Determining the circuits and signals of sleep dysfunction in Parkinson's disease through chronic intracranial recordings and closed-loop Deep Brain Stimulation

摘要 睡眠功能障碍在神经和精神领域非常普遍，并且会导致多种疾病的发生 条件。在神经退行性疾病中，包括阿尔茨海默病和帕金森病 (PD)， 睡眠结构与日间运动和神经精神症状的恶化以及 加速疾病进展。因此，这也标志着一个重大的、尚未开发的治疗机会。然而，它 目前尚不清楚哪些皮质和基底神经节结构和信号负责破坏 PD 的生理睡眠节律。该提案的基本原理是识别皮质基底信号 扰乱帕金森病的睡眠结构是开发睡眠特异性神经调节的重要下一步 疗法。迄今为止，进展的一个关键障碍是缺乏慢性颅内神经记录 睡在PD。这一迫切的需求可以通过利用传感支持的深度学习的最新发展来解决 脑刺激 (DBS)，支持患者纵向、高分辨率、多部位颅内记录 自己的家。该提案的总体目标是建立破坏性的病态网络动态 PD 中的健康睡眠以及 DBS 如何调节它们。我们的初步工作表明皮质异常 PD 不同睡眠阶段的基础 beta (13 - 30 Hz) 和 gamma (60 - 90 Hz) 振荡。我们的中央 假设是这些病理性的夜间神经节律破坏了生理睡眠信号，包括缓慢的睡眠信号 波活动（<4 Hz），并在睡眠期间引起适应不良的网络变化，从而影响白天的皮质基底层 神经活动和连接。我们将使用长期使用的具有传感功能的闭环 DBS 设备 植入 16 名 PD 患者的队列中，结合可解释的机器学习技术，以识别 PD 睡眠中断期间皮质基底信号和连接性发生变化。然后我们将评估因果关系 通过使用皮质诱发反应测量清醒连接性来研究皮质基底振荡的机制 通过应用睡眠阶段相关的闭环 DBS。弥合这一知识差距将体现出 PD 睡眠的病理网络动态并揭示连接睡眠节律的关键机制理解 唤醒网络活动。这将为闭环 DBS 方法的开发奠定基础 可以恢复帕金森病患者的正常睡眠。成功完成拟议的研究后，我们 期望我们的贡献能够确定睡眠的主要病理性皮质基底振荡动力学 PD 中断。拟议的研究具有创新性，使用新型传感 DBS 进行纵向睡眠 录音加上闭环神经调节来评估睡眠功能障碍的皮质基底网络模型 PD。这一贡献预计将是意义重大的，因为了解了神经生理学的基本原理 PD 的睡眠功能障碍代表了开发精确神经调节的关键知识差距 针对帕金森病的睡眠、日间运动/非运动症状和疾病进展的疗法，这也将提供信息 其他神经和精神疾病。

ABSTRACT Sleep dysfunction is highly prevalent and disabling across a wide range of neurological and psychiatric conditions. In neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease (PD), disruption of sleep architecture has been linked to worsening of daytime motor and neuropsychiatric symptoms, as well as accelerated disease progression. It therefore also marks a major, untapped therapeutic opportunity. However, it is currently not known which cortical and basal ganglia structures and signals are responsible for disrupting physiological sleep rhythms in PD. The rationale of this proposal is that identification of the cortical-basal signals which disrupt sleep architecture in PD is an essential next step for developing sleep-specific neuromodulation therapies. To date, a critical barrier to progress has been a lack of chronic intracranial neural recordings during sleep in PD. This urgent need can be addressed by leveraging recent developments in sensing-enabled Deep Brain Stimulation (DBS), supporting longitudinal, high-resolution, multi-site, intracranial recordings in patients’ own homes. The overall objective for this proposal is to establish the pathological network dynamics that disrupt healthy sleep in PD and how they are modulated by DBS. Our preliminary work demonstrates abnormal cortico- basal beta (13 - 30 Hz) and gamma (60 - 90 Hz) oscillations across different sleep phases in PD. Our central hypothesis is that these pathological overnight neural rhythms disrupt physiological sleep signals, including slow wave activity (<4 Hz), and induce maladaptive network changes during sleep to impact daytime cortico-basal neural activity and connectivity. We will use sensing-enabled, closed-loop, DBS devices that are chronically implanted in a cohort of 16 PD patients, combined with interpretable machine learning techniques, to identify cortico-basal signal and connectivity changes during sleep disruption in PD. We will then evaluate causal mechanisms of cortico-basal oscillations by measuring waking connectivity using cortical evoked responses and through applying sleep-stage dependent closed-loop DBS. Bridging this knowledge gap will characterize the pathological network dynamics of sleep in PD and uncover key mechanistic understandings linking sleep rhythms to waking network activity. This will provide a foundation for the development of closed-loop DBS approaches that can restore normal sleep in people with PD. Following successful completion of the proposed research, we expect our contribution to have determined the principal pathological oscillatory cortico-basal dynamics of sleep disruption in PD. The proposed research is innovative, using new sensing-enabled DBS for longitudinal sleep recordings plus closed-loop neuromodulation to evaluate cortico-basal network models of sleep dysfunction in PD. This contribution is expected to be significant because understanding the fundamental neurophysiology of sleep dysfunction in PD represents a critical knowledge gap towards developing precision neuromodulation therapies for sleep, daytime motor / non-motor symptoms and disease progression in PD, which will also inform on other neurological and psychiatric conditions.