Beyond massive univariate tests: Covariance regression reveals complex patterns of functional connectivity related to attention-deficit/hyperactivity disorder, age, sex, and response control

We applied a novel Covariate Assisted Principal (CAP) whole-matrix regression approach to identify resting-state functional connectivity (FC) brain networks associated with attention-deficit/hyperactivity disorder (ADHD) and response control. Participants included 8-12 year-old children with ADHD (n=115, 29 girls) and typically developing controls (n=102, 35 girls) with a resting-state fMRI scan and go/no-go task behavioral data. We modeled three sets of covariates to identify resting-state networks associated with ADHD, age, sex, and response control. Four networks were identified across models revealing complex interactions between subregions of cognitive control, default mode, subcortical, visual, and somatomotor networks that relate to age, response control, and a diagnosis of ADHD among girls and boys. Unique networks were also identified in each of the three models suggesting some specificity to the covariates of interest. These findings demonstrate the utility of our novel covariance regression approach to studying functional brain networks relevant for development, behavior, and psychopathology.