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

BackgroundThe clinical utility of MRI neuroimaging studies of psychopathology has been limited by a constellation of factors--small sample sizes, small effect sizes, and heterogeneity of methods and samples across studies--that hinder generalizability and specific replication. An analogy is early genomics studies of complex traits, wherein a move to large, multi-site samples and a focus on cumulative effects (polygenic scores) led to reproducible and clinically applicable effects from genome-wide association studies. A similar logic in MRI may provide a way to improve reproducibility, precision, and clinical utility for brain-wide MRI association studies. MethodsPolyneuro scores (PNS) represent the cumulative effect of brain-wide measures--in the present case, resting-state functional connectivity (rs-fcMRI) associated with ADHD symptoms. These scores were constructed and validated using baseline data from the Adolescent Brain Cognitive Development (ABCD, N=5666) study, with a reproducible matched subset as the discovery cohort (N=2801). Association between the PNS and ADHD symptoms was further tested in an independent case-control cohort, the Oregon-ADHD-1000 (N=533). ResultsThe ADHD PNS was significantly associated with ADHD symptoms in both the ABCD and Oregon cohorts after accounting for relevant covariates (p-values < 0.001). While the strongest effects contributing to the PNS were concentrated among connections involving the default mode and cingulo-opercular networks, the most predictive PNS involved connectivity across all brain networks. These findings were robust to stringent motion thresholds. In the longitudinal Oregon-ADHD-1000, non-ADHD comparison youth had significantly lower ADHD PNS ({beta}=-0.309, p=0.00142) than children with persistent ADHD (met diagnostic criteria at two or more time points from age 7 to 19). The ADHD PNS, however, did not reliably mediate polygenic risk for ADHD. Instead, the PNS and an ADHD polygenic score were independently associated with ADHD symptoms. ConclusionsA polyneuro risk score representing cumulative ADHD-associated resting-state connectivity was robustly associated with ADHD symptoms in two independent cohorts using distinct sampling designs, yet was independent of polygenic liability for ADHD, suggesting the need to examine environmental influences. The polyneuro score approach holds promise for improving the reproducibility of neuroimaging studies, identifying their clinical utility, and unraveling the complex relationships between brain connectivity and the etiology of behavioral disorders.