The Pain Is in the Brain

The biggest headache for headache researchers has always been: Where does the pain come from? The answer might seem obvious, but it's nothing less than a revolutionary discovery

By Curtis Rist, William Duke|Wednesday, March 01, 2000

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.


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A cluster-headache sufferer felt as if his eye was being forced out of its orbit’

In people with chronic headaches, the brain appears to be sensitive to such environmental factors as light and stress, monthly hormonal cycles among women, or quirky things such as eating a raw onion or playing basketball. “We’re going from research where we thought the brain wasn’t involved, where now we are sure it is,” says Goadsby. This new view has already led to the development of specific drugs that stop headaches in mid-attack and prevent them altogether.


A SHORT HISTORY OF HEADACHE MEDICATIONS

Through the ages, suffering caused by chronic headaches has been matched only by the damage wreaked by treatments. In the ancient Arab world, embedding a clove of garlic under the skin of the temple caused the formation of pus, which was thought to alleviate a headache. Other dubious cures have included injections of arsenic, potassium cyanide, and even the radioactive element thorium.

Even today, derivatives of headache medications developed in the late 19th century persist. Ergotamines, a class of drugs that constrict blood vessels, come from a toxic fungus that attacks rye. In the Middle Ages, those who consumed large amounts of ergot-infested rye flour were afflicted with St. Anthony’s Fire, a condition characterized by advanced gangrene. Now ergot is used effectively, and relatively safely, in drugs such as methysergide, to prevent migraine pain. With these ergot-derived drugs, gangrene is no longer a threat. Physicians are far more concerned about nausea and a decrease of blood flow to the heart.

“The real tragedy is that so many people don’t know there’s help available,” says neurologist David Silberstein of Philadelphia’s Thomas Jefferson University Hospital. Instead, many desperate headache sufferers abuse addictive medications, such as barbiturates and opiates. Even those who stoke themselves with over-the-counter pain relievers may not be safe. Aspirin, acetaminophen, and other analgesics can also cause rebound headaches. Severe overuse, says Silberstein, can lead to renal failure and death.


For those with headaches, this comes as welcome news: Some 6 million people in this country alone suffer from what are called chronic tension-type headaches, similar to the ones everyone has at least occasionally—except that for these people they strike almost daily. Migraines, which tend to affect one side of the head, afflict between 23 million and 26 million. Unfortunately, the number of migraine diagnoses has been steadily rising: A recent study in the journal Neurology showed that the incidence of migraine diagnosis increased by 56 percent in women and 34 percent in men during 1989 (compared to figures for 1979-1981). And approximately a million people suffer from cluster headaches, an excruciating phenomenon that hits mostly men. According to the first recorded description of such a headache, dating from the 1700s, the sufferer felt “as if his eye was slowly being forced out of its orbit with so much pain that he nearly went mad.”


‘We’re beginning to think about headaches today the way we think about cancer’


Perhaps the first clue that the brain itself might be responsible for headaches was discovered in the 1940s. Researchers in Italy found evidence that the urine of those who had just experienced a migraine contained breakdown products of the neurotransmitter serotonin. The finding hinted that serotonin played an important role in migraine headaches, but the process remained a mystery. The idea gained momentum when researchers found that injecting anyone with a serotonin-depleting chemical caused a migraine, even if the person had never suffered one before. “The quest became to develop drugs that would mimic the effects of serotonin,” says neurologist David Dodick of the Mayo Clinic in Scottsdale, Arizona. This approach paid off spectacularly, beginning in the early 1990s with the release of a class of designer drugs called triptans, sold under such brand names as Imitrex and Zomig. The drugs bind to a specific sub-type of serotonin receptor found in the meningeal blood vessels. This causes the vessels to constrict and shuts down the neuropeptide-releasing nerve endings, thus interrupting the pain-causing feedback loop. Although hardly foolproof, triptans can stop a migraine in mid-process.

With new research—such as Cutrer’s theory about the nature of aura—more possibilities for tailoring effective drugs have emerged. “We’re at the beginning of a new era in terms of treatments,” says Jes Olesen, chairman of the neurology department at the University of Copenhagen, and editor of a book called The Headaches. The most promising research focuses on understanding the role of another compound—nitric oxide. Neurologists studying headaches have long known an unusual fact: When a heart patient places a small pill of nitroglycerin under his tongue to ward off angina attacks, the nitroglycerin changes to nitric oxide in the body and immediately dilates blood vessels in the heart. Yet in some of these patients, it also triggers a migraine attack within six hours. “It’s a very common side effect,” says Olesen. “And it seems very, very likely that nitric oxide in the brain has some role in triggering migraines—not just in heart patients but in all patients.” By unlocking the precise action of nitric oxide, which appears to be linked to the breakdown of serotonin in the brain, Olesen and others believe they may be able to develop even more potent antiheadache medications than the triptans. “This is the hottest area of drug research right now,” he says.


ONE WOMAN'S SAGA

Since the birth of her second daughter in 1986, Catherine Healy, 44, a freelance photographer from Bar Harbor, Maine, has suffered from chronic, nauseating headaches. “They’re my constant daily companions,” she says. “My disease can’t be defined with a ct scan, an mri, or an X ray.” Still, the headaches have changed her life. For the first few years, Healy’s headaches struck three to five times a month, but over time, their frequency and intensity have increased. “I felt as though I couldn’t walk 50 feet,” she says. “I would try to eat and the utensils would fall out of my hand.” Doctors suspected lupus, then multiple sclerosis, and “one or two,” she said, “were even talking about psychiatrists.”

The final diagnosis—made after she visited neurologist Michael Cutrer at Massachusetts General Hospital—was migraine with visual auras. The pain is horrendous, Healy says, but the auras can be worse. “There were times I could be talking to my husband, and I realized I couldn’t see his face,” she says. Her hallucinations have included “vicious snakes flying through the air; it was terrifying.” Healy once passed her dog on the stairs and stopped in bewilderment. “She could have been painted by Picasso during his cubist era,” she says. “The image was that distorted.”

Headaches have effectively ended Healy’s career. To limit their frequency, she has cut out suspected triggers. “As a result, I live a very sterile life,” she says. She abstains from all pickled and smoked foods, chocolate, bananas, apples, oranges, and shellfish. Even vitamins can be problematic. When a class of drugs called triptans became available in the early 1990s, Healy used them, but over time their effectiveness dimmed. She now primarily takes an ergotamine called methysergide (see “A Short History of Headache Medications,” page 61), but prolonged use can result in heart and lung damage.

“I choose which devil I sleep with—migraines or tissue damage,” says Healy. To balance the two, Cutrer prescribes methysergide for six months, followed by two months when Healy takes mainly painkillers—and invariably has a migraine every day. “Migraines can be 100 things to 100 different people,” says Healy, who has started a support group for fellow sufferers. “I need to do what I can to help others.”


And increasingly, neurologists suspect that genetic abnormalities may be at the root of some, if not all, headaches. In the 1990s, researchers traced the cause of a particularly rare type of headache called familial hemiplegic migraine—which is passed in families as a dominant trait—to a single gene on chromosome 19. This chromosome codes for a component of a calcium channel in neural membranes. By modulating the intake of ions into the neuron cell, the channel controls when the neuron will fire. The mutation leaves the nerves in the arteries around the brain in a constant state of hyperactivity, causing them to register pain. “It is not yet known whether there’s actually an increase or decrease in the flow of calcium ions through the channel,” Olesen says.

Although familial hemiplegic migraine is rare, the discovery of a chromosomal origin has changed the approach to all headache research, and neurologists have begun looking at a number of chromosomal sites in headache sufferers to find other irregularities. “We’re beginning to think about headaches today the way we think about cancer,” says Goadsby. “We believe they have a specific genetic basis that is somehow triggered over the course of a person’s life.” Recently, Goadsby proved that the posterior of the hypothalamus—the part of the brain involved in circadian rhythm—is measurably larger in people who suffer from cluster headaches.

Finding a genetic cause won’t stop the pain, however. And while neurologists toil in their world of double-blind experiments, practitioners and patients search for more immediate remedies. The triptans, more effective than previous classes of drugs, are far from sure-fixes. “They may work 80 percent of the time, but in some patients they lose effectiveness for reasons we’re not sure of,” says Olesen. Patients are then forced to explore alternatives, trying everything from acupuncture (which may affect serotonin levels) to the bacterial concoction known as botulinum toxin type A, or Botox. “This is the same stuff that people have injected into their foreheads to temporarily paralyze muscles and reduce wrinkles,” says Alex Mauskop of the New York Headache Center in Manhattan. Plastic surgeons noticed that Botox injections had a surprising side effect:

They seemed to keep migraines at bay. In 1999, a study showed that the toxin can reduce migraines by as much as 50 percent among patients predisposed to them. “No one can explain the mechanism, but I’ve seen it work hundreds of times,” says Mauskop.

In the case of cluster headaches, causes and remedies are even more obscure. Cluster headaches tend to come in cycles, hitting the sufferer once or twice a day. They are more likely to strike smokers, can be triggered by alcohol, and can often be soothed by breathing pure oxygen. “One patient gets relief only by driving 60 miles an hour with his head out the window,” says Mauskop. Doctors call clusters “suicide headaches,” since some patients have been known to opt for the ultimate remedy.

Yet simply developing more effective treatments doesn’t mean patients will be able to afford them. Triptans, for example, are expensive. A single oral dose to end one migraine costs between $10 and $15; one injection costs $35. A typical sufferer might need more than six a month. But for cluster headaches, the costs increase exponentially. A New Jersey lawyer named Wayne Weiner, for instance, is one of only a handful of people who suffer from chronic cluster headaches, a rare malady in which the headaches strike as often as 10 to 12 times a day, requiring 10 to 12 doses of a triptan. One insurance plan Weiner looked at covered only six injections per month. Now self-insured through his family’s law firm, Weiner picks up his tab; last year it ran to $40,000. “Physically and financially, this is a wearying disease,” he says. “It all just wears you down.”

Aiming to reduce costs, managed- care companies try to redirect patients toward other drugs, either cheaper triptans manufactured by different drug companies, or to other classes of drugs altogether. In some cases, this can lead to disaster. “I have seen insurance companies recommending that patients switch to addictive narcotics,” says neurologist David Silberstein of Philadelphia’s Thomas Jefferson University Hospital.

Doctors are beginning to fight back. They have formed the National Headache Consortium—with Silberstein as cochairman—to establish standards for care and treatment of headache patients. “Right now, anyone who wants to can open a headache clinic—and I mean anyone, whether a medical doctor, a chiropractor, or a spiritual adviser,” says Silberstein. With tougher standards, that could change. But if stricter prescription protocols are instituted, doctors and hospitals will have the clout to force insurance companies to cover the costs of the treatments they recommend, according to Silberstein. “No insurance company is going to argue when the world’s entire medical establishment is united against them,” he says.

Until then, patients are left to sort out their own treatments, battle insurers, and wait for the next phase of research for better drugs. “I’ll probably cool it on the basketball,” says Patrick Rennich. “But I have some comfort: I know now that the problem’s not with me—it’s just with my brain.”

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