Restricted Behavior and Brain Functional Connectivity in Infants and Toddlers at Risk for Developing Autism Spectrum Disorder

Background:  Autism spectrum disorder (ASD) is a common neurodevelopmental disorder defined by impaired social communication and interaction, and restricted and repetitive behaviors. The relationships between restricted and repetitive behaviors and underlying brain function, especially during the first years of life, have yet to be elucidated. 

Objectives:  This work investigates whether particular patterns of correlations between brain regions, as measured with resting state functional connectivity MRI (fcMRI), relate to restricted behaviors, as assessed with the Repetitive Behavior Scale – Revised (RBS-R).

Methods:  This work focuses on fcMRI and RBS-R data collected from N=95 24 month old (mo) children across four sites within IBIS, an NIH ACE Network.

Cohorts: Children were classified as high risk (HR) if they had a sibling with ASD, or low risk (LR) if they had at least one sibling without ASD and no 1^st or 2^nddegree relatives with ASD. Groups were assigned by research clinical best estimate using the DSM-IV-TR checklist at 24mo (HR+/HR-/LR-: n=22/59/13).

fcMRI data: For each child, fcMRI data were processed using state-of-the-art protocols, including motion scrubbing at a conservative FD level of 0.2 mm. Analyses utilized 150 frames of clean fcMRI data from each subject. Time traces from 230 functionally-defined regions of interest (ROI) throughout the cerebrum and cerebellum were correlated to yield fc values, and grouped into each of 17 putative functional networks, identified using the Infomap community detection algorithm (Figure 1a).

Restricted behavior data: The RBS-R is a behavioral assessment composed of 43 parent/caregiver-rated items that rates the level of stereotypical, self-injurious, compulsive, sameness, ritualistic and restricted behavior of the subject (Figure 1b). These analyses focus on the restricted subscale.

Brain-behavior analysis: Enrichment analyses were used to determine which functional brain networks are most associated with restricted behaviors. Each ROI-pair fc value was correlated (Spearman) across subjects with the RBS-R restricted subscale scores. These correlation values were then thresholded at an uncorrected p-value of 0.05. Two complementary metrics (a χ²and a hypergeometric test) were used to determine if the number of strong brain-behavior correlations within each network-pair of the matrix was greater than the number expected by chance. Empirical significance levels were determined using randomization. An experiment-wide false-positive rejection rate of 5% was used.

Results:  Specific groupings of significant correlations of fc with restricted behaviors (Figure 1c-f) occurred for either an attention, a control, or the default mode network (i.e. the parietal dorsal attention network (pDAN), the default mode network (DMN), the posterior DMN (pDMN), the anterior frontoparietal task control network (aFPC), the posterior FPC (pFPC), the dorsal-anterior DMN (daDMN), the medial visual (mVis) network and the pPFC (Figure 1g)). The pPFC is also significantly enriched within its intra-network connections. 

Conclusions:  Restricted behavior and brain functional connectivity in 24mo children are strongly associated with a small set of specific functional brain networks. These involve infant-toddler manifestations of the default mode, dorsal attention, and fronto-parietal task control networks.