149: Limbic White Matter Mediates TLR4 Immunoreactivity and Widespread Pain in Female Chronic Pelvic Pain

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic widespread pain, Neuroimmunology, Neuroanatomical circuit analysis, , , , , , , ,

Background and Aims: Chronic pelvic pain is a common, debilitating condition that is often treatment-resistant. The MAPP Network has identified local and widespread pain subtypes, with widespread pain in females linked to heightened innate immune activation via Toll-like receptor 4 (TLR4) pathways (1). Because widespread pain responds preferentially to centrally-acting therapies, peripheral immunoreactivity likely reflects or drives central sensitization, yet the specific brain changes involved remain unknown. Diffusion MRI (dMRI) provides sensitivity to microstructural alterations associated with neuroinflammation that conventional imaging cannot detect (2). We apply advanced diffusion measures to identify CNS mechanisms linking TLR4-mediated immunoreactivity to pain widespreadness in chronic pelvic pain.

Methods: We studied 96 chronic pelvic pain patients (62 female; age 18–78) from MAPP with immune, imaging, and clinical data at baseline, 6, and 18 months. Whole blood stimulated via TLR4 agonism had cytokine/chemokine responses summarized by PCA (3). Participants above/below zero on Z-scored PC1 at every visit were classified as high/low immunoreactivity. Pain widespreadness was indexed across 12 body sites. dMRI yielded white matter integrity, neurite density, and microstructure across white matter and cortical/subcortical regions. Mixed-effects models pooling visits with nested random intercepts for site/subject tested immunoreactivity–pain and immunoreactivity–brain associations, with cluster-bootstrap mediation of FDR-significant regions.

Results: High (N = 49) and low (N = 47) immunoreactivity groups were defined via PC1 median split. Sex-stratified models showed immunoreactivity significantly predicted widespread pain in females (β = 2.91, p = 0.004), but not males (β = 0.31, p = 0.63). Brain analyses in females revealed that the high immunoreactivity group had higher fractional anisotropy (FA) in the right hippocampal cingulum (CGH; β = 0.040, FDR p = 0.034). No other regions survived FDR correction across white matter or gray matter. Mediation analysis demonstrated that CGH FA significantly mediated the immunoreactivity-to-widespread-pain relationship (indirect effect = −0.49, p = 0.012).

Conclusions: In females with chronic pelvic pain, TLR4-mediated immunoreactivity is associated with both greater pain widespreadness and greater CGH FA, with CGH FA partially mediating the relationship between immunoreactivity and pain widespreadness. The cingulum is a key limbic tract involved in pain-affect integration and a known target of neuromodulation therapies for intractable pain (4), making it a candidate biomarker linking peripheral immune activation to centralized pain. These findings should be confirmed in larger, age-matched samples given the modest sample size. Future work should examine whether cingulum microstructure predicts differential treatment response to centrally versus peripherally-acting therapies in immunoreactive chronic pain populations.

References: (1) Schrepf A, Bradley CS, O'Donnell M, Luo Y, Harte SE, Kreder K, Lutgendorf S; Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Toll-like receptor 4 and comorbid pain in Interstitial Cystitis/Bladder Pain Syndrome: a multidisciplinary approach to the study of chronic pelvic pain research network study. Brain Behav Immun. 2015 Oct;49:66-74. doi: 10.1016/j.bbi.2015.03.003. Epub 2015 Mar 11. PMID: 25771510; PMCID: PMC4567436.

(2) Jelescu, Ileana O., and Els Fieremans. "Sensitivity and specificity of diffusion MRI to neuroinflammatory processes." Advances in magnetic resonance technology and applications. Vol. 9. Academic Press, 2023. 31-50.

(3) Schrepf A, Kaplan C, Harris RE, Williams DA, Clauw DJ, As-Sanie S, Till S, Clemens JQ, Rodriguez LV, Van Bokhoven A, Landis R, Gallop R, Bradley C, Naliboff B, Pontari M, O'Donnell M, Luo Y, Kreder K, Lutgendorf SK, Harte SE. Stimulated whole-blood cytokine/chemokine responses are associated with interstitial cystitis/bladder pain syndrome phenotypes and features of nociplastic pain: a multidisciplinary approach to the study of chronic pelvic pain research network study. Pain. 2023 May 1;164(5):1148-1157. doi: 10.1097/j.pain.0000000000002813. PMID: 36279178; PMCID: PMC10106356.

(4) Kollenburg L, Arnts H, Green A, Strauss I, Vissers K, Vinke S, Kurt E. The cingulum: a central hotspot for the battle against chronic intractable pain? Brain Commun. 2024 Oct 16;6(5):fcae368. doi: 10.1093/braincomms/fcae368. PMID: 39479369; PMCID: PMC11522883.

Presenting Author: Ravi R. Bhatt, Ph.D
Submitting Author: Ravi Bhatt

Senior Author: Andrew D. Schrepf, Ph.D

IASP 2026 Global Year theme of Neuropathic Pain: No

• Sunanda Somu: M.S - University of Southern California
• Rhea Mukherjee: B.S - University of Southern California
• Talia M. Nir: Ph.D - University of Southern California
• Neda Jahanshad: Ph.D - University of Southern California
• Andrew D. Schrepf: Ph.D - University of Michigan