Effects of Neuromodulation and Rehabilitation of the Locomotor Network in Freezing of Gait (TMS/FOG)

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.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease With Freezing of Gait
• Intervention / Treatment: Radiation: transcranial magnetic stimulation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Subjects meeting diagnostic criteria for PD and documented FoG

-

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active TMS; 1 Hz repetitive transcranial magnetic stimulation	Radiation: transcranial magnetic stimulation; transcranial magnetic stimulation
Placebo Comparator: Sham TMS; No active stimulation	Radiation: transcranial magnetic stimulation; transcranial magnetic stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Functional Connectivity to the Supplementary Motor Area.	Change (pre vs post intervention) in resting-state fMRI connectivity (fisher z-score) of the supplemental motor area (SMA). A negative change score means there was a reduction in SMA connectivity pre to post intervention. A positive change score means there was an increase in SMA connectivity pre to post intervention.	pre and post intervention (within one week of completion)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in New Freezing of Gait Questionnaire	The new freezing of gait questionnaire is a measure of freezing severity (total score range: 0-28) wherein higher scores represent worse freezing behavior. The outcome measures represent the change in freezing of gait questionnaire score from pre to post intervention. A larger, positive value represents a greater reduction in freezing severity and a better outcome.	pre and post intervention (within one week of completion)
Change in Dual Task Time to Turn Off	The time to turn around a cone (in seconds) while dual tasking (performing a serial 7s and/or every other letter of the alphabet task) was measured while participants were in the OFF state (off of their Parkinson's medication). The assessment were performed pre to post intervention. A greater reduction in time to turn (pre versus post interverntion) is represented by a larger positive number. A larger reduction in time to turn represents a better outcome.	pre and post intervention (within one week of completion)

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Investigators: Principal Investigator: Gonzalo Revuelta, DO, Medical University of South Carolina

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2017
• Primary Completion (Actual): March 23, 2020
• Study Completion (Actual): March 23, 2020

Study Registration Dates

• First Submitted: August 28, 2017
• First Submitted That Met QC Criteria: September 2, 2017
• First Posted (Actual): September 6, 2017

Study Record Updates

• Last Update Posted (Actual): March 29, 2021
• Last Update Submitted That Met QC Criteria: March 3, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: TMS/FOG

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No