The overall aim of the present study is to assess the role of pallidotomy in the treatment of experimental parkinsonism and to explore the mechanism, in the experimental MPTP monkey model of Parkinson's disease (PD), whereby pallidotomy ameliorates the signs of PD. The recent demonstration in the primate model of parkinsonism, of increased levels of neuronal activity in the subthalamic nucleus (STN) and globus pallidus pars intima (GPi) and the finding that inactivation of either the STN of GPi can reverse akinesia, tremor, and rigidity suggests that these abnormalities results from excessive (inhibitory) pallidal output. The finding that akinesia. Furthermore, the recent elucidation of specific subchannels in the sensorimotor portion of GPi related to different precentral motor areas (motor cortex [MC], supplementary motor area [SMA], premotor cortex [PMC]) raises the questions of whether different cardinal features of PD (akinesia, bradykinesia, rigidity, tremor and drug-induced dyskineasias) are related to dysfunction of these specific sub-circuits. As yet, however, there has been little work in the monkey models of PD to explore the effects of GPI lesions on experimental parkinsonism and drug-induced dyskinesias, and whether lesions in regions of GPi which interrupt specific subchannels will have a differential effect of parkinsonian motor signs and drug-induced dyskinesia. Consistent with the hypothesis that the pallido-thalamic """"""""motor"""""""" circuits is responsible for the development of parkinsonian motor signs are earlier and recent reports that stereotactic lesions of the posteroventral (probable sensorimotor) portion of GPi in parkinsonian patients, can reverse the major motor abnormalities of PD as well as drug-induced dyskinesia. Thus, there is hope of improving motor function by surgical intervention for parkinsonian individuals who no longer derive benefit from medication or who cannot tolerate the dyskinesia and/or cognitive disturbances associated with drug therapy. Yet, much work remains to be done to determine which normalize activity in GPi while leaving the pallidothalamic projection and fibers passing through GPi intact, may be more effective. The studies in this proposal are directed at answering these questions. Specifically we will: 1) determine the optimal site of lesions in the pallidum for reversing parkinsonian motor signs and drug-induced dyskinesia, 2) determine whether specific subregions of GPi mediate specific parkinsonian signs (akinesia, bradykinesia, tremor and rigidity) and drug-induced dyskinesia, 3) determine whether bilateral lesions in GPi are more or less effective than GPi lesions in reversing parkinsonian motor sign and drug-induced dyskinesia.
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