Description

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, and 5) the influence of standardized targeting of the dmPFC in relation to individualized connectivity on outcomes.

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.