Personalized Memory Enhancement in Aging: Pattern-Optimized tACS with Closed-Loop Precision Modulation

/ABSTRACT Cognitive decline, particularly memory impairment, poses an increasing challenge in aging populations, leading to reduced quality of life and escalating healthcare costs, especially in Alzheimer's Disease and Related Dementias (ADRD). While transcranial alternating current stimulation (tACS) has emerged as a promising non- invasive approach for memory enhancement, its effectiveness is limited by a lack of precision in stimulation protocols. The primary goal of this study is to optimize high-resolution tACS intervention parameters and develop a personalized, connectivity-guided closed-loop system to improve memory performance in aging adults. This application is supported by compelling pilot data demonstrating the feasibility of personalized and adaptive tACS for memory enhancement, providing a strong foundation for the proposed study. Aim 1 will investigate the impact of personalized tACS applications within a day (patterned vs. continuous) and across multiple days (one-time vs. repeated consecutive dosing) on the durability of memory enhancement. We will compare six tACS protocols, including continuous and patterned stimulation, over one, three, or five consecutive days. This aim will also establish dose-response functions to identify the optimal stimulation frequency and application pattern that maximize memory enhancement over time. Memory and executive control abilities—such as working memory capacity, filtering efficiency, interference suppression, and long-term memory recognition—will be examined before, immediately after, and at one-week and one-month follow-ups. These cognitive metrics will be complemented by multimodal imaging (EEG, f/MRI) to investigate the neurobiological mechanisms underlying memory improvements, focusing on theta-gamma phase-amplitude coupling and theta phase synchronization, and to identify potential biomarkers of nonresponse. Aim 2 will develop a connectivity-guided closed-loop tACS system that adjusts stimulation parameters on-the-fly based on neural synchronization and memory performance. This system will track low-frequency oscillatory synchronization, an aspect of brain connectivity, in the frontotemporal cortex, periodically adjusting stimulation to optimize memory performance. We hypothesize that adaptive modulation will yield more efficient memory enhancement than static protocols, emphasizing the importance of accounting for fluctuations in functional brain state. This research aims to advance precision aging by identifying optimal tACS protocols and developing an adaptive system that tailors stimulation to individual neural connectivity patterns. The findings will provide novel causal insights into the neurobiological mechanisms of memory, with potential to inform interventions for ADRD. This work holds promise for improving cognitive function in aging adults and offers a non-pharmacological alternative or adjunct to current therapeutic options for age-related cognitive decline, with direct relevance to ADRD intervention development. Project Number: 1R01AG097619-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Robert Reinhart | Institution: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS), BOSTON, MA | Award Amount: $343,350 | Activity Code: R01 | Study Section: Human Complex Mental Function Study Section[HCMF] View on NIH RePORTER: https://reporter.nih.gov/project-details/11269712