Cortical thickness in serotonin-linked brain regions tied to psychological problems in children

A new study published in NeuroImage: Clinical has found that behavioral and emotional problems in children are linked to differences in the structure of brain regions associated with serotonin. The researchers found that 10-year-olds who reported more symptoms of attention, emotional, or externalizing difficulties tended to show altered brain morphology in serotonin-rich areas, especially in terms of cortical thickness and surface area. These findings suggest that aspects of brain development related to the serotonin system may contribute to early signs of psychological vulnerability.

Serotonin, often referred to as 5-HT, is a chemical messenger involved in regulating mood, attention, and emotional behavior. But its role begins long before those functions emerge. During early development, serotonin helps organize how the brain is wired. It guides processes such as cell growth, migration, and the formation of synapses—the connections between brain cells. Because it is widely distributed and acts on many types of receptors, serotonin influences a range of other neurotransmitter systems, including dopamine and GABA.

Importantly, the serotonin system is still maturing during childhood and adolescence. Shifts in serotonin receptors and transporters across brain regions during this period are thought to influence how circuits for emotion and behavior develop. If these systems are disrupted—by genetic variation or environmental stress—they may contribute to the emergence of psychiatric symptoms.

The new study was conducted by a research team led by Dogukan Koc and colleagues from Erasmus University Medical Centre in the Netherlands and the University of Copenhagen in Denmark. Their aim was to clarify whether the shape and size of brain regions that are especially influenced by serotonin are linked to behavioral problems in children. They used an advanced atlas of serotonin-related brain areas derived from adult brain imaging studies and applied it to brain scans from a large pediatric sample.

“Adolescence is a sensitive window for mental health, yet we still know little about how brain biology contributes to behavioral difficulties during this period,” explained Koc, a PhD candidate. “Serotonin – a chemical that helps regulate mood, anxiety, and orchestrates early brain development – is a major target for psychiatric treatments. Yet, no one had examined how serotonin-related brain structures, such as serotonin-enriched cortical regions, develop in children in a large population.”

“When a new brain map of serotonin (called the NRU 5-HT Atlas) became available, it gave us the unique opportunity to bridge molecular neuroscience with large-scale imaging in children. Then we could ask if brain regions, which are particularly subserved by serotonergic innervation, also appear critical for emotional function and behavior in children.”

The research used data from 2,492 children participating in the Generation R Study, a long-running birth cohort based in Rotterdam. At age 10, the children underwent structural MRI scans and completed a questionnaire about their behavioral and emotional experiences. The questionnaire assessed internalizing problems (such as sadness and anxiety), externalizing problems (such as aggression), and attention difficulties.

To investigate serotonin-related brain morphology, the researchers used the NRU 5-HT Atlas, a parcellation map that defines brain regions according to their density of serotonin transporters and receptors. This atlas was originally developed using positron emission tomography (PET) scans in adults, allowing the researchers to examine 10 distinct brain regions with different serotonin profiles.

The team measured two aspects of brain structure in serotonin-coupled regions: cortical surface area and cortical thickness. Cortical surface area refers to the overall size of the brain’s outer layer, or cortex, which expands as the brain grows during early development. In contrast, cortical thickness measures the depth of the cortex from the surface to the underlying white matter.

Their primary analysis focused on surface area. After adjusting for differences in head size, they found that children who reported more total behavioral problems tended to have smaller cortical surface area in two brain regions: Region 9, which includes parts of the temporal lobe and shows relative enrichment for 5-HT1A receptors, and Region 10, which includes parietal areas. Smaller surface area in these regions was also linked to more externalizing and attention problems.

In a secondary analysis, the researchers looked at cortical thickness. Here, they found that children who reported more total, internalizing, and attention problems had thicker cortex in Region 2, which includes parts of the insula and temporal cortex and is enriched with serotonin transporters (5-HTT). This association remained statistically significant even after controlling for a range of confounding factors, including socioeconomic background, parental mental health, and the child’s IQ.

“One finding really stood out,” Koc told PsyPost. “We expected that smaller brain regions would relate to more problems, but instead, we also observed that a thicker cortex in serotonin-linked brain areas was related to more emotional and attention problems. This suggests that it is not only about slower growth, but it could also be about a delayed brain maturation and functional organization known to be reflected by cortical thinning.”

To further investigate the role of 5-HTT, the team turned to an independent adult sample (n = 100) from the Cimbi neuroimaging database in Denmark. This dataset included both structural MRI and PET imaging of 5-HTT availability. They found that individuals with lower 5-HTT availability in Region 2 tended to have a thicker cortex in that region, mirroring the pattern seen in the children with more reported behavioral problems.

Overall, these findings suggest that specific serotonin-linked features of brain morphology—not just global brain size—may help explain individual differences in behavioral and emotional functioning during a critical window of development.

“We discovered that serotonin-related brain architecture is meaningfully linked to emotional and behavioral problems in early adolescence,” Koc explained. “Specifically, children with a smaller surface area in serotonin-related brain areas showed more outward behavioral problems and trouble focusing (i.e. externalizing and attention problems). On the other hand, children with thicker brain serotonin-related regions showed more inward emotional struggles (i.e. internalizing problems like anxiety or sadness) and also attention problems.

“To verify these results, we saw similar patterns in adults, which suggest that serotonin-related brain features might help explain why some children are more vulnerable for behavioral and emotional difficulties.”

While the study offers new insight into how serotonin-related brain structure may be involved in emotional and behavioral problems, there are still some limitations. One of the most important limitations is that the study is cross-sectional. This means the researchers could not determine whether differences in brain structure caused the behavioral problems, or if the difficulties experienced by the children had effects on the brain.

Another consideration is that the serotonin atlas used in the study was developed using adult brains. While it provides a detailed map of serotonin receptor and transporter distribution, it may not fully reflect the developmental changes taking place in the pediatric brain. Applying adult-based templates to children’s brains introduces some uncertainty, especially when trying to draw conclusions about neurotransmitter systems that are themselves still maturing.

The authors acknowledge these limitations and emphasize the need for longitudinal research. “We plan to follow these children over time to see how serotonin-related brain structures change as they grow and enter adolescence and whether the changes can predict later mental health outcomes,” Koc said. “Ultimately, we want to combine insights from genetics, environment, and neurotransmitter biology to better understand why some children develop psychiatric problems while others remain resilient. Ideally, this may inform preventive strategies and treatments that best optimize children’s development and mental health.”

The study, “Associations of serotonin-related brain morphology in early adolescence with behavioral and emotional problems,” was authored by Dogukan Koc, Martin Nørgaard, Melanie Ganz, Ryan L. Muetzel, Hanan El Marroun, Henning Tiemeier, and Vibe G. Frokjaer.