Mapping corpus callosum architecture: developmental, genetic, and cognitive correlates in youth
The corpus callosum (CC), the largest interhemispheric white-matter tract, plays a central role in higher-order cognitive functions and is frequently altered in neurodevelopmental and psychiatric conditions. However, most diffusion MRI studies rely on tract-averaged measures, which obscure spatially specific microstructural variation along the tract that may hold biologically and functionally meaningful information. This study aimed to provide a fine-grained characterisation of spatial variation in callosal structure and to determine its developmental, genetic, and cognitive correlates. This study leveraged multimodal data from the Philadelphia Neurodevelopmental Cohort (PNC), comprising 1342 participants aged 8-21 years. Diffusion MRI and tractography-based segmentation were used to extract fine-grained spatial variation in diffusion metrics along seven callosal tracts. A candidate gene approach targeted four genes (DCC, CDH2, AKT3, and GLI3) previously linked to the neurobiological mechanisms underlying CC formation. Five cognitive factors were derived from the Penn Computerized Neurocognitive Battery using factor analysis. A two-stage functional data analysis approach to examine global and local associations between along-tract diffusion metrics and age, candidate genetic variants, and behavioural outcomes. Results revealed distinct midline-to-cortical variations of age-related diffusion metrics change across callosal subdivisions. Frontal and parietal heteromodal callosal pathways showed pronounced distal-segment maturation (F = 13 - 23, p [≤] 2.8x10e-16), whereas posterior sensorimotor and occipital callosal tracts exhibited more stable age associations along their lengths (F = 4.2 - 4.3, p = 10e-3). Genetic variations in callosal axon-guidance genes (ROBO1, IQCJ-SCHIP1, NRP1 and DCC) were associated with spatial variation in callosal diffusion metrics, particularly in anterior (rostrum) and posterior callosal subdivisions (isthmus and splenium) (F = 4.29 - 18.61, p-values = 2.2e-16 - 1.4e-04). These regions correspond to early-forming callosal compartments, suggesting that prenatal axon- guidance mechanisms leave enduring spatial patterns on callosal organisation. Finally, spatial variation in callosal microstructure was significantly associated with behavioural performance (F = 2.9 - 21.3, P = 2.8x10e-16 - 0.04), with the strongest and most spatially heterogeneous effects observed for complex cognition and executive functioning. Across all analyses, functional data models generally outperformed tract-averaged linear models, supporting the value of explicitly preserving spatial variation along callosal tracts. Our findings converge on the CC as a spatially differentiated structure in which early genetic modulators and developmental constraints shape region- and segment-specific microstructural architecture that is behaviourally relevant through childhood and adolescence.