Altered Brain Functional Connectivity and Neurometabolite Correlations in Orofacial Chronic Pain with Central Sensitization.

Purpose: Central sensitization (CS) is one of the causes of refractory chronic orofacial pain (COFP). Chronic pain reportedly alters resting-state functional connectivity (FC) in the brain. The salience network (SN) overlaps with brain regions involved in chronic pain. Moreover, excitatory and inhibitory neural activities can alter FC. This study investigated the correlations between FC of the SN and other neural circuits, neurometabolites in anterior cingulate cortex (ACC), and CS Inventory (CSI) scores.

Patients and methods: Participants were 21 COFP patients and 21 healthy sex- and age-matched volunteers. We conducted a combined study of CSI scores, resting-state functional magnetic resonance imaging, and proton magnetic resonance spectroscopy of ACC.

Results: FC between the nucleus accumbens within the mesolimbic system and SN regions was significantly stronger in patients compared with that in controls. In patients, the results revealed positive correlations between CSI scores and FC in four pairs of regions: ACC-right putamen and ACC-right globus pallidus, left insula-right putamen, and right anterior supramarginal gyrus-right lateral prefrontal cortex. Regarding correlations between neurometabolites in ACC and FC between ACC and other cortical regions, the results revealed that bilateral ACC-anterior insula FC was negatively correlated with glutamate, glutamine, and glutathione. Additionally, aspartate, an N-methyl-D-aspartic acid receptor agonist, was negatively correlated with FC of ACC-right parietal cortex in the default mode network. Regarding FC of bilateral ACC-posterior parietal cortex in the frontoparietal network, FC on the right side was positively correlated with glutathione associated with excitatory neuronal activity, whereas that on the left side was negatively correlated with gamma-aminobutyric acid / total creatine associated with inhibitory neural activity.

Conclusion: Connectivity within the SN, and between the SN and the mesolimbic system and other networks, may be involved in CS in COFP. Neurometabolites in the ACC may modulate FC linked to the ACC.