Beyond Massive Univariate Tests: Covariance Regression Reveals Complex Patterns of Functional Connectivity Related to Attention-Deficit/Hyperactivity Disorder, Age, Sex, and Response Control

Background: Studies of brain functional connectivity (FC) typically involve massive univariate tests, performing statistical analysis on each individual connection. In this study, we apply a novel whole-matrix regression approach referred to as covariate assisted principal regression to identify resting-state FC brain networks associated with attention-deficit/hyperactivity disorder (ADHD) and response control. Methods: Participants included 8- to 12-year-old children with ADHD (n = 115; 29 girls) and typically developing control children (n = 102; 35 girls) who completed a resting-state functional magnetic resonance imaging scan and a Go/NoGo task. We modeled three sets of covariates to identify resting-state networks associated with an ADHD diagnosis, sex, and response inhibition (commission errors) and variability (ex-Gaussian parameter tau). Results: The first network includes FC between striatal-cognitive control (CC) network subregions and thalamic-default mode network (DMN) subregions and is positively related to age. The second consists of FC between CC-visual-somatomotor regions and between CC-DMN subregions and is positively associated with response variability in boys with ADHD. The third consists of FC within the DMN and between DMN-CC-visual regions and differs between boys with and without ADHD. The fourth consists of FC between visual-somatomotor regions and between visual-DMN regions and differs between girls and boys with ADHD and is associated with response inhibition and variability in boys with ADHD. Unique networks were also identified in each of the three models, suggesting some specificity to the covariates of interest. Conclusions: These findings demonstrate the utility of our novel covariance regression approach to studying functional brain networks relevant for development, behavior, and psychopathology.