PAS‐MCI: Design and rationale for a randomized controlled trial to enhance prefrontal cortical plasticity and working memory in individuals with amnestic mild cognitive impairment

Abstract

AbstractAmnestic 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 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 compared to cognitively unimpaired control (CU) 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.100 aMCI and 50 CU control participants will be assessed clinically and cognitively, and undergo 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 bilateral DLPFC. On Day 0, 7, and 28 following the PAS course, participants undergo repeat cognitive testing and PAS‐EEG to assess changes in working memory, executive function, and left DLPFC plasticity.As of February 1st, 2022, 14 aMCI and 9 CU participants consented, of which 5 aMCI and 4 CU participants completed the study. 7 aMCI participants were excluded because of: a contraindication for TMS (n = 1), having dementia (n = 1), and having non‐amnestic MCI (n = 5); 1 withdrew due to fatigue; and 1 is pending enrollment. 3 CU participants were excluded because of low cognitive scores; 1 withdrew due to not tolerating TMS; and 1 is pending enrollment.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.