Does Aura Really Initiate Migraine Attacks? Challenging the Conventional Wisdom

By Fred Schwaller | December 21, 2023 | Posted in

Neuroimaging findings from a single patient suggest that aura may be an epiphenomenon, with no causal role in the onset of an attack.

For some people with migraine, sensory symptoms and other disturbances known as aura can precede a migraine attack. A long-standing hypothesis in the field supposes that cortical spreading depression (CSD), a  wave of altered activity across the surface of the brain, underlies the migraine aura and directly spurs migraine attacks.

However, a recent study questions that assumption, suggesting that aura does not in fact initiate a migraine attack but is instead perhaps an epiphenomenon that can occur with migraine but does not causally trigger the headache.

Researchers led by Arne May, University Medical Center Hamburg-Eppendorf, Germany, gathered neuroimaging data from an individual who had migraine attacks both with and without aura. By tracking brain activity for 30 consecutive days, the investigators found that neuronal alterations became apparent 24-48 hours before a migraine attack, well before the time when aura typically occurs. Specifically, they detected hyperactivity in the hypothalamus that occurred independently of whether the patient experienced a migraine attack with aura or without it.

“This study shows there are common brain changes in migraine that are not CSD and occur in attacks of both migraine with and without aura. This indicates that CSD is not the fundamental trigger of a migraine attack,” said Andrew Charles, University of California, Los Angeles, US, in an interview with Migraine Science Collaborative. Charles, who was not part of the new research, wrote an editorial accompanying the new study.

The study and editorial appeared in the September 2023 issue of Headache.

Neuroimaging reasons to doubt the accepted wisdom
For decades, the CSD/aura-migraine hypothesis has guided thinking about migraine pathophysiology and treatment. One reason to suspect a causal role for aura in generating migraine attacks, the authors wrote in their paper, is animal research showing that CSD can activate nociceptive trigeminal neurons, whose activation is thought to trigger migraine headache.

However, the researchers, who did not respond to requests from MSC for direct comment, pointed to clinical findings that place doubt on the link between CSD/aura and the initiation of migraine attacks. For instance, some individuals who have migraine with aura can experience aura without a subsequent headache. Aura can also occur during or after the headache.

To test the hypothesis of a causal link between CSD/aura and migraine, the investigators examined brain activity in the hypothalamus before migraine attacks in their patient. Why the hypothalamus? One reason is that the authors had previously shown in longitudinal neuroimaging work that hyperactivation of this brain structure could occur in the preictal phase, two hours before an attack. (See here for a review of the role of the hypothalamus in headache and migraine.)

The investigators would gather data from one of the patients included in that earlier work for their current investigation. The patient was a 44-year-old male with a history of episodic migraine, sometimes with and sometimes without aura. The team collected functional magnetic resonance imaging (fMRI) data every day for 30 days, with a focus on brainstem and midbrain regions. fMRI can detect alterations in blood flow that accompany brain activity.

The patient experienced several migraine attacks during the 30-day period. Two attacks were included in the MRI analysis: one with aura and one without, as they met the study’s inclusion criteria that the patient be headache free for three days before an attack.

The neuroimaging data revealed hyperactivity in the hypothalamus in the preictal phase, one to two days before a migraine attack, in both the migraine with and without aura attacks. Further, the pattern of hypothalamic activity was similar throughout both types of attacks, whether looking at three days before an attack (defined in the study as the interictal phase), one to two days before an attack, or 0 to 24 hours before an attack (preictal phase), and during the migraine itself (ictal phase).

The findings thus put in doubt the role of CSD as an initiator of migraine.

“Our data … provide evidence that hypothalamic and thereby central alterations are preceding the migraine attack already two days before headache onset in both migraine attacks with aura as well as without aura,” the authors wrote. “These data strongly suggest that in terms of attack generation, the two types of migraine (with and without aura) share the same pathophysiology. The time frame of 24-48h that is obviously needed to build up a brain-driven spontaneous migraine attack contradicts CSD as the generator of attacks, as the aura usually only occurs minutes before the onset of headache,” according to the authors.

One reason for interpreting this conclusion with some caution is that the research only included one patient, which calls into question the generalizability of the results.

“There is always skepticism about ‘n of 1’ studies, which is legitimate,” said Charles. “For me, such studies show what is possible. If this possibility aligns well with other significant clinical evidence, as is the case here, then it is more likely that the findings are generalizable.”

So, what is the role of CSD after all?
Charles agreed with the authors’ conclusion that aura does not initiate migraine attacks, saying in his editorial that the findings “provide support for the concept that migraine with and without aura are not fundamentally distinct disorders, but rather the same disorder with different clinical symptomatology.”

Charles said he’s one of a very small minority of people who question the hypothesis that CSD/aura underlies the migraine attack, and questions why the hypothesis has been so persistent, but the study backs up his doubts. Part of the issue, according to Charles, is that there is little evidence in humans linking CSD and migraine.

“The phenomenon of CSD has never been definitively demonstrated during a migraine attack. This may be because it is happening on a much smaller spatial scale than it does in animal models, and therefore escapes detection by traditional EEG [electroencephalography], which may not have the spatial resolution to detect it,” he told MSC.

What, then, is the role of CSD? The study authors suggested two possibilities.

“One role may be that of one of many migraine triggers with unknown origin that further stresses a system already in distress. It is also possible that CSD is a simple epiphenomenon of the ongoing migraine attack, which could explain the aura symptoms but not the headache and may be caused by the change in neuronal activity in different areas of the brain and brainstem shortly before headache onset,” they wrote.

Finally, the new study also highlights an important role for the hypothalamus in generating migraine attacks.

“The hypothalamus makes sense as a primary site of a migraine attack. Premonitory symptoms, the relationship between migraine and sleep and hormonal function, and multiple other clinical evidence can be explained by a primary role for the hypothalamus,” Charles told MSC.

He added that a significant implication of the study is that the hypothalamus may be an important target for migraine therapies, especially anti-CGRP antibodies. Because part of the hypothalamus (the median eminence) lies outside of the blood-brain barrier, Charles says the region could also be easier and more plausible to target with pharmacological treatments.

“For example, while it is assumed that monoclonal antibodies targeting CGRP must work outside of the brain because they may not cross the blood-brain barrier, the hypothalamus may in fact be outside of the blood-brain barrier and could therefore represent a direct brain target of CGRP-targeted therapies,” he said.

Fred Schwaller, PhD, is a freelance science writer based in Germany. Follow him on Twitter @SchwallerFred

Image credit: 123RF Stock Photo.

References
Aura phenomena do not initiate migraine attacks—Findings from neuroimaging.
Mehnert et al.
Headache. 2023 Sep;63(8):1040-4.

Aura is a symptom of a migraine attack, not its cause.
Charles A.
Headache. 2023 Sep;63(8):1029-30.

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Fred Schwaller is a science writer and communicator based in Berlin, Germany. Fred spent a decade in pain research during his doctoral degree at University College London, UK, and his postdoc at the Max Delbrück Centre in Berlin, Germany. After transferring to science communication in 2020, he has been writing and podcasting about life sciences and medicine, specializing in somatosensation and pain. Follow him on Twitter @SchwallerFred.

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