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Lesion network localization of depression in multiple sclerosis

Nature Mental Health volume 1, pages 36–44 (2023)Cite this article

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Abstract

Multiple sclerosis (MS), a demyelinating disease that causes focal white matter lesions, is commonly associated with depression. However, it remains unclear whether depression risk is selectively increased by specific white matter lesion locations. Recent work shows that stroke lesions and therapeutic neuromodulation sites that modify depression severity are connected to a common brain circuit, providing an a priori template. Here we assessed whether this circuit is relevant for white matter lesions in MS. In a clinical and radiological database of individuals with MS (n = 281), we estimated the whole-brain connectivity of each person’s white matter lesion locations using a normative connectome database (n = 1,000). Functional connectivity between MS lesion locations and our a priori depression circuit was correlated with depression severity in MS (P = 0.013) and specific to depression versus other MS-related symptoms (P = 0.0058). A data-driven circuit for MS depression showed similar topography to our a priori depression circuit (P = 0.015). The peak of this data-driven MS depression circuit was in the ventral midbrain, including the ventral tegmental area (familywise-error-corrected P < 0.05). These findings lend insight into the localization of MS depression that may help guide targeting for therapeutic brain stimulation.

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Fig. 1: Dataset characteristics.
Fig. 2: Comparing MS lesions with the a priori depression circuit.
Fig. 3: Convergence across lesion etiologies associated with depression.
Fig. 4: Convergence between MS depression and brain stimulation sites that modulate depression.
Fig. 5: The peak of our data-driven MS depression circuit is in the ventral midbrain.

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Data availability

The functional connectivity data employed in this study are available online through the Harvard Dataverse at https://doi.org/10.7910/DVN/ILXIKS. Due to the potentially identifiable nature of MS lesion patterns, these data cannot be shared publicly but may be reviewed upon reasonable request with an institutional data use agreement. The final MS depression circuit is available on our website: https://siddiqi.bwh.harvard.edu/data-code/.

Code availability

The pipeline used to prepare the functional connectivity data is available at https://github.com/bchcohenlab/BIDS_to_CBIG_fMRI_Preproc2016. Statistical analyses were performed in MATLAB R2021b. Custom MATLAB scripts for spatial permutation testing are available on our website: https://siddiqi.bwh.harvard.edu/data-code/.

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Acknowledgements

The authors thank all research participants, funding bodies, allied health staff and other research staff that made this work possible. We thank M. Polgar-Turcsanyi for database management. The SysteMS study was funded by Verily Life Sciences. The present analysis was supported by the Brain & Behavior Research Foundation (S.H.S.), the Baszucki Family Foundation (S.H.S. and M.D.F.), and the National Institute of Mental Health (grant no. K23MH121657 to S.H.S.; grant numbers R01MH113929 and R01MH115949 to M.D.F.). The funders were not directly involved in the conceptualization, design, analysis, decision to publish or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Shan H. Siddiqi, Isaiah Kletenik.

  2. These authors jointly supervised this work: Charles R. G. Guttmann, Michael D. Fox.

Authors and Affiliations

  1. Center for Brain Circuit Therapeutics, Brigham and Women’s Hospital, Boston, MA, USA

    Shan H. Siddiqi, Isaiah Kletenik & Michael D. Fox

  2. Center for Brain/Mind Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Shan H. Siddiqi, Isaiah Kletenik & Michael D. Fox

  3. Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Shan H. Siddiqi & Michael D. Fox

  4. Division of Cognitive and Behavioral Neurology, Brigham and Women’s Hospital, Boston, MA, USA

    Shan H. Siddiqi, Isaiah Kletenik & Michael D. Fox

  5. Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Isaiah Kletenik, Mark C. Anderson, Tanuja Chitnis, Bonnie I. Glanz, Samar Khalil & Rohit Bakshi

  6. Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, Boston, MA, USA

    Mark C. Anderson, Tanuja Chitnis, Bonnie I. Glanz & Rohit Bakshi

  7. Center for Neurological Imaging, Brigham and Women’s Hospital, Boston, MA, USA

    Michele Cavallari, Miklos Palotai & Charles R. G. Guttmann

  8. Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Michele Cavallari, Miklos Palotai, Rohit Bakshi & Charles R. G. Guttmann

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Contributions

Conception and design of study were by S.H.S., I.K., R.B., C.R.G.G. and M.D.F. Lesion network mapping and statistical analyses were by S.H.S. and I.K. Preprocessing and preparation of data for analysis were by M.C.A., M.C., S.K. and M.P. Data collection was by R.B., C.R.G.G., M.C., T.C. and B.I.G. Writing of the manuscript was by S.H.S., I.K. and M.D.F. with input from all authors.

Corresponding author

Correspondence to Shan H. Siddiqi.

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Competing interests

S.H.S. and M.D.F. are scientific consultants for Magnus Medical. S.H.S. is a clinical consultant for Acacia Mental Health, Kaizen Brain Center and Boston Precision Neurotherapeutics. S.H.S. and M.D.F. have jointly received investigator-initiated research funding from Neuronetics. S.H.S. has served as a speaker for Brainsway and PsychU.org (unbranded, sponsored by Otsuka). S.H.S. and M.D.F. independently own intellectual property involving the use of functional connectivity to target TMS. R.B. has received consulting fees from Bristol Myers Squibb and EMD Serono and research support from Bristol Myers Squibb, EMD Serono and Novartis. C.R.G.G. has received research funding from Sanofi, the National Multiple Sclerosis Society, the International Progressive Multiple Sclerosis Alliance, the US Office for Naval Research, NIH, the Focused Ultrasound Foundation, Bristol Myers Squibb/Celgene as well as travel support from Roche Pharmaceuticals, and owns stock in Roche, Novartis, GSK, Alnylam, Protalix Biotherapeutics, Arrowhead Pharmaceuticals, Cocrystal Pharma and Sangamo Therapeutics. None of these entities was involved in the present work. The remaining authors have no conflicts of interest to declare.

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Siddiqi, S.H., Kletenik, I., Anderson, M.C. et al. Lesion network localization of depression in multiple sclerosis. Nat. Mental Health 1, 36–44 (2023). https://doi.org/10.1038/s44220-022-00002-y

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