Inside Neuroscience: Migraine Insights

Migraine — a particular type of headache that can come with visual, sensory, and other symptoms — strikes one in seven people worldwide. Researchers believe that migraine symptoms are caused by neurogenic inflammation along with vascular changes in the brain, but targeting these inflammatory effects hasn’t been as useful for patients as many scientists had hoped.

Ian Meng

“Current treatments, while effective for some people, do not provide adequate relief for many people with migraine,” said Ian Meng, a neuroscientist at the University of New England. This indicates that although blood vessel abnormalities might be present, a significant proportion of migraines may be driven by signaling within the brain itself.

“Migraine is not just a vascular disorder,” Meng said, “but really a brain network disorder as well.” In that vein, scientists are taking a closer look at functional changes in the brain and rethinking how we develop migraine treatments.

In a Neuroscience 2025 press conference titled “The Neuroscience of Migraine: Exploring Causes and Treatments,” moderated by Meng, four researchers shared new strategies for prevention, new molecular mechanisms, and new model systems for understanding migraine.

Reducing Migraine with Diet

While migraine is generally more common in women than men, veterans who served in the 1990 Gulf War are especially likely to suffer from headaches and migraines. A quarter of veterans who served in that war experience a chronic illness due to their service, generally called “Gulf War Illness.” Of those, 64% have migraines.

Ashley VanMeter, who studies neuroscience at Georgetown University, used MRI to visualize the brains of veterans with and without migraine. She found that veterans with Gulf War Illness had a thicker visual cortex, suggesting that there was some inflammation within the brain. That inflammation, she said, could indicate a leaky blood-brain barrier, allowing molecules normally sequestered from the brain to begin interacting with neurons.

Ashley VanMeter

VanMeter worked with Katie Holton, a nutritional neuroscientist at American University, who had previously developed a whole foods diet to reduce migraines specifically by minimizing glutamate. Glutamate “is an excitatory neurotransmitter, and it’s a healthy part of our brains,” VanMeter said. “Dietary intake of glutamate normally cannot enter the brain… but if we have a leaky blood-brain barrier, then the dietary glutamate is going to be entering the brain.” With excess glutamate in the brain, VanMeter added, the brain has increased “excitotoxicity”, which drives further inflammation and oxidative stress.

Glutamate is present in common foods like mushrooms, meat, and soy sauce, and in especially high concentration in foods made with monosodium glutamate (MSG). In a small clinical study of 40 veterans with Gulf War Illness, the team found that reducing dietary glutamate by eliminating these types of foods could decrease the frequency and severity of migraines. After one month of a low-glutamate diet, the percentage of participants reporting migraines dropped from 64% to 12.5%. The low-glutamate diet also returned the thickness of the visual cortex to normal.  

Although this preliminary clinical trial only included Gulf War veterans and skewed towards male participants, a new pilot study for non-veterans with migraine is in the works.

Sex Differences in Migraine Mechanism

Neuronal function within the brain is governed by a balance between excitatory and inhibitory signals, the former driven by glutamate, as described by VanMeter, and the later by GABA, a neurotransmitter that has also been implicated in migraine.

“GABA works like the brakes on a car… it prevents the brain from getting over excited,” said Anju Vasudevan, a neuroscientist at Huntington Medical Research Institutes. Vasudevan has been exploring the role of GABA in chronic migraines.

Anju Vasudevan

Vasudevan and colleagues provoked migraines in mice with repeated injections of nitroglycerine, a well-developed migraine model. Over time, male and female mice both began to develop migraines. But only the males showed reduced GABA-producing neurons in areas important for migraine, including the neocortex, hippocampus, amygdala, and the brainstem. Loss of neurons in these male mice was accompanied by sustained neuronal activation and chronic cellular stress.

But curiously, while the female mice still had migraine symptoms, they had no loss of GABA-producing neurons, pointing to sex-specific migraine mechanisms. In females, “it's triggering a completely different pathway,” Vasudevan said.

“If inhibitory neurons and stress pathways are differentially recruited in males versus females,” said Vasudevan, “then it means that migraine therapy should also be sex-specific.”

Old Drugs for Treatment-Resistant Migraine

Based on research into the inflammatory mechanisms of migraine, the past several decades have seen the development of new treatments. But Owein Guillemot-Legris, a neuroscientist at Transpharmation, has been exploring an old molecule for potential efficacy in reducing migraine severity and frequency.

Owein Guillemot-Legris

“Psilocybin has been shown to be effective in relieving pain in many clinical and preclinical settings,” said Guillemot-Legris. The active ingredient in hallucinogenic mushrooms, psilocybin has reduced migraines in small clinical studies but has also been shown to induce headaches in healthy people.

In three mouse models of migraine, Guillemot-Legris conducted head-to-head comparisons of psilocybin with the latest migraine medications, including sumatriptan (which targets blood vessel dilation) and CGRP inhibitors (which target over-sensitive nerves). Each time, psilocybin was able to decrease migraine pain, including in a model of treatment-resistant migraine.

Although the mechanism of how psilocybin functions has yet to be worked out, Guillemot-Legris hopes this will be explored in future clinical studies.

Closing the Model-Clinic Gap

Rodent models of migraine are designed to mimic a common symptom of migraine in humans: facial pain. But as noted by Meng and Guillemot-Legris, in some ways these animal models fall short, and medications designed on these models are only effective for a subset of people. This suggests a fundamental gap between the mechanism of migraine in the animal models versus the mechanism of migraine in humans.

Mark Urban

“Trying to translate the pathophysiology from the animals to the clinic — that is very, very difficult to do,” said Mark Urban, a neuroscientist at PsychoGenics. Urban is attempting to close that gap in a novel way: Rather than designing an animal model to mimic the human condition, he proposes using an experimental system of induced pain in both animals and humans. Urban is currently developing this type of experimental system using the molecule isosorbide dinitrate (ISDN), which generates facial pain in rats and headache pain in humans. ISDN works by producing nitric oxide, a molecule implicated in the development of migraine.

Urban’s plan involves three steps. The first step is to test new drugs on rats treated with ISDN. If the drug displays positive results, the second step would be to test it in a small trial of ISDN-treated humans. If that small human trial proves successful it may be worth pursuing in a larger clinical trial with humans naturally experiencing migraine. This three-step process could help identify worthwhile medications more quickly, at reduced cost, and with lower risk of failure.

Urban has found that currently available migraine treatments, including triptans and CGRP inhibitors, can reduce pain in his ISDN-treated rats, suggesting this system may be a reasonable model for migraine.