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

Sanaz Khosravani^{1

2}, Stephan T Palm^{3

4}, William Drew^{3

4}, Summer B Frandsen^{3

4}, Christopher Lin^{3

4}, Eric Tirrell⁵, Lauren Hindley⁵, Molly Schineller⁶, Arun Garimella^{3

4}, Nicole Chiulli^{3

7}, David Lawson^{3

4}, Emma Jones^{3

4}, Daniel Z Press⁶, Adam P Stern⁸, Joshua C Brown⁹, Tracy A Barbour¹⁰, Joseph J Taylor^{3

7}, Linda L Carpenter^{5

11}, Shan H Siddiqi^#^{3

7}, Michael D Fox^#^{12

13

14

15}

Affiliations

¹ Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. skhosravani@mgb.org.
² Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. skhosravani@mgb.org.
³ Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Butler Hospital TMS Clinic and Neuromodulation Research Facility, Providence, RI, USA.
⁶ Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁷ Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁹ McLean Hospital, Harvard Medical School, Belmont, MA, USA.
¹⁰ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Psychiatry and Human Behavior, Warren Alpert Medical School at Brown University, Providence, RI, USA.
¹² Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mdfox@bwh.harvard.edu.
¹³ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mdfox@bwh.harvard.edu.
¹⁴ Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mdfox@bwh.harvard.edu.
¹⁵ Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mdfox@bwh.harvard.edu.

^# Contributed equally.

PMID: 40847007
DOI: 10.1038/s41380-025-03153-3

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

Sanaz Khosravani et al. Mol Psychiatry. 2025.

. 2025 Aug 22.

doi: 10.1038/s41380-025-03153-3. Online ahead of print.

Authors

Affiliations

¹ Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. skhosravani@mgb.org.
² Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. skhosravani@mgb.org.
³ Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Butler Hospital TMS Clinic and Neuromodulation Research Facility, Providence, RI, USA.
⁶ Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁷ Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁹ McLean Hospital, Harvard Medical School, Belmont, MA, USA.
¹⁰ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Psychiatry and Human Behavior, Warren Alpert Medical School at Brown University, Providence, RI, USA.
¹² Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mdfox@bwh.harvard.edu.
¹³ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mdfox@bwh.harvard.edu.
¹⁴ Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mdfox@bwh.harvard.edu.
¹⁵ Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. mdfox@bwh.harvard.edu.

^# Contributed equally.

PMID: 40847007
DOI: 10.1038/s41380-025-03153-3

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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03276793.

Keywords: Functional connectivity; Major depressive disorder; Network mapping; Subgenual cingulate; Transcranial magnetic stimulation.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Associated data

LinkOut - more resources

Full Text Sources

Medical