Closed Loop Deep Brain Stimulation for Parkinson's Disease

摘要 脑深部电刺激（DBS）在运动障碍的管理中发挥着重要作用， 研究治疗情绪和记忆障碍。在帕金森病（PD）中，基础DBS 神经节核可以改善运动体征并减少药物诱导的运动波动和运动障碍， 以在运动机能减退状态（太少运动）和运动机能亢进状态之间频繁转换为特征 (too多运动）。然而，自从25年前引入DBS用于PD以来， 这种疗法的改进。现有的DBS设备提供"开环"刺激，连续刺激 它们的靶结构，而不管与疾病表达相关的脑回路的变化。装置 编程是一种基于"试错法"的劳动密集型过程，需要大量的临床专业知识， 这是广泛应用的障碍。在PD中，连续开环刺激可能导致次优 控制波动的运动信号、刺激引起的不良反应和短电池寿命。DBS可能是 通过递送"闭环"刺激显著改善，其中刺激参数自动地 根据反映患者临床状态的大脑信号进行调整。使用术中和慢性 通过侵入性记录技术，我们和其他人已经发现了异常的振荡活动模式，这些模式可能 提供PD中运动减退和运动过度状态的生理特征或"生物标志物"。在这里，我们计划 开发基于这些大脑信号的闭环DBS算法，使用研究性神经接口 （Medtronic Activa RC + S），可以感知和存储大脑活动以及输送DBS。我们将确定 哪些大脑信号最适合优化DBS治疗并回答关键问题，包括 控制信号检测的位置（皮层与皮层下）和控制信号所需的复杂性 （单频功率与交叉频率相互作用）。10例PD患者出现运动波动， 将在双侧植入Activa RC + S，Activa RC + S连接到丘脑底核（DBS）电极导线 以及放置在运动皮层上的皮层电图（ECoG）引线。我们将收集皮层脑电图和皮层下局部 场电位（LFP）记录，以表征每个受试者的"个性化"生理特征， 在临床环境中通过外部计算机进行数据流传输的原型刺激范例（目的1 和2）。然后，我们将在脉冲发生器中嵌入算法，以实现慢性和全闭环DBS 在一项小型双盲临床试验中（目标3）。运动功能将通过可穿戴自动化评估 检测器以及录像带和自我报告仪器的评定量表。该研究将确定 未来DBS器械设计所需的技术特性。"自编程" DBS设备提供 简化治疗并允许更多患者接受DBS的潜力。作为电生理学 识别出其他疾病中异常回路功能的特征，这种新一代闭环 这些设备将有助于在其他脑部疾病中引入新的DBS疗法。 .

Abstract Deep brain stimulation (DBS) has a major role in the management of movement disorders, and is under investigation for the treatment of disorders of mood and memory. In Parkinson's disease (PD), DBS of basal ganglia nuclei can improve motor signs and reduce medication-induced motor fluctuations and dyskinesia, characterized by frequent transitions between a hypokinetic state (too little movement) and a hyperkinetic state (too much movement). However, since the introduction of DBS for PD 25 years ago, there have been no major improvements in this therapy. Existing DBS devices deliver “open loop” stimulation, continuously stimulating their target structures regardless of changes in the brain circuits related to disease expression. Device programming is a labor-intensive process based on “trial and error” requiring significant clinical expertise, which is a barrier to widespread application. In PD, continuous open-loop stimulation may result in suboptimal control of fluctuating motor signs, stimulation-induced adverse effects, and short battery life. DBS could be significantly improved by delivering “closed-loop” stimulation, in which stimulation parameters are automatically adjusted based on brain signals that reflect the patient's clinical state. Using both intraoperative and chronic invasive recording techniques, we and others have identified abnormal patterns of oscillatory activity that may provide physiological signatures or “biomarkers” of hypokinetic and hyperkinetic states in PD. Here, we plan to develop closed-loop DBS algorithms based on these brain signals, using an investigational neural interface (Medtronic Activa RC+S) that can sense and store brain activity as well as delivering DBS. We will determine which brain signals are the most appropriate to optimize DBS therapy and answer critical questions including the site of control signal detection (cortical versus subcortical) and the required complexity of control signals (single frequency power versus cross frequency interactions). Ten PD patients with motor fluctuations and dyskinesia will be implanted bilaterally with Activa RC+S attached to a subthalamic nucleus (STN) DBS lead and an electrocorticography (ECoG) lead placed over motor cortex. We will collect ECoG and subcortical local field potential (LFP) recordings to characterize “personalized” physiological signatures for each subject and prototype stimulation paradigms by data streaming through an external computer in a clinical setting (Aims 1 and 2). We will then embed algorithms in the pulse generator to implement chronic and fully closed-loop DBS in a small double-blinded clinical trial (Aim 3). Motor function will be assessed by wearable automated detectors as well as rating scales from videotapes and self-report instruments. The study will define the technical characteristics required for the design of future DBS devices. “Self programming” DBS devices offer the potential to simplify the therapy and allow many more patients to receive DBS. As electrophysiological signatures of abnormal circuit function in other disorders are identified, this new generation of closed-loop devices will facilitate the introduction of novel DBS therapies in other brain diseases. .