Researcher out to solve mystery of migraine

Often dismissed as a minor ailment, migraine is a debilitating neurological disease affecting hundreds of thousands of New Zealanders. At the University of Otago’s School of Biomedical Sciences, world-leading research by Professor Debbie Hay and her team is unraveling its complex molecular secrets—paving the way for new treatments.

It’s often brushed off as just a bad headache, but to the one in seven New Zealanders estimated to live with them, migraine is much more.

It can mean frequent, excruciating attacks that disrupt life for days, with stories of missed workdays and time with family all too common among sufferers. Despite decades of scientific research and advocacy efforts, this neurological disease also remains surrounded by stigma.

Improving understanding of migraine—both in the laboratory and in the public domain—continues to drive much of Professor Debbie Hay’s work within the University of Otago’s School of Biomedical Sciences. Her group’s world-leading research in this space is taking us closer to answering such questions as what truly drives migraine, why it manifests differently among sufferers, and what new treatments might be possible.

Today, migraine remains one of Aotearoa’s most under-recognized health burdens, affecting an estimated 640,000 people. Prevalence is significantly higher among women than men.

A recent survey of 500 sufferers, led by the University of Otago and the Migraine Foundation Aotearoa New Zealand, found nearly one quarter of respondents lived with chronic migraine (15 or more headache days per month), while two in 10 endured near-continuous pain.

The survey further showed that half met the criteria for severe disability; more than one quarter missed five or more days of work or school within only three months; and that access to treatment through GPs remains a common barrier.

Some respondents described the condition as “misery” and “devastating.” Others—particularly women—described a feeling of being judged or simply dismissed. To Debbie, these insights were unsurprising.

The stereotyping of migraine as “a woman’s problem,” she explains, has hampered research and understanding for decades.

The mechanics of migraine

Fundamentally, people with the condition have an underlying difference in their biology, which makes them prone to attacks.

While migraine often runs in families, indicating clear genetic factors, it’s not linked to a single gene. Instead, a complex genetic makeup predisposes some individuals within those families to attacks.

And it’s not simply about head pain, but a much broader spectrum of neurological dysfunction that can unfold over several days, Debbie says. Before the painful headache phase, sufferers often experience what’s known as the prodrome, which occurs as parts of the brain, like the hypothalamus, activate and trigger symptoms such as food cravings or heightened sensitivity to light or sound.

Following the intense headache phase is the postdrome.

“This is otherwise known as the migraine hangover, where the attack resolves but sufferers will be left feeling very drained,” Debbie says.

She adds that understanding these phases, and the different brain regions involved, is key to developing more targeted treatments.

Today, among the most effective drugs for migraine are those targeting a pain-causing hormone called calcitonin gene-related peptide (CGRP), of which sufferers typically have elevated levels. When Debbie began her doctoral studies in 1999, her research focused on confirming CGRP’s receptor—the molecular mechanism it uses to exert its painful effects—so that potential drug targets could be unlocked.

Medications that block the CGRP pathway—some oral, others monthly injectables—have since proven life-changing for patients.

“Some who were living with chronic migraine have experienced essentially no migraine attacks since taking these therapeutics,” she says.

“For others, it’s meant simply being able to go about daily life without living in constant fear of an impending attack—something they previously never would have conceived of being possible.”

Ongoing research by Debbie and her team, however shows that there’s still much more to learn about CGRP. Not all patients respond to these treatments and, for those who do, their effectiveness can fade over time.

“This is partly because perhaps migraine is a very broad spectrum of things, and not everybody’s going to fit into the same box,” she says.

“So, we’ve spent time looking at the different drugs on the market and trying to understand their pharmacology.”

This work has led them to the potential explanation that a second CGRP receptor, known as AMY1, also plays a role in migraine. These insights have only added a new layer of complexity, as these particular migraine-related receptors aren’t single, simple structures but combinations of different proteins that form in a range of ways.

Finding tools to study them—whether through identifying tell-tale antibodies or using genetic approaches that switch off individual proteins—is equally tricky.

Access to human tissue is another challenge.

“It’s very difficult to access human tissue samples from people with migraine; tissue donation tends to be from people who are older, by which point migraine may have resolved.”

Burning questions and new horizons

For migraine researchers like Debbie, one of the biggest remaining mysteries is how CGRP drugs—some of which are large monoclonal antibodies generally unable to cross the blood-brain barrier—can effectively treat a neurological condition rooted in brain activity. Solving that problem could open the door to new ways of treating migraine without directly accessing the brain.

Beyond refining CGRP-targeting drugs, the field is actively exploring other avenues for treatment. These include technologies like neuromodulation devices and even Botox injections, although their precise mechanisms currently remain largely unknown.

Debbie’s laboratory is also at the forefront of investigating other molecular targets that modulate nerve activity, aiming to provide even more diverse treatment options for sufferers.

A testament to this, her team has notably collaborated with the Danish Headache Center on a substance called Amylin. Their research has demonstrated that Amylin can provoke migraine-like attacks, suggesting it as a potential new avenue for exploration that ties into their broader work on receptors like AMY1.

While New Zealand’s small size means funding opportunities can be limited, Debbie points to the benefits of the collaborative, inter-disciplinary culture within the nation’s science system.

“This culture has helped make us global leaders in this space,” she says.

She also feels proud to be mentoring the next generation of migraine researchers, which has involved bringing Ph.D. candidates to patient meetups to hear directly from sufferers.

“One of my students was just amazed and proud of what she was doing, contributing to understanding how those drugs work, that these patients are taking,” Debbie says.

Debbie feels similarly privileged to have helped raise awareness of migraine through groups like Migraine Foundation Aotearoa New Zealand, with whom she works closely. While acceptance of migraine as a real and debilitating neurological disease is slowly improving, she notes there is much more progress to be made.

“This is why advocacy is so important,” she stresses.

“And for those who live with this stigma, it’s about telling them they don’t have migraines because they ate some chocolate—and that it’s not their fault.”

Migraine In NZ: By the numbers

• One in seven people worldwide experience migraine, with the disease affecting two to three times as many women as men. More than 640,000 Kiwis are thought to live with the condition.
• Nearly one quarter (23%) of 530 people who responded to a national survey led by the University of Otago, Wellington, and the Migraine Foundation Aotearoa New Zealand, had chronic migraine (headache on 15 or more days a month).
• Of these, 20% had continuous or nearly continuous headache (five percent of all respondents) and another 22% had 24 or more days of headache per month (five percent of all respondents).