Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation therapy most widely used in depression, has shown evidence of secondary benefits for cognition in both neurologic and neuropsychiatric conditions. The recent development of more efficient stimulation protocols, such as accelerated high-dose intermittent theta burst (iTBS)-rTMS, has substantially reduced treatment burden by shortening the treatment course by >50%. This study aimed to establish the safety, feasibility, acceptability, and preliminary efficacy of iTBS-rTMS as a tool for bolstering cognition in individuals with amnestic mild cognitive impairment (aMCI).

Twenty-four patients with aMCI were enrolled in an open-label phase I trial of iTBS-rTMS; 2 withdrew prior to initiating treatment due to personal circumstances. All participants had received a diagnosis of MCI due to possible AD from a healthcare provider (i.e., neurologist or neuropsychologist) and met actuarial neuropsychological criteria for aMCI. This sample of older adults (range: 61.5-85.2 years, M = 74.1, SD = 5.71) was predominantly White/non-Hispanic (n = 23; Black/non-Hispanic: n = 1), roughly half female (n = 13), with a college education (range: 12-20 years, M = 15.9, SD = 2.5). Participants received 24 sessions of iTBS-rTMS to the left dorsolateral prefrontal cortex over 3 days (8 sessions each, lasting roughly 2 hours per day). Participants rated their perceptions and experience of common side effects during and after each treatment session as well as retrospectively at post-treatment and 4-week follow-up. They completed structural and functional brain MRI, neuropsychiatric evaluations, and neuropsychological assessments before and after treatment and were administered a subset of these measures at 4-week follow-up. MoCA scores were used to monitor for adverse neurocognitive effects, and the fluid cognition composite score from the NIH Toolbox Cognition Battery was used to test preliminary efficacy.

We achieved a high retention rate (95%), with 21 of the 22 participants completing all study procedures. There were no clinically significant adverse neuroradiological, neuropsychiatric, or neurocognitive effects of treatment. Participant reports indicated high tolerability and acceptability, with a modal rating of 0 (on a scale from 0=not at all to 10=extremely) for six common side effects (i.e., headache, pain, scalp irritation, facial twitching, fatigue, fear/anxiety), assessed both during and after each treatment session. They reported very low desire to quit despite some participants rating the treatment as moderately tiring. We observed significant, large effect-size (d = 0.98) improvements in fluid cognition from pre- to post-treatment.

Our findings support the safety, feasibility, and acceptability of iTBS-rTMS treatment in patients with aMCI. Further, although not explicitly dosed for efficacy, we provide preliminary evidence of improved fluid cognition as a function of treatment, highlighting the potential of this treatment for improving trans-domain cognitive impairment. These promising results can directly inform future trials aimed at optimizing treatment parameters, broadening the indication to other MCI subtypes, and testing the augmentation of established cognitive rehabilitation interventions when combined with rTMS.