magnetic stimulation and functional magnetic resonance imaging during simple hand movements. Underlying pathologies were brain malformations (first and second trimester lesions; n = 10), periventricular brain lesions (early third trimester lesions; n = 12), and middle cerebral artery infarctions (late third trimester lesions; n = 12). Of this cohort, eight patients with malformations and all patients with periventricular lesions have been published previously. In all three groups of pathologies, transcranial magnetic stimulation identified patients in whom the paretic hand was controlled via ipsilateral corticospinal projections from the contralesional hemisphere (n = 16). In these patients, the motor dysfunction of the paretic hand correlated significantly with the timing period of the underlying brain lesion. This demonstrates that the efficacy of reorganization with ipsilateral corticospinal tracts indeed decreases during pregnancy.     

Reduced integrity of sensorimotor projections traversing the posterior limb of the internal capsule in children with congenital hemiparesis

There is reduced integrity of corticospinal projections that traverse the posterior limb of the internal capsule (PLIC) in children with unilateral cerebral palsy (CP). It remains unclear whether there are changes in integrity of other projections traversing the PLIC. Forty children with congenital hemiparesis and 15 typically developing children underwent structural and diffusion-weighted MRI. All children with congenital hemiparesis showed lesions to the periventricular white matter. Structural images were parcellated into 34 cortical regions per hemisphere and posterior limb of the internal capsule was identified. PLIC connections to each cortical region were extracted using probabilistic tractography. Differences between hemispheres for each cortical projection (asymmetry index (AI)) and tract microstructure (fractional anisotropy (FA), mean diffusivity (MD)) were assessed. The results showed that 17 children (42.5%) with congenital hemiparesis showed bilateral lesions on structural MRI. Projections to the primary motor cortex (precentral gyrus and paracentral lobule) showed greater asymmetry in unilateral CP group compared to typically developing children and indicate reduced projections on the hemisphere contralateral to the impaired limb (i.e., contralateral hemisphere). Reduced FA and increased MD were also observed for connections with the primary motor cortex, primary sensory cortex (postcentral gyrus) and precuneus on the contralateral hemisphere in children with congenital hemiparesis. Similar changes were observed between children with unilateral and bilateral lesions on structural MRI. Notably, microstructural changes were associated with deficits in both sensory and motor function. The findings further unravel the underlying neuroanatomical correlates of sensorimotor deficits in children with congenital hemiparesis.     

Corticospinal tract development and its plasticity after perinatal injury

The final pattern of the origin and termination of the corticospinal tract is shaped during development by the balance between projection and withdrawal of axons. In animals, unilateral inhibition of the sensorimotor cortex during development results in a sparse contralateral projection from this cortex and retention of a greater number of ipsilateral projections from the more active cortex. Similarly in subjects with hemiplegic cerebral palsy if transcranial magnetic stimulation (TMS) of the damaged motor cortex fails to evoke responses in the paretic upper limb, TMS of the undamaged ipsilateral motor cortex evokes abnormally large and short-onset responses. Rather than representing a “reparative plasticity in response to injury”, this review presents evidence that increased ipsilateral projections from the non-infarcted motor cortex arise from perturbation of ongoing developmental processes, whereby reduced activity in the damaged hemipshere, leads to increased withdrawal of its surviving contralateral corticospinal projections because their terminals have been displaced by the more active ipsilateral projections of the undamaged hemisphere and thereby adding to the degree of long-term motor impairment.     

A paradox: after stroke,the non‐lesioned lower limb motor cortex may be maladaptive

What are the neuroplastic mechanisms that allow some stroke patients to regain high‐quality control of their paretic leg, when others do not? One theory implicates ipsilateral corticospinal pathways projecting from the non‐lesioned hemisphere. We devised a new transcranial magnetic stimulation protocol to identify ipsilateral corticospinal tract conductivity from the non‐lesioned hemisphere to the paretic limb in chronic stroke patients. We also assessed corticospinal tract degeneration by diffusion tensor imaging, and used an ankle tracking task to assess lower limb motor control. We found greater tracking error during antiphase bilateral ankle movement for patients with strong conductivity from the non‐lesioned hemisphere to the paretic ankle than for those with weak or no conductivity. These findings suggest that, instead of assisting motor control, contributions to lower limb motor control from the non‐lesioned hemisphere of some stroke survivors may be maladaptive.     

Is one motor cortex enough for two hands?

We report on a patient with mirror movements sustained by a mono‐hemispheric fast control of bilateral hand muscles and normal hand function. Transcranial magnetic stimulation of the right motor cortex evoked contractions of muscles in both hands while no responses were observed from the left hemisphere. Somatosensory‐evoked potentials, functional magnetic resonance, and diffusion tractography showed evidence of sensorimotor dissociation and asymmetry of corticospinal projections, suggestive of reorganization after early unilateral left brain lesion. This is the first evidence that, in certain rare conditions, good hand function is possible with ipsilateral corticospinal reorganization, supporting the role of unexplored mechanisms of motor recovery.     

Interhemispheric reorganization of motor hand function to the primary motor cortex predicted with functional magnetic resonance imaging and transcranial magnetic stimulation

The objective of this study was presurgical assessment of reorganization of motor hand function in an 11-year-old girl with intractable epilepsy and a right-sided hemiplegia resulting from an extensive perinatal left hemispheric stroke. Prior to a left functional hemispherectomy, functional magnetic resonance imaging (MRI) showed that both nonparetic and paretic motor hand function predominantly activated the right primary motor cortex, whereas no activation was found in the left hemisphere. Transcranial magnetic stimulation of the right central area yielded responses in both the nonparetic and the paretic hand, whereas no responses were obtained after stimulation of the affected hemisphere. Both techniques indicated that motor function was mediated by corticospinal fibers originating from the undamaged (primary) motor cortex and predicted no further loss of motor hand function after surgery. Indeed, subsequent functional hemispherectomy induced no new sensorimotor deficits. Functional MRI was repeated 22 months after surgery and matched preoperative sensorimotor functional MRI findings, confirming reorganization of the primary motor cortex. No additional reorganization was introduced by surgery.     

The recovery of forelimb-placing behavior in rats with neonatal unilateral cortical damage involves the remaining hemisphere

Following unilateral lesions of the somatic sensorimotor cortex (SMC) in neonatal, but not adult, rats, an aberrant ipsilateral corticospinal projection originates from the undamaged hemisphere (Hicks and D'Amato, 1970; Leong and Lund, 1973; Castro, 1975). We have evaluated the contribution of the hemisphere contralateral to a unilateral lesion of the SMC in the recovery of tactile forelimb-placing behavior. Neither adult-lesioned or neonatally lesioned animals show evidence for placing deficits with either forelimb when tested 30 or 42 d after the lesion. However, in adult-lesioned animals, a subsequent lesion of the undamaged SMC on postlesion day 42 produces placing deficits only with the forelimb contralateral to the second lesion, while such a second lesion in the neonatally lesioned rats results in placing deficits with both forelimbs. Anatomical observations in the animals used for behavioral analyses confirm previous reports of a substantial ipsilateral corticospinal projection in rats with unilateral SMC damage as neonates and demonstrate that many of these aberrant fibers recross the midline within the spinal cord to arborize extensively within the ipsilateral spinal gray. These findings indicate that, following unilateral SMC lesions in neonates, the contralateral hemisphere mediates some aspects of the recovery of forelimb placing. The aberrant ipsilateral corticospinal projection may provide the anatomical substrate through which the cortex effects this recovery.     

Evolution of cortical activation during recovery from corticospinal tract infarction

BACKGROUND AND PURPOSE: Recovery from hemiparesis due to corticospinal tract infarction is well documented, but the mechanism of recovery is unknown. Functional MRI (fMRI) provides a means of identifying focal brain activity related to movement of a paretic hand. Although prior studies have suggested that supplementary motor regions in the ipsilesional and contralesional hemisphere play a role in recovery, little is known about the time course of cortical activation in these regions as recovery proceeds. METHODS: Eight patients with first-ever corticospinal tract lacunes causing hemiparesis had serial fMRIs within the first few days after stroke and at 3 to 6 months. Six healthy subjects were used as controls. Statistically significant voxels during a finger-thumb opposition task were identified with an automated image processing program. An index of ipsilateral versus contralateral activity was used to compare relative contributions of the 2 hemispheres to motor function in the acute and chronic phases after stroke. RESULTS: Controls showed expected activation in the contralateral sensorimotor cortex (SMC), premotor, and supplementary motor areas. Stroke patients differed from control patients in showing greater activation in the ipsilateral SMC, ipsilateral posterior parietal, and bilateral prefrontal regions. Compared with the nonparetic hand, the ratio of contralateral to ipsilateral SMC activity during movement of the paretic hand increased significantly over time as the paretic hand regained function. CONCLUSIONS: The evolution of activation in the SMC from early contralesional activity to late ipsilesional activity suggests that a dynamic bihemispheric reorganization of motor networks occurs during recovery from hemiparesis.     

Functional relevance of abnormal fMRI activation pattern after unilateral schizencephaly

Brain plasticity was investigated in a child with a hemiplegia due to unilateral schizencephaly involving the sensorimotor cortex. This focal lesion led to a dramatic functional reorganization of the undamaged hemisphere, as evidenced by the unusual pattern of fMRI activation during paretic finger movements. The functional relevance of the activation in the undamaged motor cortex was supported by the finding that TMS of this area yielded a response in the paretic hand, indicating that it controls both hands. However, this reorganization was not restricted to the primary motor cortex, but also concerned other structures involved in the control of movements, as shown by the activation of contralesional SMA and thalamus. In contrast, the fMRI activation in the damaged sensorimotor cortex during paretic hand movements appears functionally irrelevant.     

Cortical Reorganization Allows for Motor Recovery after Crossed Cerebrocerebellar Atrophy

The authors report the case of a 33-year-old woman who exhibited, at the age of 17, a left-sided hemiplegia, which was followed by good motor recovery, though with a permanent deficit in fine finger movements. She had a widespread loss of neural tissue in the right hemisphere (crossed cerebrocerebellar atrophy), including (1) marked atrophy and thinning of the precentral and postcentral gyri; (2) widespread deep white matter destruction, including the corticospinal tract; and (3) crossed cerebellar atrophy. Except over the supplementary motor area (SMA), transcranial magnetic stimulation did not elicit motor evoked potentials in the affected hand. Nevertheless, during opening and closing of the affected hand, functional magnetic resonance imaging showed an activation of the lesioned primary sensorimotor cortex (SMC), as well as of the intact SMA and the parietal areas, but not of the ipsilateral motor areas. The authors speculate that recovery was achieved by a motor command generated in the SMC and the parietal cortex, passing through corticospinal axons originating in the SMA.     

Reorganization of cortical hand representation in congenital hemiplegia

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 corticospinal projections occurring in CH patients is also accompanied by a topographical rearrangement of the hand representations in the primary motor cortex (M1) remains unclear. To address this issue, we mapped, for both hands, the representation of the first dorsal interosseous 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 the damaged hemisphere of CH patients, the representation of the paretic 1DI was either found in the hand knob of M1 ( n  =   5), shifted caudally ( n  =   5), or missing ( n  =   2). In the intact hemisphere of six CH patients, an additional, ipsilateral, representation of the paretic 1DI 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 two subgroups of patients, the representation of the contralateral non-paretic 1DI was found in a more medio-dorsal position than in controls. The present study demonstrates that, besides the well-known reorganization of the corticospinal projections, early brain injuries may also lead to a topographical rearrangement of the representations of both the paretic and non-paretic hands in M1.     

Reorganisation of the sensorimotor cortex after early focal brain lesion: a functional MRI study in monozygotic twins

Sensorimotor cortical reorganization after early brain lesions was studied by means of fMRI in two pairs of monozygotic twins, in each of which one member had a focal brain injury. This offered a unique opportunity to reduce the wide intersubject variability of the controls often found in similar studies. Activation images were acquired during a motor task (sequential opposition finger movements) and a sensory task (passive brushing of palm and fingers). During the tasks with the recovered hand, constant findings in the lesioned subjects were the activation of the undamaged areas adjacent to lesion site and the activation of the ipsilateral sensorimotor cortex. Bilateral activation of the primary sensorimotor cortex was never observed in the healthy co-twin controls.     

Predicting hand function after hemispherotomy: TMS versus fMRI in hemispheric polymicrogyria

Patients with hemispheric malformations of cortical development (such as polymicrogyria) often develop medically intractable epilepsies for which hemispherotomy can be an excellent treatment option. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) are noninvasive methods used to evaluate the sensorimotor system in adults and children before surgery. Preoperative results of both methods and their predictive values regarding hand function after hemispherotomy are described in four boys with hemispheric polymicrogyria, pharmacoresistent epilepsy, and hemiparesis with preserved grasp function of the paretic hand. TMS showing ipsilateral projections from the contralesional hemisphere but no evidence of crossed corticospinal projections from the lesioned hemisphere correctly predicted preserved postoperative grasp function in all four patients. In contrast, the interpretation of sensorimotor fMRI in patients with congenital hemiparesis is more difficult, as ipsilesional activation can occur as it was the case in three of four patients in the current study. This activation might represent contralaterally preserved primary somatosensory (S1) and not primary motor (M1) representation and is apparently not necessary for the paretic hand to still perform grasp movements.     

Reorganization of the hand somatosensory cortex following perinatal unilateral brain injury

Functional magnetic resonance imaging was used to map the hand somatosensory cortices of nine hemiparetic young adult patients with perinatal unilateral brain injury in the sensorimotor area and five normal subjects. Stimulation of the paretic hand by periodic manual squeezing produced activation in the contralateral hemisphere of three patients and in the ipsilateral hemisphere of three other patients. Paretic hand stimulation produced no activation in either hemisphere of the remaining three patients. Therefore, one-third of the patients demonstrated functional "plasticity" of the brain in the form of inter-hemispheric relocation of the hand somatosensory function. The volume and pattern of activation for both hands was altered for those patients that showed evidence of cortical reorganization to the opposite hemisphere. This differs from the hand motor system, which exhibited inter-hemispheric reorganization in a higher proportion of a related group of hemiparetic subjects.     

Coherent corticomuscular oscillations originate from primary motor cortex: evidence from patients with early brain lesions

Coherent oscillations of neurons in the primary motor cortex (M1) have been shown to be involved in the corticospinal control of muscle activity. This interaction between M1 and muscle can be measured by the analysis of corticomuscular coherence in the beta-frequency range (beta-CMCoh; 14-30 Hz). Largely based on magnetoencephalographic (MEG) source-modeling data, it is widely assumed that beta-CMCoh reflects direct coupling between M1 and muscle. Deafferentation is capable of modulating beta-CMCoh, however, and therefore the influence of reafferent somatosensory signaling and corresponding neuronal activity in the somatosensory cortex (S1) has been unclear. We present transcranial magnetic stimulation (TMS) and MEG data from three adult patients suffering from congenital hemiparesis due to pre- and perinatally acquired lesions of the pyramidal tract. In these patients, interhemispheric reorganization had resulted in relocation of M1 to the contralesional hemisphere, ipsilateral to the paretic hand, whereas S1 had remained in the lesioned hemisphere. This topographic dichotomy allowed for an unequivocal topographic differentiation of M1 and S1 with MEG (which is not possible if M1 and S1 are directly adjacent within one hemisphere). In all patients, beta-CMCoh originated from the contralesional M1, in accordance with the TMS-evoked motor responses, and in contrast to the somatosensory evoked fields (SEFs) for which the sources (N20m) were localized in S1 of the lesioned hemisphere. These data provide direct evidence for the concept that beta-CMCoh reflects the motorcortical efferent drive from M1 to the spinal motoneuron pool and muscle. No evidence was found for a relevant contribution of neuronal activity in S1 to beta-CMCoh.     

Somatosensory system in two types of motor reorganization in congenital hemiparesis: topography and function

This study investigates the (re-)organization of somatosensory functions following early brain lesions. Using functional magnetic resonance imaging (fMRI), passive hand movement was studied. Transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) were used as complementary methods. fMRI data was analyzed on the first level with regard to topographical variability; second-level group effects as well as the overall integrity of the somatosensory circuitry were also assessed. Subjects with unilateral brain lesions occurring in the third trimester of pregnancy or perinatally with different types of motor reorganization were included: patients with regular, contralateral motor organization following middle cerebral artery strokes (CONTRA(MCA), n = 6) and patients with reorganized, ipsilateral motor functions due to periventricular lesions (IPSI(PL), n = 8). Motor impairment was similar, but sensory impairment was more pronounced in the CONTRA(MCA) group. Using fMRI and MEG, both groups showed a normal pattern with a contralateral somatosensory representation, despite the transhemispherically reorganized primary motor cortex in the IPSI(PL) group, as verified by TMS. Activation topography for the paretic hands was more variable than for the nonparetic hand in both groups. The cortico-cerebellar circuitry was well-preserved in almost all subjects. We conclude that in both models of motor reorganization, no interhemispheric reorganization of somatosensory functions occurred. Also, no relevant intrahemispheric reorganization was observed apart from a higher topographical variability of fMRI activations. This preserved pattern of somatosensory organization argues in favor of a differential lesion effect on motor and somatosensory functions and demonstrates a limited compensatory potential for the latter.     

Motor cortex localization using functional MRI and transcranial magnetic stimulation.

OBJECTIVE: Congenital brain lesions producing focal seizures may be accompanied by reorganization of the areas responsible for motor and sensory functions within the brain due to a phenomenon that has been termed "neuronal plasticity." This can be studied using functional MRI (fMRI) and transcranial magnetic stimulation (TMS). Using either method, the motor cortex can be localized noninvasively, but to date there have been few studies correlating the level of agreement between the two techniques. METHODS: We used fMRI and TMS to localize the motor cortex in a young woman with intractable focal seizures, congenital left arm weakness, and a dysplastic right hemisphere on MRI. RESULTS: There was excellent agreement in the localization of motor representation for each hand. Both were predominantly located in the left hemisphere. fMRI also showed an area of posterior activation in the right hemisphere, but there was no evidence of descending corticospinal projections from this site using TMS, direct cortical stimulation, and Wada testing. CONCLUSIONS: Functional MRI (fMRI) and transcranial magnetic stimulation (TMS) were successfully used to localize cortical motor function before epilepsy surgery. Each technique demonstrated migration of motor function for the left hand to the left motor cortex. After resection of the dysplastic right precentral gyrus there was no permanent increase in weakness or disability. The two techniques are complementary; fMRI indicates all cortical areas activated by the motor task, whereas TMS identifies only those areas giving rise to corticospinal projections.     

Contribution of the ipsilateral motor cortex to recovery after chronic stroke

It has been proposed that the intact (ipsilateral) motor cortex play a significant role mediating recovery of motor function in the paretic hand of chronic stroke patients, but this hypothesis has not been tested experimentally. Here, we evaluated the effects of transcranial magnetic stimulation (TMS) on motor performance of the paretic hand of chronic stroke patients and healthy controls. We hypothesized that, if activity in the intact hemisphere contributes to functional recovery, TMS should result in abnormal motor behavior in the paretic hand. We found that stimulation of the intact hemisphere resulted in delayed simple reaction times (RTs) in the contralateral healthy but not in the ipsilateral paretic hand, whereas stimulation of the lesioned hemisphere led to a marked delay in RT in the contralateral paretic hand but not in the ipsilateral healthy hand. RT delays in the paretic hand correlated well with functional recovery. Finger tapping in the paretic hand was affected by TMS of the lesioned but not the intact hemisphere. These results are consistent with the idea that recovered motor function in the paretic hand of chronic stroke patients relies predominantly on reorganized activity within motor areas of the affected hemisphere.     

Evidence of activity-dependent withdrawal of corticospinal projections during human development.

OBJECTIVE: To characterize the development of ipsilateral corticospinal projections from birth and compare to 1) development of contralateral projections in the same subjects and 2) ipsilateral corticospinal projections in subjects with unilateral lesions of the corticospinal system acquired perinatally or in adulthood. METHOD: Transcranial magnetic stimulation excited the motor cortex, and responses were recorded bilaterally in pectoralis major, biceps brachii, and the first dorsal interosseus muscles. Subjects studied included 9 neonates recruited at birth, studied longitudinally for 2 years; 85 healthy subjects aged from birth to adulthood; 10 subjects with hemiplegic cerebral palsy; and 8 with hemiplegia after stroke. RESULTS: In neonates, ipsilateral responses had significantly shorter onsets than contralateral responses but similar thresholds and amplitudes. Thresholds within both pathways increased in the first 3 months. Differential development was present from 3 months so that by 18 months ipsilateral responses were significantly smaller and had significantly higher thresholds and longer onset latencies than contralateral responses. A similar pattern of smaller and later ipsilateral responses was observed after transcranial magnetic stimulation of the intact cortex in subjects with stroke. In contrast, subjects with hemiplegic cerebral palsy had ipsilateral responses with onsets, thresholds and amplitudes similar to those of contralateral responses. Significant branching of contralateral corticospinal axons from the intact motor cortex was excluded by cross-correlation analysis. CONCLUSIONS: These data, together with previously published anatomic and radiologic studies, are consistent with activity-dependent corticospinal axonal withdrawal during development and maintenance of increased corticomotoneuronal projections from the intact hemisphere after unilateral perinatal lesions.     

Compensatory sprouting and impulse rerouting after unilateral pyramidal tract lesion in neonatal rats.

After lesions of the developing mammalian CNS, structural plasticity and functional recovery are much more pronounced than in the mature CNS. We investigated the anatomical reorganization of the corticofugal projections rostral to a unilateral lesion of the corticospinal tract at the level of the medullary pyramid (pyramidotomy) and the contribution of this reorganization and other descending systems to functional recovery. Two-day-old (P2) and adult rats underwent a unilateral pyramidotomy. Three months later the corticofugal projections to the red nucleus and the pons were analyzed; a relatively large number of corticorubral and corticopontine fibers from the lesioned side had crossed the midline and established an additional contralateral innervation of the red nucleus and the pons. Such anatomical changes were not seen after adult lesions. Intracortical microstimulation of the primary motor cortex with EMG recordings of the elbow flexor muscles were used to investigate possible new functional connections from the motor cortex of the pyramidotomy side to the periphery. In rats lesioned as adults, stimulation of the motor cortex ipsilateral to the pyramidotomy never elicited EMG activity. In contrast, in P2 lesioned rats bilateral forelimb EMGs were found. EMG latencies were comparable for the ipsilateral and contralateral responses but were significantly longer than in unlesioned animals. Transient inactivation of both red nuclei with the GABA receptor agonist muscimol led to a complete loss of these bilateral movements. Movements and EMGs reappeared after wash-out of the drug. These results suggest an important role of the red nucleus in the reconnection of the cortex to the periphery after pyramidotomy.