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 Apathy occurs when a person has lost motivation, becomes withdrawn, and stops doing things that used to be important to them.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

Inclusion Criteria:

• 40 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.

Exclusion Criteria:

• 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:

Inclusion Criteria:

• Age 18 years or older
• Is a reliable informant who has at least weekly contact with the participant and can speak to the participant's cognitive and everyday functioning.

Exclusion Criteria:

- Unable to engage with study procedures in which Co-Participant input is needed.

De-identified data may be shared in publications, ClinicalTrials.gov, or data repositories.

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.