A Neurophysiological Approach to Post-Stroke Motor Recovery

项目摘要 在美国，中风是导致残疾的主要原因。虽然在这方面已经有了进步 神经康复策略，许多患者继续遭受慢性残疾，强调了需要 以进一步研究康复的新方法。睡眠在中风中的研究相对较少 尽管有证据表明中风后睡眠不足会加剧神经症状和 长期结果。因此，在制定新的康复策略时，睡眠可能是一个有用的目标。我们 建议研究睡眠中的大脑皮层和小脑区，以阐明系统水平的神经 在恢复期内与性能提升相关的处理。我们最近的研究表明， 健康大鼠运动皮质(M1)的非快速眼动(NREM)睡眠处理与 在一项运动任务中的表现改进。此外，人们普遍认为运动技能的学习 临床上重要的持续运动与小脑相关。有趣的是，最近的研究表明 NREM睡眠纺锤波起源于小脑。众所周知，睡眠纺锤体参与了 重新激活清醒的学习活动，但这些研究更多地集中在新皮质， 海马体和丘脑。然而，NREM纺锤体在小脑中振荡的程度 与新皮质区域的纺锤波同步变化(如果它们重新激活清醒的单个神经元 这两个区域的活动)在睡眠中改善表现仍然不完全清楚。此外，它是 了解支持中风后运动的睡眠阶段和伴随的神经生理学的关键 这些结构的恢复，以及可以在多大程度上对其进行调制以提高恢复。在这 建议，我们采取系统级别的方法来：(I)了解协调的NREM睡眠过程 大脑皮质-小脑网络与完整和中风损伤大鼠的运动学习/恢复有关， 具体地说，如果纺锤活动暂时锁定在这些区域；(Ii)确定NREM睡眠的必要性- 通过光遗传学进行技能巩固和恢复的相关神经加工；以及(Iii)测试是否增强 在这些与睡眠相关的神经事件中，使用小脑电刺激可以促进康复。我们将使用 电刺激对大脑皮质-小脑网络的同步大规模电生理监测 和光遗传学在啮齿动物中风模型中测试以下假设：耦合的NREM睡眠活动在 完好和损毁的M1和对侧小脑皮质是运动学习或恢复的基础 中风，当这种同步性由于小脑的光遗传抑制而被打乱时，学习能力就会减少 当这种同步性通过电刺激 小脑。

Project Summary Stroke is a leading cause of disability in the United States. While there have been advancements in neurorehabilitation strategies, many patients continue to suffer from chronic disability, underscoring the need for further research into novel approaches to rehabilitation. Sleep remains relatively understudied in stroke studies even though there is evidence that lack of sleep following a stroke worsens neurological symptoms and long-term outcomes. Thus, sleep may be a useful target in developing new rehabilitation strategies. We propose to study the cortical and cerebellar regions during sleep to elucidate the systems-level neural processing that is linked to performance gains during the recovery period. Our recent work has shown that non-rapid eye movement (NREM) sleep processing in the motor cortex (M1) of healthy rats is linked to performance improvements in a motor task. Additionally, it is widely acknowledged that motor learning of clinically important and continuous movements has cerebellar correlates. Interestingly, recent work has shown that NREM sleep spindles have a cerebellar origin. Sleep spindles are widely known to be involved in reactivating awake learning activity, but these studies have more commonly focused on the neocortex, hippocampus, and thalamus. However, the extent to which NREM spindle oscillations in the cerebellum covary with the spindle oscillations in the neocortical regions (and if they reactivate awake single neuronal activity in both regions) during sleep to improve performance remains incompletely understood. Moreover, it is key to understand the sleep stages and accompanying neurophysiology that support post-stroke motor recovery in these structures, as well as the extent to which they can be modulated to enhance recovery. In this proposal, we take a systems-level approach to: (i) understand the coordinated NREM sleep processes in cortico-cerebellar networks that are associated with motor learning/ recovery in intact and stroke-injured rats, specifically if spindle activity is temporally locked in these regions; (ii) establish necessity of NREM sleep- related neural processing in skill consolidation and recovery through optogenetics; and (iii) test if augmentation of these sleep-related neural events using electrical stimulation of cerebellum enhances recovery. We will use simultaneous large-scale electrophysiologic monitoring of cortico-cerebellar networks with electrical stimulation and optogenetics in a rodent stroke model to test the following hypothesis: coupled NREM sleep activity in the intact and ipsilesional spared M1 and contralateral cerebellar cortex underlies motor learning or recovery after stroke, learning is reduced when this synchronization is disrupted via optogenetic inhibition of the cerebellar activity, and learning is increased when this synchronization is boosted via electrical stimulation of the cerebellum.