Cerebellar deep brain stimulation to enhance chronic post-stroke rehabilitation

项目总结/摘要 中风是工业化世界中流行病学比例的疾病，并且是长期- 残疾术语一半的中风患者患有长期的运动缺陷，严重到足以致残， 当代康复的努力，这强调了需要新的，神经恢复疗法， 促进中风后运动恢复。我们之前提出过齿状核脑深部电刺激 （DN-DBS）作为一种治疗方法，以促进慢性上肢轻偏瘫患者的运动恢复， 缺血性中风我们的工作假设是，低频DN-DBS增强兴奋性 齿状丘脑皮层输出，从而增强大脑皮层的兴奋性，促进功能性 在病灶周围皮质区的重组和进一步支持运动恢复。使用啮齿动物模型， 缺血，我们已经证明慢性刺激可以促进运动恢复， 改善伴随着兴奋性的持续增加，运动神经的重组， 表达，以及长时程增强和突触发生标记物的表达增加。 大脑皮层的病灶周围区域。本研究中提出的实验将有助于确保 成功的人类翻译这种有前途的新的治疗，同时也系统地检查其 机械基础。具体地，所提出的实验被设计为确定：a）如何 缺血核心的解剖学范围和分布影响治疗效果和 益处; B）运动相关的同步振荡活动如何穿过小脑深部核团， 脑卒中后和DN-DBS治疗后的新皮层变化，以及该活动是否可以作为 配对关联（闭环）治疗范例中的控制信号; c）梗塞时的年龄是否 负面影响治疗效果;和d）DN的解剖学和功能机制。 DBS增强运动康复。这些研究将由一个调查小组进行， 长期合作，旨在开发DN-DBS技术，用于治疗 中风后的运动障碍

PROJECT SUMMARY/ABSTRACT Stroke is a disease of epidemiological proportions in the industrialized world and is a leading cause of long- term disability. Half of all stroke patients suffer long-term motor deficits severe enough to be disabling despite contemporary rehabilitative efforts, which underscores the need for novel, neurorestorative therapies to enhance post-stroke motor recovery. We have previously proposed dentate nucleus deep brain stimulation (DN-DBS) as a therapy to facilitate motor recovery for patients with chronic upper extremity hemiparesis due to ischemic stroke. Our working hypothesis is that low-frequency DN-DBS augments excitatory dentatothalamocortical output, thereby enhancing cerebral cortical excitability, facilitating functional reorganization in perilesional cortical areas and further supporting motor recovery. Using a rodent model of ischemia, we have demonstrated that chronic stimulation can facilitate motor recovery and that the improvements are accompanied by sustained increments in excitability, reorganization of motor representation, and increased expression of markers of long-term potentiation and synaptogenesis in perilesional regions of the cerebral cortex. The experiments proposed in the present study will help to ensure successful human translation of this promising novel treatment while also systematically examining its mechanistic underpinnings. Specifically, the proposed experiments are designed to determine: a) how the anatomical extent and distribution of the ischemic core influences both treatment efficacy and carry-over of benefits; b) how movement-related, synchronized oscillatory activity across deep cerebellar nuclei and neocortex changes post-stroke and as a result of DN-DBS treatment and whether that activity could serve as a control signal in a paired-associative (closed-loop) treatment paradigm; c) whether age at the time of infarct negatively impacts therapeutic efficacy; and d) the anatomical and functional mechanisms underlying DN- DBS-enhanced motor rehabilitation. These studies will be performed by an investigative team with multiple long-standing collaborations aimed towards the development of DN-DBS technologies for the treatment of motor impairments following stroke.