PHYSIOLOGICAL AND NEUROIMMUNE EFFECTS OF MANUAL THERAPY

Abstract

Manual therapy (MT) is widely used across healthcare disciplines for the management of musculoskeletal conditions. Emerging evidence indicates that MT may also influence broader physiological systems such as the nervous and the immune systems. However, the mechanisms underlying these effects are still not well understood, and limited evidence exists regarding the neuroimmune effect of MT in neurologically impaired populations such as multiple sclerosis (MS). The overall aim of this dissertation was to investigate the physiological effects of MT, synthesizing current evidence across mechanistic domains, and generating pilot data to inform future research. This dissertation was structured around four manuscripts. The first manuscript provides a narrative review of autonomic nervous system (ANS) and visceral responses to MT, summarizing evidence of sympathetic-parasympathetic modulation and highlight- ing methodological challenges. The second manuscript reviews neuromuscular responses to high-velocity, low-amplitude spinal manipulation (HVLA-SM), identifying potential peripheral, spinal, and cortical changes but also notes the considerable variability across studies. The third manuscript offers an evidence-based guide for rehabilitation physicians, outlining the clinical effectiveness of manual therapy for common musculoskeletal conditions and emphasizing its growing integration into guideline-based practice. The fourth manuscript presents a pilot randomized sham-controlled trial in people with relapsing-remitting MS (RRMS), evaluating the effects of thoracic spinal manipulation on inflammatory cytokine profiles, neurodegenerative biomarkers, and clinical/performance- based outcomes. The narrative reviews (Chapters 2 & 3) highlighted that MT elicits ANS and neuromuscular responses, but overall findings are inconsistent due to methodological variability and small sample sizes. The quick guide to clinical evidence pertaining to the use of MT summarized (Chapter 4) the recommended, and clinically effective MT techniques for musculoskeletal conditions, while underscoring the importance of mechanistic re- search. The pilot study (Chapter 5) demonstrated that six cytokines IL-8, IL-17A, GM-CSF, MIP-1β, IFNγ, and Fractalkine showed moderate to large effect sizes at multiple timepoints post-spinal manipulation, while neurodegeneration biomarkers and most clinical/performance-based outcomes exhibited small or negligible changes. Collectively, this doctoral dissertation provides an integrated evaluation of the physiological effects of manual therapy, advances mechanistic understanding across multiple physiological systems, and identifies key biomarkers to prioritize in future randomized controlled trials.