The unique face of anxious depression: Increased sustained threat circuitry response during fear acquisition

BACKGROUND: Sensitivity to threat with dysregulation of fear learning is thought to contribute to the development of psychiatric disorders, including anxiety disorders (AD) and major depressive disorder (MDD). However, fewer studies have examined fear learning in MDD than in AD. Nearly half of individuals with MDD have an AD and the comorbid diagnosis has worse outcomes. The current study used propensity matching to examine the hypothesis that AD+MDD shows greater neural correlates of fear learning than MDD, suggesting that the co-occurrence of AD+MDD is exemplified by exaggerated defense related processes. METHODS: 195 individuals with MDD (N = 65) or AD+MDD (N=130) were recruited from the community and completed multi-level assessments, including a Pavlovian fear learning task during functional imaging. RESULTS: MDD and AD+MDD showed significantly different patterns of activation for [CSplus–CSminus] in the medial amygdala (ηp(2)=0.009), anterior insula (ηp(2)=0.01), dorsolateral prefrontal cortex (ηp(2)=0.002), dorsal anterior cingulate cortex (ηp(2)=0.01), mid-cingulate cortex (ηp(2)=0.01) and posterior cingulate cortex (ηp(2)=0.02). These differences were driven by greater activation to the CS+ in late conditioning phases in ADD+MDD relative to MDD. CONCLUSIONS: AD+MDD showed a pattern of increased sustained activation in regions identified with fear learning. Effects were consistently driven by the threat condition, further suggesting fear signaling as the emergent target process. Differences emerged in regions associated with salience processing, attentional orienting/conflict, and self-relevant processing. These findings help to elucidate the fear signaling mechanisms involved in the pathophysiology of comorbid anxiety and depression, thereby highlighting promising treatment targets for this prevalent treatment group.