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An Epilepsy Drug May Have Treatment Potential for Migraines

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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.

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Why Is Your First Instinct After Hurting Your Finger to Put It in Your Mouth?
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If you close your fingers in a car door or slam your funny bone into a wall, you might find your first reaction is to suck on your fingers or rub your elbow. Not only is this an instinctive self-soothing behavior, it's a pretty effective technique for temporarily calming pain signals to the brain.

But how and why does it work? To understand, you need to know about the dominant theory of how pain is communicated in the body.

In the 17th century, French scientist and philosopher René Descartes proposed that there were specific pain receptors in the body that "rang a bell in the brain" when a stimulus interacted with the body, Lorne Mendell, a professor of neurobiology and behavior at Stony Brook University in New York, tells Mental Floss. However, no study has effectively been able to identify receptors anywhere in the body that only respond to painful stimuli.

"You can activate certain nerve fibers that can lead to pain, but under other circumstances, they don't," Mendell says. In other words, the same nerve fibers that carry pain signals also carry other sensations.

In 1965, two researchers at MIT, Patrick Wall and Ronald Melzack, proposed what they called the gate control theory of pain, which, for the most part, holds up to this day. Mendell, whose research focuses on the neurobiology of pain and who worked with both men on their pain studies, explains that their research showed that feeling pain is more about a balance of stimuli on the different types of nerve fibers.

"The idea was that certain fibers that increased the input were ones that opened the gate, and the ones that reduced the input closed the gate," Mendell says. "So you have this idea of a gate control sitting across the entrance of the spinal cord, and that could either be open and produce pain, or the gate could be shut and reduce pain."

The gate control theory was fleshed out in 1996 when neurophysiologist Edward Perl discovered that cells contain nociceptors, which are neurons that signal the presence of tissue-damaging stimuli or the existence of tissue damage.

Of the two main types of nerve fibers—large and small—the large fibers carry non-nociceptive information (no pain), while small fibers transmit nociceptive information (pain).

Mendell explains that in studies where electric stimulation is applied to nerves, as the current is raised, the first fibers to be stimulated are the largest ones. As the intensity of the stimulus increases, smaller and smaller fibers get recruited in. "When you do this in a patient at low intensity, the patient will recognize the stimulus, but it will not be painful," he says. "But when you increase the intensity of the stimulus, eventually you reach threshold where suddenly the patient will say, 'This is painful.'"

Thus, "the idea was that shutting the gate was something that the large fibers produced, and opening the gate was something that the small fibers produced."

Now back to your pain. When you suck on a jammed finger or rub a banged shin, you're stimulating the large fibers with "counter irritation," Mendell says. The effect is "a decrease in the message, or the magnitude of the barrage of signals being driven across the incoming fiber activation. You basically shut the gate. That is what reduces pain."

This concept has created "a big industry" around treating pain with mild electrical stimulation, Mendell says, with the goal of stimulating those large fibers in the hopes they will shut the gate on the pain signals from the small fibers.

While counter irritation may not help dull the pain of serious injury, it may come in handy the next time you experience a bad bruise or a stubbed toe.

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Bill Gates is Spending $100 Million to Find a Cure for Alzheimer's
Jamie McCarthy/Getty Images for Bill & Melinda Gates Foundation
Jamie McCarthy/Getty Images for Bill & Melinda Gates Foundation

Not everyone who's blessed with a long life will remember it. Individuals who live into their mid-80s have a nearly 50 percent chance of developing Alzheimer's, and scientists still haven't discovered any groundbreaking treatments for the neurodegenerative disease [PDF]. To pave the way for a cure, Microsoft co-founder and philanthropist Bill Gates has announced that he's donating $100 million to dementia research, according to Newsweek.

On his blog, Gates explained that Alzheimer's disease places a financial burden on both families and healthcare systems alike. "This is something that governments all over the world need to be thinking about," he wrote, "including in low- and middle-income countries where life expectancies are catching up to the global average and the number of people with dementia is on the rise."

Gates's interest in Alzheimer's is both pragmatic and personal. "This is something I know a lot about, because men in my family have suffered from Alzheimer’s," he said. "I know how awful it is to watch people you love struggle as the disease robs them of their mental capacity, and there is nothing you can do about it. It feels a lot like you're experiencing a gradual death of the person that you knew."

Experts still haven't figured out quite what causes Alzheimer's, how it progresses, and why certain people are more prone to it than others. Gates believes that important breakthroughs will occur if scientists can understand the condition's etiology (or cause), create better drugs, develop techniques for early detection and diagnosis, and make it easier for patients to enroll in clinical trials, he said.

Gates plans to donate $50 million to the Dementia Discovery Fund, a venture capital fund that supports Alzheimer's research and treatment developments. The rest will go to research startups, Reuters reports.

[h/t Newsweek]

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