Perturbation of theta-gamma coupling at the temporal lobe hinders verbal declarative memory

Background: Phase-amplitude cross-frequency coupling (PAC) is characterized by the modulation of the power of a fast brain oscillation (e.g., gamma) by the phase of a slow rhythm (e.g., theta). PAC in different sub- and neocortical regions is known to underlie effective neural communication and correlates with successful long-term memory formation. Objective/Hypothesis: The present work aims to extend earlier observational data, by probing the functional role of theta-gamma PAC in the left temporal cortex in humans during verbal long-term memory encoding. Methods: In three double-blinded, placebo-controlled experiments (n = 72), we employed cross-frequency transcranial alternating current stimulation (tACS) to externally modulate ongoing PAC during a verbal-associative learning task. Three types of cross-frequency tACS protocols were used: bursts of high gamma tACS were coupled to the peak or trough of the theta tACS cycle, and a control condition where gamma tACS was continuously superimposed at theta tACS cycles. Results: Gamma bursts coupled to the trough of theta tACS induced robust behavioral impairment in memory performance (p < .01), whereas gamma burst coupled to the peak or continuously superimposed with theta tACS had no significant behavioral effects. Conclusions: Our results demonstrate direct evidence regarding the importance of theta-gamma coupling in verbal long-term memory formation.