Dentatothalamocortical electrical stimulation in post-stroke motor recovery

描述（由申请人提供）：中风是一种非常常见的疾病，每年影响近80万新的美国人。三分之一的中风患者保持长期的运动缺陷，严重到足以致残，尽管康复努力。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疗法，以增强皮质-皮质下卒中患者的运动恢复。研究人员先前已经证明，在已建立的3血管闭塞缺血性卒中啮齿动物模型中，小脑外侧（齿状）核（LCN）的电刺激可持续增加皮质兴奋性，并且慢性LCN刺激可增强运动功能的恢复。这一假说是基于1）先前的证据表明小脑-丘脑-皮质通路的作用（一个净双突触兴奋通路）在调节大脑皮层兴奋性; 2）证据表明，皮层可塑性可以通过增加皮层兴奋性增强;和3）解剖学证据表明，齿状丘脑皮质通路不仅投射到运动皮质，而且投射到运动前额叶和顶叶皮质区这些区域对应于典型的大脑中动脉梗死的病灶周围区，并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，因为脑深部电刺激（DBS）技术已经被FDA批准用于治疗运动障碍，并已被证明在40，000多个植入物中是安全的。本研究提案旨在进一步发展这一研究路线，其目标是：a）识别可能驱动运动恢复超过当前结果的刺激参数; B）解决刺激开始和终止的最佳时机的问题（即，治疗窗口），这将对成功将该方法转化为人类产生关键影响，以及c）评估慢性LCN刺激诱导的运动恢复和病灶周围皮质可塑性之间的联系。

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.