Adaptive Neurostimulation to Restore Sleep in Parkinson's Disease: An Investigation of STN LFP Biomarkers In Sleep Dysregulation and Repair

项目摘要 帕金森病(PD)是一种神经退行性疾病，既会导致运动症状，也会导致非运动症状。 虽然到目前为止还没有治愈帕金森病的方法，但已经开发出了有效地针对 帕金森病的运动症状。非运动症状对患者的致残率要高得多，在运动发作之前 十年后，症状开始时更隐蔽，临床医生不那么明显，也更少。 有效治疗。睡眠障碍往往是最令人不快的非运动症状-- 帕金森病在帕金森病患者中普遍存在，包括睡眠碎片、失眠、 白天过度嗜睡、快速眼动行为障碍和不宁腿综合症。选择是有限的 用于治疗帕金森病患者的睡眠障碍，治疗的主要方法是使用掩蔽睡眠的药物 干扰--例如镇静催眠药物--而没有解决潜在的机制。 尽管人们对帕金森病的运动症状给予了很多关注，但帕金森病患者的睡眠障碍在很大程度上是 已被忽略。睡眠对动态平衡、认知和神经系统修复至关重要，而睡眠功能失调 伴发帕金森病对运动和非运动症状都有不利影响，导致生活质量下降， 情绪和行为障碍，发病率和死亡率增加。帕金森病患者 丘脑底核(STN)深部被认为存在显著的运动波动和运动障碍 刺激性(DBS)手术。尽管STN-DBS被常规用于治疗PD运动症状，但有几项研究 据报道，STN-DBS还通过睡眠正常化为睡眠失调提供了好处 建筑。此外，从STN DBS电极记录的局部场电位被植入用于治疗 导致在STN振荡活动中识别出与以下因素相关的独特光谱模式 不同的睡眠周期，提供了对睡眠失调的洞察。在这项工作的基础上，并回应RFA-NS- 18-023，该提案将利用新的研究星形数据库电池技术(RC+S峰会系统； 美敦力)，允许探索睡眠生物标记物和闭环刺激算法的原型， 为了检验STN--基底节内高度相互连接的结节--对 对人类睡眠行为的调节和干扰，并可用于治疗优势。 具体地说，在接受STN-DBS的PD患者中，我们将确定STN振荡是否与 睡眠阶段转换，然后构建和评估感知和适应性刺激范例，以允许 持续的睡眠阶段识别，并通过适应性刺激诱导睡眠持续时间的增加 与恢复性睡眠相关的阶段。这项工作将导致解决目前未满足的问题的发现 临床需求，并与NINDS的使命和大脑倡议相关，将评估 帕金森病患者STN的适应性刺激治疗睡眠障碍。

Project Summary Parkinson’s disease (PD) is a neurodegenerative disorder that leads to both motor and non-motor symptoms. While there is as yet no cure for PD, medical and surgical therapies have been developed that effectively target the motor symptoms of PD. Non-motor symptoms are far more disabling for patients, precede the onset of motor symptoms by a decade, are more insidious in onset, have been less apparent to clinicians, and are less effectively treated. Sleep dysfunction is oftentimes the most burdensome of the non-motor symptoms—both to patients and to their caregivers—is pervasive in patients with PD, and includes sleep fragmentation, insomnia, excessive daytime sleepiness, REM behavioral disorder, and restless leg syndrome. There are limited options for treating sleep dysfunction in PD, and the mainstay of therapy is the use of agents that mask the sleep disturbance—such as the sedative-hypnotic drugs—without addressing the underlying mechanisms. Although much attention has been devoted to PD motor symptoms, sleep dysfunction in PD has largely been ignored. Sleep is vital to homeostasis, cognition, and nervous system repair, and the dysfunctional sleep accompanying PD adversely affects both motor and non-motor symptoms, resulting in diminished quality of life, impairments in mood and behavior, and increased morbidity and mortality. Patients with PD who demonstrate significant motor fluctuations and dyskinesia are considered for subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. Although STN-DBS is routinely used to treat PD motor symptoms, several studies have reported that STN-DBS also provides benefit for sleep dysregulation through normalization of sleep architecture. Additionally, local field potentials recorded from STN DBS electrodes implanted for the treatment of PD, have led to the identification of unique spectral patterns in STN oscillatory activity that correlate with distinct sleep cycles, offering insight into sleep dysregulation. Building on this work, and in response to RFA-NS- 18-023, this proposal will leverage novel investigational DBS battery technology (RC+S Summit System; Medtronic) that allows the exploration of sleep biomarkers and prototyping of closed-loop stimulation algorithms, to test the hypothesis that STN—a highly interconnected node within the basal ganglia—contributes to the regulation and disruption of human sleep behavior and can be manipulated for therapeutic advantage. Specifically, in PD patients undergoing STN-DBS, we will determine whether STN oscillations correlate with sleep stage transitions, then construct and evaluate sensing and adaptive stimulation paradigms that allow ongoing sleep-stage identification, and induce through adaptive stimulation an increase in duration of sleep stages associated with restorative sleep. This work will lead to findings that address a currently unmet clinical need, and relevant to the mission of NINDS and the BRAIN Initiative, will evaluate the use of adaptive stimulation of the STN in PD patients for the treatment of sleep dysfunction.