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Experimental Brain Pacemaker Alleviates Seizures in Rats

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Duke Health News 919-660-1306

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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