New research in mice has identified neurons in the brain that influence competitive interactions between individuals and that play a critical role in shaping the social behaviour of groups. Published in Nature by a team led by investigators at Massachusetts General Hospital (MGH), the findings will be useful not only for scientists interested in human interactions but also for those who study neurocognitive conditions such as autism athat are characterized by altered social behaviour.

“Social interactions in humans and animals occur most commonly in large groups, and these group interactions play a prominent role in sociology, ecology, psychology, economics and political science,” says lead author S. William Li, an MD/PhD student at MGH. “What processes in the brain drive the complex dynamic behaviour of social groups remains poorly understood, in part because most neuroscience research thus far has focused on the behaviours of pairs of individuals interacting alone. Here, we were able to study the behaviour of groups by developing a paradigm in which large cohorts of mice were wirelessly tracked across thousands of unique competitive group interactions.”

Li and his colleagues found that the animals’ social ranking in the group was closely linked to the results of the competition, and by examining recordings from neurons in the brains of mice in real-time, the team discovered that neurons in the anterior cingulate region of the brain store this social ranking information to inform upcoming decisions.

“Collectively, these neurons held remarkably detailed representations of the group’s behaviour and their dynamics as the animals competed together for food, in addition to information about the resources available and the outcome of their past interactions,” explains senior author Ziv M. Williams, MD, a neurosurgical oncologist at MGH. “Together, these neurons could even predict the animal’s own future success well before competition onset, meaning that they likely drove the animals’ competitive behaviour based on whom they interacted with.”

Manipulating the activity of these neurons, on the other hand, could artificially increase or decrease an animal’s competitive effort and therefore control its ability to successfully compete against others. “In other words, we could tune up and down the animal’s competitive drive and do so selectively without affecting other aspects of their behaviour such as simple speed or motivation,” says Williams.

The findings indicate that competitive success is not simply a product of an animal’s physical fitness or strength, but rather, is strongly influenced by signals in the brain that affect the competitive drive. “These unique neurons are able to integrate information about the individual’s environment, social group settings, and reward resources to calculate how to best behave under specific conditions,” says Li.

In addition to providing insights into group behaviour and competition in different sociologic or economic situations and other settings, identifying the neurons that control these characteristics may help scientists design experiments to better understand scenarios in which the brain is wired differently. “Many conditions manifest in aberrant social behaviour that spans many dimensions, including one’s ability to understand social norms and to display actions that may fit the dynamical structure of social groups,” says Williams. “Developing an understanding of group behaviour and competition holds relevance to these neurocognitive disorders, but until now, how this happens in the brain has largely remained unexplored.” 

About 1 in 44 children in the U.S. are diagnosed with autism by the age of 8, according to the 2018 Centers for Disease Control and Prevention surveillance. How a child’s DNA contributes to the development of autism has been more of a mystery. Recently, clinicians and scientists have looked more closely at new, or de novo, DNA changes, meaning they only are present in affected individuals but not in the parents. Researchers have seen that these changes could be responsible for about 30% of autism. However, which de novo variants play a role in causing autism remains unknown.

Researchers at Baylor College of Medicine and Texas Children’s Hospital have taken a new approach to looking at de novo autism genetic variants. In this multi-institutional study published in the journal Cell Reports, they applied sophisticated genetic strategies in laboratory fruit flies to determine the functional consequences of de novo variants identified in the Simons Simplex Collection (SSC), which includes approximately 2,600 families affected by autism spectrum disorder. Surprisingly, their work also allowed them to uncover a new form of rare disease due to a gene called GLRA2. 

“Autisms include complex neurodevelopmental conditions with impairments in social interaction, communication and restricted interests or repetitive behaviors. In the current study, we initiated our work based on information from a cohort of autism patients in the SSC whose genomes and those of their families had been sequenced,” said co-corresponding author Dr. Shinya Yamamoto, assistant professor of molecular and human genetics and of neuroscience at Baylor and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s. “Our first goal was to identify gene variants associated with autism that had a detrimental effect.”

The team worked with the fruit fly lab model to determine the biological consequences of the autism –associated variants. They selected 79 autism variants in 74 genes identified in the SSC and studied the effect of each autism –linked gene variant compared to the commonly found gene sequence (reference) as a control, from three different perspectives.

Co-first author, Dr. Paul Marcogliese, postdoctoral fellow in Dr. Hugo Bellen’s lab, coordinated the effort on knocking out the corresponding fly gene, and examining their biological functions and expression patterns within the nervous system. They then replaced the fly gene with the human gene variant identified in patients, or the reference sequence, and determined how it affected biological functions in the flies.

Working with fruit flies carrying either the reference human gene or the variant forms, co-first author Dr. Jonathan Andrews, postdoctoral fellow in Dr. Michael Wangler’s lab at Baylor, was the point person investigating how these gene variants affected fly behavior. As autism patients exhibit patterns of repetitive behavior as well as changes in social interaction, he evaluated the effect of the patient variants on an array of social and non-social fly behaviors, such as courtship and grooming. “It’s interesting to see that manipulation of many of these genes also can cause behavioral changes in the flies,” Andrews said. “We found a number of human genes with autism variants that altered behavior when expressed in flies, providing functional evidence that these have functional consequences.”

The third approach involved overexpressing the genes of interest in different tissue types in fruit flies. Co-first authors Samantha Deal and Michael Harnish, two graduate students in Baylor’s Graduate Programs in Developmental Biology and Genetics and Genomics, respectively, working in Dr. Yamamoto’s lab, headed these studies. “While some gene variants may lead to conditions because they produce defective proteins, others may lead to disease because they cause overabundance or aberrant function of a particular protein, which can disrupt biological processes. We investigated whether overexpressing gene variants found in individuals with autism might explain the detrimental effect for some of these genes,” Deal said.

Altogether, the team generated more than 300 fly strains in which they conducted functional studies of human gene variants associated with autiusm . Their screen elucidated 30 autism -linked variants with functional differences compared to the reference gene, which was about 40% of the genes for which they were able to perform a comparative functional assay.

“Some of the variants we studied had functional consequences that were moderately or clearly predicted to be disruptive, but other variants were a surprise. Even the state-of-the-art computational programs couldn’t predict they would have detrimental effects,” said Yamamoto. “This highlights the value of using multiple, complementary approaches to evaluate the functional consequences of genetic variants associated with autism or other conditions in a living animal. Our fruit fly approach is a valuable tool to investigate the biological relevance of gene variants associated with disease.”

In addition, the wealth of data generated by the researchers revealed gene variants not previously connected with other neurodevelopmental diseases and uncovered new aspects of the complexity of genetic diseases.

“GLRA2 was one gene we specifically focused on to follow up,” Dr. Ronit Marom, assistant professor of molecular and human genetics at Baylor and lead clinician of this work said. “We identified 13 patients, five males and eight females, carrying rare variants of this X-linked gene that had not been established as a neurological disease gene before. Furthermore, males and females carried variants with different types of functional consequences and the spectrum of neurological characteristics among these 13 patients was different between the two groups. For instance, many of the boys carried loss of function variants and had autism , while the girls did not. They mainly presented with developmental delay as the main characteristic of their condition, and carried gain of function variants.”

“The picture that emerges is that autism may not be one disorder involving many genes. It may actually be hundreds of genetic disorders, like those caused by certain GLRA2 variants,” said Wangler, assistant professor of molecular and human genetics at Baylor and co-corresponding author of the work. “We think that this information is important to physicians seeing patients with autism .”

The risk that an infant with an older sibling with autism also will develop the disorder, previously estimated at between 3 and 10 percent, is substantially higher at approximately 19 percent, a large, international, multi-site study led by researchers at the UC Davis MIND Institute has found. While the study found a combined estimated risk for all participants of nearly19 percent, it found an even more elevated risk of recurrence of over 26 percent for male infants, and over 32 percent for infants with more than one older sibling with autism.

The study is the largest prospective investigation of autism spectrum disorder and sibling recurrence to date. It is published online today and will appear in print in the September issue of the journal Pediatrics.

The study has important implications both for genetic counseling for parents and for referral to early intervention for the infant siblings of children with autism if concerns arise about their development, said Sally Ozonoff, professor of psychiatry and behavioral sciences at the MIND Institute and the study’s lead author.

“This is the largest study of the siblings of children with autism ever conducted,” Ozonoff said. “There is no previous study that identified a risk of recurrence that is this high,” she said.

Autism is a complex disorder that affects a child’s ability to think, communicate, interact socially and learn. The U.S. Centers for Disease Control and Prevention places the incidence of autism at 1 in 110 children born today.

The participants in the study were enrolled in separate studies that are part of the Baby Siblings Research Consortium, an international network supported by Autism Speaks that pools data from individually funded research sites to facilitate the study of infants at high risk of developing autism because they have an older sibling with the condition. There is strong evidence that genetic factors play a critical role in vulnerability for developing autism.

Twelve consortium sites located in the United States and Canada participated in the study, with additional sites as far away as Israel engaged in analyses and interpretation of the data. The study included 664 subjects, infants whose average age at enrollment was 8 months, with two-thirds recruited prior to 6 months of age. The researchers followed the participants’ development until 36 months, when they were tested for autism.

The study subjects were tested using the Autism Diagnostic Observation Schedule (ADOS), an autism diagnostic tool, and the Mullen Scales of Early Learning, which measures nonverbal cognitive, language and motor skills. Of the 664 participants, a total of 132 infants met the criteria for an autism spectrum disorder. Fifty-four received a diagnosis of autistic disorder and 78 received a diagnosis of Pervasive Developmental Delay Not Otherwise Specified, considered a milder form of autism.

More males than females are affected with autism — 80 percent of all affected children are male. The risk to male children held true in the current study. Among the study participants, 26.2 percent of male infants versus 9 percent of female infants were diagnosed with an autism spectrum disorder.

The overall rate of autism spectrum outcomes for all study participants was 18.7 percent. However, there was a significant difference in the recurrence rate based on whether the child had one sibling or more than one sibling with autism. In families with one older child with autism, or simplex families, the rate of incidence was 20.1 percent. Only 37 of the study participants had more than one sibling with autism. But for those families, called multiplex families, the recurrence rate was 32.2 percent.

“It’s important to recognize that these are estimates that are averaged across all of the families. So, for some families, the risk will be greater than 18 percent, and for other families it would be less than 18 percent. At the present time, unfortunately, we do not know how to estimate an individual family’s actual risk,” Ozonoff said.

Ozonoff said that the study’s large size, prospective design, the young age of study participants at enrollment and the gold-standard direct assessment methods used, as well as the geographic diversity of participants, reinforce the accuracy of its findings. The study design also minimized the effects of other factors such as “stoppage,” the tendency of families with a child with autism to stop having children, which would lead to an underestimate of potential recurrence rates. The study accounted for stoppage by studying only families with later-born siblings.

She said that the study has significant family-planning and genetic-counseling implications.

“Parents often ask what their risk of having another child with ASD is and, until now, we were really not sure of the answer,” she said.

The study also highlights the critical importance of routine surveillance and rapid referral for treatment of infant siblings of children with autism. Ozonoff said that it is of paramount importance that primary care professionals monitor these children’s development closely and refer them for early intervention immediately when concerns arise.

In practice guidelines published by the American Academy of Pediatrics in 2007, being a younger sibling of a child with autism is considered a risk factor requiring special developmental evaluation and the current investigation supported that recommendation.

“This study shows that the younger siblings of children with autism spectrum disorders need to be tracked very carefully, and this may require more than the normal surveillance that a pediatrician might typically do,” Ozonoff said. “This should include very explicitly and regularly checking in with parents on whether developmental milestones are being reached.”

Researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital have used a novel method for analyzing brain-scan data to distinguish children with autism from typically developing children. Their discovery reveals that the gray matter in a network of brain regions known to affect social communication and self-related thoughts has a distinct organization in people with autism. The findings will be published online Sept. 2 in Biological Psychiatry.

While autism diagnoses are now based entirely on clinical observations and a battery of psychiatric and educational tests, researchers have been making advances toward identifying anatomical features in the brain that would help to determine whether a person is autistic.

“The new findings give a uniquely comprehensive view of brain organization in children with autism and uncover a relationship between the severity of brain-structure differences and the severity of autism symptoms,” said Vinod Menon, PhD, a professor of psychiatry and behavioral sciences and of neurology and neurological sciences, who led the research.

“We are getting closer to being able to use brain-imaging technology to help in the diagnosis and treatment of individuals with autism,” said child psychiatrist Antonio Hardan, MD, who is the study’s other senior author and an associate professor of psychiatry and behavioral sciences at Stanford. Hardan treats patients with autism at Packard Children’s.

Brain scans are not likely to completely replace traditional methods of autism diagnosis, which rely on behavioral assessments, Hardan added, but they may eventually aid diagnosis in toddlers.

Autism occurs in about one in every 110 children. It is a disabling developmental disorder that impairs a child’s language skills, social interactions and the ability to sense how one is perceived by others.

The study compared MRI data from 24 autistic children aged 8 to 18 with scan data from 24 age-matched, typically developing children. The data was collected at the University of Pittsburgh.

“We jumped at the results,” Menon said. “Our approach allows us to examine the structure of the autistic brain in a more meaningful manner.” The new findings expand scientists’ basic knowledge of the core brain deficits in autism, he added.

The analysis method, called “multivariate searchlight classification,” divided the brain with a three-dimensional grid, then examined one cube of the brain at a time, and identified regions in which the pattern of gray matter volume could be used to discriminate between children with autism and typically developing children.

Instead of comparing the sizes of individual brain structures, as prior studies have done, the new analysis generated something akin to a topographical map of the entire brain. The scientists essentially mapped the autistic brain’s distinct cliffs and valleys, uncovering subtle differences in the physical organization of the gray matter.

Such analysis may be a more useful approach than previous tacks. Earlier studies, for instance, suggested that people with autism may have larger brains in toddlerhood or have a large defect in one brain structure. This study took a different approach and discovered several autism-associated differences in the Default Mode Network, a set of brain structures important for social communication and self-related thoughts. Specific structures that differed included the posterior cingulate cortex, the medial prefrontal cortex and the medial temporal lobes. These findings align well with recent theoretical and functional MRI studies of the autistic brain, which also point to differences in the Default Mode Network, Menon said.

Once Menon and his team had found where the differences in autistic brains were located, they were able to use their analysis to classify whether individual children in the study had autism. They used a subset of their data to “train” the mathematical algorithm, then ran the remaining brain scans through the algorithm to classify the children.

“We could discriminate between typically developing and autistic children with 92 percent accuracy on the basis of gray matter volume in the posterior cingulate cortex,” said Lucina Uddin, PhD, the study’s first author. Uddin is an instructor in psychiatry and behavioral sciences at Stanford.

In addition, the children with the most severe communication deficits, as measured on a standard behavioral scale for diagnosing individuals with autism, had the biggest brain structure differences. Severe impairments in social behavior and repetitive behavior also showed a trend toward association with more severe brain differences.

Menon and his team plan to repeat the study in younger children and to extend it to larger groups of subjects. If the results are upheld, the new method offers the possibility of several applications in autism diagnosis and treatment. For instance, brain scans might eventually help distinguish autism from other behavioral disorders such as attention deficit hyperactivity disorder, or might predict whether high-risk children, such as those with autistic siblings, will go on to develop autism themselves. Brain scanning might also be able to predict what type of deficits will occur in a child with a new autism diagnosis, allowing clinicians to target their treatments to a child’s predicted deficits.

“Scans would likely be used alongside clinical expertise, giving that extra hint from the brain data,” Uddin said.

When such integrated assessments are possible, the researchers hope they will allow clinicians to build detailed profiles of each patient. “We hope we’ll eventually be able to tell parents, ‘Your child will probably respond to this treatment, or your child is unlikely to respond to that treatment,'” Hardan said. “In my mind, that’s the future.”

The criminal justice system (CJS) is failing autistic people, argue researchers at the Autism Research Centre, University of Cambridge, after a survey of lawyers found that an overwhelming majority of their clients were not provided with adequate support or adjustments.

This comes on the back of an Equality and Human Rights Commission report in June 2020 that warned that the CJS is failing those with learning disabilities and autistic people. However, there is almost no research investigating how autistic defendants are being treated within the CJS.

The team set out to fill this gap by conducting a survey of 93 defence lawyers about autistic people they have represented in the last five years to find out about their defendants’ experiences of navigating the CJS. In their study, published today in Autism Research, the researchers found the CJS is failing autistic people.

The study found that only half of autistic people (52%) were considered by the police to be vulnerable adults, even though the law recognises all autistic people as vulnerable.

Over a third (35%) of autistic defendants were not given an ‘appropriate adult’ during police investigations, even though their diagnosis was known to police, and despite all autistic people being entitled under the law to have an appropriate adult present when being interviewed by the police. A further 18% did not have an ‘appropriate adult’ present because their diagnosis was not known to the police.

Appropriate adults act to safeguard the interests and rights of vulnerable defendants by ensuring that they are treated in a just manner and are able to participate effectively during an investigation.

Only a quarter (25%) of autistic people were given ‘reasonable adjustments’, with 38% not given any even though lawyers stated that this would have been beneficial. This is despite all autistic people being entitled to reasonable adjustments under the law. A further 33% did not receive any adjustments because their autism diagnosis was unknown at the time. Of the autistic people whose case went to trial, more than one in five (22%) were not given any reasonable adjustments even though their lawyers stated that this would have been helpful.

Reasonable adjustments, such as using visual aids to assist with communication and allowing extra time to process information, can be made by the police to assist the detainee.

Dr Rachel Slavny-Cross, who led the study, said: “Our research shows quite clearly that autistic adults are not receiving fair treatment within the criminal justice system. Without reasonable adjustments or support, this could place them at a significant disadvantage.”

In just under half of the cases that included a trial by jury (47%), the jury was not informed that the defendant was autistic. 59% of prosecution barristers and 46% of judges or magistrates said or did something during the trial that made them concerned that they did not have an adequate understanding of autism.

Dr Carrie Allison, a member of the research team, said: “It’s vital that jurors are provided with information about a defendant’s autism and its implications, otherwise they are likely to misinterpret atypical behaviour exhibited by the defendant in court. Similarly, judges may fail to take into consideration mitigating factors that might otherwise influence sentencing.”

The study found that lawyers were more likely to be concerned that their autistic clients would engage in self-harm behaviours, compared with their non-autistic clients, and were more likely to report that their autistic clients experienced ‘meltdowns’ as a result of their involvement in the CJS.

Dr Sarah Griffiths. another member of the research team, said: “Autistic adults are particularly vulnerable to mental health problems, such as stress and heightened anxiety, with many autistic people experiencing meltdown and shutdown as a result. This is likely to have shaped their interactions with the criminal justice system and their ability to cope with the stress of being subject to criminal proceedings.”

The study also found that those working within the CJS may be unaware that an individual is autistic, or of the implications of an autism diagnosis. They found that many autistic people do not disclose their diagnosis at the point of police contact or are themselves unaware they are autistic. However, as the study shows, even autistic defendants who disclose their diagnosis are failing to receive reasonable adjustments.

However, a positive finding was that, in cases where their client was found to have committed a crime, 60% of judges saw the defendant’s autism as a mitigating factor, and in these cases the majority of autistic people were given a suspended or reduced sentence.

Professor Sir Simon Baron-Cohen, Director of the Autism Research Centre at Cambridge and a member of the research team, added: “There’s an urgent need across the criminal justice system for increased awareness about autism. The police, lawyers, judges and jurors should be given mandatory training to be aware of how autism affects an individual’s behaviour, so that autistic defendants are treated fairly within the criminal justice system.”