Accelerated rTMS for Post-Stroke Apathy
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 1 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Repetitive transcranial magnetic stimulation All participants will receive accelerated, high-dose repetitive transcranial magnetic stimulation (rTMS) at the medial prefrontal cortex (mPFC) delivered in runs of 600 pulses, twelve times per day, for three treatment days (contiguous or non-contiguous) within a seven-day period. |
Device: MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System
Treatment will consist 12 approximately-three-minute sessions on each of three treatment days within a seven-day period. To promote participant adherence and retention, treatment days will not need to be contiguous. A single session consists of 600 pulses delivered to the dmPFC at an intensity of 120% resting motor threshold (rMT). 50 hz triphasic bursts will be delivered for two seconds, followed by an 8 second inter-train interval. Trains will be repeated every 10 seconds, 10 times total, for a total of 190 seconds per session. An intersession interval of at least 15 minutes will be employed between each of the 12 sessions. Each treatment day will thus last approximately 3-4 hours in duration.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Change in apathy symptoms, as measured by the Lille Apathy Rating Scale (LARS) [Pre-treatment, immediately post-treatment, and weekly for four weeks post-treatment]
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.
- Incidence of Treatment-Emergent Adverse Events and Side Effects as assessed by iTBS Review of Systems [After each session of rTMS during each of three treatment days within one week]
This study will be demonstrating the safety of using accelerated rTMS in chronic stroke patients by assessing adverse events and side effects using an institutional 16-item intermittent transcranial brain stimulation (iTBS) Review of Systems questionnaire. The minimum value of the iTBS scale is 0 and the maximum is 75 with higher scores correlating with more severe side effects and poorer tolerability.
Secondary Outcome Measures
- Change in caregiver burden, as measured by the Zarit Burden Interview [Pre-treatment, immediately post-treatment, and weekly for four weeks post-treatment]
The Zarit Burden Interview is a clinically validated instrument used to assess the degree burden experienced by caregivers of dependent individuals. The self-reported scale comprises 22 items rated on a 5-point Likert scale. Total scores range from 0 to 88 with higher scores correlating with a higher degree of caregiver burden.
- Change in global cognition, as measured by the Montreal Cognitive Assessment (MoCA) [Pre-treatment, immediately post-treatment, and weekly for four weeks post-treatment]
The Montreal Cognitive Assessment (MoCA) is a clinical assessment of cognitive function. The MoCA assesses multiple cognitive domains including memory, visuospatial skills, executive function, attention, concentration, calculation, language, abstraction, and orientation. The MoCA can be administered in approximately 10 minutes and total scores range from 0 to 30 with lower scores correlating with greater degree of cognitive impairment.
- Change in quality of life, as measured by the Stroke Specific Quality of Life Scale (SS-QOL) [Pre-treatment, immediately post-treatment, and weekly for four weeks post-treatment]
The Stroke Specific Quality of Life Scale (SS-QOL) is a validated clinical assessment used to assess health-related quality of life in individuals who have experienced strokes. The SS-QOL includes 49 self-rated items across 12 subdomains including mobility, energy, upper extremity function, work/productivity, mood, self-care, social roles, family roles, vision, language, thinking, and personality. Each item is scored along a 5-point Likert scale, and lower total scores correlate a higher degree of health-related quality of life.
- Change in apathy symptoms, as measured by the Apathy Evaluation Scale (AES) [Pre-treatment, immediately post-treatment, and weekly for four weeks post-treatment]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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40 years old or greater
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Right- or left-hemisphere ischemic or hemorrhagic stroke with at least 6 months chronicity
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Symptomatic apathy as confirmed by (A) total score on the Apathy Evaluation Scale (AES)27 of ≥39 or (B) affirmative responses to three or more out of five general apathy screening questions
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Intact cortex under the coil at the stimulation target site confirmed by neuroimaging
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Ability to participate in psychometric testing and cognitive tasks
Exclusion Criteria:
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Extra-axial hemorrhage
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Concomitant neurological disorders affecting motor or cognitive function (e.g. dementia)
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Moderate or severe global aphasia
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Visual impairment precluding completion of cognitive tasks
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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;
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Pregnancy (to be later confirmed by UPT in any premenopausal female participants)
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History of a seizure disorder
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Preexisting scalp lesion, wound, bone defect, or hemicraniectomy
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Claustrophobia precluding the ability to undergo an MRI
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Active substance use disorder
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Psychotic disorders
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Bipolar 1 Disorder
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Acute suicidality as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) or suicide attempt in the previous year
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Medical University of South Carolina Brain Stimulation Lab | Charleston | South Carolina | United States | 29403 |
Sponsors and Collaborators
- Medical University of South Carolina
Investigators
- Principal Investigator: Parneet Grewal, MD, Medical University of South Carolina
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- 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.
- 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. Erratum In: J Am Geriatr Soc. 2019 Sep;67(9):1991.
- Seng BK, Luo N, Ng WY, Lim J, Chionh HL, Goh J, Yap P. Validity and reliability of the Zarit Burden Interview in assessing caregiving burden. Ann Acad Med Singap. 2010 Oct;39(10):758-63.
- 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.
- Williams LS, Weinberger M, Harris LE, Clark DO, Biller J. Development of a stroke-specific quality of life scale. Stroke. 1999 Jul;30(7):1362-9. doi: 10.1161/01.str.30.7.1362.
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