Relationship between brain metabolites and chronic pain mechanisms in knee osteoarthritis pre- and post-total knee replacement

Impaired descending modulation and heightened pain sensitivity are thought to contribute to pain in knee osteoarthritis (KOA) and its persistence after total knee arthroplasty (TKA). These mechanisms can be assessed using quantitative sensory testing (QST), including pressure pain thresholds (PPT), conditioned pain modulation (CPM), and mechanical temporal summation (MTS). Magnetic resonance spectroscopy (MRS) enables non-invasive quantification of neurometabolites, including gamma-aminobutyric acid (GABA), glutamate + glutamine (Glx), myoinositol (Myo), and choline (tCho), which are suggested to modulate pain perception. This study investigated region-specific neurometabolite levels and their associations with pain mechanisms in individuals with KOA before and after TKA. Single-voxel MRS quantified neurometabolites in the anterior cingulate cortex, anterior insula, posterior insula, and somatosensory cortex in 20 female KOA patients and 19 pain-free controls. We found that anterior cingulate GABA was significantly lower in KOA patients prior to TKA compared to controls (p = 0.012). Prior to TKA, significant metabolite-QST interactions included: anterior cingulate Myo was associated with improved descending modulation (p = 0.0017; interaction p < 0.001), whereas controls showed the opposite in the anterior insula (p = 0.014; interaction p = 0.012). Following TKA, increases in somatosensory Myo (p = 0.016) and tCho (p = 0.031) were associated with worsened pain sensitivity (lower pain thresholds), whereas increases in anterior cingulate Myo (p = 0.018) and anterior insula tCho (p = 0.027) were associated with improved descending modulation and pain sensitization relative to pre-TKA, respectively. These results provide a foundation for future studies investigating neurochemical contributions to pain mechanisms and their potential relevance for pain phenotyping.