The Pathophysiology of Network Synchrony in Parkinson's Disease

项目总结/摘要 帕金森病（PD）运动症状的病理生理机制仍不完全 最近关于基底神经节内不同节点神经元活动变化的相互矛盾的报道理解了这一点。 神经节-丘脑皮质（BGTC）运动回路。一个统一的方法，占相互矛盾的结果是 needed.强调电路中节点之间相对未被充分探索的动态关系， 假设夸大的网络水平耦合是病理生理过程的基础， PD的僵硬和运动迟缓通过阻碍有效的信息流。因此，我们建议调制 网络偶联是药物和手术治疗的共同治疗机制;其他 生理性后遗症是治疗干预的靶点所特有的， 文学作品我们将同时评估皮质和皮质下生理与临床症状的关系 以及对患者的脑深部电刺激（DBS）、皮层刺激和药物治疗的反应 接受DBS植入手术。这种方法能够对空间特异性皮层进行上级研究 与手术外研究相比。我们认为，理解 扩展的BGTC网络的功能连接，不仅包括运动皮层与丘脑底核 核（nucleus），但也与苍白球内（GPi，最后共同的）连接。 基底神经节的输出）和补充运动区（SMA）和背侧运动前皮质（PMd）， 是苍白球接受丘脑区域主要投射的地方。此外，我们的分析将集中在 低与高β振荡相对于正常运动功能的不同生理意义， 疾病和治疗干预。在具体目标1中，我们的目标是了解 未治疗的BGTC运动网络在PD在休息和运动，利用特定的优势，时间 疾病分类学的变化（用客观临床评定量表和综合 运动学），同时记录网络连接性的测量。在具体目标2中，我们将使用 皮层下和皮层刺激，以特异性地扰乱BGTC运动网络中的不同节点， 证实网络耦合是治疗性脑刺激的常见机制，无论 的靶点，并确定靶点特异性效应，这些效应可以解释DBS在以下条件下的已知临床差异： 与GPi相比。最后，在具体目标3中，我们将评估BGTC运动的药理学调节 网络，旨在了解症状改善和网络之间的时间关系 调变综上所述，我们将通过以下方式显著增强现有的BGTC电机网络接线图： 阐明运动网络耦合在PD中的作用。解决这一基本知识差距将有助于 治疗创新，包括可用于闭环DBS的控制信号的识别 提供了BGTC马达电路的接线图，可以指导药理学的创新。

Project Summary/Abstract The pathophysiology underlying the motor symptoms of Parkinson’s disease (PD) remains incompletely understood with recent conflicting reports of changes in neuronal activity in distinct nodes within the basal ganglia-thalamocortical (BGTC) motor circuit. A unified approach that accounts for conflicting results is needed. Emphasizing the relatively underexplored dynamic relationship between nodes in the circuit, we build upon the hypothesis that exaggerated network-level coupling is the pathophysiologic process underlying the rigidity and bradykinesia of PD by impeding effective information flow. Accordingly, we propose that modulation of network coupling is the common therapeutic mechanism across pharmacologic and surgical therapies; other physiologic sequelae are specific to the target of therapeutic intervention and account for disparate results in the literature. We will simultaneously assess cortical and subcortical physiology in relation to clinical symptoms and in response to deep brain stimulation (DBS), cortical stimulation and pharmacologic therapy in patients undergoing DBS implantation surgery. This approach enables superior investigation of spatially specific cortical phenomena compared to extraoperative studies. We propose that it is critically important to understand the functional connectivity of the extended BGTC network, including not only the motor cortex with subthalamic nucleus (STN) as most studies do, but also connectivity with globus pallidus internus (GPi, the final common output of the basal ganglia) and the supplementary motor area (SMA) and dorsal premotor cortex (PMd), which are to where pallidal-receiving thalamic regions dominantly project. Moreover, our analyses will focus on the differential physiological significance of low vs high β oscillations with respect to normal motor function, disease, and therapeutic intervention. In Specific Aim 1, we aim to understand the clinical correlates of the untreated BGTC motor network in PD both at rest and with movement, taking specific advantage of temporal variation in disease symptomatology (as measured with objective clinical rating scales and comprehensive kinematics) with simultaneously recorded measures of network connectivity. In Specific Aim 2, we will use subcortical and cortical stimulation to specifically perturb distinct nodes in the BGTC motor network, in order to confirm that network coupling is the common mechanism underlying therapeutic brain stimulation, regardless of target, and to also identify target specific effects that can account for known clinical differences in DBS at STN vs GPi. Finally, in Specific Aim 3, we will evaluate pharmacologic modulation of the BGTC motor network, with an aim to understand the temporal relationships between symptom amelioration and network modulation. Taken together, we will significantly enhance the existing BGTC motor network wiring diagram by elucidating the role of motor network coupling in PD. Addressing this fundamental knowledge gap will facilitate therapeutic innovations, including identification of control signals that can be used for closed loop DBS as well as provide a wiring diagram of the BGTC motor circuit that could guide pharmacologic innovation.