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Hippocampal functional connectivity after whiplash injury is linked to the development of chronic pain

Nature Mental Health volume 2, pages 1362–1370 (2024)Cite this article

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Abstract

Brain-centric theories propose that chronic pain is driven and maintained by maladaptive negative emotional learning, with the hippocampus playing a crucial role in the transition from acute to chronic pain. However, little is known about what triggers this maladaptive learning in the first place, especially in the early acute stages following injury. We imaged 110 patients within days of whiplash and mild traumatic brain injury and tested whether hippocampal adaptations impart risk for chronic pain one year later. Patients who went on to develop chronic pain one year later showed increased connectivity between the hippocampus and its posterior network, as well as increased network connectivity across posterior hippocampal network nodes and the amygdala bilaterally. This connectivity was linked to anxiety and increased with time lapse from injury to brain scans. Our findings link rapid hippocampal network reorganization with the development of chronic pain.

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Fig. 1: Hippocampal functional connectivity within days after injury was associated with pain chronicity 1 year later.
Fig. 2: Hippocampal functional connectivity increased with the time lag from the accident to the brain scan and with anxiety for participants who develop chronic pain.
Fig. 3: NBS also showed upregulated connectivity for the amygdala and several posterior hippocampal network regions in patients who developed chronic pain.

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Data availability

After finishing our planned data analyses, the full imaging data will be provided at our data repository, http://www.openpain.org. Until then, data will be shared on reasonable request.

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Acknowledgments

We thank all members of the Apkarian lab for their feedback on the manuscript. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs under award W81XWH-15-1-0603 to D.Y. and A.V.A. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. This work was further supported by National Institutes of Health grant P50 DA044121 and grant R01AR074274, both to A.V.A.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Paulo Branco & A. Vania Apkarian

  2. Center for Translational Pain Research, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Paulo Branco, Andrew D. Vigotsky & A. Vania Apkarian

  3. Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel

    Noam Bosak, Yelena Granovsky & David Yarnitsky

  4. Department of Neurology, Rambam Health Care Campus, Haifa, Israel

    Noam Bosak, Yelena Granovsky & David Yarnitsky

  5. Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Andrew D. Vigotsky & A. Vania Apkarian

  6. Departments of Biomedical Engineering and Statistics, Northwestern University, Evanston, IL, USA

    Andrew D. Vigotsky

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  1. Paulo Branco
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Contributions

D.Y., Y.G., and A.V.A. designed the study, coordinated data collection, and obtained funding. N.B. collected data. P.B. performed imaging analyses. P.B. and A.D.V. performed statistical analyses. P.B. drafted the manuscript. P.B., N.B., A.D.V., and A.V.A. further edited and revised the manuscript. All authors discussed the results, contributed to, and approved the final manuscript.

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Correspondence to A. Vania Apkarian.

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Nature Mental Health thanks Jacklynn Fitzgerald and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Branco, P., Bosak, N., Vigotsky, A.D. et al. Hippocampal functional connectivity after whiplash injury is linked to the development of chronic pain. Nat. Mental Health 2, 1362–1370 (2024). https://doi.org/10.1038/s44220-024-00329-8

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