Optogenetics shows ways to soothe epilepsy

27 Nov 2024

California project combines optics and gene therapy to curb abnormal neural activity.

A project at UC San Francisco, UC Santa Cruz, and UC Berkeley has employed optogenetics to study the mechanisms of epilepsy, and to indicate possible routes to future treatment.

The optics-based approach could ultimately replace the surgical procedures currently used to remove the brain tissue where seizures originate, according to the project, offering a less invasive option for patients whose symptoms cannot be controlled with medication.

Optogenetics, in which light acts on genetically modified proteins to either stimulate neurons to fire or prevent them from doing so, has had a dramatic impact on studies of neural behavior and the workings of the brain.

The pioneers of the technique have received multiple awards, and the light delivery systems used to precisely stimulate the genetically modified neurons have become increasingly sophisticated.

Published in Nature Neuroscience, the new study is said to be the first demonstration that optogenetics can be used to control seizure activity in living human brain tissue, an environment where achieving the expression of light-sensitive proteins needed for optogenetics to work has proven difficult. It could also open the door to new treatments for other neurological diseases and conditions.

"This represents a giant step toward a powerful new way of treating epilepsy and likely other conditions," said Tomasz Nowakowski, an assistant professor of neurological surgery at UC San Francisco.

The researchers used brain tissue that had been removed from epilepsy patients as part of their treatment. To keep the tissue alive long enough to complete the study, which took several weeks, the researchers used a nutrient medium to create an environment mimicking conditions inside the skull.

Subtle and effective control over seizures

The light delivery system employed by the project was designed in the UC Santa Cruz lab of Mircea Teodorescu, and included a customized system to both optically stimulate the tissue and record the neurons' electrical activity.

The Teodorescu lab also wrote software that let the experimental platform be controlled remotely, so the group could direct experiments from Santa Cruz on the tissue located in a UC San Francisco lab.

"This was a very unique collaboration to solve an incredibly complex research problem," Teodorescu said. "The fact that we actually accomplished this feat shows how much farther we can reach when we bring the strengths of our institutions together."

In trials on their tissue samples, the researchers could see which types of neurons and how many of them were needed to start a seizure, and then determine the lowest intensity of light needed to change the electrical activity of those neurons in live brain slices. The ways that a seizure can also be inhibited, rather than propagated, by interactions between neurons were also observed.

One particular finding relates to a harmful feedback loop in a region of the brain called the dentate gyrus, leading to a seizure-like event in which neurons organize their activity into wave-like patterns propagating first in one direction, and then much larger wavelike patterns that propagate at 90 degrees to the initial waves.

Further investigation with techniques like the ones from this project could help scientists further pin down exactly what biological mechanisms predispose these neurons to self-organize in this way and become seizure-producing.

"These insights could revolutionize care for people with epilepsy," said Edward Chang from UC San Francisco. "We’ll be able to give people much more subtle, effective control over their seizures while saving them from such an invasive surgery."