Migraines are a battle of the sexes that women might prefer not winning. Each year, roughly three times more women than men—up to 18% of all women—suffer from the debilitating headaches, as tallied by epidemiological surveys in Europe and the United States. A new brain imaging study may explain the divide: The brains of women with migraines appear to be built differently than those of their male counterparts.

To conduct the study, researchers headed by David Borsook, a neurologist and neurobiologist of Boston Children’s Hospital and Harvard Medical School, recruited 44 men and women, half of whom were migraine sufferers. The women who had migraines rated them as being as intense as the men did, but they tended to find them more unpleasant. Borsook says the distinction is analogous to the loudness of fingernails scratching on a chalkboard versus the torment of hearing the sound.

The team then scanned the brains of the volunteers. The researchers gathered two kinds of data sets, one that captured brain shapes and features, and one that measured brain activity. Female migraine sufferers showed slightly thicker gray matter in two regions: one, the posterior insula, is well-known in pain processing; the other, the precuneus, has been recently linked to migraines but is more widely known as a fundamental brain hub that may house a person's consciousness or sense of self. The other volunteers, including the male migraine sufferers, did not show this thickening. All of the scans were done when people did not have a migraine.

To figure out what those structural changes meant, lead author Nasim Maleki, a medical physicist at Boston Children's Hospital and Harvard Medical School, returned to the MRI scans of only those men and women with episodic migraines. The team compared brain activity while the volunteers experienced pain—in this case, three 15-second bursts of heat to the hand, spaced 30 seconds apart, generated through a small metal cube, akin to touching a too-hot cup of coffee. In women with migraines, "these thicker areas talk to each other and work together to respond to pain" in a pattern not seen in the men, Maleki says.

When Maleki checked for sex differences in well-defined pain networks, most of the structures that responded stronger in women were part of the emotional network. "In men, the pain comes in, and the brain says 'ouch,' " Maleki says. "In women, the brain says 'OUCHHHHH!' " Overall, the results suggest that "it's not just one area that underlies the sex differences in migraines, but a network of areas, a system that leads to the problem or progression,” she says.

In only men, those with migraines had a stronger reaction to the heat pain in a specific area—the nucleus accumbens—that is part of the reward circuitry and is extensively studied in the addiction research, Maleki says. "Interestingly, as much as pain syndromes are more prevalent in women and disproportionate relative to men, in addiction it is the opposite,” she says. “Men are more likely to develop addictions, and the prevalence is higher in men. So, is the reward circuitry somehow involved in migraine pathophysiology in men? Are there overlaps between pain pathways and reward pathways? The answer is that we don't know. But I think these results just help us ask more targeted questions in understanding how migraine works." The study is published this month in the journal Brain.

The findings reveal a clearly different brain pattern that may explain why so many more women than men have migraines, says neurologist Peter Goadsby of the University of California, San Francisco, who was not involved in the study. "Migraines have traditionally not been appreciated as a significant brain disorder," adds Andrew Charles, a neurologist at the University of California, Los Angeles. "Studies like this take migraines out of the realm of the subjective and show fundamental brain changes responsible for these differences. It's quite validating for people with migraines who understand something quite significant is happening in their heads."

Most interesting to Andrew Ahn, a neuroscientist at the University of Florida College of Medicine in Gainesville, are the findings that emphasize the emotional processing of pain. "Pain is an experience, a product of processing by the brain of a stimulus plus the way your brain interprets that stimulus," he says. "It's exciting that the pain field has come to recognize changes that occur in brains of people with chronic pain."

The greater activation of emotional pain processing regions in women "could correlate with the greater sense of unpleasantness that is experienced by women with migraine and the higher prevalence of depression and anxiety in women with migraine," speculates Todd Schwedt, a neurologist at the Mayo Clinic in Phoenix.

For Schwedt and others, the study provokes many new questions. Are the brain differences a cause or effect of migraines? Are they permanent or transient? And are they a response to pain in general or migraines in particular?

The study also highlights therapeutic issues for both men and women. Even with the best medical management, medication reportedly works in about only half of all people and then in about only half of all migraine attacks. More attention may need to be paid to gender in research, Maleki says. Most of the animal studies have involved male rodents, she says, and women are disproportionately represented in clinical studies by an 8:1 margin.

Still, Goadsby cautions that there are no immediate clinical implications. "It's fair to say that these are subtle changes in a research study and not ones that we would expect to see in ordinary imaging," he says. "There is no reason to go out and have your brain imaged."

ScienceNOW, the daily online news service of the journal Science

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