PROJECT SUMMARY PD is a complex neurodegenerative disease with a broad spectrum of motor and non-motor features. The cardinal motor features include resting tremor, rigidity, bradykinesia (or akinesia), and postural instability. Over the past decade, deep brain stimulation (DBS) has largely replaced ablative techniques in the surgical Although clinical phenotypes of PD such as tremor dominant (TD) and postural instability and gait difficulty (PIGD) subtypes have been identified since the mid-1990s, to our knowledge, no neurobiomarkers have been identified to describe them and assist with decision-making regarding the DBS therapeutic target. treatment of PD. Very limited data exists regarding the electrophysiological abnormalities within the basal ganglia and associated structures which likely accompany the symptom severity or the phenotypic subtypes of PD. This proposal seeks to overcome these limitations by investigating the spatio-spectral dynamics of local field potentials (LFPs) and single unit activity recorded from the subthalamic nucleus (STN) and globus pallidus internus (GPi) and relate them to symptom manifestations, in an attempt to define the differences in PD motor phenotypes. In our preliminary studies and to the best of our knowledge, we are the first to show initial evidence that high frequency oscillations of microelectrode LFPs and their nonlinear interaction with the beta band in the form of phase amplitude coupling can distinguish PD motor phenotypes in the territories of STN. Based on our preliminary observations, this project will investigate these phenotypic LFP patterns in large patient populations in STN and GPi. Specifically, by employing machine learning techniques, neural signatures in STN and GPi will be discovered to differentiate motor phenotypes in PD. The project will investigate to what extent the extracted neural patterns can serve as objective neurobiomarkers to identify the territories of basal ganglia causing symptom differences. In addition, retrospectively, the project will also explore to what extent localization of these phenotypic LFP patterns with directional macro electrodes can describe the efficacy of chronic DBS. If successful, these advancements will provide unique opportunities to understand symptom manifestation and personalization of DBS in patients with PD.