Whole Brain White Matter Tract Deviation and Idiosyncrasy From Normative Development in Autism and ADHD and Unaffected Siblings Link With Dimensions of Psychopathology and Cognition.

OBJECTIVE:The heterogeneity of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) preclude definitive identification of neurobiomarkers and biological risks. High clinical overlap suggests multifaceted circuit-level alterations across diagnoses, which remains elusive. This study investigated whether individuals with ADHD or ASD and their unaffected siblings constitute a spectrum of neurodevelopmental conditions in terms of white matter etiology. METHODS:Sex-specific white matter tract normative development was modeled from diffusion MRI of 626 typically developing control subjects (ages 5-40 years; 376 of them male). Individualized metrics estimating white matter tract deviation from the age norm were derived for 279 probands with ADHD, 175 probands with ASD, and their unaffected siblings (ADHD, N=121; ASD, N=72). RESULTS:ASD and ADHD shared diffuse white matter tract deviations in the commissure and association tracts (rho=0.54; p<0.001), while prefrontal corpus callosum deviated more remarkably in ASD (effect size=-0.36; p<0.001). Highly correlated deviance patterns between probands and unaffected siblings were found in both ASD (rho=0.69; p<0.001) and ADHD (rho=0.51; p<0.001), but only unaffected sisters of ASD probands showed a potential endophenotype in long-range association fibers and projection fibers connecting prefrontal regions. ADHD and ASD shared significant white matter tract idiosyncrasy (rho=0.55; p<0.001), particularly in tracts connecting prefrontal regions, not identified in either sibling group. Canonical correlation analysis identified multiple dimensions of psychopathology/cognition across categorical entities; autistic, visual memory, intelligence/planning/inhibition, nonverbal-intelligence/attention, working memory/attention, and set-shifting/response-variability were associated with distinct sets of white matter tract deviations. CONCLUSIONS:When conceptualizing neurodevelopmental disorders as white matter tract deviations from normative patterns, ASD and ADHD are more alike than different. The modest white matter tract alterations in siblings suggest potential endophenotypes in these at-risk populations. This study further delineates brain-driven dimensions of psychopathology/cognition, which may help clarify within-diagnosis heterogeneity and high between-diagnosis co-occurrence.