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Migraine Really Is a Brain Disorder
Medscape Medical News
July 02, 2013

BOSTON, Massachusetts ? Positron emission tomography of patients experiencing the premonitory phase of migraine, prior to the headache setting in, shows activation in several areas of the brain, indicating that migraine is a brain disorder and not a response to pain stimuli.

The results are significant in terms of understanding the neurobiology of migraine and could have future implications for drug treatment, said study author Peter James Goadsby, MD, PhD, professor, neurology, and director, Headache Program, University of California at San Francisco, and president, International Headache Society.

"This is an important step in solidifying our ideas that migraine is fundamentally a disorder of the brain, not a disorder of structures outside the brain," said Dr. Goadsby. "We were able to address the question that people have wondered about for many, many years, that is, what is the degree to which pain is driving the initial symptomatology ? and we got clear answers to that."

Dr. Goadsby and his colleagues won the Harold G. Wolff Lecture Award for this research during the 2013 International Headache Congress (IHC).

Subtle Symptoms
Premonitory symptoms of migraine can include yawning, neck discomfort, nausea, thirst, photophobia, phonophobia, craving sweet or savory foods, and mood swings. It's not clear what proportion of patients with migraine experience these early symptoms, which are often quite subtle, Dr. Goadsby said. Estimates vary widely, from about a third to 80%.

In the past, this symptomatology has not received much medical attention, said Dr. Goadsby. Physicians might not ask about premonitory symptoms because this information doesn't influence their diagnosis.

In years gone by, people used to think of migraine as a disorder of the blood vessels. In more recent times, the view has been that migraine is a reaction to pain stimuli. "I think our new research suggests that this is just not true," said Dr. Goadsby.

Using nitroglycerin, a well-documented trigger for migraine, researchers induced premonitory symptoms in patients who have migraine without aura. Instead of waiting for headache onset to begin scanning the patients' brains, as has been done in the past, researchers did the scanning during the premonitory phase. Eight patients had at least 1 premonitory scan without pain.

"Before this, all the imaging of migraine has been during the headache and the question has risen as to the degree to which what's happening in the brain is just a response to pain, or is something more fundamental, a part of the process of the migraine," said Dr. Goadsby. "By studying the premonitory symptoms, you get rid of that question because these patients don't have any pain."

Neuronal Activation
Researchers used H2 15O (radioactive water) to measure regional cerebral blood flow as a surrogate marker for neuronal activation.

They found that compared with baseline scans, there was activation in several key areas, including the hypothalamus, an area involved in low-level regulation of sleep, appetite, mood, and fluids. "It seems likely that the hypothalamus is pivotal in the onset of migraine," commented Dr. Goadsby.

Other structures that were activated included the midbrain, around the periaqueductal grey, which has been shown to be active during a migraine attack, and an area in the pons that past migraine imaging has also shown to be active.

"This shows you the areas of the brain that are involved at the earliest in the attack," said Dr. Goadsby.

Scans of the 8 patients plus another 2 patients experiencing photophobia symptoms, again before they felt any pain, showed activation in the visual cortex. "This suggests that the photophobia experience can be dissected away from the pain experience," said Dr. Goadsby.

Similarly, scans of patients experiencing nausea had activation of an area of the medulla that includes nausea and vomiting centers. "So it's entirely plausible that those areas are activated by the migraine process and that's why nausea and vomiting are so common in migraine; it's not simply a response to the pain," said Dr. Goadsby.

"It was thought that nausea and pain were highly linked, but that doesn't seem to necessarily be the case," he added.

Dr. Goadsby hopes the research will "shift thinking" to consider migraine as a brain disorder, but he stressed that this should not lessen the importance of the pain that migraine patients suffer.

From a big picture treatment perspective, this says to me that we probably won't get away with developing drugs that don't get into the brain to have substantial effects on migraine prevention. Dr. Peter James Goadsby

The research could have ramifications for treatment in that the most obvious target would be the brain, but developing targeted therapies that don't have adverse effects could be challenging.

"From a big picture treatment perspective, this says to me that we probably won't get away with developing drugs that don't get into the brain to have substantial effects on migraine prevention," said Dr. Goadsby.

He noted that to date, the best proven migraine prevention therapies are anticonvulsant drugs, tricyclic antidepressants, and the β-blocker propranolol, all of which affect the brain. This, he said, is consistent with the theory that migraine is a disorder of the brain.

Relevant to Clinicians
Asked to comment on the study, Elizabeth E. Loder, MD, president, American Headache Society, associate professor, neurology, Harvard Medical School, and head, Division of Headache and Pain, Brigham and Women's Hospital, Boston, said it's nice to have a biological explanation for what patients experience and that the research might eventually lead to treatment.

"I was particularly heartened by the fact that this year's winner [of the Wolff Lecture Award] was able to say so many things that were relevant to clinicians," said Dr. Loder. "We all see patients who describe knowing through various signs and symptoms that they are likely to get a migraine attack and it's good to hear what the biological underpinnings for that recognition of an impending attack might be."

Dr. Loder said she and her colleagues wonder how this new information might be exploited to prevent attacks, not only with drugs but also behaviorally.

She doesn't think clinicians ignore the premonitory phase of migraine so much as lack the evidence to support making recommendations about what to do in these circumstances. "Most patients?already know what to do; for example, if they're hungry and feel an attack coming that eating may help or to putting sunglasses on in a bright sunny place."
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