Abstract
Transcranial magnetic stimulation (TMS) is effective for major depressive disorder (MDD) and anxious depression despite imprecise scalp-based targeting. Retrospective connectomics analyses suggest that targeting one brain circuit preferentially improves “dysphoric” symptoms, while targeting a different brain circuit preferentially improves “anxiosomatic” symptoms. Here, we tested this hypothesis prospectively by randomizing adults with MDD (n = 40, age 18-65) who had moderate-to-severe symptoms of depression (Beck Depression Inventory (BDI) ≥ 20) and anxiety (Beck Anxiety Inventory (BAI) ≥ 16) to a 30-treatment TMS course at the dysphoric circuit target (MNI coordinates [-32, 44, 34], close to the conventional left dorsolateral prefrontal cortex target for MDD), or at the anxiosomatic circuit target (MNI coordinates [0, 48, 46], a dorsomedial target not routinely used). As hypothesized, dysphoric circuit targeting (n = 16) improved BDI more than BAI (ratio 1.08, IQR 0.69-2.02), while anxiosomatic circuit targeting (n = 20) improved BAI more than BDI (ratio 0.70, IQR 0.01-1.01) (Wilcoxon rank-sum test p = 0.0195). Both targets improved BDI (55 vs 54%), but BAI improved significantly more with anxiosomatic circuit targeting (58 vs 36%, p = 0.0301), even when controlling for BDI (p < 0.001). Thus, TMS targeting different connectome-derived brain circuits differentially modulates anxiety that is comorbid with major depressive disorder. Future studies could target according to baseline symptom profile, a step toward precision psychiatry. Trial Registration Number NCT04604210.
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Data availability
Data from this study are available for sharing upon reasonable request with an institutional data use agreement. The circuit maps used in the study are publicly available here: https://siddiqi.bwh.harvard.edu/portfolio-item/ajp-symptom-specificity/ and here: https://neurovault.org/images/787858/” neurovault.org NeuroVault: Dysphoric-anxiosomatic targeting atlas As in Figure 5, Siddiqi et al., AJP 2020 Positive values are hypothesized to be better TMS targets for anxiosomatic symptoms. Negative values are hypothesized to be better TMS targets for dysphoric symptoms https://doi.org/10.1176/appi.ajp.2019.19090915.
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Funding
This work was funded by the Brain and Behavior Research Foundation and the NIMH R21MH126271, K23MH121657. JJT: Behavior Research Foundation (31081), NIMH (K23MH129829, R01MH113929,), NIAAA (1R21AA030372), and a Mass General Brigham Accelerator Grant. SS: NIH (K23MH121657, R21MH126271, R01MH113929), Brain and Behavior Research Foundation Young Investigator Grant, Neuronetics investigator-initiated grant, Baszucki Brain Research Fund, BrainsWay investigator-initiated grant, and Department of Veterans Affairs (I01CX002293). MDF: funded by the Nancy Lurie Marks Foundation, the Kaye Family Research Endowment, Baszucki Brain Research Fund, and the NIH (R01MH113929, R21MH126271, R56AG069086, R01MH115949, and R01AG060987). No other authors report funding.
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JJT: conceptualization, methodology, investigation, resources, writing – original draft, writing – reviewing and editing, supervision, project administration, JL: software, investigation, data curation, writing – reviewing and editing, project administration, CL: software, investigation, data curation, writing – reviewing and editing, project administration, EJ: validation, data curation, writing – reviewing and editing, visualization, project administration, SF: investigation, writing – reviewing and editing, CRB: investigation, writing – reviewing and editing, WD: software, writing – reviewing and editing, DHJ: investigation, writing – reviewing and editing, SJ: investigation, writing – reviewing and editing, JL: investigation, writing – reviewing and editing, SP: investigation, writing – reviewing and editing, LS: investigation, writing – reviewing and editing, ES: investigation, writing – reviewing and editing, LS: data curation, writing – reviewing and editing, NC: writing – reviewing and editing, visualization, JM: formal analysis, writing – reviewing and editing, SB: investigation, writing – reviewing and editing, IG: investigation, writing – reviewing and editing, supervision, SL: investigation, writing – reviewing and editing, supervision, SBS: investigation, writing – reviewing and editing, supervision, MDF: conceptualization, methodology, resources, writing – reviewing and editing, supervision, funding acquisition, SHS: conceptualization, methodology, software, validation, formal analysis, resources, data curation, writing – reviewing and editing, visualization, supervision, funding acquisition.
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SS: 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). None of these entities were involved in the present manuscript. MDF: Scientific consultant for Magnus Medical, owns independent intellectual property involving the use of functional connectivity to target TMS. This intellectual property was not used in the present manuscript. All other others deny competing of interest.
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Taylor, J.J., Li, J., Lin, C. et al. Circuit-targeted modulation of anxiety symptoms in individuals with major depression: A randomized head-to-head TMS trial. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03535-1
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DOI: https://doi.org/10.1038/s41380-026-03535-1
