A new study has identified an important factor behind the varied outcomes seen in children with autism. Researchers at the University of California, San Diego, found that differences in the biological development of the brain during the early 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 autismhelps to better understand why some children with autism develop severe problems that last their entire lives, while others have milder symptoms that improve over time.
The research team sought to solve a long-standing puzzle: Why do symptoms of autism spectrum disorder (ASD) vary so much from child to child? Some children with autism have profound social, linguistic and cognitive difficulties and may be nonverbal, while others show significant improvements as they grow older.
Understanding the biological roots of these differences is critical to developing more effective and tailored treatments and interventions for autism. Previous studies have suggested that autism has prenatal origins, but no study has yet established a definitive link between early brain development and the severity of autism symptoms.
To conduct their research, 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 derived from blood samples from 10 toddlers diagnosed with autism and six neurotypical toddlers who served as controls. The iPSCs were then used to create cerebral cortical organoids (BCOs), three-dimensional models that mimic the cerebral cortex during early embryonic development. These “mini-brains” allowed the researchers to study developmental processes in a controlled environment.
This method allowed the researchers to observe and measure brain development as it might occur during the first weeks and months of embryogenesis. One important finding was that BCOs derived from toddlers with ASD grew to be much larger – about 40 percent larger – than those derived from neurotypical toddlers.
One of the most important findings of the study was the correlation between the size of the BCOs and the severity of autism symptoms seen in the children. Toddlers with the most severe form of autism, called profound autism, had the largest BCOs.
In contrast, toddlers with milder autism symptoms had only moderately enlarged BCOs. This relationship suggests that the extent of excessive brain growth during embryonic development may be predictive of the severity of autism symptoms later in life.
“We found that the larger the embryonic BCO size, the more severe the child’s later social symptoms of autism,” said Eric Courchesne, the study’s lead researcher and co-director of the Autism Center of Excellence at the University of California, San Diego. “Toddlers with profound autism, which is the most severe type of autism, had the greatest proliferation of BCOs during embryonic development. Those with mild social symptoms of autism had only mild proliferation.”
The study also incorporated brain imaging to better understand differences in brain development between children with autism spectrum disorder (ASD) and neurotypical children. Imaging was performed on a subset of 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 MRI scan results revealed significant differences in brain structure between toddlers with ASD and neurotypical controls. Children with ASD, particularly those with profound autism, showed marked overgrowth in several brain regions. For example, the primary sensory cortices, which are involved in processing auditory, visual, and tactile information, were significantly larger in children with profound autism compared with controls. This overgrowth was also evident in the social and language-related cortices.
In addition to excessive growth, 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 could contribute to the sensory and social attention problems commonly seen in children with severe ASD.
The imaging results were consistent with findings from cerebral cortical organoids (BCOs) grown from iPSCs. The correlation between BCO size and structural abnormalities observed in brain scans provided compelling evidence that the excessive growth observed during embryonic development persisted into early childhood. Furthermore, the imaging data corroborated behavioral observations, linking larger brain size and excessive growth to more severe social and cognitive symptoms.
“Bigger brains are better is not necessarily true,” said Alysson Muotri, director of the Sanford Stem Cell Institute’s Center for Integrated Space Stem Cell Research and lead author of the study.
Further analysis revealed a potential mechanism behind this excessive growth. The researchers found that the protein and enzyme NDEL1, which plays a key role in regulating brain growth, were reduced in BCOs from children with ASD. Specifically, lower expression levels of NDEL1 were associated with larger BCO sizes. This finding indicates 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 results, the study has some 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 by which NDEL1 and other factors influence brain development in ASD.
The research team plans to continue studying the genetic and molecular underpinnings of excessive brain growth in autism. By identifying the exact causes, they hope to develop interventions that can alleviate the developmental abnormalities seen in children with profound autism.
The study, “Embryonic Origin of Two ASD Subtypes of Social Symptom Severity: Larger Cerebral Cortical Organoid Size, Greater 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.