The Pathophysiology of Network Synchrony in Parkinson's Disease

项目摘要/摘要 帕金森病(PD)运动症状的病理生理学基础尚不完全 与最近关于基底节内不同节点神经元活动变化的相互矛盾的报道相一致 神经节-丘脑皮质(BGTC)运动回路。一种解决相互冲突的结果的统一方法是 需要的。强调了电路中节点之间相对未被探索的动态关系，我们建立了 基于夸大的网络水平耦合是基础的病理生理过程的假说 通过阻碍有效的信息流，导致帕金森病的僵化和运动迟缓。因此，我们提出了调制 网络耦合是跨药物治疗和外科治疗的共同治疗机制；其他 生理性后遗症是特定于治疗干预的目标的，并解释了不同的结果 文学作品。我们将根据临床症状同时评估皮质和皮质下的生理学。 以及对脑深部刺激(DBS)、皮质刺激和药物治疗的反应 正在接受脑深部刺激(DBS)植入手术。这种方法能够更好地调查 与术外研究相比，在空间上特定的皮质现象。我们认为，这是一种严重的 了解扩展的BGTC网络的功能连接非常重要，不仅包括电机 与大多数研究一样，带丘脑底核的皮质(STN)也与苍白内球相连 (GPI，基底节的最终共同输出)、辅助运动区(SMA)和背侧 运动前皮质(PMD)，这是主要投射苍白球的丘脑区域。而且，我们的 分析将集中在低和高β振荡的区别生理学意义上 运动功能正常、疾病及治疗干预。在具体目标1中，我们的目标是了解 未经治疗的BGTC运动网络在静息和运动中的临床相关性 疾病症状学时间变异的优势(用客观临床评定量表衡量) 和综合运动学)，同时记录网络连通性的测量。具体而言 目标2，我们将使用皮质下和皮质刺激来特异性地干扰BGTC运动中不同的结节 网络，以证实网络耦合是治疗脑的共同机制 刺激，而不考虑目标，并确定目标特定的影响，可以解释已知的临床 STN与GPI的DBS差异。最后，在特定的目标3中，我们将评估药物对 BGTC运动网络，旨在了解症状改善之间的时间关系 和网络调制。综上所述，我们将显著增强现有的BGTC电机网络布线 通过阐明运动网络耦合在帕金森病中的作用。解决这一根本的知识鸿沟 将促进治疗创新，包括识别可用于闭环系统的控制信号 DBS，以及提供BGTC马达电路的接线图，以指导药物创新。

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 deep brain stimulation (DBS) implantation surgery. This approach enables superior investigation of spatially specific cortical phenomenon 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 is 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 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.