Cerebellar deep brain stimulation to enhance chronic post-stroke rehabilitation

项目摘要/摘要 在工业化世界中，中风是一种流行病，是导致长期中风的主要原因。 长期残疾。一半的中风患者患有长期的运动障碍，严重到足以致残 当代康复努力，这强调了需要新颖的神经恢复疗法来 促进中风后的运动恢复。我们之前已经提出了齿状核深部脑刺激 (dN-DBS)促进慢性上肢偏瘫患者运动功能恢复的研究 到缺血性中风。我们的工作假设是低频dN-dbs增强了兴奋性。 牙齿皮质输出，从而增强大脑皮层的兴奋性，便于功能性 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，我们已经证明了慢性刺激可以促进运动恢复，并且 伴随着改善的是兴奋性的持续增加，运动的重组 长时程增强和突触发生标记物的表达和表达增加 大脑皮层的周边区域。本研究中提出的实验将有助于确保 这一有希望的新疗法的成功人类翻译，同时也系统地研究了它的 机械的基础。具体地说，拟议的实验旨在确定：a)如何 脑缺血核心的解剖范围和分布影响治疗效果和预后 好处；b)运动相关的、跨小脑深核的同步振荡活动和 卒中后新皮质的变化和糖尿病肾病-DBS治疗的结果以及这种活动是否可以作为 配对联合(闭环系统)治疗范例中的控制信号；c)是否在梗死时年龄 对治疗效果产生负面影响；以及d)糖尿病肾病的解剖和功能机制。 DBS-增强型运动康复。这些研究将由一个调查小组进行，调查小组将 长期合作，旨在开发用于治疗糖尿病的糖尿病肾病-DBS技术 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.