Migraine is more than a headache — a radical rethink offers hope to one billion people Research is starting to untangle the reasons why

Drugs that can prevent or relieve migraine attacks are only effective for some people

Andrea West remembers the first time she heard about a new class of migraine medication that could end her decades of pain. It was 2021 and she heard a scientist on the radio discussing the promise of gepants, a class of drug that for the first time seemed to prevent migraine attacks. West followed news about these drugs closely, and when she heard last year that atogepant was approved for use in the United Kingdom, she went straight to her physician.

West had endured migraines for 70 years. Since she started taking the drug, she hasn’t had one. “It’s marvellous stuff. It’s genuinely changed my life,” she says.

For ages, the perception of migraine has been one of suffering with little to no relief. In ancient Egypt, physicians strapped clay crocodiles to people’s heads and prayed for the best. And as late as the seventeenth century, surgeons bored holes into people’s skulls — some have suggested — to let the migraine out. The twentieth century brought much more effective treatments, but they did not work for a significant fraction of the roughly one billion people who experience migraine worldwide.

Now there is a new sense of progress running through the field, brought about by developments on several fronts. Medical advances in the past few decades — including the approval of gepants and related treatments — have redefined migraine as “a treatable and manageable condition”, says Diana Krause, a neuropharmacologist at the University of California, Irvine.

At the same time, research is leading to a better understanding about the condition — and pointing to directions for future work. Studies have shown, for example, that migraine is a broad phenomenon that originates in the brain and can manifest in many debilitating symptoms, including light sensitivities and aura, brain fog and fatigue. “I used to think that disability travels with pain, and it’s only when the pain gets severe that people are impaired. That’s not only false, but we have treatments to do something about it,” says Richard Lipton, a neurologist at the Albert Einstein College of Medicine in New York City.

Researchers are trying to discover what triggers a migraine-prone brain to flip into a hyperactive state, causing a full-blown attack, or for that matter, what makes a brain prone to the condition. A new and broader approach to research and treatment is needed, says Arne May, a neurologist at the University Medical Center Hamburg–Eppendorf in Germany. To stop migraine completely and not just headache pain, he says, “we need to create new frameworks to understand how the brain activates the whole system of migraine”.

Wonder drugs?

When May started researching migraine in the 1990s, the leading hypotheses were that migraine was either a psychological issue or a vascular headache disorder, with throbbing pain caused by dilation of blood vessels. The psychological associations came with stigma, May says. “No one believed people who had migraine, they just thought they didn’t want to work. Nearly all of my patients at that time had to see a psychologist or psychiatrist.” The field, Krause says, is still recovering from these ideas. Most clinicians have abandoned the idea that the problem is psychological, but the notion that migraine is akin to a particularly bad headache persists even now.

A lot changed in the 1990s, when May and others began conducting brain scans of people with migraine. The researchers saw for the first time that brain regions were activated during headache attacks, showing that it was more than just a vascular issue¹. “From that point on, a lot of things changed. It was the very first time someone could point to migraine and say it’s a biological disease,” says May.

Researchers found that changes in the brain’s activity start appearing at what’s known as the premonitory phase, which begins hours to days before an attack (see ‘Migraine is cyclical’). The premonitory phase is characterized by a swathe of symptoms, including nausea, food cravings, faintness, fatigue and yawning. That’s often followed by a days-long migraine attack phase, which comes with overwhelming headache pain and other physical and psychological symptoms. After the attack subsides, the postdrome phase has its own associated set of symptoms that include depression, euphoria and fatigue. An interictal phase marks the time between attacks and can involve symptoms as well.

Source: N. Karsan & P. J. Goadsby *Nature Rev. Neurol*. 14, 699–710 (2018).

But the type, severity and causes of migraine symptoms can differ between people. Dom Horton, who is 53 and an editor in the United Kingdom, never gets headaches. But he experiences other migraine symptoms all the time. “Constant dizziness and a swimming mind are always present,” he says, and they sometimes build to a severity that prevents him from leaving his house. Fiona Gartside, a 60-year-old veterinary surgeon in Scotland, experiences sensitivities to noise, light and movement, overwhelming exhaustion and headaches that get so severe that she occasionally loses consciousness, “which is a relief”, she says. Migraine can even drive full-blown visual hallucinations similar to the ‘reflections of the living light’ painted by Hildegard von Bingen, a twelfth-century abbess who was thought to have experienced a condition that is now called migraine with aura.

Despite the variety of symptoms, it was research into normal, non-migraine associated headaches that led to revolutionary treatments for migraine. Gepant drugs and a handful of monoclonal antibodies have been designed to block activity of the calcitonin gene-related peptide (CGRP). They came from decades of research on the role of CGRP in headache and are a real “bench to bedside success story”, according to Peter Goadsby, a neurologist at King’s College London, who pioneered the research along with Lars Edvinsson, a neuroscientist at Lund University, Sweden, and collaborators in the 1980s.

Headache begins when sensory nerves called nociceptors in the meninges become sensitized, sending information to the brain to evoke pain. Goadsby’s work showed that CGRP is a key factor in sensitizing these nociceptors. Clinical trials of drugs that block the peptide in people with migraine proved effective both in alleviating headache and sometimes in preventing attacks from starting². Goadsby says it’s been stunning to see the completeness of people’s responses to gepants. “Patients come back and literally cry,” he says. “They’d forgotten before what normal was.”

From the successes of CGRP blockers, it’s tempting to view CGRP as a ‘factor X’ of migraine. Yet it’s clear that other elements are at play. CGRP blockers work only for a subset of people, as few as one in five according to some studies³. And for those who do respond well to the drugs, some migraine symptoms often persist. West, for example, still has bouts of nausea even though the drug she takes, atogepant, stops her migraine attacks. And although atogepant has minimized Gartside’s symptoms, migraine still dominates her life. “There is a constant juggle between prevention, medication, trigger avoidance, fatigue, fear and anticipation of attacks,” she says.

Migraine in the brain

Goadsby says the mixed results of CGRP blockers show a huge gap in the biological understanding of migraine. “This tells us there are other frameworks of migraine that need to be discovered, and other pathways,” he says. May agrees. He thinks the field needs a radical change in thinking to find new mechanisms of migraine. “We’re focusing too much on migraine as a headache disease,” he says. “The thinking for most people stops at CGRP, but CGRP isn’t the only answer.” The problem, he says, is that scientists don’t fully understand what a migraine attack looks like in the brain.

Studies in the past seven years or so have solidified the hypothalamus as a centre of the condition⁴. “It must involve the limbic system, of which the hypothalamus is the king,” May says. The limbic system is a group of interconnected brain structures that process sensory information and regulate emotions. Studies that scanned the brains of people with migraine every few days for several weeks showed that hypothalamic connectivity to various parts of the brain increases just before a migraine attack begins, then collapses during the headache phase⁵.

May and others think that the hypothalamus loses control over the limbic system about two days before the attack begins, and it results in changes to conscious experiences that might explain symptoms such as light- and sound-sensitivity, or cognitive impairments. At the same time, the breakdown of hypothalamic control puts the body’s homeostatic balance out of kilter, which explains why symptoms such as fatigue, nausea, yawning and food cravings are common when a migraine is building up, says Krause.

Goadsby agrees that the hypothalamus is important, but thinks it’s more complex than simply a loss of control. He hypothesizes that an attack could begin when any part of a ‘migraine network’, potentially including the hypothalamus, thalamus and limbic system, is overstimulated. Researchers have yet to pinpoint precisely which brain regions are part of the network, or the “exact order of batting” of when these regions are activated during an attack, Goadsby says.

Predispositions and triggers

Migraine researchers now talk of a hypothetical ‘migraine threshold’ in which environmental or physiological triggers tip brain activity into a dysregulated state.

The list of potential triggers is extensive. West’s migraines are closely linked to certain foods and to hunger, stress and hormonal changes. She used to get terrible headaches with her period, then after menopause they developed into full-blown three-day migraines. More than half of women with migraine experience attacks every month during menstruation. And migraine is also three times more prevalent in women than in men; it’s the number one debilitating issue for cisgender women in their reproductive years, and it seems equally prevalent in transgender women taking hormone replacement therapy.