Autism spectrum disorder-specific changes in white matter connectome edge density based on functionally defined nodes.

ABSTRACT

Introduction: Autism spectrum disorder (ASD) is associated with both functional and microstructural connectome disruptions. We deployed a novel methodology using functionally defined nodes to guide white matter (WM) tractography and identify ASD-related microstructural connectome changes across the lifespan. Methods: We used diffusion tensor imaging and clinical data from four studies in the national database for autism research (NDAR) including 155 infants, 102 toddlers, 230 adolescents, and 96 young adults - of whom 264 (45%) were diagnosed with ASD. We applied cortical nodes from a prior fMRI study identifying regions related to symptom severity scores and used these seeds to construct WM fiber tracts as connectome Edge Density (ED) maps. Resulting ED maps were assessed for between-group differences using voxel-wise and tract-based analysis. We then examined the association of ASD diagnosis with ED driven from functional nodes generated from different sensitivity thresholds. Results: In ED derived from functionally guided tractography, we identified ASD-related changes in infants (pFDR ≤ 0.001-0.483). Overall, more wide-spread ASD-related differences were detectable in ED based on functional nodes with positive symptom correlation than negative correlation to ASD, and stricter thresholds for functional nodes resulted in stronger correlation with ASD among infants (z = -6.413 to 6.666, pFDR ≤ 0.001-0.968). Voxel-wise analysis revealed wide-spread ED reductions in central WM tracts of toddlers, adolescents, and adults. Discussion: We detected early changes of aberrant WM development in infants developing ASD when generating microstructural connectome ED map with cortical nodes defined by functional imaging. These were not evident when applying structurally defined nodes, suggesting that functionally guided DTI-based tractography can help identify early ASD-related WM disruptions between cortical regions exhibiting abnormal connectivity patterns later in life. Furthermore, our results suggest a benefit of involving functionally informed nodes in diffusion imaging-based probabilistic tractography, and underline that different age cohorts can benefit from age- and brain development-adapted image processing protocols.