The Role of Sleep for Motor Recovery Post Stroke

在美国，中风仍然是导致运动障碍的主要原因；目前还没有已知的可靠的改善康复的治疗方法。一些临床研究表明，睡眠可能在决定损伤后的结果和进一步优化康复效果方面发挥重要作用。重要的是，越来越多的文献强调，睡眠期间的离线处理可以改善运动表现。然而，睡眠阶段如何促进中风/脑损伤后的运动恢复仍不清楚。利用大鼠脑卒中模型的长期大规模电生理监测、闭环刺激（CLS）和细胞类型特异性神经调节，我的目的是操纵睡眠依赖的皮层加工，以增强脑卒中后的运动恢复。为了实现CLS，我将描述一个睡眠时间，可以最佳地促进运动恢复，阐明潜在的神经机制，并测试离线处理期间基于大脑状态的CLS是否可以增强运动恢复。指导阶段：目标是：(1)研究睡眠的时间和机制，可以作为CLS的最佳触发因素，(2)测试睡眠期间CLS到皮质周围（PLC）是否促进恢复。我在大鼠中风模型中进行的初步实验表明，在非快速眼动睡眠期间，纺锤波与慢波（即慢振荡/SO和delta波）的时间相互作用可能是恢复的重要生物标志物。我将找到一个更精确的离线恢复处理机制，并测试CLS调节纺锤体的时间或纺锤体期间的兴奋性的效果。独立阶段：自上而下的皮层内转移，例如前额叶皮层（PFC）到运动区，与睡眠依赖的记忆处理密切相关，并且在SO中观察到类似的分层流动。这种区域间的相互作用也与中间神经元的活动有关。使用脑卒中的转基因大鼠（PV-Cre），我将：(3)找到离线恢复处理的最佳抑制时间/速率，并测试在SO期间CLS增强PFC- PLC相互作用的效果。这些将结合多分辨率电生理学（尖峰、局部场电位和皮质电图）和最先进的光学监测。当我提出通过光遗传学技术的方法时，我也试图确定替代的调节方法（例如GABAA受体阻滞剂），这些方法可能通过更多的临床手段和与CLS范例的协同组合来确定卒中恢复。我的长期目标是成为一名独立的研究者，专注于推进新的神经技术，以调节大脑计算和促进运动控制为目标，特别是在损伤恢复期间。在这个项目中，我将(1)获得多位点长期记录和刺激方面的专业知识，(2)进一步熟练掌握新型数据分析，(3)获得同步神经操作，生理学，光学记录和更具侵入性的啮齿动物中风模型方面的专业知识，(4)提高临床方面的知识，(5)获得独立的终身助理教授职位，并在2年内转入R00部分，并且，(6)在本提案生效后5年内获得R01资助。

Stroke remains the leading cause of motor disability in the United States; there are no current therapies known to reliably improve recovery. A few clinical studies have suggested that sleep may play an important role in determining outcomes after injury and further in optimizing the effects of rehabilitation. Importantly, there is a growing body of literature highlighting that offline processing during sleep can improve motor performance. However, what/how sleep stages contribute to motor recovery after stroke/brain injury remains unclear. Using long-term large-scale electrophysiology monitoring, closed-loop stimulation (CLS), and cell-type-specific neural modulation in rats stroke models, I aim to manipulate sleep-dependent cortical processing that can enhance the motor recovery post-stroke. To implement a CLS, I will delineate a timing of sleep that can optimally promote motor recovery, elucidate underlying neural mechanisms, and test if brain state based CLS during offline processing can enhance motor recovery. Mentored Phase: the objective is: (1) to find RESEARCH the timing of sleep and mechanisms that can serve as optimal triggers for CLS, and (2) to test if CLS to the perilesional cortex (PLC) during sleep promotes the recovery. My pilot experiments in rats stroke models suggest that the temporal interactions of spindles to slow-waves (i.e. slow-oscillations/SO and delta-waves) during NREM sleep may be an important biomarker of recovery. I will find a more precise mechanism of offline recovery processing and test the effects of CLS modulating either spindles' timing or excitability during spindles. Independent Phase: Top-down intracortical transfers, e.g. prefrontal cortex (PFC) to the motor area, are closely related to sleep-dependent memory processing and similar hierarchical flows are observed in SO. This inter- regional interaction is also linked to interneurons' activity. Using transgenic rats (PV-Cre) with stroke, I will: (3) find an optimal timing/rate of inhibitions for offline recovery processing and test effects of CLS enhancing PFC- PLC interactions during SO. These will combine multi-resolution electrophysiology (spikes, local-field potential, and electrocorticography) and state-of-the-art optical monitoring. While I propose the approach by optogenetics technique, I also seek to identify alternative modulation methods (e.g. GABAA receptor blocker) that might be identified through more clinical means and synergistic combinations with the CLS paradigm for stroke recovery. My long-term goal is to become an independent investigator focusing on advancing new neurotechnologies that target modulating brain computation and facilitate motor control, especially during recovery from an injury. In this project, I will (1) gain expertise in multi-site long-term recordings and stimulation, (2) acquire further proficiency in new-fashioned data analyses, (3) gain expertise in simultaneous neural manipulations, physiology, and optical recording and more invasive rodent stroke models, (4) improve knowledge in the clinical aspects, (5) obtain an independent tenure-track assistant professor position and transfer to the R00 portion within 2 years, and, (6) to obtain R01 funding within 5 years of this proposal.