Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States.
Clinical Research Division, Korean Institute of Oriental Medicine, Daejeon, South Korea.
Pain. 2020 Jul;161(7):1555-1564. doi: 10.1097/j.pain.0000000000001815.
Noninvasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton magnetic resonance spectroscopy (H-MRS) metabolites have been linked with glial activity (ie, choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting functional magnetic resonance imaging connectivity and H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (aIns) (P = 0.03), with greater choline levels linked with worse pain interference (r = 0.41, P = 0.01). In addition, reduced resting functional connectivity between aIns and putamen was associated with both pain interference (whole brain analysis, pcorrected < 0.01) and elevated aIns choline (r = -0.37, P = 0.03). In fact, aIns/putamen connectivity statistically mediated the link between aIns choline and pain interference (P < 0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. To further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory H-MRS metabolites are linked with ex vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r = 0.49, P = 0.03). Choline, a putative neuroinflammatory H-MRS-assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.
非侵入性的神经炎症过程测量方法可能会极大地帮助许多疾病的诊断和治疗开发，包括慢性疼痛。几种质子磁共振波谱（H-MRS）代谢物与神经胶质活性（即胆碱和肌醇）有关，并发现慢性疼痛患者的代谢物发生改变，但它们在神经炎症级联反应中的作用尚不清楚。我们的多模态研究评估了 43 名纤维肌痛患者和 16 名健康对照者的岛叶皮层静息功能磁共振连接和 H-MRS 代谢物浓度。患者的前岛叶（aIns）胆碱（但不是肌醇）升高（P = 0.03），胆碱水平越高，疼痛干扰越严重（r = 0.41，P = 0.01）。此外，aIns 与壳核之间的静息功能连接减少与疼痛干扰有关（全脑分析，p 校正 < 0.01），并且 aIns 胆碱升高（r = -0.37，P = 0.03）。事实上，aIns/putamen 连接在统计学上介导了 aIns 胆碱与疼痛干扰之间的联系（P < 0.01），突出了神经炎症如何影响临床疼痛功能障碍的途径。为了进一步阐明观察到的影响的分子基础，我们研究了在神经炎症的非人类灵长类动物模型中，假定的神经炎症 H-MRS 代谢物与体外组织炎症标志物之间的关系。结果表明，皮质胆碱水平与胶质纤维酸性蛋白（GFAP）相关，GFAP 是星形胶质细胞增生的已知标志物（Spearman r = 0.49，P = 0.03）。胆碱是纤维肌痛患者中升高的神经炎症 H-MRS 评估的代谢物，与疼痛干扰有关，可能与这些患者的星形胶质细胞增生有关。
