To anyone but a neurologist, Patrick Rennich's migraines would seem a curse. With perverse regularity, they strike after he plays sports like soccer or basketball--anything that requires sprinting up and down a field or court. Not long before he's hit with nauseating pain on one side of his head, Rennich experiences something called a visual aura--a neurological disturbance that starts with a slowly expanding blind spot near the center of his left visual field. Soon after, Rennich sees static, like on a television screen. The aura looks "like I'm moving through boiling water." The pattern is so predictable that Rennich, a 28-year-old electrical engineer from Acton, Massachusetts, can say, "If you want me to get a migraine with aura at two in the afternoon, I can give you a migraine with aura at two." That's exactly what neurologist Michael Cutrer wanted. Based at both Boston's Massachusetts General Hospital and Brigham and Women's Hospital, Cutrer had been looking for someone like Rennich for years. The neurologist hoped that a magnetic resonance imaging (MRI) scan of such a patient's brain during the aura would provide clues to what happens inside his skull. Before 1998, no one had done this, and for good reason: Almost no migraine sufferer can summon an aura on command, and few are willing to lie in a claustrophobia-inducing MRI tube to wait for one to occur. Cutrer had come across a few prospects, but none had worked out. One patient promised that raw onion would do the trick, "but we had him lying in there crunching away--and nothing," says Cutrer. Rennich seemed worth a try, so Cutrer asked him and his wife, Jean, to come to the ymca next door to his research lab. The couple played games of free throws, the loser running sprints back and forth across the basketball court, with one modification: "If I lost, I ran," says Rennich. "And if my wife lost, I also ran."


After an hour, Rennich began to notice distortions in his vision and hustled next door to the lab, where he lay prone inside the opaque white tube of the mri machine. Once in, he focused his eyes on an alternating checkerboard pattern projected onto a screen inside the tube. Meanwhile, the mri monitored the activity in Rennich’s cerebral cortex, specifically the sections that control vision. Later, the results would be processed and color coded—red indicating areas of high neural activity, hues of orange and yellow showing lower levels, and white corresponding to the smallest amount. According to the mri results, 38 minutes after Rennich entered the tube, an area of darkness—of no color at all—appeared on the image of his brain, indicating that the neurons in a small region of the cerebral cortex were no longer transmitting visual information. The region grew slowly, “like ripples from a pebble tossed into a pond,” says Cutrer. Rennich’s aura had begun.

A decade ago, Rennich’s doctor would never have examined his brain to find the source of his migraine. In fact, the idea that the brain itself could be causing the problem has been difficult for headache researchers to accept. “Even as little as 15 years ago it would have been almost heresy to suggest it,” says Peter Goadsby, a neurologist at University College London. For one thing, the brain itself feels no sensation, even if jabbed with a probe through an incision in the skull. “Since the brain is insensate, the pain of a headache lies in the periphery, so that is where many assumed the problem was,” says Goadsby. But growing evidence implicates the brain as not just an accessory to pain but as the prime suspect.


The idea that the brain is the problem has been difficult for researchers to accept.
Observing the brain’s electrochemical activity during a migraine aura is just one of the new routes to understanding the mysteries of headaches. Neurologists have long understood the physical evidence. Blood vessels in the outer covering of the brain, the meninges, become overdilated and hypersensitive to the blood coursing through them. But finding the actual reason for headache pain has frustrated neurologists—and patients—for years. With developments like Cutrer’s mri, the mystery becomes more vexing. The path to the pain is clearly marked, but why that path exists at all remains unknown.

The activity of neurons, though complex, is usually predictable. When the neuron is stimulated, sodium ions rush into the cell and potassium ions rush out, leaving the neuron with a positive electrochemical charge. This forces the cell to fire and thus transmit information to other neurons. In a migraine sufferer, however, neurons cease to behave rationally. Cutrer believes that during Rennich’s aura, his visual neurons began firing slightly out of sync with one another; they seemed to be discharging without passing information on to each other, and not in response to a visual stimulus. On the mri this almost synchronous firing pattern resembled a wave rolling toward a shoreline. The phenomenon, observed before only in animal experiments, is called cortical spreading depression. The dark area on Rennich’s mri, Cutrer believes, is a photographic record of this process and reveals the progression of Rennich’s expanding blind spot. The scintillations of light that Rennich also saw in his aura, Cutrer says, were most likely a result of sodium ions flooding and overexciting the visual neurons.
If research increasingly points the finger of blame for chronic headaches at genetics, how could environmental factors—from chocolate and nuts to sunlight and stress—be triggers? For decades, scientists assumed certain food additives contributed to headaches. Tyramine, for example, a chemical present in red wines and aged cheeses, is thought to dilate blood vessels. “But people have given tyramine in extract to headache sufferers, and they don’t get headaches,” says neurologist Jes Olesen, of the University of Copenhagen.
Although coffee, with its caffeine content, was an early and effective headache remedy because it can act as a blood-vessel constrictor, many physicians now view the drug in any form—coffee, tea, or cola—as a potent headache trigger. “Caffeine’s properties make it similar to opiates,” says Alex Mauskop of the New York Headache Center. “When you take it regularly, your body develops a tolerance to it, as well as a physical dependence.”

Studies have shown that people habituated to as few as two-and-a-half cups of coffee a day develop headaches if they go cold turkey, a phenomenon known as rebound headaches. “But for someone prone to headaches, the effects can be even more extreme,” says Mauskop. Not surprisingly, his first step in treating new patients is to wean them off caffeine. “Otherwise, none of the other treatments can ever be effective.”

After about 30 minutes, Rennich’s aura subsided, and he felt relatively normal for nearly an hour. Then his migraine began. The visual neurons, which had fired abnormally during the cortical spreading depression, had released large amounts of potassium ions. Over time, the potassium spread from the visual cortex to the pain-controlling neurons in the meninges. These neurons, located in the walls of the meningeal blood vessels, began to fire and released neuropeptides, telling the brain to register pain and the blood vessels to dilate. The dilated vessels then prompted the pain neurons to fire again. Essentially, a pain-causing feedback loop was set in motion, creating the agony of a migraine. For migraine patients with with no auras, the cause of the pain is less apparent. Some neurologists suspect that the cortical spreading depression may begin in a section of the brain not involved in sensory processing, so the initial effects aren’t noticeable.

BIGGER BRAINS, MORE HEADACHES?

The origins of the major types of headaches remain a conundrum: Headaches seem to result from the abnormal brain functions of a completely normal brain structure. But, recently, a team led by neurologist Peter Goadsby of University College London produced evidence of structural differences within the brains of a group of people suffering from cluster headaches. “The current view of the neurobiology of cluster headaches requires complete revision,” he says.

Beginning in 1997, Goadsby’s team began using functional imaging to compare the brains of cluster-headache sufferers with those of normal patients. The results, published in 1998 in The Lancet and in 1999 in Nature Medicine, show that cluster patients have an abnormally enlarged area within the hypothalamus, the part of the brain that regulates circadian rhythm—which could explain why these headaches tend to strike cyclically. Goadsby doesn’t know yet if the brain cells involved are bigger than those in normal patients or if there are simply more of them; that would require the dissection of a brain. “We have a few older patients with cluster headaches we’re looking after,” he says, “but it’s clear right now that the central nervous system is where the action is.”

At some time, most of us have had a headache—a signal that we are under stress or overtired or that we drank too much alcohol the night before. But some 40 million Americans suffer debilitating headaches that have no discernible cause. For years, researchers were convinced that the problem was either within the meningeal blood vessels, or, more often, the patients themselves. “If someone gets kicked in the knee, they feel that stimulus as pain; that’s rational,” says Goadsby. “But what we find in people with chronic headaches is the pain without the physical stimulus; that’s irrational.” When physicians ran out of possible explanations, they often referred patients to psychiatrists. “Since doctors didn’t know what the problem was, they would sometimes try to blame the patients for imagining things,” says Cutrer, who has suffered from migraines since age 14. “Now we know that the brain itself is the new arena for headache research.”




The Mayo Clinic Web site has up-to-date headache information: www.mayohealth. org/index.htm.