Abstract
BACKGROUND: Irritability predicts concurrent and prospective psychiatric disorders across the lifespan. Anxiety commonly co-occurs with irritability, and such comorbidity complicates care. Understanding the mechanisms of comorbid traits is necessary to inform treatment decisions. This study aimed to disentangle neural mechanisms of irritability from anxiety in the context of attentional shifting toward and away from emotional faces in youths from treatment-seeking families. METHODS: Youths (N = 45), mean age = 14.01 years (standard deviation = 1.89) completed a dot-probe task during functional magnetic resonance imaging acquisition. Whole-brain activation analyses evaluated the effect of irritability on neural reactivity in the context of varying attentional shifting toward and away from emotional faces, both depending on and above and beyond anxiety (i.e., with anxiety as [a] a moderator and [b] a covariate, respectively). RESULTS: Higher irritability levels related to distinct task-related patterns of cuneus activation, depending on comorbid anxiety levels. Increased irritability also related to distinct task-related patterns of parietal, temporal, occipital, and cerebellar activation, controlling for anxiety. Overall, youths with higher levels of irritability evinced more pronounced fluctuations in neural reactivity across task conditions. CONCLUSION: The present study contributes to a literature delineating the unique and shared neural mechanisms of overlapping symptom dimensions, which will be necessary to ultimately build a brain- and behavior-based nosology that forms the basis for more targeted and effective treatments.