California Team Looks to Optogenetics for Treating Epilepsy

by James Cavuoto, editor

November, 2024 issue

New neuromodulation therapies for treating epilepsy have emerged in recent years, offering hope to patients who are resistant to drug therapy. Cyberonics’ vagus-nerve stimulation system became the first implanted neuromodulation device to treat epilepsy more than two decades ago. That company's successor, LivaNova, was later joined by NeuroPace, with its closed-loop epidural stimulation system, and Medtronic, with its DBS system.

A European firm called Synergia Medical has developed an optical VNS system which minimizes the use of metallic components by using innovative materials such as quartz, polymer optical fibers, and miniaturized photovoltaic cells. The company implanted its NAO.VNS system in the first two patients in September as part of the AURORA study.

Earlier this month, a team of researchers from UC San Francisco, UC Santa Cruz, and UC Berkeley used optogenetics techniques to prevent seizure-like activity in neurons in brain tissue taken from epilepsy patients as part of their treatment, in what could one day become a new treatment for epilepsy. Eventually, they hope the technique will replace surgery to remove the brain tissue where seizures originate, providing a less invasive option for patients whose symptoms cannot be controlled with medication.

When the brain is acting normally, neurons send signals at different times and frequencies in a predictable, low-level chatter. But during a seizure, the chatter synchronizes into loud bursts of electrical activity that overwhelm the brain’s casual conversation.

The team used the light pulses to prevent the bursts by switching off neurons that contained light-sensitive proteins.

“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 UCSF and a co-senior author of the study, which appears in Nature Neuroscience.

To keep the surgically removed tissue alive long enough to complete the study, which took several weeks, the researchers created an environment that mimics conditions inside the skull.

John Andrews, a resident in neurosurgery, placed the tissue on a nutrient medium that resembles the cerebrospinal fluid that bathes the brain. David Schaffer, a biomolecular engineer at UC Berkeley found the best virus to deliver the genes, so they would work in the specific neurons the team was targeting. Andrews then placed the tissue on a bed of electrodes small enough to detect the electrical discharges of neurons communicating with each other.

First, the team needed to find a way to run their experiments without disturbing the tissue. The electrodes were only 17 microns apart and the smallest movement of the brain slices could skew their results.

Mircea Teodorescu, an associate professor of electrical and computer engineering at UCSC and co-senior author of the study, designed a remote-control system to record the neurons’ electrical activity and deliver light pulses to the tissue.

Teodorescu’s lab wrote software that enabled the scientists to control the apparatus, so the group could direct experiments from Santa Cruz on the tissue in Nowakowski’s San Francisco lab. That way, no one needed to be in the room where the tissue was being kept.

“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.”

The technology allowed the team to see that they could stop the seizure-like activity by stimulating a surprisingly small number of neurons as well as determine the lowest intensity of light needed to change the electrical activity. They were also able to observe how neurons interact while inhibiting a seizure.

These insights provide a deeper understanding of how the approach might be used to tightly regulate brain activity that leads to seizures and could spare patients the invasiveness and side effects of having brain tissue removed, said Edward Chang, chair of neurological surgery at UCSF.

“This kind of approach could really improve care for people with epilepsy,” said Chang, who, along with Nowakowski, is a member of the UCSF Weill Institute for Neurosciences. “We’ll be able to give people much more subtle, effective control over their seizures while saving them from such an invasive surgery.”