Modeling Shared and Specific Variances of Irritability, Inattention, and Hyperactivity Yields Novel Insights Into White Matter Perturbations

Abstract

Irritability, inattention, and hyperactivity, common presentations of childhood psychopathology, have been associated with perturbed white matter microstructure. However, similar tracts have been implicated across these phenotypes; such non-specificity could be rooted in their high co-occurrence. To address this problem, we employ a bifactor approach parsing unique and shared components of irritability, inattention, and hyperactivity, which we then relate to white matter microstructure. We developed a bifactor model based on the Conners Comprehensive Behavioral Rating Scale in a sample of youth with no psychiatric diagnosis or a primary diagnosis of Attention-Deficit/Hyperactivity Disorder or Disruptive Mood Dysregulation Disorder (N = 521). We applied the model to an independent yet sociodemographically and clinically comparable sample (N = 152), where we tested associations between latent variables and fractional anisotropy (FA). The bifactor model fit well (CFI=.99; RMSEA=.07). The shared factor was positively associated with an independent measure of impulsivity (rS=0.88, pFDR<.001) and negatively related to whole-brain FA (r=-0.20), as well as FA of the corticospinal tract and the anterior thalamic radiation (all pFWE<.05). FA increased with age and deviation from this curve, indicating altered white matter maturation, was associated with the hyperactivity-specific factor (r=-0.16, pFWE<.05). Inattention- and irritability-specific factors were not linked to FA. Perturbed white matter microstructure may represent a shared neurobiological mechanism of irritability, inattention, and hyperactivity related to heightened impulsivity. Further, hyperactivity might be uniquely associated with a delay in white matter maturation.