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Peer-reviewedCC BY-NC-NDBrain stimulation

Proximity to an SGC–DLPFC individualized functional target and electric-field modeling do not predict clinical outcomes of rTMS for treatment-resistant depression

  • Elizabeth Gregory1
  • Shan Siddiqi2
  • Michael Fox2
  • Daniel M. Blumberger3
  • Jonathan H. Downar4
  • Zafiris Jeff Daskalakis5
  • Katharine Dunlop4
  • Fidel Vila‐Rodriguez6
6 affiliations
  1. 1Non-Invasive Neurostimulation Therapies (NINET) Laboratory, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
  2. 2Center for Brain Circuit Therapeutics, Brigham & Women's Hospital, Boston, MA, USA
  3. 3Departments of Psychiatry, Pharmacology & Toxicology, and Institute of Medical Science, University of Toronto, Canada
  4. 4Departments of Psychiatry, Pharmacology & Toxicology, and Institute of Medical Science, University of Toronto, Canada; Centre for Depression and Suicide Studies, St. Michael's Hospital, Toronto, ON, Canada
  5. 5Department of Psychiatry, School of Medicine, University of California, San Diego Health, San Diego, CA, USA
  6. 6Non-Invasive Neurostimulation Therapies (NINET) Laboratory, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada. Electronic address: [email protected]
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Abstract

BACKGROUND: Targeting methods for repetitive transcranial magnetic stimulation (rTMS) in patients with depression now include individual functional magnetic resonance imaging (fMRI) scans to target specific functional connectivity (FC) patterns. Potential biomarkers of rTMS response include target FC with the subgenual anterior cingulate cortex (SGC) or the causal depression circuit (CDC), each of which may be candidates for individualized functional targets (iFTs). We retrospectively assessed the relationship of these two approaches to outcomes in secondary analyses of two large rTMS clinical trials. METHODS: 501 subjects with moderate to severe depression underwent 4-6 weeks of daily rTMS to the left dorsolateral prefrontal cortex (DLPFC), targeted using neuronavigation to an optimized DLPFC-SGC-FC group-based functional target. Baseline resting-state scans were used to retrospectively compute iFTs using either SGC-DLPFC or CDC-DLPFC FC. Proximity (Euclidean distance) of the stimulated target to iFTs were correlated with outcomes. Electric field magnitude at iFTs was computed to capture non-linear stimulation propagation. RESULTS: Most iFTs were within 2 cm of their group-target. Proximity to either an SGC- or CDC-iFT was not associated with better outcomes. Sensitivity analyses accounting for treatment target FC, methodology, data quality, or treatment parameters did not change results. Electric field-based measures were highly similar to Euclidean distance and likewise showed no association with outcomes. CONCLUSIONS: Under the specific fMRI acquisition parameters used, proximity to optimized DLPFC-SGC-iFTs was not associated with better outcomes in patients receiving neuronavigated rTMS to an optimized DLPFC-SGC group-target. Prospective randomized clinical trials definitively assessing the clinical utility of iFTs are warranted.

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Cite

BibTeXRIS
BibTeX
@article{gregory2026proximity,
  title = {{Proximity to an SGC–DLPFC individualized functional target and electric-field modeling do not predict clinical outcomes of rTMS for treatment-resistant depression}},
  author = {Elizabeth Gregory and Shan Siddiqi and Michael Fox and Daniel M. Blumberger and Jonathan H. Downar and Zafiris Jeff Daskalakis and Katharine Dunlop and Fidel Vila‐Rodriguez},
  journal = {Brain stimulation},
  year = {2026},
  month = jul,
  doi = {10.1016/j.brs.2026.103173},
  url = {https://doi.org/10.1016/j.brs.2026.103173},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Proximity to an SGC–DLPFC individualized functional target and electric-field modeling do not predict clinical outcomes of rTMS for treatment-resistant depression
AU  - Elizabeth Gregory
AU  - Shan Siddiqi
AU  - Michael Fox
AU  - Daniel M. Blumberger
AU  - Jonathan H. Downar
AU  - Zafiris Jeff Daskalakis
AU  - Katharine Dunlop
AU  - Fidel Vila‐Rodriguez
PY  - 2026
DA  - 2026/07/25
JO  - Brain stimulation
DO  - 10.1016/j.brs.2026.103173
UR  - https://doi.org/10.1016/j.brs.2026.103173
AB  - BACKGROUND: Targeting methods for repetitive transcranial magnetic stimulation (rTMS) in patients with depression now include individual functional magnetic resonance imaging (fMRI) scans to target specific functional connectivity (FC) patterns. Potential biomarkers of rTMS response include target FC with the subgenual anterior cingulate cortex (SGC) or the causal depression circuit (CDC), each of which may be candidates for individualized functional targets (iFTs). We retrospectively assessed the relationship of these two approaches to outcomes in secondary analyses of two large rTMS clinical trials. METHODS: 501 subjects with moderate to severe depression underwent 4-6 weeks of daily rTMS to the left dorsolateral prefrontal cortex (DLPFC), targeted using neuronavigation to an optimized DLPFC-SGC-FC group-based functional target. Baseline resting-state scans were used to retrospectively compute iFTs using either SGC-DLPFC or CDC-DLPFC FC. Proximity (Euclidean distance) of the stimulated target to iFTs were correlated with outcomes. Electric field magnitude at iFTs was computed to capture non-linear stimulation propagation. RESULTS: Most iFTs were within 2 cm of their group-target. Proximity to either an SGC- or CDC-iFT was not associated with better outcomes. Sensitivity analyses accounting for treatment target FC, methodology, data quality, or treatment parameters did not change results. Electric field-based measures were highly similar to Euclidean distance and likewise showed no association with outcomes. CONCLUSIONS: Under the specific fMRI acquisition parameters used, proximity to optimized DLPFC-SGC-iFTs was not associated with better outcomes in patients receiving neuronavigated rTMS to an optimized DLPFC-SGC group-target. Prospective randomized clinical trials definitively assessing the clinical utility of iFTs are warranted.
SN  - 1876-4754
SN  - 1935-861X
ER  -