IF YOU have ever absent-mindedly rubbed your eyes or nose after chopping up chilli peppers, you’ll have some idea of the suffering of one group of scientists in the name of medical research. A team at the Institute of Neurology in London have been injecting chilli juice into each others’ foreheads. Lab technician Paul Hammond, who got roped into the experiment, says it felt like acid was burning into his skin. “It was one of the most excruciating pains you can imagine,” he recalls.
The researchers weren’t sadomasochists, as far as we know. Their actions were part of a much larger research effort that has been shedding light on migraine. For although in the past few decades we have learned a great deal about the condition, we still have no idea of its root cause. And while we have drugs that help some patients, some of the time, understanding the underlying defect is the best way to boost our chances of discovering a sure-fire cure.
Now a leading headache researcher at the institute, Peter Goadsby, has a radical theory. Perhaps, he says, the pain is an illusion. That sounds crazy to anyone who’s ever had a migraine. But Goadsby is suggesting that what feels like agony is really the brain responding abnormally to non-painful stimuli. He thinks that in most migraine cases, patients’ brains allow overlarge signals to pass through their sensory systems, turning the normal background activity of pain-sensing neurons into torture. “The concept takes the disorder away from being a pain problem to being a sensory disturbance,” he says.
Many researchers disagree with this explanation, and there are other competing theories. But a few scientists working independently of Goadsby have come up with intriguing findings that seem to support his views. And even some critics agree that the brains of migraineurs appear to work a bit differently to those of non-sufferers – and not just during an attack. It seems that migraineurs may constantly experience and react to the world in an unusual way.
So what exactly does a migraine feel like? Anyone who’s ever had one knows full well that this is no ordinary headache. It is one of the most awful experiences you can have. My mother says hers can be worse than childbirth. Mine feel like a nail driven into my skull, eye or brow. But the pain has a more disturbing and emotional quality than any broken bone or wound. The pain is organic – it moves and grows, like an alter ego, yanking at my stomach, filling every thought. It absorbs every last drop of consciousness.
And migraine is far more than head pain. Sufferers may also get a stiff neck, sore eyes, throbbing sinuses, violent sickness or stomach ache. They may find lights become painfully bright, noises excruciatingly loud, or smells nauseating. You can throw in lethargy, inability to concentrate, yawning, depression, dizziness, hallucinations, blind spots, pins and needles, even one-sided temporary paralysis in rare cases.
One in six of us will experience this condition at some point in our lives. About one in 20 has to write off more than one day a month to the condition, and a wretched few have one every day.
The field of migraine research is still adjusting to its most recent revolution in thinking. It is well accepted that the brain itself contains no pain-sensing neurons. Instead it is the meninges, the membranes covering the surface of the brain (which are inflamed in meningitis) that seem to be where the pain is felt. For most of the past 50 years, most doctors were convinced migraines stemmed from a problem with the blood vessels supplying the meninges – the so-called vascular theory. According to this, the strange visual disturbances or “auras” seen by some sufferers before an attack were due to the blood vessels contracting. Later there would be a rebound dilation of the vessels, causing the pain. The vascular theory was even the basis of a new class of anti-migraine drugs called triptans that contract blood vessels and help many patients.
But over the past decade or so, several research findings have shifted the blame from blood vessels to neurons – in particular the fine branches of the trigeminal nerve, which innervate blood vessels around the meninges, among other things. One reason was that brain scans during migraines have shown that dilation fails to coincide exactly with the pain. Also, triptans were found to calm hyperactive nerves as well as constricting blood vessels. And the merciless chilli experiments carried out a few years ago by Goadsby and another group showed that blood vessel dilation is a consequence of head pain, not the cause. “It’s a disorder of the nervous system,” he says. “The blood vessels are doing what they’re told to.”
So the key question to answer has become what causes the neurological problem in the first place.
An important step came in 1995, when Cornelius Weiller, then based at the University of Essen in Germany, and his colleagues PET-scanned the brains of nine people during migraines. They found that several areas were abnormally active, including parts of the brainstem, through which pass all neurons from the spinal cord to the brain, including pain signals.
After the migraine had begun, the patients were given triptans, which saw off their headaches. The activity levels returned to normal in most brain areas, but not in the brainstem, suggesting that there the abnormality was intrinsic to the migraine process, not a result of the pain.
Another clue about the cause of migraines has come from genetic research. In 1996 a mutation in a calcium channel gene was found to be responsible in people with a rare form of the disease called familial hemiplegic migraine. Calcium channels are proteins that span the cell membranes of neurons. They allow an influx of calcium ions that helps to regulate neuronal impulses. And this February a mutation in a channel that pumps sodium and potassium ions in and out of neurons was also found to cause the condition.
The commoner forms of migraine have not yet been linked to any mutations, but they do run in families, with complex inheritance patterns that suggest several genes may be jointly to blame.
Goadsby believes that a big hint about the cause of migraine comes from the many other strange symptoms that people experience besides head pain. During an attack, patients may feel that lights are too bright, sounds too loud or smells unpleasantly strong. Goadsby thinks that this mis-sensing of the world might be not just a weird side effect, but a fundamental part of the condition. “Migraine is primarily a disorder of sensory processing,” he says, “not a disorder of pain at all. Migraine is like the world shouting at you.”
His theory is that while the signals in the trigeminal nerve are no stronger than normal, the reaction to them in the brainstem is huge – effectively generating pain from almost nothing. The peculiar “premonitory” symptoms that migraineurs may develop in the hours before an attack – including yawning, concentration problems, stiff neck and mood changes – could signal that the brainstem is beginning to misbehave.
So where in the brainstem could everything be going wrong? The trigeminal nerve enters at a region called the pons (see Diagram), from where some neurons travel up past an area called the periaqueductal grey (PAG) and into the rest of the brain. There are neurons that return from the PAG to the pons, to damp down trigeminal signalling in a negative feedback loop. The German researchers suspected it was the PAG showing up in their brain scan study, as it was already known to be involved in pain signalling – but the scans’ resolution wasn’t good enough to tell.
Goadsby and his colleagues investigated by injecting a chemical called agatoxin, which blocks the guilty calcium channel, into the PAGs of anaesthetised rats. In response to a small stimulus to the meninges they saw higher firing rates in the trigeminal neurons compared with control animals. If the rats hadn’t been unconscious they would have been having the mother of all migraines. Blocking the calcium channels somehow reduced the activity of the negative feedback neurons, allowing greater activity in the trigeminal neurons, the researchers proposed in their paper (The Journal of Neuroscience, vol 22, p RC(1-6)).
But Goadsby no longer thinks the PAG is the only source of trouble. That’s because this year his group performed PET scans of eight patients in the middle of a migraine attack, using higher-resolution cameras than those of the German researchers. The new study, presented in April at the American Academy of Neurology meeting in Honolulu, showed the pons lighting up, not the PAG. Goadsby thinks it was in fact the pons that was active in Weiller’s earlier scans.
Goadsby says the pons “fits even better” with his theory than the PAG. Animal studies have shown the pons is an “attention centre”, controlling how much notice the brain pays to sensory information. The region also helps control our sleeping and waking patterns, which go awry in migraine, and altered sleep patterns are one common trigger of attacks.
Stephen Silberstein, a prominent migraine researcher at the Thomas Jefferson University Hospital in Philadelphia, calls Goadsby’s latest findings “very exciting”. Not only might Goadsby have explained at least one way to cause a migraine, but the rat studies suggest new ways to test the effectiveness of drugs, something which has been especially hard to judge in the early stages of drug testing, says Silberstein.
If Goadsby is right, you’d expect migraineurs to experience other types of pain differently, not just that in the head. This does indeed seem to be the case. In a series of experiments over the past few years, Marina de Tommaso from the University of Bari in Italy found that during an attack, there is a general increase in pain sensitivity all over the body.
This year she published a study (Pain, vol 101, p 25) showing that even between attacks, migraineurs experience pain differently. She used a laser to heat a patch of their skin to produce mild pain, while giving them distracting tasks such as word games. Such diversions normally cause the pain threshold to rise, but in migraineurs it didn’t change. “Possibly there is some problem with their attention to a stimulus,” she says – a finding that would fit with Goadsby’s faulty pons idea.
Migraineurs also seem to differ in the way they pay attention to non-painful sensations. If people are exposed to repeated sounds or images, the neuron responses in the cortex of the brain usually decline over time. Jean Schoenen from the University of Liège in Belgium showed in 1998 that in migraineurs, such cortical activity fails to decline. In some, the electrical activity even increased.
And Frances Abbott of McGill University in Toronto found that migraineurs seem to suffer more aches and pains and have lower thresholds to cold pain, even between attacks (New Scientist, 16 November 2002, p 22). She also found that her migraine group were more likely to be very mildly depressed. But Abbott is unconvinced that her findings back Goadsby’s theory. She thinks that migraine may be a subtype of depression, with the headache and other symptoms being side effects. After all, chronic pain conditions and depression have long been associated, she says. And rather than the pain being generated in the head, she suggests that what makes the body more sensitive could be an increased number of sensory nerve endings in the peripheral nervous system.
Rami Burstein of the Beth Israel Deaconess Medical Centre in Boston also thinks the problem could lie outside the brain. He says Goadsby’s theory is “very attractive, but it lacks evidence”. Burstein thinks that peripheral sensitisation, as seen in migraineurs’ oversensitive skin sensations, means the process starts with sensory neurons releasing chemicals that make the brain’s neurons more responsive. It sounds similar to Goadsby’s idea, but the key question is whether the pain is real, triggered from bona fide sensory signals, or an artefact of oversensitive brain neurons. It’s an important distinction, because it could affect where treatments should be targeted.
But Stephen Silberstein thinks both could be right. It could be either peripheral or brain sensitisation that sets the process off, he suggests, or even something else. It may well vary from person to person. “They are probably both right,” he says. After all, he points out: “Migraine is not a single disorder, it’s a group of disorders.”
And there are competing ideas about the root cause of migraine. One of the leading theories concerns the strange visual disturbance known as an aura that is experienced before migraine in a minority of patients (estimates range from one-fifth to one-third). The aura seems to coincide with a wave of abnormal brain activity known as “cortical spreading depression”, which travels from the back of the head to the front.
Last year, Michael Moskowitz of Harvard Medical School showed that in rats at least, this wave seems to activate the trigeminal nerve (Nature Medicine, vol 8, p 136). He found that trigeminal nerve activity seems to cause the leakage of proteins from the blood into the meninges, which could cause irritation and pain, not to mention blood vessel dilation.
Few researchers doubt Moskowitz’s findings. Silberstein calls the work “clear and definitive”, but the fact remains that it doesn’t seem to explain the majority of patients who don’t get an aura before their migraine. Silberstein thinks that this is where Goadsby’s theory could come into its own, explaining the non-aura group. Other researchers argue that a subtle aura could well be present, just unnoticed, even in supposedly non-aura migraine sufferers. Goadsby himself believes the brainstem problems could start well before any aura.
Whoever is right, understanding the basic biological process that causes migraines is likely to point the way to better treatments. Goadsby has ideas for drugs that would damp down the oversensitivity in the brainstem, although he won’t give details yet. Ideally they would be able to stop a migraine in its tracks if taken during the premonitory stage, when patients first experience those strange sensations. Other new classes of drug are also coming through clinical trials, and may well help, despite the uncertainties surrounding migraine’s origins.
But Goadsby, at least, is convinced we won’t get far without considering his radical theory, however strange it sounds. “To say the pain is not really happening is quite a leap of faith,” he acknowledges. But when light feels painfully bright, we know it hasn’t really become brighter, or a painful sound any louder. “So maybe it’s not so hard to believe that there’s not really any worse pain, but that the brain is somehow misreading the signals.”
Many migraines appear to occur spontaneously. But some people find there are triggers that make their attacks more likely. These can be as mysterious and variable as the condition itself. Some are easier to avoid than others.
Red wine and cheese cause attacks for many, while for others it may be matured, smoked or fermented foods. The chemicals tyramine and phenylethylamine, known as biogenic amines, may be to blame. Bacteria known as lactobacilli are used in manufacturing to decompose bitter-tasting compounds, making wine and fruit juices taste better. These bacteria produce biogenic amines, which are also found in fermented or matured products such as soya foods, mature cheese, smoked and tinned fish.
For nearly two-thirds of female sufferers, attacks seem to be set off by variations in oestrogen levels during the menstrual cycle. The trouble zone may be menstruation itself or ovulation. Conversely, migraines may reduce in frequency during pregnancy. Some women may also be sensitive to the synthetic forms of hormones in the contraceptive pill or hormone replacement therapies.
Both the presence of stress or its sudden removal – such as the start of a weekend or holiday – can trigger a migraine attack. Too little or too much sleep, or jet lag, can have the same effect. Escaping the stress of work, perhaps coupled with a lie-in, can make weekends the prime attack time for many migraine sufferers.
Missed meals can also be to blame. Low blood sugar, or a sudden sugar rush can be bad. Caffeine, which is in some painkillers, may be a trigger. Even a change in the weather or atmospheric pressure can bring on a migraine. Other possible triggers include toothache, a hot bath or extreme emotions, such as anger or grief.