Obstacles behind understanding world’s second-leading cause of disability

More than 1.2 billion people around the world regularly live with migraine, a neurological disorder that ranks as the second leading cause of disability globally. Despite its enormous social and economic impact as the second most prevalent cause of disability in the world, migraine disorder remains one of the least understood medical conditions. For decades, most treatments have focused on easing symptoms rather than addressing the underlying biological causes. Now, a growing body of research is beginning to challenge that approach, offering new insight into how migraine develops in the brain and raising hopes for more effective, targeted therapies.

More and more medics highlight that migraine is not simply a bad headache, but is a complex neurological condition that can disrupt every aspect of daily life, from work and education to family relationships and mental health. Yet scientific progress has been slow. Despite the suffering it causes millions of people, an article by the BBC explores why research into such a widespread and disabling condition has lagged behind other areas of neurology.

“I would say that it's probably among the most poorly understood neurological disorders, or disorders in general,” says Gregory Dussor, chair in behavioural and brain sciences at the University of Texas at Dallas, in the United States. His assessment is shared by many specialists who argue that migraine’s complexity, combined with long-standing cultural and institutional biases, has left major gaps in understanding its biology.

One of the most significant barriers to progress has been the historical perception of migraine. For centuries, headaches associated with migraine were dismissed as a “feminine whim,” a label that continues to influence research priorities today. According to historical accounts cited by the BBC, migraine in the 18th and 19th centuries was often portrayed as a condition affecting only clever, charming and beautiful women said to possess “migraine personalities.” Although about three-quarters of people who experience migraine are women, this gendered framing fostered stigma rather than scientific curiosity.

“People thought of it as a disease of hysteria,” says Teshamae Monteith, chief of the headache division at the University of Miami Health System. That legacy has had lasting consequences. Even today, only a small number of universities host dedicated migraine research centres, and funding for migraine research remains far lower than for other neurological disorders with comparable or even smaller impacts.

The language used to describe migraine has also evolved as scientific understanding improves. Experts now discourage the use of the term “migraines,” which implies that headache itself is the disease. Instead, they urge the public and medical professionals to use “migraine disorder,” recognising that headache is only one symptom of a broader neurological condition. A “migraine attack” refers to a flare-up of this underlying disorder, which can manifest in many different ways.

Clinicians distinguish between episodic and chronic migraine based on frequency. Episodic migraine involves fewer than 15 headache days per month, while chronic migraine is diagnosed when headaches occur on 15 or more days each month. But frequency alone does not capture the full burden of the condition.

Blurred line between triggers and symptoms

One of the major challenges in studying migraine is the extraordinary range of symptoms it can produce. Head pain that varies in intensity and often moves across different regions of the head is the most recognisable feature, but many patients experience far more than that. Nausea, vomiting, vertigo, abdominal pain, and heightened sensitivity to light and sound are common. More than half of patients report extreme fatigue, while others notice food cravings or excessive yawning in the early stages of an attack. Around 25% of people with migraine experience auras — visual disturbances such as jagged bright shapes, shimmering lines or blurred patches that resemble light leaks on film.

“The entire migraine attack is a very complicated thing,” Dussor says. “It's not just pain. It's a whole series of events that are happening well before a headache ever starts.”

Migraine attacks are often associated with specific triggers, which patients learn to identify through experience. These can include lack of sleep, fasting, stress, hormonal changes and certain foods or drinks such as chocolate, aged cheese, coffee or white wine. For years, researchers have puzzled over why migraine triggers seem so numerous and inconsistent, varying not only between patients but also from one attack to the next in the same person.

Increasingly, scientists are questioning whether many so-called triggers are actually early symptoms of an attack rather than its cause. Research suggests that changes in the brain may begin hours or even days before pain is felt, subtly influencing behaviour and perception.

A patient might, for example, start craving certain foods during the very early stages of an attack. Chocolate or cheese is then blamed for triggering the migraine, even though the neurological process may already be underway. This confusion between cause and effect is easy to understand, says Debbie Hay, professor of pharmacology and toxicology at the University of Otago in Dunedin, New Zealand.

The BBC article’s author offers a personal reflection to illustrate the point: “Personally, I've always wondered whether perfume was responsible for giving me a migraine attack. Yet I wear perfume every day, and I realise, I only notice its scent enough to try to blame it for my attack on the days when I actually do get one. If I don't get a migraine attack, I don't tend to focus on what I smell like too much.”

Peter Goadsby, professor of neurology at King’s College London, says this is “a classic example with the causal attribution probably being wrong.” His research supports the idea that biological changes in the brain may heighten sensitivity to certain stimuli before an attack becomes obvious.

Goadsby has compared brain scans of migraine patients who believe light triggers their attacks with those who do not report light sensitivity as a trigger. Only the former group showed increased activity in the brain regions responsible for vision shortly before an attack began. This suggests that their brains were already primed to be more sensitive to light. “Unquestionably, something is going on biologically,” Goadsby says.

Genetic component

Genetics is another key piece of the migraine puzzle. Studies of twins have consistently shown that migraine has a strong hereditary component. If close family members experience migraine, the likelihood of inheriting the condition increases significantly. Inherited genes are estimated to account for 30% to 60% of migraine risk, with environmental and behavioural factors contributing to the rest, according to Dale Nyholt, a geneticist at Queensland University of Technology in Australia.

Nyholt has been analysing genetic data from thousands of people in an effort to pinpoint the specific genes involved. The task has proved daunting. “More complex than what we were ideally hoping for,” he says. In a major study published in 2022, his team compared the genetic profiles of 100,000 people with migraine to those of 770,000 people without the condition. The analysis identified 123 genetic “risk snips” — tiny variations in DNA associated with migraine.

He is now expanding the research to include data from 300,000 migraine patients, expecting to uncover many more genetic markers. “There are probably thousands,” he says. Some of the genetic signals already identified overlap with genes linked to depression and diabetes, as well as differences in the size and structure of certain brain regions. Nyholt believes these findings point to a “constellation” of related conditions that may arise from shared biological pathways affecting the brain.

Is it in the blood or brain?

For much of the 20th century, migraine was widely thought to be primarily a vascular disorder. The throbbing quality of migraine pain led researchers to suspect that attacks were caused by blood vessels dilating and allowing increased blood flow into the brain. However, decades of research failed to establish a simple or consistent relationship between blood flow and migraine onset.

“It just cannot be as simple as ‘blood vessel does X’,” Dussor says. “You can give every human on Earth a drug that's going to cause blood vessels to dilate and not everybody's going to get a migraine.”

This does not mean blood vessels are irrelevant. Many of the genetic risk factors identified by Nyholt are involved in regulating blood vessels, and abnormal dilation does occur during migraine attacks. Medications that constrict blood vessels can help relieve pain in some patients. Still, most scientists now believe that vascular changes are part of a broader neurological process rather than the root cause of migraine.

Attention has increasingly shifted to the brain’s electrical activity. One leading theory proposes that migraine involves a phenomenon known as cortical spreading depression — a slow-moving wave of abnormal electrical activity that travels across the brain’s cortex. This wave suppresses normal brain function and activates pain pathways, triggering inflammation and a cascade of symptoms.

The cortical spreading depression wave essentially “dumps out all kinds of bad molecules into the brain,” says Michael Moskowitz, professor of neurology at Harvard Medical School in Cambridge, Massachusetts. Yet many questions remain unanswered: why the wave starts, where it spreads, and how it produces such a wide array of symptoms.

In March 2025, scientists captured this wave in real time while monitoring the brain of a 32-year-old patient preparing for surgery. Using 95 electrodes placed through her skull, researchers observed the wave spreading from the visual cortex — helping to explain light sensitivity and visual auras — and continuing to travel across the brain for more than 80 minutes.

Researchers increasingly believe that migraine arises from the interaction of multiple factors rather than a single cause. “I think it's that ultimately, there may be one common denominator, but there's multiple paths to migraine,” says Amynah Pradhan, director of the Centre for Clinical Pharmacology at Washington University in St. Louis. “Maybe even more than that, I think within an individual. There are multiple ways to get migraine and everybody's got a cocktail of things going on.”

One of the most significant breakthroughs in recent years has come from the search for a reliable biological marker of migraine. Scientists have identified unusually high levels of calcitonin gene-related peptides, or CGRPs, in people with migraine. These neuromodulators help regulate how sensitive neurons are, acting like dimmer switches for nerve activity.

Research by Goadsby and others has shown that CGRP levels rise during migraine attacks and may also be elevated even between attacks in people with migraine. This discovery has led to the development of a new class of drugs that target CGRPs directly, either stopping attacks once they begin or preventing them altogether.

The impact has been substantial. In an October 2025 study of more than 570 patients treated with CGRP-targeting drugs for a year, 70% experienced a 75% reduction in the frequency of their migraine attacks, and about 23% became completely attack-free. For many patients who had not responded to older treatments, the results have been life-changing.

Still, researchers caution that CGRPs are unlikely to be the whole answer. No one knows exactly why these molecules appear in such high concentrations during attacks, and migraine is increasingly viewed as a chronic, spectrum-like condition that affects the entire body, not just the brain.

As scientific understanding deepens, migraine is slowly emerging from the shadows of stigma and misunderstanding. While many questions remain, the shift toward viewing migraine as a complex neurological disorder — shaped by genetics, brain activity and systemic factors — is opening new paths for research and treatment, offering renewed hope to the millions of people worldwide who live with its disabling effects.

By Nazrin Sadigova