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Brain Functional Connectome Defines a Transdiagnostic Dimension Shared by Cognitive Dysfunction and Psychopathology in Preadolescents

The search for biomarkers of psychiatric disorders has remained elusive, in part, due to high comorbidity, low specificity, and poor concordance between neurobiological abnormalities and existing diagnostic categories. Developmental factors that have impacts on symptom expression and brain function further complicate biomarker identification. Growing evidence suggests that incorporating cognition into studies of psychopathology may be a path forward, as cognitive dysfunction is a common feature across psychiatric disorders. Recent neuroimaging advances have allowed for characterization of functional connectomes, the collective set of functional connectivity across the whole-brain, using resting-state fMRI. Functional connectomes may be useful psychiatric biomarkers as they have been shown to underlie individual differences in cognition and explain variance in psychopathology across individuals. In the present study, we sought to identify brain-based dimensions that are associated with general cognitive capacity and psychopathology using canonical correlation analysis in a sample of 7,383 preadolescents from the Adolescent Brain Cognitive Development study. Our analysis revealed patterns of functional connectivity correlated with cognitive control capacity and psychopathology. In particular, we identified a principal connectome-based latent brain variate that was positively correlated with cognitive measures across domains and negatively correlated with parent-reported psychopathology across diagnoses and domains. Functional connectivity loadings of the brain variate were across distributed cortical and subcortical brain networks and showed a dose-dependent relationship with the cumulative number of current psychiatric disorders in present. These findings provide preliminary evidence for a connectome-based biomarker that underlies individual differences in cognitive function and predicts transdiagnostic psychopathology in a dose-dependent fashion. Significance Statement Adolescence is a critical developmental window when most psychiatric disorders emerge, meanwhile comorbidity among disorders is prevalent. Using functional MRI and behavioral assessments from a large community-based sample of preadolescents aged 9-10, we identified a specific pattern of functional connectome (the regional activity synchronization across brain at rest) that showed directionally opposite associations with cognitive capacity and mental health problems. Specifically, the connectome pattern predicted individual differences in the performance on a range of cognitive tasks and the severity of parent-reported psychopathological problems. Notably, it predicted the comorbidity of current psychiatric disorders, pointing to a dose-response relationship. Our findings provide preliminary support that this connectome-based brain measure could represent a resiliency biomarker for protection against transdiagnostic psychopathology during preadolescence.