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 nigrostriatal dopamine neurons with resulting striatal dopamine depletion. The causes of dystonia are more numerous. 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 equivalent degrees of 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 PET imaging will be used to measure the severity of dystonia, 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: 1) to determine to determine the relationship of resting pallidal discharge rates, patterns, and synchronization to dystonia and parkinsonism;2) to determine specific changes in movement-related neuronal activity that accompany dystonia and parkinsonism;3) to determine whether there is loss of somatotopic selectivity in the sensorimotor region of putamen and whether the loss of somatotopic selectivity in globus pallidus is due to abnormal signal processing in the putamen.
These aims will test specific hypotheses of basal ganglia dysfunction related to dystonia and parkinsonism. The results from this study will advance our understanding of the pathophysiology of parkinsonism and dystonia in ways not possible from studies in rodent models or in human subjects. Better understanding of the pathophysiology may lead to new therapies or improved application of currently available therapies.
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