Spatial Working Memory in Humans Depends on Theta and High Gamma Synchronization in the Prefrontal Cortex

Previous, albeit correlative, findings have shown that the neural mechanisms underlying working memory critically require cross-structural and cross-frequency coupling mechanisms between theta and gamma neural oscillations. However, the direct causality between cross-frequency coupling and working memory performance remains to be demonstrated. Here we externally modulated the interaction of theta and gamma rhythms in the prefrontal cortex using novel cross-frequency protocols of transcranial alternating current stimulation to affect spatial working memory performance in humans. Enhancement of working memory performance and increase of global neocortical connectivity were observed when bursts of high gamma oscillations (80–100 Hz) coincided with the peaks of the theta waves, whereas superimposition on the trough of the theta wave and low gamma frequency protocols were ineffective. Thus, our results demonstrate the sensitivity of working memory performance and global neocortical connectivity to the phase and rhythm of the externally driven theta-gamma cross-frequency synchronization. [Display omitted] •Both theta and theta-gamma tACS improve working memory performance•Theta-gamma tACS protocols have greater effect on working memory than theta tACS•High gamma power over the peak, but not over the trough, of theta wave boosts memory•The optimal gamma frequencies manifest in the 80 to 100 Hz frequency range Alekseichuk et al. demonstrate the role of theta-gamma cross-frequency coupling in human prefrontal cortex for working memory by using causal inference. They applied cross-frequency transcranial alternating current stimulation and showed the phase and frequency specificity of theta-gamma rhythms during working memory performance.