Dual-site theta stimulation modulates connectivity, but not sequence memory in older adults

Understanding and modulating memory functions in older adults continues to be a fundamental challenge for neuroscientific research. Given age-associated declines in long-range connectivity, network approaches targeting these connections are of particular interest. We investigated whether dual-site transcranial alternating current stimulation can modulate episodic (sequential) memory in cognitively healthy older adults (N = 44, aged 60-80 years). In a sham-controlled crossover design, participants received in-phase (0°) and anti-phase (180°) transcranial alternating current stimulation during a temporal order memory task, with a counterbalanced order of conditions. We computed source analysis-based weighted phase lag indices and corrected amplitude envelope correlation between left hemispheric fronto-parietal stimulation targets from resting-state electroencephalography to quantify modulation of functional connectivity, and conducted analyses of phase angles between these targets. No overall memory effects were observed in either active stimulation conditions, compared with sham. However, the results showed an interaction between memory modulation and age, indicating that the older the participants the higher the memory improvement in the anti-phase condition. Functional coupling increase was observed in both anti- and in-phase conditions as an elevated weighted phase lag indices theta change, compared with sham. No differences were observed for weighted phase lag indices in other frequency bands (alpha, beta) or for the corrected amplitude envelope correlation (theta, alpha, beta). Theta phase angle shifts were increased in the anti-phase compared with the sham condition. Further, in the anti-phase condition, the increase in theta connectivity was linked to age and memory improvement, indicating a potential mechanistic link between neurophysiological and cognitive outcomes. In sum, our findings suggest that dual-site anti-phase stimulation may increase functional connectivity in older adults with large interindividual variability in memory effects, warranting further investigation to optimize stimulation strategies.