Neuromodulation for motor recovery in stroke patients

Programa de Doctorado en NeurocienciasStroke is a leading cause of disability worldwide. Seeking new therapeutic options is mandatory for improving existing motor rehabilitation techniques to obtain a better motor recovery. Stroke patients undergo some spontaneous degree of functional recovery; this process may occur even beyond the resolution of acute changes and could be due to the reorganization of remaining neural circuits. This reorganization falls into the concept of plasticity that could be defined as any enduring change in cortical properties. Plasticity is continuously modified by experience and learning and seems to be enhanced after brain lesions. In the last decades, plasticity of human brain after a lesion has been studied in vivo by means of non invasive brain stimulation (NIBS): neurophysiologic and biologic substrate of plasticity should provide a rational basis for tailoring specific strategies for therapeutic intervention for stroke recovery. Functional neuroimaging studies have demonstrated that recovered motor function in the paretic hand of chronic stroke patients relies predominantly on reorganized activity within motor areas of the affected hemisphere. Furthermore, changes in gamma-aminobutyric acid (GABA)-ergic activity in perilesional cortex after stroke seem to have a central role in recovery. It can be hypothesized that shaping reorganization in the adjacent intact cortex, and contralateral healthy hemisphere could facilitate functional recovery of the brain after stroke. NIBS can modulate cerebral cortex excitability not invasively and seem to be a promising tool for driving plasticity in damaged brain. The changes induced by NIBS are related to long-term changes in synaptic transmission analogue to long-term potentiation (LTP) and long-term depression (LTD) seen in the hippocampus after repeated activation. Several recent studies demonstrated that induction of LTP-like effects (by facilitatory rTMS and tDCS) in the stroke hemisphere and LTD-like effects (by inhibitory rTMS and tDCS) in healthy hemisphere can enhance the effects of motor rehabilitation after stroke, following the ¿rivalry¿ model theory. Nonetheless, the effects were limited and variable. On the other hand, it was recently demonstrated that rTMS could improve learning via a different mechanism that involves the phenomenon of ¿homeostatic¿ plasticity: a protocol capable of inducing LTD-like effects strongly facilitates motor learning while protocols inducing LTP-like effects have a less pronounced and short-lived facilitatory effect on learning. In the context of stroke this would predict that, contrary to usual practice that uses facilitatory protocols on the affected hemisphere, an inhibitory rTMS protocol (that induces LTD-like effects) over the stroke hemisphere would lead to better relearning in stroke patients through mechanisms of homeostatic metaplasticity. In sum, non-invasive brain stimulation techniques offer the opportunity to evaluate the stroke-induced change in motor cortex functionality and to modify the intra-cortical networks to promote recovery. To this aim, in a group of acute stroke patients we explored intracortical excitability of both hemisphere and looked for a possible correlation with motor recovery. Subsequently, in a different study, we tested whether the contemporary application of an excitatory neuromodulation over the affected hemisphere and an inhibitory neuromodulation over the unaffected hemisphere (following the idea of the rivalry theory) in the sub-acute phase of a stroke could enhance motor recovery. Furthermore we also tested, in a different group of patients, if the application of an inhibitory neuromodulation over the affected hemisphere, in chronic stroke patients could improve motor functionality by means of homeostatic metaplasticity. We found that the acute stroke-induced reduction of intracortical inhibition, indexed by short latency afferent inhibition (SAI), positively correlated with motor improvement at 6 months after stroke. Nevertheless, when a contemporary inhibition of the excitability of healthy hemisphere and a facilitation of the affected hemisphere were induced by means of bilateral tDCS (delivered for 40 minutes daily for 5 consecutive days) during the acute phase after a stroke, a significantly reduction of inter-hemispheric imbalance between affected and unaffected hemispheres was found without any significant change in hand motor function. At last, when an inhibitory plasticity was induced in the affected hemisphere (to achieve any metaplastic change to promote re-learning of motor function) in chronic stroke patients by means of cTBS (1 daily session for 2 weeks), a short lasting improvement in hand motor function was seen. Our studies demonstrated that NIBS, by means of repetitive TMS or tDCS, could be considered a safe procedure to apply in stroke patients both in the acute and chronic phases. On the other hand, we demonstrated that NIBS are able to change motor cortex excitability in stroke patients toward an inter-hemispheric re-balance when applied to increase stroke hemisphere excitability (or decrease unaffected hemisphere excitability) Furthermore, although larger and multi-centric studies are warranted to draw stronger conclusions, the induction of metaplasticity in the affected hemisphere by means of inhibitory protocols could be considered as a useful and promising tool to restore learning and improve motor function also years after a stroke.Universidad Pablo de Olavide de Sevilla. Departamento de Fisiología, Anatomía y Biología CelularPostprin

Fatigue in multiple sclerosis: general and perceived fatigue does not depend on corticospinal tract dysfunction.

Background: Multiple sclerosis (MS) is an autoimmune disorder of the CNS in which inflammation, demyelination, and axonal damage of the central nervous system coexist. Fatigue is one of the most disabling symptoms in MS and little is known about the neurophysiological mechanisms involved. Methods: To give more mechanistic insight of fatigue in MS, we studied a cohort of 17 MS patients and a group of 16 age-matched healthy controls. Baseline Fatigue Severity Scales and Fatigue Rating were obtained from both groups to check the level of fatigue and to perform statistical correlations with fatigue-induced neurophysiologic changes. To induce fatigue we used a handgrip task. During the fatiguing task, we evaluated fatigue state (using a dynamometer) and after the task we evaluated the Borg Rating of Perceived Exertion Scale. Transcranial magnetic stimulation and peripheral electric stimulation were used to assess corticospinal tract and peripheral system functions before and after the task. Results: Clinically significant fatigue and central motor conduction time were greater in patients than in controls, while motor cortex excitability was decreased and maximal handgrip strength reduced in patients. Interestingly, fatigue state was positively correlated to perceived fatigue in controls but not in patients. Furthermore, in the presence of similar fatigue state over time, controls showed a significant fatigue-related reduction in motor evoked potential (a putative marker of central fatigue) whereas this effect was not seen in patients. Conclusions: in MS patients the pathogenesis of fatigue seems not driven by the mechanisms directly related to corticospinal function (that characterize fatigue in controls) but seems probably due to other “central abnormalities” upstream to primary motor cortex.post-print1473 K

Direct current motor cortex stimulation for amyotrophic lateral sclerosis: a proof of principle study

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Direct Current Motor Cortex Stimulation for Amyotrophic Lateral Sclerosis: A Proof of Principle Study

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Reduction of disease progression in a patient with amyotrophic lateral sclerosis after several years of epidural motor cortex stimulation

[no abstract available

Direct Current stimulation modulates long-term potentiation (LTP) and zif 268 Expression in rat hippocampus.

Introduction: Direct current stimulation (DCS) can produce a lasting polarity-specific modulation of cortical excitability in the brain and its therapeutic potential is being investigated in several neurological diseases, including stroke, epilepsy, movement disorders and major depression. Some evidence suggests that the after-effects of DCS might be mediated by the interaction with molecular mechanisms of activity-dependent synaptic plasticity. Immediate early genes, such as c-fos and zif268, are rapidly induced following neuronal activation and may act as regulators of downstream target genes responsible for long-term functional modifications of synaptic function. Objectives: 1) To assess the effect of DCS on the induction of one of the most studied NMDA receptor-dependent forms of LTP of synaptic activity; 2) to shed light on the molecular basis of DCS after-effects. Methods: We investigated the effect of anodal and cathodal DCS on LTP induction at CA3-CA1 hippocampal synapses of rat brain slices. We also explored by immunohistochemistry the effect of DCS on the expression of c- fos and zif268 proteins in CA and DG regions of the hippocampus. Results: DCS determined a bidirectional modulation of LTP that was increased by anodal and reduced by cathodal DCS. Moreover both polarities of DCS produced a marked and consistent sub-region-specific increase in the expression of zif268 in the CA region of the hippocampus. Conclusions: Present data demonstrate that it is possible to modulate LTP induction by DCS and provide the rationale for the use of DCS in neurological diseases in order to promote adaptive and suppress maladaptive forms of brain plasticity

Use of transcranial magnetic stimulation of the brain in stroke rehabilitation

Preliminary studies suggest that stimulation of the motor cortex enhances motor recovery after stroke. Most of these studies employed transcranial magnetic stimulation of the brain and two different approaches have been evaluated. The first approach is based on the use of protocols of stimulation that increase cortical excitability, targeting the hemisphere in which the stroke occurred in order to enhance the output of the motor cortex and the response to physiotherapy. The second approach is based on the use of protocols of stimulation that suppress cortical excitability, targeting the intact hemisphere in order to counteract the imbalance due to the increased interhemispheric inhibition onto the lesioned cortex, and reducing the potential negative interference of the intact hemisphere with the function of the affected one. Cumulatively, preliminary studies suggest that transcranial magnetic stimulation might be a suitable method to combine with physiotherapy and improve recovery of useful limb function in stroke patients. However, further studies are needed to determine the best stimulation parameters and how to select patients who are likely to respond to this treatment

Motor cortex stimulation for ALS: open label extension study of a previous small trial

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Direct current stimulation modulates LTP and protein expression in rat hippocampus.

Introduction: Transcranial direct current stimulation (tDCS) can produce a lasting polarity-specific modulation of cortical excitability in the brain and it is increasingly used in experimental and clinical settings. A large amount of evidence supports the view that the after-effects of tDCS are mediated by the interaction with molecular mechanisms of activity-dependent synaptic plasticity. The level of this interaction is unknown. Some immediate early genes, such as c-fos and zif268, are rapidly induced following neuronal activation and may act as regulators of downstream target genes in coupling short-term events with long-term functional modifications of synaptic function. Objectives: (1) To assess the effect of DCS on the induction of one of the most studied NMDA receptor-dependent forms of long-term potentiation (LTP) of synaptic activity; (2) to shed light on the molecular basis of DCS after-effects. Methods: We investigated the effect of anodal and cathodal DCS, applied to rat brain slices, on LTP induction at CA3-CA1 hippocampal synapses (Shaffer collateral pathway). In the same experimental model, we also explored by immunohistochemistry the effect of DCS on the expression of c-fos and zif268 proteins in CA and DG regions of the hippocampus. Results: DCS determined a bidirectional modulation of LTP, that was increased by anodal and reduced by cathodal DCS. Moreover, we found that both polarities of DCS produce a marked and consistent increase in the expression of zif268 in the CA region of the hippocampus, while the same protocols of stimulation produce a less pronounced increase in c-fos expression, that was observed in both the CA and DG regions. Conclusions: The present data confirm the interaction of DCS with the molecular pathways underlying activity-dependent synaptic plasticity. The modulation of this processes might become of use in neurological diseases to help enhancing the adaptive and suppress the maladaptive forms of brain plasticity

Inhibitory theta burst stimulation of affected hemisphere in chronic stroke: a proof of principle, sham-controlled study

Non-invasive brain stimulation is presently being tested as a potential therapeutic intervention for stroke rehabilitation. Following a model of competitive interactions between the hemispheres, these interventions aim to increase the plasticity of stroke hemisphere by applying either excitatory protocols to the damaged hemisphere or inhibitory protocols to the non-stroke hemisphere. Here we test the safety and feasibility of using an inhibitory protocol on the stroke hemisphere to improve the response to conventional therapy via a homeostatic increase in learning capacity. Twelve chronic stroke patients received TBS to stroke hemisphere (6 patients inhibitory TBS and 6 sham TBS) followed by physical therapy daily for 10 working days. Patients and therapists were blinded to the type of TBS. Action Research Arm Test (ARAT), Nine-Hole Pegboard Test (NHPT) and Jebsen\u2013Taylor Test (JTT) were the primary outcome measures, grip and pinch-grip dynamometry were the secondary outcome measures. All patients improved ARAT and JTT scores for up to 3 months post-treatment. ARAT scores improved significantly in both real and sham groups, but only patients receiving real TBS significantly improved on the JTT: 3 months post-treatment mean execution time was reduced compared to baseline by 141 s for real group and by 65 s for the sham group. This small exploratory study suggests that ipsilesional inhibitory TBS is safe and that it has the potential to be used in a larger trial to enhance the gain from a late rehabilitation program in chronic stroke patients