fMRI correlates of ICD-11 taxonomies of chronic primary pain and chronic secondary musculoskeletal pain: systematic reviews and meta-analyses

Importance: Chronic pain encompasses complex mechanisms that remain incompletely understood. The World Health Organisation’s recent classifications of chronic primary pain and chronic secondary musculoskeletal pain in International Classification of Disease, 11th revision, highlights the need to examine their neural substrates systematically. Neuroimaging studies have shown inconsistent results, underscoring the importance of synthesising evidence on neural mechanisms underlying chronic pain. Objective: This thesis investigates the neural substrates associated with chronic primary pain and chronic secondary musculoskeletal pain using fMRI meta-analyses. Data extraction and Synthesis: Twenty-three whole-brain coordinate-based meta-analyses, explores whether differences in brain activity during provoked and ongoing pain converge spatially within and between chronic primary pain, chronic secondary musculoskeletal pain, and pain-free individuals. Analyses applied activation likelihood estimation, incorporating robust statistical controls for multiple comparisons to reduce false positives by enhancing sensitivity and spatial specificity. Results: For chronic primary pain, meta-analyses of 48 studies (75 experiments, 1,206 patients, 846 pain-free) conjunction analysis revealed significant convergence in the dorsal anterior insula, mid-cingulate cortex, and medial frontal gyrus (MFG). Contrasts highlighted stronger activation in the ventral anterior insula for chronic primary pain and the superior frontal gyrus for pain-free. Behavioural data confirmed higher pain levels in chronic primary pain patients without publication bias. For chronic secondary musculoskeletal pain, 28 studies (62 experiments, 3,217 patients, 1,079 pain-free) showed significant differences in the subcallosal gyrus, inferior frontal gyrus (IFG), and MFG, compared to pain-free. Combined chronic secondary musculoskeletal pain (symptoms and no symptoms) analyses highlighted cerebellar and parahippocampal activity. While both chronic primary pain and chronic secondary musculoskeletal pain showed involvement of the claustrum, IFG, and anterior cingulate cortex, variability across studies was high. Conclusions and Relevance: This thesis calls for larger meta-analyses integrating within- and between-subject designs to refine chronic primary pain and chronic secondary musculoskeletal pain classifications. Improved methodological consistency and reporting are crucial for understanding shared and distinct neural substrates, advancing diagnostic frameworks and translational potential in neuroscience.