PATHOPHYSIOLOGY OF DYSTONIA AND PARKINSONISM

在北美，帕金森氏症(PD)影响着近100万人，肌张力障碍影响着多达50万人。人们普遍认为帕金森病的运动表现是由于黑质纹状体多巴胺神经元的退化而导致纹状体多巴胺的耗竭。最近的证据表明，肌张力障碍(产生扭转姿势的非自愿肌肉收缩)也可能与纹状体多巴胺神经传递不足有关。已有研究表明，颈内动脉注射MPTP所致的单侧纹状体多巴胺耗竭可引起双相障碍，表现为一过性肌张力障碍，继而是稳定型帕金森病。肌张力障碍和帕金森综合症与纹状体多巴胺缺乏的关联提出了关于这些疾病的基本病理生理学的问题。本项目的目的是通过记录训练为执行触达任务的猴子服用MPTP前后苍白球神经元的活动，来研究帕金森病和肌张力障碍的病理生理学。定量行为学方法和[18F]FDOPA PET成像将用于测量帕金森综合症和多巴胺耗竭的严重程度。在MPTP前、MPTP后一过性肌张力障碍期和慢性帕金森病病期记录到猴苍白球内段(GPI)和外段(GPE)单个神经元的活动。其具体目标是：1)确定静息苍白球放电频率和模式与肌张力障碍和帕金森病的关系；2)确定肌张力障碍和帕金森病是否普遍存在纹状体多巴胺缺乏所致的躯体感觉感受野扩大；3)确定伴随肌张力障碍和帕金森病的运动相关神经元活动的具体变化。这些目标将检验与肌张力障碍和帕金森症相关的基底节功能障碍的具体假设。这项研究的结果将补充该计划中其他项目的结果，并将进一步了解帕金森症和肌张力障碍的病理生理学。更好地了解病理生理学可能会导致新的治疗方法或改进目前可用的治疗方法的应用。

Parkinson's disease (PD) affects nearly one million people and dystonia affects up to 500,000 people in North America. It is generally accepted that the motor manifestations of PD are due to degeneration of nigrastriatal dopamine neurons with resulting striatal dopamine depletion. Recent evidence has indicated that dystonia (involuntary muscle contractions that produce twisting postures) can also be associated with deficiencies in striatal dopamine neurotransmission. In monkeys, it has been shown that unilateral striatal dopamine depletion induced by intracarotid injection of MPTP causes a biphasic disorder with transient dystonia followed by stable parkinsonism. The association of both dystonia and parkinsonism with striatal dopamine deficiency raises questions about the fundamental pathophysiology of these conditions. The purpose of this project is to investigate the pathophysiology of parkinsonism and dystonia by recording the activity of globus pallidus neurons before and after the administration of MPTP in monkeys trained to perform a reaching task. Quantitative behavioral methods and [18F]FDOPA PET imaging will be used to measure the severity of parkinsonism and dopamine depletion. The activity of single neurons in globus pallidus internal segment (GPi) and external segment (GPe) will be recording in monkeys before MPTP and in the transient dystonic phase and chronic parkinsonian phase after MPTP. The specific aims are l) to determine the relationship of resting pallidal discharge rates and patterns to dystonia and parkinsonism, 2) to determine if there is expansion of somatosensory receptive fields due to striatal dopamine deficiency that is common to both dystonia and parkinsonism, and 3) to determine specific changes in movement-related neuronal activity that accompany dystonia and parkinsonism. These aims will test specific hypotheses of basal ganglia dysfunction related to dystonia and parkinsonism. The results from this study will complement those from the other projects in this program and will further understanding of the pathophysiology of parkinsonism and dystonia. Better understanding of the pathophysiology may lead to new therapies or improved application of currently available therapies.