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Multiple sclerosis lesions that impair memory map to a connected memory circuit

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Abstract

Background

Nearly 1 million Americans are living with multiple sclerosis (MS) and 30–50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit.

Methods

We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes.

Results

Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit.

Conclusions

Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS.

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Acknowledgements

The authors thank the patients who participated in the SysteMS study and the research staff at the Brigham MS Center for assistance, especially Mark Anderson. The authors thank Dr. Margaret O’Connor and Dr. Rebecca Amariglio for their advice and guidance. The authors thank the members of the Center for Brain Circuit Therapeutics for assistance especially Christopher Lin. Data were provided, in part, by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University.

Funding

AC was funded by NIH/NIMH K23MH120510, the Child Neurology Foundation, and the Simons Foundation Autism Research Initiative. M.D.F. was supported by the Nancy Lurie Marks Foundation, the Mather’s Foundation, the Ellison/Baszucki Foundation, the Kaye Family Research Endowment and National Institutes of Health grants R21 MH126271, R56 AG069086, R01 MH113929, R01 MH115949, and R01 AG060987. The SysteMS cohort of the CLIMB study was supported in part by Verily Life Sciences. The CLIMB study is supported in part by the Watercove Foundation.

Author information

Authors and Affiliations

  1. Division of Cognitive and Behavioral Neurology, Brigham and Women’s Hospital, 60 Fenwood Road, 9016H, Boston, MA, 02115, USA

    Isaiah Kletenik, Gad A. Marshall & Michael D. Fox

  2. Department of Neurology, Brigham and Women’s Hospital, Boston, USA

    Isaiah Kletenik, Michael A. Ferguson, Shahamat Tauhid, Gad A. Marshall, Tanuja Chitnis, Rohit Bakshi & Michael D. Fox

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

    Isaiah Kletenik, Alexander L. Cohen, Michael A. Ferguson, Jing Li, William Drew, Shan H. Siddiqi & Michael D. Fox

  4. Harvard Medical School, Boston, MA, USA

    Isaiah Kletenik, Alexander L. Cohen, Michael A. Ferguson, Shan H. Siddiqi, Gad A. Marshall, Tanuja Chitnis, Charles R. G. Guttmann, Rohit Bakshi & Michael D. Fox

  5. Department of Neurology, Boston Children’s Hospital, Boston, MA, USA

    Alexander L. Cohen

  6. Computational Radiology Laboratory, Department of Radiology, Boston Children’s Hospital, Boston, MA, USA

    Alexander L. Cohen

  7. Brigham Multiple Sclerosis Center, Brigham and Women’s Hospital, Harvard Medical School Boston, Boston, MA, USA

    Bonnie I. Glanz, Mariann Polgar-Turcsanyi, Tanuja Chitnis & Rohit Bakshi

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

    Miklos Palotai, Charles R. G. Guttmann, Rohit Bakshi & Michael D. Fox

  9. Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA, USA

    Shan H. Siddiqi & Michael D. Fox

  10. Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Boston, MA, USA

    Gad A. Marshall

  11. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    Gad A. Marshall & Michael D. Fox

  12. Center for Neurological Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Charles R. G. Guttmann

  13. Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA

    Michael D. Fox

Authors
  1. Isaiah Kletenik
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  2. Alexander L. Cohen
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  3. Bonnie I. Glanz
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  4. Michael A. Ferguson
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  5. Shahamat Tauhid
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  6. Jing Li
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  7. William Drew
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  8. Mariann Polgar-Turcsanyi
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  9. Miklos Palotai
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  10. Shan H. Siddiqi
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  11. Gad A. Marshall
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  12. Tanuja Chitnis
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  13. Charles R. G. Guttmann
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  14. Rohit Bakshi
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  15. Michael D. Fox
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Contributions

Study concept and design: all authors; data acquisition and analysis: all authors; drafting the text or figures: IK, ALC, RB, MDF.

Corresponding author

Correspondence to Isaiah Kletenik.

Ethics declarations

Conflicts of interest

Rohit Bakshi has received consulting fees from Bristol-Myers Squibb and EMD Serono and research support from Bristol-Myers Squibb, EMD Serono, and Novartis. The other authors report no competing interests.

Ethical standards

The study was approved by Mass General Brigham/Partners Institutional Review Board Protocols 2015P001248, 2020P002987 and 2020P000737 and all participants provided written informed consent. This study has been approved by the appropriate ethics committee and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Data availability statement

The functional connectivity data equivalent to that used in this study is available online through the Harvard Dataverse at: https://doi.org/10.7910/DVN/ILXIKS and the pipeline used to prepare the functional connectivity data is available at: https://github.com/bchcohenlab/BIDS_to_CBIG_fMRI_Preproc2016. The code to prepare structural connectivity maps is available at: http://www.bcblab.com/BCB/Disconnectome.html and the structural connectivity data is available at: https://www.humanconnectome.org/study/hcp-young-adult/document/1200-subjects-data-release. Statistical analyses were performed in MatLab (version 2019b) or SPSS (version 27.0.1.0). MS lesion data is available for review upon reasonable request.

Supplementary Information

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Supplementary file1 (DOCX 10551 kb)

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Kletenik, I., Cohen, A.L., Glanz, B.I. et al. Multiple sclerosis lesions that impair memory map to a connected memory circuit. J Neurol 270, 5211–5222 (2023). https://doi.org/10.1007/s00415-023-11907-8

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  • DOI: https://doi.org/10.1007/s00415-023-11907-8

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