Sex-Specific Associations of Irritability With Subcortical Brain Volumes

Irritability is transdiagnostic and associated with considerable impairment. The behavioral presentation of irritability may vary with age, sex, and diagnosis. Although inconsistent, clinical evidence indicates that irritability may present as temper tantrums associated with neurodevelopmental disorders in young boys, whereas irritability in girls may manifest in adolescence associated with negative mood. Functional activation of subcortical regions is characteristic of irritability, but the structural correlates of irritability in these regions are underexplored. We hypothesized that age, sex, and diagnosis would modify subcortical correlates of irritability.

False discovery rate-corrected regression models tested whether associations between irritability and subcortical structures were moderated by sex, age, or diagnosis in 1792 youths from the Healthy Brain Network dataset (release 11.0), a cohort weighted for psychiatric problems. Irritability was measured via the Affective Reactivity Index. FreeSurfer 6.0.1 extracted subcortical structures.

Effect modification by sex indicated higher irritability associated with smaller reward-related volumes (right nucleus accumbens, bilateral caudate) in boys and with larger threat-related volumes (left amygdala) in girls. Effect modification by age or diagnosis was not significant.

Sex-specific subcortical correlates may explain sex-specific differences in the behavioral presentation of irritability. In models of irritability, the subcortex governs initiation of angry responses, which are dampened by prefrontal cortices. The altered volumes in reward-related regions in boys and threat-related regions in girls reported herein may be markers of early risk for irritability and/or possible targets for brain-informed interventions. Girls may benefit from irritability treatments targeting threat-based pathways, and boys may benefit from treatments targeting reward-based pathways.