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，其导致运动和非运动症状。 虽然目前还没有治愈PD的方法，但已经开发出了有效靶向治疗PD的药物和手术疗法。 帕金森病的运动症状非运动症状对患者的致残性要大得多， 症状，发病时更隐蔽，临床医生不太明显， 有效治疗。睡眠功能障碍通常是最沉重的非运动性疾病， 患者和他们的父母-在PD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征。选择有限 用于治疗PD中的睡眠功能障碍，并且治疗的支柱是使用掩蔽睡眠功能障碍的药物。 干扰-如镇静催眠药物-没有解决潜在的机制。 虽然很多注意力都集中在PD运动症状上，但PD的睡眠功能障碍在很大程度上被忽视了。 忽视睡眠对体内平衡、认知和神经系统修复至关重要，而睡眠障碍 伴随的PD不利地影响运动和非运动症状，导致生活质量降低， 情绪和行为障碍，发病率和死亡率增加。表现出以下症状的PD患者 在丘脑底核（subthalamic nucleus，简称STN）脑深部， DBS手术。尽管STN-DBS常规用于治疗PD运动症状，但一些研究 据报道，STN-DBS还通过睡眠正常化为睡眠失调提供益处 架构此外，从为治疗植入的DBS电极记录的局部场电位 PD的研究，导致识别出STN振荡活动中与PD相关的独特光谱模式 不同的睡眠周期，提供对睡眠失调的洞察。在这项工作的基础上，为了响应RFA-NS- 18-023，该提案将利用新型研究DBS电池技术（RC+S Summit系统; Medtronic），其允许探索睡眠生物标志物和闭环刺激算法的原型， 为了验证这一假设，即基底神经节内高度相互连接的节点-有助于 调节和破坏人的睡眠行为，并且可以操纵以获得治疗优势。 具体而言，在接受STN-DBS的PD患者中，我们将确定是否存在与 睡眠阶段转换，然后构建和评估感测和自适应刺激范例， 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。这项工作将得出结论，解决目前尚未得到满足的 临床需求，并与NINDS和BRAIN计划的使命相关，将评估 适应性刺激帕金森病患者的小脑顶，以治疗睡眠功能障碍。

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.