Connectome-Wide Network Analysis of Male Youth with Autism Spectrum Disorder with and without Impaired Self-Regulation

Background: Individuals with autism spectrum disorder (ASD) commonly present with impaired self-regulatory ability (dysregulation), in affect, cognition, and behavior domains, which would exacerbate social functional impairment in ASD and increase the burden on caregivers. The characterization of dysregulation and its neural correlates in ASD remains elusive and is a priority.

Objectives: Following our earlier structural MRI studies, we aimed to further characterize effects of dysregulation on intrinsic functional connectivity networks in youths with ASD

Methods: We conducted a multivariate connectome-wide association study (CWAS) examining dysconnectivity with resting state functional magnetic resonance imaging in a sample of 52 male youths with ASD, 49 neurotypical male comparators, age range 8-17 years. Dysregulation was defined by the sum of T-scores of the Attention, Aggression, and Anxiety/Depression subscales in the Child Behavior Checklist greater than 180. There were 36 and 16 boys with ASD in the ASD+Dysregulation and ASD-Dysregulation groups, respectively. ICA-based strategy for Automatic Removal of Motion Artifacts was applied to address in-scanner head motion. We investigated CWAS differences among the ASD+Dysregulation, ASD-Dysregulation and neurotypical groups. Significant CWAS findings were thresholded at Z > 1.65, and controlled for family-wise error rate using Gaussian Random Field (GRF) theory (cluster size threshold p< 0.05). Follow-up analyses used the clusters identified by CWAS as the basis for seed-based connectivity analyses.

Results: In CWAS, comparisons of ASD+Dysregulation and neurotypical youths revealed multiple regions where the multivariate pattern of connectivity differed between groups, implicating the dorsal anterior cingulate cortex (dACC) and left inferior frontal gyrus (L-IFG), bilateral precuneus, and right inferior parietal lobule (IPL). Comparisons of ASD-Dysregulation and neurotypical groups showed between-group dysconnectivity in the bilateral sensorimotor cortex. Comparisons of ASD youths with and without dysregulation identified group differences in the left posterior insula. Follow-up seed-based analyses identified increased dACC-bilateral superior temporal gyrus, decreased L-IFG-bilateral precuneus, increased bilateral precuneus-right IPL, increased bilateral precuneus-right IFG/anterior insula, alongside reduced bilateral precuneus-right sensorimotor connectivity in ASD+Dysregulation, relative to neurotypicals. ASD-Dysregulation youths had weaker connectivity between the bilateral sensorimotor cortex and bilateral precuneus/posterior cingulate cortex compared to neurotypical boys. The ASD+Dysregulation group had hyperconnectivity between the left posterior insula and bilateral precuneus/calcarine, between the left posterior insula and left insula, and between the left posterior insula and right supramarginal gyrus, as compared to the ASD-Dysregulation group.

Conclusions: The current findings of distinct intrinsic connectivity patterns in ASD with and without dysregulation suggest ASD with severe dysregulagtion may constitute a distinct subgroup on the spectrum, and the dysregulation level may be a potential yardstick to dissect heterogeneity of ASD. Dimensional neural correlates of dysregulation in ASD based on resting-state functional MRI warrant further investigation.