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

摘要 睡眠障碍在多种神经科和精神科疾病中非常普遍并致残 条件。在包括阿尔茨海默氏症和帕金森氏病(PD)在内的神经退行性疾病中， 睡眠结构与白天运动和神经精神症状的恶化有关，以及 加速了疾病的发展。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节结构和信号对脑电活动的干扰负责 帕金森病患者的生理睡眠节律。这一建议基本原理是识别皮质-基础信号 帕金森病患者睡眠结构的破坏是发展睡眠特异性神经调节的关键下一步 治疗。到目前为止，进展的一个关键障碍是缺乏慢性颅内神经记录 睡在警局。这一迫切需求可以通过利用支持传感的深度技术的最新发展来解决 脑刺激(DBS)，支持患者的纵向、高分辨率、多部位、颅内记录 拥有自己的家。这项提议的总体目标是建立破坏的病理性网络动态 帕金森病患者的健康睡眠以及DBS如何对其进行调节。我们的初步工作显示皮质醇异常- 帕金森病患者的基础贝塔(13-30赫兹)和伽马(60-90赫兹)在不同的睡眠时相有振荡。我们的中央 假设这些病理性的夜间神经节律扰乱了生理睡眠信号，包括慢 波活动(4赫兹)，并在睡眠期间诱导适应不良的网络变化，以影响白天的皮质-基底 神经活动和连通性。我们将使用支持传感的闭环DBS设备，这些设备 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 帕金森病患者睡眠中断期间皮质-基础信号和连接性的变化。然后我们将评估因果关系 用皮质诱发反应测量觉醒连通性的皮层-基底振荡机制 通过应用睡眠阶段相关的闭环DBS。弥合这一知识鸿沟将使 帕金森病患者睡眠的病理网络动力学及其与睡眠节律相关的关键机制研究 到唤醒的网络活动。这将为开发闭环式DBS方法提供基础 可以恢复帕金森病患者的正常睡眠。在成功完成建议的研究后，我们 期待我们的贡献已经确定了睡眠的主要病理振荡皮层-基础动力学 警局的分裂。这项拟议的研究是创新的，使用新的具有传感功能的DBS来进行纵向睡眠 记录加闭环神经调节以评估睡眠障碍的皮质-基础网络模型 警察。这一贡献预计将是重大的，因为理解了脑瘫的基本神经生理学 帕金森病患者的睡眠障碍是发展精确神经调节的关键知识鸿沟 睡眠、日间运动/非运动症状和帕金森病的疾病进展的治疗，这也将有助于 关于其他神经和精神疾病的报告。

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.