Cortical surface area drives volumetric and cognitive deficits in complex congenital heart disease

Individuals with complex congenital heart disease (CHD) are at increased risk for cognitive impairments linked to altered brain structure, including reduced cortical volume. Cortical volume is determined by two distinct morphometric measures: cortical thickness (CT) and surface area (SA), each with unique developmental, genetic, and evolutionary origins. Despite their importance, few studies have examined the differential contributions of CT and SA to cortical volume alterations and cognitive outcomes in CHD. Exploring these individual cortical morphometric changes may provide additional insight into the origin of cortical volume changes in CHD, and their relationships with cognitive function. High-resolution 3D T1-weighted images, IQ and executive function (EF) scores were acquired from a final sample of 49 patients with CHD and 80 controls (mean age=13.16, male:54.3%). Cortical reconstruction and volumetric analyses were performed using Freesurfer version 7.1. Group differences in cortical volume, CT, and SA, as well as their associations with cognitive measures, were investigated through vertex-wise multivariate general linear modelling. While both SA and CT were significantly reduced in the CHD group, both globally and regionally, SA was more affected than CT, and total SA showed a stronger and more consistent correlation with cortical volume. Furthermore, SA, but not CT, was strongly associated with IQ and EF across the brain. These relationships were especially prominent in the frontal and occipitotemporal cortices, where patients with CHD exhibited stronger associations between SA and cognitive performance compared to controls. These findings indicate that cortical volume reductions observed in CHD primarily reflect reduced cortical surface area rather than cortical thinning. While structure-function associations between cortical morphology and cognition are established in healthy populations, our data suggest that these relationships are accentuated in CHD, likely due to disrupted neurodevelopmental processes. This study underscores the importance of differentiating cortical morphometric features to improve our understanding of brain-behaviour associations and the neurobiological underpinnings of cognitive impairment in CHD.ss