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.
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