Neurophysiological Mechanisms Underlying Parkinsonian Motor Signs

项目摘要/摘要 这项提议的目标是表征神经元活动和连接性的变化的演变 发生在基底节丘脑皮质(BGTC)环路的结点内和结点之间 帕金森病(PD)的非人灵长类(NHP)模型。来自多个种群的同步录音 神经元和局部场电位(LFP)活动将由基底节、运动和感觉产生 丘脑、初级运动(MC)和感觉皮质(S1)以及背侧前运动(PMD)、辅助运动 1-甲基-4-苯基-1，2，3，6-四氢吡啶的面积(SMA)和背外侧前额叶(DLPFC)皮质 (MPTP)帕金森病进行性模型。数据将在休息和运动时收集，在L-多巴和 药物性运动障碍时L-多巴的研究。受试者内的设计将被用于动物从 正常至轻度、中度和重度帕金森氏症。具体目标1将描述 发生在丘脑底核、丘脑内侧段和外侧段之间的耦合和连接。 苍白球、运动丘脑(腹前(VA)、腹外(VLO)、腹后(VLO) 参与运动计划、准备和执行的外侧肌、口部(VPLo)和皮质区 (PMD、DLPFC、SMA和MC)。具体目标2将检查多巴胺能疗法(L-多巴)对 皮质下↔皮质连通性及其与运动体征和运动功能改善的关系 L-多巴诱发运动障碍(LID)的研究进展具体目标3将描述变化和贡献 丘脑↔皮质和皮质↔皮质环路(MC-S1)感觉运动处理的改变。这项提议将 定义中同步振荡活动的变化与有效连通性之间的关系 在皮质下↔皮质和皮质↔皮质区域之间的更广泛的BGTC网络到帕金森病运动 症状随着病情的发展、严重程度的进展，并随着L-多巴的改善而改善。它还将描述变化的作用 在不同的频谱中准备、计划和执行动作，以及 丘脑皮质环路感觉障碍在帕金森病患者运动功能障碍中的作用。更好的 了解单个马达回路的作用和发生的生理变化类型 这些电路以及它们与单个运动标志的发展之间的关系将为 旨在恢复更正常活动模式的新靶点和神经调节疗法的开发 在BGTC电路中。

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.