New research published in translational psychiatry Researchers suggest that miniature brain models produced in the lab can reveal different patterns of electrical activity in different types of autism. By analyzing brain tissue grown from patients’ urine samples, the scientists provided evidence that these models can accurately distinguish between neurotypical people and people with various autism profiles. These discoveries tend to provide new ways to understand the biological causes of autism and test individualized treatments.
Autism is a neurodevelopmental condition characterized by differences in social communication and restricted and repetitive behaviors. Although some cases are associated with a specific genetic mutation known as syndromic autism, most cases have no known cause and are classified as idiopathic.
Traditional animal models often have difficulty reproducing the complex features of the human brain. This makes it difficult to study how specific genetic changes affect human brain function. Patient-derived brain organoids offer a biological solution to this problem.
Brain organoids are small three-dimensional clusters of brain cells grown in the laboratory to mimic the development of early human brains. Because they are grown from a patient’s own cells, that individual’s unique genetic makeup is retained. This will allow scientists to study human brain networks in a highly individualized way.
“During my PhD in neuroscience, I researched new ways to develop and deliver drugs for neurological and psychiatric disorders, with a focus on autism spectrum disorders,” said study author Nissim Peretz, CEO and co-founder of Itay&Beyond.
“I published several papers on the use of nanoparticles (exosomes) as a potential treatment and delivery for autism. These papers became well-known in the field, and one day I was approached by a high-tech entrepreneur whose son was diagnosed with low-functioning autism. Together we founded Itay&Beyond and decided to start with ‘simulations’ of patient brains in order to develop and test a new generation of drugs and compounds based on the patient’s biology rather than the animal. model. ”
To conduct the study, researchers collected urine samples from 15 participants. This group included 11 individuals diagnosed with autism and 4 neurotypical controls. Of the participants with autism, 10 had symptomatic autism associated with five specific gene mutations and one had idiopathic autism.
Specific genetic conditions studied included mutations in the SHANK3, PPP2R5D, SCN2A, GRIN2B, and STXBP1 genes. These genes are known to play different roles in how brain cells develop, send signals, and form neural connections. The researchers extracted epithelial cells, the cells that line the urinary tract, from urine.
These cells were then reprogrammed into induced pluripotent stem cells. These are special types of cells that can be induced to become almost every cell type in the human body. The scientists directed these stem cells to grow into more than 400 individual brain organoids over about 60 days.
Once the organoids were mature, the researchers placed them on a multi-electrode array. These are small microchips with sensors that can record electrical signals sent between neurons. Neurons are the main cells in the brain responsible for sending and receiving information.
The scientists recorded the organoid’s resting electrical activity for five minutes. They then applied a short electrical stimulus and recorded their activity for an additional 5 minutes. This procedure allowed us to measure 18 different electrical characteristics.
These features include the neuron’s firing rate, the frequency of synchronous bursts of activity, and the overall connectivity of the neural network. To make sense of this complex data, the researchers used a mathematical technique called principal component analysis. This method compresses complex data into a simplified visual map that allows researchers to group similar electrical patterns.
Scientists found distinct differences in electrical activity in organoids derived from autism patients compared to controls. Organoids from the four neurotypical controls showed highly consistent electrical patterns. Data analysis shows that they cluster closely and have low variability.
“Some results exceeded expectations,” Peretz said. “Our first question was whether there were differences in organoid activity between autism patients and control patients, but when we started analyzing the data, we found that there were also interesting differences between subpopulations of patients with autism spectrum disorders.”
Organoids from patients with idiopathic autism tended to show decreased electrical activity. These samples had significantly lower firing rates and fewer bursts of activity than control samples.
Most organoids derived from patients with syndromic autism provided evidence of hyperactivity. For example, samples associated with STXBP1, PPP2R5D, and GRIN2B mutations showed significantly increased firing rates. The SCN2A sample showed mixed firing rates but had a markedly reduced amplitude of the electrical signal compared to controls.
The researchers also observed differences in how the neural networks responded to electrical stimulation. In this part of the experiment, we measured short-term synaptic plasticity. Synaptic plasticity is the ability of neural networks to adapt by strengthening or weakening connections between neurons over short periods of time.
Scientists specifically focused on short-term depression and short-term potentiation. Short-term depression involves a temporary decrease in neural transmission, whereas short-term potentiation involves a temporary increase. Data suggest that certain genetic mutations can significantly alter this natural balance.
For example, organoids with STXBP1 and SHANK3 mutations had significantly reduced short-term potentiation and increased short-term inhibition compared to controls. In control organoids, the network maintained relatively stable feature size and density after stimulation. Many autism-derived organoids showed altered structural responses to this electrical input.
Organoids with STXBP1 mutations showed a marked early collapse of network connectivity after stimulation. Samples associated with the PPP2R5D mutation maintained high connectivity before stimulation, but showed a sharp decline immediately after. This suggests an underlying network vulnerability or reduced ability to recover from external inputs.
The researchers noted that even organoids taken from patients with the exact same genetic mutation can exhibit different electrical profiles. For example, abnormal rhythmic bursts were seen in samples from patients with a history of seizures, but not in all samples from that genetic group. This observation is consistent with the fact that people with the exact same genetic diagnosis can have very different symptoms every day.
“We were able to show that our technique is not only non-invasive, but also able to distinguish between lab-grown brain tissue from autism spectrum disorder and control patients. Furthermore, the data show that our system is able to distinguish between different autism subpopulations based on the electrophysiological activity of lab-grown brain tissue,” Peretz told PsyPost.
Although these models provide detailed insights into neural activity, scientists caution against overstating the technology’s current capabilities. Brain organoids are still in the developmental stages of research. They do not simulate the complete structure or complex anatomy of a fully formed human brain.
Organoid networks are simplified models. This means that it cannot capture all aspects of how the entire mature brain functions and experiences the world. Future research aims to use this technology to develop and test new drugs for a variety of psychiatric and neurological disorders.
“Itay&Beyond aims to develop and test a new generation of drugs for neurological and psychiatric disorders, including autism, epilepsy, dementia, schizophrenia and more, and to provide patient-based functional information on drug efficacy and safety,” Peretz added.
“Our technology is already being used by pharmaceutical companies and academic institutions to test drugs and compounds and support research. We are also testing and developing unique medicines for subpopulations of autism and other disorders.”
“Interestingly, our technology is a platform for human-brain-computer interaction that can extend far beyond drug development and testing. Some of our collaborations are not in the field of medicine or drug development, but in deep technologies and new models of brain-computer interfaces, such as biological neuron networks and computationally energy-efficient models of AI.”
The study, “Patient-derived brain organoids reveal diverse neuronal activity across autism spectrum disorder subpopulations,” was authored by Nisim Perets, Liya Kerem, Nir Waiskopf, Noa Horesh, Itay Goldman, Jasmine Avichzer, Doron Bril, William Tobelaim, Milcah Barashi, Liat David, and Ariel Tenenbaum.
