Background and objectives :
Cluster headache and migraine have circadian characteristics at multiple levels (cellular, systems, and behavioral). A deep understanding of their circadian characteristics informs their pathophysiologies.
Methods:
A librarian created search criteria in Medline Ovid, Embase, PsycINFO, Web of Science, and Cochrane Library. Two clinicians independently conducted the remainder of the systematic review/meta-analysis using PRISMA guidelines. Apart from the systematic review/meta-analysis, we performed a genetic analysis for genes with a circadian expression pattern (clock-controlled genes or CCGs) by cross-referencing genome-wide association studies (GWAS) of headache, a study of CCG non-human primates in a variety of tissues, and recent reviews of brain areas relevant in headache disorders.
Together, this allowed us to catalog circadian characteristics 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 level cellular (central circadian genes and CCG).
Results :
For the systematic review and meta-analysis, 1513 studies were found and 72 met the inclusion criteria; for 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 in 16 studies, with a clear circadian peak between 21:00 and 03:00 and circadian peaks in spring and autumn. Chronotype was highly variable between studies. At the systems level, lower levels of melatonin and higher levels of cortisol were reported. At the cellular level, cluster headache was associated with the core circadian genes CLOCK and REV-ERBα, and five of the nine cluster headache susceptibility genes were CCG.
Migraine : Behaviorally, meta-analyses showed a circadian pattern of attacks in 50.1% (2698/5385) of participants in eight studies, with a clear circadian trough between 11:00 p.m. and 7:00 a.m. and a broad circadian peak between April and October. Chronotype was highly variable between studies. At a 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 the core circadian genes CK1δ and RORα, and 110 of the 168 migraine susceptibility genes were CCG.
Discussion : Cluster headache and migraine are highly circadian at multiple levels, reinforcing the importance of the hypothalamus. This review provides a pathophysiological basis for circadian rhythm-focused research into these disorders.
Comments
Do your headaches occur at the same time of day?
Meta-analysis : Cluster headache and migraine have strong links to the circadian system
Both cluster headache and migraine have strong links to the circadian system, the internal clock that regulates the body’s processes, according to a meta-analysis published in the issue of Neurology ®, the medical journal of the American Academy of Neurology. .
The meta-analysis included all available studies on cluster headache and migraine that included circadian features. This included information on the timing of headaches during the day and during the year, as well as studies on whether genes associated with the circadian clock are more common in people with these headaches.
The researchers also looked at studies on cluster headache and migraine and hormones related to the circadian system, including cortisol and melatonin .
"The data suggest that these two headache disorders are highly circadian at multiple levels, especially cluster headache," said study author Mark Joseph Burish, MD, PhD, of the U.S. Health Sciences Center. University of Texas in Houston, Texas, and member of the American Academy of Neurology. “This reinforces the importance of the hypothalamus, the area of the brain that houses the master biological clock, and its role in cluster headache and migraine. "It also raises the question of the genetics of triggers, such as changes in sleep, which are known migraine triggers and are signals of the body’s circadian rhythm."
For cluster headache, the meta-analysis found a circadian pattern of headache attacks in 71% of people. The attacks peaked in the late night into early morning hours. During the year, people had more attacks in spring and fall. At the genetic level, cluster headache was associated with two major circadian genes, and five of the nine genes that increase the likelihood of having cluster headache are genes with a circadian expression pattern.
People with cluster headaches also had higher levels of cortisol and lower levels of melatonin than people without cluster headaches.
For migraine, the meta-analysis showed a circadian pattern of attacks in 50% of people. While the peak of seizures during the day was broad, from late morning to evening, there was a circadian trough during the night when few seizures occurred. Migraine was also associated with two core circadian genes, and 110 of the 168 genes associated with migraine were genes with a circadian expression pattern.
People with migraines had lower levels of melatonin in their urine than people without migraines. Additionally, melatonin levels were lower during a migraine attack.
“These results raise the potential for the use of circadian rhythm-based treatments for headache disorders,” Burish said. "This could include both circadian rhythm-based treatments, such as taking medications at certain times of day, and treatments that cause circadian changes, which certain medications can do."
One limitation of the study was that the researchers did not have information about factors that might influence the circadian cycle, such as medications, other disorders such as bipolar disorder, or circadian rhythm problems such as night shift work.
The study was supported by the Will Erwin Headache Research Foundation.
