Neural correlates of extinguished threat recall underlying the commonality between pediatric anxiety and irritability

Abstract Background Anxiety and irritability frequently co-occur in youth and are mediated by aberrant threat responses. However, empirical evidence on neural mechanisms underlying this co-occurrence is limited. To address this, we apply data-driven latent phenotyping to data from a prior report of a well-validated threat extinction recall fMRI paradigm. Methods Participants included 59 youth (28 anxiety disorder, 31 healthy volunteers; Mage=13.15 yrs) drawn from a transdiagnostic sample of 331 youth, in which bifactor analysis was conducted to derive latent factors representing shared vs. unique variance of dimensionally-assessed anxiety and irritability. Participants underwent threat conditioning and extinction. Approximately three weeks later, during extinction recall fMRI, participants made threat-safety discriminations under two task conditions: current threat appraisal and explicit recall of threat contingencies. Linear mixed-effects analyses examined associations of a “negative affectivity” factor reflecting shared anxiety and irritability variance with whole-brain activation and task-dependent amygdala connectivity. Results During recall of threat-safety contingencies, higher negative affectivity was associated with greater prefrontal (ventrolateral/ventromedial, dorsolateral, orbitofrontal), motor, temporal, parietal, and occipital activation. During threat appraisal, higher negative affectivity was associated with greater amygdala-inferior parietal lobule connectivity to threat/safety ambiguity. Limitations Sample included only healthy youth and youth with anxiety disorders. Results may not generalize to other diagnoses for which anxiety and irritability are also common, and our negative affectivity factor should be interpreted as anxiety disorders with elevated irritability. Reliability of some subfactors was poor. Conclusions Aberrant amygdala-prefrontal-parietal circuitry during extinction recall of threat-safety stimuli may be a mechanism underlying the co-occurrence of pediatric anxiety and irritability.