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White matter pathways mediating dorsolateral prefrontal TMS therapy for depression

Nature Neuroscience volume 29, pages 1048–1053 (2026) Cite this article

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Abstract

We use connectome modeling to map polysynaptic fiber pathways underlying transcranial magnetic stimulation (TMS) therapy for depression. We propose putative cortical and subcortical routes that connect stimulation sites in the dorsolateral prefrontal cortex to the subgenual cingulate cortex via intermediate regions. Here we show that route length explains both TMS treatment response in two independent patient cohorts and the clinical efficacy of functional magnetic resonance imaging-guided TMS targeting. Our results illuminate the neuroanatomical basis of TMS therapy for depression.

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Fig. 1: Association between DLPFC–SGC white matter pathways and TMS treatment response.
The alternative text for this image may have been generated using AI.
Fig. 2: Neuroanatomical DLPFC–SGC pathways.
The alternative text for this image may have been generated using AI.
Fig. 3: Structural and functional DLPFC–SGC maps.
The alternative text for this image may have been generated using AI.

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Data availability

Clinical data (TMS coordinates and rates of symptom improvement) from cohort I are publicly available as part of the Supplementary Information of ref. 6. Clinical data from cohort II (ACTRN12610001071011)7 remain subject to privacy and ethical restrictions. The two normative connectome datasets are publicly available through refs. 30,36. The publicly available data used in the analyses of the present manuscript can be found at https://github.com/caioseguin/tms_dep_pathways. Source data are provided with this paper.

Code availability

Code to reproduce the analyses of the present manuscript is available at https://github.com/caioseguin/tms_dep_pathways. Network communication models were computed using the Brain Connectivity Toolbox52. Surrogate connectomes were computed using code available through ref. 55.

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Acknowledgements

S.M.L. was supported by the Singapore National Medical Research Council (OFYIRG25jan-0049). J.L. was supported by the Brain and Mind Centre Research Development Grant, the USYD-Fudan Brain and Intelligence Science Alliance Flagship Research Program, the Moyira Elizabeth Vine Fund for Research into Schizophrenia Program and the ARC Discovery Project (DP240102161). L.P. was supported by the National Institute of Mental Health of the National Institutes of Health under award number R00MH127296. P.B.F. was supported by a National Health and Medical Research Council of Australia investigator grant (1193596). R.F.H.C. was supported by the Australian National Health and Medical Research Council (Emerging Leadership Investigator grant no. 2017527). A.Z. was supported by the Australian Research Council (Future Fellowship, FT220100091) and the Rebecca L. Cooper Foundation.

Author information

Author notes

  1. These authors contributed equally: Robin F. H. Cash, Andrew Zalesky.

Authors and Affiliations

  1. Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia

    Caio Seguin, Sina Mansour L., Robin F. H. Cash & Andrew Zalesky

  2. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA

    Caio Seguin

  3. Centre for Sleep & Cognition & Centre for Translational Magnetic Resonance Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Sina Mansour L.

  4. Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA

    Richard F. Betzel

  5. Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN, USA

    Richard F. Betzel

  6. Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA

    Evgeny J. Chumin

  7. Medical Imaging Research Institute, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA

    Evgeny J. Chumin

  8. Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Evgeny J. Chumin

  9. Department of Computer, Control, and Management Engineering, University of Rome La Sapienza, Rome, Italy

    Maria Grazia Puxeddu

  10. School of Neuroscience, Virginia Tech, Blacksburg, VA, USA

    Maria Grazia Puxeddu

  11. Sydney Medical School, School of Biomedical Engineering, and Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia

    Jinglei Lv

  12. Department of Psychiatry, Brain Health Institute, Rutgers University, Piscataway, NJ, USA

    Linden Parkes

  13. School of Medicine and Psychology, College of Health and Medicine, The Australian National University, Canberra, Australian Capital Territory, Australia

    Paul B. Fitzgerald

  14. Monarch Research Institute, Monarch Mental Health Group, Melbourne, Victoria, Australia

    Paul B. Fitzgerald

  15. Department of Biomedical Engineering, Faculty of Engineering and Information Technology, The University of Melbourne, Melbourne, Victoria, Australia

    Robin F. H. Cash & Andrew Zalesky

Authors
  1. Caio Seguin
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Contributions

Conceptualization: C.S., R.H.F.C. and A.Z. Methodology: C.S., S.M.L., R.F.B. and R.F.H.C. Formal analysis: C.S. Resources: C.S., S.M.L., R.F.B., E.J.C., M.G.P., J.L., L.P., P.B.F. and R.F.H.C. Data curation: R.F.B., P.B.F. and R.F.H.C. Visualizations: C.S. and S.M.L. Writing, original draft: C.S. Writing, review and editing: all authors.

Corresponding author

Correspondence to Caio Seguin.

Ethics declarations

Competing interests

R.F.H.C. and A.Z. are involved in a not-for-profit clinical neuromodulation center (Queensland Neurostimulation Centre) that offers neuroimaging-guided neurotherapeutics. In the last 3 years, P.B.F. has received equipment for research from Brainsway. He has also acted as a founder and board member for TMS Clinics Australia and Resonance Therapeutics. The other authors declare no competing interests.

Peer review

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Nature Neuroscience thanks Aaron Boes, Casey Paquola and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Source data

Source Data Fig. 1 (download XLSX )

1b, TMS and SGC coordinates; 1c, treatment response and DLPFC–SGC number of white matter hops (cohort I); 1d, Rmap values.

Source Data Fig. 2 (download XLSX )

2b, Distribution of DLPFC–SGC number of white matter hops; 2c, top mediators and paths.

Source Data Fig. 3 (download XLSX )

3c, DLPFC map of white matter hops to the SGC, Lausanne connectome; DLPFC map of functional connectivity to the SGC, Lausanne connectome. 3f, DLPFC map of white matter hops to the SGC, Schaefer connectome; DLPFC map of functional connectivity to the SGC, Schaefer connectome.

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Seguin, C., Mansour L., S., Betzel, R.F. et al. White matter pathways mediating dorsolateral prefrontal TMS therapy for depression. Nat Neurosci 29, 1048–1053 (2026). https://doi.org/10.1038/s41593-026-02248-6

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