Cathrin M. Bütefisch

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.

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.

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.

Bimanual recoupling by visual cueing in callosal disconnection.

Abstract 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.

Functional activation within the PI-DWI mismatch region in recovery from ischemic stroke: preliminary observations.

In this study, we sought to investigate if brain tissue affected by ischemia can accommodate areas of activation related to restoration of brain function following ischemic stroke. In two patients perfusion imaging (PI) and diffusion weighted imaging (DWI) obtained in the acute phase after stroke was coregistered with BOLD imaging of brain functions acquired when profound recovery had occurred. Both patients suffered from thrombembolic brain infarction due to dissection of the internal carotid artery (ICA) characterized by a severe PI-DWI mismatch in the acute stage of stroke. Following ICA recanalization and clinical recovery BOLD imaging showed task-specific activation adjacent to the infarct lesion within the former PI-DWI mismatch area. The data in these two stroke patients provide evidence that brain tissue at risk of infarction as shown by the PI-DWI mismatch can survive and, thereby, constitute the major site underlying post-ischemic recovery.

Reorganization of cerebral circuits in human brain lesion

Recovery after focal brain lesions is supposed to be mediated by cerebral reorganization. Stroke is a powerful model to study these processes in the human brain, since middle cerebral artery infarction is a common neurological disease with a clearly defined onset of a lateralized sensorimotor deficit syndrome. Brain tumours constitute a further model differing from stroke by their slow lesion dynamics. Evidence from functional neuroimaging and transcranial magnetic stimulation will be presented showing that recovery of hand function is related to reorganization of local perilesional and large-scale circuits involving the contralesional hemisphere.

Chapter 25 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.

Remote cortical excitability changes after stroke

Changes in the cerebral metabolism and in the excitability of brain areas remote from a lesion have been reported in animals and humans and implicated as mechanism relevant for functional recovery (termed diaschisis)l,2. The question whether in stroke patients the activity of excitatory and inhibitory interneurons in the motor cortex contralateral to the affected hemisphere is disturbed is unclear at present. The aim of the study was to determine the thresholds of inhibitory and excitatory activity of intemeurons in motor cortex of the non-affected hemisphere in stroke patients and compare these to the threshold of normal volunteers.

Chapter 37 Neural correlates of cerebral plasticity after brain infarction

Publisher Summary Plasticity is the process of use-dependent enhancement of synaptic efficacy and shaping of connectivity, underlying the physiological development, learning, and post-lesional recovery. Brain diseases, such as ischemic brain infarction, impair brain function by direct interference, with key node areas in the functional brain networks, but allow for deficit compensation by brain plasticity. Functional neuroimaging methods, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRl), provide the means to study these mechanisms of reorganization in the living human brain. These methods reveal that not only the infantile brain but also the brains of adults and even aged people could reorganize in response to imposed demands. While plasticity can be maladaptive and may give rise to neurological disorders, such as dystonia, epilepsy, and pain, it is usually beneficial, occurring in relation to memory and learning, and to deficit compensation in neurological diseases, such as stroke. In acute stroke, a number of processes that become sequentially operative determine postischemic recovery. The events include rapid reperfusion because of acute therapeutic interventions, spontaneous regression of perilesionaI and remote dysfunction in the subacute phase after infarction, and reorganization of large-scale networks in both cerebral hemispheres, extending into the chronic stage of the disease. In acute brain infarction, the location and extent of impaired brain tissue perfusion and of the changes of tissue diffusion are of paramount importance for functional recovery, because they determine the development of the manifest stroke lesion and, thus, to what degree the different mechanisms of cerebral reorganization may come into play, subsequently.