Associations of serotonin-related brain morphology in early adolescence with behavioral and emotional problems

We aimed to investigate the association of brain morphology with behavioral and emotional problems in early adolescence using a brain atlas of the serotonin system. This pre-registered study used data from the Generation R Study, a large birth cohort in Rotterdam, the Netherlands. A total of 2492 children were included at age 10 years, with neuroimaging data and self-reported behavioral and emotional problems. Cortical surface area and thickness were measured in ten serotonin-coupled brain regions. Our primary analysis revealed that higher total, attention, and externalizing problem scores were associated with smaller cortical surface area in Regions 8, 9, and 10 (covering cingulate, orbitofrontal, temporal, and parietal areas) after adjusting for intracranial volume, highlighting region-specific effects less confounded by overall head size. Among these regions, only Region 9 showed relative enrichment for 5-HT_1A receptors, suggesting potential serotonergic involvement in externalizing problems. Secondary analyses showed that greater cortical thickness in Region 2, enriched with serotonin transporters (5-HTT) and involving parts of the temporal cortex and insula, was associated with higher total, attention, and internalizing problem scores (β = 0.07, PFDR = 0.003). A follow-up analysis in an independent adult sample (n = 100), with the same-subject structural MRI and molecular 5-HTT imaging, revealed a specific negative association between 5-HTT availability and cortical thickness in Region 2 (β = -0.22, P = 0.02). These findings suggest selective serotonergic contributions to cortical morphology related to behavioral problems.