Effects of intermittent theta-burst stimulation on cognition and glymphatic system activity in mild cognitive impairment and very mild Alzheimer's disease: a randomized controlled trial.

Background: Repetitive transcranial magnetic stimulation (rTMS) has demonstrated efficacy in alleviating cognitive symptoms in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Although animal studies suggest rTMS may enhance glymphatic system efficiency and reduce amyloid deposits, its impact on human glymphatic activity remains uncertain.

Methods: This double-blind, randomized, sham-controlled trial investigated the effects of intermittent theta-burst stimulation (iTBS), a novel rTMS technique, on cognitive function and glymphatic system activity using diffusion tensor image analysis along the perivascular space (DTI-ALPS) in 52 participants with amnestic MCI or very mild AD. Participants underwent 10 sessions of iTBS targeting the left dorsolateral prefrontal cortex over two weeks. Cognitive and glymphatic assessments were conducted at baseline, week 2, and week 6. Of the 52 participants, 28 received active iTBS, while 24 received sham stimulation. After the first two weeks, the sham group transitioned to active iTBS.

Results: Significant cognitive improvements were observed at week 6 in the iTBS group, indicating delayed cognitive enhancement, though no immediate changes in cognition or glymphatic system activity (measured by the ALPS index) were observed. No adverse events were reported.

Conclusions: These findings suggest that iTBS can produce delayed cognitive enhancement in individuals with amnestic MCI and very mild AD, while the impact on the glymphatic system remains uncertain and requires further investigation.

Trial registration: Clinicaltrials.gov (NCT04555941).