Exploring the Relationship Between Brain Neurochemistry, Cervical Impairments and Pain Sensitivity in People with Migraine, Whiplash-Headache, Low Back Pain and Healthy Controls: A Secondary Analysis of a Cross-Sectional Case-Control Study
Authors: Peek Aimie L. , Liang Zhiqi , Treleaven Julia , Rebbeck Trudy 
Published: February 2025

Background/Objectives: Gamma-Aminobutyric Acid (GABA) and glutamate are the main inhibitory and excitatory neurochemicals of the central nervous system. Recently, increased GABA+ (GABA+ macromolecules) and Glx (glutamate and glutamine) levels have been reported in migraine. Conversely, decreased GABA+ and Glx levels have been reported in conditions such as chronic musculoskeletal pain and other chronic widespread pain conditions. This has led to the hypothesis that unique neurochemical profiles may underpin different headache and pain conditions. What is currently unknown is how neurochemical levels correlate with different clinical presentations of local and widespread pain sensitivity. The aims of this study were therefore to (i) explore the relationship between brain neurochemicals and clinical presentations of different headache and pain conditions and (ii) use a novel approach to explore how participants cluster based on their neurochemical profiles and explore the clinical characteristics of the participants in these neurochemical clusters. Methods: In this exploratory secondary analysis of a cross-sectional study, participants with migraine (n = 20), whiplash-headache (n = 20), and low back pain (n = 20), and healthy controls (n = 21) completed pain, disability and psychological distress questionnaires, received Magnetic Resonance Spectroscopy (MEGAPRESS), and underwent cervical musculoskeletal and quantitative sensory testing. Participants were classified based on cervical musculoskeletal impairment, increased cervical pain sensitivity, and central sensitization. Correlations between neurochemical levels and clinical classifications were explored. Cluster analysis was used to determine how participants grouped based on their neurochemical profiles. Pain, disability and psychological distress scores and clinical classifications were then compared between the resultant clusters. Post hoc testing explored increased cervical pain sensitivity within the clusters. Results: GABA+ levels moderately correlated with increased cervical pain sensitivity (r2 = 0.31, p = 0.006), with no other significant correlations. Cluster analysis revealed three neurochemical profiles, Cluster 1 (Low GABA+ levels) had moderate disability, Cluster 2 (highest Glx levels) had the lowest pain and disability, and Cluster 3 (highest GABA+ levels) had the highest pain and disability. Post hoc testing demonstrated that the cluster with the highest GABA+ levels (Cluster 3) had the most cervical pain sensitivity. Conclusions: This study suggests that considering the pain condition or presence of central sensitization alone is not sufficient to explain GABA+ and Glx levels. Our findings suggest that increased cervical pain sensitivity might be more reflective of GABA+ levels than pain condition or central sensitization and would benefit from further investigation to further elucidate the relationship between brain neurochemicals and clinical characteristics of pain sensitivity.