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Neurodevelopmentally rooted epicenters in schizophrenia: sensorimotor-association spatial axis of cortical thickness alterations

Molecular Psychiatry volume 31, pages 929–940 (2026)Cite this article

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Abstract

Pathological disturbances in schizophrenia have been suggested to propagate via the functional and structural connectome across the lifespan. However, how the connectome guides early cortical reorganization of developing schizophrenia remains unknown. Here, we used early-onset schizophrenia (EOS) as a neurodevelopmental disease model to investigate putative early pathologic origins propagating through the functional and structural connectome. We compared 95 patients with antipsychotic-naïve first-episode EOS and 99 typically developing controls (total n = 194; 120 females; 7–17 years of age). While patients showed widespread cortical thickness reductions, thickness increases were observed in primary cortical areas. Using normative connectomics models, we found that epicenters of thickness reductions were located in association regions linked to language, affective, and cognitive functions, while epicenters of thickness increases in EOS were located in sensorimotor regions subserving visual, somatosensory, and motor functions. Using post-mortem transcriptomic data of six donors, we observed that the epicenter map differentiated oligodendrocyte-related transcriptional changes at its sensory apex, whereas the association end was related to the expression of excitatory/inhibitory neurons. More generally, the epicenter map was associated with dysregulation of neurodevelopmental disorder genes and human accelerated region genes, suggesting potential common genetic determinants across diverse neurodevelopmental conditions. Taken together, our results highlight the developmentally rooted pathological origins of schizophrenia and its transcriptomic overlap with other neurodevelopmental disorders.

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Fig. 1: Disease epicenters for early-onset schizophrenia (EOS).
Fig. 2: Associations with the neurodevelopmental, functional, and cognitive continuum.
Fig. 3: Underlying transcriptomic architecture.
Fig. 4: Relevance with major brain disorders and human accelerated region (HAR) genes.
Fig. 5: Similarities between EOS epicenters and replicated epicenter patterns.

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Data availability

Functional and structural disease epicenter maps of EOS and other data supporting our findings are available at https://github.com/Yun-Shuang/Neurodevelopmentally-rooted-epicenters-in-schizophrenia. The neurodevelopmental axis ranking data are available at https://github.com/PennLINC/S-A_ArchetypalAxis. Human gene expression data are available at https://human.brain-map.org/. Additional information can be made available upon reasonable request to the authors.

Code availability

Custom code was made publicly available under https://github.com/Yun-Shuang/Neurodevelopmentally-rooted-epicenters-in-schizophrenia. Epicenter calculation was based on ENIGMA Toolbox (https://enigma-toolbox.readthedocs.io/en/latest/); cognitive meta-analysis code was adapted from https://github.com/CNG-LAB/cngopen/blob/main/transdiagnostic_gradients/Scripts/Hettwer2022_Figure2_Transdiagnostic_Gradients.m; gene expression analyses were performed by the abagen toolbox (https://abagen.readthedocs.io/), combined with code under https://github.com/netneurolab/hansen_genescognition; gene enrichment analyses by metascape (https://metascape.org/gp/index.html#/main/step1); statistically analyses were carried out by BrainStat (https://github.com/MICA-MNI/BrainStat); visualizations were based on workbench (https://www.humanconnectome.org/software/connectome-workbench) and ggseg (https://ggseg.github.io/ggseg/), combined with ColorBrewer (https://github.com/scottclowe/cbrewer2).

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Acknowledgements

We are grateful to all the participants and their guardians in this study. We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript. This work was supported by the National Natural Science Foundation of China (62403105, 62333003, 82121003, 62373079), the China Postdoctoral Science Foundation (2023M740524), Sichuan Province Innovative Talent Funding Project for Postdoctoral Fellows, Medical-Engineering Cooperation Funds from University of Electronic Science and Technology of China (ZYGX2021YGLH201), the Science and Technology Bureau of Chengdu Program (2024-YF05-00873-SN), the Youth Innovation Project of Sichuan Provincial Medical Association (Q23078), Medical Research Project of Chengdu (2024150). S.L.V. was also funded in part by Helmholtz Association’s Initiative and Networking Fund under the Helmholtz International Lab grant agreement InterLabs-0015, and the Canada First Research Excellence Fund (CFREF Competition 2, 2015–2016) awarded to the Healthy Brains, Healthy Lives initiative at McGill University, through the Helmholtz International BigBrain Analytics and Learning Laboratory (HIBALL). M.D.H. was funded by the Max Planck Society and the German Ministry of Education and Research (BMBF).

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  1. These authors contributed equally: Sofie Louise Valk, Huafu Chen.

Authors and Affiliations

  1. The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China

    Yun-Shuang Fan, Pengfei Yang, Wei Sheng, Mi Yang & Huafu Chen

  2. Lise Meitner group Neurobiosocial, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany

    Yun-Shuang Fan, Meike Dorothee Hettwer & Sofie Louise Valk

  3. Department of Clinical Psychology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China

    Yong Xu

  4. Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), Research Centre Jülich, Jülich, Germany

    Meike Dorothee Hettwer & Sofie Louise Valk

  5. Max Planck School of Cognition, Leipzig, Germany

    Meike Dorothee Hettwer

  6. Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Meike Dorothee Hettwer & Sofie Louise Valk

  7. The School of Computer and Artificial Intelligence, Zhengzhou University, Zhengzhou, China

    Chong Wang

  8. Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland

    Matthias Kirschner

  9. MOE Key Lab for Neuroinformation, Brain-Computer Interface & Brain-Inspired Intelligence Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, China

    Huafu Chen

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Contributions

Y-SF, SLV and HC contributed to the conception and design of the work. YX, HC and MY contributed to the acquisition and interpretation of data for the work. Y-SF, PY, WS and CW contributed to the analysis of data. Y-SF wrote the manuscript. MDH, MK, and SLV revised it critically for important intellectual content. All authors reviewed initial drafts and approved the final version of the manuscript.

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Correspondence to Sofie Louise Valk or Huafu Chen.

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Fan, YS., Xu, Y., Hettwer, M.D. et al. Neurodevelopmentally rooted epicenters in schizophrenia: sensorimotor-association spatial axis of cortical thickness alterations. Mol Psychiatry 31, 929–940 (2026). https://doi.org/10.1038/s41380-025-03193-9

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