The candidate is a fellowship trained academic movement disorder neurologist and deep brain stimulation specialist with a long-term goal of becoming an independent clinical investigator in the field of freezing of gait (FoG) in Parkinson's disease (PD). A comprehensive training plan is proposed, including didactic training in: 1) imaging, 2) gait analysis, and 3) clinical research methodology. The long-term goal of this research is to address current barriers to the development of effective therapies for FoG, including: 1) poor understanding of the pathophysiology of FoG and 2) lack of objective outcome measures for FoG severity. The objective is to characterize the network changes underlying FoG and identify the quantifiable gait parameters associated with these changes. Our central hypothesis is that dopaminergic response in FoG is dictated by the underlying pathology affecting pathways arising from the mesencephalic locomotor region (MLR) to cortical structures (locomotor pathways). The rationale is to quantify connectivity along locomotor pathways and determine which gait parameters are most closely associated to these connectivity changes. We will accomplish this by evaluating the structural connectivity locomotor network using diffusional kurtosis imaging (DKI) in patients with FoG. We will then quantify multiple gait parameters (velocity, stride and step length, cadence, time to turn) under varying cognitive loads to determine which parameters are most closely linked to network changes. The study aims to assess the degree of structural connectivity in the locomotor pathway in three groups of PD patients characterized by their response to dopamine (non-freezers, dopa-responsive-freezers and dopa- unresponsive freezers). Here we hypothesize that structural connectivity of the locomotor pathway will differ according to dopa-response. We will then determine how relevant gait parameters are associated with connectivity of the locomotor network. At the conclusion of this study we expect to have determined how locomotor pathway connectivity differs depending on dopa-response, and which objective gait parameters are most closely linked to these changes. This would have a significant positive impact by validating the locomotor network as a therapeutic target for neuromodulator, and addressing the most critical issue for the treatment of FoG: dopaminergic response. The significance of our contribution will be to clarify the pathophysiology of dopa-unresponsive FoG and correlate these findings clinically with the goal of facilitating therapeutic development. The proposed research is innovative since it uses a novel imaging technique (DKI) in a novel way (to explore the pathophysiology underlying dopaminergic response), and aims to identify markers of FoG severity based on their link to the underlying pathophysiology.
of the proposed project to the mission of the NIH is to address the current barriers to developing effective therapies for one of the most debilitating and untreatable conditions experienced by Parkinson's disease patients; freezing of gait. Identifying how changes in connectivity are associated with dopa response and quantifiable gait parameters will facilitate validation of novel therapeutic targets.
