Such a systemic investigation of aura can identify mechanisms responsible for this migraine subtype. By sparking an aura in someone and then putting that person under a brain scanner, researchers hope to illuminate what an aura episode looks like on a neurologic level. Scientists say that until they are able to do so they can make very little progress toward identifying targets for drug development. Animal models can only take the research so far—mice and rabbits simply can’t describe whether they’re experiencing auras or not. A human model of migraine aura is needed.
“It would be better if migraine research was more firmly rooted in directions coming from human data than speculation coming from animal data,” says Peter Goadsby, director of the University of California–San Francisco Headache Center. “Knowing what’s going on in the aura phase could give us better clues about how to prevent the problem,” adds Andrew Charles, director
don’t get any migraines,” Stærmose says. By carefully limiting his exposure to potential trigger factors, Stærmose figures that he now suffers only around one migraine, complete with a preceding aura, each month.
But on a couple of occasions in 2011, he forwent his usual strategy of tactically avoiding problematic stimuli. Under the watch of neurologists, Stærmose instead actively tried to set off the experience of aura. He ran up stairs at full tilt. He rode an exercise bicycle while wearing heavy rain gear, at times with a strobe light flashing in his face—all in the name of science. Stærmose, who, inspired in part by this experience as a research subject, is now studying to be a doctor at Aarhus University in Denmark, was one of 27 participants of a clinical trial at the Danish Headache Center (DHC), located at the Glostrup Hospital on the outskirts of Copenhagen, which sought to determine a reliable and reproducible way to invoke aura attacks in the laboratory.
Tobias Stærmose was an avid runner. As a teenager, he competed in track competitions, winning several medals in the individual and relay sprinting events at the national youth championships in his native Denmark. But debilitating migraine headaches sidelined his athletic career. During practice, or more often on his way home afterward, a tiny bright spot would appear on one side of his vision. It would grow across his field of view and fill with wavy lines—like “heat waves,” Stærmose says. His aura had begun. Pounding waves of pain in his head soon followed.
The 22-year-old now avoids all strenuous exercise. He doesn’t run anymore. He never showers after he wakes up (the hot water is a reliable stimulus, but only in the morning) and he makes sure to wear sunglasses whenever a cloud-filled sky beams down a certain hue of bluish-yellow light. “It’s a constant regulation of what I know I can do and what my body is telling me I can do so I
It begins as a slowly expanding spot of light or similar visual disturbance, often accompanied by phantom noises and other sensory distortions. People who experience such ‘auras’ know all too well that these early warning signs will culminate in a head-splitting migraine, yet scientists have little idea what causes the debilitating deluge of symptoms. Elie Dolgin talks to neurologists hoping to change that—by triggering auras in the laboratory in order to study them.
Illus
trat
ions
by
Sydn
ey S
mith
NATURE MEDICINE VOLUME 19 | NUMBER 9 | SEPTEMBER 2013 1083
of CSD through measurements of cerebral blood flow. But “it’s very, very difficult to do studies during the spontaneous attacks because they’re unpredictable,” says Messoud Ashina, director of the Human Migraine Research Group at the DHC and an associate professor of neurology at the University of Copenhagen. “It’s much better to do experimental attacks so you have a controlled condition.”
Some research groups have published isolated case reports describing spontaneous migraines captured by computed tomography or MRI. But the logistical difficulties of getting people into the scanner in a timely fashion has meant that these studies have typically been restricted either to small numbers of staff members at major medical centers who happen to have migraines with aura3 or to patients seeking ambulatory help for other ailments who also had aura symptoms as well4. Even then, in these rare instances, the first minutes after the onset of aura are usually missed.
Michael Moskowitz and his colleagues at the Massachusetts General Hospital Neuroscience Center in the Boston area described the most famous report of a controlled study involving a person experiencing aura in a lab in 2001. They identified a patient, named Patrick, who could reliably induce his aura by playing basketball. The researchers arranged for Patrick and his wife to shoot hoops next door to their research center at a YMCA gym. After about an hour of exercise, Patrick then jumped into a functional MRI machine at the clinic and waited for his aura to begin. In this way, Moskowitz and his team tracked changes in Patrick’s brain before, during
of aura can include tingling, dizziness and ringing in the ears. For these migraineurs, aura attacks can last anywhere from five minutes to over an hour before full-blown headaches come on—although some people, usually older adults, are prone to ‘acephalgic migraines’ (also known as ‘silent migraines’) in which they experience aura and a subsequent range of symptoms such as nausea and chills but no headache. There is no available treatment for the signs and symptoms of aura.
A phenomenon known as cortical spreading depression (CSD) is thought to underlie migraine aura. First described in the 1940s in the brain of a rabbit, CSD involves a slowly spreading wave of suppressed neuronal activity that propagates across the cerebral cortex. CSD makes sense as the cause of aura since the wave of neuronal and glial depolarization travels at 3–5 millimeters per minute—about the same speed that auras march across people’s visual fields. More recently, scientists have proposed that CSD might be the ultimate cause of migraines without aura, as well. Proponents cite experimental evidence in rodents linking CSD with inflammatory changes that stimulate pain receptors on the trigeminal nerves. However, these data remain controversial, and many still believe that aura and CSD are mechanistically distinct from the ensuing migraine.
Human subjects could help tease apart the neurologic underpinnings of both aura and headaches. CSD can be observed directly by implanting electrodes on the brain, but this procedure is considered a no-no for otherwise healthy migraineurs. Imaging techniques such as magnetic resonance imaging (MRI) allow for indirect evaluation
of the Headache Research and Treatment Program at the University of California–Los Angeles David Geffen School of Medicine.
Using self-reported triggers does not seem to be the solution to the problem, though. “I gave it everything I had,” recalls Stærmose, but “it didn’t seem to work.” Although he sometimes had the sensation that an aura might be imminent, none ever appeared.
Stærmose wasn’t alone. Of the 26 other participants in the study, only three developed aura-filled migraines after being provoked with light, exercise or both supposed triggers; three others reported headaches without aura attacks. The results, published earlier this year in Neurology1, were consistent with the findings of an earlier study at Henry Ford Hospital in Detroit that used photostimulation alone to trigger aura in just four of 23 subjects, two of whom had symptoms similar to their usual auras and two who had atypical visual symptoms2.
Anders Hougaard, a neurology resident and PhD student at the DHC who ran the Danish trial, isn’t quite sure why natural triggers failed to elicit aura in most volunteers. Perhaps participants, withdrawn from their usual routines, simply didn’t experience the normal levels of stress that help bring about their auras. Or maybe they had misidentified their personal trigger factors. Whatever the reason, one thing is clear: “If we want to study aura, we need to trigger aura,” he says. “But unfortunately, we don’t know of any good methods currently.”
Spread the wordAbout 20–30% of migraine sufferers experience aura. Besides the kinds of visual disturbances felt by Stærmose, the symptoms
Score an aura: Researchers have struggled to reproduce aura episodes in patients.
1084 VOLUME 19 | NUMBER 9 | SEPTEMBER 2013 NATURE MEDICINE
NATURE MEDICINE VOLUME 19 | NUMBER 9 | SEPTEMBER 2013 1085
N E W S F E AT U R E
and after self-described aura attacks on two separate occasions3.
“We were lucky as hell to get this patient,” says Moskowitz. But neither he nor any of his coauthors have found anyone like Patrick since. Nor has any other neurologist anywhere, for that matter. Patrick’s story was a one-off. And, to this day, it remains a mystery why basketball was such a trigger for him. Was it the exertion? The visual effect of the dribbling ball? The fluorescent lighting of the gymnasium? All of the above? “It was never totally clear what his unique trigger was,” says study author Michael Cutrer, a neurologist at the Mayo Clinic in Rochester, Minnesota, who previously worked in Moskowitz’s lab.
Trigger unhappyFrustrated by the unreliability of natural triggers of aura, many researchers have turned to pharmacological stimulants. A drug called calcitonin gene–related peptide (CGRP) causes headaches in the majority of migraineurs, whether they experience aura or not, but not in healthy controls. Ditto the nitric oxide–releasing agent nitroglycerin. The only problem: those drug-induced headaches in the lab are rarely preceded by aura in those who regularly suffer such episodes5–8. And even when they are, the effect is not always reproducible.
Three years ago, for example, Ashina and his colleagues reported that CGRP could elicit aura symptoms in four of 14 migraineurs who normally experience auras8. Yet, when those same four individuals who tested positive came back into the lab recently for another dose of CGRP, only one experienced an aura. The other three didn’t have headaches at all. Using CGRP to induce aura “is not consistent, it’s unreliable and it’s not efficient,” says Hougaard, who presented the unpublished follow-up work in June at the International Headache Congress in Boston. The triggering of aura simply seems to be different from the instigation of migraines. Further evidence for this conclusion comes from studies of people with familial hemiplegic migraine (FHM), a rare inherited subtype of migraine with aura. DHC researchers have given intravenous infusions of nitroglycerin9,10 and CGRP11,12
to volunteers with FHM and have found that fewer than 25% of patients are triggerable to any sort of attack (see ‘Score an aura’).
The only method that has been proven to dependably work to create aura episodes in patients is carotid angiography, an invasive procedure that involves inserting a catheter
into the common carotid artery in the neck. Jes Olesen, the founder and codirector of the DHC, used this technique to consistently induce aura in his patients while working at a different Copenhagen area hospital in the 1980s13. However, it’s no longer considered ethical to conduct such an intrusive and risk-prone procedure on people who don’t medically need it.
Some might still worry about the ethics of inducing undue pain in study subjects
through any migraine provocation technique, not just invasive procedures. But as most experts point out, the methods used today—intravenous drugs, natural trigger factors—do not cause long-term problems, and patients are free to ask for antimigraine medications at any time during the trials. “You can always say to patients, ‘Apart from getting an extra headache, no other dreadful thing is going to happen,’” notes Goadsby.
Something in the airThe Danish team now has some new ideas for how to induce auras. Perhaps different pharmacological agents could work. Or maybe intravenous injections of tiny air bubbles. Or possibly another natural trigger factor, such as sleep deprivation, either alone or in combination with exercise. However, the main tactic being pursued now is to deprive people of oxygen in order to create a pathological condition known as hypoxia.
“Some things point to hypoxia as a trigger,” Hougaard says. First, spending time at high altitudes, where oxygen levels are lower, can lead to acute mountain sickness, and many alpine climbers who succumb to this disease develop symptoms that fulfill the criteria for migraine. Second, chronic exposure to
high altitudes has been associated with an increased prevalence of migraine (mostly with aura) in some mountain-dwelling communities14. And third, short-term drops in oxygen levels in neuronal tissue have been linked to CSD in mice15, thereby providing a possible mechanistic link.
Researchers at the Leiden University Medical Center in the Netherlands previously used hypoxia exposure to trigger migraine attacks in 16 people, including eight who
regularly experience aura. Although no one in the small exploratory study reported aura, around half the participants suffered headaches after 20 minutes of breathing nitrogen-enriched air16.
Building on these pilot findings, Hougaard and Ashina are now equipping people with a mask through which they are forced to breathe air with low oxygen concentrations. Earlier this year, they tested the experimental setup on healthy volunteers to prove that the technique was safe. Beginning this month, they hope to start evaluating the method in regular aura sufferers. If the experiment works, they will then repeat the study with participants lying inside an MRI machine.
“I don’t give up,” Ashina says. “I will try to get the aura in the scanner and try to figure out what goes on in the brains of these patients.”
Elie Dolgin is senior news editor of Nature Medicine in Cambridge, Massachusetts.
1. Hougaard, A., Amin, F.M., Hauge, A.W., Ashina, M. & Olesen, J. Neurology 80, 428–431 (2013).
