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Predictive value of subgenual cingulate normative connectivity to TMS treatment site for antidepressant response in routine clinical practice: a prospective, multisite cohort study

Molecular Psychiatry (2025)Cite this article

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Abstract

Small single-site studies found that transcranial magnetic stimulation (TMS) targets with better antidepressant response were more negatively functionally connected to the subgenual cingulate cortex (SGC). These led to “anti-subgenual” TMS targeting in recent clinical trials. We conducted a larger prospective multi-site observational study to test the robustness of this observation in more diverse clinical populations. Sixty-six treatment-seeking individuals with major depressive disorder (MDD) received 3–8 weeks of daily rTMS to the left dorsolateral prefrontal cortex using scalp-based targeting as part of standard clinical care. Stimulation sites were recorded with MRI neuronavigation on multiple days. Our primary outcome was the correlation between change in Beck Depression Inventory (BDI-II) score and connectivity of each individual’s TMS site to the SGC, computed using resting-state functional connectivity data from 1000 healthy individuals. Secondary (post hoc) analyses incorporated additional clinical covariates. No relationship was found between antidepressant response and normative connectivity of TMS site to SGC (r = 0.1, p = 0.39). This was not due to inconsistency in the location of the TMS sites, which showed smaller within- than between-individual variance (p < 0.0001). Post hoc analyses showed significant associations when adding clinical covariates (r = −0.27, p = 0.014). Baseline anxiety (p < 0.0001) and comorbid psychiatric conditions (p < 0.001) accounted for the most variance in response. Atlas-based connectivity of TMS site to the SGC accounted for minimal variance in antidepressant response in this diverse sample. The “anti-subgenual” target derived based on normative connectome may be suboptimal for MDD patients with high baseline anxiety or psychiatric comorbidities.

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ClinicalTrials.gov Identifier: NCT03276793.

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Fig. 1: Overview of individual involvement and reasons for study termination.
Fig. 2: Variability in TMS target locations (in MNI space) across 66 individuals with MDD.
Fig. 3: Functional connectivity of TMS sites to the SGC as a predictor of antidepressant response.
Fig. 4: The impact of baseline ASI or comorbid diagnoses on clinical outcome improvement following rTMS for three example MDD individuals.

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Data availability

The data for this study (R01MH113929-01) is available through the NIMH Data Archive (NDA), collection ID C2816. Access requires permission and can be requested at (https://nda.nih.gov).

Code availability

All custom MATLAB scripts used in this study are publicly available in the following GitHub repository: (https://github.com/sanazkhosravani/Khosravani_Fox_MPsy_2025_MATLAB_Scripts/tree/main). As an analogous normative connectome to the one used in this study [27], researchers may consider using the GSP connectome [85], which is openly accessible.

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Funding

This research was supported by a grant from the U.S. National Institutes of Health (R01 MH113929-01) awarded to MDF. Additional support was provided in part by the NIGMS-funded COBRE Center for Neuromodulation at Butler Hospital (P20GM130452). MDF has intellectual property on the use of brain connectivity imaging to analyze lesions and guide brain stimulation, is a consultant for Magnus Medical, Soterix, Abbott, and Boston Scientific, and has received research funding from Neuronetics. MDF was supported by grants from the NIH (R01MH113929, R21MH126271, R56AG069086, R21NS123813, R01NS127892, R01MH130666, UM1NS132358), Neuronetics, the Kaye Family Research Endowment, the Ellison / Baszucki Family Foundation, and the Manley Family. SHS is the owner of intellectual property involving the use of brain connectivity to target TMS, scientific consultant for Magnus Medical, investigator-initiated research funding from Neuronetics and Brainsway, speaking fees from Brainsway and Otsuka (for PsychU.org), shareholder in Brainsway (publicly traded) and Magnus Medical (not publicly traded). LLC reports clinical trials contracts with Brown University, Janssen, Neuronetics, and Neurolief; consulting income from Janssen, Neuronetics, Neurolief, Sage Therapeutics, Otsuka, Universal Brain, and Magnus Medical; and a research equipment loan from Nexstim. TB serves as a site Principal Investigator for the Magnus Medical Open Label Clinical Trial. APS is an employee of the Thermo Fisher Scientific with equity compensation. MS is the executive assistant to the CEO of the Nia Therapeutics, Inc.

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Author notes

  1. These authors contributed equally: Shan H. Siddiqi, Michael D. Fox.

Authors and Affiliations

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

    Sanaz Khosravani, Stephan T. Palm, William Drew, Summer B. Frandsen, Christopher Lin, Arun Garimella, Nicole Chiulli, David Lawson, Emma Jones, Joseph J. Taylor, Shan H. Siddiqi & Michael D. Fox

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

    Sanaz Khosravani, Stephan T. Palm, William Drew, Summer B. Frandsen, Christopher Lin, Arun Garimella, David Lawson, Emma Jones & Michael D. Fox

  3. Butler Hospital TMS Clinic and Neuromodulation Research Facility, Providence, RI, USA

    Eric Tirrell, Lauren Hindley & Linda L. Carpenter

  4. Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Molly Schineller & Daniel Z. Press

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

    Nicole Chiulli, Joseph J. Taylor, Shan H. Siddiqi & Michael D. Fox

  6. Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Adam P. Stern

  7. McLean Hospital, Harvard Medical School, Belmont, MA, USA

    Joshua C. Brown

  8. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Tracy A. Barbour

  9. Department of Psychiatry and Human Behavior, Warren Alpert Medical School at Brown University, Providence, RI, USA

    Linda L. Carpenter

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

    Michael D. Fox

Authors
  1. Sanaz Khosravani
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  2. Stephan T. Palm
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  3. William Drew
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  4. Summer B. Frandsen
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  5. Christopher Lin
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  6. Eric Tirrell
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  7. Lauren Hindley
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  8. Molly Schineller
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  9. Arun Garimella
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  10. Nicole Chiulli
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  11. David Lawson
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  12. Emma Jones
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  14. Adam P. Stern
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  15. Joshua C. Brown
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  16. Tracy A. Barbour
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  17. Joseph J. Taylor
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  18. Linda L. Carpenter
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  19. Shan H. Siddiqi
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  20. Michael D. Fox
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Contributions

MDF conceptualized the study and secured funding. MDF, SHS, LLC, JJT, JCB, DP, APS, STP, WD, SF, CL, ET, LH contributed to data collection. MDF, SK, SHS, JJT, TB, STP, WD, SF, CL, AG, NC, EJ, DL conducted the data analysis. MDF, SK drafted the manuscript. All co-authors provided critical revisions to the manuscript.

Corresponding authors

Correspondence to Sanaz Khosravani or Michael D. Fox.

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Khosravani, S., Palm, S.T., Drew, W. et al. Predictive value of subgenual cingulate normative connectivity to TMS treatment site for antidepressant response in routine clinical practice: a prospective, multisite cohort study. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03153-3

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  • DOI: https://doi.org/10.1038/s41380-025-03153-3

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