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Stanford University School of Medicine

“Choke point” for most-common form of childhood epilepsy identified

Epilepsy, a pattern of recurrent seizures, affects 1 in 26 people over their lifetime. So-called absence epilepsy (also called petit mal seizures) is most common among children ages 6 to 15 and accounts for about 1 in 20 epilepsy cases. Absence seizures are characterized by a sudden loss of consciousness accompanied by a behavioral "freezing in place" that persists for up to 15 seconds. A child experiencing an absence seizure usually has no recollection of it and may simply resume mid-sentence from the point he or she was at when the seizure hit.

"These seizures can be so subtle that they go unnoticed or are mistaken for a lack of attention," Stanford neuroscientist John Huguenard, PhD, told me when I interviewed him about a new study in Neuron.

Huguenard, who has spent many years studying the "wiring diagram" of absence seizures, has implicated a deep-brain structure called the thalamus, whose normal functions include relaying sensory information to the cerebral cortex via a nerve projection called, unsurprisingly, the thalamocortical tract.

Here's what Huguenard has learned, as described in my news release on the study:

The thalamocortical tract's excitatory nerve cells are somewhat like excitable second-graders. Imagine a classroom filled with children who share an inability to stay completely quiet for more than five seconds. Imagine, further, a teacher who doesn't mind the occasional loud whisper or random outburst but who will not abide noise above a certain threshold. When the din exceeds that level, the teacher shouts a show-stopping, 'Quiet!' The inevitable result of this enforced silencing: Five seconds later, the room will erupt in a burst of noise, in turn inducing an authoritarian cease-and-desist command, followed by another eruption, and so forth. The very act of inhibition drives a pattern of rhythmic firing.

Back in the thalamus, inhibition (the teacher's "shut up" signal in the analogy above) is meted out to the thalamocortical tract's excitatory nerve cells by a different set of thalamic cells whose job it is to generate useful rhythms in this brain structure. A gentle, rhythmic firing pattern in the thalamocortical tract is typical during normal sleep.

It makes sense, when you need sleep, to tune out disruptive sensory inputs from the thalamus to the cortex. But in absence epilepsy, this useful, rhythmic thalamocortical lullaby is hijacked and amplified into the distortion range. Subtle defects within the circuitry predispose the thalamocortical tract's firing to slip too easily into lockstep synchrony.

In the new study, Huguenard, his then-postdoc Jeanne Paz, PhD, (now at the Gladstone Institute in San Francisco), and their colleagues identified the thalamocortical tract as a "choke point" for absence seizures, which could be induced or halted at, literally, the flick of a switch in test animals.  The researchers used gene therapy to render those animals' excitatory thalamocortical nerve cells sensitive to particular wavelengths of light: Shining yellow laser light on them was like yelling at them to shut up in the analogy above, which induced seizures. Shining blue light made them more excitable, so they tended to fire out of synch -- this suppressed seizure activity.

Treatments that can guide excitatory thalamocortical nerve cells from a tightly synchronized to a more chaotic firing pattern may be able to halt absence seizures and, maybe, other forms of epilepsy, too, Hugenard said.

Previously: The brain makes its own Valium: Built-in seizure brake?, Light-switch seizure control? In a bright new study, researchers show how and Possible trigger for childhood seizures identified
Image by geralt

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