Brain Stimulation and Cognitive Training for MCI (RISE pilot)

Combining Brain Stimulation With Computerized Cognitive Training for MCI

This is a randomized clinical trial of a treatment that combines non-invasive brain stimulation with computerized cognitive training (CCT) for people with mild cognitive impairment (MCI). The form of brain stimulation used in this study is accelerated intermittent theta burst stimulation (iTBS). All participants receive the same amount of iTBS and are randomly assigned to engage in one of two types of CCT. The goals of the study are to see if this combined treatment is feasible and acceptable to people with MCI and whether combined iTBS and CCT improves memory, thinking skills, mood, and daily function.

Study Overview

• Status: Recruiting
• Conditions: Neurocognitive Disorders; Cognitive Dysfunction; Mild Cognitive Impairment (MCI); Cognition Disorders; Mild Neurocognitive Disorder
• Intervention / Treatment: Device: Accelerated iTBS; Device: Computerized Cognitive Training; Device: Sham Computerized Cognitive Training

Detailed Description

This is a randomized, sham-controlled trial of combined intermittent theta burst stimulation (iTBS) and computerized cognitive training (CCT) for people with mild cognitive impairment (MCI). The primary objectives of this study are to determine the feasibility, acceptability, and preliminary effect sizes of 3-day combined iTBS+CCT for improving neurocognitive and psychosocial function in MCI.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kaitlin Cox; Phone Number: 843-608-1674; Email: coxkai@musc.edu

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • Medical University of South Carolina
      • Contact: Kaitlin Cox; Phone Number: 843-608-1674

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 60-85 (inclusive).
2. English as a first/primary language.
3. Adequate sensorimotor function and verbal expressive abilities to complete all assessments.
4. 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.

5. Meets the following requirements for current and prior medications and treatments:

   1. Is on fixed pharmacotherapy (i.e. stable dose of medication/s) for ≥ 4 weeks before enrollment. This includes, but is not limited to, cholinesterase inhibitors, NMDA receptor antagonists, and antidepressants.

   2. Anti-amyloid monoclonal antibody therapy for AD/MCI:

      • Prior treatment is permitted if last infusion occurred ≥ 8 weeks before enrollment.
      • Current treatment is permitted if the dose has been stable for ≥ 12 weeks before enrollment, with no planned dose change during study participation.
   3. Prior TMS treatment is permitted if the last stimulation session was ≥ 24 weeks before enrollment.
6. Documented diagnosis of MCI per NIA-AA criteria or Mild Neurocognitive Disorder per DSM-5 criteria by a healthcare provider within the past year, with a presumed etiology of possible or probable AD 7. Met actuarial neuropsychological criteria for MCI43 within the past year (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).

Exclusion Criteria:

1. Telephone Interview for Cognitive Status (TICS) score of ≤ 22 suggestive of dementia.
2. Prior diagnosis of Dementia (NIA-AA) or Major Neurocognitive Disorder (DSM-5).
3. Daily/weekly anticholinergic or sedative use. Stimulants may be allowed pending investigator review.
4. 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), severe mental illness (e.g., bipolar disorder, psychoses), alcohol or substance use disorder, 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).
5. Plan to initiate treatment for AD/MCI with monoclonal antibody therapy during study participation.
6. For those currently receiving monoclonal antibody therapy, documented history of clinically significant amyloid-related imaging abnormalities (ARIA) in their medical record.
7. Current use of any implanted brain stimulation device.
8. Enrolled in a clinical trial or has received an investigational medication or device in the last 30 days that may impact cognition or mood.
9. MRI contraindications (e.g., ferromagnetic implants, claustrophobia).
10. Unable or unwilling to engage in BrainHQ activities.
11. TMS contraindications (e.g., ferromagnetic implants, conditions or treatments that lower seizure threshold, taking medications that have short half-lives) or no identifiable motor threshold.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: iTBS+CCT; Participants will receive 12 sessions of accelerated iTBS and 11 sessions of active CCT on each of 3 treatment days.	Device: Accelerated iTBS; A MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System with Brainsight neuronavigation will be used. All participants will receive active treatment: 12 sessions (3 min each) of iTBS on each of 3 treatment days within an 8-day span. A single session = 600 pulses of 50 Hz iTBS triplets delivered every 200ms in 2s trains repeated every 10s (8s inter-train interval) for 190s. Stimulation intensity is 120% resting motor threshold (rMT) delivered at the left dorsolateral prefrontal cortex. Total pulses = 21,600. Inter-session intervals will be approx. 15 min.; Device: Computerized Cognitive Training; CCT will be delivered through the online BrainHQ platform. Participants will engage in adaptive visual speed of processing training during the 15-min breaks between iTBS sessions (11 sessions on each treatment day, total CCT time = 495 min).
Sham Comparator: iTBS+shamCCT; Participants will receive 12 sessions of accelerated iTBS and 11 sessions of sham CCT on each of 3 treatment days.	Device: Accelerated iTBS; A MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System with Brainsight neuronavigation will be used. All participants will receive active treatment: 12 sessions (3 min each) of iTBS on each of 3 treatment days within an 8-day span. A single session = 600 pulses of 50 Hz iTBS triplets delivered every 200ms in 2s trains repeated every 10s (8s inter-train interval) for 190s. Stimulation intensity is 120% resting motor threshold (rMT) delivered at the left dorsolateral prefrontal cortex. Total pulses = 21,600. Inter-session intervals will be approx. 15 min.; Device: Sham Computerized Cognitive Training; Sham CCT will be delivered through the online BrainHQ platform. Participants will engage in non-adaptive control games during the 15-min breaks between iTBS sessions (11 sessions on each treatment day, total sham CCT time = 495 min).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Retention	Percent of participants who completed all study procedures(i.e., Week 0 pre-treatment assessments, all treatment sessions, and Week 2 and Week 6 follow-up assessments). This will be calculated as a binary count (1=yes, 0=no) of completers divided by the total number of participants.	From enrollment to the end of study at week 6 (1-month post-treatment assessment).
Adherence	Percent of treatment sessions completed. This will be calculated as the number of full iTBS and CCT sessions completed by each participant divided by the prescribed number of sessions.	On each of the 3 treatment days during Week 1
Acceptability	Ratings of treatment acceptability on the Theoretical Framework of Acceptability (TFA) Questionnaire. The TFA is a self-report measure on which participants rate their perceptions of treatment acceptability via 5-point Likert-scale ratings on 8 items regarding the following: affective attitude, burden, perceived effectiveness, intervention coherence, self-efficacy, opportunity costs, ethicality, and general acceptability. Item scores will be averaged (ranging from 0-5), with higher scores indicating greater intervention acceptability.	Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment)
Change in NIH Toolbox-Cognition Battery (NIHTB-CB) Fluid Composite	The NIHTB-CB is a performance-based, iPad-administered ~30-minute suite of 7 tests that ascertain abilities in different cognitive domains (e.g. executive function, episodic memory, working memory, processing speed, language). It was developed using advanced psychometric techniques to minimize measurement error and produces normed subtest and composite scores. We will use the fully-corrected T-score (range T=0-100; Mean T=50, SD=10; higher scores indicate better cognition) of the Fluid Cognition Composite (normed for age and years of education).	Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment), and Week 6 (4 weeks post-treatment)
Change in Preclinical Alzheimer's Cognitive Composite (Mayo-PACC) Z-score	The Mayo-PACC is a composite derived from a brief battery of three neuropsychological tests of verbal episodic memory, processing speed, and semantic fluency. Z-scores will be computed for each test using a cognitively unimpaired normative reference; these will be averaged to create a single composite Z-score (Mean Z=0, SD=1; higher scores indicate better cognition).	Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment), and Week 6 (4 weeks post-treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Quick Dementia Rating System (QDRS) Total Score	The QDRS is an informant-rated measure used to evaluate changes in participants' memory, orientation, and functional abilities on a 5-point scale (0, 0.5, 1, 2, 3). Item scores are summed, and higher scores suggest greater impairment.	Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment), and Week 6 (4 weeks post-treatment)
Change in Informant-rated Everyday Cognition (ECog-II) Scale Total Score	The ECog-II scale is an informant-rated questionnaire of change in participants' everyday cognitive and functional abilities in six domains: memory, language, visuospatial function, and executive function. Each item is scored on a 4-point scale (0-"Better or no change", 1-"Questionable/occasionally worse", 2-"Consistently a little worse", 3-"Consistently much worse"). Each item also has an "I don't know" response option, which does not contribute to their score. Item scores will be averaged (range: 0-3), with higher scores indicating greater impairment.	Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment), and Week 6 (4 weeks post-treatment)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PROMIS Cognitive Function, Depression, Anxiety, Sleep Disturbance, and Fatigue T-scores	These are self-report questionnaires to which respondents rate their perceived (i.e., subjective) cognitive abilities and symptoms (i.e., depression, anxiety, fatigue, sleep disturbance) on a 5-point scale (from 1-"Not at all"; "Never" to 5-"Very much"; "Always", respectively) during the specified timeframe. It is a computer adaptive test given as a REDCap survey that yields normed T-scores (range T=0-100; Mean T=50, SD=10). Higher scores indicate more of the respective symptom.	Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment), and Week 6 (4 weeks post-treatment)

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Collaborators: National Institutes of Health (NIH); National Institute on Aging (NIA)
• Investigators: Principal Investigator: Stephanie Aghamoosa, Medical University of South Carolina

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2026
• Primary Completion (Estimated): May 31, 2030
• Study Completion (Estimated): May 31, 2030

Study Registration Dates

• First Submitted: April 2, 2026
• First Submitted That Met QC Criteria: April 8, 2026
• First Posted (Actual): April 13, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Mild Cognitive Impairment; Aging; Transcranial Magnetic Stimulation; cognitive training; Alzheimers; Memory Loss
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Neurobehavioral Manifestations; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Cognitive Dysfunction; Neurocognitive Disorders; Memory Disorders; Cognition Disorders
• Other Study ID Numbers: Pro00138352; 1K23AG090691-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data and MRI images will be shared via OpenNeuro and with approved researchers per NIH data sharing policies.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes