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Heterogeneous patterns of brain atrophy in schizophrenia localize to a common brain network

Nature Mental Health volume 3, pages 19–30 (2025)Cite this article

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Abstract

Understanding the neuroanatomy of schizophrenia remains elusive due to heterogeneous findings across neuroimaging studies. Here we investigated whether patterns of brain atrophy associated with schizophrenia would localize to a common brain network using a coordinate network mapping meta-analysis approach. Utilizing the human connectome as a wiring diagram, we identified a connectivity pattern, a schizophrenia network, uniting heterogeneous results from 90 published studies of atrophy in schizophrenia (total n > 8,000). This network was specific to schizophrenia, differentiating it from atrophy in individuals at high risk for psychosis (n = 3,038), normal aging (n = 4,195), neurodegenerative disorders (n = 3,707) and other psychiatric conditions (n = 3,432). The network was also stable with disease progression and across different clusters of schizophrenia symptoms. Patterns of brain atrophy in schizophrenia were negatively correlated with lesions linked to psychosis-related thought processes in an independent cohort (n = 181). Our results propose a unique, stable, and unified schizophrenia network, addressing a significant portion of the heterogeneity observed in previous atrophy studies.

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Fig. 1: Heterogeneity analyses.
Fig. 2: Mapping atrophy coordinates in schizophrenia to brain networks.
Fig. 3: Mapping atrophy patterns in schizophrenia to a common brain network.
Fig. 4: Comparing schizophrenia subgroups: spatial permutation tests (two-sided).
Fig. 5: Schizophrenia versus high-risk individuals.
Fig. 6: Lesion-based validation.

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Data availability

All atrophy coordinates used in this work are derived from previously published studies, as referenced in previous meta-analyses23,49,50. The functional connectivity data utilized in this study can be accessed online through the Harvard Dataverse at https://doi.org/10.7910/DVN/ILXIKS. For inquiries related to the Vietnam Head Injury Study, please contact J. Grafman at [email protected]. The final schizophrenia network map is available via NeuroVault (https://neurovault.org/images/889224/).

Code availability

The processing pipeline for functional connectivity data can be found at https://github.com/bchcohenlab/BIDS_to_CBIG_fMRI_Preproc2016. The statistical analyses were conducted using MATLAB R2022b. MATLAB code for spatial permutation testing can be accessed via Zenodo at https://zenodo.org/records/13851081 (ref. 54).

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Acknowledgments

We express our gratitude to the participants who volunteered for the studies analyzed in this paper. We thank A. Cohen, M. Ferguson, C. Lin, and L. Soussand for their efforts in developing the computational methods used in this study. We also thank P. Flynn and L. Sterina for administrative support. This work was supported by the following sources: Harvard Medical School (Dupont Warren Fellowship Award) and the NIH (grant no. R01MH113929) (A.T.M.); Canadian Institutes of Health Research Vanier Scholarship and a University of British Columbia Friedman Award for Scholars in Health (J.L.S.); Harvard Medical School (Dupont Warren Fellowship Award and Livingston Award), Brain and Behavior Research Foundation Young Investigator Grant (no. 31081), Sidney R. Baer, Jr. Foundation, Baszucki Brain Research Fund, and the NIH (grant nos K23MH129829 and R01MH113929) (J.J.T.); the Nancy Lurie Marks Foundation, the Kaye Family Research Endowment, the Baszucki Brain Research Fund and the NIH (grant nos. R01MH113929, R21MH126271, R56AG069086, R01MH115949, and R01AG060987) (M.D.F.); the NIH (grant nos. K23MH121657, R21MH126271, and R01MH136248), the Brain and Behavior Research Foundation Young Investigator Grant, the Baszucki Brain Research Fund and the Department of Veterans Affairs (grant no. I01CX002293) (S.H.S.).

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Authors and Affiliations

  1. Center for Brain Circuit Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Ahmed T. Makhlouf, William Drew, Jacob L. Stubbs, Joseph J. Taylor, Michael D. Fox & Shan H. Siddiqi

  2. Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Ahmed T. Makhlouf, Joseph J. Taylor, David Silbersweig, Michael D. Fox & Shan H. Siddiqi

  3. Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Jacob L. Stubbs

  4. Department of Psychology, University of Turin, Turin, Italy

    Donato Liloia

  5. Shirley Ryan AbilityLab and Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Jordan Grafman

  6. Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Michael D. Fox

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  1. Ahmed T. Makhlouf
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Contributions

A.T.M., D.S., M.D.F., and S.H.S. conceived and designed the study. A.T.M., W.D., J.L.S., M.D.F., and S.H.S. designed the analytical procedures. A.T.M., W.D., J.L.S., J.J.T., and D.L. preprocessed and prepared the data for analysis. A.T.M., W.D., J.L.S., J.J.T., and S.H.S. performed the neuroimaging and statistical analyses. D.L., J.J.T., J.L.S., and J.G. contributed the data. A.T.M. and S.H.S. wrote the paper, with input from all authors.

Corresponding author

Correspondence to Ahmed T. Makhlouf.

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Competing interests

S.H.S. holds intellectual property related to using individualized resting-state network mapping for targeting TMS, filed in 2016, which has not generated royalties and is unrelated to this work. S.H.S. also serves as a scientific consultant for Magnus Medical, has received investigator-initiated research funding from Neuronetics (2019) and Brainsway (2022), received speaking fees from Brainsway (2021) and Otsuka (for PsychU.org, 2021) and holds shares in Brainsway (publicly traded) and Magnus Medical (privately held). M.D.F. is a scientific consultant for Magnus Medical and owns separate intellectual property related to using functional connectivity to target TMS for depression, filed in 2013, which has not generated royalties and is unrelated to this work. The other authors declare no competing interests.

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Nature Mental Health thanks Richard Dear, Golia Shafiei, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Makhlouf, A.T., Drew, W., Stubbs, J.L. et al. Heterogeneous patterns of brain atrophy in schizophrenia localize to a common brain network. Nat. Mental Health 3, 19–30 (2025). https://doi.org/10.1038/s44220-024-00348-5

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