Researchers have isolated sex differences in the brains of females with autism spectrum disorder and aligned those results with their genetics, providing valuable insights into a population that has long been understudied.

In particular, the study, authored by researchers at Yale University and other institutions and published April 16 in Brain, sought to determine how the brains of females with ASD respond to other people's facial, hand and body movements that typically aid in social interactions — and whether those neural responses differ from those of neurotypical females and males with ASD. 

Previous ASD studies have skewed predominantly male, according to Allison Jack, a developmental neuroscientist and an assistant professor at George Mason University, as well as the paper's lead author. "There's this whole vast swath of the autism spectrum that we really know very little about and that we currently make assumptions about based on our research on, say, boys," Jack told The Academic Times. Male participants have been more prevalent in neurological studies by a ratio of as much as seven-to-one. 

The study was made possible through equal contributions from geneticists and neurologists, said Abha Gupta, an assistant professor in the department of pediatrics at the Yale School of Medicine and the paper's senior author. Scientists already believe there are more rare copy number variants — the number of copies of a specific gene represented in a person's genome — in females with ASD than in males with ASD.

"But we wanted to dig deeper and see if we could really make sense of the imaging data in terms of the genetics analysis," Gupta said.

The researchers tracked 184 children, ages 8 to 17, in a functional magnetic resonance imaging machine as they watched two movies, both consisting of a light array made up of tiny dots. One movie showed dots that moved randomly across the screen with no perceptible pattern. Another video showed the dots moving in the form of a somewhat abstract animation of a human in motion, resembling someone in a motion-tracking suit on a film set. 

As researchers had expected, neurotypical children showed more brain activity when viewing images of humans in motion compared with their counterparts with ASD, indicating that they could more effectively identify and separate patterns that resemble humans in the environment. But females with ASD showed markedly less activation in the striatum — an area deep within the brain that is responsible for allocating attention to incoming stimuli and preparing the motor system accordingly — compared with neurotypical females. Males with ASD also displayed reduced activity in the striatum and, broadly speaking, showed patterns of brain activity similar to those in females with ASD in brain regions other than the striatum.

After assessing participants' genetic makeups, researchers found females with ASD had more copy number variations that corresponded directly with the functions of the striatum. "We're always looking for convergence, but I think we were even surprised by how well this worked out," Gupta said. According to Gupta, the comparison "gives us a lot more confidence that the spot that we're landing on in the brain, where this dysfunction might arise, is the striatum."

Researchers also noticed that there were brain changes between neurotypical males and neurotypical females, with neurotypical females showing greater activation of additional systems, such as the salience network and the executive function network. This told the researchers that, in general, females may have used more attentional resources than males when viewing the abstract human animation.

Males are around three times as likely as females to be diagnosed with ASD. There may be some protective properties that make it rarer for females to be diagnosed with ASD, such that a greater variety of genetic or environmental risk factors are required in order for the disorder to emerge in females. But to some degree, social and cultural factors may play a role in the discrepancy as well, the researchers noted. For instance, gender norms may dictate that females learn to internalize or suppress symptoms of ASD, while males receive more attention and are under less pressure to not express symptoms such as obsessive behavior, aggression or hyperactivity. 

Although the results mark a step forward for autism research, neurologists would still like to know what is causing the changes they observed — "indications that could help us, down the line, learn to detect girls on the spectrum better and get people diagnosed who are going undiagnosed, and [thus] not getting services," Jack said. It may be the case that children with ASD have learned to respond differently to their environment as a strategy to better navigate through the world, with their brains developing accordingly. "Alternatively, there might be parts of that brain response that are related to something that happens differently in the prenatal period, when the brain is developing, or in early infancy," Jack added.

The work was funded and supported by the National Institutes of Health through an Autism Center of Excellence award. The same group of researchers will conduct subsequent rounds of studies with participants as they grow up to gain a more comprehensive view of brain development in people with ASD. The researchers are also interested in identifying more volunteers to participate in studies that will take place at Yale University, the University of Washington, the University of Virginia and other institutions across the country.

One limitation of the study, Jack noted, is that it could not take into account each participant's gender identity, which may differ from the sex they were assigned at birth. Because not all of the children included in the study may grow up to identify as women, subsequent rounds of research, which will take place when the children are older, will carefully consider participants' gender identities. There may be more gender diversity in the ASD population compared with the neurotypical population, providing an additional avenue of inquiry for researchers.

This team is also thinking through ways that they could improve their procedures for studying brain activity in people with ASD. Those innovations may include focusing on structural images of the brain that can be captured while volunteers are asleep, using simple saliva swabs to obtain genetic information or developing new surveys or clinical tools to more effectively diagnose autism in females. "It's a really long road to get from some discovery that you make, down into something that's a really usable tool," Jack said. "But we're starting to take little baby steps along that road."

The study "A neurogenetic analysis of female autism," published April 16 in Brain, was authored by Allison Jack, George Mason University; Catherine A.W. Sullivan, James C. McPartland, Abha R. Gupta and Jeffrey Eilbott, Yale School of Medicine; Elizabeth Aylward, Seattle Research Children's Institute; Sara J. Webb, Seattle Research Children's Institute and University of Washington; Susan Y. Bookheimer, Daniel H. Geschwind and Mirella Dapretto, University of California, Los Angeles, School of Medicine; Nadine Gaab, Boston Children's Hospital, Harvard Medical School and Harvard Graduate School of Education; Charles A. Nelson, Boston Children's Hospital and Harvard Medical School; Zachary Jacokes, John D. Van Horn and Kevin A. Pelphrey, University of Virginia; Carinna M. Torgerson, University of Southern California; Raphael A. Bernier, University of Washington; and the GENDAAR Consortium.