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地改善康复的疗法。一些临床研究表明，睡眠可能在决定损伤后的结果以及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时的离线处理可以提高运动能力。然而，睡眠阶段对中风/脑损伤后运动恢复的贡献仍不清楚。通过对大鼠卒中模型的长期大规模电生理监测、闭合环刺激(CLS)和特定细胞类型的神经调制，我的目标是操纵睡眠依赖的皮质处理，以促进卒中后的运动恢复。为了实现CLS，我将描绘一个可以最佳地促进运动恢复的睡眠时间，阐明潜在的神经机制，并测试离线处理过程中基于大脑状态的CLS是否可以促进运动恢复。指导阶段：目标是：(1)研究CLS的睡眠时间和机制，以及(2)测试CLS在睡眠期间对周围皮质(PLC)的CLS是否促进康复。我在大鼠中风模型上的初步实验表明，在NREM睡眠期间，纺锤波与慢波(即慢振荡/SO和增量波)的时间相互作用可能是恢复的一个重要生物标志。我将找到一种更精确的离线恢复处理机制，并测试CLS调制主轴的计时或主轴期间的兴奋性的效果。独立阶段：自上而下的皮质内转移，例如前额叶(PFC)到运动区，与睡眠依赖的记忆加工密切相关，在SO中也观察到类似的层次化流动。这种区域间的相互作用也与中间神经元的活动有关。利用卒中转基因大鼠(PV-CRE)，我将：(3)寻找离线恢复处理的最佳抑制时机/抑制率，并检测CLS增强SO期间PFC-PLC相互作用的效果。这将结合多分辨率电生理学(棘波、局域场电位和皮层脑电图术)和最先进的光学监测。虽然我通过光遗传学技术提出了这一方法，但我也试图寻找替代的调制方法(如GABAA受体阻滞剂)，这些方法可以通过更多的临床手段和与CLS范例的协同组合来识别，以实现卒中的恢复。我的长期目标是成为一名独立的研究员，专注于推进新的神经技术，这些技术旨在调节大脑计算并促进运动控制，特别是在受伤恢复期间。在这个项目中，我将(1)获得多点长期记录和刺激方面的专业知识，(2)获得新型数据分析方面的进一步熟练，(3)获得同时神经操作、生理学和光学记录以及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)获得独立的终身教席助理教授职位，并在2年内转到R00部分，以及(6)在本提案提出后5年内获得R01资金。

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.