Atypical Causal Influences Between Brain Regions in Children with Autism Spectrum Disorder

Background:  

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders affecting multiple brain systems. Effective connectivity is defined as the causal influence one neural system exerts over another, and can be used to quantitatively examine links underlying information processing dynamics in the brain. In typically developing (TD) children and adults, the right fronto-insular cortex (rFIC) is part of a salience network (SN) thought to mediate interactions between other large-scale brain networks supporting internally-oriented and social cognitive processes and externally-oriented goal-directed behaviors.

Objectives:  

We aimed to characterize causal influences between the rFIC and other brain systems in children with ASD compared with TD children. Specifically, we sought to assess the causal influence of the rFIC on major nodes of the default mode network (DMN) and executive control network (ECN), two brain systems for internally-oriented and externally-oriented processing, respectively.

Methods:  

Functional MRI data was collected from 7-12 year old children with ASD and age-, gender-, and IQ-matched groups of TD children across various cognitive states; 1) task-free resting state (n = 20 ASD/20 TD), 2) arithmetic processing (n = 15 ASD/15 TD), and 3) social attention (n = 12 ASD/12 TD). Causal interactions between key nodes of the SN, DMN, and ECN were examined and compared between groups for each cognitive state using multivariate Granger causal analysis. Network nodes were identified from a previous published study. We followed methods as described by Seth et al. to test for causal influences between regions of interest (ROIs). Those directed connections whose mean across subjects in the group was significantly different from the mean of the null (F-value) distribution were identified using a stringent threshold (p< 0.01, FDR corrected for multiple comparisons).

Results:  

Across all cognitive states, for both TD and ASD groups, the rFIC was found to be a causal outflow hub in that this region that had a high number of causal outflow connections and low number of causal inflow connections. We found atypical patterns of causal influences emanating from the rFIC in children with ASD both during resting and task states. In the resting state, there were greater causal influences from the rFIC to nodes of both the DMN (VMPFC) and CEN (rPPC) in TD children compared to children with ASD. There were greater causal interactions within the SN (rFIC-ACC) as well as atypical causal interactions between the CEN and SN (rDLPFC-ACC) in children with ASD compared to TD children. During performance of an arithmetic verification task, there were greater causal influences from rFIC to ACC in TD children compared to children with ASD. During performance of a social attention task, no group differences in causal connectivity were observed.

Conclusions:  

The current results are in line with the hypothesis that aberrant effective connectivity of the rFIC and other key network nodes may contribute to the autistic phenotype.