From the Departments of Neurology (B.B.), Biochemistry and Molecular Biology (S.Y.K., C.H., C.T., Z.C., S.-H.Y.), and Neurosurgery (Y.Y., M.J.B.), UTHealth Houston; Department of Physiology and Systems Bioscience (N.K., K.Y.), Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Japan; and Texas Medical Center Library (E.S.), The University of Texas Health Science Center at Houston.
Neurology. 2023 May 30;100(22):e2224-e2236. doi: 10.1212/WNL.0000000000207240. Epub 2023 Mar 29.
Cluster headache and migraine have circadian features at multiple levels (cellular, systems, and behavioral). A thorough understanding of their circadian features informs their pathophysiologies.
A librarian created search criteria in MEDLINE Ovid, Embase, PsycINFO, Web of Science, and Cochrane Library. Two physicians independently performed the remainder of the systematic review/meta-analysis using Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Separate from the systematic review/meta-analysis, we performed a genetic analysis for genes with a circadian pattern of expression (clock-controlled genes or CCGs) by cross-referencing genome-wide association studies (GWASs) of headache, a nonhuman primate study of CCGs in a variety of tissues, and recent reviews of brain areas relevant in headache disorders. Altogether, this allowed us to catalog circadian features at the behavioral level (circadian timing, time of day, time of year, and chronotype), systems level (relevant brain areas where CCGs are active, melatonin and corticosteroid levels), and cellular level (core circadian genes and CCGs).
For the systematic review and meta-analysis, 1,513 studies were found, and 72 met the inclusion criteria; for the genetic analysis, we found 16 GWASs, 1 nonhuman primate study, and 16 imaging reviews. For cluster headache behavior, meta-analyses showed a circadian pattern of attacks in 70.5% (3,490/4,953) of participants across 16 studies, with a clear circadian peak between 21:00 and 03:00 and circannual peaks in spring and autumn. Chronotype was highly variable across studies. At the systems level, lower melatonin and higher cortisol levels were reported in cluster headache participants. At the cellular level, cluster headache was associated with core circadian genes and , and 5 of the 9 cluster headache susceptibility genes were CCGs. For migraine behavior, meta-analyses showed a circadian pattern of attacks in 50.1% (2,698/5,385) of participants across 8 studies, with a clear circadian trough between 23:00 and 07:00 and a broad circannual peak between April and October. Chronotype was highly variable across studies. At the systems level, urinary melatonin levels were lower in participants with migraine and even lower during an attack. At the cellular level, migraine was associated with core circadian genes and , and 110 of the 168 migraine susceptibility genes were CCGs.
Cluster headache and migraine are highly circadian at multiple levels, reinforcing the importance of the hypothalamus. This review provides a pathophysiologic foundation for circadian-targeted research into these disorders.
The study was registered with PROSPERO (registration number CRD42021234238).
丛集性头痛和偏头痛在多个层次（细胞、系统和行为）上具有昼夜节律特征。深入了解其昼夜节律特征有助于了解其病理生理学。
一名图书管理员在 MEDLINE Ovid、Embase、PsycINFO、Web of Science 和 Cochrane 图书馆中创建了检索标准。两名医生使用系统评价和荟萃分析的首选报告项目指南，独立进行了其余的系统评价/荟萃分析。除了系统评价/荟萃分析，我们还通过交叉引用头痛的全基因组关联研究（GWAS）、各种组织中昼夜节律基因（生物钟控制基因或 CCGs）的非人类灵长类动物研究以及最近对与头痛障碍相关的大脑区域的综述，对具有昼夜节律表达模式的基因（生物钟基因或 CCGs）进行了遗传分析。总的来说，这使我们能够对行为水平（昼夜节律时间、一天中的时间、一年中的时间和时间类型）、系统水平（生物钟基因或 CCGs 活跃的相关大脑区域、褪黑素和皮质醇水平）和细胞水平（核心生物钟基因和 CCGs）的昼夜节律特征进行分类。
在系统评价和荟萃分析中，发现了 1513 项研究，其中 72 项符合纳入标准；在遗传分析中，我们发现了 16 项 GWAS、1 项非人类灵长类动物研究和 16 项影像学综述。对于丛集性头痛行为，荟萃分析显示，在 16 项研究中的 70.5%（3490/4953）参与者中存在发作的昼夜节律模式，在 21:00 至 03:00 之间有明显的昼夜节律高峰，在春季和秋季有节律高峰。时型在不同研究中差异很大。在系统水平上，丛集性头痛患者的褪黑素水平较低，皮质醇水平较高。在细胞水平上，丛集性头痛与核心生物钟基因和有关，9 个丛集性头痛易感性基因中有 5 个是 CCGs。对于偏头痛行为，荟萃分析显示，在 8 项研究中的 50.1%（2698/5385）参与者中存在发作的昼夜节律模式，在 23:00 至 07:00 之间有明显的昼夜节律低谷，在 4 月至 10 月之间有广泛的节律高峰。时型在不同研究中差异很大。在系统水平上，偏头痛患者的尿褪黑素水平较低，在发作时甚至更低。在细胞水平上，偏头痛与核心生物钟基因和有关，168 个偏头痛易感性基因中有 110 个是 CCGs。
丛集性头痛和偏头痛在多个层次上具有高度的昼夜节律性，这强化了下丘脑的重要性。本综述为这些疾病的昼夜节律靶向研究提供了病理生理学基础。
该研究在 PROSPERO（注册号 CRD42021234238）中进行了注册。
