Clinical trial NCT05878457: Accelerated rTMS for Post-Stroke Apathy
Official title: Accelerated rTMS for Post-Stroke Apathy: Targeting Amotivation Toward Improving Whole Health and Rehabilitation Engagement
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Apathy
Stroke Sequelae
Stroke (CVA) or TIA
Stroke/Brain Attack
Motivation
Abulia
Lead sponsor: Medical University of South Carolina
Sponsor class: OTHER
First posted: 2023-05-26
Enrollment: 14
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: single group, open-label pilot investigation
Primary purpose: DEVICE_FEASIBILITY

Brief summary: This pilot study will investigate the safety, feasibility, tolerability, and preliminary efficacy of accelerated high-dose repetitive transcranial magnetic stimulation (rTMS) targeting the medial prefrontal cortex (mPFC) to address apathy symptoms in individuals with chronic stroke.

Detailed description: Repetitive transcranial magnetic stimulation (rTMS) is a well-established FDA-approved treatment for several psychiatric indications including treatment-resistant depression, obsessive-compulsive disorder, and smoking cessation. Traditional rTMS targets the dorsolateral prefrontal cortex (dlPFC) with repetitive treatments delivered for six weeks. Recent innovations have led to the development of accelerated, high-dose rTMS protocols, with recent FDA-approval, that are capable of delivering a full treatment course within a single week.

Accumulating evidence suggests that similar neuromodulation protocols may be helpful in targeting neuropsychiatric symptoms across a range of neurologic and neurodegenerative conditions including dementia, movement disorders, and stroke. Apathy is a distinct neuropsychiatric symptom characterized by loss of motivation, withdrawal, and decreased goal-directed activity seen across a wide range of neuropsychiatric conditions. Apathy contributes significantly to lower quality of life, caregiver burnout, and poorer rehabilitation outcomes. Meanwhile, there are currently no FDA-approved treatments targeting apathy specifically. The mPFC has been well-established as a safe and feasible target for traditional rTMS, and may be a desirable stimulation site in targeting apathy due to its superficial location and integral association with other brain structures implicated in apathy pathophysiology such as the anterior cingulate cortex (ACC) and ventral striatum (VL).

This phase I open-label pilot study will investigate high-dose, accelerated rTMS at the medial prefrontal cortex (mPFC) to target apathy in individuals with chronic stroke. The primary aims of the study will be to: (1) establish the safety, feasibility, tolerability, and acceptability of an accelerated repetitive transcranial magnetic stimulation (rTMS) protocol for apathy in chronic stroke; (2) establish the feasibility of individualized resting-state functional magnetic resonance imaging (fMRI) connectivity for targeting rTMS in post-stroke apathy; (3) establish preliminary efficacy of an accelerated rTMS protocol for post-stroke apathy. Given the limited power of this small pilot study, this aim will be considered exploratory with the intention to guide future research.

Sixteen chronic stroke patients with symptomatic apathy will complete (1) structural as well as resting state functional MRI at baseline for targeting parcellations. (2) A battery of validated clinical assessments of apathy-related symptoms (3) a battery of neuropsychological, cognitive, and symptom measures to assess safety, tolerability, and feasibility. Treatment will consist of open-label, high-dose rTMS to left mPFC delivered following a standard protocol consisting of 600 pulses, twelve times per day, for three treatment days (contiguous or non-contiguous) within a seven-day period. Safety assessments will be monitored throughout treatment. A battery of clinical assessments will be repeated at the end of treatment and weekly for one month post-treatment.

Eligibility criteria: Inclusion Criteria:

1. 40 years old or greater
2. Right- or left-hemisphere ischemic or hemorrhagic stroke with at least 6 months chronicity
3. Symptomatic apathy as confirmed by (A) total score on the Apathy Evaluation Scale (AES) of ≥39 as rated by the participant or caregiver informant
4. Intact cortex under the coil at the stimulation target site confirmed by neuroimaging
5. Ability to participate in psychometric testing and cognitive tasks

Exclusion Criteria:

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

Primary outcomes:
measure: Change in apathy symptoms, as measured by the Lille Apathy Rating Scale (LARS) compared to baseline
timeFrame: Pre-treatment, immediately post-treatment, and weekly for four weeks post-treatment
measure: Incidence of Treatment-Emergent Adverse Events and Side Effects as assessed by change in the Review of Systems Criteria compared to baseline
timeFrame: After each session of rTMS during each of three treatment days within one week
measure: Change in global cognition, as measured by the Montreal Cognitive Assessment (MoCA) compared to baseline
timeFrame: Pre-treatment, immediately post-treatment, and at one month post-treatment follow-up
measure: Change From Baseline Cognition, as Measured by the Fluid Cognition Composite Score From the NIH Toolbox Cognition Battery compared to baseline
timeFrame: Pre-treatment, immediately post-treatment
measure: Participant retention rate
timeFrame: calculated at the end of the study follow-up assessment period (one month post-treatment)
measure: Patient perception of treatment acceptability as assessed by study-specific questionnaire
timeFrame: After each session of rTMS during each of three treatment days within one week, and at one month post-treatment follow-up
Secondary outcomes:
measure: Change in apathy symptoms, as measured by the Apathy Evaluation Scale (AES) compared to baseline
timeFrame: Pre-treatment, immediately post-treatment, and at one month post-treatment follow-up
measure: Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Short Form
timeFrame: Pre-treatment, immediately post-treatment, and weekly for four weeks post-treatment
Other outcomes:
Locations:
city: Charleston
country: United States
facility: Medical University of South Carolina Brain Stimulation Lab
state: South Carolina
Study officials:
affiliation: Medical University of South Carolina
name: Parneet Grewal, MD
role: PRINCIPAL_INVESTIGATOR
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