The unique face of comorbid anxiety and depression: Increased frontal, insula and cingulate cortex response during Pavlovian fear-conditioning

Background: Dysregulation of fear processing through altered sensitivity to threat is thought to contribute to the development of anxiety disorders and major depressive disorder (MDD). However, fewer studies have examined fear processing in MDD than in anxiety disorders. The current study used propensity matching to examine the hypothesis that comorbid MDD and anxiety (AnxMDD) shows greater neural correlates of fear processing than MDD, suggesting that the co-occurrence of AnxMDD is exemplified by exaggerated defense related processes. Methods: 195 individuals with MDD (N N = 65) or AnxMDD (N N = 130) were recruited from the community and completed multi-level assessments, including a Pavlovian fear learning task during functional imaging. Visual images paired with threat (conditioned stimuli: CS+) +) were compared to stimuli not paired with threat (CS-). Results: MDD and AnxMDD showed significantly different patterns of activation for CS+ + vs CS- in the dorsal anterior insula/inferior frontal gyrus (partial eta squared; eta p2 2 = 0.02), dorsolateral prefrontal cortex (eta p2 2 = 0.01) and dorsal anterior/mid cingulate cortex (eta p2 2 = 0.01). These differences were driven by greater activation to the CS+ + in AnxMDD versus MDD. Limitations: Limitations include the cross-sectional design, a scream US rather than shock and half the number of MDD as AnxMDD participants. Conclusions: AnxMDD showed a pattern of increased activation in regions identified with fear processing. Effects were consistently driven by threat, further suggesting fear signaling as the emergent target process. Differences emerged in regions associated with salience processing, attentional orienting/conflict, self-relevant processing and executive functioning in comorbid anxiety and depression, thereby highlighting potential treatment targets for this prevalent and treatment resistant group.