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: 9356357
• 负责人: NADER POURATIAN
• 金额: $ 52.64万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9356357
• 关键词: Address; Apomorphine; Area; Basal Ganglia; Behavior; Behavioral; Biological Markers; Bradykinesia; Brain; Clinical; Conflict (Psychology); Coupling; Deep Brain Stimulation; Development; Disease; Dorsal; Electrophysiology (science); Evolution; Frequencies; Functional disorder; Globus Pallidus; Goals; Health Expenditures; Investigation; Knowledge; Lead; Literature; Measures; Mediating; Monitor; Motor; Motor Cortex; Movement; Neurons; Operative Surgical Procedures; Output; Parkinson Disease; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Physiological Processes; Physiology; Precision therapeutics; Prevalence; Process; Quality of life; Reporting; Resolution; Rest; Role; Signal Transduction; Site; Structure of subthalamic nucleus; Symptoms; System; Techniques; Testing; Thalamic structure; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Variant; Work; behavior measurement; design; disability; implantation; improved; innovation; kinematics; motor disorder; motor symptom; network dysfunction; novel; novel therapeutics; response; symptomatology; targeted treatment; theories; therapeutic target

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.

项目摘要/摘要 帕金森氏病（PD）运动症状（PD）的病理生理学仍然不完全 了解基本不同节点中神经元活动变化的最新报道 神经节 - 丘脑皮质（BGTC）电路。解决结果相互矛盾的统一方法是 需要。强调电路中节点之间的相对不充实的动态关系，我们构建 在夸张的网络级耦合的假设是基础的病理生理过程 通过阻碍有效的信息流，PD的刚性和头肌障碍。根据，我们提出了调制 网络耦合是药物和手术疗法的常见治疗机制；其他 生理后遗症特定于理论干预的目标，并解释了不同的结果 文学。我们将简单地评估与临床症状有关的皮质和皮质生理。 并响应大脑刺激（DBS），患者的皮质刺激和药物结肠疗法 接受DBS植入手术。这种方法使得对空间特定皮质的卓越投资 现象与司法研究相比。我们建议理解 扩展BGTC网络的功能连通性，不仅包括丘脑下丘脑的运动皮质 核（STN）和大多数研究一样 基底神经节的输出）和补充运动区域（SMA）和背侧前皮层（PMD）的输出 苍白接收的丘脑地区主要投射出来。此外，我们的分析将集中在 低β振荡相对于正常运动功能的高β振荡的差异性物理意义， 疾病和治疗干预。在特定目标1中，我们旨在了解 在休息和移动时，未经处理的BGTC电动机网络在PD中都具有特定的优势 疾病症状学的变化（通过客观的临床评级量表和全面测量 运动学）简单地记录了网络连接性的度量。在特定目标2中，我们将使用 皮质和皮质刺激在BGTC电动机网络中特异性驱动不同的节点，以便为了 确认网络耦合是治疗性脑刺激的基础机制，无论如何 目标，还可以确定目标特定效应，以说明DBS的已知临床差异 STN与GPI。最后，在特定的目标3中，我们将评估BGTC电动机的药物结肠调制 网络，目的是了解症状改善与网络之间的临时关系 调制。综上所述，我们将通过 阐明电动机网络耦合在PD中的作用。解决这个基本知识差距将有助于 治疗创新，包括识别可用于闭环DB的控制信号 如提供了BGTC电机电路的接线图，该电路可以指导药物创新。