As per a systematic review, meta-analysis, and genetic analysis issued in “Neurology”, both cluster headache and migraine are affected by circadian rhythms, the internal clock that aids in the regulation of body processes. In Cochrane Library, Web of Science, PsycINFO, Embase, and Medline Ovid, search criteria were set by a librarian. The remaining steps of the systematic review/meta-analysis were carried out separately by two doctors utilizing PRISMA standards.

By cross-referencing genome-wide association studies of headache, a non-human primate study of clock-controlled genes or CCGs in a range of tissues, and recent reviews of brain regions relevant to headache disorders, a genetic analysis was carried out for genes with a circadian pattern of expression (CCGs). This assisted in cataloguing the circadian features at the behavioral level (chronotype, time of year, time of day, circadian timing), cellular level (core circadian genes, CCGs), and systems level (melatonin and corticosteroid levels, relevant brain areas where CCGs are active).

In total, 1513 papers were detected for the systematic review and meta-analysis, of which 72 satisfied the requirements for inclusion. For the genetic analysis, 16 genome-wide association studies, 1 non-human primate research, and 16 imaging reviews were noted. In 70.5% (3490/4953) of people, meta-analyses revealed a circadian pattern of attacks across sixteen studies behaviorally, with  circannual peaks in autumn and spring and clear circadian peak between 21:00-03:00. Across the studies, chronotype varied greatly. Cortisol levels were greater and melatonin levels were observed to be decreased at the systems level.

Notably, 5 of the 9 cluster headache susceptibility genes were CCGs, and cluster headache was correlated at the cellular level with the key circadian genes REV-ERBα and CLOCK. In 50.1% (2698/5385) of people across 8 studies, the study illustrated a circadian pattern of attacks behaviorally with a broad circannual peak between April and October and a clear circadian trough between 23:00-07:00.

Across the studies, chronotypes varied greatly. Urinary melatonin levels were reduced in migraine patients at the systems level and considerably reduced during an attack. Notably, 110 of the 168 genes related to migraine risk were CCGs, and at the cellular level, migraine was linked to the core circadian genes RORα and CK1δ. At multiple levels, cluster headache and migraine are highly circadian, thus reinforcing the significance of the hypothalamus. This study offered a pathophysiological foundation for circadian-targeted investigations into these disorders.