Overview

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.

Eligibility

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. 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.

vi. 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 AD42 vii. 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:

i. Telephone Interview for Cognitive Status (TICS) score of ≤ 22 suggestive of dementia.

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.

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), 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).

v. Plan to initiate treatment for AD/MCI with monoclonal antibody therapy during study participation.

vi. For those currently receiving monoclonal antibody therapy, documented history of clinically significant amyloid-related imaging abnormalities (ARIA) in their medical record.

vii. Current use of any implanted brain stimulation device. viii. Enrolled in a clinical trial or has received an investigational medication or device in the last 30 days that may impact cognition or mood.

ix. MRI contraindications (e.g., ferromagnetic implants, claustrophobia). x. Unable or unwilling to engage in BrainHQ activities. xi. 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.