The migraine—a common but debilitating brain disorder characterized by severe headaches, often with accompanying nausea and visual auras—has perplexed neurologists for decades. There are so many types of migraine, and each person’s physiology responds differently to the few drugs and treatments available.
In the hunt for an umbrella drug to treat all migraines, researchers at the University of British Colombia have investigated a potential new treatment for migraine with aura, which affects about one-third of migraine sufferers: pregabalin (brand name Lyrica). In a class of drugs called gabapentinoids, pregabalin is an anticonvulsant used to treat epilepsy, neuropathic pain, and fibromyalgia. The researchers published their results today in Proceedings of the National Academy of Sciences (PNAS).
Migraines begin in the brain before they’re ever visualized as an aura or felt as an intense headache. Researchers believe migraines are triggered by a brain pattern known as cortical spreading depression, or SD. Though triggers can be numerous, the SD starts in the brain as a “depolarization of neurons in a particular area of the brain,” Stuart Cain, lead author and a neurophysiologist at University of British Columbia, Vancouver tells mental_floss. “This causes a wave of excitation that travels across the brain.”
After the excitation period, there’s a long period of inactivity in which the neurons become stuck in this inactive state. “It’s this wave of inactivity that is actually causing spreading depression, and that causes the migraine aura,” he explains. Though the mechanisms are still not fully understood, they also believe this SD triggers the trigeminal nerve, one of the most widely distributed nerves in the head. That is what causes the headache pain.
As the SD travels slowly through the brain, it may go into the visual cortex and stimulate visual hallucinations, or even the auditory cortex, causing auditory hallucinations. In regular mice, the SD is constrained to the cortex, known as cortical spreading depression, which is typical migraine without aura. But in the mutant mice they used for the study, genetically modified to exhibit high susceptibility to the familial hemiplegic migraine (FHM) gene, FHM-1, which are associated with migraines accompanied by a visual aura, the SD enters the subcortical structures of the hippocampus, causing this type of migraine.
Migraines, strokes, and epilepsy are all known as calcium channel disorders; among other things, calcium channels play a role in cell depolarization and excitability. The FHM-1 patients have mutations in the P2 voltage-gated calcium channel. Pregabalin has been shown in previous studies to bind to the alpha-2 delta subunit of voltage-gated calcium channels, modulating the amount of calcium coming into the cell through this channel. When pregabalin inhibits the calcium, it also suppresses SD, which can stop migraines from starting.
To test the effects of pregabalin on the mutant mice, the researchers anesthetized the mice and induced migraine through implanted carbon fiber electrodes in the occipital cortex. Then, they injected them with a dose of pregabalin mixed with saline. (Humans would take an oral dose.)
“Mice have very fast metabolism, so you can’t wait too long,” Cain says. So 45 minutes later, they took eight consecutive image slices using a special form of MRI known as “diffusion weighted” MRI or “DW-MRI” over 13 minutes to track the SD in the mouse brains. “When SD occurs, the brain cells swell, and this changes the brightness of intensity on the MRI image. So we can view it as a movie traveling through the brain,” Cain says.
As they theorized, the pregabalin did indeed have an effect on SD. It slowed the speed and intensity of the SD waves. It also helped clear up a question neurologists have had about whether SD ever goes into the cerebellum, a structure in the very back of the brain that controls movement. “We were excited to see if the SD went into that structure in mutant mice, but it never did, so that was quite a big finding for the field," he says. "We now know that ataxia [a loss of voluntary muscle control] has nothing to do with SD.”
While they can’t recreate this same study design in human trials, since that would require inserting electrodes into the brain, they do have plans to combine MRI diagnostics with administration of pregabalin to attempt to improve outcomes for migraine patients. Cain is optimistic about the drug’s possibilities. “What the study shows is that more clinical trials are definitely warranted so we can properly validate its use for migraines,” he says.
For migraine patients, any new treatment in the already limited arsenal may bring hope.