Using optogenetics, researchers used pulses of light to prevent seizure-like activity in neurons. This is the first use of optogenetics to modulate seizure activity at the network level in human brain tissue. Because epilepsy is a disease of aberrant neuronal activity—an imbalance of excitation and inhibition—controlling neurons in the pathologic circuits of epilepsy could allow for control of the disease.
The researchers used brain tissue that had been removed from epilepsy patients as part of their treatment. 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.
This work is published in Nature Neuroscience in the paper, “Multimodal evaluation of network activity and optogenetic interventions in human hippocampal slices.”
The optogenetics method employed an AAV vector to deliver light-sensitive genes to neurons in the brain that can be switched on and off with pulses of light. More specifically, the slices were transduced with “AAV9 carrying an HcKCR1 transgene driven by a CAMK2A promoter and a fluorescent tag (enhanced yellow fluorescent protein (eYFP)).” HcKCR1 encodes a kalium channelrhodopsin which is a potassium-selective, light-sensitive ion channel that hyperpolarizes the neuronal membrane. This reduces the probability of spiking when activated by 530 nm light.
This work is the first demonstration that optogenetics can be used to control seizure activity in living human brain tissue, and it opens 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, PhD, an assistant professor of neurological surgery at the University of California, San Francisco (UCSF).
To keep the tissue alive long enough to complete the study, which took several weeks, the researchers created an environment that mimics conditions inside the skull. The team hoped to use the light pulses to prevent the bursts by switching off neurons that contained light-sensitive proteins. The team needed to find a way to run their experiments without disturbing the tissue. They designed a remote-control system to record the neurons’ electrical activity and deliver light pulses to the tissue.
“This was a very unique collaboration to solve an incredibly complex research problem,” said Mircea Teodorescu, PhD, an associate professor of electrical and computer engineering at UCSF. “The fact that we actually accomplished this feat shows how much farther we can reach when we bring the strengths of our institutions together.”
John Andrews, MD, a resident in neurosurgery at UCSF placed the tissue on a nutrient medium that resembles the cerebrospinal fluid that bathes the brain. David Schaffer, PhD, a biomolecular engineer at UC Berkeley, identified the AAV to deliver the genes. Teodorescu designed a remote-control system to record the neurons’ electrical activity and deliver light pulses to the tissue.
The team demonstrated “AAV–mediated, optogenetic reductions in network firing rates of human hippocampal slices recorded on high-density microelectrode arrays under several hyperactivity-provoking conditions.” They could see which types of neurons—and how many of them—were needed to start a seizure. And they determined the lowest intensity of light needed to change the electrical activity of the neurons in live brain slices. The researchers could also see how interactions between neurons inhibited a seizure.
Edward Chang, MD, the chair of neurological surgery at UCSF, said these insights could revolutionize care for people with epilepsy. “We’ll be able to give people much more subtle, effective control over their seizures while saving them from such an invasive surgery,” he said.
