Change in prefrontal activity and executive functions after action-based cognitive remediation in bipolar disorder: a randomized controlled trial.

Cognitive impairment is prevalent in bipolar disorder (BD) but treatments with pro-cognitive effects are lacking. Insight concerning the neurocircuitry of cognitive improvement could provide a biomarker for pro-cognitive effects to advance treatment development. The dorsal prefrontal cortex (dPFC) is a promising region for such treatment target engagement. The aim of this functional magnetic resonance imaging (fMRI) study was to examine the effects of action-based cognitive remediation (ABCR) on early change in the dPFC blood-oxygen-level-dependent response in patients with BD in remission, and whether the observed neural change predicted improved executive functions following 10 weeks of treatment. Forty-five participants with remitted BD (ABCR: n = 26, control treatment: n = 19) completed a spatial n-back working memory task during fMRI and executive function tasks outside the scanner before and after two weeks of ABCR/control treatment, and an additional assessment of executive function at treatment completion. Thirty-four healthy controls underwent a single fMRI and executive function assessment for baseline comparisons. We found an early reversal of pretreatment hypo-activity in the dorsolateral prefrontal cortex (dlPFC) following ABCR vs. control during both high-load (2-back > 1-back) working memory (WM) (F(1,43) = 5.69, p = 0.02, η = 0.12) and general WM (2-back > 0-back) (F(1,43) = 5.61, p = 0.02, η = 0.12). This dlPFC activity increase predicted improved executive functions at treatment completion (high-load WM: B = -0.45, p = 0.01, general WM: B = -0.41, p < 0.01), independent of changes in subsyndromal symptoms. In conclusion, early dPFC increase may provide a neurocircuitry-based biomarker for pro-cognitive effects. Future cognition trials should include fMRI assessments to confirm the validity of this putative biomarker model across disorders with cognitive impairment.