Integrating Functional Transdiagnostic Dimensions of Psychopathology with Cortical Organization

Childhood and adolescence represent a critical period in which neurodevelopmental psychiatric conditions emerge; traditional case-control approaches often underestimate the complexity and co-occurrence of psychiatric conditions, calling for a transdiagnostic approach as a complementary measure. Open-access data sharing initiatives provide an opportunity to decipher structural- and functional-based organisational constraints on the relationship between brain connectivity and psychopathology. Using a highly heterogenous and comorbid neurodevelopmental sample of children and adolescents aged between 6 and 17 years old at-risk of neurodevelopmental conditions (N = 174, 114 males, mean age 10.72 {+/-} 2.21 years), and age-matched neurotypical controls (N = 27, 12 males, mean age 10.65 {+/-} 2.07 years), we identified a multivariate association, or latent variable, between resting-state functional connectivity and psychopathology. We extensively benchmarked this latent construct to develop a more parsimonious account of childhood psychopathology though an analytical framework spanning biological maps, brain connectivity, and behaviour. Participant-level expression of this latent brain-behaviour association differed by diagnostic burden and symptomatology, and pre-empted longitudinal psychopathology. Whilst diagnostic status was useful for interpretation, the latent construct transcended traditional diagnostic borders, revealing a neurotypical-neurodivergent continuum. The relationship between functional connectivity and neurodevelopmental psychopathology was circumscribed by functional connectivity networks (visual, fronto-parietal, and dorsal attention) and cytoarchitectonic class (primary/secondary sensory and primary sensory cortices). The latent variable aligned with magnetoencephalography-defined electrophysiological alpha (), high-gamma ({gamma}), and theta ({theta}) frequency bands, and was enriched across cortical distributions of astrocytes and excitatory neurones. The connectivity signature was significantly aligned with the archetypal sensorimotor-to-association axis and validated in an independent sample of pre-adolescents (N = 3504), with the strongest alignment with the principal component of gene expression and myelination and were relatively less enriched in cortical regions related to language, indicating a protective effect, and more positively enriched in regions related to executive functioning, conferring greater risk of psychopathology. Together, our findings suggest that the predictive link between functional connectivity and common symptoms of neurodevelopmental psychopathology are circumscribed by underlying macroscale anatomical, functional, and cognitive-related hierarchies.