Memory Enhancement in Aging With Optimal Dosing

Cognitive decline, especially in memory and executive control, poses an escalating public health challenge as the population ages, contributing to loss of independence, reduced quality of life, and increased healthcare costs associated with Alzheimer's disease and related dementias (ADRD). Despite decades of research, there are few effective, non-pharmacological interventions capable of slowing or reversing these cognitive losses. Transcranial alternating current stimulation (tACS) has recently emerged as a promising, safe, and non-invasive technique for modulating neural rhythms that support memory. However, existing approaches remain limited by one-size-fits-all stimulation schedules that fail to account for individual brain connectivity patterns or dynamic fluctuations in cognitive state.

This project aims to advance precision neuromodulation for cognitive aging by optimizing and personalizing high-resolution tACS protocols to enhance memory in older adults. Building on strong pilot data demonstrating the feasibility of personalized and adaptive stimulation, we will use multimodal imaging (EEG and fMRI) to track changes in frontotemporal synchrony, specifically theta-gamma phase-amplitude coupling and theta phase synchronization, that are known to support memory formation and retrieval.

Aim 1 will establish how stimulation pattern (patterned vs. continuous waveforms) and schedule (one, three, or five consecutive days) shape the durability of memory enhancement. By comparing six systematically varied dosing protocols, we will determine the optimal pattern and repetition schedule that maximize and sustain improvements in working memory capacity, interference control, and long-term memory recognition over one month.

By integrating behavioral, electrophysiological, and neuroimaging measures with adaptive control algorithms, this research will identify reliable biomarkers of responsiveness, elucidate causal mechanisms linking neural synchrony to memory, and yield a new class of personalized, connectivity-guided interventions for cognitive decline. The findings will lay a foundation for scalable, non-invasive, and mechanism-driven treatments for ADRD and age-related memory loss, advancing the broader NIH mission of promoting healthy cognitive aging.

• 1-day patterned tACS (Device): Device: High definition transcranial electrical current stimulation Low-intensity, noninvasive application of electrical current to the human scalp with the goal of modulating levels of neuronal excitability.
• 3-day patterned tACS (Device): Device: High definition transcranial electrical current stimulation Low-intensity, noninvasive application of electrical current to the human scalp with the goal of modulating levels of neuronal excitability.
• 5-day patterned tACS (Device): Device: High definition transcranial electrical current stimulation Low-intensity, noninvasive application of electrical current to the human scalp with the goal of modulating levels of neuronal excitability.
• 1-day continuous tACS (Device): Device: High definition transcranial electrical current stimulation Low-intensity, noninvasive application of electrical current to the human scalp with the goal of modulating levels of neuronal excitability.
• 3-day continuous tACS (Device): Device: High definition transcranial electrical current stimulation Low-intensity, noninvasive application of electrical current to the human scalp with the goal of modulating levels of neuronal excitability.
• 5-day continuous tACS (Device): Device: High definition transcranial electrical current stimulation Low-intensity, noninvasive application of electrical current to the human scalp with the goal of modulating levels of neuronal excitability.

Primary outcomes

• Visual working memory capacity measured behaviorally [Baseline, 1-week after intervention, 1-month after intervention]: Behavioral k-capacity estimate derived from the change-detection task
• Interruption suppression measured behaviorally [Baseline, 1-week after intervention, 1-month after intervention]: Memory accuracy performance difference between interruption and control trials on the interruption working memory task
• EEG phase locking value (PLV) during working memory retention [Baseline, 1-week after intervention, 1-month after intervention]: Phase locking value between frontotemporal EEG electrodes within the theta frequency band during the memory retention interval of the visual working memory task
• EEG phase amplitude coupling (PAC) during working memory retention [Baseline, 1-week after intervention, 1-month after intervention]: Theta phase gamma amplitude cross-frequency coupling at temporal EEG electrodes during the memory retention interval of the visual working memory task

Sex: All, ages: 65 Years to any, accepts healthy volunteers

Inclusion Criteria:

* 65 years of age or older
* normal or corrected-to-normal vision
* color vision

Exclusion Criteria:

* pregnant
* metal implants in head
* implanted electronic devices
* history of neurological problems or head injury
* skin sensitivity
* claustrophobia
* dementia (normal Montreal Cognitive Assessment > 25)
* depression (normal Geriatric Depression Scale < 10)
* history of psychosis
* cognitive deficits (MoCA>25)
* any psychoactive medication

• Robert Reinhart, PhD, Principal investigator, Boston University Charles River Campus