Organoids, made from induced pluripotent stem cells, aggregate into three-dimensional forms to resemble miniature human organs. Now, researchers used two different approaches to study the patterns of electrical activity inside brain organoids. One involved inserting a probe into each organoid to measure brain activity, the other watched the brain cells in action under a microscope. The team’s findings showed organized waves of activity similar to those found in living human brains. In addition, the team observed patterns of electrical activity resembling seizures when studying organoids from patients with Rett syndrome. This work illustrates the value of these human cell–based models in investigating the underlying causes of diseases and testing potential therapies.

The study, published in the journal Nature Neuroscience, is titled, “Identification of neural oscillations and epileptiform changes in human brain organoids.

“This work demonstrates that we can make organoids that resemble real human brain tissue and can be used to accurately replicate certain features of human brain function and disease,” said Bennett Novitch, PhD, professor of neuroscience at the Broad Stem Cell Research Center and senior author of the study.

When it comes to the human brain, however, creating an organoid that mimics the organ’s structural complexity—getting the cells to organize like they would in a human brain—is particularly challenging. The cells must connect with one another and function like neurons would in a human brain. Healthy human brain cells not only send electrical signals throughout the brain in response to stimuli, but also have coordinated waves of activity called neural oscillations or brainwaves. Distinct patterns of brainwaves are associated with specific activities and abnormalities in these patterns can be an indication of disease.

The analysis showed multiple kinds of neural oscillations. Some of the information the researchers gathered in the study was akin to the data scientists would normally find in brain scans called electroencephalograms, or EEGs.

“With many neurological diseases, you can have terrible symptoms but the brain physically looks fine,” said Ranmal Samarasinghe, MD, PhD, a neurologist at the David Geffen School of Medicine at UCLA and first author of the paper. “So to be able to seek answers to questions about these diseases, it’s very important that with organoids we can model not just the structure of the brain but the function as well.”

“I hadn’t anticipated the range of oscillation patterns we would see,” said Novitch. “By learning how to control which oscillation patterns an organoid exhibits, we may be able to eventually model different brain states.”

Next, the team developed brain organoids using cells from people with Rett syndrome, a genetic disorder associated with learning delays, repetitive movements, and seizures. While the organoids appeared normal in structure and organization, their neural oscillations were abnormal: they lacked the variety of oscillations demonstrated in the non-Rett organoids. Instead, the Rett organoids had fast, disorganized activity resembling what clinicians see in EEGs of people with Rett syndrome and related disorders.

When Novitch and Samarasinghe treated the Rett organoids with the experimental drug Pifithrin-alpha, the seizure-associated activity patterns disappeared, and the organoids’ neural activity became more normal.

“This is one of the first tangible examples of drug testing in action in a brain organoid,” said Samarasinghe. “We hope it serves as a stepping stone toward a better understanding of human brain biology and brain disease.”

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