Brain charts harness population neuroscience to unlock neurodiversity of ADHD
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Background
Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition influenced by complex genetic and environmental factors, necessitating a population neuroscience approach to understand its etiology. Reclassifying ADHD subtypes through efficient and universally applicable measurements offers the potential to address its heterogeneity, thereby advancing personalized diagnosis and treatment.
Methods
This cross-sectional study leverages normative brain charts derived from 123,984 structural magnetic resonance images alongside extensive multimodal data – including blood, brain, behavioral, and environmental measurements – to unlock the neurodiversity of ADHD. We established centile scores of brain morphology in 270 children with ADHD (6-17 years) to identify deviations from the normative models adjusted from the lifespan brain charts. Using partitioning around medoids, ADHD individuals were clustered based on these deviations to identify trait constellations underlying ADHD’s clinical heterogeneity. Multidimensional data, including clinical symptoms, neurocognitive outcomes, brain function, and genetic and environmental risk factors, were compared to dissect the heterogeneity and support more customized early diagnosis or therapeutic approaches from a population neuroscience framework.
Findings
Regional deviations in cortical volume among children with ADHD were widely distributed, indicating pronounced individual differences. Further analysis revealed two subgroups of ADHD with distinct brain development patterns: delayed brain growth (DBG-ADHD) and precocious brain growth (PBG-ADHD). DBG-ADHD children exhibited significant neurocognitive impairments and higher functional homotopy within the default-mode network. Differentially expressed genes in this group were related to neurodevelopment, and more prenatal risk factors that affect brain development were identified. Conversely, PBG-ADHD was linked to elevated levels of disruptive behaviors, enhanced functional homotopy within language and somatomotor networks, and genetic pathways related to neurogenesis, while no significant prenatal environmental risk factors were identified.
Interpretations
Despite having similar core symptoms, ADHD encompasses two distinct subgroups characterized by fundamentally different developmental characteristics. One subgroup exhibited comprehensive developmental delays influenced by genetic and prenatal environmental factors. The other displayed congenital brain abnormalities that stem from atypical brain morphogenesis or surrounding unfriendly environmental factors, often associated with disruptive behaviors. These findings span a population neuroscience framework to provide actionable neurotargets to advance clinical practice through more tailored approaches.
Funding
The STI 2030 major projects (2021ZD0200500), the National Key R&D Program of China (2024YFC3308300), the National Natural Science Foundation of China (81220108014), the Capital’s Funds for Health Improvement and Research, the National Key Basic Research Program of China, the CAMS Innovation Fund for Medical Sciences, and the China Postdoctoral Science Foundation (2023M740147).
