Enhancing Affective Cognitive Control in Bipolar Disorder Using Transcranial Alternating Current Stimulation: A Double‐Blind, Randomized, Sham‐Controlled Clinical Trial and Proof of Concept Study

INTRODUCTION: Persistent emotion lability and impulsive behavior in bipolar disorder (BD) are thought to be due to impaired affective cognitive control. Neural synchrony via theta-gamma phase-amplitude coupling (PAC) in the prefrontal cortex facilitates cognitive control and is impaired in BD. This pilot study aimed to investigate the feasibility and efficacy of transcranial alternating current stimulation (tACS) in targeting the neural coordination (i.e., theta-gamma PAC) of cognitive control in a double-blind, randomized, controlled crossover trial. METHODS: Participants (N = 18) with BD completed an emotional Go/No-Go task during six 5-min stimulation blocks interleaved with 2-min resting blocks. Participants received active- and sham-stimulation 1 week apart; sham comprised a ramp up/down at the beginning and end of the block to mimic stimulation sensations. Tolerability was measured using a side effect questionnaire after active and sham stimulation. Behavioral measures of discriminability (d') and reaction time during the task, and EEG measures of theta-power and theta-gamma PAC during the interleaved resting states were compared for active versus sham. RESULTS: Active did not differ from sham stimulation on any side effects (all p's > 0.11). Effect sizes when comparing discriminability, theta-power, and PAC across active versus sham were small but showed a consistent pattern of improvement in the active relative to the sham condition. CONCLUSION: This pilot study showed that 30-min tACS is tolerable to BD patients and demonstrated preliminary promise in enhancing affective cognitive control. Future studies should determine the optimal dosage to produce more substantial and enduring effects. TRIAL REGISTRATION: ClinicalTrials: NCT05480124.