Targeted Alternating Current and Cognitive Training Intervention for Cognitive Control in Bipolar Disorders

Veterans with bipolar disorder (BD) are at elevated risk for suicide, recurrent homelessness, and disability, and existing pharmacological and psychosocial treatments show limited efficacy for the cognitive dysfunction that underlies these outcomes. Cognitive control (CC) - encompassing response inhibition, error monitoring, and adaptive responding to changing contingencies - is a core, trait-like neurocognitive deficit in BD that persists across mood states (mania, depression, euthymia) and is mechanistically linked to symptom severity and suicidality. No prior studies have examined neuromodulation targeting CC processes in Veterans with BD. This study is a randomized, double-blind, sham-controlled trial testing whether transcranial alternating current stimulation (tACS) targeting frontal theta oscillations, delivered concurrently with CC-relevant cognitive training, improves neural and behavioral indices of CC beyond cognitive training alone. Ninety-two Veterans with a DSM-5 diagnosis of Bipolar I, Bipolar II, or Other Specified Bipolar Disorder will complete a baseline assessment battery, including self-report measures, EEG (resting-state and task-based), and behavioral paradigms indexing CC in both affective and non-affective contexts (e.g., Go/NoGo, Dot Pattern Expectancy, Monetary Incentive Delay tasks). Participants will then be randomized 1:1 to 10 sessions of active (5Hz, 1mA) or sham frontal theta-frequency tACS (electrodes at F3/F4), each paired with concurrent computerized cognitive training (BrainHQ) targeting working memory, inhibitory control, set-shifting, and attention. All intervention sessions will be self-administered in participants' homes under real-time remote supervision via videoconference. Follow-up assessments repeating the baseline CC battery will occur at approximately 1-week and 2-months post-intervention. An additional 46 Veterans without major psychopathology will complete an identical assessment schedule (baseline and two follow-up visits) without any intervention, in order to establish practice-effect benchmarks independent of neuromodulation, cognitive training, or mood symptomatology - a design feature intended to isolate true intervention effects from repeated-testing effects, consistent with methodological recommendations for cognitive intervention trials in serious mental illness. Primary outcomes include change over time in behavioral (d' on Affective and non-affective Go/NoGo and Dot Pattern Expectancy tasks; Trail Making Test-B completion time) and EEG (frontal theta amplitude during the Monetary Incentive Delay task; error-related positivity during the Go/NoGo task) indices of CC, comparing active versus sham tACS groups relative to the practice-effect benchmark established by the control cohort. Secondary outcomes include self-report CC measures (UPPS-P, MPQ-BF Control subscale), qualitative acceptability data from semi-structured exit interviews with the BD cohort, and cross-sectional associations between baseline CC indices and lifetime severity of (hypo)mania, depression, and suicidality. Exploratory analyses will examine intervention effects on general cognitive functioning and the influence of subthreshold mood symptoms on treatment response. This study is the first to test remotely delivered tACS combined with cognitive training in Veterans with BD, and is designed to establish feasibility, acceptability, and preliminary efficacy data to inform future trials examining long-term effects on BD illness course, including suicidality and functional outcomes.