Brain inflammation and its predictive value for post-operative pain in total knee arthroplasty patients

Zeynab Alshelh; Ludovica Brusaferri; Erin Janas Morrissey; Angel Torrado-Carvajal; Minhae Kim; Oluwaseun Akeju; Grace Grmek; Courtney Chane; Jennifer Murphy; Andrew Schrepf; Richard E Harris; Young-Min Kwon; Hany Bedair; John Siliski; Antonia F Chen; Christopher Melnic; Mohamed Jarraya; Vitaly Napadow; Mattia Veronese; Lucia Maccioni; Robert R Edwards; Nikos Efthimiou; Mehrbod Mohammadian; Ekim Luo; Lauren E Pollak; Ciprian Catana; Nicola Toschi; Marco L Loggia

doi:10.1016/j.bbi.2025.05.008

Brain inflammation and its predictive value for post-operative pain in total knee arthroplasty patients

Brain Behav Immun. 2025 May 10:128:703-712. doi: 10.1016/j.bbi.2025.05.008. Online ahead of print.

Authors

Zeynab Alshelh¹, Ludovica Brusaferri², Erin Janas Morrissey³, Angel Torrado-Carvajal⁴, Minhae Kim³, Oluwaseun Akeju⁵, Grace Grmek³, Courtney Chane³, Jennifer Murphy³, Andrew Schrepf⁶, Richard E Harris⁷, Young-Min Kwon⁸, Hany Bedair⁸, John Siliski⁸, Antonia F Chen⁹, Christopher Melnic⁸, Mohamed Jarraya³, Vitaly Napadow¹⁰, Mattia Veronese¹¹, Lucia Maccioni¹², Robert R Edwards¹², Nikos Efthimiou³, Mehrbod Mohammadian³, Ekim Luo³, Lauren E Pollak¹³, Ciprian Catana³, Nicola Toschi¹⁴, Marco L Loggia¹⁵

Affiliations

¹ Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States; Brain and Mind Centre, University of Sydney, Sydney, Australia.
² Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States; Department of Computer Science and Digital Technology, College of Technology and Environment, London South Bank University, London, UK.
³ Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States.
⁴ Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States; Medical Image Analysis and Biometry Laboratory, Universidad Rey Juan Carlos, Madrid, Spain.
⁵ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
⁶ Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States.
⁷ Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States; Susan Samueli Integrative Health Institute, School of Medicine, University of California at Irvine, Irvine CA, United States; Department of Anesthesiology and Perioperative Care, School of Medicine, University of California at Irvine, Irvine CA, United States.
⁸ Department of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
⁹ Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
¹⁰ Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States; Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Charlestown, MA, United States.
¹¹ Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Information Engineering, University of Padua, Italy.
¹² Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
¹³ Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States.
¹⁴ Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States; Department of Biomedicine and Prevention, University of Rome, "Tor Vergata", Rome, Italy.
¹⁵ Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. Electronic address: Marco.loggia@mgh.harvard.edu.

PMID: 40354834
DOI: 10.1016/j.bbi.2025.05.008

Abstract

Recent evidence suggests that chronic pain patients exhibit elevated brain levels of the neuroinflammation marker 18 kDa translocator protein (TSPO). However, the clinical significance of brain TSPO elevations, and their responses to pain interventions, remain unknown. To explore these questions, we studied patients with knee osteoarthritis (KOA) undergoing total knee arthroplasty (TKA), a procedure which is curative for most, but carries a relatively high risk of persistent post-surgical pain. Pre-surgical KOA patients (n = 41) and healthy controls (n = 22) underwent brain positron emission tomography/magnetic resonance imaging, using the TSPO radioligand [¹¹C]PBR28. A subset of KOA patients (n = 27) returned for a second scan one-year post-TKA. When compared groups, pre-surgical KOA patients exhibited widespread [¹¹C]PBR28 PET signal elevations (Standardized Uptake Value Ratio), with pituitary uptake positively correlating with knee pain severity (rho = 0.51; p = 0.003). A voxel-wise paired t-test revealed that while most brain regions showed no change post-surgery, the [¹¹C]PBR28 PET signal significantly decreased in the thalamus and caudate, reaching control levels. Additionally, a Support Vector Machine model based on pre-surgical imaging, clinical, and demographic features, achieved a correlation of rho = 0.487 (p = 0.001) between the predicted and actual pain improvement. Top predictive features included [¹¹C]PBR28 uptake in the pituitary gland, cuneal cortex, amygdala and other regions. This study suggests that neuroinflammation 1) is widespread in KOA and, in some regions, 2) is linked to pain severity, 3) undergoes normalization following TKA, and 4) can predict post-surgical TKA outcomes. Understanding the neuroinflammatory mechanisms in KOA and post-surgical pain may guide targeted interventions and improve patient outcomes.

Keywords: Knee arthritis; Neuroinflammation; PET; Prediction; Total knee arthroplasty.