The motor network in Parkinson's disease: Mechanisms of therapy

我们的长期目标是了解大脑节律的具体迹象和症状， 运动障碍在快速的时间尺度，确定脑深部电刺激（DBS）对这些大脑的影响 节奏，并利用这些知识来开发闭环或“自适应”刺激。苍白球DBS (GP)越来越多地用于帕金森病（PD），基于其在以下方面的更大安全性： 与丘脑底核DBS相比，DBS在认知和情绪方面有显著的差异，但其机制尚不清楚。 人类基底神经节中的侵入性场电位记录导致了一个有影响力的假设， 异常振荡同步的特定模式是PD的运动体征的基础。心律失常 β带（13-30 Hz）被认为是“反运动”，而更高频率（60-90 Hz）节律 “促动剂”其他频率可能是“震颤”。我们的一般方法是扩展这个概念 基础运动皮层和利用网络分析从同时皮层和皮层下记录。 在2014- 2018年的初始资助期间，我们专注于脑及其皮质相互作用。在这里，我们将研究 苍白球和苍白球皮质对左旋多巴和苍白球DBS的反应，利用开发的技术方法 在上一个资助期：基底神经节和皮层的慢性多部位场电位记录 电极，利用完全可植入的双向神经接口。我们雇了一个新来的助手 生成接口，RC+S（Medtronic），在记录质量方面具有实质性优势 和第一代器件（PC+S）的可编程性。我们将用这个装置来了解 抗帕金森病药物（目的1）和治疗性苍白球DBS（目的2）对 基底神经节丘脑皮层电路;并建立在这些结果的原型算法，自适应 其中脑信号被用于根据改变的脑来调整刺激参数的刺激 需求（目标3）。除了在规定的药物状态（开或关）下进行门诊记录外，我们还将使用家庭记录 记录，从植入设备和可穿戴监视器连续“数据流”， 增加生物标记识别的可能性。 这些研究的影响将是：1）提供一个机械的理解的影响， 基底节-丘脑皮质回路上的治疗性苍白球DBS。这可以转化为改善 电极放置的生理标准以及合理和简化的编程策略。2)创建 为“自适应”DBS的发展奠定了基础，这可能是DBS治疗的第一个重大技术进步 自25年前推出以来。3)在人类神经科学中开发一种新的范式，即慢性 在完全自然的环境中记录动态大脑网络，为回答 基底神经节-皮质相互作用的基本问题。本研究阐明的机制可能是 适用于DBS已显示出治疗前景的其他脑回路障碍。

Our long-term goal is to understand the brain rhythms underlying specific signs and symptoms of movement disorders at fast time scales, determine the effects of deep brain stimulation (DBS) on these brain rhythms, and utilize this knowledge to develop closed loop or “adaptive” stimulation. DBS of the globus pallidus (GP) is increasingly performed for Parkinson's disease (PD), based on its greater safety with respect to cognition and mood compared with subthalamic nucleus (STN) DBS, but its mechanism is not well understood. Invasive field potential recordings in the basal ganglia in humans has led to the influential hypothesis that specific patterns of abnormal oscillatory synchronization underlie the motor signs of PD. Abnormal rhythms in the beta band (13-30 Hz) are thought to be “antikinetic” while higher frequency (60-90 Hz) rhythms are “prokinetic.” Other frequencies may be “tremorogenic”. Our general approach is to extend this conceptual foundation to motor cortex and utilize network analyses from simultaneous cortical and subcortical recordings. In the initial grant period 2014-18, we focused on STN and its cortical interactions. Here, we will study pallidal and pallidocortical responses to levodopa and pallidal DBS, utilizing the technical approach developed in the previous grant period: chronic multisite field potential recording from basal ganglia and cortical electrodes, utilizing a totally implantable bidirectional neural interface. We employ a newly available second generation interface, RC+S (Medtronic) which holds substantial advantages with respect to recording quality and programmability over the first generation device (PC+S). We will use this device to understand electrophysiologic effects of antiparkinsonian medications (Aim 1) and of therapeutic pallidal DBS (Aim 2) on the basal-ganglia thalamocortical circuit; and build on these results to prototype algorithms for adaptive stimulation in which brain signals are utilized to adjust stimulation parameters according to changing brain needs (Aim 3). In addition to in-clinic recordings in defined medication states (on or off), we will use home recordings, with continuous “data streaming” from the implanted device and from wearable monitors, to increase the odds of biomarker identification. The impact of these studies will be to: 1) Provide a mechanistic understanding of the effects of therapeutic pallidal DBS on the basal ganglia-thalamocortical circuit. This may translate into improved physiological criteria for electrode placement and to rational and streamlined programing strategies. 2) Create a foundation for the development of “adaptive” DBS, perhaps the first major technical advance in DBS therapy since its introduction 25 years ago. 3) Develop a novel paradigm in human neuroscience, that of chronic ambulatory brain network recording in totally naturalistic environments, providing a platform for answering fundamental questions on basal ganglia-cortical interactions. Mechanisms elucidated in this study may be applicable to other disorders of brain circuits for which DBS has shown therapeutic promise.