Mental health problems frequently first appear during childhood and adolescence, yet the biological processes that accompany their emergence have remained difficult to pin down. A new study published in Translational Psychiatry set out to trace how the developing cortex changes in young people who go on to develop specific psychiatric conditions, and to connect those physical brain changes to the molecular landscape of the cortical tissue itself. The researchers drew on longitudinal data from the Adolescent Brain Cognitive Development (ABCD) study, one of the largest long-term investigations of adolescent brain development in the United States.
The team focused on youth who developed attention-deficit/hyperactivity disorder (ADHD), conduct problems, anxiety, depression, oppositional defiant problems, or somatic problems over a two-year follow-up period, comparing each group with healthy controls. Brain structure and function were assessed across five neuroimaging modalities, including structural MRI, resting-state functional MRI, and task-based fMRI. This multi-modal approach allowed the researchers to capture cortical changes from several angles rather than relying on a single type of scan.
When the imaging data were analyzed, significant neurodevelopmental alterations emerged in only two of the groups: the adolescents who developed ADHD and those who developed conduct problems. The internalizing conditions—anxiety, depression, and somatic complaints—did not show comparable cortical changes in this analysis. This selectivity itself is informative, suggesting that externalizing problems, which involve difficulties with self-regulation and impulse control, may be tied to measurable shifts in cortical development during early adolescence.
To move beyond describing where the brain changed, the researchers applied partial least squares (PLS) regression, a statistical technique that links spatial patterns across the cortical surface. They related the maps of neurodevelopmental change to cortical gene expression profiles drawn from the Allen Human Brain Atlas (AHBA), a reference resource that charts where thousands of genes are active across different regions of the human cortex. The goal was to determine whether the brain regions showing the strongest developmental alterations also share a characteristic molecular signature.
The analysis revealed significant spatial associations between neurodevelopmental changes and gene expression distributions in both the ADHD and conduct problem groups, with Spearman rank correlations exceeding 0.64. In practical terms, this means the cortical regions that changed most in these adolescents were not randomly distributed; they aligned systematically with regions where particular sets of genes are highly or weakly expressed. Pathway enrichment was then assessed using spin-permutation-derived gene rankings, a method that accounts for the spatial autocorrelation of the cortex to avoid false positives.
For the ADHD group, the enriched pathways pointed squarely at cellular energy metabolism. Genes involved in mitochondrial respiration, oxidative phosphorylation, aerobic electron transport, ATP synthesis, and mitochondrial organization were highlighted, indicating that the cortical areas undergoing atypical development in ADHD are those where the machinery of energy production is prominently expressed. Alongside this positive enrichment, the analysis found additional negative-end enrichment for pathways related to synaptic protein interactions, suggesting a complementary pattern in which genes supporting synaptic connectivity show expression profiles opposite to the ADHD imaging phenotype.
The conduct problems group presented a strikingly different molecular picture. All significant pathways in this group were enriched among genes whose cortical expression patterns were inversely aligned with the conduct-problem imaging phenotype—meaning the regions that changed most were those where these genes are least active, or vice versa. The affected pathways involved translational machinery, ribosomal function, mitochondrial respiration, mitochondrial translation, protein targeting to mitochondria, and broader RNA and protein regulatory processes. Rather than a simple mirror of the ADHD pattern, this inverse arrangement represents a distinct transcriptional context for cortical development in conduct problems.
Despite the differences, a common thread runs through both sets of findings: mitochondria. In ADHD, mitochondrial energy metabolism emerged as a prominent molecular correlate of cortical development, while in conduct problems, mitochondrial respiration and mitochondrial translation appeared among the inversely aligned pathways. This convergence suggests that the energy demands of developing cortical tissue may be a relevant factor in how externalizing problems manifest neurodevelopmentally, even as the specific gene programs involved differ between the two conditions.
The authors interpret these results as evidence that adolescent-onset ADHD and conduct problems are associated with neurodevelopmental alterations embedded within distinct cortical molecular contexts. Because the study is longitudinal, it captures changes that precede or accompany the emergence of symptoms rather than differences present only after diagnosis. However, the findings describe associations between imaging-derived developmental patterns and gene expression maps; they do not establish causal mechanisms, and the analysis was limited to the externalizing groups that showed significant imaging changes.
As a whole, the study offers a template for connecting large-scale developmental neuroimaging with molecular neuroanatomy. By showing that the cortical regions most affected in adolescent-onset ADHD and conduct problems carry distinguishable gene expression signatures—centered on mitochondrial function in one case and inversely aligned translational and regulatory programs in the other—the work narrows the search for the biological underpinnings of conditions that often take root during the teenage years.
Subject of Research: Neuroimaging and cortical gene expression analysis of brain development in adolescents who develop ADHD and conduct problems
Article Title: Integrative neuroimaging-transcriptomic analysis of neurodevelopment in adolescent-onset mental health problems
Article References: Hou, J., van Wingen, G., van de Mortel, L., Smit, D. J. A., & Liu, S. (2026). Integrative neuroimaging-transcriptomic analysis of neurodevelopment in adolescent-onset mental health problems. Translational Psychiatry. https://doi.org/10.1038/s41398-026-04543-z
Image Credits: AI Generated
DOI: 10.1038/s41398-026-04543-z
Keywords: adolescent brain development, ADHD, conduct problems, cortical gene expression, mitochondrial respiration, ABCD study, neuroimaging, Allen Human Brain Atlas, partial least squares, translational psychiatry, oxidative phosphorylation, externalizing problems
News Source: Juliet Wilcox. (November 5, 2026). Brain Development and Gene Activity Diverge in Teens Who Develop ADHD and Conduct Problems. Scienmag.
