偏头痛患者治疗前后的功能连接和疼痛诱导脑激活的纵向变化：依瑞奈玛单抗的功能 MRI 研究。

BACKGROUND: Migraine involves central and peripheral nervous system mechanisms. Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody with little central nervous system penetrance, is effective for migraine prevention. The objective of this study was to determine if response to erenumab is associated with alterations in brain functional connectivity and pain-induced brain activations. METHODS: Adults with 6-25 migraine days per month during a 4-week headache diary run-in phase underwent pre-treatment brain functional MRI (fMRI) that included resting-state functional connectivity and BOLD measurements in response to moderately painful heat stimulation to the forearm. This was followed by two treatments with 140 mg erenumab, at baseline and 4 weeks later. Post-treatment fMRI was performed 2 weeks and 8 weeks following the first erenumab treatment. A longitudinal Sandwich estimator analysis was used to identify pre- to post-treatment changes in resting-state functional connectivity and brain activations in response to thermal pain. fMRI findings were compared between erenumab treatment-responders vs. erenumab non-responders. RESULTS: Pre- and post-treatment longitudinal imaging data were available from 32 participants. Average age was 40.3 (+/- 13) years and 29 were female. Pre-treatment average migraine day frequency was 13.8 (+/- 4.7) / 28 days and average headache day frequency was 15.8 (+/- 4.4) / 28 days. Eighteen of 32 (56%) were erenumab responders. Compared to erenumab non-responders, erenumab responders had post-treatment differences in 1) network functional connectivity amongst pain-processing regions, including higher global efficiency, clustering coefficient, node degree, regional efficiency, and modularity, 2) region-to-region functional connectivity between several regions including temporal pole, supramarginal gyrus, and hypothalamus, and 3) pain-induced activations in the middle cingulate, posterior cingulate, and periaqueductal gray matter. CONCLUSIONS: Reductions in migraine day frequency accompanying erenumab treatment are associated with changes in resting state functional connectivity and central processing of extracranial painful stimuli that differ from erenumab non-responders. TRIAL REGISTRATION: clinicaltrials.gov (NCT03773562).

背景：偏头痛涉及中枢和外周神经系统机制。依瑞奈单抗是一种抗降钙素基因相关肽（CGRP）受体的单克隆抗体，对中枢神经系统的穿透力较小，对偏头痛的预防有效。本研究的目的是确定依瑞奈单抗的反应是否与大脑功能连接的改变和疼痛引起的大脑激活有关。

方法：在为期 4 周的头痛日记启动阶段，每月有 6-25 天偏头痛的成年人接受了预处理脑功能磁共振成像（fMRI），包括静息状态功能连接和对前臂中度疼痛热刺激的 BOLD 测量。然后，在基线和 4 周后进行两次 140mg 依瑞奈单抗治疗。第一次依瑞奈单抗治疗后 2 周和 8 周进行了治疗后的 fMRI。使用纵向 Sandwich 估计器分析来确定静息状态功能连接和热痛反应的大脑激活的预处理到后处理变化。将依瑞奈单抗治疗反应者与依瑞奈单抗无反应者的 fMRI 结果进行了比较。

结果：32 名参与者中有 32 名提供了预治疗和后治疗的纵向成像数据。平均年龄为 40.3（+/-13）岁，29 名女性。预处理时平均偏头痛日频率为 13.8（+/-4.7）/28 天，平均头痛日频率为 15.8（+/-4.4）/28 天。32 名患者中有 18 名（56%）是依瑞奈单抗的反应者。与依瑞奈单抗无反应者相比，依瑞奈单抗反应者在后处理中存在以下差异：1）疼痛处理区域之间的网络功能连接，包括更高的全局效率、聚类系数、节点度、区域效率和模块性，2）包括颞极、缘上回和下丘脑在内的几个区域之间的区域间功能连接，以及 3）中脑、后扣带回和导水管周围灰质的疼痛诱导激活。

结论：依瑞奈单抗治疗伴随偏头痛日频率的降低与静息状态功能连接和对外周疼痛刺激的中枢处理的改变有关，与依瑞奈单抗无反应者不同。

试验注册：clinicaltrials.gov（NCT03773562）。