Article In Brief
Investigators reported that MRI in individuals with episodic migraine showed areas of thinned cortex compared with controls, suggested that areas with cortical abnormalities in migraine may serve as potential targets for noninvasive neuromodulatory therapies.
A new multicenter trial using 3-Tesla MRI found significant clusters of thinner cortex in patients with episodic migraine compared with control subjects, according to a study published online December 10, 2018 in Cephalalgia, a journal of the International Headache Society.
“There seems to be a typical pattern of cortical thinning in several brain areas in migraineurs,” Till Sprenger, MD, the study's senior author, told Neurology Today.
“This may, in the future, be the basis for diagnosing patients in an objective way using brain imaging data together with machine-learning algorithms,” said Dr. Sprenger, professor and head of the department of neurology at DKD Helios Clinic in Wiesbaden, Hessen in Germany.
In the study, MRI in migraineurs showed areas of thinned cortex bilaterally in the central sulcus, in the left middle-frontal gyrus, in left visual cortices, and the right occipito-temporal gyrus.
The frequency of migraine attacks and the duration of the disorder had a major influence on cortical thickness in the sensorimotor cortex and middle-frontal gyrus.
Patients without aura exhibited thinner cortex than controls bilaterally in the central sulcus and in the middle frontal gyrus, in the left primary visual cortices, in the left supramarginal gyrus, and in the right cuneus.
Conversely, in patients with aura, there were clusters of thinner cortex bilaterally in the subparietal sulcus (between the precuneus and posterior cingulate cortex), in the left intraparietal sulcus, and in the right anterior cingulate.
“Some of the observed abnormalities may reflect a genetic susceptibility towards developing migraine attacks, while others are probably a consequence of repeated head pain attacks,” the authors wrote.
Previous studies have explored cortical abnormalities, particularly cortical thickness, in patients with migraine, but the findings were variable. The authors noted that the relatively small cohorts of patients in most earlier investigations may account partially for those deviations.
“Using a collaborative approach, we aimed at studying a larger group of migraineurs and to assess potential cortical abnormalities,” Dr. Sprenger told Neurology Today.
Investigators undertook the study to enhance their understanding of the underlying brain mechanisms of this common and debilitating disorder. Eventually, cortical abnormalities could be a biomarker of episodic migraine, with the potential to predict or monitor treatment efficacy, or both, he said.
“In principle, areas with cortical abnormalities in migraine may serve as potential targets for noninvasive neuromodulatory approaches, such as transcranial magnetic stimulation or transcranial direct current stimulation,” Dr. Sprenger said.
Study Design, Results
Researchers analyzed three Tesla MRI data for a total of 246 patients—131 patients (38 with aura and 93 without) and 115 control subjects, ranging in age from 18-55 years old. They controlled for age, gender, and MRI scanner to investigate differences of cortical thickness between control subjects and migraineurs. The objective was to assess the impact of clinical factors on cortical thickness measures.
MRI and clinical data from four academic headache centers were previously pooled to evaluate subcortical changes in migraine. This time, investigators studied cortical abnormalities in the same patients and control subjects. The participating centers were located in Munich and Hamburg, Germany; Glostrup, Denmark; and at the University of California, San Francisco. Data analysis was conducted in Basel, Switzerland.
All patients met the criteria for episodic migraine as set forth by the International Classification of Headache Disorders, second edition. Studies were performed interictally, and none of the patients had medication overuse headache. Investigators excluded patients with a prior history of cardiovascular or neurological disease other than migraine. Infrequent episodic tension-type headache was permitted in both groups.
Female participants represented 83 percent of migraineurs and 70 percent of control subjects. Fifty patients had a lateralized headache (left: 23, right: 27), and 68 had bilateral headache; the side was not recorded in 10 patients.
“The pathophysiological mechanisms underlying the observed cortical thinning of migraineurs compared with control subjects, as well as the difference between patients with and without aura, are still unclear,” the authors wrote.
They continued: “One may speculate that the differences observed at the cortical level relate to brain plasticity induced by attacks (e.g. with repeated pain stimulation) with changes of dendritic complexity or numbers of synapses. The genetic background may also play a role and cause such changes.”
The study “brings to light that migraine is a brain disease, and that over time can change brain structure,” said Jessica Ailani, MD, FAHS, associate professor in the department of neurology and director of the MedStar Georgetown Headache Center at Georgetown University Hospital in Washington, DC.
As a follow-up to various studies by other institutions, the investigators mentioned that complex algorithms have calculated the effect of chronic migraine on brain volume, she noted. “The more frequent the migraines, the more severe the brain changes. With the new study, one implication is that even if migraine frequency is low, it is impacting the brain,” Dr. Ailani said.
These findings also raise some interesting questions. “Who knows what that means long-term?” she speculated. While many migraine patients worry about developing dementia, Dr. Ailani wonders if there are any implications for “long-term changes in mood, or the way a person with migraine functions day to day.”
Although it would be premature to alter current practice based on one study, perhaps eventually neurologists could consider treating patients with infrequent migraine. “Maybe brain changes are starting earlier than we think,” Dr. Ailani said.
Deciding to treat a patient with migraine is based on the frequency of attacks, not on imaging abnormalities, said Stephen D. Silberstein, MD, FAAN, FAHS, FACP, professor of neurology and director of the Jefferson Headache Center at Thomas Jefferson University in Philadelphia.
Guidelines from the American Academy of Neurology have stated that there is no value in pursuing neuroimaging in patients with typical episodic migraine, Dr. Silberstein said. He is in the process of writing similar guidelines for the American Headache Society, and they are expected to uphold that recommendation. Furthermore, Dr. Silberstein said, insurers generally do not cover imaging costs for episodic migraine.
“The results of this study are interesting and important, but the relevance to clinical practice is uncertain,” he said. “The fundamental issue is, are these imaging abnormalities a cause of or a result of migraine?”
As the authors noted, the findings are indicative of an association between brain changes and migraine, but they are not necessarily causative, said Noah L. Rosen MD, FAHS, director of Northwell Health's Headache Center in Great Neck, NY, and associate professor of neurology at Hofstra University's Zucker School of Medicine in Hempstead, NY.
More research needs to be undertaken with an even greater number of migraineurs, both with and without aura, to confirm the study's results, Dr. Rosen said.
However, a large cohort and the enrollment of patients across multiple sites “definitely increases the validity” of this study, he said. “It's much more comprehensive than any previous study in this area.”
Improved imaging resolution has facilitated the capability of in-depth brain studies. “Technology has advanced,” Dr. Rosen said, “and it has allowed us to look at cortical thinning much better than we could in the past.”
Imaging could help distinguish between migraine with or without aura. Clinicians often have to rely solely on patient histories, which may be inaccurate, to arrive at a diagnosis. For instance, Dr. Rosen said, women who have migraine with aura are at a higher risk of stroke, yet they may not recognize migraine aura symptoms in themselves.
In addition, “there's still a lot of information that I would like to know that might have been captured in the database and may not have presented to readers,” he said, citing patients' handedness and psychiatric co-morbidities, such as depression and anxiety, as examples of “other more granular differences.”
Studies following participants over more extensive durations are needed as well. Much like epilepsy, migraine is “a chronic, intermittent condition, and you can debate how you define remission,” Dr. Rosen said, with peak incidence in the teenage years and a peak population prevalence by the mid-40s.
“The brain does change over time, and especially for a chronic condition over decades, longer studies would be useful,” he said.
Dr. Tiller reported no conflicts. As a consultant and/or advisory panel member, Dr. Stephen Silberstein receives, or has received, honoraria from Abide Therapeutics, Alder Biopharmaceuticals, Allergan, Inc., Amgen, Avanir Pharmaceuticals, Inc., Biohaven Pharmaceuticals, Cefaly, Curelator, Inc., Dr. Reddy's Laboratories, Egalet Corporation, GlaxoSmithKline Consumer Health Holdings, LLC., eNeura Inc., electroCore Medical, LLC, Lilly USA, LLC, Medscape, LLC., Satsuma Pharmaceuticals, Supernus Pharmaceuticals, Inc., Teva Pharmaceuticals, Theranica, and Trigemina, Inc. Dr. Rosen receives an honorarium from serving on the speaker's bureau for Allergan, receives an editorial honorarium from Current Pain and Headache Reports, and serves on advisory boards of Allergan, Amgen, Biohaven, Eli Lilly, Promius, Supernus, and Teva. Dr. Ailani receives honoraria for serving on the speaker's bureau for Alder, Avanir, Amgen, Allergan, Eli Lilly and Company, electroCore, Promius, and Teva. She has received honoraria from Alder, Amgen, Allergan, Eli Lilly and Company, electroCore, Promius, Teva, Impel, Satsuma, Avant, Medical Insights, Miller Medical Communications, and Alpha sites consulting; she has also received payment for editorial services for Current Pain and Headache Reports.