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

我们的长期目标是了解隐藏在特定体征和症状下的大脑节律 快速时间尺度下的运动障碍，决定了脑深部刺激(DBS)对这些大脑的影响 节律，并利用这一知识开发出闭合回路或“适应性”刺激。苍白球星形脑病 (GP)越来越多地用于帕金森氏病(PD)，因为它相对于 认知和情绪与丘脑底核(STN)DBS相比，但其机制尚不清楚。 人类基底节的有创场电位记录导致了一种有影响力的假说 帕金森病的运动体征以异常振荡同步的特定模式为基础。不正常的节律 β频段(13-30赫兹)被认为是“反动力”的，而更高频率(60-90赫兹)的节律则是 “促进动力。”其他频率可能是“震颤”。我们的总体方法是扩展这一概念 建立到运动皮质的基础上，并利用来自皮质和皮质下同步记录的网络分析。 在2014-18年的初始赠款期间，我们将重点放在STN及其皮质相互作用上。在这里，我们将学习 利用开发的技术方法，对左旋多巴和苍白球DBS的苍白球和苍白球皮质反应 在前一批赠与期：基底节和大脑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。我们雇用了一名新来的替补。 生成接口，RC+S(美敦力)，在记录质量方面具有实质性优势 和可编程性超过第一代设备(PC+S)。我们将使用这个设备来理解 抗帕金森病药物(目标1)和治疗苍白球DBS(目标2)的电生理效应 基底节丘脑皮质回路；并在这些结果的基础上建立自适应的原型算法 一种利用大脑信号根据大脑变化调整刺激参数的刺激方法 需要(目标3)。除了在规定的用药状态下(开或关)进行门诊记录外，我们还将使用HOME 从植入的设备和可穿戴式显示器通过持续的“数据流”进行录制， 增加生物标志物识别的几率。 这些研究的影响将是：1)提供对以下影响的机械性理解 基底神经节-丘脑皮质环路的治疗性苍白球DBS。这可能会转化为改进 电极放置的生理标准以及合理和简化的编程策略。2)创建 发展“适应性”DBS的基础，或许是DBS治疗的第一个重大技术进步 自25年前推出以来。3)发展人类神经科学的新范式--慢性神经科学 在完全自然的环境中进行移动大脑网络录音，提供一个回答问题的平台 基底节-皮质相互作用的基本问题。这项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大脑回路障碍。

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.