Forevery man with a migraine, three women are struck by the severe headaches thatoften come with nausea, sensitivity to light and sound, and aura. That means astaggering 18 to 25 percent of women suffer from migraines, making it one ofthe most common disabling conditions faced by women around the globe.
This3-to-1 ratio raises the obvious question: Why? The reason, suggest researchersat UCLA, is that women may have a faster trigger than men for activating thewaves of brain activity thought to underlie migraines. If the theory is correct,this triggering mechanism may be a new target for migraine treatment.
Reporting in the Annals of Neurology, currently online,Dr. Andrew Charles, director of the Headache Research and Treatment Program inthe UCLA Department of Neurology; Dr. Kevin C. Brennan, a clinical and researchfellow in Charles' lab; and colleagues used a mouse model to discover a bigdifference between males and females with regard to a phenomenon calledcortical spreading depression (CSD), which is thought to be a chief culprit incausing migraines. In a separate study, to be published in the September issueof the Journal of Headache and Pain, the researchers report preliminary successin preventing migraines using memantine, a drug that blocks CSD waves.
Migraines were once thought to be caused primarily byconstriction and dilation of blood vessels, Charles said. Now, thanks tovarious neuroimaging techniques, it has been shown that migraines may begin asa problem of brain excitability. Patients with migraines show corticalspreading depression, which is characterized by dramatic waves of activity thatspread across the surface of the brain. CSD may in turn trigger not only thepain of migraine but the visual symptoms, nausea, dizziness and difficultyconcentrating so common in migraine patients.
Brennan,working in Charles' lab, used imaging techniques to visualize the initiationand spread of CSD in anesthetized male and female mice. Female mice showed asignificantly lower threshold for CSD when compared with males. In other words,it was much easier to evoke the waves of brain activity believed to underliemigraine in females than it was in males.
"Theresults were very clear," said Charles. "The strength of the stimulus requiredto trigger CSD in males was up to two or three times higher than that requiredto trigger the response in females."
A variety of factors may reduce the CSD threshold in bothsexes, making them more susceptible to migraines — these include genes,hormones and environmental triggers such as stress, diet, changes in sleeppatterns and a host of others. While it is known that migraines in femalesfluctuate with the menstrual cycle and are more frequent during the menstrualperiod, the study results appear to be independent of a specific phase of the cycle,according to Charles.
"Wedidn't monitor the estrous cycle in the female mice, so it's likely we sampledfrom different estrous phases in different animals," Charles said. "Yet westill found a consistent difference in the CSD threshold between males andfemales. Our results suggest that the female brain has an intrinsicexcitability that predisposes them to migraine that may not be simply linked toa specific phase of the menstrual cycle."
Theseresults are exciting, Charles said, because they may represent a model forunderstanding the mechanisms underlying the increased prevalence of migraine inwomen. In addition, they add to growing evidence that CSD is a key target forthe development of new migraine treatments.
In a separate study, the researchers identifiedwhat they hope will eventually be a new treatment option for migraine. Theyfound that a medication called memantine (brand name Namenda), which iscurrently approved for the treatment of Alzheimer's disease, inhibits CSD andappears to be a highly effective treatment for some patients with frequentmigraine. In the retrospective study, 54 patients who were treated withmemantine for at least two months were asked to fill out a survey describingtheir experience with the medication. The majority, 36, reported a substantialreduction in estimated headache frequency. These were all patients who hadpreviously tried other treatments without success.
While Charles cautioned that these results needto be confirmed with a larger study, the encouraging results are an example ofhow new insights into the basic mechanisms of migraine are leading to novelapproaches for therapy for the hundreds of millions of individuals worldwidewho suffer from this disabling condition.
The full text of the journal article can befound at www3.interscience.wiley.com/cgi-bin/fulltext/114230925/HTMLSTART.
Fundingfor the CSD study was provided by the National Institutes of Health. Other authorsincluded Marcela Romero-Reyes, Hector E. Lopez Valdes and Arthur P. Arnold forthe CSD study, and Romero-Reyes and Charles Flippen for the memantine study.
TheUCLA Department of Neurology encompasses more than a dozen research, clinicaland teaching programs. These programs cover brain-mapping and neuroimaging,movement disorders, Alzheimer's disease, multiple sclerosis, neurogenetics,nerve and muscle disorders, epilepsy, neuro-oncology, neurotology,neuropsychology, headaches and migraines, neurorehabilitation, andneurovascular disorders. The department ranked No. 1 in 2005 among its peersnationwide in National Institutes of Health funding. For more information, see http://neurology.medsch.ucla.edu.