Terumitsu Makoto, Takado Yuhei, Fukuda Ken-Ichi, Kato Eisuke, Tanaka Sei, Tha Khin Khin
Division of Dental Anesthesiology, School of Dentistry, Department of Human Biology and Pathophysiology, Health Sciences University of Hokkaido, Hokkaido, Japan.
Division of Special Needs Dentistry and Orofacial Pain, Department of Oral Health and Clinical Science, Tokyo Dental College, Tokyo, Japan.
J Pain Res. 2025 Jun 9;18:2849-2863. doi: 10.2147/JPR.S507893. eCollection 2025.
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.
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.
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.
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.
中枢敏化（CS）是难治性慢性口面部疼痛（COFP）的病因之一。据报道，慢性疼痛会改变大脑的静息态功能连接（FC）。突显网络（SN）与参与慢性疼痛的脑区重叠。此外，兴奋性和抑制性神经活动均可改变功能连接。本研究调查了SN的功能连接与其他神经回路、前扣带回皮质（ACC）中的神经代谢物以及CS量表（CSI）评分之间的相关性。
参与者包括21例COFP患者和21名年龄及性别匹配的健康志愿者。我们对CSI评分、静息态功能磁共振成像以及ACC的质子磁共振波谱进行了联合研究。
与对照组相比，患者中脑边缘系统内伏隔核与SN区域之间的功能连接显著更强。在患者中，结果显示CSI评分与四对区域的功能连接呈正相关：ACC-右侧壳核和ACC-右侧苍白球、左侧岛叶-右侧壳核以及右侧缘上回-右侧外侧前额叶皮质。关于ACC中的神经代谢物与ACC和其他皮质区域之间的功能连接的相关性，结果显示双侧ACC-前岛叶功能连接与谷氨酸、谷氨酰胺和谷胱甘肽呈负相关。此外，N-甲基-D-天冬氨酸受体激动剂天冬氨酸与默认模式网络中ACC-右侧顶叶皮质的功能连接呈负相关。关于额顶叶网络中双侧ACC-后顶叶皮质的功能连接，右侧的功能连接与兴奋性神经元活动相关的谷胱甘肽呈正相关，而左侧的功能连接与抑制性神经活动相关的γ-氨基丁酸/总肌酸呈负相关。
SN内部以及SN与中脑边缘系统和其他网络之间的连接可能参与了COFP中的中枢敏化。ACC中的神经代谢物可能调节与ACC相关的功能连接。
