Migraine Aura at Altitude?
University of Utah Researchers Investigate a Mountain West Mystery
Migraine Aura at Altitude?
University of Utah Researchers Investigate a Mountain West Mystery
New University of Utah research suggests that living at higher elevations may increase the likelihood of experiencing migraine aura. By combining nationwide patient data with laboratory studies, researchers are uncovering how altitude may influence the brain and identifying pathways that could eventually lead to new migraine treatments.
Shimmering rainbow triangles. Silver sheets of water. Blind spots. Zigzag patterns. Migraine sufferers know when they see one of these, pain will follow.
Called migraine aura, this symptom affects roughly one in three migraine sufferers. Yet scientists don't fully understand why some people experience aura while others do not.
Now, researchers in the University of Utah Department of Neurology’s Headache Physiology Lab have uncovered an important clue, one particularly relevant for people living in Utah and throughout the Mountain West.
The research team, led by UHealth headache specialist K.C. Brennan, MD, found that migraine aura is more common among people living at higher elevations. The findings emerged from several large human studies and were supported by laboratory mouse model studies.
The researchers' study, "Increased occurrence of migraine aura and susceptibility to spreading depolarizations at altitude," (currently under peer review) points to a possible relationship between elevation and the biological processes that cause migraine aura.
It All Started with an Observation
Why Researchers Suspected Altitude Could Affect Migraine Aura
When Brennan decided to join the U, two longtime headache specialists at the institution, Susan Baggaley, FNP-BC, MSN, and Kathleen Digre, MD, shared an observation made over years of treating patients.
Brennan remembers Baggaley saying, "When you come here, you’ll notice something. We think there’s more frequent migraine aura in Salt Lake City."
At the time, nobody knew whether the observation reflected a real phenomenon or simply a quirk of the city’s population. Then Brennan arrived.
"I come to Salt Lake, I start seeing patients, and I find it’s really true,'" he said. "I'm seeing more people with migraine aura."
But noticing a pattern is not the same as proving one. Scientists are trained to be skeptical, even of their own ideas. As Brennan explains, "If you're going to be decent at science, you have to be your own worst critic."
Looking for Evidence
How Researchers Investigated the Link Between Altitude and Migraine Aura
The first step was straightforward. Baggaley, Digre, and Brennan, along with colleagues in Seattle, reviewed patient records from their headache clinics in both locations. These two cities are separated by more than geography. Salt Lake City sits at 4,200 feet above sea level. Seattle is basically at sea level.
The chart review suggested that migraine aura was substantially more common among patients seen in Utah. But chart reviews have limitations.
"It's susceptible to all sorts of biases," Brennan said. "People write their notes differently. People classify things differently. It's a weak form of evidence."
So, the researchers designed more rigorous studies carried out over several years.
Headache fellow Zubair Ahmed, MD, developed a standardized questionnaire, the Visual Aura Rating Scale, to evaluate migraine patients in Salt Lake City. Later, after moving to the Cleveland Clinic—at lower altitude—he used the questionnaire to evaluate patients there.
The result?
"We again saw a significant difference in aura prevalence between the higher and lower elevation locations," Brennan said.
That was encouraging, but still not enough. The researchers questioned whether they were seeing an altitude effect or simply something unique to Salt Lake City.
"Is there some sort of weird Salt Lake effect?" Brennan recalled wondering. "Is this not altitude but potentially something else?"
Expanding the Search Nationwide
Nationwide Data Revealed a Consistent Altitude-Migraine Pattern
To answer that question, the team turned to two national databases, the American Registry for Migraine Research and Epic Cosmos. With the help and expertise of lead authors Melissa Cortez, DO, and Cecilia Martindale, MS, they were now able to comb through massive amounts of de-identified information from millions of U.S. patients.
Using geographic data linked to where patients live, researchers examined migraine diagnoses across thousands of counties nationwide.
Again, the pattern appeared. Patients living at higher elevations were more likely to experience migraine aura.
"Four different sources of data, each one with its strengths and weaknesses, all pointing in the same direction," Brennan said. “The weaknesses started to cancel out, and the common directionality of the data started to convince us."
From Patients to the Laboratory
What Happens in the Brain During Migraine Aura?
Finding a pattern in people raised a new question. Why would altitude affect migraine aura?
To investigate, the researchers turned to the Headache Physiology Lab’s specialty: a phenomenon called spreading depolarization (SD). SD is widely considered the biological event that produces migraine aura. It is a wave of electrical and chemical activity that moves across the brain before migraine.
If altitude truly influences aura, Brennan reasoned, perhaps it also affects the brain's susceptibility to SD. Fortunately, his team had a way to test that idea.
Building Mountains for Mice
How University of Utah Researchers Simulated Altitude in the Lab
The laboratory experiments required a little engineering.
"Gary Urry, in our lab, who's a bit of an engineer, built tiny mouse altitude chambers, about the size of a crock pot," Brennan said.
The chambers allowed Kate Reinhard, PhD, a postdoc in the lab, to simulate different elevations while carefully controlling environmental conditions.
One chamber simulated sea level. Another, conditions like Salt Lake City’s. A third represented much higher elevations.The mice were housed and acclimated in these chambers before researchers measured how easily SD could be triggered in the brain.
The goal was not to create migraine headaches in animals. Instead, researchers were studying the measurable brain event associated with aura. The results mirrored what was seen in people.
"Kate saw an increased susceptibility to spreading depolarization in mice when she and Gary varied their altitude in an altitude chamber," Brennan said.
For researchers, that finding was especially important because it provided a possible biological explanation for the human data.
How Do You Know When a Mouse Has a Migraine?
One of the most common questions about laboratory migraine research is simple: If mice can't tell us they have a headache, how can scientists study migraine?
For this particular study, researchers weren't measuring headache pain itself. They were measuring spreading depolarization, the brain event believed to cause migraine aura.
"For our altitude project, we didn’t need the mouse to tell us it had a migraine," Brennan explained. "We just needed to see that wave moving across the brain."
But in other studies, you do need to know that the mouse has something resembling a migraine attack, or the research is not helpful. Several methods can be used to identify migraine-like symptoms in animals.
Brennan continued: “It is difficult for a mouse to tell us, ‘Not now Honey, I have a headache.’ But migraine is not just headache. Nearly every migraine attack is accompanied by sensory sensitivities: light hurts, sound hurts, touch hurts, among other things. And we can measure these sensitivities in mice.”
For example, mice can be tested for increased sensitivity to touch using tiny flexible filaments that apply precise amounts of pressure. Researchers also use a device called a "light-dark box" to measure light sensitivity.
Another important aspect to modeling migraine in mice is using animals that carry genes from human families with migraine. Brennan’s lab was instrumental in developing one of these types of mice (and one of the families was from Utah!). But they and other labs may often use several different genetic models to ask a question in different ways.
No animal model perfectly recreates the human experience of migraine. Instead, like with the altitude study, scientists combine multiple measurements to study specific biological processes involved in the disease.
“Our mouse models help researchers investigate questions that would be impossible to answer in humans alone,” said Brennan. “And they can ultimately lead to discoveries that improve patient care.”
What the Findings Mean for People Living at High Altitude
For migraine sufferers, especially those living in Utah and other high-elevation regions, the findings may resonate with personal experience.
Many patients report changes in migraine symptoms when they travel between elevations. Some say symptoms improve at lower elevations, while others notice changes when moving to mountain communities.
The new study doesn't mean that altitude is the only trigger of migraine, and it doesn't mean moving to sea level is a migraine treatment. Brennan emphasizes that migraine is influenced by many factors and that individual experiences vary considerably.
“For every individual migraine attack, there are likely multiple influences: your genetics, stress levels, hydration, inflammation, the weather. And, yes, now we know that altitude is also an influence,” he explains. “But you don’t need to change your life around for one trigger. We can address this sort of thing in clinic.
“In fact, for years our headache faculty have been treating altitude-related migraine aura triggering. We need more research to fully validate these treatments (stay tuned), but they are safe and have been quite helpful.”
Importantly, for patients, the research on altitude provides scientists with a new avenue for understanding how migraine begins.
"If we can understand what altitude is doing to make the brain more susceptible," Brennan said, "we may learn something fundamentally important about migraine itself. And if we know that, we are on the road to truly novel treatments for this disease.”
Could Altitude Research Lead to New Migraine Treatments?
This U of U study is an important starting point. It raises intriguing questions that Brennan’s team is now working to answer through additional research.
A project that began as a clinical observation in Salt Lake City may ultimately help researchers better understand a condition affecting millions worldwide, including many who call the Mountain West home.
University of Utah research team members who contributed to this study:
- Katelyn M. Reinhart,PhD
- Melissa M. Cortez, DO
- J. Gary Urry, BS
- Kendra Pham, MD
- Jared Bartell, MD
- Kathleen B. Digre, MD
- Susan K. Baggaley, FNP-BC, MSN
- K.C. Brennan, MD
- Cecilia Martindale, MS
- Zubair A. Ahmed, MD
- Anna Newman
Reviewed by:
KC Brennan, MD
Director, Headache Physiology Laboratory
University of Utah Department of Neurology