Brain-immune correlates of quality of life in adolescents with chronic musculoskeletal pain.

Chronic musculoskeletal (MSK) pain affects a substantial proportion of youth, with 5 % reporting high-impact symptoms. Chronic pain in youth leads to multifaceted negative consequences that profoundly affect adolescents' quality of life (QoL) and future outcomes. Recent studies suggest that neuro-immune interactions significantly contribute to chronic pain. However, how systemic immune dysregulation influences brain function, and how these brain changes affect well-being and functioning in chronic pain remains unclear. This study aims to examine the convergence between immune function and brain processing during a multisensory task to identify novel mechanistic pathways that may explain reduced QoL in adolescents with chronic MSK pain (N = 129). We used a multisensory fMRI task designed to mimic the unpleasant sensory experiences that adolescents and adults with chronic pain often encounter in daily life. Higher task-evoked activation in the rostral anterior cingulate and dorsomedial prefrontal cortices (rACC-dmPFC), which support threat appraisal and response regulation, was associated with lower physical QoL (pFWE = 0.005). Lower physical QoL was also associated with augmented functional connectivity between the rACC-dmPFC region and sensory processing areas in the somatosensory (pFWE = 0.002) and visual (pFWE = 0.049) cortices. Higher systemic pro-inflammatory activity in immature neutrophils was also associated with lower physical QoL (p = 0.01). Furthermore, task-evoked brain activation in the rACC-dmPFC partially mediated the relationship between neutrophil-mediated inflammatory responses and reduced physical QoL. These findings suggest a potential neuro-immune pathway through which systemic immune alterations may affect brain function and QoL in adolescents with chronic MSK pain.