Prefrontal cortical (PFC) activation during the anticipation and performance of a working memory task appears to be an important biological marker for discriminating between bipolar disorder (BD) and major depressive disorder (MDD). A study conducted among individuals recruited from community, universities, counseling, and medical centers in the United States was published in Neuropsychopharmacology.

Although patients with BD and MDD experience aberrant working memory and anticipatory processing, the role played by these processes in distinguishing BD from MDD remains to be elucidated. The investigators sought to evaluate brain activation patterns corresponding to anticipation and performance of easy vs difficult working memory tasks involving emotional stimuli in patients with BD, those with MDD, and healthy controls.

A total of 18 participants with BD, 23 individuals with MDD, and 23 healthy controls were enrolled in the study. All of the participants were right-handed and fluent in English, and the control sample was age-, gender-, and IQ-matched. The participants were all scanned while they carried out a working memory task, in which they had to anticipate performance on 1-back (ie, easy) or 2-back (ie, difficult) tasks with happy, fearful, or neutral faces, then had to carry out the actual task. Both anticipation-associated and task-associated brain activation was measured in all of the participants’ brains via functional magnetic resonance imaging (MRI).Variable selection was conducted with the use of elastic net regression; a random forest classifier was used to distinguish BD from MDD.

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Patients with BD and MDD were significantly more symptomatic compared with healthy controls (P <.05). Moreover, patients with BD had more severe symptoms of depression, hypomania, irritability, and mood instability over their lifetimes and were significantly more depressed at the time of the MRI scan than those with MDD (P <.05).

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An analysis of variance (ANOVA) revealed the significantly main effect of task difficulty on both accuracy and reaction time (both P <.001). Study findings showed that the participants were slower and less accurate for the 2-back task compared with the 1-back task, thus confirming the fact that the 2-back task was more difficult than the 1-back task. Neither reaction time nor accuracy was significantly affected by group, emotional condition, or interactions among the group, task difficulty, and emotional condition (P >.05).

BD vs MDD was classified with 70.7% accuracy (P <.01) according to MRI measures alone, with an 80.5% accuracy time (P <.001) based on clinical measures alone, and with an 85.4% accuracy (P <.001) based on clinical and neuroimaging measures together. The lateral and medial PFC appeared to play a role in distinguishing MDD from BD.

The investigators concluded that additional research is warranted, which should be aimed at understanding how modulating PFC activation during mental preparation for difficult working memory tasks improves cognitive functioning among those with BD and MDD.


Manelis A, Iyengar S, Swartz HA, Phillips ML. Prefrontal cortical activation during working memory task anticipation contributes to discrimination between bipolar and unipolar depression [published online February 18, 2020]. Neuropsychopharmacology. doi: 10.1038/s41386-020-0638-7.