A brain-circuit defect that triggers the most common form of childhood epilepsy has been identified by Stanford University School of Medicine researchers.
The researchers showed for the first time how defective signaling between two key brain areas -- the cerebral cortex and the thalamus -- can produce in mice the brief loss of consciousness and brain oscillations that characterize so-called absence seizures in children, according to a study published Aug. 21 online in Nature Neuroscience.
Young patients can spontaneously experience these seizures up to hundreds of times per day. The new findings could lead to a better understanding of how ordinary, waking, sensory experiences can ignite seizures, said the study's senior author, John Huguenard, a professor of neurology, neurological sciences and molecular and cellular physiology.
Epilepsy, a pattern of recurrent seizures, affects about one in 26 people over their lifetime, according to Huguenard. Absence, or petit-mal, seizures -- the form that epilepsy usually takes among children ages 6-15 -- feature a sudden loss of consciousness lasting 15 seconds or less.
These seizures can be so subtle that they aren't noticed, or are mistaken for lack of attention. The patient remains still for several seconds, as if frozen in place. Usually, a person who experiences an absence seizure has no memory of the episode.
"It's like pushing a pause button," Huguenard said.
Inside the brain, however, things more resemble an electrical storm than a freeze-frame, according to the researchers.
During an absence seizure the brain's electrical signals spontaneously go into rhythmic oscillations, beginning in the neighborhood of the cortex and thalamus. Exactly where or how this pattern is initiated has been a source of controversy, said the study's lead author, Jeanne Paz, a postdoctoral researcher in Huguenard's lab.
The cortex assesses sensory information, draws conclusions, makes decisions and directs action. To keep from being constantly bombarded by distracting sensory information from other parts of the body and the outside world, the cortex sends a steady stream of signals down to the thalamus, which act like an executive assistant.
The thalamus sifts through sensory inputs from the eyes, ears and skin, and translating their insistent patter into messages relayed up to the cortex, the researchers said.
These upward- and downward-bound signals would soon lead to out-of-control excitement, similar to a microphone being placed too close to a speaker. But an inhibitory nerve tract monitors the signals and dampens activity, keeping the system well modulated, researchers said.
But the Stanford team discovered that in bio-engineered mice a protein in the inhibitory cells that is critical to turning them on is missing. Mice affected with the missing protein are prone to the petit-mal seizures, they said.
When the researchers selectively turned on and off the stimulating signals from the cortex or thalamus nerves, something strange happened. While one nerve tract did turn off the signals as expected, the other, which comes from the thalamus, continued to fire signals.
This forced the cells from the thalamus nerve tract into overdrive, which caused the dampening cells to become overactive. They silenced all signaling from the thalamus to the cortex -- a key first step in a seizure, the researchers said.
But the shutdown was transitory. When the signaling stopped, the dampening cells ceased their output. The thalamus nerve-tract cells resumed a strong volley of signaling that overloaded the system again.
These oscillations of alternating quiet and exuberant periods repeated over the course of 10 or 15 seconds, constituting a seizure, researchers said.
The importance of this defect in humans is not yet known, Huguenard said. Most individuals who suffer from these seizures appear to have "normal" nerve cells and circuits indistinguishable from those of non-epileptics. But researchers now have an experimental system to study why ordinary everyday experiences can trigger these seizures.
Behavioral experiments are under way in Huguenard's lab to see what can trip off a similar circuit malfunction in normal mice. The resulting observations may someday help patients control their own exposures to minimize seizures, Huguenard said.
— Sue Dremann
