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

Official title

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

Overview

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.

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.

Interventions

• 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 1
• 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.

Primary outcome measures

• Severity of depressive symptoms [Time frame: baseline, after 2,4,6,8,10 and 12 weeks of treatment]

Secondary outcome measures (3)

• six-minute walk test [Time frame: baseline, after 2,4,6,8,10 and 12 weeks of treatment]
• Step activity monitoring [Time frame: baseline, after 2,4,6,8,10 and 12 weeks of treatment]
• Stroke Impact Scale [Time frame: baseline, after 2,4,6,8,10 and 12 weeks of treatment]

Eligibility criteria

Inclusion criteria

• age >21
• stroke at least 12 months prior
• screen positive for depressive symptoms (PHQ-9 > 5) and HAM-D17 ≥ 12
• 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. I
• All subjects who screen for major depressive disorder will be formally diagnosed by the project psychiatrist at each site using the Structured Clinical Interview for DSM5 (SCID-5).
• All subjects who meet criteria for the training portion must complete an exercise tolerance test and be cleared for participation by the study physician.

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Single blind

Primary purpose

Treatment

Study locations

United States · 2 centers

• Duke University School of Medicine — Durham
• Medical University of South Carolina — Charleston

Identifiers

NCT: NCT07050355 · Pro00137804 · R01HD113299

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗