I WAS 15 years old and halfway through a family meal when the blow to my head came out of nowhere. It felt as if someone had clobbered me on the side of the skull with a mallet, the sudden pain making me drop my fork. Then came a second hit. And a third. I remember pleading with my sister to stop her noisy whingeing before running to hide under a duvet until the pain eventually subsided. I had experienced my first migraine.

Twenty years later, my migraine-coping technique remains largely unchanged, except that it is now my toddler whose whining becomes unbearable. Migraine treatments don’t really work for me. They don’t really work for a lot of people.

Despite migraine being among the most common neurological conditions, affecting around , we know incredibly little about what causes them, how to avoid them and how best to treat them.

That is partly because migraines are so complex. They impact people differently, can be unpredictable and affect many more women than men. Migraine research has been dismissed, derided and underfunded. But a handful of dedicated scientists have spent decades trying to make progress. For the first time, they have uncovered a mechanism behind migraines in the brain, and with this knowledge have developed treatments not only to relieve them when they strike, but possibly to stop them occurring. Finally, migraine science is having its moment.

For those lucky enough to be unfamiliar with migraines, they can seem far-fetched. Someone can be fine one minute, then suddenly unable to speak or see. The symptoms are varied, and can last from a few hours to days. “We talk about migraine collectively, but actually migraine comes in lots of different forms,” says . While many people experience headaches – often severe – a migraine is much more than that and can involve other symptoms. “The famous saying is that migraine is just a headache, which is a little bit annoying because it isn’t just a headache – it’s a brain disorder,” says . “Headache is just one of the features of migraine.”

Premonitions and auras

Migraine attacks can begin with what is known as a premonitory phase, or prodrome, which can involve a range of symptoms, such as mood changes, neck stiffness and yawning. My prodrome is marked by a vague feeling that something bad is going to happen.

The prodrome is usually followed by the migraine attack itself, which is often associated with pain. The pain can be debilitating and might be preceded by an aura. Aura symptoms – sensory disturbances that might affect a person’s vision, speech or movement – can range from mild to unbearable. This can occur independently of any headache. However, the headache tends to be the most debilitating symptom, lasting for minutes, hours or days, depending on the attack and the effectiveness of treatment.

Finally, there is the migraine “hangover”, or postdrome, in which some people can continue to feel tired or unwell for days.

Migraine is the third most prevalent disorder in the world and the third-highest cause of disability. The annual indirect cost of migraine due to missed work and reduced productivity alone – and that doesn’t include the substantial cost of treatment.

Despite all this, headache research . Funding for research on other common chronic conditions, such as asthma and diabetes, received, on average, $153.90 per person experiencing them. The figure for migraine, on the other hand, was a mere 36 cents. People with migraine can be let down at the clinical level, too. Only around . In the UK, a quarter of those with a diagnosis say they had been having attacks for over two years beforehand, according to . Most of those who responded were never referred to a headache specialist, and many struggled to get a prescription for migraine treatments.

At a science conference, I once heard a pain specialist dismiss pain in those who experience migraines as “psychological”. “I don’t believe this is a one-off experience,” says Hay. “The neurologists I speak to in my department are fighting against this all the time.”

Some of this prejudice can be attributed to the fact that pain is such a subjective experience, and so hard to unravel, and because migraine causes such varied symptoms. Added to which, migraine has been derided as an affliction of hysterical women, says Peter Goadsby at King’s College London. “The peak prevalence is at age 40, three women experience it for every male and it manifests around periods,” says Goadsby. “It’s a prejudice born in prejudice heaven.”

Finally, migraine doesn’t result in the severe damage to the brain that is seen in degenerative conditions such as Alzheimer’s and Parkinson’s disease, and in stroke, all of which also affect life expectancy, so understandably attract more funding.

This is something that . He found it almost impossible to get funding for his migraine research in the 1980s and 1990s. In the end, he secured funding to study stroke, which “kept me going in science”, he says. His migraine research became something of a side project. But he persevered with it and this paid off. Last year it won him, along with three other migraine researchers including Goadsby, award of 10 million Danish krone (around £1.1 million) in recognition of pioneering work in neuroscience. One revolutionary discovery that led to the win was that neurons, as well as blood vessels, play a vital role in migraines.

The idea that blood vessel dilation causes migraine was originally based on the fact that people who have migraines usually experience a throbbing headache, says Gazerani. This hypothesis was supported by research that involved injecting volunteers with drugs to dilate their blood vessels, which tends to cause headaches and can trigger migraines. The success of . These drugs, introduced in the 1990s, were the first designed specifically to treat migraine – and seemed to work by constricting blood vessels.

But cracks in the dilation theory had been starting to appear well before then, when neuroscientists developed tools to better measure blood flow in the brain. They saw that people experiencing a migraine didn’t appear to have dilated vessels as expected. Even where there was dilation, it didn’t seem to trigger the headache, with studies finding it started afterwards and outlasted the pain.

Then, 40 years ago, came the discovery of a chemical called calcitonin gene-related peptide (CGRP) that seemed to influence the function of neurons in the nervous system and the brain, and could also dilate blood vessels. Around the same time, Michael Moskowitz at Harvard Medical School, another of the four 2021 Brain Prize winners, identified the trigeminal nerve – which connects the brain to the face – and its associated blood vessels as .

In 1988, Edvinsson teamed up with Goadsby to learn more about what CGRP might be doing. By the mid-1990s, the pair and their colleagues had discovered that CGRP was released from the trigeminal nerve during a migraine attack, pinpointing for the first time a brain chemical that could be triggering migraines. The fourth 2021 prizewinner, Jes Olesen at the University of Copenhagen in Denmark, was part of a team that confirmed this by showing that giving CGRP to people who are prone to migraines caused an attack, and that natural CGRP release could be prevented with sumatriptan, the most often-prescribed triptan drug. Finally, the group had discovered a mechanism for migraine and a possible way to treat it, other than the one type of drug available.

That was desperately needed because triptans come with their own issues. Because they act to constrict blood vessels as well as restrict CGRP, you can’t take them if you have a history of stroke, for example. And there are side effects, including nausea, fatigue and neck, jaw and chest tightness. What’s more, they don’t work for everyone: studies show triptans to be effective in stopping pain within 2 hours in 42 to 76 per cent of people, and even then, they act only on the pain, not the aura.

With CGRP as a target for new treatments, research has now led to new types of drugs for migraine. These block the action of CGRP, but, unlike triptans, don’t constrict blood vessels, so can be taken by more people. Some of these are monoclonal antibodies, which are injected every few months to help prevent migraines. Erenumab – one such drug that was found to halve the number of migraine days experienced by volunteers in a clinical trial – was approved by the US Food and Drug Administration (FDA) in 2018, becoming the first new migraine drug since the 1990s. Others have followed, and still more are under review.

“What this tells us, for the first time, is that we can treat migraine acutely and preventatively via the same mechanism,” says Hay. “It was always thought it has to be different” This suggests we are targeting a key part of the migraine pathway.”

Goadsby and his colleagues have also been developing new CGRP-targeting drugs, called gepants, that don’t have to be injected. , and there is evidence that one might also be useful for preventing the onset of attacks.

Getting real

The discovery of the CGRP mechanism and the development of new migraine-specific drugs have gone a long way to highlight the status of migraine as a real neurological condition, too. “Now we have mechanisms, and we have specific drugs, and that makes a difference,” says Edvinsson. “You can’t argue with biology,” says Goadsby.

Despite these breakthroughs, we are still some way from understanding exactly what causes an attack in the first place – in other words, what fires up the trigeminal nerve. The aura that many people experience offers some clues to the pain side. Brain-imaging studies have shown that, during an aura, there is a wave of changes in brain activity, starting from the occipital lobe at the back of the head. Neurons first switch on, then off again, and this pattern spreads across the brain. This helps to explain some of the common symptoms of aura – flashing lights are thought to result from the switching on of neurons in the visual cortex, while blind spots are likely to occur when nerves switch off, says Goadsby.

, or that it triggers the trigeminal nerve to release CGRP.

Goadsby, however, thinks that aura and pain are two separate phenomena that both happen to be triggered by something that occurs in the prodrome. “It’s not that aura causes pain, it’s that something else causes both,” he says.

Other mysteries remain, too. One elephant in the room is the fact that migraine affects so many more women than men. People tend to experience their first migraines around puberty, and the incidence rises throughout adulthood, before declining after menopause. Some people find that their migraines disappear during pregnancy or become more frequent during perimenopause, which precedes the menopause.

All this implicates certain hormones. “We have found that trigeminal neurons contain receptors for oestrogen and oxytocin,” says Edvinsson. So the hormones might influence the perception of pain in migraine, he says. Both hormones are known to fluctuate with menstrual cycles and are more stable in men.

At Leiden University in the Netherlands, Gisela Terwindt is part of a team trying to unpack the link through a study looking at levels of several sex hormones in blood samples from female volunteers who experience migraine to see if they fit with the timing or symptoms of migraine attacks. The team is also giving volunteers contraceptive pills containing synthetic oestrogen to see whether this helps with migraine, a commonly touted treatment despite a lack of evidence. “It’s not without side effects, so we need clear proof,” says Terwindt.

Another lingering question is why there is so much variation in symptoms between people who have migraines. My auras usually start with flashing lights. A friend of mine sees light in zigzags during her migraines, and some people develop blind spots or tingling sensations.

“It might be that we’re classifying it too broadly, and actually there are multiple individual diseases here that we haven’t quite got a handle on diagnosing,” says Hay. “It could be an individual combination of different genes in a person that’s creating their unique experience.”

Terwindt has spent much of her career trying to understand the genetic factors. She was part of the team that identified the first gene linked to familial hemiplegic migraine – a subtype that is thought to have an especially strong genetic component – in the 1990s.

Heritable headaches

Since then, Terwindt has been looking for genetic factors that might explain more common types of migraine. After all, , there is a 50 to 75 per cent chance that person will experience attacks too. “We recently published that ,” she says. “It’s quite complex.”

On top of all that, we still haven’t answered perhaps the biggest questions: why and how migraines start in the first place.

People who experience migraines often have a list of things that seem to trigger them, and are usually advised to keep a migraine diary, so they can keep track of any changes in their routines, diets or anything else that seems to reliably occur before a migraine.

But how might things like stress, a lack of sleep or a cheese-laden snack lead to an attack? Some researchers believe that the brains of people who get migraines have a lower threshold for responding to stimulation, and that certain stimuli can essentially tip them over the edge, switching on neural activity that leads to the attack. Given the common early signs, such as yawning and tiredness, it might also be that some sort of change in the brain’s hypothalamus, which is linked to things like this, is triggering the attack (see “How does a migraine start?“). And some apparent triggers, such as food cravings or bright lights, might simply be a result of the attack already being under way. “If you think chocolate gives you headache, but actually the craving starts during the premonitory phase, then avoiding chocolate doesn’t make [any] difference,” says Goadsby. “Punishing yourself for things doesn’t make any sense.”

What is clear is that, given the huge variation in migraine, what works for one person won’t necessarily work for another. Some trials in which people take a high daily dose of vitamin B2 have found that some, but not all, of them experience fewer migraines. One man made headlines in November for . That doesn’t mean that others should start swapping triptans for kale.

It is also clear that more treatments are desperately needed. No single drug so far works for everyone. And many of those who do benefit still experience migraine attacks, even if they are reduced in number or severity. “That tells us we haven’t quite figured out that system properly, or that there are more factors involved,” says Hay.

“Migraines affect three women for every man. It’s prejudice heaven”

Until we discover what those factors are, there are things that doctors, employers and all of us can do to make life better for people who get migraines. One step is to improve knowledge among doctors. “The amount of training healthcare professionals receive is abysmally small,” says Hay. She is also a proponent of changing the language used for migraines, to bring it in line with the way we describe other neurological conditions. “You don’t have a migraine, you live with migraine, and sometimes you have an attack,” she says.

I’m one of the lucky ones – my migraines have decreased in frequency and severity since I entered my 30s, perhaps due to the hormonal changes of pregnancy. Given the propensity for migraine to run in families, I hope that the new buzz around migraine research will mean my whingeing toddler won’t have to hide under her own duvet a decade or so from now.

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Losing weight won’t necessarily help you live longer, and the best predictors of a long and healthy life are mobility, strength and balance.

That’s what at the Children’s Hospital at Montefiore in New York and her colleagues found when they looked at the outcomes of older women who had participated in a long-running study.

“I have a lot of family members who are on the elderly side, and they talk a lot about losing weight,” says Underland. “There’s a lot of talk in the media, in our society and in medical circles about weight loss.”

To get a better picture of the link between weight loss and mortality, Underland and her colleagues looked at data from the Women’s Health Initiative, a series of studies involving more than 161,000 volunteers in the US that has been running since 1992.

The team looked at 5039 women who were over 65 in 2012, with an average age of 79. Around this time, each woman took a series of tests to determine their physical strength, balance and mobility, which included measuring their grip strength and their ability to stand up from sitting in a chair, for example.

Underland and her colleagues also looked at how much weight the women had gained or lost since they first enrolled in the study, 14 to 18 years prior to the tests. They then noted how many of the women were still alive around five years after they took the tests.

The team found that women who lost weight were much more likely to die within the follow-up period than those that didn’t. Those who had lost 5 per cent of their body weight in previous years were 61 per cent more likely to die within the following five years.

The weight loss is unlikely to have been caused by illness, as women with cancer were excluded from the study, and the team controlled for other conditions that might affect weight.

People who performed well in physical tests appeared to have the best survival odds. Women who scored in the top quartile for strength, balance and mobility were 71 per cent more likely to be alive five years later than those whose scores were in the bottom quartile.

Weight gain, on the other hand, had no effect on mortality. “This information doesn’t tell everybody to go out and buy a bunch of Cheetos,” says Underland. “Keep moving, eat a healthy diet – focus on that.”

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Book

Stuck: How vaccine rumors start – and why they don’t go away

Heidi Larson

Oxford University Press

RHETT KRAWITT was just 7 years old when he petitioned local law-makers in California to tighten restrictions on who could avoid vaccinating their children. Rhett had been through years of chemotherapy for leukaemia, so wasn’t able to receive the MMR vaccine, which protects against measles, mumps and rubella. This left him, and others like him, vulnerable to these diseases.

But many of the parents of healthy children in the state were turning down the MMR vaccine, using the “personal belief exemption”. Such refusal is thought to have contributed to a measles outbreak tied to a Disneyland theme park, which was linked to 147 measles cases across seven states.

The story is one of many that demonstrates how emotions, as well as misinformation and culture, come into play in debates surrounding vaccination. As anthropologist Heidi Larson demonstrates in her new book, Stuck, such debates aren’t new and crop up continually around the world, and the fact that they are so persistent suggests we need a new approach to them.

The book, largely written before the covid-19 pandemic, is a guide to many of the problems faced by vaccination campaigns. Larson, based at the London School of Hygiene & Tropical Medicine, and who founded the Vaccine Confidence Project to better understand how people feel about vaccines, points out that rumours have always played a role in the misinformation and fear around vaccines. This has been the case since the first vaccines were introduced for smallpox.

If the thoroughly debunked belief that 5G phone masts were responsible for the covid-19 outbreak sounded familiar, that might be because similar ideas linked 3G to the SARS outbreak of 2002-2003, and 4G to swine flu.

Rumours and misinformation may be nothing new, but they can still have devastating effects. And the rising use of the internet and social media has only contributed to their spread, says Larson.

“Emotions, culture and misinformation come into play when debates surrounding vaccination come up”

In extreme cases, people administering vaccines have been killed. We have also seen, most recently with measles, how a drop in vaccination can lead to the loss of herd immunity, and the resurgence of diseases that claim lives.

So how do we tackle them? Larson points out that simply countering misinformation with facts isn’t enough. She quotes epidemiologist Stephen Ledeer, who wrote that “facts are not rejected because they are seen as being wrong, but because they are seen as being irrelevant”. Larson herself describes this as “a near reversal of the Age of Enlightenment”.

Instead, it is important to understand the emotions that drive these rumours. A common problem is people feeling that vaccination of their children is something that is out of their control, for example. And it is important to acknowledge that vaccines do have risks, even if the risks of side effects are minimal, says Larson.

In the book, Larson draws on the need for open dialogue to share information, and the importance of including those who oppose vaccination for whatever reason, and treating them with empathy and kindness. Frustratingly, given her obvious expertise, there is no direct call to action, or clear suggestion for a solution to the problem.

Having highlighted the fatal consequences of vaccine misinformation and avoidance, Larson says “the global vaccine enterprise needs to reboot” and that the scientific community is pondering how to manage people’s relationship with information, and misinformation, surrounding vaccines. Larson concludes by writing that she is a “patient optimist”, but given what’s at stake, this doesn’t seem quite enough.