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残疾的主要原因；目前尚无已知的疗法可以可靠地改善康复。一些临床研究表明，睡眠可能在确定受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期间的离线处理可以提高运动表现。然而，睡眠阶段对中风/脑损伤后运动恢复有何贡献/如何贡献尚不清楚。在大鼠中风模型中使用长期大规模电生理学监测、闭环刺激（CLS）和细胞类型特异性神经调节，我的目标是操纵睡眠依赖性皮层处理，以增强中风后的运动恢复。为了实施 CLS，我将描绘一个可以最佳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) 研究睡眠时间和可作为 CLS 最佳触发因素的机制，以及 (2) 测试睡眠期间对病灶周围皮质 (PLC) 的 CLS 是否能促进恢复。我在大鼠中风模型中进行的初步实验表明，NREM 睡眠期间纺锤体与慢波（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 调节纺锤体计时或纺锤体兴奋性的效果​​。独立阶段：自上而下的皮质内传输，例如前额皮质（PFC）到运动区，与睡眠依赖性记忆处理密切相关，并且在 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。使用患有中风的转基因大鼠（PV-Cre），我将：（3）找到离线恢复处理的最佳抑制时间/抑制率，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。虽然我提出了通过光遗传学技术的方法，但我还寻求确定替代的调节方法（例如 GABAA 受体阻滞剂），这些方法可以通过更多的临床手段以及与中风恢复的 CLS 范式的协同组合来确定。 我的长期目标是成为一名独立研究者，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，特别是在受伤恢复期间。在这个项目中，我将（1）获得多站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、生理学和光学记录方面的专业知识和更多侵入性啮齿动物中风模型，（4）提高临床方面的知识，（5）获得独立终身教授助理教授职位并在2年内转移到R00部分，以及（6）获得R01该提案生效后 5 年内提供资金。