The overall goal of this proposal is to examine the changes in cortical network activity in the parkinsonian state and how these are modified during DBS or administration of levodopa and improvement in motor signs. Although multiple studies have examined the changes in basal ganglia activity that occur in the parkinsonian state, there are few studies and little understanding of the changes in cortical neuronal activity, function, how these changes mediate the development of motor signs, or how they are modulated during deep brain stimulation (DBS). In our previous proposal we have made significant strides in characterizing the changes in neuronal activity in the supplementary and motor cortices (SMA and MC) in the parkinsonian condition and during STN or GPi DBS using the MPTP monkey model of PD. The current proposal continues and broadens this work to include the dorsolateral prefrontal and dorsal premotor cortices (DLPFC and PMd), areas with known anatomical connections to the basal ganglia, which are intimately involved in motor control and in the development of parkinsonian motor signs but have been largely ignored in nonhuman primate studies of PD pathophysiology. In this proposal we will examine cortical network function in PD by characterizing the changes in neuronal activity that occur within and across the DLPFC, PMd, SMA and MC in the parkinsonian state using the MPTP monkey model of PD, examine how DBS in the internal and external segments of the globus pallidus (GPi and GPe, respectively) and subthalamic nucleus (STN) modify this activity, and how the changes associated with DBS compare to that which occurs with administration of levodopa. We will simultaneously record from populations of cells in the DLPFC, PMd, SMA and MC using Utah arrays in the DLPFC, PMd, and MC, and Gray Matter devices in the SMA, at rest and during passive and active movement and compare results across the following conditions: normal, parkinsonian, parkinsonian + DBS in three different sites (GPe, GPi and STN), and parkinsonism + L-dopa (alone and in combination with DBS in each of the three sites). We will explore the role of GPe as an alternative target to STN and GPi DBS given our previous studies demonstrating its suppressive effects on both STN and GPi. Characteristics of neuronal activity and connectivity changes will be correlated with the development of parkinsonian motor signs, their amelioration during DBS and L-dopa and to changes in the planning, initiation and execution of movement.
Millions of people in the U.S. and worldwide have been diagnosed with Parkinson?s disease, a progressively debilitating disorder characterized by abnormal movement function. Fortunately, many patients with advanced disease who no longer respond adequately to medications have been successfully treated with an FDA- approved implantable device that provides electrical stimulation deep within the brain, a therapy known as deep brain stimulation (DBS). While DBS may significantly reduce symptoms in many cases, there is still much that is unknown about the way it works, especially under different conditions. Our goal is to obtain a better understanding of how DBS and medical therapy change brain function to improve movement in patients with PD and to apply this knowledge to optimize DBS and medical therapy for patients affected by Parkinson?s disease.