Brain functional-structural gradient coupling reflects development, behavior and genetic influences.

Abstract

Gradients provide low-dimensional representations of macroscale brain organization, yet how structural-functional gradient coupling develops and relates to behavioral and molecular features remains unclear. Here, we studied structural-functional gradient coupling across multiple metrics and spatial scales using high-resolution structural and functional connectivity from 5343 children in the Adolescent Brain Cognitive Development study and 875 adults from the Human Connectome Project. We find that gradient coupling shows developmental refinement from childhood to adulthood and distinct sex-specific patterns. Gradient coupling metrics are significantly associated with cognitive and mental health measures and enable robust out-of-sample prediction. Heritability analyses reveal that gradient coupling is strongly influenced by genetic factors. Transcriptomic analyses further demonstrate that highly heritable coupling patterns are enriched for genes expressed in deep-layer excitatory neurons. Together, our findings establish structural-functional gradient coupling as a biologically meaningful feature of brain organization that bridges macroscale connectivity, cognition, behavior, and molecular architecture.