Abulia, Apathy, Motivation, Stroke/Brain Attack, Stroke (CVA) or TIA, Stroke Sequelae
Conditions
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.
Interventions
DEVICEMagVenture 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.
Sponsors
Medical University of South Carolina
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DEVICE_FEASIBILITY
Masking
NONE
Intervention model description
single group, open-label pilot investigation
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Apathy Symptoms, as Measured by the Lille Apathy Rating Scale (LARS) Compared to Baseline | Pre-treatment, immediately post-treatment, and at one-month follow-up | The Lille Apathy Rating Scale (LARS) is a validated 33-item structured interview assessing apathy across 9 domains, including intellectual curiosity, emotion, action initiation, self-awareness, productivity, interests, novelty seeking, motivation, and social engagement. Total scores range from -36 to +36, with higher scores indicating greater severity of apathy (worse outcome) and lower (more negative) scores indicating less apathy (better outcome). The total score is calculated by summing responses across all items and domains to generate a composite score. |
| Treatment-Emergent Adverse Events and Side Effects as Assessed by Intermittent Theta Burst Stimulation Review of Systems (iTBS ROS) | Across the 3 rTMS treatment days | A review of systems questionnaire (Intermittent Theta Burst Stimulation Review of Systems; iTBS ROS) was administered repeatedly during each treatment day to assess treatment-emergent symptoms. Symptoms were rated on a scale from 0 to 5 (0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = marked, 5 = severe), with higher scores indicating greater symptom severity (worse outcome). Values reported represent the average symptom severity across all assessments collected during the 3 treatment days for each participant, and then averaged across participants. |
| Change in Global Cognition, as Measured by the Montreal Cognitive Assessment (MoCA) Compared to Baseline | Pre-treatment, immediately post-treatment, and at one-month follow-up | 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 From Baseline Cognition, as Measured by the Fluid Cognition Composite Score From the NIH Toolbox Cognition Battery Compared to Baseline | Pre-treatment, immediately post-treatment | 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 5 NIHTB-CB tests: the flanker inhibitory control, list sorting working memory, pattern comparison processing speed, dimensional change card sort tests, and picture sequence memory. T-Scores have a mean of 50 and a standard deviation of 10. Lower scores indicate worse performance. There are no established thresholds or cutoffs for clinically distinct or diagnostic categories. |
| Participant Retention Rate | calculated at the end of the study follow-up assessment period (one month post-treatment) | Percentage of participants who completed the study relative to all participants who initiated treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Apathy Symptoms, as Measured by the Apathy Evaluation Scale (AES) Compared to Baseline | Pre-treatment, immediately post-treatment, and at one-month follow-up | 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, behavioral and cognitive aspects of apathy. Total scores on the AES range from 18 to 72 with high scores correlating with greater severity of apathy. |
| Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Short Form | Pre-treatment, immediately post-treatment, and at one-month follow-up | The Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Short Form is a validated patient-reported outcome measure assessing depressive symptoms, including negative mood, cognitive symptoms, and decreased positive affect. Scores are reported as T-scores standardized to the U.S. general population, where a T-score of 50 represents the population mean and 10 represents the standard deviation. Higher T-scores indicate greater depressive symptom severity (worse outcome), while lower T-scores indicate fewer depressive symptoms (better outcome). T-scores of approximately 60 or greater are generally considered indicative of at least mild clinically elevated depressive symptoms, with higher thresholds reflecting increasing severity. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORParneet Grewal, MD
Medical University of South Carolina
Participant flow
Recruitment details
A total of 21 participants provided informed consent and were considered enrolled. Of these, 6 participants were excluded prior to treatment initiation due to ineligibility or withdrawal. Fifteen participants were assigned to the intervention and initiated treatment.
Pre-assignment details
Of 21 participants who provided informed consent (enrolled), 6 were excluded prior to treatment initiation due to MRI contraindications (n=3), failure to meet apathy inclusion criteria (n=1), new neurological diagnosis (n=1), and claustrophobia (n=1). Fifteen participants met eligibility criteria and were assigned to the intervention and initiated treatment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.79 years STANDARD_DEVIATION 14.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 13 / 15 |
| serious Total, serious adverse events | 0 / 15 |
Outcome results
None listed