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Non-invasively targeting, probing and modulating a deep brain circuit for depression alleviation

Nature Mental Health volume 1, pages 1033–1042 (2023)Cite this article

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Abstract

Effective repetitive transcranial magnetic stimulation (rTMS) treatment for depression has often focused on modulating the subgenual anterior cingulate cortex (sgACC), but no studies have related TMS-evoked responses in the sgACC to clinical effects following rTMS. Here we use interleaved single-pulse TMS/functional magnetic resonance imaging (fMRI) to demonstrate circuit engagement via TMS-evoked responses in the sgACC to stimulation of functionally connected cortical targets in a cohort study of unmedicated depressed patients (n = 36; ClinicalTrials.gov ID NCT04014959). Targets were identified using resting-state fMRI scans seeding the sgACC to identify individualized connectivity clusters. TMS/fMRI was assessed before and after a three-day open label intervention using intermittent theta burst stimulation (iTBS) rTMS targeting the sgACC pathway. TMS-evoked fMRI blood oxygen level-dependent (BOLD) responses in the sgACC and depression symptom scores were assessed pre- and post-intervention. Pre-intervention TMS-evoked response magnitude in the sgACC predicted depression improvement, with more negative evoked responses being associated with greater clinical improvement. Larger post-intervention changes in evoked responses were also associated with depression improvement. The prognostic sgACC associations were specific to the intervention pathway and significantly associated with depression but not anxiety improvement. Here we demonstrate causal evidence of sgACC engagement with TMS/fMRI and show the clinical relevance of engagement and modulation of the targeted prefrontal–sgACC circuit.

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Fig. 1: Participant flow.
Fig. 2: Experimental sessions and TMS stimulation sites.
Fig. 3: Pre-intervention TMS-evoked sgACC is associated with depression improvement.
Fig. 4: TMS-evoked brain changes pre- and post-intervention.
Fig. 5: TMS-evoked brain change associations with symptom improvements.

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Data availability

The baseline MRI and demographic data are available from https:/nda.nih.gov as per the National Institutes of Health funding mandate. TMS/fMRI data are not available publicly at this time due to ongoing analyses. The first author (oathes@pennmedicine.upenn.edu) can be contacted for a possible data-use agreement.

Code availability

No special code was developed for the presented analyses. The software used for processing, the statistical packages and tools are described in the text.

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Acknowledgements

This work was funded in part by the National Institute of Mental Health grants nos. MH120811 and MH116920 (D.J.O.) and U01109991 (Y.I.S.) as well as a Brain Behavior Research Foundation NARSAD Young Investigator grant (D.J.O.). The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of data; nor were they involved in the decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Department of Psychiatry, Center for Brain Imaging and Stimulation, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Desmond J. Oathes, Romain J-P. Duprat, Justin Reber, Ximo Liang, Morgan Scully, Hannah Long, Joseph A. Deluisi, Yvette I. Sheline & Kristin A. Linn

  2. Penn Brain Science, Translation, Innovation, and Modulation Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Desmond J. Oathes & Yvette I. Sheline

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

    Desmond J. Oathes, Romain J-P. Duprat, Justin Reber, Ximo Liang, Morgan Scully, Hannah Long, Joseph A. Deluisi & Yvette I. Sheline

  4. Departments of Neuroscience, Neurology, Neurosurgery and Bioengineering, Perelman School of Medicine, Philadelphia, PA, USA

    Desmond J. Oathes

  5. Departments of Radiology and Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Yvette I. Sheline

  6. Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Kristin A. Linn

  7. Penn Statistics in Imaging and Visualization Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Kristin A. Linn

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Contributions

D.J.O. conceived the research and designed the experiments. D.J.O. secured funding. R.J.-P.D., M.S., H.L. and J.A.D. collected data. D.J.O. analyzed data with analysis tools and input from K.A.L. D.J.O. and Y.I.S. supervised the intervention sessions. R.J.-P.D. and X.L. processed and quality-controlled the imaging data with supervision from D.J.O. R.J.-P.D., J.R. and D.J.O. generated figures. All authors contributed manuscript reviews and edits.

Corresponding author

Correspondence to Desmond J. Oathes.

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Nature Mental Health thanks Florian Müller-Dahlhaus, Shan Siddiqi and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Results, Tables 1–4 and Figs. 1–5.

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Oathes, D.J., Duprat, R.JP., Reber, J. et al. Non-invasively targeting, probing and modulating a deep brain circuit for depression alleviation. Nat. Mental Health 1, 1033–1042 (2023). https://doi.org/10.1038/s44220-023-00165-2

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