Engagement-Dependent Neural Entrainment Underlies Dissociable tACS Effects on Item and Sequence Working Memory

A central challenge in neuromodulation research is to elucidate how exogenous electrical stimulation interacts with endogenous neural dynamics to shape cognitive function. Drawing on empirical evidence for dissociable oscillatory mechanisms underpinning item versus sequence working memory (WM), we employed transcranial alternating current stimulation (tACS) and magnetoencephalography (MEG) to establish a causal separation and characterize the underlying neurophysiological basis. We observed a clear behavioral and neural dissociation: prefrontal 6-Hz theta stimulation selectively enhanced item WM, whereas frontoparietal in-phase theta stimulation specifically improved sequence WM. MEG further revealed task-specific modulation effects: during sequence WM, where frontoparietal theta synchrony predicted memory success, in-phase theta stimulation selectively amplified inter-regional synchronization. In contrast, during item WM, where local theta power was indicative of memory success, the identical stimulation overall exerted no significant modulation effect. Critically, across both tasks and oscillatory measures (inter-regional synchronization and theta power), the magnitude of stimulation-induced modulation scaled with each region's or connection's contribution to memory performance, indicating that tACS proportionately amplifies actively engaged oscillatory processes. This engagement-dependent principle explains task- and region-specific neurophysiological effects and the variability in behavioral outcomes, providing a framework for designing precise, functionally aligned stimulation protocols to enhance translational efficacy.