August 09, 2011
By CJ Janovy
|Nancy Berman, PhD|
Nancy Berman, PhD, kept finding herself in front of audiences, trying to explain how she knew if a mouse had a headache. After all, it's not as if mice pop a couple of aspirin and crawl into bed.
Berman, a professor of anatomy and cell biology at the University of Kansas Medical Center, had become an expert on migraines as a result of previous research into "cortical spreading depression" - a wave of electrophysiological hyperactivity, usually in the part of the brain that controls vision, followed by a wave of inactivity. Physiologically, Berman says, cortical spreading depression is the equivalent of what's known as the migraine aura, when sufferers see lights and then have a sensation of blindness before a headache.
"I got hooked because I didn't understand this thing, the migraine," Berman says. "The more I learned, the more I realized nobody understood it."
Thirty million people in the United States suffer from migraines. That's nearly 10 percent of the population. "It's the most common neurological disorder," Berman says, "but there's been surprisingly little research done on it."
She points to a 2009 study by Robert Shapiro at the University of Vermont, who found that, from 1987 to 2007, the National Institutes of Health (NIH) had awarded between $6.8 and $13 million in grants for research on migraines.
"By comparison to NIH funding of research on 10 chronic medical conditions relative to disease burden, headache research funding should exceed $103 million annually," Shapiro concluded.
Even more problematic, Berman says, was that most researchers who were studying migraines were studying the problem in males. Clinicians had been able to link migraines to drops in estrogen during the female reproductive cycle. But research on female animal models was difficult because their reproductive systems are different from that of the human female. Researchers "didn't want to deal with the complications of the hormone cycles," Berman says.
Which is troubling, because 75 percent of the country's 30 million migraine sufferers are women.
Berman and her colleagues at KU Medical Center are taking the problem of women's pain seriously. The group of 18 researchers are attacking migraines - along with fibromyalgia, endometriosis and pelvic pain - as part of the Women's Pain Division at the medical center's Institute for Neurological Disorders. In addition to basic scientists such as Berman, the team includes pharmacologists and surgeons, as well as experts in gynecology and obstetrics, neurology, psychology, psychiatry and behavior science, allergies, immunology and rheumatology, trauma and critical care, integrative medicine and pediatrics.
Besides the research going on in the Women's Pain Division, five other similarly massive efforts are underway at the Institute for Neurological Disorders. Researchers have teamed up in divisions dedicated to brain injury and repair; neuromuscular and movement disorders; neurodegenerative disorders; hearing and equilibrium disorders; and cognitive and behavioral health.
But the mission in the Women's Pain Division is to come up with better treatments and cures for pain problems that disproportionately affect women.
"We've already proven that estrogen increases the number of pain-sensing connections that bring information into the central nervous system," says Peter Smith, PhD, professor of molecular and integrative physiology and director of the both the Institute for Neurological Disorders and its Women's Pain Division.
More than ten years ago, Smith says, tryptamine-based drugs revolutionized the treatment of migraines by blocking inflammatory molecules from acting on pain receptors. Newer drugs awaiting approval may be able to block the early events in migraine, possibly preventing migraines in the very early stages. But none of the common treatments is ideal. The most common pain treatments, opiates and nonsteroidal anti-inflammatory pain medications (NSAIDs, such as aspirin, ibuprofen and naproxen), all have downsides.
Berman knew that migraines were related to serotonin levels, so she zeroed in on the cells surrounding the brain's largest nerve. Studying female mice, she found links between the natural hormonal cycle and expression of genes related to serotonin function. Berman has since developed an animal model for testing new headache drugs. "We can check a drug's effects on any organ and determine if it has unanticipated effects," she says. "We can compare several migraine drugs and learn more about the mechanism of their action."
Now Berman knows when a mouse has a headache. In the process of developing the animal model, Berman discovered that rodents with headaches behave much the same as humans - they avoid light and sound, and they're aggravated by routine movements.
Another IND study is looking at how vitamin D could be a source of hope for migraine sufferers.
"We know that if you're vitamin-D deficient, you have more wires in your muscles to receive pain signals," Smith notes. "There is evidence that increasing vitamin D reduces or eliminates pain, but it's anecdotal. We hope to be the first to have a good randomized clinical trial in place, which should provide us with evidence to show what's going on."
All of which address a relatively new area of interest within the National Institutes of Health. The NIH's National Center for Complementary and Alternative Medicine (NCCAM), established in 1998, is funding research on approaches that are "not generally considered part of conventional medicine."
Last year, the agency committed to strengthening its research portfolio in the area of chronic pain treatment. When the agency issued a request for proposals to fund Centers for Excellence to conduct new research on pain, it caught the attention of the IND scientists, who knew they had already had an expert in complementary and alternative medicine.
Before joining KU Medical Center in November 2009, Joy Weydert, MD, now an associate professor of pediatrics, spent more than a decade using complementary and alternative medicine to treat young patients between the ages of 8 and 20, first in private practice and then at Children's Mercy Hospitals & Clinics in Kansas City.
"Many of the kids that I was seeing had already been to multiple other doctors -primary care doctors, neurologists, orthopedists, neurosurgeons, rheumatologists, psychiatrists," Weydert says. "They had been on multiple combinations of drugs to treat pain - headaches, fibromyalgia, back pain, limb pain. The pain was just enough that it was interfering with their daily lives."
Weydert combines a psychological approach with therapies such as acupuncture, herbs, dietary supplements and massage. She, too, is intrigued about the therapeutic potential of vitamin D. "We recognize that vitamin D likely could help because of its known effects on the anti-inflammatory pathways and how it may affect the serotonin pathways and neurotransmitter pathways."
Michael Rapoff, PhD, a specialist in behavioral pediatrics and the Ralph L. Smith Professor of Pediatrics, has been teaching children how to change their behavior to fight their own headaches. He uses cognitive therapy and is the co-inventor of an online "e-health intervention" called Headstrong that guides patients through relaxation techniques.
"Before puberty, migraines affect boys and girls equally," Rapoff notes. After puberty, though, it's a different story - and disabling pain is especially hard on female teens. "It compromises their quality of life, and they're more likely to develop secondary depression and feel isolated and discouraged," Rapoff says.
As a clinician, Weydert says working with basic scientists to solve problems is the way of the future. "This is the first time in my professional experience to have this breadth of knowledge, and to have so many different groups coming together," Weydert says of her colleagues in the Institute for Neurological Disorders.
For 22 million U.S. women, the effort is long overdue.
Find more information about KUMC's Institute for Neurological Disorders here.