Brain Functional-Structural Gradient Coupling Reflects Development, Behavior and Genetic Influences

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Abstract
Gradients are increasingly used to characterize the brain’s macroscale organization, offering low-dimensional representations of structural and functional connectivity. However, how structural-functional gradient coupling evolves during development 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 7,025 children in the Adolescent Brain Cognitive Development study and 913 adults from the Human Connectome Project. We found that gradient coupling exhibits clear developmental refinement from childhood to adulthood and shows distinct sex-specific patterns. Gradient coupling metrics were significantly associated with a broad range of cognitive and mental health measures and enabled robust out-of-sample prediction under learning methods. Heritability analyses revealed that gradient coupling is strongly influenced by genetic factors. Transcriptomic analyses further demonstrated that highly heritable coupling patterns are enriched for genes expressed in deep-layer excitatory neurons, suggesting that gradient coupling reflects underlying cell-type-specific transcriptional architecture. 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.

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