The Pathophysiology of Network Synchrony in Parkinson's Disease

帕金森病网络同步的病理生理学

• 批准号: 10429875
• 负责人: NADER POURATIAN
• 金额: $ 24.65万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429875
• 关键词: Pathophysiology; Network; Synchrony; Parkinson; Disease

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.

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 接受脑深部电刺激（DBS）植入手术。这种方法可以上级地调查 与手术外研究相比，空间特异性皮质现象。我们认为， 重要的是要了解扩展的BGTC网络的功能连接，不仅包括电机 与大多数研究一样，大脑皮层与丘脑底核（subthalamic nucleus，ENA）相连，但也与苍白球内部相连 (GPi基底神经节的最终共同输出）和辅助运动区（SMA）以及背侧 运动前皮质（PMd），其是苍白球接收丘脑区域主要投射的地方。而且我们 分析将集中在低与高β振荡的不同生理意义上， 正常运动功能、疾病和治疗干预。在具体目标1中，我们旨在了解 未治疗的BGTC运动网络在休息和运动时的临床相关性， 疾病分类学中时间变化的优势（用客观临床评定量表测量 和综合运动学），同时记录网络连接性的测量。在特定 目的2，我们将使用皮层下和皮层刺激，专门扰动不同的节点在BGTC运动 网络，以确认网络耦合是治疗脑的共同机制 刺激，而不管目标，并且还识别可以解释已知临床症状的目标特异性效应。 DBS与GPi的差异。最后，在具体目标3中，我们将评估 BGTC运动网络，目的是了解症状改善之间的时间关系 和网络调制。综上所述，我们将大大加强现有的BGTC电机网络布线 图通过阐明运动网络耦合在PD中的作用。解决这一基本知识差距 将促进治疗创新，包括识别可用于闭环控制的控制信号。 DBS，以及提供BGTC电机电路的接线图，可以指导药理学创新。