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.

项目概要/摘要 帕金森病 (PD) 运动症状的病理生理学仍然不完全 最近关于基底核内不同节点神经活动变化的相互矛盾的报告可以理解 神经节-丘脑皮质 (BGTC) 运动回路是解决相互矛盾的结果的统一方法。 强调电路中节点之间相对未被充分探索的动态关系，我们建立了。 假设夸大的网络级耦合是潜在的病理生理过程 通过阻碍有效信息流来缓解PD的僵化和运动迟缓因此，我们建议进行调制。 网络耦合是药物和手术治疗的共同机制； 生理后遗症因治疗干预的目标而异，并导致不同的结果 我们将同时评估与临床症状相关的皮质和皮质下生理学。 以及对患者深部脑刺激（DBS）、皮质刺激和药物治疗的反应 接受 DBS 植入手术，这种方法可以对空间特定的皮质进行更好的研究。 与术外研究相比，我们认为了解这一现象至关重要。 扩展 BGTC 网络的功能连接，不仅包括运动皮层与底丘脑 正如大多数研究所做的那样，它与苍白球核（STN）相连，而且还与苍白球内部（GPi，最后的常见 基底神经节的输出）以及辅助运动区（SMA）和背侧前运动皮层（PMd）， 此外，我们的分析将集中于苍白球接收丘脑区域的主要投射位置。 低β振荡与高β振荡相对于正常运动功能的不同生理意义， 在具体目标 1 中，我们旨在了解疾病的临床相关性。 未经治疗的 BGTC 运动网络在静息和运动时的 PD 中均发挥了特定的优势 疾病症状的变化（通过客观的临床评级量表和综合评估来衡量） 在特定目标 2 中，我们将使用同步记录的网络连接测量。 皮质下和皮质刺激专门扰乱 BGTC 运动网络中的不同节点，以便 确认网络耦合是治疗性脑刺激的共同机制，无论 的目标，并确定可以解释 DBS 已知临床差异的目标特异性效应 STN 与 GPi 最后，在具体目标 3 中，我们将评估 BGTC 运动的药理调节。 网络，旨在了解症状改善与网络之间的时间关系 综合起来，我们将通过以下方式显着增强现有的 BGTC 电机网络接线图。 阐明运动网络耦合在局部放电中的作用将有助于解决这一基本知识差距。 治疗创新，包括识别可用于闭环 DBS 的控制信号 提供了 BGTC 运动电路的接线图，可以指导药理学创新。