Dentatothalamocortical electrical stimulation in post-stroke motor recovery

描述(申请人提供)：中风是一种非常常见的疾病，每年影响近800.000新的美国人。尽管进行了康复治疗，三分之一的中风患者仍长期存在严重的运动障碍，足以致残。需要新的治疗方法来改善中风后的运动结果。这项研究的长期目标是开发一种神经恢复性疗法，以促进皮质下中风患者的运动恢复。研究人员先前已经证明，电刺激小脑外侧齿状核(LCN)可使皮质兴奋性持续增加，并且慢性LCN刺激可促进已建立的3支血管闭塞的缺血性卒中啮齿动物模型的运动功能的恢复。这一假说是基于1)先前的证据表明小脑-丘脑-皮质通路(一种净的双突触兴奋通路)在调节大脑皮质的兴奋性中所起的作用；2)证据表明皮质的可塑性可以通过增强皮质的兴奋性来增强；以及3)解剖学证据表明齿状皮质通路不仅投射到运动皮质，而且投射到运动前的额叶和顶叶皮质区域。这些区域对应于典型大脑中动脉梗塞的周围区域，被认为参与了与中风后运动恢复相关的局部重组。到目前为止，我们的结果是有希望的，人类翻译是可行的，因为脑深部刺激(DBS)技术已经被FDA批准用于治疗运动障碍，并已在40,000多个植入物中被证明是安全的。这项研究建议旨在进一步发展这一研究路线，目的是：a)确定可能推动运动恢复的刺激参数，使其超出目前的结果；b)解决刺激开始和终止的最佳时机问题(即治疗窗口)，这将对这一方法成功地应用于人类具有至关重要的影响；c)评估慢性LCN刺激诱导的运动恢复与皮层周围可塑性之间的联系。

DESCRIPTION (provided by applicant): Stroke is a very common condition in the population, affecting nearly 800.000 new American every year. A third of stroke patients maintain long term motor deficits severe enough to be disabling, despite rehabilitative efforts. New therapies to improve motor outcomes after stroke are needed. The long-term goal of this line of investigation is to develop a neurorestorative therapy to enhance motor recovery for patients who have suffered cortico-subcortical strokes. The investigators have demonstrated previously that electrical stimulation of the lateral cerebellar (dentate) nucleus (LCN) produces sustained increment in cortical excitability and that chronic LCN stimulation enhance recovery of motor function in an established 3-vessel occlusion rodent model of ischemic stroke. The hypothesis was developed based on 1) prior evidence suggesting a role for the cerebello-thalamo-cortical pathway (a net disynaptic excitatory pathway) in modulating cerebral cortical excitability; 2) evidence that cortical plasticity can be enhanced by augmenting cortical excitability; and 3) anatomical evidence that indicates the dentatothalamocortical pathway projects not only to the motor cortex but also to the premotor frontal and parietal cortical areas. These areas correspond to the perilesional zone in typical middle cerebral artery infarcts and are thought to be involved in local reorganization associated with motor recovery after stroke. Thus far, our results are promising and human translation is feasible given that the technology for deep brain stimulation (DBS) is already FDA approved for the treatment of movement disorders and has been proven safe in over 40,000 implants. This research proposal was designed to further develop this line of investigation with the goals of: a) identifying stimulation parameters that may drive motor recovery beyond the current results; b) addressing the question of optimal timing for stimulation onset and termination (i.e., therapeutic window), which will have a crucial impact in successful translation of this approach to humans and c) assessing a link between chronic LCN stimulation-induced motor recovery and perilesional cortical plasticity.