PATHOPHYSIOLOGY OF DYSTONIA AND PARKINSONISM

点击翻译按钮获取中文摘要

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.