Autism severity rooted in embryonic brain growth, study suggests

A new study has discovered an important factor behind the different outcomes observed in children with autism. Researchers at the University of California, San Diego found that changes in the brain’s biological development during the first weeks and months of embryonic growth play an important role in the severity of autism symptoms later in life.

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

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

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

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

This method allowed researchers to observe and measure brain development as it might have occurred in the first weeks and months of embryogenesis. A significant finding was that BCOs derived from toddlers with ASD were significantly 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. Young children with the most severe form of autism, called profound autism, showed the largest BCOs.

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

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

The study also included brain imaging to further understand differences in brain development between children with autism spectrum disorder (ASD) and neurotypical children. Imaging was performed on a subset of infants 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.

Results from MRI scans revealed significant differences in brain structure between young children with ASD and neurotypical controls. Children with ASD, especially those with profound autism, showed marked growth in several brain regions. For example, the primary sensory cortices, which are involved in the processing of auditory, visual and tactile information, were significantly larger in children with profound autism compared to controls. This overgrowth was also evident in the social and language cortices.

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

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

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

Further analysis revealed a potential mechanism underlying this excess growth. The researchers found that the protein and enzyme NDEL1, which plays a key role in regulating brain growth, was reduced in the BCO of children with ASD. Specifically, lower levels of NDEL1 expression were associated with larger BCO sizes. This finding indicated that NDEL1 dysfunction may 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 several limitations. The sample size was relatively small, with only 10 toddlers with ASD and six neurotypical controls. Larger studies are needed 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 basis of brain overgrowth in autism. By determining the exact causes, they hope to develop interventions that can mitigate the developmental abnormalities seen in children with profound autism.

The study, “Embryonic origins 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. Lombar. de Souza, Mirian AF Hayashi, and Alysson R. Muotri.

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