Autism severity rooted in embryonic brain growth,

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Autism severity rooted in embryonic brain growth, study suggests
by Eric W. Dolan July 2, 2024in Autism, Neuroimaging


A new study has uncovered an important factor behind the varied outcomes observed in children with autism. Researchers at the University of California San Diego found that differences in the biological development of the brain during the first weeks and months of embryonic growth play a significant role in the severity of autism symptoms later in life.

This discovery, published in the journal Molecular Autism, provides a deeper understanding of why some children with autism develop severe, lifelong challenges, while others experience milder symptoms that improve over time.

The research team aimed to solve a longstanding puzzle: why do the symptoms of autism spectrum disorder (ASD) vary so greatly among children? Some children with autism struggle with profound difficulties in social, language, and cognitive skills and might be non-verbal, while others show significant improvements as they grow older.


Understanding the biological roots of these differences is essential for developing more effective, tailored treatments and interventions for autism. Previous studies had suggested that autism has prenatal origins, but no study had definitively linked early brain development with the severity of autism symptoms until now.

To investigate, the researchers used a groundbreaking approach involving inducible pluripotent stem cells (iPSCs). These stem cells, which can be reprogrammed to become any type of human cell, were derived from blood samples of 10 toddlers diagnosed with autism and six neurotypical toddlers as controls. The iPSCs were then used to create brain cortical organoids (BCOs), which are three-dimensional models mimicking the brain’s cortex during early embryonic development. These “mini-brains” allowed the researchers to study the development processes in a controlled environment.

This method enabled the researchers to observe and measure brain development as it might occur in the first weeks and months of embryogenesis. A significant finding was that BCOs derived from toddlers with ASD grew substantially larger—about 40% larger—than those derived from neurotypical toddlers.


One of the most critical findings of the study was the correlation between the size of the BCOs and the severity of autism symptoms observed in the children. Toddlers with the most severe form of autism, termed profound autism, exhibited the largest BCOs.

On the other hand, toddlers with milder autism symptoms had only moderately enlarged BCOs. This relationship suggested that the extent of brain overgrowth during embryonic development could be predictive of the severity of autism symptoms later in life.

“We found the larger the embryonic BCO size, the more severe the child’s later autism social symptoms,” said UC San Diego’s Eric Courchesne, the study’s lead researcher and co-director of the Autism Center of Excellence. “Toddlers who had profound autism, which is the most severe type of autism, had the largest BCO overgrowth during embryonic development. Those with mild autism social symptoms had only mild overgrowth.”


The study also incorporated brain imaging to further understand the differences in brain development between children with autism spectrum disorder (ASD) and neurotypical children. The imaging was conducted on a subset of the toddlers using magnetic resonance imaging (MRI). This advanced imaging technique allowed the researchers to capture detailed structural images of the brain, focusing on regions critical for social and language development.

The results from the MRI scans revealed significant differences in brain structure between the toddlers with ASD and the neurotypical controls. The children with ASD, particularly those with profound autism, showed marked overgrowth in several brain regions. For instance, the primary sensory cortices, which are involved in processing auditory, visual, and tactile information, were significantly larger in the children with profound autism compared to the controls. This overgrowth was also evident in the social and language-related cortices.

In addition to overgrowth, the imaging data highlighted specific areas of the brain where growth was reduced. Notably, the visual cortex in children with profound autism was found to be smaller than that in neurotypical children. This reduction in size might contribute to the sensory and social attention issues commonly observed in children with severe ASD.


The imaging results were consistent with the findings from the brain cortical organoids (BCOs) developed from the iPSCs. The correlation between the size of the BCOs and the structural abnormalities observed in the brain scans provided compelling evidence that the overgrowth observed during embryonic development persisted into early childhood. Furthermore, the imaging data corroborated the behavioral observations, linking larger brain size and overgrowth to more severe social and cognitive symptoms.

“The bigger the brain, the better isn’t necessarily true,” said Alysson Muotri, the director of the Sanford Stem Cell Institute’s Integrated Space Stem Cell Orbital Research Center and senior author of the study.

Further analysis revealed a potential mechanism underlying this excessive growth. The researchers discovered that the protein and enzyme NDEL1, which plays a key role in regulating brain growth, was reduced in the BCOs of children with ASD. Specifically, lower expression levels of NDEL1 were associated with larger BCO sizes. This finding indicated that the malfunction of NDEL1 might be a key factor contributing to the abnormal brain growth observed in ASD-derived organoids.


“Determining that NDEL1 was not functioning properly was a key discovery,” Muotri said.

Despite its groundbreaking insights, the study has some limitations. The sample size was relatively small, with only 10 toddlers with ASD and six neurotypical controls. Larger studies are necessary to confirm these findings and explore the full spectrum of ASD severity. Further research is also needed to understand the exact mechanisms through which NDEL1 and other factors influence brain development in ASD.

The research team plans to continue exploring the genetic and molecular underpinnings of brain overgrowth in autism. By pinpointing the exact causes, they hope to develop interventions that can mitigate the developmental abnormalities observed in children with profound autism.


The study, “Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms,” was authored by Eric Courchesne, Vani Taluja, Sanaz Nazari, Caitlin M. Aamodt, Karen Pierce, Kuaikuai Duan, Sunny Stophaeros, Linda Lopez, Cynthia Carter Barnes, Jaden Troxel, Kathleen Campbell, Tianyun Wang, Kendra Hoekzema, Evan E. Eichler, Joao V. Nani, Wirla Pontes, Sandra Sanchez Sanchez, Michael V. Lombardo, Janaina S. de Souza, Mirian A. F. Hayashi, and Alysson R. Muotri.