Relationship between interhemispheric inhibition and motor cortex excitability in subacute stroke patients.

BACKGROUND: Studies of stroke patients using functional imaging and transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) demonstrated increased recruitment and abnormally decreased short interval cortical inhibition (SICI) of the M1 contralateral to the lesioned hemisphere (contralesional M1) within the first month after infarction of the M1 or its corticospinal projections. OBJECTIVE: The authors sought to identify mechanisms underlying decreased SICI of the contralesional M1. METHODS: In patients within 6 weeks of their first ever infarction of the M1 or its corticospinal projections, SICI in the M1 of the lesioned and nonlesioned hemisphere was studied using paired-pulse TMS. Interhemispheric inhibition (IHI) was measured by applying TMS to the M1 of the lesioned hemisphere and a second pulse to the homotopic M1 of the nonlesioned hemisphere and vice versa with the patient at rest. The results were compared to M1 stimulation of age-matched healthy controls. RESULTS: SICI was decreased in the M1 of lesioned and nonlesioned hemispheres regardless of cortical or subcortical infarct location. IHI was abnormally decreased from the M1 of the lesioned on nonlesioned hemisphere. In contrast, IHI was normal from the M1 of the nonlesioned on the lesioned hemisphere. Abnormal IHI and SICI were correlated in patients with cortical but not with subcortical lesions. CONCLUSIONS: In subacute stroke patients, abnormally decreased SICI of a contralesional M1 can only partially be explained by loss of IHI from the lesioned on nonlesioned hemisphere. As decreased SICI of the contralesional M1 did not result in excessive IHI from the nonlesioned on lesioned hemisphere with subsequent suppression of ipsilesional M1 excitability and all patients showed excellent recovery of motor function, decreased SICI of the contralesional M1 may represent an adaptive process supporting recovery.

Gerstmann-Sträussler-Scheinker: a new phenotype with 'curly' PrP deposits.

Gerstmann-Sträussler-Scheinker (GSS) is a hereditary prion disease typically associated with prion protein (PrP)-containing plaques. The protease-resistant, scrapie PrP (PrPSc) is represented by internal fragments, whereas the C-terminal fragments associated with the other prion diseases are generally underrepresented. Different histopathologic and PrPSc features associated with at least 13 PrP gene (PRNP) mutations have been described in GSS. We report the histopathology and PrP characteristics in a father and son carrying a mutation at PRNP codon 187 that substitutes histidine (H) with arginine (R) and is coupled with valine (V) at position 129 (H187R-129V). The PrP plaques were present in both cases but with different structure and topography and minimal spongiform degeneration. A distinctive, "curly" PrP immunostaining was prominent in one case. The protease-resistant PrPSc differed in amount in the 2 cases, possibly depending on whether plaques or the curly immunostain was present. Two protease-resistant PrP fragments of 14 kDa and 7 kDa with, in at least one case, N-terminus between residues 90-99 and 82-90, respectively, codistributed with the plaques, whereas only very small amounts of the PK-resistant PrP were present in the curly staining regions. PK-resistant PrP recovered from the plaque and curly staining regions appeared to be full length.

Post-lesional cerebral reorganisation: evidence from functional neuroimaging and transcranial magnetic stimulation.

Reorganisation of cerebral representations has been hypothesised to underlie the recovery from ischaemic brain infarction. The mechanisms can be investigated non-invasively in the human brain using functional neuroimaging and transcranial magnetic stimulation (TMS). Functional neuroimaging showed that reorganisation is a dynamic process beginning after stroke manifestation. In the acute stage, the mismatch between a large perfusion deficit and a smaller area with impaired water diffusion signifies the brain tissue that potentially enables recovery subsequent to early reperfusion as in thrombolysis. Single-pulse TMS showed that the integrity of the cortico-spinal tract system was critical for motor recovery within the first four weeks, irrespective of a concomitant affection of the somatosensory system. Follow-up studies over several months revealed that ischaemia results in atrophy of brain tissue adjacent to and of brain areas remote from the infarct lesion. In patients with hemiparetic stroke activation of premotor cortical areas in both cerebral hemispheres was found to underlie recovery of finger movements with the affected hand. Paired-pulse TMS showed regression of perilesional inhibition as well as intracortical disinhibition of the motor cortex contralateral to the infarction as mechanisms related to recovery. Training strategies can employ post-lesional brain plasticity resulting in enhanced perilesional activations and modulation of large-scale bihemispheric circuits.

Task-dependent intracortical inhibition is impaired in focal hand dystonia.

We tested whether task-dependent modulation of inhibition within the motor cortex is impaired in patients with dystonia. Paired-pulse transcranial magnetic stimulation (TMS) at an interstimulus interval of 2 msec was used to measure the effect of two different tasks on short ISI intracortical inhibition (SICI) in dystonic and normal subjects. In two experiments, SICI of the fourth dorsal interosseus (4DIO) and abductor pollicis brevis (APB) muscles were measured before and at the end of the training task. In the first experiment, subjects performed a nonselective task consisting of abducting the thumb, where the APB acted as agonist and the 4DIO as synergist. In the second experiment, the function of the 4DIO was changed as the subjects were asked to consciously inhibit this muscle while abducting the thumb (selective task). Therefore, while the APB was activated in both tasks, the 4DIO was activated in the nonselective task but was in the inhibitory surround in the selective task. We found that performance of the selective but not the nonselective task resulted in increased SICI in the 4DIO of normal but not in dystonic subjects. We conclude that task-dependent SICI is disturbed in patients with dystonia.

Reorganisation of cerebral circuits in human ischemic brain disease.

Animal experiments suggest that reorganisation of cerebral representations is the neurobiological basis of post-lesional recovery. In human ischemic brain disease recovery is a dynamic and sustained process beginning after stroke manifestation. The mechanisms underlying recovery can be investigated non-invasively in the human brain using functional neuroimaging and transcranial magnetic stimulation (TMS). In the acute stage, the mismatch area of the perfusion deficit and the impaired water diffusion as assessed by magnetic resonance imaging (MRI) shows the brain tissue that potentially can be rescued by thrombolysis or emergency carotid endarterectomy. Since spontaneous motor recovery is a function of the corticospinal tract integrity, early reperfusion of ischemic tissue is critical. In the subacute and chronic stage after stroke, recovery of motor function was shown to take place irrespective of a concomitant affection of the somatosensory system. Functional MRI with simultaneous recordings of the electromyogram provides evidence that the abnormal activation of motor and premotor cortical areas in both hemispheres related to finger movements has a large interindividual variability. As evident from TMS, recovery results from regression of perilesional inhibition and from remote intracortical disinhibition. Repetitive training, constraint induced training and motor imagery can augment recovery promoting a re-emerging activation in the affected hemisphere. Evolution of altered local perilesional and large-scale bihemispheric circuits appears to allow for post-lesional deficit compensation.

Plasticity in the human cerebral cortex: lessons from the normal brain and from stroke.

The adult brain maintains the ability for reorganization or plasticity throughout life. Results from neurophysiological and neuroanatomical experiments in animals and noninvasive neuroimaging and electrophysiological studies in humans show considerable plasticity of motor representations with use or nonuse, skill learning, or injury to the nervous system. An important concept of reorganization in the motor cortex is that of a distributed neuronal network in which multiple overlapping motor representations are functionally connected through an extensive horizontal network. By changing the strength of horizontal connections between motor neurons, functionally different neuronal assemblies can form, thereby providing a substrate to construct dynamic motor output zones. Modulation of inhibition and synaptic efficacy are mechanisms involved. Recent evidence from animal experiments indicates that these functional changes are accompanied by anatomical changes. Because plasticity of the brain plays a major role in the recovery of function after stroke, the knowledge of the principles of plasticity may help to design strategies to enhance plasticity when it is beneficial, such as after brain infarction.

Enhancing encoding of a motor memory in the primary motor cortex by cortical stimulation.

Motor training results in encoding of motor memories, a form of use-dependent plasticity. Here we tested the hypothesis that transcranial magnetic stimulation (TMS) synchronously applied to a motor cortex engaged in a motor training task could enhance this plastic process. Healthy volunteers were studied in four sessions: training consisting of performance of directionally specific voluntary thumb movements (Train alone), training with TMS delivered during the execution of the training movement in a strictly temporal relationship to the motor cortex contralateral (Train+TMS synchronous(contra)) and ipsilateral (Train+TMS synchronous(ipsi)) to the training hand, and training with TMS delivered asynchronous to the training movement to the motor cortex contralateral to the training hand (Train+TMS asynchronous(contra)). Train alone, Train+TMS synchronous(contra), and Train+TMS asynchronous(contra) but not Train+TMS synchronous(ipsi) elicited a clear motor memory. The longevity of the encoded memory was significantly enhanced by Train+TMS synchronous(contra) when compared with Train alone and Train+TMS asynchronous(contra). Therefore use-dependent encoding of a motor memory can be enhanced by synchronous Hebbian stimulation of the motor cortex that drives the training task and reduced by stimulation of the homologous ipsilateral motor cortex, a result relevant for studies of cognitive and physical rehabilitation.

Bimanual recoupling by visual cueing in callosal disconnection.

The cerebral control of bimanual movements is not completely understood. We investigated a 59-year-old, right-handed man who presented with an acute bimanual coordination deficit. Magnetic resonance imaging showed a lesion involving the entire corpus callosum, which was found on stereotactic biopsy to be an ischemic infarct. Paired-pulse transcranial magnetic stimulation indicated that the patient had a lack of interhemispheric inhibition, while intracortical inhibition in motor cortex of either side was normal. Functional magnetic resonance imaging showed activation of the left SMA, the bilateral motor cortex and anterior cerebellum during spontaneous bimanual thumb-index oppositions, which were uncoupled as evident from simultaneous electromyographic recordings. In contrast, when the bimanual thumb-index oppositions were cued by a visual stimulus, the movements of both hands were tightly correlated. This synchronized activity was accompanied by additional activations bilateral in lateral occipital cortex, dorsal premotor cortex and cerebellum. The data suggest that the visually cued movements of both hands were recoupled by action of a bihemispheric motor network.

Remote changes in cortical excitability after stroke.

Changes in the cerebral metabolism and the excitability of brain areas remote from an ischaemic brain lesion have been reported in animals and humans and implicated as a mechanism relevant to functional recovery. The aim of the present study was to determine whether changes in the inhibitory and excitatory activity in motor cortex of the non-affected hemisphere are present in stroke patients, and whether these changes are related to the extent of the patients' recovery of function. Transcranial magnetic stimulation (TMS) was used to study the first dorsal interosseus muscle (FDI) of the non-affected hand in 13 patients with good recovery of hand function after stroke, and was compared with left hemispheric stimulation in 13 healthy age-matched volunteers. In the first experiment, paired-pulse TMS with the conditioning stimulus (CS) set at 80% of the subject's motor threshold (MT) and interstimulus intervals (ISIs) of 2, 3, 10 and 15 ms was used. In the second experiment, different intensities of CS were used to study its inhibitory effect on a succeeding suprathreshold test stimulus at an ISI that was kept constant at 2 ms. In a third experiment, the rise in motor evoked potential (MEP) amplitudes with increasing stimulus intensities was measured. In two additional control experiments, the effect of left versus right hemispheric stimulation in normal volunteers and good versus poor recovery of hand function in patients after stroke on the excitability of inhibitory and excitatory activity was studied. MT, mean test MEP and recruitment curves were similar in patients and healthy volunteers. In those patients with good recovery, paired-pulse excitability was increased at ISIs of 2 and 3 ms, similar to healthy volunteers at ISIs of 10 and 15 ms. When tested with different CS intensities at an ISI of 2 ms, inhibitory activity was similar in patients and healthy subjects at small CS intensities, but faded rapidly at higher CS intensities in patients. In contrast, in patients with poor recovery, this increase in cortical excitability at higher CS intensities was not seen. The similarity of MT, mean test MEP and recruitment curves in patients and healthy volunteers indicates that the overall corticomotoneuronal excitability has not changed in patients. The similarity of the inhibitory effect at low CS intensities in the patients with good recovery and healthy subjects, and the steeper increase of conditioned MEP amplitude at higher CS intensities in the recovering patients suggest that in the patients' contralesional motor cortex the balance of excitatory and inhibitory activity was shifted towards an increase of excitatory activity in the neuronal circuits tested at ISIs of 2 and 3 ms. This shares similarities to mechanisms implicated as relevant for reorganizational processes after experimental brain injury and may be relevant for functional recovery after stroke. The absence of changes in cortical excitability in patients with poor recovery supports the relevance of our findings for recovery.

Modulation of use-dependent plasticity by d-amphetamine.

Use-dependent plasticity, thought to contribute to functional recovery after brain injury, is elicited by motor training. The purpose of this study was to determine if administration of d-amphetamine facilitates the effects of motor training on use-dependent plasticity. Healthy human volunteers underwent a training period of voluntary thumb movements under the effects of placebo or d-amphetamine in different sessions in a randomized double-blind, counterbalanced design. Previous work in a drug-naive condition showed that such training causes changes in the direction of thumb movements evoked by transcranial magnetic stimulation and in transcranial magnetic stimulation-evoked electromyographic responses. The endpoint measure of the study was the magnitude of training-induced changes in transcranial magnetic stimulation-evoked kinematic and electromyographic responses in the d-amphetamine and in the placebo conditions. Motor training resulted in increased magnitude, faster development and longer lasting duration of use-dependent plasticity under d-amphetamine compared to the placebo session. These results document a facilitatory effect of d-amphetamine on use-dependent plasticity, a possible mechanism mediating the beneficial effect of this drug on functional recovery after cortical lesions.