Dentatothalamocortical electrical stimulation in post-stroke motor recovery

描述（由申请人提供）：中风是人群中非常常见的疾病，每年影响近80万美国新患者。三分之一的中风患者长期保持严重的运动障碍，即使经过康复治疗也足以致残。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修复疗法，以增强皮质-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（齿状）外侧核（LCN）产生皮层兴奋性的持续增加，并且慢性LCN刺激增强了建立的三血管闭塞缺血性卒中啮齿动物模型的运动功能恢复。这一假设是基于1)先前的证据表明小脑-丘脑-皮层通路（一个净失突触兴奋通路）在调节大脑皮层兴奋性中的作用；2)增强皮质兴奋性可增强皮质可塑性的证据；3)解剖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。这些区域与典型的大脑中动脉梗死的病灶周围区相对应，被认为与脑卒中后运动恢复相关的局部重组有关。到目前为止，我们的结果是有希望的，人类翻译是可行的，因为深部脑刺激（DBS）技术已经被FDA批准用于治疗运动障碍，并且在超过40,000次植入中被证明是安全的。本研究计划旨在进一步发展这一研究路线，其目标是：a)确定可能推动运动恢复超出当前结果的刺激参数；b)解决刺激开始和结束的最佳时间（即治疗窗口）的问题，这将对成功地将这种方法应用于人类产生关键影响；c)评估慢性LCN刺激诱导的运动恢复与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. PUBLIC HEALTH RELEVANCE: The goal of this study is to explore a new therapy for improving rehabilitation of motor function after ischemic strokes. Strokes are very common in the population, affecting more than 500.000 Americans per year. Up to 30% of strokes cause permanent weakness. This therapy will be first tested in a rat model of strokes and then translated to humans. The equipment for use of this therapy is humans are already available and FDA approved for the treatment of patients with advanced Parkinson's disease and tremor. Hence translating this therapy for rats to humans will be simple. The connections between the brain hemispheres and the cerebellar hemispheres are well known. The cerebellum has excitatory input to the cerebral cortex on the opposite side, via the thalamus. The main connection goes through the dentatothalamocortical (DTC) pathway. In this study, we will assess how stimulation of a nucleus in the cerebellum (the origin of the DTC) will influence motor recovery.