Brain hyperconnectivity in children with autism and its links to social deficits

Abstract

Autism spectrum disorder (ASD), a neurodevelopmental disorder affecting nearly 1 in 88 children, is thought to result from aberrant brain connectivity. Remarkably, there have been no systematic attempts to characterize whole-brain connectivity in children with ASD. Here, we use neuroimaging to show that there are more instances of greater functional connectivity in the brains of children with ASD in comparison to those of typically developing children. Hyperconnectivity in ASD was observed at the whole-brain and subsystems levels, across long- and short-range connections, and was associated with higher levels of fluctuations in regional brain signals. Brain hyperconnectivity predicted symptom severity in ASD, such that children with greater functional connectivity exhibited more severe social deficits. We replicated these findings in two additional independent cohorts, demonstrating again that at earlier ages, the brain of children with ASD is largely functionally hyperconnected in ways that contribute to social dysfunction. Our findings provide unique insights into brain mechanisms underlying childhood autism.

Figure 1. Functional brain hyper-connectivity in children with ASD

(a) 588 pairs (15%) of anatomical regions showed higher correlations in children with ASD, compared to the TD group (p < 0.05, corrected for multiple comparisons). No pairs of regions showed higher correlations in the TD, compared to the ASD group. (b) Mean whole-brain connectivity was higher in children with ASD compared to TD children (p < 0.05, d′ = 0.67). (c) Within subsystems, mean connectivity was higher in children with ASD in primary sensory, paralimbic, and association areas (p < 0.05, d′ > 0.70). 25% of the total functional connections within primary sensory, 10% within paralimbic, and 19% within association areas showed greater functional connectivity in ASD than TD. (d) Across subsystems, mean functional connectivity between primary sensory and paralimbic, between primary sensory and association, and between paralimbic and association areas were greater in children with ASD (p < 0.05, d′ > 0.49). 18% of functional connections between primary sensory and paralimbic, 17% between primary sensory and association, and 17% between paralimbic and association areas were greater in children with ASD. No links, either within or between subsystems, showed greater connectivity in the TD, compared to the ASD, group. * p < 0.05. Error bars represent standard error of mean. See also Figure S1, S4.

Figure 2. Functional brain hyper-connectivity in children with ASD as a function of interregional distance

Connections across all distances showed higher levels of hyper-connectivity in children with ASD, compared to TD children. Connectivity values that were stronger in children with ASD are shown in blue, connections that were stronger in TD children are in red (none in this cohort). Interregional distance d was computed by calculating the Euclidean distance between region centroids. See also Figure S2, S5.

Figure 3. Higher levels of amplitude of BOLD oscillations are associated with functional brain hyper-connectivity in children with ASD

(a) fMRI timeseries averaged across all gray-matter voxels in the brain from a representative child with ASD (blue) and a TD child (red), illustrating abnormally high amplitude fluctuations in children with ASD. (b) Mean amplitude of fMRI BOLD oscillations (ALFF) was greater in ASD than TD (p < 0.05, d′ = 0.68). (C) Higher regional ALFF was associated with higher levels of whole-brain connectivity in children with ASD (r = 0.54, p = 0.01). * p < 0.05. Error bars represent standard error of mean. See also Figure S3, S6.