Autistic brains show differences in a fetal fold linked to social cognition

The physical arrangement of brain folds in an area linked to social and emotional processing appears altered in young males with autism spectrum disorder. A recent analysis of brain imaging data shows that neurotypical boys often exhibit a lopsided folding pattern that is less common in their autistic peers. The researchers published their work in the journal Cerebral Cortex.

The human brain is characterized by its heavily wrinkled outer layer, known as the cerebral cortex. This structure is packed with elevated ridges and deep grooves. Together, these folds function to maximize the sheer amount of neural tissue that can fit inside the cramped space of the human skull.

The valleys or grooves pushing deep into the brain tissue are called sulci. Most of the surface area of the cerebral cortex actually sits buried within these hidden grooves. Because the cortex coordinates higher-order mental functions, scientists actively study the shape and location of these folds to better understand human cognition and neurodevelopment.

One specific sub-region of this outer layer is the anterior cingulate cortex. This region operates as a central hub for emotional regulation, cognitive control, and social cognition. These represent broad areas of mental processing that are often affected in individuals with autism spectrum disorder, or ASD.

A prominent anatomical feature stretching within the anterior cingulate cortex is the paracingulate sulcus. The paracingulate sulcus is a tertiary brain fold that runs parallel to the main groove of the region. Unlike some major brain folds that appear practically identical in every human, this specific groove exhibits extreme physical variation across the population.

Some people develop a long, prominent paracingulate sulcus in both the left and right hemispheres of their brain. Others completely lack this secondary fold on both sides. When the fold is present, its exact shape and trajectory differ wildly from person to person.

In neurotypical populations, the presence of the paracingulate sulcus is usually asymmetrical. People frequently develop this fold in the left hemisphere of the brain, while the right hemisphere remains relatively smooth in that specific area. Past studies indicate that variations in this left-to-right pattern correlate with performance in executive function tasks and the ability to infer what others are thinking.

Because these cognitive traits closely overlap with the varied expressions of autism, researchers wanted to map the paracingulate sulcus in autistic individuals. Ethan Willbrand and Enrique Martinez, neuroscientists at the University of Wisconsin-Madison and the University of California, Berkeley, led the investigative team. They aimed to outline the precise characteristics of this particular sulcus in young people with autism.

The research team utilized existing structural magnetic resonance imaging, or MRI, scans of 200 young males ranging in age from five to 18. Half of the participants were previously diagnosed with autism spectrum disorder. The other half were neurotypical individuals.

To ensure their analytic frameworks were robust and accurately represented reality, the scientists split these participants equally into a primary discovery group and a secondary replication group. This split-sample method allows researchers to verify their initial statistical models against an entirely separate batch of data.

Trained raters manually evaluated the MRI scans of each participant to determine the presence or absence of the paracingulate sulcus in both brain hemispheres. A fold had to measure at least 20 millimeters in length and four millimeters in depth to be officially classified as functionally present. Defining the limits of an elusive fold manually is recognized as the gold standard in neuroanatomy research.

In addition to checking for the basic presence of the fold, the team used computer algorithms to extract exact geometrical proportions. They measured the overall length of the paracingulate sulcus by tracing its longest unbroken path. They also calculated the maximum sulcal depth and the average thickness of the gray matter lining the inside of the groove.

The analysis revealed a consistent difference in how the paracingulate sulcus was distributed across the left and right brain hemispheres. Neurotypical participants were highly likely to have an asymmetrical folding pattern, typically featuring the groove on the left side of the brain but lacking it on the right side. In contrast, participants with autism spectrum disorder exhibited increased structural symmetry.

For the autistic participants, the specific left-heavy asymmetry was greatly reduced. They were much more likely to possess a matching set of features, either harboring the groove on both sides of the brain or lacking it uniformly across both sides. The likelihood of having an asymmetric paracingulate sulcus was substantially higher for neurotypical boys than for autistic boys.

This structural difference remained constant even when the researchers adjusted their statistical models to account for potential confounding variables. The team controlled for the participants’ ages, their measured intelligence quotients, and the physical location of the medical centers where the MRI scans were conducted.

While the overall structural symmetry behaved differently among the groups, the specific physical dimensions of the groove did not. Statistical tests indicated that the length, depth, and cortical thickness of the paracingulate sulcus did not differ between the autistic and neurotypical brains. The findings for these specific geometric measurements were not statistically significant in either the primary discovery group or the replication group.

This contrast highlights a well-known distinction between different features of human neuroanatomy. Tertiary brain folds like the paracingulate sulcus begin to form internally well before birth, usually initiating around the 36th week of human gestation. This structural blueprint reflects very early biological constraints placed on the growing fetal brain.

Such early formation suggests a prenatal origin for the observed symmetry differences in autistic youth. The relatively symmetrical layout found in the autistic brains likely points to early biological variations in the genetic factors or cellular mechanics that dictate how the fetal brain physically folds itself. Once these basic folds are set in utero, their layout remains largely stable throughout life.

Measurements like a fold’s depth or the thickness of its outer gray matter, on the other hand, are remarkably dynamic. Cortical thickness changes throughout childhood development, shrinking or growing in response to life experiences, learning, and physical maturation. Because these dynamic measurements did not differ between the groups, the researchers suggest the neuroanatomical differences associated with autism operate primarily at distances rooted in a person’s earliest prenatal development.

While the anatomical variation is notable, the current study comes with multiple limitations. The participant pool included only young males under the age of 20. Autism spectrum disorder presents with immense biological diversity, and brain folding patterns are occasionally known to differ heavily based on biological sex. This means the researchers’ findings cannot simply be generalized to autistic females or older adults.

Additionally, the researchers could not directly link the anatomical differences to specific behavioral or cognitive traits in this exact population. The public imaging database they relied upon did not include uniform cognitive testing details for all 200 participants. Understanding how the symmetry of this central brain fold actually influences everyday mental tasks will require a dedicated follow-up project.

Mapping human brain folds by hand also takes a substantial amount of time. This limits the total number of scans scientists can reasonably analyze in a single anatomical project. The research team recommends that future work direct investments into the development of automated computer-based tools that can accurately trace brain folds that are not instinctively universally present.

Such advanced technology would allow anatomical experts to process thousands of scans simultaneously. This would eventually help map the highly variable physical landscape of the human brain on a much larger scale, revealing exactly how a tiny prenatal fold shapes human behavior over an entire lifetime.

The study, “Anterior cingulate folding pattern is altered in autism spectrum disorder,” was authored by Ethan H. Willbrand, Enrique Martinez, Jacob J. Ludwig, Samira A. Maboudian, and Kevin S. Weiner.