PATHOPHYSIOLOGY OF DYSTONIA AND PARKINSONISM

帕金森病（PD）影响近一百万人，肌张力障碍影响北美多达50万人。一般认为，PD的运动表现是由于黑质纹状体多巴胺神经元变性导致纹状体多巴胺耗竭。最近的证据表明，肌张力障碍（产生扭曲姿势的不自主肌肉收缩）也可能与纹状体多巴胺神经传递的不足有关。在猴子中，已经表明，由颈动脉内注射MPTP诱导的单侧纹状体多巴胺耗竭导致双相障碍，即短暂性肌张力障碍，随后是稳定的帕金森综合征。肌张力障碍和帕金森综合征与纹状体多巴胺缺乏症的相关性提出了关于这些疾病的基本病理生理学的问题。本项目的目的是研究帕金森综合征和肌张力障碍的病理生理学通过记录苍白球神经元的活动之前和之后的管理MPTP在猴子训练执行达到的任务。定量行为方法和[18 F]FDOPA PET成像将用于测量帕金森综合征和多巴胺耗竭的严重程度。在MPTP前、MPTP后的短暂张力障碍期和慢性帕金森病期记录猴苍白球内段（GPi）和外段（GPe）单个神经元的活动。具体目的是：1）确定静息苍白球放电率和模式与肌张力障碍和帕金森综合征的关系，2）确定是否存在由于纹状体多巴胺缺乏引起的躯体感觉感受野扩大，这是肌张力障碍和帕金森综合征的共同点，3）确定伴随肌张力障碍和帕金森综合征的运动相关神经元活动的具体变化。这些目标将测试与肌张力障碍和帕金森症相关的基底神经节功能障碍的特定假设。这项研究的结果将补充该项目中其他项目的结果，并将进一步了解帕金森综合征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善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.