DBS AND MOTOR CORTICAL FUNCTION IN AN MPTP MODEL OF PD

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DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) of either the internal segment of the globus pallidus (GPO or the subthalamic nucleus (STN) is an effective treatment for most if not all symptoms of Parkinson's disease (PD). Several aspects of the reduction of symptoms with DBS provide tantalizing hints that different symptoms may be mediated by distinct pathways and/or physiological processes involving the motor and premotor cortices. The goals of this project are to use a non-human primate model of PD to gain a better understanding of the cortical mechanisms by which DBS produces clinical benefit, as well as to determine if different symptoms have different neuroanatomic/physiologic substrates. Animals will perform tasks that measure symptom-relevant behavioral parameters: movement selection/initiation/sequencing (akinesia), movement kinematics (bradykinesia), and rigidity. Neuronal activity at multiple locations in the four principal motor cortices [in different animals, primary motor (M1), ventral premotor (PMv), dorsal premotor (PMd), or mesial premotor (SMA)] will be monitored using a multielectrode array. Single cell activity will be assessed for changes in resting firing rate, task-related activity, and cell-to-cell interactions (synchronized firing) in response to DBS in GPI or STN before and after animals are rendered parkinsonian by intracarotid infusion of MPTP. The predictions are that: DBS-related changes in resting discharge will not be correlated with specific changes in symptoms. Increased activity and synchrony in SMA will be associated with reduced akinesia. Increases of the same in M1 will accompany reduced bradykinesia. Reductions in rigidity will be linked with a drop in M1 responses to passive movement and increased directional specificity in movement related activity. In addition, DBS may reduce abnormally-increased activity in PMv and PMd These hypotheses will be tested in three specific aims: Specific aim I will study the interacting effects of DBS and the type of motor task being performed. Specific aims 2 and 3 will identify cortical activities that change in concert with the time course (SA 2) and parametric relations (SA 3, DBS location, frequency, and strength) of symptom reduction with DBS. The results of these experiments will improve understanding of both the neuronal basis of different symptoms of PD and the mechanisms of action of DBS. Ultimately, these studies will advance a more complete pathophysiologic model of PD by incorporating the full array of parkinsonian symptoms.