A Phase 1/2 interventional study of MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System (Active) and MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System (Sham) in Apathy, Stroke and Stroke Sequelae, sponsored by Medical University of South Carolina. Recruiting at 1 site in United States. Open to participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2026-07-08.
Sponsored by Medical University of South Carolina · Phase 1/2, Interventional, and Treatment
Apathy is a common set of symptoms seen in many people following a stroke. Apathy occurs when a person has lost motivation, becomes withdrawn, and stops doing things that used to be important to them. Apathy has a large negative impact on a person's quality of life, and can also have a large impact the people who take care of them. There are currently no FDA-approved treatments to help with apathy, and other services like therapy may be difficult to access for people who have had a stroke. To address this problem, investigators are conducting a study to find out if a form of treatment called repetitive transcranial magnetic stimulation (rTMS) can be safe and helpful for people struggling with apathy after a stroke. This study will apply a new form of rTMS which can be delivered quickly to a part of the brain called the medial prefrontal cortex (mPFC). This study will help establish whether this treatment is safe, comfortable, and effective for people with apathy after a stroke, and will help researchers develop new forms of treatment.
Apathy is a significant source of disability in a wide range of neurodegenerative conditions, including prominently in stroke (40-60% of stroke survivors). Furthermore, the amotivation that characterizes apathy fundamentally interferes with quality of life and specifically with rehabilitation. At the extreme, it has been associated with post-stroke suicide risk.
Notably, previous research has demonstrated that apathy is distinct from post-stroke depression, fatigue, and other affective and cognitive impairments and often persists despite improvements in these associated domains. Existing literature has implicated the anterior cingulate cortex (ACC) in transdiagnostic amotivation and apathy. The dorsal medial prefrontal cortex (dmPFC) lies immediately superficial to the ACC and, via strong functional and structural interconnections and, makes this a promising target for repetitive transcranial magnetic stimulation (rTMS) to modify the substrates of apathy and is a safe and acceptable stimulation target.
Furthermore, rTMS is especially promising for post-stroke apathy (PSA) as it provides the flexibility for personalizing TMS coil placement in relation to post-stroke brain network anomalies, which vary significantly across stroke survivors. A typical course of rTMS entails one treatment/day for 4 to 6 weeks (30-40 sessions), which can be burdensome and reduce adherence, particularly for those with mobility limitations, as is common in stroke. Accelerated rTMS, a recent innovation in which multiple sessions are delivered each day to reduce treatment burden, is safe and effective in depression.
As a first test of suitability in post-stroke apathy (n=14), investigators conducted an open-label pilot trial that delivered 12 sessions of 600 pulses of accelerated intermittent theta burst (iTBS)-rTMS on each of three days within one week to dmPFC (36 total sessions; 21,600 total pulses). Targeting was standardized using neuronavigation and MNI coordinates to position the TMS coil over the left dmPFC. No adverse neuroradiological, neurocognitive, or neuropsychiatric effects were noted coupled with high retention (>80%) and acceptability ratings. Furthermore, while this Phase I pilot trial was not dosed for efficacy, investigators observed significant effect size (Cohen's d on the Lille Apathy Rating Scale from baseline to one-month was 0.61 along with improvements in apathy, improved quality of life with reduced caregiver burden.
In a separate ongoing dose-response study in the MUSC Brain Stimulation Lab, accelerated iTBS to left dlPFC was applied for up to 10 sessions per day for 5 days, maximum 50 active sessions, 30,000 individual total pulses among individuals with moderate to severe anxiety and depression. The preliminary findings suggest that psychosocial functioning/quality of life improves at higher doses, and the emerging dose-response curve suggests the asymptote is likely above the maximum dose tested (i.e., 10 sessions/day).
Taken together, 1) accelerated rTMS is safe and effective, 2) has the potential to rapidly remediate cross-domain neuropsychiatric impairment in chronic stroke, including apathy and 3) examining higher dose is warranted to optimize outcomes.
In this present study we will examine 1) the efficacy of active relative to sham stimulation in a double-blind, randomized design, 2) safety, acceptability, and efficacy of higher dosing in stroke patients 3) durability, 4) generalizability of gains in other neuropsychiatric and neurocognitive domains outside apathy.
Specifically, we will conduct a double-blind, randomized, sham controlled phase I/II trial of accelerated iTBS-rTMS for PSA and associated impairments in chronic stroke. 36 patients (age 40-80 years) with PSA secondary to ischemic or hemorrhagic stroke (≥6 months chronicity) will be recruited and randomized 1:1 to two stimulation groups: 1) active iTBS to left dmPFC targeted to standardized MNI coordinates, or 2) electrical sham.
Protocol, target location, and assessments will mirror our Phase 1 trial, in which investigators observed large open-label effects, except in this study, investigators will increase to 6 days of treatment over 2 weeks (total 72 sessions; 43,200 total pulses), enabling assessment of efficacy and durability over follow-up.
Participants will undergo clinical assessments at baseline, immediately post-treatment, and 1-month follow-up. Brain MRIs will be collected at pre- and immediately post-treatment.
8,255 studies on the registry are indexed under Stroke; 2,056 are open to participants now.
This study's planned enrollment of 40 is below the median of 49 across 6,024 interventional studies indexed under Stroke.
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Inclusion Criteria:
Exclusion Criteria:
For CO-PARTICIPANT/CAREGIVER:
Inclusion Criteria:
Exclusion Criteria:
- Unable to engage with study procedures in which Co-Participant input is needed.
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
This group will receive active accelereated iTBS-rTMS
Device: MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System (Active) · Other: Brainsight Neuronavigation System
This group will receive sham accelerated iTBS-rTMS
Device: MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System (Sham) · Other: Brainsight Neuronavigation System
Active treatment will consist of high-dose iTBS-rTMS to left dmPFC delivered in runs of 600 pulses at an intensity of 120% resting motor threshold (rMT). iTBS triplets at 50 Hz will be delivered for 2 seconds, repeated every 10 seconds for a total of 190 seconds. Each session will be separated by at least 10-15 minutes and a total of 12 sessions will be given on each treatment day (3-4 hours per study day). A total of 43,200 pulses will be delivered over the entire six days of treatment.
Also known as: Active TMS
For the sham stimulation group, a focal electric sham will be used which is indistinguishable from active TMS including a pretreatment individualized sham titration, sham outputs noises synchronized to pulse delivery, and an individualized level of sham stimulation throughout the treatment. Technicians administering active vs sham TMS will be masked by using a random code generated by the statistician that will indicate whether to use the active or sham side of the coil. Treatments will appear identical to the technician regardless of whether active or sham TMS is administered.
Also known as: Sham TMS
A brainsight neuronavigation system will be used during TMS treatments to target treatment location using individual MRI data
Change in apathy symptoms, as measured by the Lille Apathy Rating Scale (LARS) compared to baseline
The Lille Apathy Rating Scale (LARS) is a clinically validated 33-item structured interview assessing clinical symptoms of apathy. The structured interview is broken into 9 sub-scales including everyday productivity, interests, taking the initiative, novelty seeking, motivation, emotional responsiveness, concern, and social life. Total scores can range from -36 to +36 and are further stratified by factorial sub-scores including intellectual curiosity, emotion, action initiation, and self-awareness.
Time frame: Pre-treatment, immediately post-treatment, and at one month post-treatment follow-up
Change in apathy symptoms as measured by the Apathy Evaluation Scale (AES) - Self and Informant Versions
The Apathy Evaluation Scale (AES) clinically validated rating scale assessing symptoms of apathy. The AES is comprised of 18 items rated on a four-point Likert-Scale assessing and quantifying emotional, behavioural and cognitive aspects of apathy. Total scores on the AES range from 18 to 72 with high scores correlating with greater severity of apathy.
Time frame: Pre-treatment, immediately post-treatment, and weekly for four weeks post-treatment.
Incidence of Treatment-Emergent Adverse Events and Side Effects as assessed by change in the Review of Systems Criteria compared to baseline
A review of systems questionnaire will be administered to rate the subjective symptom (headache, scalp pain, arm/hand pain, other pain(s), numbness/tingling, other sensation(s), weakness, loss of dexterity, vision/hearing change(s), ear ringing, nausea/vomiting, appetite loss, rash, skin change(s) or any other symptom(s)) on a scale of 0 to 5 (none, minimal, mild, moderate, marked, severe).
Time frame: After each session of rTMS during each of six treatment days within two weeks
Change From Baseline Cognition, as Measured by the Fluid Cognition Composite Score From the NIH Toolbox Cognition Battery compared to baseline
Fluid cognition was measured using the iPad-administered NIH Toolbox Cognition Battery (NIHTB-CB). Fluid Cognition Composite scores were calculated by averaging the demographically adjusted (age, education, sex, race/ethnicity; Casaletto et al., 2015) T-scores for 4 NIHTB-CB tests: the flanker inhibitory control, list sorting working memory, pattern comparison processing speed, and dimensional change card sort tests. T-Scores have a mean of 50 and a standard deviation of 10. Lower scores indicate worse performance.
Time frame: Pre-treatment, immediately post-treatmen
Participant retention rate
Percentage of participants who completed the study relative to all participants who initiated treatment. Percentage of participants who completed the study relative to all participants who initiated treatment. Percentage of participants who completed the study relative to all participants who initiated treatment.
Time frame: calculated at the end of the study follow-up assessment period (one month post-treatment)
Patient perception of treatment acceptability as assessed by study-specific questionnaire
A 15-item study-specific questionnaire of rTMS treatment acceptability, with each item rated on a scale from 1 to 5 (1 = not at all, 3 = somewhat, 5 = very much so). Higher scores indicate better acceptability for the first 10 items, lower scores indicate better acceptability for the last 5 items.
Time frame: After each session of rTMS during each of three treatment days within one week, and at one month post-treatment follow-up
Frontal Systems Behavior Scale (FrSBE)-Apathy scale
The Frontal Systems Behavior Scale (FrSBE) assesses behavioral changes associated with frontal lobe dysfunction, including apathy, disinhibition, and executive deficits. In this study, apathy-as measured by the FrSBE Apathy subscale-is the primary outcome.
Time frame: Pre-treatment, post-treatment and at 4 weeks post treatment
Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Short Form
Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Short Form The Patient-Reported Outcomes Measurement Information System (PROMIS) is a clinically validated adaptive clinical assessment tool designed under the NIH to capture patient-reported symptoms in several psychiatric symptom domains for use in clinical research.
Time frame: Pre-treatment, immediately post-treatment, and weekly for four weeks post-treatment
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