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Distinguishing bipolar disorder (BD) from major depressive disorder (MDD) is clinically challenging, especially during depressive episodes. While both groups are characterized by aberrant working memory and anticipatory processing, the role of these processes in discriminating BD from MDD remains unexplored. In this study, we examine how brain activation corresponding to anticipation of and performance on easy vs. difficult working memory tasks with emotional stimuli contributes to discrimination among BD, MDD, and healthy controls (HC). Depressed individuals with BD (n = 18), MDD (n = 23), and HC (n = 23) were scanned while performing a working memory task in which they had to first anticipate performance on 1-back (easy) or 2-back (difficult) tasks with happy, fearful, or neutral faces, and then, perform the task. Anticipation-related and task-related brain activation was measured in the whole brain using functional magnetic resonance imagining. We used an elastic-net regression for variable selection, and a random forest classifier for BD vs. MDD classification. The former selected the activation differences (1-back minus 2-back) in the lateral and medial prefrontal cortices (PFC) during task anticipation and performance on the working memory tasks with fearful and neutral faces as variables relevant for BD vs. MDD classification. BD vs. MDD were classified with 70.7% accuracy (p &lt; 0.01) based on the neuroimaging measures alone, with 80.5% accuracy (p = 0.001) based on clinical measures alone, and with 85.4% accuracy (p &lt; 0.001) based on clinical and neuroimaging measures together. These findings suggest that PFC activation during working memory task anticipation and performance may be an important biological marker distinguishing BD from MDD.

Prefrontal cortical activation during working memory task anticipation contributes to discrimination between bipolar and unipolar depression