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: 10753285
• 负责人: NADER POURATIAN
• 金额: $ 67.07万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753285
• 关键词: Accounting; Address; Affect; Apomorphine; Area; Basal Ganglia; Behavior; Behavioral; Bradykinesia; Brain; Clinical; Communication; Coupling; Deep Brain Stimulation; Development; Disease; Dissociation; Dorsal; Entropy; Etiology; Event; Failure; Frequencies; Functional disorder; Globus Pallidus; Goals; Health Expenditures; Impairment; Information Theory; Knowledge; Laws; Measurement; Modeling; Monitor; Motor; Motor Cortex; Movement; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Nature; Operative Surgical Procedures; Parkinson Disease; Pathologic; Pathology; Pathway Analysis; Patients; Pattern; Phase; Physiological; Physiology; Population; Prevalence; Probability; Publishing; Quality of life; Reporting; Research; Rest; Signal Transduction; Site; Structure of subthalamic nucleus; Symptoms; System; Techniques; Testing; Thalamic structure; Therapeutic; Treatment Efficacy; Variant; Work; biomarker identification; design; disability; dynamic system; implantation; improved; innovation; insight; kinematics; motor symptom; network dysfunction; novel; novel therapeutics; pharmacologic; programs; success; symptomatology; temporal measurement; volunteer

Project Summary/Abstract The physiological underpinning of motor symptoms in Parkinson disease (PD) remains incompletely understood. We propose that the dynamic nature of basal ganglia thalamocortical (BGTC) network activity accounts for and is critical for understanding the dynamic symptomatology of PD and the pathophysiology of disease. We believe that the failure to focus on and investigate the non-stationarity of BGTC physiology and movement kinematics significantly contributes to inconsistency in published results and has impeded progress. We propose and investigate a novel model that accounts for the underexplored temporally dynamic cascade of physiological events occurring between nodes in the BGTC motor circuit. We hypothesize that transient exaggerations in network-level coupling that result in impaired information flow trigger pathophysiological and motor sequelae of PD, including rigidity and bradykinesia, allowing for and differentiating pathological and non-pathological synchrony. We hypothesize that the likelihood of pathological synchrony resulting in impaired information flow depends on the “movement” state, accounting for disproportionate difficulty with movement initiation in PD. We also hypothesize that treatment (dopaminergic and deep brain stimulation [DBS]) decreases the probability of a synchrony-triggered pathological cascade, with some common final changes in the network (e.g., cortical phase amplitude coupling) but with specific differences in physiological effects due to distinct sites of therapeutic action. We will build on prior success of investigating PD network physiology in patients undergoing DBS implantation surgery by simultaneously assessing population level activity from multiple BGTC nodes, including motor cortex, dorsal premotor cortex (to where pallidal-receiving thalamic regions project), subthalamic nucleus (STN), and globus pallidus (GPi, in separate patients), in relation to clinical symptoms and behavior. We now also integrate single unit physiology and synchronized dynamic tasks to test our model. In Aim 1, we will establish the dynamic relationship between network synchronization, local oscillations, and pathophysiologic sequelae under different therapeutic conditions, including STN and GPi DBS and dopaminergic therapy. We hypothesize an increased probability of synchrony leading to pathologic sequelae in the “off” state and test specific hypotheses about both common and distinct physiological effects of the different therapies, depending on site of action. In Aim 2, we hypothesize and aim to demonstrate that movement-related brain states affect sequelae of network synchrony both physiologically and behaviorally, differentially impacting movement initiation and ongoing activity. Finally, in Aim 3, we will distinguish normal and pathologic synchrony (across therapeutic and movement conditions) using a novel information theoretic frameowrk, with a focus on the impact of criticality, complexity matching, and impairments in information flow. This work will enhance the BGTC functional wiring diagram by defining the pathophysiologic significance of network synchrony in PD. Addressing this gap will facilitate therapeutic innovations, including identification of signals for adaptive DBS and to guide pharmacologic innovation.

项目概要/摘要 帕金森病 (PD) 运动症状的生理基础仍不完全清楚。 我们提出基底神经节丘脑皮质（BGTC）网络活动的动态性质解释和 对于理解帕金森病的动态症状和疾病的病理生理学至关重要。我们相信 未能关注和研究BGTC生理学和运动运动学的非平稳性 极大地导致了已发表结果的不一致并阻碍了进展。我们建议并 研究一种新模型，该模型解释了尚未充分探索的生理学时间动态级联 BGTC 电机电路中的节点之间发生的事件。我们假设短暂的夸大 导致信息流受损的网络级耦合会引发病理生理和运动后遗症 PD，包括强直和运动迟缓，允许并区分病理性和非病理性 同步。我们假设病理同步导致信息流受损的可能性 取决于“运动”状态，解释了 PD 中运动启动的不成比例的困难。我们 还假设治疗（多巴胺能和深部脑刺激 [DBS]）会降低 同步触发的病理级联，网络中存在一些常见的最终变化（例如，皮质阶段 幅度耦合），但由于治疗作用的不同部位，生理效应存在特定差异。 我们将在先前成功调查接受 DBS 植入的患者的 PD 网络生理学的基础上 通过同时评估多个 BGTC 节点（包括运动皮层）的群体水平活动来进行手术， 背侧前运动皮层（苍白球接收丘脑区域投射的地方）、丘脑底核（STN）和 苍白球（GPi，在不同的患者中）与临床症状和行为的关系。我们现在还整合了 单个单元生理学和同步动态任务来测试我们的模型。在目标 1 中，我们将建立动态 不同条件下网络同步、局部振荡和病理生理后遗症之间的关系 治疗条件，包括 STN 和 GPi DBS 以及多巴胺能疗法。我们假设增加 同步导致“关闭”状态下的病理后遗症的概率，并测试关于两者的具体假设 不同疗法的共同和独特的生理效应取决于作用部位。在目标 2 中，我们 假设并旨在证明与运动相关的大脑状态会影响网络同步的后遗症 在生理和行为上，对运动开始和持续活动产生不同的影响。最后， 在目标 3 中，我们将区分正常和病理同步（跨治疗和运动条件） 使用新颖的信息理论框架，重点关注关键性、复杂性匹配和 信息流通障碍。这项工作将通过定义以下内容来增强 BGTC 功能接线图： 网络同步在 PD 中的病理生理学意义。解决这一差距将有助于治疗 创新，包括识别自适应 DBS 信号并指导药理学创新。

项目成果

Propofol-induced Changes in α-β Sensorimotor Cortical Connectivity.

丙泊酚诱导的α-β感觉运动皮质连通性的变化。

• DOI: 10.1097/aln.0000000000001940
• 发表时间: 2018-03
• 期刊: Anesthesiology
• 影响因子: 8.8
• 作者: Malekmohammadi M;AuYong N;Price CM;Tsolaki E;Hudson AE;Pouratian N
• 通讯作者: Pouratian N

Impulsivity Relates to Relative Preservation of Mesolimbic Connectivity in Patients with Parkinson Disease.

冲动与帕金森病患者中脑边缘连接的相对保留有关。

• DOI: 10.1016/j.nicl.2020.102259
• 发表时间: 2020
• 期刊: NeuroImage. Clinical
• 作者: Sparks,Hiro;Riskin-Jones,Hannah;Price,Collin;DiCesare,Jasmine;Bari,Ausaf;Hashoush,Nadia;Pouratian,Nader
• 通讯作者: Pouratian,Nader

Dorsal visual stream is preferentially engaged during externally guided action selection in Parkinson Disease.

• DOI: 10.1016/j.clinph.2021.11.077
• 发表时间: 2022-04
• 期刊: Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology
• 作者: Sparks H;Cross KA;Choi JW;Courellis H;Thum J;Koenig E;Pouratian N
• 通讯作者: Pouratian N

Pallidal stimulation in Parkinson disease differentially modulates local and network β activity.

• DOI: 10.1088/1741-2552/aad0fb
• 发表时间: 2018-10
• 期刊: Journal of neural engineering
• 影响因子: 4
• 作者: Malekmohammadi M;Shahriari Y;AuYong N;O'Keeffe A;Bordelon Y;Hu X;Pouratian N
• 通讯作者: Pouratian N

Movement-Modulation of Local Power and Phase Amplitude Coupling in Bilateral Globus Pallidus Interna in Parkinson Disease.

• DOI: 10.3389/fnhum.2018.00270
• 发表时间: 2018
• 期刊: Frontiers in human neuroscience
• 影响因子: 2.9
• 作者: AuYong N;Malekmohammadi M;Ricks-Oddie J;Pouratian N
• 通讯作者: Pouratian N