Nov. 8, 2000 DURHAM, N.C. - Duke University Medical Center researchers have discovered a promising new way to alleviate epileptic seizures by stimulating a facial nerve that extends into the brain, disrupting the cycle of seizure activity. Their experiments in rats also involved testing the concept of a "brain pacemaker," which could be reduced to a small device that could detect potential seizure activity and stimulate the nerve to prevent seizures in humans.
Their findings, reported in the Nov.1 issue of the Journal of Neuroscience, offer hope of greatly improved seizure control for the 10 percent to 50 percent of epileptic sufferers whose disorder is resistant to antiepileptic medication or surgery.
In the paper, Associate Professor of Neurobiology Miguel Nicolelis and colleagues Erika Fanselow and Ashlan Reid report that stimulating one of the two trigeminal nerves in rats given a seizure-producing drug could reduce those seizures up to 78 percent. Stimulation of both trigeminal nerves, which carry sensory information from either side of the jaw into the brain, proved even more effective.
"It has been long known that electrically stimulating cranial nerves such as the vagus nerve can have powerful effects in the cortex," said Nicolelis. "And it was known that these effects include desynchronizing neurons that are firing together in synchrony - the highest level of such synchrony being a seizure.
"Such stimulation of the vagus nerve has proven somewhat useful in stopping seizures, and in fact is now used in patients," Nicolelis said. "However, since the vagus nerve is so powerful, controlling the heart, lungs and other autonomic functions, such stimulation is relatively risky, perhaps disrupting heart function, for example." According to Nicolelis, the powerful effects of vagus nerve stimulation also meant that only one vagus nerve, the one that does not affect the heart, could be stimulated in attempts to reduce seizures.
Thus, Nicolelis and his colleagues reasoned that the trigeminal cranial nerve -- which seemed more benign because it innervates only the face -- might prove a more effective route to preventing seizures.
The scientists tested their theory by treating rats with a seizure-producing drug and attempting to reduce or eliminate those seizures through trigeminal nerve stimulation.
"We found that such stimulation clearly relieved seizures, which was a big surprise because nobody had thought about it, even though the basic understanding that stimulating cranial nerves affected the brain has been available for 50 years," Nicolelis said.
The scientists' finding lends support to the theory that nerve stimulation reduces seizures by activating a non-specific "arousal" mechanism in the brain. Such non-specificity implies that any nerve reaching into the appropriate brain regions can be stimulated to disrupt synchrony.
The scientists also found that they could stimulate both trigeminal nerves using a lower current and yet achieving even greater seizure reduction. The ability to use lower voltages reduces the chance of nerve damage or pain from nerve stimulation, said Nicolelis.
"When we found that such trigeminal nerve stimulation was so successful, we believed that we could achieve even more effective seizure prevention, as well as reduce the risk of nerve damage, by stimulating only when a seizure appeared imminent," Nicolelis said. In contrast, he said, current vagus nerve stimulation in humans is manually operated, either on a fixed intermittent cycle, or by the patient who is having a seizure or feeling one coming on.
Thus, the neurobiologists, working with Duke biomedical engineers, developed and tested a system in the rats that would monitor their brain wave patterns via brain electrodes and automatically activate the trigeminal nerve stimulation only when the tell-tale patterns marking a seizure appeared.
The seizure-related system proved almost 40 times more effective at seizure reduction per second of stimulation than was periodic stimulation not related to seizure activity, the scientists said.
"These findings lead us to believe that we could develop a system that would work like the brain equivalent of a heart pacemaker to actually prevent seizures," Nicolelis said. "It could continuously monitor brain wave patterns, using non-invasive EEG electrodes on the person's scalp, in order to detect the well-known pathological signature of seizures from a few seconds to a minute before they start. Then, the system could stimulate the trigeminal nerves to prevent the seizures."
Microchip technology could allow the EEG detection and pattern-analysis circuitry to be reduced to a tiny size, said Nicolelis, and he and his biomedical engineering colleagues are now developing such microcircuitry. Also, he said, such pattern analysis could be highly sophisticated, using multiple methods, or algorithms, for recognizing pre-seizure brain wave patterns and "voting" on whether a seizure was imminent. Using such multiple methods could increase the accuracy of detection of pre-seizure activity, Nicolelis said.
"We have now demonstrated for the first time the concept of unsupervised seizure detection and seizure therapy systems in awake animals," he said. "And the level of seizure reduction we have achieved is above what the FDA has considered justifiable for the vagus nerve implant that is already in clinical use. Thus, we believe that the first clinical application of this technique could be possible in about five years."
Besides developing the "neurochips" for such a brain pacemaker, Nicolelis and his colleagues will also explore the ability of trigeminal nerve stimulation to reduce or prevent a wide variety of seizures. The scientists' work was supported by the Klingenstein Foundation.
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