Objective: Childhood irritability is a common, impairing problem with changing agerelated manifestations that predict long-term adverse outcomes. However, more work is needed on its overall and age-specific neural correlates. Since irritable youth exhibit exaggerated responses to frustrating stimuli, we used a frustrating functional magnetic resonance imaging (fMRI) paradigm to examine associations between irritability and neural activation and tested the moderating effect of age. Method: We studied a transdiagnostic sample of 195 youths with varying levels of irritability (52 disruptive mood dysregulation disorder, 42 anxiety disorder, 40 attention deficit/hyperactivity disorder, and 61 healthy volunteers). Irritability was measured by parent- and child-reports on the Affective Reactivity Index. The fMRI paradigm was a cued-attention task differentiating neural activity in response to frustration (rigged feedback) from activity during attention orienting in the trial following frustration. Results: Whole-brain activation analyses revealed associations with irritability during attention orienting following frustration. Irritability was positively associated with frontalstriatal activation, specifically in dorsolateral prefrontal cortex, inferior frontal gyrus, and caudate (rs=.31-.40, ps<.05). Age moderated the association between irritability and activation in some frontal and posterior regions (anterior cingulate cortex [ACC], medial frontal gyrus, cuneus, precuneus, superior parietal lobule; F1,189=19.04–28.51, ps<.001, ηp2=.09-.13). Specifically, higher irritability was more strongly related to increased activation in younger relative to older youths. Conclusions: Following frustration, levels of irritability correlate with activity in neural systems mediating attention orienting, top-down regulation of emotions, and motor execution. While most associations were independent of age, dysfunction in ACC and posterior regions was more pronounced in young children with irritability.

It remains unclear the degree to which youths with episodic mania (bipolar disorder; BD) vs. those with chronic, severe irritability (severe mood dysregulation, SMD) should be placed in similar or distinct diagnostic groups. Addressing this clinically meaningful question requires greater understanding of the neural alterations underlying both disorders. We evaluated resting state functional magnetic resonance imaging data of 53 youths (14 BD, 20 healthy volunteers (HV), and 19 SMD, ages 9–18.5 years). Seed regions of interest were the bilateral basolateral, superficial and centromedial amygdala, defined using the Juelich probabilistic atlas. We found a significant between-group difference in functional connectivity between the left basolateral amygdala and the medial aspect of the left frontal pole plus the posterior cingulate/precuneus. This finding was driven by hyperconnectivity among BD vs. HV or SMD youths. As with earlier data, these findings suggest that the pathophysiology of BD and SMD may differ.

These data suggest that two networks show abnormal intrinsic functional connectivity in BD. Regions in these networks have been implicated previously in BD. We observed similar dysconnectivity in youths and adults with BD. These findings provide guidance for refining models of network-based dysfunction in BD.

No abstract