Mass General Brigham study finds chronic pain linked to altered skull bone marrow activity

Researchers found that activity in the skull bone marrow is altered in people with chronic back and knee pain, suggesting a possible therapeutic target for this widespread and debilitating health problem.

Chronic pain affects almost one-quarter of U.S. adults. Yet, for most people, current treatment approaches provide only limited relief. Recent research has pointed to bone marrow found in the skull as an important site of communication between the brain and the immune system. In a study published in Science Translational Medicine, investigators at Mass General Brigham found an association between worse symptom severity, including pain and depression, and higher levels of a protein linked to inflammation in the skull bone marrow.

“These findings suggest a new direction for pain research,” said Marco Loggia, PhD, senior author of the study and principal investigator at the Pain and Neuroinflammation Imaging Lab at Mass General Brigham. “Better understanding how the skull bone marrow is involved in chronic pain could lead to new ways to treat pain and reduce its burden on patients.”

The study included 125 adults with chronic pain, including 88 participants with chronic low back pain and 37 with knee osteoarthritis, along with 22 healthy controls. PET/MRI imaging showed significantly higher levels of 18 kDa translocator protein (TSPO), a marker associated with immune cell density, in people with chronic pain compared to those without chronic pain. The increases were observed in both groups with chronic low back pain and knee osteoarthritis, although they were more pronounced in the osteoarthritis group.

Importantly, TSPO levels were associated with symptom severity. Higher skull bone marrow TSPO levels were linked to greater pain intensity and pain-related psychological and functional symptoms, including higher levels of anxiety and depression.

In collaboration with researchers at the University of Texas at Dallas, investigators conducted postmortem analyses of human skull bone marrow. Imaging findings from these analyses showed a higher density of TSPO-positive cells in tissue from a donor with severe headaches and peripheral neuropathy, compared with a donor without chronic pain. The postmortem findings offer preliminary support for the patterns observed in the imaging analyses.

The study does not establish whether these immune changes cause chronic pain or result from it. However, the research identifies the skull bone marrow as potentially important in diagnosing and/or treating chronic pain.

The authors conclude that further research could explore whether skull bone marrow immune activity decreases in people who receive effective pain therapy and whether therapies targeting the skull bone marrow could improve outcomes for people living with chronic pain.

Authorship: In addition to Loggia, Mass General Brigham authors include Mehrbod Mohammadian, Nikos Efthimiou, Ludovica Brusaferri, Joya Cooper-Hohn, Minhae Kim, Jennifer P. Murphy, Zeynab Alshelh, Grace Grmek, Jack H. Schnieders, Courtney A. Chane, Thomas G. Carmichael, Danika Yang, Ciprian Catana, Steven M. Stufflebeam, Robert R. Edwards, Vitaly Napadow, Matthias Nahrendorf, and Jodi M. Gilman. Additional authors include Katherin Gabriel, Julia J. Schubert, Federico E. Turkheimer, Rafael A. Cazuza, Peter M. Grace, Kimberly Sullivan, and Theodore J Price.

Disclosures: Loggia has consulted for Ono Pharma INC and Sensorium Therapeutics. Loggia and Gilman received a research grant from Jazz Pharmaceuticals. Napadow is a paid consultant for Cala Health. Loggia, Mohammadian, Brusaferri and Gilman are named inventors on a pending, unpublished Patent Cooperation Treaty (PCT) application. This application relates to aspects of the work described in this manuscript and is currently considered confidential. The authors are not aware of any material transfer agreements, issued patents, or third-party pending patent applications that would restrict readers’ or researchers’ non-commercial research use of the methods, techniques, materials, or findings described in this article. Any rights associated with the pending application are not intended to restrict research use, but commercial use may be subject to applicable patent rights if such rights issue.

Funding: This study was supported by the National Institute of Neurological Disorders and Stroke (grants 1R01NS094306-01A1, 1R01NS095937-01A1, U19NS120608), the National Institute on Drug Abuse (grant 5R01DA053316-05), the Department of Defense (grants HT9425-24-1-0109, W81XWH-22-1-1003, W81XWH-19-1-0765), and National Institutes of Health (R01 NS126252). This manuscript reflects the views of the authors and may not reflect the opinions or views of the National Institutes of Health.

Paper cited: Mohammadian, M et al. “Elevated translocator protein in skull bone marrow is linked to human chronic pain”  Science Translational Medicine.  DOI: 10.1126/scitranslmed.aed8729

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