Sub-Additive Effects of Autism-ADHD Comorbidity on Resting-State Pupillary and Oculomotor Phenotypes

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) share substantial clinical and physiological overlap. While naturalistic and sensory-driven paradigms increasingly capture evoked neurophysiological responses, the intrinsic baseline physiology of these conditions remains poorly defined. We characterized resting-state pupillary volatility and oculomotor stability across the ASD-ADHD spectrum using dimensional and categorical (DSM-5) frameworks.

We analyzed resting-state eye-tracking data from a large pediatric cohort (N = 2,315) from the Healthy Brain Network, extracting Pupil Relative Volatility (Coefficient of Variation [CV]) and Bivariate Contour Ellipse Area (BCEA) to index pupillary and spatial gaze stability. Data were evaluated via continuous regressions against Social Responsiveness Scale (SRS) and SWAN inventories, then 2×2 factorial ANCOVAs based on clinical diagnoses, with sensitivity analyses for extreme values, hardware heterogeneity, and psychostimulant medication.

Dimensional models revealed no significant association between either metric and continuous ASD or ADHD trait severity, apart from a modest sub-additive SRS × SWAN interaction on pupillary CV; an apparent pooled BCEA-trait association proved attributable to hardware differences and was absent within hardware-consistent subgroups. Categorical models showed robust diagnostic differentiation for both metrics: isolated ASD was associated with elevated CV and impaired BCEA, with ADHD additionally impairing BCEA. Comorbid ASD+ADHD produced a sub-additive CV interaction robust across outlier-resistant, hardware-stratified, and medication-adjusted analyses; an analogous BCEA interaction was directionally consistent but not significant under standard estimation.

Categorical diagnostic status was consistently associated with baseline pupillary and oculomotor physiology across the ASD-ADHD spectrum in this cohort, with a shared sub-additive comorbidity effect most robustly expressed in pupillary volatility; continuous trait severity showed little independent association with either metric. These findings, obtained using a rigorously validated, hardware-heterogeneous multi-site sample, establish a foundation for future naturalistic and sensory-evoked investigations of the shared physiological architecture underlying ASD-ADHD comorbidity.