Neurophysiological Mechanisms Underlying Parkinsonian Motor Signs

帕金森运动体征背后的神经生理机制

• 批准号: 10443540
• 负责人: LUKE Aaron JOHNSON
• 金额: $ 63万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443540
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Anterior; Area; Basal Ganglia; Bradykinesia; Brain region; Cells; Characteristics; Coupling; Data; Deep Brain Stimulation; Development; Diagnosis; Disease; Dopamine; Dorsal; Drug-Induced Dyskinesia; Dyskinetic syndrome; Electric Stimulation; Evolution; Frequencies; Functional disorder; Funding; Future; Gait; Globus Pallidus; Goals; Individual; L-DOPA induced dyskinesia; Levodopa; MPTP model; Magnetism; Modeling; Motor; Motor Cortex; Movement; Neurons; Nodal; Parkinson Disease; Parkinsonian Disorders; Pattern; Peripheral Nerve Stimulation; Persons; Physiological; Population; Prefrontal Cortex; Preparation; Rest; Role; Sensory; Severities; Site; Somatosensory Cortex; Structure; Structure of subthalamic nucleus; Thalamic structure; Transcranial magnetic stimulation; Work; base; design; gene therapy; improved; motor disorder; motor symptom; neurophysiology; neuroregulation; nonhuman primate; receptive field; response; sensory cortex; somatosensory; targeted treatment; therapy development

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to characterize the evolution of changes in neuronal activity and connectivity that occur within and across nodal points in the basal ganglia thalamocortical (BGTC) circuit using a progressive nonhuman primate (NHP) model of Parkinson’s disease (PD). Simultaneous recordings from populations of neurons as well as local field potential (LFP) activity will be made from the basal ganglia, motor and sensory thalamus, primary motor (MC) and sensory cortex (S1) as well as dorsal premotor (PMd), supplementary motor area (SMA) and dorsolateral prefrontal (DLPFC) cortices in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) progressive model of PD. Data will be collected during both rest and movement, on and off L-dopa and on L-dopa during drug-induced dyskinesia. A within-subject design will be used as animals progress from the normal to mild, moderate and severe conditions of parkinsonism. Specific Aim 1 will characterize changes in coupling and connectivity that occur between the subthalamic nucleus, internal and external segments of the globus pallidus, motor thalamus (ventralis anterior (VA), ventralis lateralis, pars oralis (VLo), ventralis posterior lateralis, pars oralis (VPLo), and cortical areas involved in the planning, preparation and execution of movement (PMd, DLPFC, SMA, and MC). Specific Aim 2 will examine the effect of dopaminergic therapy (L-dopa) on subcortical↔cortical connectivity and the relationship of these changes to improvement in motor signs and the development of L-dopa induced dyskinesia (LID). Specific Aim 3 will characterize the changes and contribution of altered sensorimotor processing in thalamo↔cortical and cortical↔cortical circuits (MC-S1). This proposal will define the relationship between changes in synchronized oscillatory activity in, and effective connectivity between, subcortical↔cortical and cortical↔cortical regions of the broader BGTC network to parkinsonian motor signs as they develop, progress in severity, and improve with L-dopa. It will also characterize the role of changes in different frequency spectrums to the preparation, planning and execution of movement, as well as the contribution of sensory dysfunction in thalamocortical circuits to the motor dysfunction observed in PD. A better understanding of the role of individual motor circuits and the types of physiological changes that occur within these circuits and how they relate to the development of individual motor signs will provide the rationale for the development of new targets and neuromodulation therapies directed at restoring a more normal pattern of activity in the BGTC circuit.

项目总结/摘要 该提案的目标是描述神经元活动和连接变化的演变， 发生在基底神经节丘脑皮质（BGTC）回路中的节点内和节点之间， 帕金森病（PD）的非人灵长类动物（NHP）模型。同时记录了 神经元以及局部场电位（LFP）活动将由基底神经节、运动和感觉神经元产生。 丘脑、初级运动（MC）和感觉皮层（S1）以及背侧运动前区（PMd）、辅助运动区 1-甲基-4-苯基-1，2，3，6-四氢吡啶中的SMA和背外侧前额叶（DLPFC）皮质 （MPTP）PD的进展模型。数据将在休息和运动期间、服用和不服用左旋多巴期间收集， 在药物诱发的运动障碍中服用左旋多巴当动物从以下阶段进展时，将使用受试者内设计： 正常至轻度、中度和重度帕金森病。具体目标1将描述 发生在丘脑底核、大脑内节和外节之间的耦合和连接 苍白球、运动丘脑（腹前肌（VA）、腹外侧肌、口部（VLo）、腹后肌 外侧部、口部（VPLo）和参与运动的计划、准备和执行的皮质区 (PMd、DLPFC、SMA和MC）。具体目标2将检查多巴胺能治疗（左旋多巴）对 皮层下参与皮层连接以及这些变化与运动体征改善的关系， L-多巴诱导的运动障碍（LID）的发展。具体目标3将描述变化和贡献 丘脑参与皮层和皮层参与皮层回路（MC-S1）的感觉运动处理改变。这项建议会 定义同步振荡活动变化与有效连通性之间的关系 在更广泛的BGTC网络的皮质下参与皮质和皮质参与皮质区域之间， 随着病情的发展，病情的严重程度逐渐加重，并在左旋多巴的治疗下有所改善。它还将描述变化的作用， 在不同的频谱，以准备，规划和执行的运动，以及 丘脑皮层回路中感觉功能障碍对PD中观察到的运动功能障碍的贡献。更好的 了解个体运动回路的作用和发生在体内的生理变化的类型 这些回路以及它们如何与个体运动标志的发展相关，将为以下研究提供理论基础： 开发新的靶点和神经调节疗法，旨在恢复更正常的活动模式 在BGTC电路。