Double-blind, randomized clinical trial targeting theta oscillations with transcranial alternating current...

Methamphetamine use disorder is associated with significant cognitive control deficits, and effective treatments remain limited. Frontal midline theta (FM-theta) oscillations are implicated in cognitive control, but whether theta-frequency transcranial alternating current stimulation (theta-tACS) can improve proactive and reactive control in this population remains unclear. This study initially enrolled 68 male participants diagnosed with methamphetamine use disorder according to DSM-5 criteria. Among them, 56 individuals completed all study procedures and were included in the final analysis. Cognitive control was assessed using a conditional stop-signal task with concurrent EEG recording. The stimulation protocol comprised 15 consecutive daily sessions, during which participants received either active theta-tACS or sham stimulation (2 mA, FCz - Pz montage) in a double-blind design. Following the 15-day theta-tACS stimulation, patients exhibited a significant improvement in preparation cost (p = 0.001) and an increased inhibition rate (p = 0.003). EEG analyses showed that tACS selectively enhanced late-stage proactive control-related theta power (p = 0.026), without significantly modulating theta activity associated with reactive control (p > 0.05). Importantly, the tACS stimulation restored the functional coupling between FM-theta activity and proactive control performance (p = 0.04), and baseline late-stage theta power at T0 positively predicted improvement in preparation cost (ΔT1 - T0) during proactive control (p = 0.01). Finally, a mediation analysis revealed that the tACS-induced improvement in inhibition rate was mediated by the enhanced preparation cost. These findings suggested theta-tACS enhances proactive control by restoring the functional coupling between FM-theta activity and proactive control, which in turn triggers a cascading improvement in reactive control.