The aim of this study is to assess the effect of deep brain stimulation (DBS) within different nodal portions of the basal ganglia-thalamocortical circuit, i.e., the internal and external segments of the pallidum (GPi and GPe) and subthalamic nucleus (STN), on parkinsonian motor signs (PMS) in MPTP treated monkeys. Deep brain stimulation is increasingly being used for the treatment of patients with medically refractory Parkinson's disease (PD). This has occurred as a result of the success of DBS in the thalamus for amelioration of both parkinsonian and essential tremor and because of the increased risk of significant complications associated with bilateral ablative procedures, currently used for the treatment of PD, i.e., pallidotomy and thalamotomy. Implantation of DBS devices in the STN and GPi have recently been used to treat the signs and symptoms of PD. Results, however, have been variable, with some centers reporting 60-90 percent improvement, while others report no significant change in PMS. A number of questions regarding the use of DBS for the treatment of PD remain. The optimal site is unclear and the mechanisms underlying its effects are not known. There is an urgent need for a controlled study to assess the effects of DBS on PMS in the MPTP monkey model of PD where detailed, quantitative evaluations of DBS can be conducted in different sites in the pallidum and STN (current targets in humans) and the physiologic effects of DBS on neural and metabolic activity in the pallido- thalamocortical circuit can be evaluated. In this study, single unit recording techniques and 18F- fluorodeoxyglucose (FDG) PET studies will be employed to assess the effect of DBS on mean discharge rates and metabolic activity of specific sites within the pallido-thalamocortical circuit. In addition, quantitative measures of motor performance will be obtained during a variety of behavioral paradigms including step- tracking, torque perturbation and reach and retrieval tasks. Parkinsonian motor signs will also be assessed using established non-human primate clinical rating scales, computer assessments of spontaneous activity, as well as quantitative measures of rigidity, tremor and bradykinesia. These will be obtained in the normal and parkinsonian state and in the parkinsonian state following fiber sparing lesions in the GPe both prior to and during DBS in the STN and GPe as well as anterior (nonmotor) and posterior (motor) portions of Gpi. This study will compare the relative efficacy and determine the optimal location for DBS within the STN and anterior and posterior portions of the pallidum to maximally alleviate PMS in MPTP treated parkinsonian monkeys. In addition, this study will characterize the mechanism(s) underlying the effect of DBS in the pallidum and STN on PMS using single cell recording techniques and 18F-fluorodeoxyglucose (FDG) PET studies together with fiber sparing lesions in the GPe to further examine the role of GPe in the development of PMS and in mediating the effect of DBS on these signs.
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