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.

项目摘要/摘要 帕金森氏病（PD）中运动症状的身体基础尚不完全理解。 我们建议基底神经节丘脑皮质（BGTC）网络活动的动态性质是占和 对于理解PD的动态症状和疾病的病理生理至关重要。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 显着导致已发表的结果不一致，并阻碍了进步。我们提出了建议 研究一个新的模型，该模型解释了生理的暂时动态级联 发生在BGTC电机电路中的节点之间的事件。我们假设在 网络级耦合导致信息流动流动触发病理生理和运动后遗症的受损 PD，包括刚度和铁趋化力，允许并区分病理学和非病理学 同步。我们假设病理同步的可能性导致信息流量受损 取决于“运动”状态，这是PD中运动计划的不成比例困难。我们 还假设治疗（多巴胺能和深脑刺激[DBS]）降低了 同步触发的病理级联反应，网络中有一些常见的最终变化（例如，皮质期 振幅耦合），但由于治疗作用的不同部位而与物理效应有特定的差异。 我们将在研究DBS植入的患者中研究PD网络生理的成功基础 通过简单地评估来自多个BGTC节点的人口水平活动，包括运动皮层， 背侧前皮层（到苍白的丘脑区域项目），丘脑核核us（STN）和 与临床症状和行为有关的Globus Pallidus（GPI，在单独的患者中）。我们现在也整合了 单位生理和同步动态任务以测试我们的模型。在AIM 1中，我们将建立动态 网络同步，局部振荡和病理生理后遗症之间的关系 治疗状况，包括STN和GPI DBS以及多巴胺能疗法。我们假设增加 同步的概率导致“ OFF”状态下的病理后遗症，并检验有关两者的特定假设 不同疗法的常见和独特的物理作用，具体取决于作用部位。在AIM 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 在身体和行为上，影响不同的运动计划和持续的活动。最后， 在AIM 3中，我们将区分正常和病理同步（交叉治疗和运动条件） 使用新型信息理论框架，重点是临界，复杂性匹配和 信息流的障碍。这项工作将通过定义 PD网络同步的病理生理意义。解决此差距将有助于治疗 创新，包括标识自适应DBS的信号和指导药理学创新。

项目成果

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

• 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 low β-low γ phase-amplitude coupling inversely correlates with Parkinson disease symptoms.

• DOI: 10.1016/j.clinph.2017.08.001
• 发表时间: 2017-11
• 期刊: Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology
• 作者: Tsiokos C;Malekmohammadi M;AuYong N;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