Freezing of gait (FOG) is a common and debilitating manifestation of advanced Parkinson’s disease (PD) for which there are limited treatment options. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in approximately half of patients with FOG (PwF), and its effects wane over time. We propose a multimodal neuroimaging study which uses diffusion MRI to understand the structural connections of the individual stimulation area, as well as the microstructural integrity of key nodes in the network. This study will also study the blood oxygen level dependent (BOLD) response to STN-DBS in PwF. The long-term goal of this research is to optimize FOG response to STN-DBS by identifying contributing modifiable factors. We propose to do so by: 1) studying differences in BOLD response to STN-DBS between responders and non-responders, 2) studying how the site of stimulation affects structural connectivity in responders compared to non-responders, and 3) studying differences in microstructural integrity of regions directly affected by STN-DBS (STN, GPi, PPN). Specifically, we aim to: 1) identify differences in BOLD activation based on FOG response to STN-DBS, 2) identify differences in structural connectivity to the stimulation site based on FOG response to STN-DBS and 3) identify differences in microstructural integrity of key network nodes. We will recruit PwF selected to undergo DBS surgery and perform structural imaging and behavioral assessments at baseline followed by combined DBS/fMRI studies and further behavioral assessments postoperatively and longitudinally. By achieving these aims we will have evaluated the contribution of lead placement, stimulation parameters, structural connectivity, and BOLD activation to FOG response which will be integrated to generate a mechanistic model of FOG response to STN-DBS. The proposed study is innovative in two major ways: 1) we propose a novel conceptual framework incorporating intrinsic and extrinsic factors that may affect FOG response to STN-DBS, and 2) we propose a novel approach which integrates structural connectivity with microstructural integrity along the circuit and to identify in-vivo functional network effects of STN-DBS activation in PwF. By developing a comprehensive integrated mechanistic model of STN-DBS response we can begin to develop optimization strategies to enhance engagement of the network. This approach will also further our understanding of the long-term therapeutic effects of STN-DBS by capturing longitudinal changes in functional network activation.

The proposed research is relevant to public health because its overarching goal is to develop an effective therapy for one of the most debilitating manifestations of Parkinson’s disease: freezing of gait. The study proposes to develop novel imaging biomarkers to optimize response to deep brain stimulation (DBS) for patients with freezing of gait. The project is relevant to NIH’s mission because it aims to further the understanding of factors that underlie effective response to DBS in patients with freezing of gait in order to improve efficacy.