Learning objectives (up to 3)
The overall aim of this symposium is to describe new developments implicating neuroimmune contributions to certain persistent pain conditions including whiplash-associated disorder (WAD), using cutting-edge techniques to identify peripheral nerve pathology and examine its relationship to the immune system.
At the end of the symposium, attendees will be able to:
1. Describe the relevance of peripheral nerve pathology to clinical practice in some common persistent MSK conditions.
2. Discuss research and clinical methods used to identify peripheral nerve pathologies.
3. Describe the growing evidence base for links between the immune system, nervous system, and symptoms in some common persistent MSK conditions.
• Description (this must be evidence based)
Persistent MSK conditions such as low back pain, neck pain, and WAD account for high numbers of days of work loss with resultant high financial losses. For example, in 2019/2020 in the UK, 480,000 employees presented with work-related MSK conditions which resulted in an estimated 8.9 million lost working days(1). Current treatments for persistent MSK pain conditions typically demonstrate modest effects(2, 3) and this may reflect our incomplete understanding of the underpinning mechanisms.
Despite not being traditionally considered neuropathic pain conditions, many of these musculoskeletal conditions have signs of nerve pathology (4-6). Such signs include abnormal sensory detection thresholds using quantitative sensory testing; signs of nerve inflammation on magnetic resonance imaging (MRI); and structural degeneration of small nerve fibres in skin biopsies (4-6).
Findings of nerve pathology in some persistent MSK conditions may result from a direct nerve injury (eg after WAD) but many could result from neuroimmune changes as has been previously demonstrated using animal models (7). For example, it is well established that stress is associated with increased inflammatory markers (8) and signs of nerve dysfunction. Posttraumatic stress found in some conditions such as WAD have been associated with persistent pain (9), and higher levels of stress have been demonstrated to mediate the trajectory of acute to persistent low back pain (10).
Overall, our symposium will explore pathophysiological neuroimmune involvement in certain persistent MSK conditions, with a particular focus on WAD. We will do this by describing new developments enabled by cutting-edge research methods, including:
1. Detailed assessments of nerve structure and function using a range of clinical and research methods. We will highlight quantitative sensory testing (11), histological analysis from skin biopsies (12), as well as validated bedside clinical tests (13, 14). This section will be presented by Dr Joel Fundaun.

2. Novel MRI sequences and analyses to measure signs indicative of nerve inflammation (5) and structural nerve changes (15) (e.g., demyelination and nerve degeneration). This section will be presented by Dr Colette Ridehalgh.

3. Characterisation of systemic and local inflammation using blood markers, genome-wide association studies and gene-expression analyses. We will explore evidence for raised inflammatory markers in WAD, persistent spinal and widespread pain based on clinical (16), biobank (17) and genetic (18) data, including relationships with clinical presentation. Links between nerve pathology and skin inflammatory cytokine gene expression will be reported. This section will be presented by Dr Scott Farrell.
The symposium will discuss each of the above methods within the context of people with persistent MSK pain. It will discuss the clinical implications of how knowledge of such pathophysiological mechanisms can influence patient management.
• Implications/conclusions
An improved understanding of the mechanisms related to persistent MSK pain is critical to improve patient outcomes. This symposium will explore the accumulating evidence for peripheral nerve pathology and links to the neuro-immune system in people with persistent MSK pain whilst detailing innovative interdisciplinary research methods. This session aims to provide a clear overview of these findings and explain their relevance to clinical management. Additionally, it will assist attendees to understand the application of simple bedside clinical tests and their important role in a detailed assessment of neurologic function in MSK persistent pain.

• References
1. Health and Safety executive. Work related Musculoskeletal Disorde Statistics (WRMSDs) in Great Britain. UK:HSE. 2020.
2. Sterling M, de Zoete RMJ, Coppieters I, Farrell SF. Best Evidence Rehabilitation for Chronic Pain Part 4: Neck Pain. J Clin Med. 2019;8(8).
3. Hayden JA, Ellis J, Ogilvie R, Malmivaara A, van Tulder MW. Exercise therapy for chronic low back pain. Cochrane Database Syst Rev. 2021;9(9):Cd009790.
4. Fundaun J, Kolski M, Baskozos G, Dilley A, Sterling M, Schmid AB. Nerve pathology and neuropathic pain after whiplash injury: a systematic review and meta-analysis. Pain. 2021.
5. Greening J, Anantharaman K, Young R, Dilley A. Evidence for Increased Magnetic Resonance Imaging Signal Intensity and Morphological Changes in the Brachial Plexus and Median Nerves of Patients With Chronic Arm and Neck Pain Following Whiplash Injury. J Orthop Sports Phys Ther. 2018;48(7):523-32.
6. Farrell SF, Sterling M, Irving-Rodgers H, Schmid AB. Small fibre pathology in chronic whiplash-associated disorder: A cross-sectional study. Eur J Pain. 2020;24(6):1045-57.
7. Winkelstein BA. How can animal models inform on the transition to chronic symptoms in whiplash? Spine (Phila Pa 1976). 2011;36(25 Suppl):S218-25.
8. Marsland AL, Walsh C, Lockwood K, John-Henderson NA. The effects of acute psychological stress on circulating and stimulated inflammatory markers: A systematic review and meta-analysis. Brain, Behavior, and Immunity. 2017;64:208-19.
9. Sterling M, Hendrikz J, Kenardy J. Similar factors predict disability and posttraumatic stress disorder trajectories after whiplash injury. Pain. 2011;152(6):1272-8.
10. Bernier Carney KM, Guite JW, Young EE, Starkweather AR. Investigating key predictors of persistent low back pain: A focus on psychological stress. Applied Nursing Research. 2021;58:151406.
11. Rolke R, Baron R, Maier C, Tölle TR, Treede DR, Beyer A, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain. 2006;123(3):231-43.
12. Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger JM, Mellgren SI, et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010;17(7):903-12, e44-9.
13. Zhu GC, Böttger K, Slater H, Cook C, Farrell SF, Hailey L, et al. Concurrent validity of a low-cost and time-efficient clinical sensory test battery to evaluate somatosensory dysfunction. Eur J Pain. 2019;23(10):1826-38.
14. Ridehalgh C, Sandy-Hindmarch OP, Schmid AB. Validity of Clinical Small-Fiber Sensory Testing to Detect Small-Nerve Fiber Degeneration. J Orthop Sports Phys Ther. 2018;48(10):767-74.
15. Schmid AB, Campbell J, Hurley SA, Jbabdi S, Andersson JL, Jenkinson M, et al. Feasibility of Diffusion Tensor and Morphologic Imaging of Peripheral Nerves at Ultra-High Field Strength. Invest Radiol. 2018;53(12):705-13.
16. Farrell SF, de Zoete RMJ, Cabot PJ, Sterling M. Systemic inflammatory markers in neck pain: A systematic review with meta-analysis. Eur J Pain. 2020;24(9):1666-86.
17. Farrell SF, Armfield NR, Elphinston R, Cabot PJ, Sterling M. C-reactive protein and chronic pain risk in the UK Biobank. Back & Neck Pain Forum Global Virtual Conference; Virtual2021.
18. Farrell S, Sterling M, Klyne D, Mustafa S, Campos A, Kho P-F, et al. Genetic impact of blood C-reactive protein levels on chronic spinal and widespread pain. 2023.