Researchers from three University of California (UC) campuses collaborated on an optogenetics-based approach to controlling abnormal neural activity in humans. Their findings could someday provide an alternative to surgery for patients who have seizures that cannot be managed with medication. A team comprising scientists from UC San Francisco, UC Santa Cruz, and UC Berkeley delivered genes for light-sensitive proteins to human hippocampal slices that had been removed from epilepsy patients as part of their treatment. A virus that is widely used in gene therapy conveyed the light-activated proteins to select neurons in the hippocampal tissue. The researchers arranged the tissue on a bed of tiny electrodes spaced 17 μm apart. The purpose of the electrode array was to detect the electrical discharges from neurons in the tissue when they communicated with each other. To keep the tissue alive long enough to complete the weeks-long study, the researchers placed the tissue on a medium that resembled the cerebrospinal fluid surrounding the brain. The researchers designed a software system to remotely control the electrode array without disturbing the tissue. This system enabled the team to deliver light pulses, manage experiments, and record electrical activity of brain tissue located in a lab at UC San Francisco from a UC Santa Cruz location. The optogenetics technique could replace surgery performed to remove the brain tissue where seizures originate, providing a less invasive option for patients whose epilepsy cannot be controlled with medication. Courtesy of the University of California, Santa Cruz. During normal brain activity, neurons send signals in a predictable manner. During an epileptic seizure, this low-level chatter synchronizes into loud bursts of electrical activity that overwhelm the normal communication between neurons. The researchers aimed to prevent these bursts of activity by using light pulses to deactivate abnormally behaving neurons containing light-sensitive proteins. The team demonstrated optogenetic reductions in the network firing rates of the brain tissue and recorded them on the electrode arrays under several hyperactivity-provoking conditions. A detailed analysis of the recordings revealed a harmful feedback loop leading to a seizure-like event in the dentate gyrus region of the brain. By analyzing the recordings of thousands of neurons at the onset of the seizure, the researchers gained new insight into what triggers such events. They found that neurons that were connected in a feedback circuit organized their activity into wave-like patterns propagating in one direction, and then into much larger wavelike patterns that propagated at 90 degrees to the initial waves, achieving synchronization via a phase-locked loop. Optogenetics enabled the researchers to focus on discrete sets of neurons in the tissue. They observed which types of neurons — and how many of them — were needed to instigate a seizure, and how interactions between neurons could inhibit a seizure. They also determined the lowest intensity of light required to modify the electrical activity of neurons in living brain tissue. Additional investigation using optogenetics could help scientists increase their knowledge of the biological mechanisms that predispose neurons to producing seizures, opening the door to new treatments for epilepsy and other neurological disorders. According to the researchers, this is the first study to show that optogenetics can be used to control seizure activity in living human brain tissue. Edward Chang, the chair of Neurological Surgery at UC San Francisco, believes the research could transform treatment 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. Optogenetics has been effective at stopping seizure-like activity in nonhuman disease models by increasing inhibitory tone or decreasing excitation. Many of the genetic means for achieving channelrhodopsin expression in nonhuman models are not possible in humans, and vector-mediated methods are susceptible to species-specific effects that could influence their translational potential. The new technique for uncovering the source of epileptic seizures, combining optogenetics with gene therapy, could help bridge the gap between human and animal studies, by exploring genetic interventions on network activity in human brain tissue. “This represents a giant step toward a powerful new way of treating epilepsy and likely other conditions,” UC San Francisco professor Tomasz Nowakowski said. The research was published in Nature Neuroscience (www.doi.org/10.1038/s41593-024-01782-5).
