Irritability in early to middle childhood: Cross-sectional and longitudinal associations with resting state amygdala and ventral striatum connectivity

Abstract

Background: Irritability is a common symptom that may affect children's brain development. This study aims to (1) characterize age-dependent and age-independent neural correlates of irritability in a sample of 4-8 year old children, and (2) examine early irritability as a predictor of change in brain connectivity over time.

Methods: Typically developing children, ages 4-8 years, with varying levels of irritability were included. Resting state fMRI and parent-rated irritability (via Child Behavior Checklist; CBCL) were collected at up to three time points, resulting in a cross-sectional sample at baseline (N = 176, M = 6.27, SD = 1.49), and two subsamples consisting of children who were either 4 or 6 years old at baseline that were followed longitudinally for two additional timepoints, one- and two-years post-baseline. That is, a "younger" cohort (age 4 at baseline, n = 34, M age = 4.44, SD = 0.25) and an "older" cohort (age 6 at baseline, n = 29, M age = 6.50, SD = 0.30). Across our exploratory analyses, we examined how irritability related to seed-based intrinsic connectivity via whole-brain connectivity ANCOVAs using the left and right amygdala, and left and right ventral striatum as seed regions.

Results: Cross-sectionally, higher levels of irritability were associated with greater amygdala connectivity with the posterior cingulate, controlling for child age. No age-dependent effects were observed in the cross-sectional analyses. Longitudinal analyses in the younger cohort revealed that early higher vs. lower levels of irritability, controlling for later irritability, were associated with decreases in amygdala and ventral striatum connectivity with multiple frontal and parietal regions over time. There were no significant findings in the older cohort.

Conclusions: Findings suggest that irritability is related to altered neural connectivity during rest regardless of age in early to middle childhood and that early childhood irritability may be linked to altered changes in neural connectivity over time. Understanding how childhood irritability interacts with neural processes can inform pathophysiological models of pediatric irritability and the development of targeted mechanistic interventions.

Keywords: Development; Early childhood; Irritability; Middle childhood; Resting state fMRI.

Fig. 1

Whole-brain Connectivity Analyses. Main Effect of Irritability (controlling for age). Left amygdala connectivity with posterior cingulate. Scatterplot represents the relationship between whole-brain connectivity and irritability at baseline (N = 176). Brain regions represent axial sections (left=left) with threshold set at whole-brain FDR-corrected p < .05. The scatterplot is displayed for illustrative purposes to depict the direction of the association.

Fig. 2

Whole-brain Connectivity Analyses (younger cohort). A) Age 4 Irritability predicting connectivity change from age 4 to 5 (n = 34). Left amygdala connectivity with right precentral gyrus and right amygdala connectivity to middle frontal gyrus. B) Age 5 Irritability predicting connectivity change from age 5 to 6 (n = 31). Left ventral striatum connectivity with left caudate and bilateral posterior cingulate. C) Age 4 Irritability predicting connectivity change from age 4 to 6 (n = 32). Right amygdala connectivity with left lingual gyrus. Graph represents relationship between irritability and change in connectivity (adjusting for irritability at a later timepoint) for left amygdala connectivity with the right precentral gyrus. Directionality of the predicted change in connectivity was similar across all significant clusters in the longitudinal analyses. Brain regions represent axial sections (left=left) with threshold set at whole-brain FDR-corrected p < .05. Graph is displayed for illustrative purposes to depict the direction of the association.