Transcranial Magnetic Stimulation for MCI
Purpose
The goal of this phase II study is to establish the dose-response curves of a safe and clinically feasible non-invasive brain stimulation technique (accelerated Transcranial Magnetic Stimulation (TMS)) to improve both depression and cognitive function in Mild Cognitive Impairment (MCI) patients with comorbid depression. It is known that TMS can effectively treat depression. Identifying the right dose of accelerated TMS in MCI patients is necessary prior to designing subsequent trials to determine efficacy. These results will inform future clinical trials of accelerated TMS for MCI, with the long-term goal of developing an efficacious treatment to prevent dementia.
Conditions
- Mild Cognitive Impairment
- Depression
Eligibility
- Eligible Ages
- Between 60 Years and 85 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
i. Age 60-85 (inclusive). ii. English as a first/primary language. iii. Adequate sensorimotor function and verbal expressive abilities to complete all assessments. iv. Must have a Co-Participant (e.g. spouse, adult child or relative, sibling, cohabitator, friend, caregiver) who has at least weekly in-person contact with the participant and is willing to participate in the study as a collateral informant. v. Is on fixed pharmacotherapy (i.e. a stable dose of medication/s) for at least 4 weeks prior to enrollment. vi. A documented diagnosis of MCI per NIA-AA criteria or Mild Neurocognitive Disorder per DSM-5 criteria by a healthcare provider within the past 2 years, with a presumed etiology of either (or both): vi.a Possible or probable AD vi.b Chronic cerebrovascular disease (CVD), specifically small vessel disease as defined in STRIVE-2 which includes small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, cerebral micro bleeds, cortical superficial siderosis, or cortical cerebral microinfarcts. . vii. Met actuarial neuropsychological criteria for MCI within the past 2 years (i.e. ≥2 impaired scores within one cognitive domain, or ≥1 impaired scores in ≥3 domains, where an impaired score is defined as ≤16th percentile using appropriate demographically-corrected norms). viii. Major Depressive Disorder of at least mild severity per DSM-5 and a HAM-D Total ≥ 8.
Exclusion Criteria
i. A TICS score of ≤ 19 suggestive of dementia and a PHQ-8 score of 0-4, indicating the absence of major depressive disorder. ii. Prior diagnosis of Dementia (NIA-AA) or Major Neurocognitive Disorder (DSM-5). iii. Daily/weekly anticholinergic or sedative use. Stimulants may be allowed pending investigator review. Cholinesterase inhibitors, NMDA receptor antagonists, and antidepressants are allowed if on a stable regimen for at least 4 weeks prior to enrollment. iv. History of significant or unstable condition/s or treatments for these condition/s that may impact cognition (as determined by the study investigators) such as significant cardiac (e.g. heart failure), infectious (e.g. HIV, urinary tract infection), or metabolic disease (e.g. labile diabetes), cancer (e.g. brain cancer, chemotherapy-induced cognitive impairment), developmental disorder (e.g. autism spectrum disorder, intellectual disability), or other neurologic disease (e.g. movement disorder, multiple sclerosis, moderate to severe brain injury, seizures). v. Past or current treatment for AD/MCI with monoclonal antibody therapy. vi. Enrolled in a clinical trial or has received an investigational medication or device in the last 30 days. vii. MRI and TMS contraindications (e.g. ferromagnetic implants, claustrophobia, conditions or treatments that lower seizure threshold, taking medications that have short half-lives, no identifiable motor threshold). viii. Current alcohol or substance use disorder, bipolar disorder, schizophrenia spectrum or other psychotic disorder, suicidal/homicidal intent within the past month, or any suicide attempts within the past year.
Study Design
- Phase
- N/A
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Intervention Model Description
- Each participant will be randomized to one of six possible dose-steps for the duration of the 6 treatment days (of their choosing) within a span of 2 weeks. We will use the FDA-approved MagVenture MagPro TMS System. Total treatment time will be controlled; all participants will perceive receiving treatment for 10 3-min stimulation sessions with 10-15 min inter-session intervals, resulting in a 2-3 hour treatment day. In addition to block randomization to dose step (which determines how many total active sessions they receive), the order of daily active and/or sham sessions will also be randomized. For example, if a participant is assigned to receive 4 active sessions in a day, 6 sham sessions will be given at random. The sequence of active and/or sham sessions for each treatment day is assigned a random code that is entered into the TMS system by the coordinator to maintain the integrity of the blind.
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
- Masking Description
- Each participant will be randomized to one of six possible dose-steps for the duration of the 6 treatment days (of their choosing) within a span of 2 weeks.
Arm Groups
Arm | Description | Assigned Intervention |
---|---|---|
Sham Comparator Dose Step 1 - 0 Active Accelerated iTBS Sessions |
Participant will receive 10 sessions of accelerated iTBS on each of 6 treatment days, including 0/10 active sessions and 10/10 sham sessions per day for a total of 0 active sessions |
|
Experimental Dose Step 2 - 12 Active Accelerated iTBS Sessions |
Participant will receive 10 sessions of accelerated iTBS on each of 6 treatment days, including 2/10 active sessions and 8/10 sham sessions per day for a total of 12 active sessions (7,200 active pulses). |
|
Experimental Dose Step 3 - 24 Active Accelerated iTBS Sessions |
Participant will receive 4/10 active sessions and 6/10 sham sessions per day for a total of 24 active sessions (14,400 active pulses). |
|
Experimental Dose Step 4 - 36 Active Accelerated iTBS Sessions |
Participant will receive 6/10 active sessions and 4/10 sham sessions per day for a total of 36 active sessions (21,600 active pulses). |
|
Experimental Dose Step 5 - 48 Active Accelerated iTBS Sessions |
Participant will receive 8/10 active sessions and 2/10 sham sessions per day for a total of 48 active sessions (28,800 active pulses). |
|
Experimental Dose Step 6 - 60 Active Accelerated iTBS Sessions |
Participant will receive 10/10 active sessions and 0/10 sham sessions per day for a total of 60 active sessions (36,000 active pulses). |
|
Recruiting Locations
More Details
- Status
- Recruiting
- Sponsor
- Medical University of South Carolina
Detailed Description
Mild Cognitive Impairment (MCI) is a heterogenous syndrome of cognitive and neuropsychiatric symptoms, with as much as 40% of patients being diagnosed with comorbid depression. The goal of this phase II trial is to establish the functional form of the dose-response curves for accelerated intermittent theta burst stimulation (iTBS) to ameliorate depression and cognitive function in MCI. Identifying the right dose is necessary prior to designing subsequent trials to ascertain the efficacy of accelerated iTBS for MCI. In our two phase I trials, we chose treatment parameters based on robust prior literature on accelerated, high-dose rTMS delivery (i.e. accelerated iTBS, 600 pulses at 50 Hz per session), intensity (at 120% resting motor threshold [rMT]), stimulation site left dorsolateral prefrontal cortex (l-dlPFC), and site targeting (Beam F3). The course of treatment was guided by our clinical experience with mild cognitive impairment and vascular cognitive impairment patients as to what we hypothesized they would comfortably tolerate, which was confirmed by the acceptability ratings. In this phase II trial, we focus on manipulating one dosing parameter - total number of active pulses - to rigorously model the dose-response curves such that future phase II/III trials can be more efficient, decrease treatment burden, and accelerate response time. Aim 1: Establish the dose-response curves for reduced depression following accelerated iTBS in MCI. Aim 2: Establish the dose-response curves for improved cognition following accelerated iTBS in MCI. Exploratory Aim 1: Examine alterations in functional connectivity following accelerated iTBS-rTMS in MCI. Exploratory Aim 2: Examine blood-based biomarkers of neurodegeneration as effect modifiers.