Accelerated rTMS vs. Sham for Stroke Apathy

NCT07113067 | Recruiting Phase 1 DMC FDA Device

• 1 other identifier: Pro00144684
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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 Apathy occurs when a person has lost motivation, becomes withdrawn, and stops doing things that used to be important to them.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.

Conditions

Apathy; Stroke; Stroke Sequelae; Stroke/Brain Attack; Stroke/ Cerebrovascular Accident (Ischemic or Hemorrhagic); Motivation; Abulia

Keywords

Depression; Stroke; Stroke Recovery; Apathy; TMS; Motivation; Abulia; Amotivation

Outcome Measures

Primary Outcomes (7)

• 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.

  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.

  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).

  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.

  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.

  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.

  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.

  Pre-treatment, post-treatment and at 4 weeks post treatment

Secondary Outcomes (1)

• Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Short Form

  Pre-treatment, immediately post-treatment, and weekly for four weeks post-treatment

Study Arms (2)

Active TMS

EXPERIMENTAL

This group will receive active accelereated iTBS-rTMS

Device: MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System (Active); Other: Brainsight Neuronavigation System

Sham TMS

SHAM COMPARATOR

This group will receive sham accelerated iTBS-rTMS

Device: MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System (Sham); Other: Brainsight Neuronavigation System

Interventions

MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System (Active) DEVICE

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

Active TMS

MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System (Sham) DEVICE

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

Sham TMS

Brainsight Neuronavigation System OTHER

A brainsight neuronavigation system will be used during TMS treatments to target treatment location using individual MRI data

Active TMS; Sham TMS

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years old or greater
• Right- or left-hemisphere ischemic or hemorrhagic stroke with at least 6 months chronicity
• Symptomatic apathy as confirmed by (A) total score on the Apathy Evaluation Scale by the participant or the caregiver/co-participant (AES) of ≥39
• Ability to participate in psychometric testing and cognitive tasks
• Intact cortex at the TMS target site as confirmed by pre-treatment MRI
• Ability to have a co-participant/caregiver who meets the criteria as detailed below.

You may not qualify if:

• Primary extra-axial hemorrhage (subdural or subarachnoid) without ischemic stroke or intraparenchymal hemorrhage
• Concomitant neurological disorders affecting motor or cognitive function (e.g. dementia)
• Moderate or severe global aphasia
• Visual impairment precluding completion of cognitive tasks
• Presence of contraindications to MRI or TMS including electrically, magnetically or mechanically activated metal or nonmetal implants such as cardiac pacemaker, intracerebral vascular clips or any other electrically sensitive support system;
• Pregnancy (to be later confirmed by UPT in any premenopausal female participants)
• History of a seizure disorder
• Preexisting scalp lesion, wound, bone defect, or hemicraniectomy
• Claustrophobia precluding ability to undergo an MRI
• Active substance use disorder
• Psychotic disorders
• Bipolar 1 Disorder
• Acute suicidality as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)30 or suicide attempt in the previous year
• For CO-PARTICIPANT/CAREGIVER:
• Age 18 years or older

Sponsors & Collaborators

• Medical University of South Carolina: lead

Study Sites (1)

Medical University of South Carolina Brain Stimulation Lab

Charleston, South Carolina, 29403, United States

RECRUITING

Related Publications (10)

• Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res. 1991 Aug;38(2):143-62. doi: 10.1016/0165-1781(91)90040-v.

  PMID: 1754629 BACKGROUND

• Casaletto KB, Umlauf A, Beaumont J, Gershon R, Slotkin J, Akshoomoff N, Heaton RK. Demographically Corrected Normative Standards for the English Version of the NIH Toolbox Cognition Battery. J Int Neuropsychol Soc. 2015 May;21(5):378-91. doi: 10.1017/S1355617715000351. Epub 2015 Jun 1.

  PMID: 26030001 BACKGROUND

• Sockeel P, Dujardin K, Devos D, Deneve C, Destee A, Defebvre L. The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2006 May;77(5):579-84. doi: 10.1136/jnnp.2005.075929.

  PMID: 16614016 BACKGROUND

• Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x.

  PMID: 15817019 BACKGROUND

• Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex. 2006 Jul;16(7):916-28. doi: 10.1093/cercor/bhj043. Epub 2005 Oct 5.

  PMID: 16207933 BACKGROUND

• Jorge RE, Starkstein SE, Robinson RG. Apathy following stroke. Can J Psychiatry. 2010 Jun;55(6):350-4. doi: 10.1177/070674371005500603.

  PMID: 20540829 BACKGROUND

• Santa N, Sugimori H, Kusuda K, Yamashita Y, Ibayashi S, Iida M. Apathy and functional recovery following first-ever stroke. Int J Rehabil Res. 2008 Dec;31(4):321-6. doi: 10.1097/MRR.0b013e3282fc0f0e.

  PMID: 19008681 BACKGROUND

• Le Heron C, Apps MAJ, Husain M. The anatomy of apathy: A neurocognitive framework for amotivated behaviour. Neuropsychologia. 2018 Sep;118(Pt B):54-67. doi: 10.1016/j.neuropsychologia.2017.07.003. Epub 2017 Jul 8.

  PMID: 28689673 BACKGROUND

• Sasaki N, Hara T, Yamada N, Niimi M, Kakuda W, Abo M. The Efficacy of High-Frequency Repetitive Transcranial Magnetic Stimulation for Improving Apathy in Chronic Stroke Patients. Eur Neurol. 2017;78(1-2):28-32. doi: 10.1159/000477440. Epub 2017 Jun 3.

  PMID: 28578330 BACKGROUND

• Holtzheimer PE 3rd, McDonald WM, Mufti M, Kelley ME, Quinn S, Corso G, Epstein CM. Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression. Depress Anxiety. 2010 Oct;27(10):960-3. doi: 10.1002/da.20731.

  PMID: 20734360 BACKGROUND

MeSH Terms

Conditions

Lethargy; Stroke; Ischemia; Depression

Interventions

Transcranial Magnetic Stimulation; Drug Delivery Systems

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics; Drug Therapy

Study Officials

• Parneet Grewal, PhD

  Medical University of South Carolina

  PRINCIPAL INVESTIGATOR

• Lisa McTeague, PhD

  Medical University of South Carolina

  PRINCIPAL INVESTIGATOR

• Kevin Caulfield, PhD

  Medical University of South Carolina

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Parneet Grewal, MD

CONTACT

843-792-3020; grewalp@musc.edu

Lisa McTeague, PhD

CONTACT

843-792-8274; mcteague@musc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All participants and members of the research team except for the statistician will be blinded as to which arm participants are in until the conclusion of the study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 2, 2025
• First Posted: August 8, 2025
• Study Start: August 8, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027
• Last Updated: October 22, 2025

Record last verified: 2025-10

Locations

US (1)