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; 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.

项目摘要/摘要 该提案的目的是表征神经元活动和连通性变化的演变 使用渐进性，发生在基底神经节丘脑皮质（BGTC）电路中的淋巴结点内和跨点。 帕金森氏病（PD）的非人类灵长类动物（NHP）模型。同时记录 神经元以及局部场电位（LFP）活性将由巴萨神经节，运动和感觉 丘脑，主电动机（MC）和感觉皮层（S1）以及背侧预运动器（PMD），补充电动机 1-甲基-4-苯基-1,2,3,6-二亚吡啶的区域（SMA）和背外侧前额叶（DLPFC）皮质 （MPTP）PD的渐进模型。数据将在休息和移动期间，在L-DOPA内外收集 在药物引起的运动障碍期间在L-DOPA上。主体内设计将被用作动物从 特定的目标1将表征变化 丘脑下核，内部和外部段之间发生的耦合和连通性 Globus pallidus，运动丘脑（Ventralis前（VA），ventralis furnalis，Pars Oralis（VLO），ventralis后部 外侧，pars Oralis（VPLO）和涉及运动计划，准备和执行的皮质区域 （PMD，DLPFC，SMA和MC）。具体目标2将检查多巴胺能疗法（L-DOPA）对 皮层下皮层连通性以及这些变化与运动迹象的改善和 L-DOPA诱导运动障碍（LID）的发展。特定目标3将表征变化和贡献 丘脑皮质和皮质cortical圈（MC-S1）中的感觉运动加工的改变。该提议将 定义同步振荡活动的变化与有效连通性之间的关系 在帕金森氏电机的较宽BGTC网络的皮层皮层和皮层↔皮质和皮质区域之间 随着符号的发展，严重程度的进展以及L-DOPA的改善。它还将表征变化的作用 在不同的频谱中，运动的准备，计划和执行以及 丘脑皮质圆中感觉功能障碍对PD中观察到的运动功能障碍的贡献。更好 了解单个电机电路的作用以及内部发生的身体变化的类型 这些电路及其与单个电机标志的发展如何相关 开发旨在恢复活动模式的新靶标和神经调节疗法 在BGTC电路中。