Closed Loop Deep Brain Stimulation for Parkinson's Disease

摘要 深部脑刺激(DBS)在运动障碍的管理中发挥着重要作用，目前正在 情绪和记忆障碍的治疗研究。在帕金森病(PD)中，DBS的基础 神经节核团可以改善运动体征，减少药物引起的运动波动和运动障碍， 以运动不足状态(运动太少)和运动过度状态之间频繁转换为特征的 (运动太多)。然而，自从25年前为PD引入DBS以来，没有重大的 这种疗法的改进。现有的DBS设备提供“开环”刺激，持续刺激 他们的目标结构与与疾病表达相关的大脑回路的变化无关。装置 编程是基于需要大量临床专业知识的“反复试验”的劳动密集型过程， 这是广泛应用的障碍。在帕金森病中，持续的开环刺激可能导致次优 控制波动的运动体征、刺激引起的不良反应和较短的电池寿命。星展银行可能是 通过提供“闭环式”刺激显著改进，其中刺激参数自动 根据反映患者临床状态的大脑信号进行调整。术中和慢性联合使用 侵入性记录技术，我们和其他人已经确定了振荡活动的异常模式，可能 提供帕金森病运动不足和运动亢进状态的生理信号或“生物标记物”。在这里，我们计划 使用研究性神经接口，基于这些大脑信号开发闭环系统DBS算法 (美敦力RC S)，它可以感知和存储大脑活动以及提供DBS。我们将决定 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(皮质与皮质下)以及控制信号所需的复杂性 (单频功率与交叉频率相互作用)。10例伴有运动波动的帕金森病患者 运动障碍将在Activa RC S连接到丘脑底核(STN)DBS导联的情况下双侧植入 以及放置在运动皮质上的皮层脑电(ECoG)导联。我们将收集ECoG和皮质下局部 场电位(LFP)记录以表征每个受试者的“个性化”生理特征 临床环境中通过外部计算机传输数据的原型刺激范例(目标1 和2)。然后将算法嵌入到脉冲发生器中，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式自动化进行评估 探测器以及录像带和自我报告仪器的评级标尺。这项研究将界定 未来DBS设备设计所需的技术特征。“自编程”DBS设备提供 简化治疗并允许更多患者接受DBS的可能性。作为电生理学 在其他疾病中识别出异常电路功能的特征，这是新一代闭环系统 设备将促进在其他大脑疾病中引入新的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. .