The Role of Sleep for Motor Recovery Post Stroke

睡眠对中风后运动恢复的作用

• 批准号: 10300707
• 负责人: Jaekyung Kim
• 金额: $ 9.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-29 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300707
• 关键词: Animals; Area; Biological Markers; Brain; Brain Injuries; Cells; Clinical; Clinical Research; Cortical Synchronization; Coupling; Data; Data Analyses; Electric Stimulation; Electrocorticogram; Electrodes; Electrophysiology (science); Funding; Goals; Imaging Techniques; Injury; Interneurons; Knowledge; Link; Literature; Mediating; Memory; Mentors; Methods; Monitor; Motor; Motor Cortex; Neurons; Optics; Outcome; Paper; Parvalbumins; Performance; Phase; Physiology; Play; Polymers; Positioning Attribute; Prefrontal Cortex; Process; Rattus; Recovery; Rehabilitation therapy; Research; Research Personnel; Resolution; Rodent; Role; Site; Sleep; Sleep Stages; Slow-Wave Sleep; Stimulus; Stroke; Structure; System; Techniques; Testing; Time; Training; Transgenic Organisms; United States; Work; base; cell type; clinical translation; clinically relevant; disability; experimental study; forgetting; improved; in vivo; in vivo calcium imaging; injury recovery; memory consolidation; memory process; motor control; motor recovery; motor rehabilitation; neural stimulation; neuromechanism; neuroregulation; neurotechnology; non rapid eye movement; novel strategies; optogenetics; post stroke; professor; receptor; relating to nervous system; sensory cortex; stroke model; stroke recovery; tenure track

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.

中风仍然是美国运动障碍的主要原因;目前还没有已知的可靠的治疗方法来改善恢复。一些临床研究表明，睡眠可能在确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，睡眠阶段如何有助于中风/脑损伤后的运动恢复仍不清楚。在大鼠脑卒中模型中，使用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制，目的是操纵睡眠依赖的皮层处理，以增强脑卒中后的运动恢复。为了实现CLS，我将描绘一个睡眠的时间，可以最佳地促进运动恢复，阐明潜在的神经机制，并测试如果大脑状态为基础的CLS在离线处理可以提高运动恢复。指导阶段：目标是：（1）研究睡眠的时间和机制，可以作为CLS的最佳触发器，（2）测试CLS是否在睡眠期间对病灶周围皮层（PLC）促进恢复。我在大鼠中风模型中的初步实验表明，在NREM睡眠期间纺锤波与慢波（即慢振荡/SO和δ波）的时间相互作用可能是恢复的重要生物标志物。我将找到一种更精确的离线恢复处理机制，并测试CLS调制纺锤波的时间或纺锤波期间的兴奋性的效果。独立阶段：自上而下的皮层内转移，如前额叶皮层（PFC）到运动区，与睡眠依赖的记忆加工密切相关，在SO中观察到类似的分层流。这种区域间的相互作用也与中间神经元的活动有关。使用中风的转基因大鼠（PV-Cre），我将：（3）找到离线恢复加工的最佳抑制时间/速率，并测试CLS在SO期间增强PFC- PLC相互作用的效果。这些将结合联合收割机多分辨率电生理学（尖峰、局部场电位和皮质电描记术）和最先进的光学监测。虽然我提出了光遗传学技术的方法，但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范式的协同组合来确定，用于中风恢复。 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，特别是在受伤后的恢复过程中。在这个项目中，我将（1）获得多部位长期记录和刺激的专业知识，（2）获得新型数据分析的进一步熟练程度，（3）获得同步神经操作，生理学和光学记录以及更具侵入性的啮齿动物中风模型的专业知识，（4）提高临床方面的知识，（5）获得一个独立的终身助理教授职位，并在2年内转移到R 00部分，以及（6）在本提案的5年内获得R 01资金。