Freezing of gait (FoG) is a common and debilitating condition in Parkinson's Disease (PD) patients. FoG is described as an episodic inability to walk, which often triggers falls, hospitalization and is an important predictor of poor quality of life. As locomotor regions degenerate in PD, gait automaticity is impaired. Patients compensate by increasing volitional control of gait, however, this adaptation has been found to worsen FoG severity. We hypothesize that increased cortical control of gait is maladaptive, and therapies to improve gait automaticity will not be effective unless cortical control of gait is reduced. The long-term goal of this project is to develop a therapeutic approach for FoG that simultaneously reduces cortical control and increases automaticity of gait. The objective is to determine the locomotor network abnormalities responsible for FoG and demonstrate how neuromodulation and rehabilitation can modulate the network. The rationale of this study is that increased connectivity between brainstem locomotor regions and cortical structures represents increased cortical governance of gait, and it can be reversed by the proposed intervention. We will accomplish this by combining a course of inhibitory rTMS (1Hz) to the cortex (supplementary motor area) with a rehabilitation protocol designed to increase gait automaticity (dual task training). We have designed a study that will carefully assess the locomotor network of freezers with resting state functional, diffusion and interleaved TMS/BOLD MRI studies, before and after intervention. Behavioral measures including gait analysis, cognitive and motor assessments will also be conducted at baseline and post treatment. The study aims to determine the effects of our intervention on the locomotor network (assessed with imaging), as well as on FoG severity as quantified through multiple markers obtained through gait analysis. At the conclusion of the study we expect to have determined the network changes central to the pathophysiology of FoG, the effects of 1Hz rTMS + rehabilitation on this network, and on FoG severity.

The relevance of this study to public health is to develop a non-invasive effective therapeutic option for one of the most debilitating and untreatable conditions affecting the lives of one million Americans suffering from PD; freezing of gait.

Subjects meeting diagnostic criteria for PD and documented freezing of gait will be recruited from the MUSC Movement Disorder Clinic by clinical staff. Subjects will undergo identical imaging protocols before and after intervention. Subjects will undergo ten, 20 minute, dual task training sessions immediately following each rTMS session. Subjects will be randomized to either active rTMS + rehabilitation or rehabilitation alone at a 2:1 ratio (10 active: 5 control). The primary outcome measure will be dual task interference for turning.

Inclusion Criteria:

Subjects meeting diagnostic criteria for PD and documented FoG

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Exclusion Criteria:

• Subjects with contraindications to MRI, or TMS (no history of seizures, no metal implants in head, no pregnancy) dementia, or inability to complete the walk 30 feet in the off state without assistance will be excluded.

The participants were continuously assessed for the duration of the TMS administration sessions and at pre and post intervention visits. This occurred over the time course of two weeks in which the participant was actively participating in the study.

Multiple variables were collected with gait analysis (i.e. velocity, step length, time) however, we hypothesized dual task time to turn during the OFF conditions would be most likely to change pre to post intervention. In order to minimize multiple comparisons among gait measures dual task time to turn was selected as the most important variable to detect freezing since turning and dual tasking are common triggers.