Mapping Superficial White Matter Anomaly in Autism Spectrum Disorder: Effects on Functional Networks and Behavior

Background:

Autism spectrum disorders (ASD) are life-long developmental conditions characterized by atypical social cognition, communication, and repetitive behaviors/interests ¹. Multiple neuroimaging studies have shown alterations in cortical morphology in this syndrome ². White matter changes remain less well understood, particularly their association to cortical structure and function.

Objectives:

We focused on the superficial white matter (SWM), a compartment that has gained only little attention so far in ASD neuroimaging. In addition to its role in genesis and maturation of the folded cortex ^{3, 4}, its spatial proximity to the cortical ribbon ensures intrinsic correspondence, making it an ideal candidate for integrative studies on cortical grey matter morphology, function, and white matter organization in ASD.

Methods:

From the Autism Brain Imaging Data Exchange repository, we selected three sites that contained: i) males and females, ii) children and adults, and iii) diffusion MRI and T1-weighted MRI data. Following cortical surface extraction and its QC, our sample included 53 ASD and 57 controls. To examine the SWM, we generated a surface 2mm below the cortex by following a Laplacian potential field towards the ventricles (Fig 1A). Surface-wide statistics mapped alterations in fractional anisotropy (FA), mean diffusivity (MD), and a multivariate aggregate of both in ASD compared to controls, controlling for age, sex, and site. We carried out seed based functional connectivity analyses from significant clusters to evaluate pathological structure-function coupling. Finally, we examined associations to behavioral symptoms of ASD by correlating inter-individual differences in SWM measures with ADOS scores, and built path analytical models, evaluating the role of functional connectivity on the relation between diffusion anomalies and ADOS scores. Multiple comparisons were corrected using random-field theory at p_FWE<0.05.

Results:

Multivariate analysis mapped SWM diffusion anomalies in ASD compared to controls (Fig 1B) in bilateral precuneus and posterior cingulate (PCU/PCC) and the right temporo-parietal cortex. Effects were consistent in children and adults and across sites. Notably, functional connectivity analysis from these regions revealed decreased intrinsic connectivity in ASD compared to controls, with right PCC/PCU being disconnected from adjacent cuneus and with the right temporo-parietal cortex from insular and superior parietal cortex (Fig 2A-C). Again, connectivity reductions were similar across sites (Fig 2D). Notably, in the ASD group, inter-individual differences in SWM anomalies in both right hemispheric clusters correlated with degrees of functional connectivity reductions (SWM_TPJ: r=-0.38, p<0.0025; SWM_PCC/PCU: r=-0.25, p<0.037, Fig 2E). SWM anomalies were also correlated to more severe ASD symptoms, as indexed by total ADOS (r=0.27, p<0.04). Finally, associations between SWM anomalies and total ADOS scores were found to be partially mediated by reduced functional connectivity (z=1.93, p<0.06), suggesting a disease-related path between SWM alterations, functional connectivity, and behavioral symptoms (Fig 2F).

Conclusions:

Our study targeting the SWM in ASD offers a novel perspective on the interplay between white matter anomalies and atypical functional networks, providing a potential window to better understand the complex biological factors contributing to its diverse behavioral symptoms.