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

摘要 睡眠功能障碍是一种非常普遍的疾病，在神经系统和精神系统中广泛存在， 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）， 睡眠结构与白天运动和神经精神症状的恶化有关， 加速疾病进展。因此，它也标志着一个重大的，尚未开发的治疗机会。但 目前尚不清楚哪些皮质和基底神经节结构和信号负责干扰 生理性睡眠节律这个建议的基本原理是， 是开发睡眠特异性神经调节的重要下一步 治疗迄今为止，进展的一个关键障碍是缺乏慢性颅内神经记录， 在警局睡觉这种迫切的需求可以通过利用最近的发展，在传感功能的深度 脑刺激（DBS），支持患者的纵向、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病理网络动态， 帕金森病的健康睡眠以及DBS如何调节它们。我们的初步研究显示异常的皮质- 基础β（13 - 30 Hz）和γ（60 - 90 Hz）振荡在PD的不同睡眠阶段。我们的中央 一种假说是，这些病理性的夜间神经节律扰乱了生理睡眠信号，包括缓慢的睡眠信号。 波活动（<4 Hz），并在睡眠期间诱导适应不良的网络变化，以影响白天的皮质-基底动脉 神经活动和连通性我们将使用感知功能的闭环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， 帕金森病患者睡眠中断时皮质-基底神经信号和连通性的变化然后我们将评估因果关系 通过使用皮层诱发反应测量清醒连接的皮层基底振荡机制， 通过应用依赖于睡眠阶段的闭环DBS。弥合这一知识差距将是 帕金森病患者睡眠的病理网络动力学，并揭示睡眠节律之间的关键机制 to waking唤醒network网络activity活动.这将为闭环DBS方法的开发提供基础 能让帕金森病患者恢复正常睡眠在成功完成拟议的研究后，我们 我希望我们的贡献能够决定睡眠的主要病理性振荡皮质-基底动力学 在PD的干扰。拟议的研究是创新的，使用新的传感启用DBS纵向睡眠 记录加闭环神经调节，以评估睡眠功能障碍的皮质基底网络模型， 警局这一贡献预计将是重要的，因为了解基本的神经生理学， PD中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 PD患者的睡眠、日间运动/非运动症状和疾病进展的治疗，这也将告知 其他神经和精神方面的疾病

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.