Background & Aims

Chronic low back pain (CLBP) is a major cause of disability worldwide and its treatment remains challenging (1). This may be in part the result of maintenance or amplification of the pain experienced by CLBP patients by the central nervous system (CNS) (2,3) as supported by previous brain imaging studies showing an association between persistent CLBP and heightened brain functional connectivity (4,5). Physical exercise training (PExT) has emerged as a promising therapeutic approach for CLBP (6,7), However, our current understanding of how PExT impacts CNS mechanisms related to CLBP remains limited. The objective of this study was to investigate the pathophysiological mechanisms underlying the resolution of pain using transcriptomics in peripheral immune cells and brain functional connectivity in CLBP patients by PExT program.

Methods

Blood samples were collected from 35 participants experiencing CLBP who underwent 14 weeks of PExT, consisting of both aerobic and resistance exercise. The first blood draw was done after an initial 2-week period of low-intensity training to familiarize patients with the exercises, with the second draw occurring after the completion of the full training program. To examine the impact of PExT on the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) functional connectivity, we performed a seed-to-voxel analysis with the seed being the anatomically defined bilateral NAc. Pain ratings were collected two weeks before the start of the program and then two weeks after the end of the study. We tested causal relationships of any changes in CLBP before and after PExT with the brain connectivity and blood transcriptomics by a regression-based causal-mediation analysis approach using regmedint (8,9), performed biological pathway analysis on significant gene-sets using gProfiler (10).

Results

Participants who experienced lower pain intensity over the study span had a higher number of significantly differentially expressed pathways (N=2,741). Mechanistic interaction was found between change in gene expression levels and functional brain connectivity for 8,566 genes associated with lower CLBP intensity through PExT. A predominance of immune system genes contributed to the interaction effects, impacting on function as follows: Interleukin-15 receptor activity, immune receptor activity, and defense response. In the mediation analysis, the entire effect of NAc-mPFC connectivity on pain was mediated by 238 blood transcripts which were previously associated in the interaction model. The mediation effects included genes-sets from both immune and nervous system pathways including immune system regulation, neural development, synaptic transmission regulation, and the dopaminergic pathway (False Discovery Rate < 0.1).

Conclusions

Brain imaging and blood transcriptomics findings support the hypothesis that regular engagement in PExT program decreases NAc-mPFC connectivity while upregulating the immune system in patients with CLBP. The complex multidimensional interplay of the immune system with brain connectivity may provide new transformative insight for novel targets for clinical management and treatment of CLBP.

References

1. Disease, G.B.D., Injury, I. & Prevalence, C. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1789-1858 (2018).
2. Clauw, D.J. Diagnosing and treating chronic musculoskeletal pain based on the underlying mechanism(s). Best Pract Res Clin Rheumatol 29, 6-19 (2015).
3. Fitzcharles, M.A., et al. Nociplastic pain: towards an understanding of prevalent pain conditions. Lancet 397, 2098-2110 (2021).
4. Baliki, M.N., et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci 15, 1117-1119 (2012).
5. Vachon-Presseau, E., et al. Corticolimbic anatomical characteristics predetermine risk for chronic pain. Brain : a journal of neurology 139, 1958-1970 (2016).
6. Geneen, L.J., et al. Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews. Cochrane Database of Systematic Reviews (2017).
7. Qaseem, A., et al. Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med 166, 514-530 (2017).
8. Yoshida K, et al. regmedint: Regression-Based Causal Mediation Analysis with Interaction and Effect Modification Terms. R package version 1.0.0, (2022).
9. VanderWeele, T. Explanation in causal inference: Methods for mediation and interaction. Oxford University Press, (2015).
10. Liis Kolberg L., et al. g:Profiler—interoperable web service for functional enrichment analysis and gene identifier mapping, Nucleic Acids Research, (2023).

Presenting Author

Goodarz Kolifarhood

Poster Authors

Goodarz Koli Farhood

Postdoctoral scholar

McGill University

Lead Author

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Audrey Grant (PhD)

McGill University

Lead Author

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S.J. Thompson

Lead Author

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M. Bergevin

Université de Montréal, Montreal, Qc, Canada

Lead Author

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B. Pageaux

Université de Montréal, Montreal, Qc, Canada

Lead Author

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A. Woznowski-Vu

Lead Author

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T.H. Wideman

Lead Author

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Ivan Chumakov

Lead Author

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Sahel Jahangiri Esfahani

McGill University

Lead Author

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Marc Parisien

McGill University

Lead Author

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L. Stone

University of Minnesota Twin Cities

Lead Author

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L. Bherer

Lead Author

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E. Vachon-Presseau

McGill University

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Luda Diatchenko

McGill University

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Mathieu Roy

Dept. of Psychology, McGill University, Montreal, Qc., Can., H3A 1G1

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Topics

  • Pain Imaging