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Using causal network mapping to clarify pre-clinical brain stimulation results

Neuropsychopharmacology volume 50, pages 1752–1753 (2025)Cite this article

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We read with interest Teferi et al.’s [1] double-blinded, sham-controlled, cross-over trial in which intermittent theta-burst stimulation (iTBS) to individualized right dorsolateral prefrontal cortex targets unexpectedly increased laboratory anxiety [1]. This was particularly surprising given that prior results showed the same effect using continuous TBS (cTBS) [2], which is believed to affect brain circuits in the opposite way. We hypothesized that incidental intersection with our group’s causal anxiosomatic circuit could clarify these findings.

We calculated TMS site connectivity to the anxiosomatic circuit by modeling sites as concentric spheres of decaying intensity, generating sphere-site seed-maps using a normative connectome [3], and correlating seed-maps with the anxiosomatic circuit. This method was used to derive the anxiosomatic circuit [4] and has been validated by our group [5]. We used linear models to test relationships between anxiosomatic circuit connectivity and changes in anxiety.

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Fig. 1: TMS site connectivity to the anxiosomatic circuit shapes anxiety potentiated startle.

References

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Funding

SHS is primarily supported by public funds from the National Institute of Mental Health, but also has foundation funds from The Brain & Behavior Research Foundation and the Baszucki Family Foundation, and investigator-initiated grants from BrainsWay Ltd and Neuronetics Inc. SHS owns intellectual property involving the use of brain connectivity to target TMS, is a scientific consultant for Magnus Medical, investigator-initiated research funding from Neuronetics and Brainsway, has received speaking fees from Brainsway and Otsuka (for PsychU.org), and is a shareholder in Brainsway (publicly traded) and Magnus Medical (not publicly traded). None of these entities was directly involved in the present work. NB received 2 NARSAD Young Investigator Grants from the Brain & Behavior Research Foundation (NLB: 2018, 2021) and a K01 award K01MH121777 (NLB) that supported the studies this Commentary focuses on.

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Authors and Affiliations

  1. Department of Psychiatry, Mass General Brigham, Harvard Medical School, Boston, MA, USA

    Ryan D. Webler & Shan H. Siddiqi

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

    Ryan D. Webler & Shan H. Siddiqi

  3. Center for Neuromodulation in Depression and Stress Department of Psychiatry University of Pennsylvania, Philadelphia, PA, USA

    Diana King & Nicholas L. Balderston

  4. Center for Brain Imaging and Stimulation Department of Psychiatry University of Pennsylvania, Philadelphia, PA, USA

    Diana King & Nicholas L. Balderston

  5. Penn Brain Science, Translation, Innovation, and Modulation Center University of Pennsylvania, Philadelphia, PA, USA

    Diana King & Nicholas L. Balderston

Authors
  1. Ryan D. Webler
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  2. Diana King
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  3. Nicholas L. Balderston
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  4. Shan H. Siddiqi
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Contributions

CRediT author statement according to: https://www.elsevier.com/authors/policies-and-guidelines/credit-author-statement. Conceptualization: RDW, SHS. Methodology: RDW, SHS. Data collection: NLB, Formal analysis: RDW. Writing - Original Draft: RDW, SHS. Writing - Review & Editing: DK, NLB.

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Correspondence to Ryan D. Webler.

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Webler, R.D., King, D., Balderston, N.L. et al. Using causal network mapping to clarify pre-clinical brain stimulation results. Neuropsychopharmacol. 50, 1752–1753 (2025). https://doi.org/10.1038/s41386-025-02153-9

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  • DOI: https://doi.org/10.1038/s41386-025-02153-9

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