ABSTRACT
Introduction Amnestic Mild Cognitive Impairment (aMCI) is a prodromal stage to Alzheimer's disease dementia (AD). Improving prefrontal cortical function in individuals with MCI could prevent progression from aMCI to AD. A key mechanism that has been linked to memory formation and thus may underlie this progression is cortical plasticity. Paired Associative Stimulation (PAS) is an intervention that uses transcranial magnetic stimulation (TMS) to enhance cortical plasticity. When delivered to the prefrontal cortex in individuals with AD, it has shown promise to improve prefrontal cortical plasticity and working memory. PAS-MCI is a randomized controlled trial (RCT) that aims to assess: (1) dorsolateral prefrontal cortex (DLPFC) plasticity in individuals with aMCI and compare it to cognitively unimpaired control participants, (2) the efficacy of PAS delivered for 10 days bilaterally to the DLPFC of individuals with aMCI in enhancing their DLPFC plasticity, working memory, and executive function, and (3) whether changes in DLPFC plasticity mediate changes in working memory and executive function. Methods 100 aMCI and 50 cognitively unimpaired (CU) control participants will be assessed clinically and cognitively, and then undergo a baseline PAS combined with electroencephalography (PAS-EEG) to characterize left DLPFC plasticity. The aMCI participants are randomized (1:1) to receive 10 daily sessions of either active or sham PAS delivered to the left and right DLPFC. On Day 0, 7, and 28 following the 10-day PAS course, participants undergo repeat cognitive testing and PAS-EEG to assess changes in working memory, executive function, and left DLPFC plasticity. Results Recruitment started on October 12, 2020 and as of October 16, 2021, we have already consented 9 aMCI and 7 CU participants. Of the 16 participants, 4 MCI and 4 CU participants were enrolled and 3 MCI and 4 CU completed the study (1 MCI participant is still active). Among the 5 participants who did not enroll, 3 were excluded because of: a contraindication for TMS (n = 1), having dementia and not MCI (n = 1), and having non-amnestic MCI (n = 1);1 withdrew before enrolment due to fatigue;and 1 is still undergoing eligibility assessments. Among the 3 CU participants who did not enroll, 2 were excluded because of low cognitive scores and 1 is still undergoing eligibility assessments. Conclusions Despite the COVID-19 pandemic, we were able to initiate recruitment over the past year. If successful, this RCT will establish the short-term efficacy of PAS, a new TMS approach to enhance prefrontal cortical function in individuals with aMCI. A follow-up longer-term trial will be then needed to assess whether PAS could prevent cognitive decline and progression to AD. This research was funded by Canadian Institutes of Health Research (CIHR) Project Grant # 201809 (PI: Rajji)