Shared and distinct intrinsic functional network centrality in autism and attention-deficit/hyperactivity disorder

Abstract

Background: Individuals with autism spectrum disorders (ASD) often exhibit symptoms of attention-deficit/hyperactivity disorder (ADHD). Across both disorders, observations of distributed functional abnormalities suggest aberrant large-scale brain network connectivity. Yet, common and distinct network correlates of ASD and ADHD remain unidentified. Here, we aimed to examine patterns of dysconnection in school-age children with ASD and ADHD and typically developing children who completed a resting state functional magnetic resonance imaging scan.

Methods: We measured voxelwise network centrality, functional connectivity metrics indexing local (degree centrality [DC]) and global (eigenvector centrality) functional relationships across the entire brain connectome, in resting state functional magnetic resonance imaging data from 56 children with ASD, 45 children with ADHD, and 50 typically developing children. A one-way analysis of covariance, with group as fixed factor (whole-brain corrected), was followed by post hoc pairwise comparisons.

Results: Cortical and subcortical areas exhibited centrality abnormalities, some common to both ADHD and ASD, such as in precuneus. Others were disorder-specific and included ADHD-related increases in DC in right striatum/pallidum, in contrast with ASD-related increases in bilateral temporolimbic areas. Secondary analyses differentiating children with ASD into those with or without ADHD-like comorbidity (ASD(+) and ASD(-), respectively) revealed that the ASD(+) group shared ADHD-specific abnormalities in basal ganglia. By contrast, centrality increases in temporolimbic areas characterized children with ASD regardless of ADHD-like comorbidity. At the cluster level, eigenvector centrality group patterns were similar to DC.

Conclusions: ADHD and ASD are neurodevelopmental disorders with distinct and overlapping clinical presentations. This work provides evidence for both shared and distinct underlying mechanisms at the large-scale network level.

Keywords: ADHD; amygdala; autism; caudate; functional connectivity; network centrality; precuneus; resting state fMRI.

Figure 1. Effects of Diagnostic Group on Degree Centrality

The top panel depicts the statistical brain maps of the F-contrast results from the one-way ANCOVA revealing voxels in which degree centrality (DC) z scores differ as a function of group (Typically Developing Children [TDC] vs. Attention-Deficit/Hyperactivity Disorder [ADHD] vs. Autism Spectrum Disorders [ASD]). Gaussian random field theory was employed to carry out cluster-level correction for multiple comparisons (min Z > 2.3; cluster significance: p < 0.05, corrected). Significant clusters are presented on inflated surface maps (left side) and axial and coronal maps (right side) generated using Analysis of Functional NeuroImages (AFNI) and Surface Mapping with AFNI (SUMA) software (http://afni.nimh.nih.gov/afni/suma). Lateral and medial views are shown for left and right hemispheres (LH, RH, respectively). For illustration purposes, results were resampled from 4mm³ to 1mm³ using sinc interpolation (FLIRT). The scatter plots in the bottom panel illustrate individual participant z scores, for the five clusters (indexed with capital letters from A to E) in which ASD, ADHD, or both differed from TDC, based on pair-wise post-hoc group comparisons (Tukey corrected at p< 0.05). Solid black lines depict means and standard errors. Horizontal capped lines designate pairwise comparisons reaching statistical thresholds: ***, p<0.0001; **, p<0.001; and *, p<0.05. ADHD specific clusters A and B designate regions in which ADHD differ from both TDC and ASD; ASD specific clusters C and D designate regions in which ASD differ from both TDC and ADHD; Cluster E designates a region in which both clinical groups exhibited decreased DC relative to TDC. Figure S5 in Supplement 1 shows cluster F, in which ASD and ADHD differed from each other, although neither differed from TDC. See Table S2 in Supplement 1 for anatomical labels, group statistics and peaks detected within clusters.

Figure 2. Contributions of ADHD-Like Comorbidity to ASD-Related Differences in Degree Centrality

Histograms illustrate degree centrality (group mean z scores and standard errors of the mean) in children with Autism Spectrum Disorders (ASD) with and without Attention-Deficit/Hyperactivity Disorder (ADHD) comorbidity (ASD⁺ and ASD⁻, green squares and yellow fill, respectively). For illustration, we also present the histograms for children with ADHD and Typically Developing Children (TDC). With respect to degree centrality, ASD⁺ and ASD⁻ differ significantly only in a cluster encompassing the right striatum and pallidum (See Table S3 in Supplement 1 for group statistics). The right panels show the coronal and axial brain images depicting the statistical maps of the five clusters identified in primary analyses. From the top, these are the right striatum/pallidum (z=4), the left postcentral cortex (z=23), the left (y=4) and right (y=2) temporolimbic areas, and the precuneus (z=64) (min Z > 2.3; cluster significance: p < 0.05, corrected). Brain maps were generated using Analysis of Functional NeuroImages (AFNI) (http://afni.nimh.nih.gov/afni). For illustration purposes, results were resampled from 4mm³ to 1mm³ using sinc interpolation (FLIRT). *p=.017.