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: 10643904
• 负责人: LUKE Aaron JOHNSON
• 金额: $ 63.14万
• 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/10643904
• 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; MPTP non-human primate; 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; 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.

项目概要/摘要 该提案的目标是描述神经活动和连接变化的演变特征，这些变化 使用渐进式，发生在基底节丘脑皮质 (BGTC) 回路的节点内和节点之间 帕金森病（PD）的非人类灵长类动物（NHP）模型的同时记录。 神经元以及局部场电位 (LFP) 活动将由基底神经节、运动神经节和感觉神经节产生 丘脑、初级运动 (MC) 和感觉皮层 (S1) 以及背侧前运动 (PMd)、辅助运动 1-甲基-4-苯基-1,2,3,6-四氢吡啶中的区域（SMA）和背外侧前额叶皮层（DLPFC） (MPTP) PD 渐进模型将在休息和运动期间收集左旋多巴和非左旋多巴的数据。 当动物从药物引起的运动障碍期间进行左旋多巴治疗时，将使用受试者内设计。 正常至轻度、中度和重度帕金森病的特征是特定目标 1 的变化。 丘脑底核、丘脑内部和外部部分之间发生的耦合和连接 苍白球、运动丘脑（前腹肌 (VA)、外侧腹肌、口部 (VLo)、后腹肌 外侧肌、口部 (VPLo) 和参与运动规划、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-多巴）对患者的影响。 皮质下↔皮质连接以及这些变化与运动体征改善和 左旋多巴诱发的运动障碍 (LID) 的发展将描述变化和贡献。 该提案将改变丘脑↔皮质和皮质↔皮质回路中的感觉运动处理。 定义同步振荡活动的变化与有效连接之间的关系 更广泛的 BGTC 网络的皮质下↔皮质和皮质↔皮质区域之间到帕金森运动 随着症状的发展、严重性的进展以及左旋多巴的改善，它也将表征变化的作用。 在不同的频谱中进行运动的准备、计划和执行，以及 丘脑皮质回路中的感觉功能障碍对 PD 中观察到的运动功能障碍的影响更好。 了解各个运动回路的作用以及内部发生的生理变化类型 这些电路以及它们与各个运动信号的发展的关系将为以下问题提供理论基础： 开发新靶点和神经调节疗法，旨在恢复更正常的活动模式 在BGTC电路中。

项目成果

Thalamic post-inhibitory bursting occurs in patients with organic dystonia more often than controls.

器质性肌张力障碍患者的丘脑抑制后爆发比对照组更常见。

• DOI: 10.1016/j.brainres.2013.10.006
• 发表时间: 2013-12-06
• 期刊: BRAIN RESEARCH
• 影响因子: 2.9
• 作者: Kobayashi, K.;Liu, C. C.;Jensen, A. L.;Vitek, J. L.;Mari, Z.;Lenz, F. A.
• 通讯作者: Lenz, F. A.

Standard guidelines for publication of deep brain stimulation studies in Parkinson's disease (Guide4DBS-PD).

• DOI: 10.1002/mds.23151
• 发表时间: 2010-08-15
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Vitek JL;Lyons KE;Bakay R;Benabid AL;Deuschl G;Hallett M;Kurlan R;Pancrazio JJ;Rezai A;Walter BL;Lang AE
• 通讯作者: Lang AE