Non-Invasive Brain Stimulation to Enhance Post-Stroke Recovery

My God., the big words used here are incomprehensible. Was that the point?


http://journal.frontiersin.org/article/10.3389/fncir.2016.00056/full?
Nathalie Kubis^1,2*

• ¹Service de Physiologie Clinique, AP-HP, Hôpital Lariboisière, Paris, France
• ²Université Paris Diderot, Sorbonne Paris Cité, CART, INSERM U965, Paris, France

Brain plasticity after stroke remains poorly understood. Patients may improve spontaneously within the first 3 months and then more slowly in the coming year. The first day, decreased edema and reperfusion of the ischemic penumbra may possibly account for these phenomena, but the improvement during the next weeks suggests plasticity phenomena and cortical reorganization of the brain ischemic areas and of more remote areas. Indeed, the injured ischemic motor cortex has a reduced cortical excitability at the acute phase and a suspension of the topographic representation of affected muscles, whereas the contralateral motor cortex has an increased excitability and an enlarged somatomotor representation; furthermore, contralateral cortex exerts a transcallosal interhemispheric inhibition on the ischemic cortex. This results from the imbalance of the physiological reciprocal interhemispheric inhibition of each hemisphere on the other, contributing to worsening of neurological deficit. Cortical excitability is measurable through transcranial magnetic stimulation (TMS) and prognosis has been established according to the presence of motor evoked potentials (MEP) at the acute phase of stroke, which is predictive of better recovery. Conversely, the lack of response to early stimulation is associated with a poor functional outcome. Non-invasive stimulation techniques such as repetitive TMS (rTMS) or transcranial direct current stimulation (tDCS) have the potential to modulate brain cortical excitability with long lasting effects. In the setting of cerebrovascular disease, around 1000 stroke subjects have been included in placebo-controlled trials so far, most often with an objective of promoting motor recovery of the upper limb. High frequency repetitive stimulation (>3 Hz) rTMS, aiming to increase excitability of the ischemic cortex, or low frequency repetitive stimulation (≤1 Hz), aiming to reduce excitability of the contralateral homonymous cortex, or combined therapies, have shown various effects on the functional disability score and neurological scales of treated patients and on the duration of the treatment. We review here the patients’ characteristics and parameters of stimulation that could predict a good response, as well as safety issues. At last, we review what we have learnt from experimental studies and discuss potential directions to conduct future studies.

Introduction

Stroke is the second leading cause of death, the second leading cause of dementia (Joray et al., 2009; Ovbiagele and Nguyen-Huynh, 2011; Roger et al., 2011) and the first cause of morbidity in industrialized countries. Reperfusion therapies such as thrombolysis using recombinant tissue plasminogen activator (Hacke et al., 2008), and more recently thrombectomy with a stent retriever, can rescue brain tissue of the penumbra (a rim of mild to moderate ischemic tissue around the core of the infarct), and improves the final neurological outcome (Fransen et al., 2014). Yet, it remains accessible to less than 5–10% of the population since the therapeutic window is restricted to 6 h (Wahlgren et al., 2016). In addition, the development of neuroprotective pharmacological treatments to limit the neuronal loss induced by ischemia proved disappointing when translating from experimental studies to clinical studies (Klein et al., 1999). The dogma, according to which, any brain injury is irreversible in adults and cannot be repaired has long prevailed both in medical schools and at the bedside. Yet, after a stroke, patients can improve spontaneously within the first 3 months (Maulden et al., 2005) and then more slowly in the following year. The first day, decreased oedema and partial reperfusion of the ischemic penumbra may possibly explain these phenomena, but the improvement of neurological deficit in the following weeks suggests plasticity phenomena and brain cortical reorganization (Chen et al., 2002). Restoring arm and hand skill after a stroke remains challenging, even though stroke rehabilitation programs have proven partial efficacy. Due to the worldwide increasing number of strokes predicted for 2030 (Béjot et al., 2016), and to the restricted number of centers able to provide reperfusion therapies in a limited therapeutic window, there is a need to develop new strategies that aim to enhance spontaneous cerebral plasticity. The complication comes from that, in stroke, post-lesional brain plasticity may be beneficial or “adaptive” or, detrimental or “maladaptive” and thus hamper neurological recovery.

The aim of this study is not to extensively review all the clinical studies published so far in the literature (for very complete reviews refer to Simonetta-Moreau (2014), dedicated to stroke, or Lefaucheur et al. (2014), about Non-Invasive Brain Stimulation [NIBS] in general neurology). The purpose of this review is rather to propose mechanisms from clinical and experimental data, and how up-coming clinical trials could be designed to better address these issues.

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