Fronto‐limbic emotional‐processing markers signal risk of onset rather than risk of recurrence in mood disorders: Evidence from a longitudinal twin study

AIMS: Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are highly heritable and linked to fronto-limbic circuit dysfunction. This longitudinal fMRI study examined whether baseline responses of the amygdala, anterior cingulate cortex (ACC), and ventrolateral prefrontal cortex (vlPFC) evoked by facial emotional expressions predicted first-onset or recurrence of mood episodes over 7 years in monozygotic twins. METHODS: The sample comprised 68 unaffected twins (UT) without a history of mood disorders but varying familial risk, and 62 affected twins (AT) in remission from MDD or BD. At baseline, participants underwent functional Magnetic Resonance Imaging (fMRI) of fearful and happy face processing and completed behavioral measures of emotional processing, which were repeated at follow-up. RESULTS: Lower baseline activation of the bilateral amygdala (left hazard ratio, HR = 1.69, 95% CI 1.15-2.45; right HR = 1.80, 95% CI 1.23-2.25), dorsal ACC (HR = 1.27, 95% CI 1.02-1.57), and right anterior vlPFC (HR = 2.28, 95% CI 1.56-3.26) by fearful (vs. happy) faces was associated with higher risk of first-onset mood episodes in the UT group. In the AT group, baseline fronto-limbic emotional activations were not associated with recurrence risk. Behaviorally, the UT group that later developed a mood episode showed slower recognition of happy faces and greater avoidance of subliminal fearful faces compared with the UT group that remained well. CONCLUSION: Dysfunctional fronto-limbic processing of facial emotions indicates increased propensity to develop a mood disorder, but is not associated with increased risk for recurrence of mood episodes. This dissociation suggests that distinct neural mechanisms underlie the first-onset versus the recurrence of mood disorders.