Plasticity Using Stimulation and Habit: A Pilot Open-label rTMS Study for MCI

Study Overview
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Brief Summary
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The goal of this pilot study is to determine whether a high-dose form of non-invasive brain stimulation is a promising and safe treatment for Mild Cognitive Impairment (MCI). Transcranial magnetic stimulation (TMS) is an FDA approved treatment for depression. In studies of TMS for depression and other disorders, individuals have experienced improved cognitive function. Thus, the current study is testing whether TMS is safe, feasible and effective in improving cognition in individuals with MCI.

Official Title
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High-dose Accelerated Repetitive Transcranial Magnetic Stimulation to Cognitive Control Neurocircuitry in Mild Cognitive Impairment: A Safety and Feasibility Study

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Device: High-dose accelerated rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 60-85 English as a first/primary language Has been diagnosed with MCI by a healthcare provider within the past two years per National Institute on Aging - Alzheimer's Association (NIA-AA) criteria: (1) Concern regarding cognitive decline reported by patient, informant, or clinician, (2) Objective evidence of impairment for age in 1+ cognitive domains, typically memory, (3) Preserved independent function, (4) no dementia. Has met actuarial neuropsychological criteria for amnestic MCI: (1) ≥2 impaired scores (i.e. ≤16th %ile) within one cognitive domain, or (2) ≥1 impaired scores (i.e. ≤16th %ile) in ≥3 cognitive domains, using demographically-corrected normative data. (1) and (2) must include the Memory domain. The primary suspected etiology of amnestic MCI must be neurodegenerative, with competing differential diagnoses (e.g. psychiatric disorder, movement disorder, reversible causes, substance use) ruled out as the primary etiology/ies following a clinical evaluation by a healthcare provider. Ability to provide independent informed consent, consistent with the MCI diagnostic criterion of preserved independent function. Exclusion Criteria: Dementia diagnosis per the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) or NIA-AA criteria. Daily/weekly use of anticholinergics, neuroleptics, sedatives, or bupropion. Stimulant use may be allowed pending investigator review. Cholinesterase inhibitors, NMDA receptor antagonists, and antidepressants are allowed if on a stable regimen of four weeks prior to enrollment. History of significant or unstable condition/s that may impact cognition such as significant cardiac, cerebrovascular, or metabolic disease, severe mental illness (e.g. bipolar disorder, psychoses), alcohol or substance use disorder, developmental disorder, or other neurologic disease (e.g. severe brain injury, seizures). MRI and TMS contraindications (e.g., implants, claustrophobia, conditions/treatments that lower seizure threshold, taking medications that have short half-lives, no quantifiable motor threshold, active substance use disorder, bipolar disorder). Is enrolled in a clinical trial and/or has received an investigational medication within the last 30 days.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-dose accelerated rTMS<br> | Device: High-dose accelerated rTMS<br>* A MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System will be utilized. All participants will receive open-label treatment for approximately eight, 3-minute sessions of intermittent theta burst rTMS on each of three days within an eight-day span. A single session = 600 pulses at 120% resting motor threshold (rMT), intermittent Theta Burst Stimulation (iTBS) triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 s to left dorsolateral prefrontal cortex. Total pulses = 14,400. To enable adherence and retention, the days do not need to be contiguous. Same day sessions will be separated by 10-15 minutes, but more accounting for participant comfort.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Significant Structural Brain Change on T1- and T2-weighted Magnetic Resonance Imaging (MRI) | Clinically significant structural brain change were determined by a board-certified neuroradiologist who reviewed both the pre-treatment and post-treatment structural (T1- and T2-weighted) MRI scans to identify the presence of any changes from pre- to post-treatment based on their clinical read of the images. | Baseline prior to treatment and at follow-up within 1 week post-treatment | 
| Change From Baseline Global Cognition, as Measured by the Montreal Cognitive Assessment (MoCA) | The MoCA is a psychometrist-administered brief cognitive assessment tool with raw total scores ranging from 0 to 30, with higher values indicating better cognition. For this analysis raw total scores were converted to age- and education-adjusted Z-scores using published norms (Rossetti et al., 2011). Z-scores have a mean of 0 and a standard deviation of 1. Lower scores indicate worse performance. The outcome measure reported below is the mean Z-score score at the 1-week post-treatment assessment. The statistical analysis compares this mean score to the mean score at Baseline. | Baseline prior to treatment and at follow-up within 1 week post-treatment | 
| Change in the Review of Systems Criteria Compared to Baseline | A review of systems questionnaire will be administered to rate the subjective symptom (headache, scalp pain, arm/hand pain, other pain(s), numbness/tingling, other sensation(s), weakness, loss of dexterity, vision/hearing change(s), ear ringing, nausea/vomiting, appetite loss, rash, skin change(s) or any other symptom(s)) on a scale of 0 to 5 (none, minimal, mild, moderate, marked, severe). | Baseline prior to treatment and at follow-up within 1 week post-treatment | 
| Patient Perception of Treatment Acceptability | A 15-item study-specific questionnaire of rTMS treatment acceptability, with each item rated on a scale from 1 to 5 (1 = not at all, 3 = somewhat, 5 = very much so). Higher scores indicate better acceptability for the first 10 items, lower scores indicate better acceptability for the last 5 items. | Administered at post-treatment | 
| Retention Rate | Percentage of participants who completed the study (n=21) relative to all participants who initiated treatment (n=22). | Baseline prior to treatment and at follow-up within 1 week post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Depression, as Measured by the Hamilton Depression Rating Scale (HAM-D) | The Hamilton Depression Rating Scale (Ham-D) is a 17-item interviewer-administered structured questionnaire designed to assess symptoms of depression with scores ranging from 0 to 53, with higher scores indicating more depressive symptoms. The outcome measure reported below is the mean score at the 1-week post-treatment assessment. The statistical analysis compares this mean score to the mean score at Baseline. | Baseline prior to treatment and at follow-up within 1 week post-treatment | 
| Change From Baseline Depression, as Measured by the Geriatric Depression Scale (GDS) | The Geriatric Depression Scale (GDS) is a 30-item scale that evaluates the severity of depressive symptoms in older adults with scores ranging from 0 to 30, with higher scores indicating more depressive symptoms. The outcome measure reported below is the mean score at the 1-week post-treatment assessment. The statistical analysis compares this mean score to the mean score at Baseline. | Baseline prior to treatment and at follow-up within 1 week post-treatment | 
| Change From Baseline Cognition, as Measured by the Fluid Cognition Composite Score From the NIH Toolbox Cognition Battery | 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 4 NIHTB-CB tests: the flanker inhibitory control, list sorting working memory, pattern comparison processing speed, and dimensional change card sort tests. T-Scores have a mean of 50 and a standard deviation of 10. Lower scores indicate worse performance. The outcome measure reported below is the mean T-score at the 1-week post-treatment assessment. The statistical analysis compares this mean score to the mean score at Baseline. | Baseline prior to treatment and at follow-up within 1 week post-treatment |