Combining rTMS & Aerobic Exercise to Treat Depression and Improve Post-Stroke Walking (RESTORATION)

Combining rTMS & Aerobic Exercise to Treat Depression and Improve Post-Stroke Walking (RESTORATION)

Investigators primary aim is to carry out a two-site, randomized, double-blind, sham-controlled, phase II trial to systematically examine the potential for aerobic exercise (AEx) to enhance the anti-depressant benefits of rTMS in individuals with post-stroke depression (PSD).

Investigators propose to determine the efficacy of combining two known anti-depressant treatments shown to be effective in non-stroke depression, aerobic exercise (AEx) and repetitive transcranial magnetic stimulation (rTMS), on post-stroke depressive symptoms. This project is based on the idea that depression negatively affects the potential for the brain to adapt in response to treatment such that rehabilitation may not produce the same changes that it does in non-depressed individuals. Investigators believe that effective treatment for PSD will result in a virtuous cycle whereby reducing depression enhances response to rehabilitation, thereby facilitating functional gains. That is, effectively treating depression will enable individuals to better recover from stroke.

Study Overview

• Status: Recruiting
• Conditions: Stroke; Depression - Major Depressive Disorder; Walking Impairment
• Intervention / Treatment: Device: rTMS; Behavioral: AEx

Detailed Description

This project will determine whether aerobic exercise enhances the anti-depressant benefits rTMS in individuals with PSD through a two-site, prospective, randomized trial. Over a five-year period, 96 subjects (12-60 months post-stroke) will be assigned to complete 12 weeks of treatment with rTMS, treadmill AEx or both (i.e., rTMS+AEx). Treatments will take place three times per week on non-consecutive days. Assessments of depression (HAM-D17) and walking capacity (6MWT) will be performed at two-week intervals throughout treatment as well as 12- and 24-weeks following cessation of treatment, allowing determination of the efficacy (and persistence) of training on these outcomes. Secondary outcomes will include measures of community walking (steps per day) and quality of life (Stroke Impact Scale) collected pre-, mid- and post-training, as well as at the follow-up time points. Last, investigators will explore potential biomarkers of response via assessment of PAS-induced neuroplastic potential and MR imaging to identify changes in cortical grey matter thickness.

• Study Type: Interventional
• Enrollment (Estimated): 96
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Chris Gregory, PhD; Phone Number: (843)792-1078; Email: gregoryc@musc.edu

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Active, not recruiting
      • Duke University School of Medicine
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • Medical University of South Carolina
      • Contact: Chris Gregory, PhD; Phone Number: 843-792-1078; Email: gregoryc@musc.edu
      • Contact: Catherine Vandewrwerker, PhD, PT; Email: vanderwe@musc.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• age 21-70
• stroke within the past 12 to 60 months
• screen positive for probable major depressive disorder (PHQ-9 > 10) and HAM-D17 ≥ 14
• residual paresis in the lower extremity (Fugl-Meyer LE motor score <34)
• ability to walk without assistance and without an AFO at speeds ranging from 0.2-1.0 m/s
• not currently on antidepressant medications or no changes in antidepressant dosage in the last 4 weeks and clinically stable
• HAM-D17 question #9 regarding suicide <2
• provision of informed consent.

Exclusion Criteria:

• unable to ambulate at least 150 feet prior to stroke, or experienced intermittent claudication while walking
• history of congestive heart failure, unstable cardiac arrhythmias, hypertrophic cardiomyopathy, severe aortic stenosis, angina or dyspnea at rest or during ADL's
• history of COPD or oxygen dependence
• history of traumatic brain injury
• blindness or severe visual impairment
• history of psychosis or other Axis I disorder that is primary
• life expectancy <1 yr.
• severe arthritis or problems that limit participation in testing or training
• history of DVT or pulmonary embolism within 6 months
• uncontrolled diabetes with recent weight loss, diabetic coma, or frequent insulin reactions
• severe hypertension with systolic >200 mmHg and diastolic >110 mmHg at rest
• attempt of suicide in the last 2 years or suicidal risk assessed by SCID
• history of seizures or currently prescribed anti-seizure medications
• current enrollment in a trial to enhance motor recovery
• currently participating in behavioral treatment for depression
• currently exercising ≥ 2 times per week (≥20 minutes)
• contraindications to TMS
• pregnancy or other contraindications to MRI.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: rTMS; repetitive transcranial magnetic stimulation	Device: rTMS; Subjects will undergo rTMS to the left dorsolateral prefrontal region as a treatment for depression. Treatment will be performed three times per week for 12 weeks (36 sessions) . We will use a standard resting motor threshold (rMT) determination from unaffected abductor pollicis brevis. Treatments will be delivered at the EEG coordinate for F3 (approximating the left DLPFC) and will be found using the Beam-F3 method. A total of 5000 pulses/session will be delivered at 10Hz with an intensity of 120% of rMT.
Active Comparator: AEx; treadmill aerobic exercise	Behavioral: AEx; The goal of AEx will be 20 minutes of continuous walking at an intensity of ~70% of heart rate reserve (HRR calculated via the Karvonen method). The desired intensity will be achieved by a combination of increasing treadmill speed and incline. Rest breaks will be allowed as needed during training with the goal of progressing to 20 minutes of continuous walking.
Experimental: rTMS + AEx; combination of repetitive transcranial magnetic stimulation and treadmill aerobic exercise	Device: rTMS; Subjects will undergo rTMS to the left dorsolateral prefrontal region as a treatment for depression. Treatment will be performed three times per week for 12 weeks (36 sessions) . We will use a standard resting motor threshold (rMT) determination from unaffected abductor pollicis brevis. Treatments will be delivered at the EEG coordinate for F3 (approximating the left DLPFC) and will be found using the Beam-F3 method. A total of 5000 pulses/session will be delivered at 10Hz with an intensity of 120% of rMT.; Behavioral: AEx; The goal of AEx will be 20 minutes of continuous walking at an intensity of ~70% of heart rate reserve (HRR calculated via the Karvonen method). The desired intensity will be achieved by a combination of increasing treadmill speed and incline. Rest breaks will be allowed as needed during training with the goal of progressing to 20 minutes of continuous walking.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of depressive symptoms	The Hamilton Depression Rating Scale (HAM-D17) is the gold-standard for clinical trial outcomes and samples a broad array of depressive symptoms. Critically, the rater administering the HAM-D17 will be clinically trained and will blinded to all other aspects of the study. For this trial, depression severity will be classified as moderate (HAM-D17 = 14-19) or severe (HAM-D = 20-25) for the purpose of stratification and diagnosed upon enrollment using the Structured Clinical Interview for Depression according to the Diagnostic & Statistical Manual of Mental Disorders, 5th Edition (DSM-V).	baseline, after 2,4,6,8,10 and 12 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
six-minute walk test	Distance walked in 6 minutes	baseline, after 2,4,6,8,10 and 12 weeks of treatment
Step activity monitoring	Daily step count	baseline, after 2,4,6,8,10 and 12 weeks of treatment
Stroke Impact Scale	Assesses multiple domains of stroke recovery on a scale from 0 to 100, including strength, hand function, activities of daily living and instrumental activities of daily living, mobility, communication, emotion, memory and thinking, and participation, with higher scores representing better recovery	baseline, after 2,4,6,8,10 and 12 weeks of treatment

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Duke University; National Institutes of Health (NIH)

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2024
• Primary Completion (Estimated): August 31, 2029
• Study Completion (Estimated): August 31, 2029

Study Registration Dates

• First Submitted: April 3, 2025
• First Submitted That Met QC Criteria: June 24, 2025
• First Posted (Actual): July 3, 2025

Study Record Updates

• Last Update Posted (Actual): July 14, 2025
• Last Update Submitted That Met QC Criteria: July 9, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: exercise; stroke; rehabilitation; walking; neuromodulation; TMS
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Mental Disorders; Behavioral Symptoms; Mood Disorders; Stroke; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: Pro00137804; R01HD113299 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Unknown at this time

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.: Yes