Cumulative Effects of Resting-state Connectivity Across All Brain Networks Significantly Correlate with ADHD Symptoms

Identification of replicable neuroimaging correlates of ADHD has been hindered by small sample sizes, small effects, and heterogeneity of methods. Given considerable evidence that ADHD is associated with alterations in widely distributed brain networks, and the small effects of individual brain features, a whole-brain perspective focusing on cumulative effects is warranted. Use of large, multi-site samples is crucial for improving reproducibility and clinical utility of brain-wide MRI association studies. To address this, a polyneuro score (PNRS) representing cumulative, brain-wide, ADHD-associated resting-state functional connectivity was constructed and validated using data from the Adolescent Brain Cognitive Development (ABCD, N=5543 , 51.5% female) study. Association between the PNRS and ADHD symptoms was further tested in the independent Oregon-ADHD-1000 case-control cohort (N=553, 37.4% female). The ADHD PNRS was significantly associated with ADHD symptoms in both the ABCD and Oregon cohorts after accounting for relevant covariates (p-values <0.001). The most predictive PNRS involved all brain networks, though the strongest effects were concentrated among connections involving the default mode and cingulo-opercular networks. In the longitudinal Oregon-ADHD-1000, non-ADHD youth had significantly lower PNRS (Cohen's d =-0.318, robust p=5.5e-4) than children who met ADHD diagnostic criteria at >2 time points (age 7-19). The PNRS, however, did not mediate polygenic risk for ADHD. Brain-wide connectivity was robustly associated with ADHD symptoms in two independent cohorts, providing further evidence of widespread dysconnectivity in ADHD. Evaluation in enriched samples demonstrates the promise of the PNRS approach for improving reproducibility in neuroimaging studies and unraveling the complex relationships between brain connectivity and behavioral disorders. Significance Statement Neuroimaging studies of ADHD have been hindered by small sample sizes, small effects, and differences among study methods. We demonstrate that an ADHD polyneuro risk score (PNRS), representing brain-wide connectivity patterns, was robustly associated with ADHD symptoms in two independent cohorts. The study used data from the Adolescent Brain Cognitive Development Study and the Oregon-ADHD-1000 cohort, and provides further evidence of widespread dysconnectivity in ADHD. The findings highlight the promise of approaches examining cumulative, brain-wide effects, and the importance of using large samples for improving reproducibility of neuroimaging studies.