Brain Imaging Reveals Neuroinflammation in Migraine With Aura

Batya Swift Yasgur, MA, LSW

April 11, 2019

Migraine with aura is associated with neuroinflammation, suggesting a potential link between cortical spreading depression (CSD) and glial activation, new research shows.

Investigators used integrated whole-brain PET/MRI to compare migraineurs with aura to healthy control persons and found elevations in the standardized uptake value ratio (SUVR) — a marker of glial activation.

Participants with migraine demonstrated SUVR elevations in areas associated with nociceptive processing as well as areas associated with CSD, suggesting that migraine with aura is associated with neuroimmune activation, especially through the possible connection between CSD and glial activation, which was previously observed only in animals.

"We found that people who have migraine with aura show neuroinflammation in the brain in areas that process the pain and also areas that have been involved in the generation of CSD," senior author Nouchine Hadjikhani, MD, PhD, associate professor of radiology, Harvard Medical School, and director of neurolimbic research, Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, told Medscape Medical News.

"Although these findings don't directly translate into clinical practice at the moment, they are one more proof — if there still needs to be proof — that migraine is a real neurological disorder, not just something one can ignore, and that it leaves traces in the brain," she said.

The study was published online March 27 in Neurology.

Ripple Effect

"Migraine is very common and many people suffer from it, but we still don't completely understand its pathophysiology, and so I've been working a long time to understand the chain of events that lead to a migraine," said Hadjikhani.

CSD is now understood to be the mechanism underlying migraine aura. Recent data from animal models demonstrate the cascade of inflammatory events that result from CSD and that lead to pain.

"CSD is the abnormal firing of neurons, comparable to throwing a pebble in water and seeing the ripples going from there. It's a spreading of activity in neurons that slowly moves 3 to 5 mm/min, and that is the basis of what people experience when they have a migraine aura," said Hadjikhani.

If the CSD occurs in the visual cortex, patients experience scintillation that starts in the center and moves toward the periphery.

In 2001, Hadjikhani and her team reported that CSD was the basis of the aura, but "what was still missing was what goes on between the event and the headache, and there was also no direct proof of inflammation in the brain."

Her team also previously demonstrated that patients with chronic low back pain exhibit elevated levels of the 18-kDa translocator protein (TSPO), a marker of glial activation.

TSPO is constitutively expressed at low levels in the healthy central nervous system by multiple cell types, including glia and neurons.

During neuroinflammatory states, TSPO is substantially upregulated, particularly in astrocytes and microglia — a process that can be quantified by the PET ligand [11C]PBR28.

"I thought that using this new tracer might be able to show whether there was neuroinflammation [during migraine aura]," Hadjikhani added.

The researchers state, "We hypothesized that individuals who experience migraine with aura would exhibit increased glial activation, as indicated by elevated TSPO PET signal, in brain regions contributing to aura presentation and in regions involved in nociceptive processing, compared to healthy controls."

To investigate the question, they compared patients with migraine to 16 healthy control persons who were matched in regard to age, sex, and TSPO polymorphism (case patients: n = 13; mean age, 31.2 ± 13; 10 women; control persons: n = 16; mean age, 37.0 ± 11; 10 women).

Migraineurs were required meet 2004 International Headache Society criteria for migraine with aura and to be experiencing a minimum of one and a maximum of 15 attacks monthly.

They were also required to have been experiencing migraines for at least a year and to be willing to abstain from use of nonsteroidal anti-inflammatory drugs (NSAIDs) during the 2 weeks prior to scanning.

Participants with major psychiatric disorders or known inflammatory diseases or who used illicit drugs were excluded. No migraineurs were taking medications to prevent migraine.

The researchers performed dynamic [11C]PBR28 scans using an integrated MRI/PET scanner.

Objective Measure

SUVR in migraineurs was elevated in the left thalamus, the left insula, and V1 (corrected P-values: .002, .016, and .008, respectively).

It was also higher, on average, for the right spinal trigeminal nucleus, the right S1 face area, and the right insula (corrected P-values: .056, .08, and .096, respectively), although these differences were not statistically significant.

Voxelwise group comparison showed statistically significant elevations in [11C]PBR28 signal in migraineurs vs control persons in several brain regions, including the posterior insula; the frontoinsular cortices; the primary and secondary somatosensory cortex; the primary motor, visual, and auditory cortices; the dorsolateral, ventrolateral, and ventromedial prefrontal cortex; the orbitofrontal cortex; and the putamen.

"Notably" increased PET signal was also observed in motion-processing areas MT and V3A, in addition to the primary visual cortex, the authors report.

In migraineurs, the number of migraines per month preceding the scan was positively correlated with SUVR in the left S1 face area region of interest (r = 0.737; P = .006, uncorrected).

Additionally, migraine frequency was found to be positively associated with SUVR in V1 (r = 0.549; P = .065, uncorrected), although this association did not meet statistical significance.

Voxelwise regression analyses showed positive correlations of SUVR with the number of monthly migraine attacks in several brain regions, including the right posterior insula/S2, the right S1, the left frontoinsular cortex, and the pregenual anterior cingulate cortex.

"This [approach] may serve in the future as a marker to follow how a treatment [for migraine] is helping," Hadjikhani commented.

"For the moment, when you try a new treatment, often you only have the number of migraines or intensity of the pain to inform treatment impact, and these are very subjective measures of efficacy of a treatment, so this is something that could potentially objectively measure how efficient a treatment is in decreasing migraine headaches," she said.

Targeting Neuroinflammation

Commenting on the study for Medscape Medical News, Daniel Franc, MD, PhD, Saint John's Medical Center, Santa Monica, California, who was not involved with the study, said anti-inflammatory treatments have "long been a mainstay of migraine treatment, from NSAIDs for acute migraine to oral or IV steroids for status migrainosus."

It is therefore "not surprising that advanced imaging has confirmed the presence of inflammation and chronic migraine in patients."

The study "suggests treatments targeting neuroinflammation and glial cell activation may be effective for the treatment and prevention of migraine," he said.

Hadjikhani added that it is too soon to recommend dietary approaches, such as use of omega-3 fatty acids or antioxidants, specifically to combat inflammation in patients with migraine.

However, "I think it's a good thing as a general rule to follow this type of diet," she said.

The study was supported by the National MS Society, the Department of Defense–US Army, the National Institutes of Health, the National Center for Advancing Translational Science, the National Center for Research Resources, a Harvard Catalyst Advanced Imaging Pilot Grant, the Harvard Clinical and Translational Science Center, and financial contributions from Harvard University and its affiliated academic healthcare centers. The authors and Franc have disclosed no relevant financial relationships.

Neurology. Published online March 27, 2019. Abstract

For more Medscape Neurology news, join us on Facebook and Twitter

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....

Recommendations