Project Summary – Project 4 Parkinson’s disease (PD) is associated with behavioral impulsivity and deficits in motor control which result in an inability to cancel planned actions or stop ongoing movements. These behaviors are affected by deep brain stimulation (DBS) and levodopa treatment. The prefrontal cortex and its connections to the subthalamic nucleus (STN), the main target of DBS therapy for PD, have been implicated in the control of these ‘response inhibition’ functions. It has been proposed that modulation of prefrontal-STN connections by DBS can change response inhibition behavior, but clinical studies of this interaction have been conflicting, and clinical programming of DBS devices continues to focus on the optimization of the motoric outcome of DBS, with little attention to the potential changes in cognition and behavior which may result from DBS. The effects of dopaminergic medications on motor response inhibition are also not well understood. While large-scale changes such as outright compulsive disorders are often recognized, more subtle shifts in behavior are not usually acknowledged. The proposed experiments will study the pathophysiologic underpinning of response inhibition abnormalities in PD, asking which cortical mechanisms are engaged in different aspects of motor inhibitory control (proactive vs reactive; discrete vs continuous) in patients off and on levodopa therapy, compared to healthy controls, and examine whether the effects of STN DBS on response inhibition correlates with the degree of activation of the prefrontal cortico-STN pathway. We will use invasive and non-invasive electrophysiology methods, as well as computa- tional modeling. We will study patients longitudinally (before, during and after DBS procedures) and measure their performance and cortical activity while they perform two response inhibition tasks. We will define the degree of prefrontal cortico-STN pathway activation by different stimulation settings, using both direct electrophysiologic recordings (subcortico-cortical evoked potentials) and state-of-the-art computational biophysical models. We will also study how behavior and the underlying electrophysiologic activity change with levodopa treatment, and how these alterations relate to the results of standard clinical neuropsychological tests. In addition to the PD patients, we will study control subjects to understand to what extent changes in PD differ from healthy behavior and physiology. We hypothesize that the stimulation location and the extent of stimulation field produced by STN- DBS determine the degree of prefrontal cortex engagement and impact the patient’s ability to inhibit actions. We postulate that by developing a detailed understanding of how these changes arise, both locally and throughout the cognitive and motor networks, we can design stimulation strategies that maximize motor benefit and minimize negative behavioral side effects of DBS. Successful completion of the proposed studi...