Exploring Neuroimmunological Mechanisms in Neck Pain and the Impact of Musculoskeletal Physiotherapy

This PhD thesis explores the neuroimmune mechanisms in neck pain and investigates if musculoskeletal physiotherapy affects these mechanisms. The research aims to better understand the physiological processes of neck pain by examining both systemic inflammatory markers and spinal neuroinflammation, and by assessing how musculoskeletal interventions influence these neuroimmune responses. The thesis is divided into three parts. Part I: Systemic Inflammatory Markers in Neck Pain This section investigates whether people with neck pain exhibit elevated levels of systemic inflammatory markers compared to pain-free controls and how these markers relate to symptoms and pain persistence. It includes four chapters: Chapter 1 reviews neuroimmune interactions in musculoskeletal conditions, detailing the role of the immune and nervous systems and their interplay in spinal pain and nerve injury. It also discusses prospects for targeted therapies. Chapter 2 addresses the complexity of interpreting systemic inflammatory markers, cautioning against oversimplified conclusions due to potential confounding variables. Chapter 3 presents a cross-sectional study identifying associations between systemic neuroimmune markers and clinical, psychological, and lifestyle factors in people with non-specific neck pain and painful cervical radiculopathy. Chapter 4 describes a prospective cohort study that follows people with acute neck pain over six months, identifying distinct recovery trajectories based on inflammatory, clinical, and psychological profiles. Part II: Spinal Neuroinflammation in Cervical Radiculopathy This part focuses on developing and applying neuroimaging techniques to assess localised inflammation in the spinal cord and neuroforamina of patients with painful cervical radiculopathy. It includes two chapters: Chapter 5 introduces a pharmacokinetic model using the radiotracer [11C]DPA713 with dynamic PET/CT imaging to quantify neuroinflammation. The study establishes the model’s test-retest reliability. Chapter 6 applies this method to show that patients with painful cervical radiculopathy have increased tracer binding, indicating neuroinflammation, at affected sites compared to controls. It also explores correlations with clinical symptoms. Part III: Effects of Musculoskeletal Physiotherapy on Neuroimmune Mechanisms This section evaluates how musculoskeletal physiotherapy impacts systemic and localised neuroimmune responses. It includes five chapters: Chapter 7 is a systematic review and meta-analysis that suggests joint and nerve mobilisation can influence neuroimmune responses in animal models and some human studies, though research in humans remains limited. Chapter 8 introduces the CROM-VAS Test, a novel tool to assess short-term changes in pain intensity post-treatment. The test is shown to have good inter-rater reliability. Chapter 9 outlines the protocol for a randomised, placebo-controlled trial examining the effects of joint mobilisation and manipulation on systemic neuroimmune markers in people with persistent neck pain. Chapter 10 presents the results of this trial, which found no significant short-term changes in systemic markers following a single session of treatment. Chapter 11 shifts focus to localised inflammation, evaluating spinal neuroinflammation before and after a six-week neural tissue management intervention in two patients. The intervention showed potential in reducing neuroinflammation. The thesis concludes with a comprehensive discussion of the findings (Chapter 12), summaries in Dutch and English (Chapter 13), appendices (Chapter 14), and author information and publications (Chapter 15). Overall, this thesis highlights the complex neuroimmune landscape of neck pain and provides foundational evidence for the potential, yet still limited, impact of musculoskeletal physiotherapy on local neuroinflammation. It underscores the need for more mechanistic research for a better understanding of neck pain and the workingmechanisms of musculosksletal physiotherapy.