Circadian Features of Cluster Headache and Migraine: A Systematic Review, Meta-analysis, and Genetic Analysis

Background and objectives:Cluster headache and migraine have circadian features at multiple levels (cellular, systems, and behavioral). A thorough understanding of their circadian features informs their pathophysiologies.Methods: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 PRISMA 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 (GWAS) of headache, a non-human 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).Results:For the systematic review and meta-analysis, 1513 studies were found and 72 met inclusion criteria; for the genetic analysis we found 16 GWAS, 1 non-human primate study, and 16 imaging reviews.Cluster headache:Behaviorally, meta-analyses showed a circadian pattern of attacks in 70.5% (3490/4953) of participants across 16 studies, with a clear circadian peak between 21:00-03:00 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. At the cellular level, cluster headache was associated with core circadian genesCLOCKandREV-ERBα, and five of the nine cluster headache susceptibility genes were CCGs.Migraine:Behaviorally, meta-analyses showed a circadian pattern of attacks in 50.1% (2698/5385) of participants across eight studies, with a clear circadian trough between 23:00-07:00 and a broad circannual peak between April-October. Chronotype was highly variable across studies. At the systems level, urinary melatonin levels were lower in migraine participants and even lower during an attack. At the cellular level, migraine was associated with core circadian genesCK1δandRORα, and 110 of the 168 migraine susceptibility genes were CCGs.Discussion:Cluster headache and migraine are highly circadian at multiple levels, reinforcing the importance of the hypothalamus. This review provides a pathophysiological foundation for circadian-targeted research into these disorders.Trial Registration Information:The study was registered with PROSPERO (registration number CRD42021234238).