OJAI, CA—Understanding and integrating the multiple factors that determine periodic susceptibility to migraine, such as sleep and circadian rhythms, may allow clinicians to better predict attacks, said Robert Shapiro, MD, PhD, at the Fifth Annual Winter Conference of the Headache Cooperative of the Pacific.

According to Dr. Shapiro, Professor of Neurology at the University of Vermont College of Medicine in Burlington, headache disorders do not occur at random times. “There’s this complicated dance between sleep disorders and biorhythmic issues and headache disorders,” he said, noting that sleep is known as a terminator of migraine and that the transition between sleep and awakening may be a time when migraine is more likely to begin.

Dr. Shapiro cited research proposing that the REM stage of sleep, which occurs later during sleep, could provoke migraine in some patients. “There may be similarities between what’s going on in REM and what’s going on in migraine,” he said. Both migraine and REM can be suppressed by tricyclics or MAO inhibitors and are less frequent later in life.

Ambient Light
Research also suggests that migraine may result from interactions with ambient light internal cycles. Cluster headaches are an example of this phenomenon, said Dr. Shapiro, as they tend to occur in six- to eight-week periods around midsummer or midwinter, often at the same hour each day.

To explore ambient light’s influence on migraine, researchers studied populations in the light and dark extremes of arctic Norway, as well as those living in more temperate climates, such as Italy. The investigators found that each population displayed differences in seasonal migraine peaks and in the time of day of migraine occurrence—some peaked on awakening, some peaked midday, and some peaked in late afternoon.

These distinctions could be due to both social cues and ambient light cues, according to the research. Determining the dominant trigger for migraines in populations is “complicated,” said Dr. Shapiro.

Finding a Gene
To better understand the causes of migraine, Dr. Shapiro and his colleagues studied a family with both migraine and advanced sleep phase syndrome, which causes patients to operate on a shortened internal clock. “We’ve been able to identify a gene responsible for advanced sleep phase syndrome that is actually also responsible for migraine,” he said.

The gene, casein kinase 1δ (CK1δ), operates differently than the current channel-based model for genes with migraine. A member of the ser/thr protein kinase family, casein kinase is a post-translational modifier of cell function. The gene phosphorylates a number of proteins, including the circadian clock protein hPER, neurotransmitter receptors, and ions channels such as connexin 43, which plays a role in astrocyte signaling.

After identifying a T44A mutation involved in both advanced sleep phase syndrome and migraine, the researchers developed a mouse with the mutation and then isolated mutated mice and wild-type mice in different scenarios of lightness and darkness.

The T44A CK1δ mice displayed several traits consistent with migraine. The mutated mice showed a hyperexcitable cortex with respect to cortical spreading depression, the physiologic substrate for migraine aura. Also, similar to humans with migraine, the T44A mice had an exaggerated allodynia to nitroglycerin. In addition, once the mice were phase advanced, “animals that have the mutation didn’t easily phase back,” said Dr. Shapiro.

Dr. Shapiro speculated that casein kinase’s function as a “housekeeping enzyme” that interacts with many proteins could explain the comorbidity of migraine and sleep disorders. “Maybe the T44A mutation in casein kinase impairs phosphorylation of multiple substrates. A change in one or more substrates might cause migraine while others might cause advanced sleep phase syndrome or other co-morbid traits.”

Other Migraine Triggers
Investigators have explored other mechanisms that may contribute to migraine as well. According to Dr. Shapiro, diurnal rhythm is part of the complex triggering process and is determined by both circadian rhythm and a sleep homeostatic factor. Adenosine, which accumulates with wakefulness, is a good candidate for a sleep homeostatic factor and is a migraine trigger with receptors that are antagonized by caffeine, said Dr. Shapiro. He added that withdrawing from chronic caffeine exposure leads to cortical hyperexcitability and headaches.

Furthermore, migraine tends to occur mostly in women and at the time of menses onset. “Hormonal factors are an important driver,” said Dr. Shapiro, and onset for a typical migraine is “early in life but not necessarily pediatric.”

Although researchers have begun to understand the many factors that cause migraine, there is still more work to do. “If we understood all those factors, we might be able to integrate them and predict when migraine is going to occur,” said Dr. Shapiro. “And if that were the case, we could give better advice to patients about what things to avoid, and, perhaps, we may be able to target therapy at certain times,” he concluded.

—Lauren LeBano

Migraine Attacks Affected by Sleep, Circadian Rhythms, and Other Factors