For release: Friday, November 16, 2007
Migraine headaches are a source of disabling pain for millions of people. Now, a study in mice suggests that these headaches may be linked to tiny areas of stroke-like brain damage. The findings suggest that treatment to prevent migraines may also prevent longer-term cognitive problems.
The study, led by Takahiro Takano, Ph.D, and Maiken Nedergaard, M.D., Ph.D., of the University of Rochester Medical Center in New York, focused on a phenomenon called cortical spreading depression (CSD), which occurs in migraines as well as stroke and traumatic brain injury. In CSD, a slow-moving wave of potassium ions causes large numbers of neurons to signal at once, followed by a period when normal neuronal activity in that area is halted.
Drs. Takano and Nedergaard investigated the effects of CSD in the brain using mice. They injected a drug to trigger CSD and watched the effects using a technique called two-photon microscopic imaging. They also used microelectrodes to measure the amount of oxygen in the tissues while the wave of CSD passed through the brain. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appeared in the June 2007 issue of Nature Neuroscience.
The researchers found that CSD caused a short-term drop in oxygen levels and obvious swelling in the neurons. It also caused a temporary loss of dendritic spines, which are tiny projections on neurons that form junctions (synapses) with other neurons. These changes are signs of hypoxia – a state where neurons have too little oxygen to function normally. Hypoxia usually results from reduced blood flow in part of the brain and is what causes brain damage in strokes and transient ischemic attacks (TIAs). In the new study, however, the researchers saw signs of hypoxia even though the amount of blood flow in the brain temporarily increased.
“It is critical for the brain to keep normal levels of potassium,” Dr. Nedergaard explains. It takes a great deal of energy to reduce CSD-related potassium levels in the brain. Producing this energy requires oxygen. Dr. Nedergaard believes the brain’s attempts to reduce excess potassium and halt CSD prompt the temporarily increased blood flow associated with CSD. Unfortunately, however, the study showed that neurons close to the tiny blood vessels in the brain used up most of the increased oxygen. This caused small pockets of hypoxia in brain tissue that was farther away from the blood vessels. The hypoxia lasted for more than two minutes.
“Our study puts forth a new concept: that hypoxia can occur even without reduced blood flow when there is a high energy demand,” Dr. Nedergaard says.
The researchers also investigated whether they could decrease the hypoxia associated with CSD by increasing the percentage of oxygen in the air around the mice. They found that 100 percent oxygen shortened the duration of CSD, while decreasing the concentration of oxygen prolonged the duration. Very low oxygen even triggered spontaneous waves of CSD in some mice.
This study is the first to show that CSD can cause severe hypoxia, neuronal swelling, and loss of dendritic spines in animals. These changes appeared to be temporary. However, since the hypoxia continued for several minutes, it is possible that it could cause lasting changes in brain function, Dr. Nedergaard says. “In humans, the dendrites may recover in the short term, but if there are 20 or 100 spreading depression waves, the damage may accumulate,” she adds. Previous studies have shown that visual processing is impaired in some people who experience migraines, and that migraine with aura is a risk factor for stroke. Some studies also have found subtle problems with memory, reaction time, and attention in people who experience migraines, although other findings have contradicted those results.
Many studies have shown that migraines with aura are linked to CSD, Dr. Nedergaard says. Auras are symptoms such as visual disturbances, dizziness, or numbness that precede migraines in some people. The new work suggests that these auras actually are caused by the temporary hypoxia linked to CSD. Recent studies have suggested that migraines without aura are also linked to CSD, although it may be less pronounced or it may affect different parts of the brain in people who do not experience auras. Animal studies have shown that CSD also irritates the trigeminal nerve, which transmits pain signals and triggers inflammation in the membranes that surround the brain. Many researchers now believe that this inflammation contributes to the pain associated with migraines.
The findings suggest that drugs which prevent migraine might also prevent damage to neurons and nerve connections in the brain, and they support the idea that CSD inhibitors may be useful for treating migraine. The anti-seizure drug topiramate prevents CSD and is sometimes used to prevent migraines. Another CSD inhibiting drug, tonabersat, is now being tested in clinical trials.
The new findings may be significant not only for migraine, but also for other neurological diseases. CSD frequently occurs after stroke and head trauma and may literally add insult to injury, Dr. Nedergaard says. One study even found that people with more CSD waves after a head injury had a worse outcome than people with fewer waves. CSD also occurs during seizures.
While hyperbaric chambers with increased levels of oxygen are sometimes used to treat migraine with aura, this treatment is unlikely to reduce CSD because the CSD happens early in the migraine process, before people would get to a hospital, Dr. Nedergaard says. However, the increased oxygen might help to relieve the blood vessel constriction that follows CSD and reduce the pain of migraine, she adds.
Drs Takano and. Nedergaard now plan to examine whether dendrites damaged by CSD regain their normal structures.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
-By Natalie Frazin
Takano T, Tian G-F, Peng W, Lou N, Lovatt D, Hansen AJ, Kasischke KA, Nedergaard M. “Cortical spreading depression causes and coincides with tissue hypoxia.” Nature Neuroscience, June 2007, Vol. 10, No. 6, pp. 754-762.
Last Modified November 16, 2007