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NCT Number: NCT07050355

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

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.

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Key information

Conditions

Stroke Behavior Brain Diseases Cardiovascular Diseases Central Nervous System Diseases Cerebrovascular Disorders Depression - Major Depressive Disorder Motor Activity Nervous System Diseases Vascular Diseases Walking Impairment

Age range

21 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Duke University School of Medicine, Durham, North Carolina, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

rTMS

Device

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.

AEx

Behavioral

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.

Primary outcomes

  1. Severity of depressive symptoms

    Time frame: baseline, after 2,4,6,8,10 and 12 weeks of treatment

    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).

Secondary outcomes

  1. six-minute walk test

    Time frame: baseline, after 2,4,6,8,10 and 12 weeks of treatment

    Distance walked in 6 minutes

  2. Step activity monitoring

    Time frame: baseline, after 2,4,6,8,10 and 12 weeks of treatment

    Daily step count

  3. Stroke Impact Scale

    Time frame: baseline, after 2,4,6,8,10 and 12 weeks of treatment

    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

Study contacts

Contact information is provided by the study sponsor or research team.

Chris Gregory, PhD

CONTACT

[email protected]

(843)792-1078

Sponsors and collaborators

Lead sponsor

Medical University of South Carolina

Other

Collaborators

  • Duke University
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • National Institutes of Health (NIH)

Registry information

Official study title

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

Acronym: RESTORATION

Important dates

Study start
2024
Primary completion
2029
Study completion
2029
First posted
Jul 3, 2025
Registry last updated
Jul 14, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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