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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS091391-05
Application #
9750829
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Sieber, Beth-Anne
Project Start
2015-09-15
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Neurology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29407
Chhatbar, Pratik Y; Kautz, Steven A; Takacs, Istvan et al. (2018) Evidence of transcranial direct current stimulation-generated electric fields at subthalamic level in human brain in vivo. Brain Stimul 11:727-733
Fryml, Leah D; Williams, Kristen R; Pelic, Christopher G et al. (2017) The Role of Amantadine Withdrawal in 3 Cases of Treatment-Refractory Altered Mental Status. J Psychiatr Pract 23:191-199
Williams, N R; Bentzley, B S; Sahlem, G L et al. (2017) Unilateral ultra-brief pulse electroconvulsive therapy for depression in Parkinson's disease. Acta Neurol Scand 135:407-411
Factor, Stewart A; Hatcher-Martin, Jaime M; Morse, Amy S et al. (2016) Freezing of gait that disappears: Should there be rest before rehab? Parkinsonism Relat Disord 28:169-70
Williams, Nolan R; Hopkins, Thomas R; Short, E Baron et al. (2016) Reward circuit DBS improves Parkinson's gait along with severe depression and OCD. Neurocase 22:201-4
Badran, Bashar W; Glusman, Chloe E; Austelle, Chris W et al. (2016) A Double-Blind, Sham-Controlled Pilot Trial of Pre-Supplementary Motor Area (Pre-SMA) 1?Hz rTMS to Treat Essential Tremor. Brain Stimul 9:945-947
Revuelta, Gonzalo J; Embry, Aaron; Elm, Jordan J et al. (2015) Pilot study of atomoxetine in patients with Parkinson's disease and dopa-unresponsive Freezing of Gait. Transl Neurodegener 4:24