Theory Behind Migraine Emerges

by Jim Schnabel

March, 2008

In the way lightning flashes on the horizon before a storm, so can the “aura” of migraine warn of approaching pain. Often it begins with a scintillating spot in the left or the right visual field, then broadens into an arc of flickering light and jagged lines, leaving a temporary dimness or even blindness in its wake. Then come the pounding waves of pain.

The connection between the pain and the aura has long been a mystery. But an emerging theory of migraines tightly links the two.

Cortical Spreading Depression

One of proponents of the new theory is Richard Kraig, a migraine researcher at the University of Chicago. Kraig argues that a seizurelike phenomenon in the brain known as cortical spreading depression (CSD) is the underlying cause of both migraine auras and migraine pain.

CSD, explains Kraig, “is a spreading wave of electrical silence in which cortical neurons go quiet. There’s no firing at all.”

First described in 1944 in the brain of a rabbit, CSD only recently has begun to yield up its secrets. In a 2005 study, Kraig and his colleagues found that CSD can be triggered when the normal flow of electric currents within and around brain cells is somehow reversed. If a sufficiently large group of cells is affected all at once, the reversal may spread outward through the cortex—“like a ripple on a pond,” says Kraig—with a flurry of abnormal brain-cell activity at the wavefront and temporarily exhausted, electrically “depolarized” cells in its wake.

CSD frequently begins in the visual or somatosensory cortex, which explains why the aura is commonly experienced visually or as a tactile tingling. “The scintillating lights you often see in the leading edge are likely to be from that flurry of neural activity” at the CSD wavefront,” Kraig says. 

Direct study of CSD in humans has been rare. “It has been difficult to find somebody who can reliably evoke their migraine aura,” explains Michael Moskowitz, a migraine researcher at Harvard. But in 2001 Moskowitz and his colleagues reported finding one such subject, an engineer who was able to trigger his auras by playing 80 minutes of basketball beforehand. Moskowitz’s team used functional MRI to track cortical spreading depression in this subject and two others, definitively showing the link between CSD and auras.

Only 20 to 30 percent of migraine sufferers report auras. But Moskowitz suspects that CSD can cause migraines without the sufferer noticing an aura or connecting it to the headache.

     Moskowitz cites 1994 research in which researchers at UCLA studied a young woman who developed a migraine-like headache while she lay in a positron emission tomography (PET) scanner for an unrelated project.

“She didn’t really describe any aura or other aura-like symptoms,” Moskowitz relates. “But when they looked at the blood flow measurements they saw a phenomenon that resembled cortical spreading depression.”

How Can CSD Cause Pain?

The sensory disturbances of the aura are not painful; the pain typically comes minutes to hours later. But Moskowitz and Kraig reported in 1993 that when CSD was evoked in the brain of a rat, it caused the activation of the pain-transmitting “trigeminal” nerve system in the meninges, the sensitive membranes that cover the brain.

Kraig and Moskowitz believe that when neurons and other cells experience the electrical surge of the passing CSD wavefront, they abnormally spurt nerve-irritating chemicals into the brain. “Neurotransmitters and potassium and hydrogen ions and all sorts of bad actors get released into the extracellular space,” says Moskowitz, “and we think they accumulate at the surface where the meningeal tissues lie and the trigeminal nerve endings travel.”

Moskowitz points out another link between CSD and migraine pain, reported in a study conducted by his lab in 2006: “We found out that if you chronically administer to experimental animals the most commonly used migraine prophylactic drugs, you can significantly raise the threshold for evoking cortical spreading depression.”

At the same time, he notes, “when mutated genes that have been identified in certain families with migraine are ‘knocked in’ to a mouse model, the mouse is pretty normal except it has a much higher susceptibility for evoking cortical spreading depression.”

The idea that CSD is the ultimate cause of migraine is still controversial. Some researchers argue that migraine pain can be caused instead by abnormal functioning of pain-processing neurons in the brain stem.

Others suggest a blend of both concepts. “I think that CSD is one part of it, and I think that brain stem modulation is another,” says Stephen Silberstein, a professor of neurology at Jefferson University in Philadelphia and an author of several textbooks on migraines. “But I do believe with Dr. Moskowitz that cortical spreading depression is a big part of the picture. And I think his work is very elegant, clearly showing the link between the aura of migraine and the headache.”

What Triggers Cortical Spreading Depression?

Studies have suggested that genetic factors—still largely unknown—are at least as important as environmental factors in creating a susceptibility to migraines. Kraig also notes that “migraineurs” as a group are more likely to have other neuropsychiatric conditions, from depression to panic disorder.

“I think they are inherently more juiced up,” he says—their brain cells are more vulnerable to migraine triggers such as stress, hormonal swings, caffeine withdrawal, and metabolic changes caused by lack of food or sleep.

Researchers also are studying whether small blood clots might somehow trigger CSDs and migraines by narrowing or blocking tiny vessels in the brain. Migraineurs with heart valve defects that can potentially admit such clots into brain vessels have sometimes noticed their migraines lessen in frequency or disappear altogether after valve surgery.

A potent clot-prevention drug, clopidogrel (brand name Plavix), is now being tested in a clinical trial that will enroll nearly 300 migraine sufferers over the next three years. The trial is being run by John Chambers, a cardiologist at Guy’s Hospital in London who recently observed that the drug successfully cleared migraines in some of his patients—even those with no diagnosis of heart valve defects.

“These are just anecdotal findings,” he says. “But, for example, I had one patient who was getting almost daily migraines for 20 years, so his life was made a misery. And the day after starting clopidogrel, he had no further migraines.”

Moskowitz agrees that such links should be investigated, although he notes that migraines conceivably can cause clots to form, rather than the other way around. In CSD, he says, the deactivation of brain cells slows the flow of blood to those cells, and so people with stickier-than-usual blood platelets might “have a higher probability of clotting in an area of low blood flow during an attack.”

“But the truth is that no one really knows yet,” adds Moskowitz. “We still have a lot of work to do.”