Association of White Matter Structure With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder

Abstract

Importance: Clinical overlap between autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) is increasingly appreciated, but the underlying brain mechanisms remain unknown to date.

Objective: To examine associations between white matter organization and 2 commonly co-occurring neurodevelopmental conditions, ASD and ADHD, through both categorical and dimensional approaches.

Design, setting, and participants: This investigation was a cross-sectional diffusion tensor imaging (DTI) study at an outpatient academic clinical and research center, the Department of Child and Adolescent Psychiatry at New York University Langone Medical Center. Participants were children with ASD, children with ADHD, or typically developing children. Data collection was ongoing from December 2008 to October 2015.

Main outcomes and measures: The primary measure was voxelwise fractional anisotropy (FA) analyzed via tract-based spatial statistics. Additional voxelwise DTI metrics included radial diffusivity (RD), mean diffusivity (MD), axial diffusivity (AD), and mode of anisotropy (MA).

Results: This cross-sectional DTI study analyzed data from 174 children (age range, 6.0-12.9 years), selected from a larger sample after quality assurance to be group matched on age and sex. After quality control, the study analyzed data from 69 children with ASD (mean [SD] age, 8.9 [1.7] years; 62 male), 55 children with ADHD (mean [SD] age, 9.5 [1.5] years; 41 male), and 50 typically developing children (mean [SD] age, 9.4 [1.5] years; 38 male). Categorical analyses revealed a significant influence of ASD diagnosis on several DTI metrics (FA, MD, RD, and AD), primarily in the corpus callosum. For example, FA analyses identified a cluster of 4179 voxels (TFCE FEW corrected P < .05) in posterior portions of the corpus callosum. Dimensional analyses revealed associations between ASD severity and FA, RD, and MD in more extended portions of the corpus callosum and beyond (eg, corona radiata and inferior longitudinal fasciculus) across all individuals, regardless of diagnosis. For example, FA analyses revealed clusters overall encompassing 12121 voxels (TFCE FWE corrected P < .05) with a significant association with parent ratings in the social responsiveness scale. Similar results were evident using an independent measure of ASD traits (ie, children communication checklist, second edition). Total severity of ADHD-traits was not significantly related to DTI metrics but inattention scores were related to AD in corpus callosum in a cluster sized 716 voxels. All these findings were robust to algorithmic correction of motion artifacts with the DTIPrep software.

Conclusions and relevance: Dimensional analyses provided a more complete picture of associations between ASD traits and inattention and indexes of white matter organization, particularly in the corpus callosum. This transdiagnostic approach can reveal dimensional relationships linking white matter structure to neurodevelopmental symptoms.

Figure 1.. Results of Categorical Analyses

The x, y, and z are Montreal Neurologic Institute coordinates. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) showed significant influences of diagnosis. Statistically significant clusters converged in the corpus callosum, especially the anterior portions. FWE indicates familywise error; R, right; and TFCE, threshold-free cluster enhancement. The numbers in the Venn diagram denote the number of voxels in the clusters that were significant for each diffusion tensor imaging metric alone or combined with any of the others. Secondary post hoc group comparisons showed that these differences were driven by autism spectrum diagnosis (eFigure 6 in the Supplement).

Figure 2.. Results of Dimensional Analyses for the Social Responsiveness Scale by Parents (SRS-P)

The x, y, and z are Montreal Neurologic Institute coordinates. The dimensional approach identified clusters in which fractional anisotropy (FA), radial diffusivity (RD), and mean diffusivity (MD) were associated with SRS-P total T scores. Clusters identified by these 3 diffusion tensor imaging metrics converged in the corpus callosum from its anterior to posterior regions. The numbers in the Venn diagram denote the number of voxels in the clusters that were significant for each diffusion tensor imaging metric alone or combined with any of the others. In the right column, scatterplots show the relationship across all participants between each diffusion tensor imaging metric and SRS-P total T scores (residuals accounting for the nuisance covariates included in the model are plotted). ADHD indicates attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; FWE, familywise error; R, right; TDC, typically developing children; and TFCE, threshold-free cluster enhancement.