The Autism studies/research thread

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The core symptoms of Autism Spectrum Disorder (ASD) are impairments in social interaction/communication and the presence of stereotyped and repetitive behaviour. The amygdala and hippocampus are involved in core functions in the “social brain” and, thus, may be of particular interest in ASD. Previous studies demonstrated inconsistent results, revealing both increased and reduced volume of these brain structures in individuals with ASD. In this study, we investigated the grey and white matter volumes of amygdala and hippocampus in primary-school-aged children with and without ASD. Also, we assessed the relationships between the volume of brain structures and behavioural measures in children with ASD.

A new neuroimaging study provides evidence of increased amygdala and face cortical network activation in individuals with autism spectrum disorder (ASD) in response to face-like (or pareidolic) stimuli. These findings support the hypothesis of an overly connected subcortical face-processing network in ASD, potentially resulting from an early imbalance between excitatory and inhibitory systems. The study was recently published in Cortex.

The researchers were interested in studying the neural mechanisms underlying face perception in individuals with autism because there is evidence of an over-sensitivity of the subcortical system, particularly the amygdala, during face processing in autism. Previous research has shown increased amygdala activation in response to facial expressions of fear in autistic individuals compared to non-autistic controls.

The researchers proposed that this over-arousal to face stimuli in autism is a result of an over-connection between the amygdala and the rest of the face-processing system, which may be caused by an early imbalance of excitatory and inhibitory systems in the brain.

“I have been interested in face perception in autism for more than 20 years,” said study author Nouchine Hadjikhani, an associate professor at Harvard Medical School and director of Neurolimbic Research at the Martinos Center for Biomedical Imaging. “In 2004, I published a paper that demonstrated that, contrary to what had been said by others, autistic individual actually demonstrated activation similar to that of a control group in the fusiform face area (FFA), a occipitotemporal brain area specialized in face processing – as long as one made sure that people were actually looking at the faces.”

“This led me to try to understand face and gaze avoidance in autism, and I have published a number of papers around this topic. The problem is that when one uses ‘real’ faces, there is always a social component, together with the presence of eyes, that may confound the results if one thinks that there is something more fundamental to the gaze avoidance issue. Hence the idea of using pareidolic objects, that we had shown to activate the FFA with the same timing as real faces, back in 2009, using magnetoencephalography (MEG).”

“So the idea here was to test the hypothesis that there is a hyperconnectivity in autism within the subcortical system that is dedicated to face detection using stimuli that did not have eyes, or social content,” Hadjikhani explained.

The researchers conducted their study using functional magnetic resonance imaging (fMRI) to examine brain activation patterns in response to visual stimuli. They recruited a total of 71 participants, including individuals diagnosed with autism spectrum disorder (ASD) and non-autistic controls (CON).

The visual stimuli consisted of 42 face-like objects and 42 matched control objects without pareidolic properties. The stimuli were presented on a screen during the fMRI scan, and participants viewed them through a mirror attached to the coil. The stimuli were grayscale images presented for a duration of 1600ms, followed by a blank interval of 400ms. Participants performed a one-back task to indicate stimulus repeats and maintain attention.

The researchers aimed to compare the brain activation patterns in response to pareidolic faces and control objects, focusing on the subcortical system, particularly the amygdala. They hypothesized that individuals with ASD, who have been shown to exhibit over-sensitivity in the subcortical system during face perception, would also demonstrate heightened activation in response to pareidolic faces.

The researchers observed a significant increase in amygdala activation in individuals with ASD compared to controls when exposed to face-like stimuli. The extended face-processing network, which includes the primary visual cortex, the orbitofrontal cortex (OFC), the superior temporal sulcus (STS), and the temporal pole, also showed higher activation in individuals with ASD compared to controls when processing face-like stimuli.

“I was surprised to see how big of a difference there was between groups, I would have expected a bit more activation in the control group, given our previous MEG results,” Hadjikhani told PsyPost. “But on the other hand, fMRI does not have a very high temporal resolution, so it is possible that this is the reason why we did not see much in the controls, as it may have been a short-lived activation in that group.”

The researchers propose that the increased sensitivity of the amygdala in ASD for pareidolic objects may be evidence of over-connection between the amygdala and the rest of the face-processing system. This over-connection could result from an early imbalance between excitatory and inhibitory systems in autism.

The findings indicate “that the basis of eye contact avoidance in autism is the result of an abnormal sensitivity of the threat processing system,” Hadjikhani said. “From early on after birth, the subcortical face processing system is too sensitive to basic face configuration and gets over-connected. Since this system over time gets involved in gaze perception, this is experienced as a stressful thing.”

However, the study also had some limitations. The participants were approximately 20 years old on average. But ASD typically develops early in childhood, with symptoms often becoming apparent in the first two years of life.

“As long as we cannot show this in infants, all this remains speculative, but I think there is accumulating evidence to show that eye contact avoidance in autism results from a hypersensitive subcortical face processing system,” Hadjikhani said.

“Given these observations, and also given first person reports from autistic individuals, it is important to remember that faces, and in particular eye contact can be overwhelming for autistic people, and that forcing them to engage in it may not be such a great idea. However, being aware of it and trying to habituate them may help them having a better read on others.”

Professor Evan Elliott of the Bar-Ilan University in Israel says the new study reveals 'the profound influence of the gut-brain axis on the biology of autism'

A global team of researchers uncovered evidence that links gut microbiome to autism spectrum disorder (ASD), offering potential new avenues for therapeutic interventions. The study was published in the journal Nature Neuroscience.

The study identified consistent differences in the gut microbiome of individuals with ASD, suggesting that these changes are a common characteristic associated with autism. Correlations were also found with immune factors, including inflammatory marker IL-6.

A key researcher involved in the study, Professor Evan Elliott of the Azrieli Faculty of Medicine of Bar-Ilan University, stated "our collaborative study presents a significant breakthrough, revealing the profound influence of the gut-brain axis on the biology of autism."

The Bar-Ilan statement said the study supported a notion that the “gut-brain axis” could be targeted as a “therapeutic approach for a specific subgroup of individuals with autism.” Then, the identification of specific markers could be used as a means for clinicians to better treat individuals who would benefit from microbiome-related interventions.

A personalized approach would then be able to “significantly improve outcomes and quality of life for those on the autism spectrum,” the statement continued. Furthermore, there were “pilot studies involving fecal microbiome treatment that demonstrated the ability to impact the dysregulated microbial species” of individuals with ASD.

The Israeli researchers said they wanted to work with participating families, from the Israel Autism Biobank and Registry, to continue unraveling the “complex interactions” which would inform future therapies.

Researchers found that compared with their peers, school-age kids with autism showed more difficulty managing memory tasks. They often had a hard time remembering faces — something seen in past studies — but also in recalling words and other types of information.

What's more, the researchers were able to trace the memory deficits to particular brain circuitry that was "hyperconnected”.

The findings suggest that memory challenges may be a bigger issue for kids with autism than generally recognized. And that should be taken into consideration at school and in services for those children, the researchers say.

Kids with "high-functioning" autism often go to mainstream schools and receive the same instruction as their peers, said lead author Jin Liu, a postdoctoral researcher at Stanford University School of Medicine, in California.

But, she said, the new findings suggest that even though those children may have high IQs, they can still struggle with memory issues.

"So they may need extra help," Liu said.

When it comes to memory issues, research has been fairly limited. Some studies have found that kids with autism can have a harder time remembering faces, compared with typically developing children. Less is known about whether they tend to have broader difficulties with memory.

It's an important question, Liu said, because memory skills are key to school and work performance. They also play an under-appreciated role in social relationships, she noted.

Socializing is complex, and requires people to draw upon many skills, including episodic memory — recalling the details of an event, like your first day at school, and the emotions associated with it.

Even the seemingly simple memory for objects can matter for school kids' interactions, Liu pointed out — if, for example, a child with autism has a hard time remembering that a classmate's backpack looks like theirs, but is not theirs.

For the new study — published July 10 in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging — Liu and her colleagues recruited 25 children with autism and 29 typically developing kids. All were between the ages of 8 and 12, and had average to above-average IQ.

On average, kids with autism scored lower on standard memory tests, versus the comparison group. The tests gauged kids' ability to recognize whether they'd seen an image or heard a word before, and their ability to recall the details of those past experiences. Some images were of faces and others were completely "non-social" — that is, included no people.

The researchers also found another performance difference. Among kids without autism, face and non-social memory were typically consistent: If one was good, so was the other.

But among kids with autism, the two did not always match up. Face memory might be worse than non-social memory, for example.

Some clues as to why turned up when the researchers used functional MRI scans to track the children's brain activity.

Among kids with autism, two distinct brain "circuits" were linked to memory difficulties. Problems with general memory were traced to hyperactivity in the hippocampus, a brain structure well known to be involved in memory. But struggles with face memory were tied to a brain area called the posterior cingulate cortex, which has a role in social abilities and the capacity to distinguish oneself from other people.

That does not, however, prove that abnormal activity in those brain circuits actually cause kids' memory problems, Liu said.

To parents, the findings might not come as a surprise. They know their kids best, Liu said, and may well have noticed any difficulties with general memory.

The study does not answer the question of how to best help kids with memory difficulties.

But it does raise awareness, said Alycia Halladay, chief science officer for the nonprofit Autism Science Foundation.

"This study emphasizes the need to look beyond the core autism symptoms when evaluating the needs of individuals on the spectrum," said Halladay, who was not involved in the study.

She agreed that memory challenges can have far-reaching effects, not only on things like school performance but also daily living and well-being.

"It's important to understand these memory impairments, even in those who do not have an intellectual disability," Halladay said.

About 1 percent of people not diagnosed with autism have rare variants in genes associated with the condition, a new study finds.

The results support the idea that a variety of social and biological factors help determine whether a person is ultimately diagnosed as autistic.

“If you carry a genetic variation, there is very often a diversity of outcomes that will depend on the genetic and environmental context of each carrier,” says lead investigator Thomas Bourgeron, director of the Human Genetics and Cognitive Function Unit at the Institut Pasteur in Paris, France.

More than 100 genes are associated with autism. But there has been little research on the prevalence of rare variants in these genes in people not diagnosed with autism, or about the effects they may have in this group.

Bourgeron and his colleagues analyzed genetic data on 13,091 people who have an autism diagnosis and 213,558 who do not, including 19,488 first-degree relatives of the autistic participants. The data came from the Simons Simplex Collection, SPARK, the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) and the UK Biobank projects. (The Simons Simplex Collection and SPARK are funded by the Simons Foundation, Spectrum’s parent organization.)

Among 185 genes linked to autism with high confidence, 134 show loss-of-function variants in at least one person not diagnosed with autism, the researchers found.

Carriers of these variants had, on average, slightly lower scores on tests of fluid intelligence, or abstract reasoning, than did people who lack the variants, the study shows. Similar group discrepancies were seen for income, the highest educational or professional qualification reached, and metrics related to wealth, such as employment and home ownership.

“Such metrics are important if we want to understand the cumulative effect of the genetic variants on outcome,” says study investigator Thomas Rolland, a researcher at the French National Center for Scientific Research in Paris. He and his colleagues detailed their findings 26 June in Nature Medicine.

“The relationship between income, cognition, material deprivation and variants is very interesting and previously unexplored,” says Stephan Sanders, professor of pediatric neurogenetics at the University of Oxford in the United Kingdom, who did not contribute to the work.

The variants’ links to the outcomes may not be causal, the researchers caution. A variety of social and biological resilience factors could explain why some people with these variants flourish or not.

“Rather than claiming that genes hold an exceptional explanatory power when it comes to developmental diversity, the authors embrace the complexity of development,” says Kristien Hens, a bioethicist and professor of philosophy at the University of Antwerp in Belgium, who was not involved in study but co-authored a commentary about it. “Straightforwardly linking specific genetic variants with human flourishing in general and with neurodivergent flourishing in particular is next to impossible.”

“It is very tempting to interpret findings in population genetics in terms of a simplistic ‘genes for IQ’ or ‘genes for autism’ narrative,” Hens says. But “genetic information is a small part of what it means to function or flourish, and while genetic research is part of what helps us understand organisms, it is specifically the entanglement with other factors, such as environment and sociocultural expectations, that is in need for further study.”

Although the new study analyzed more than 200,000 people, Rolland notes it still lacks the statistical power to identify definitive links between mutations and specific outcomes.

Congenital heart malformations used to be a death sentence for many newborns. But as medical care and surgeries have improved, most infants born with heart defects — nearly 1 in 100 babies in the United States — live to adulthood. As they do, another matter has come to light: As many as half of people with congenital heart disease (CHD) have neurodevelopmental issues such as autism.

Having CHD may raise the chances of being diagnosed with autism by anywhere from about one-third to sixfold, according to estimates from the past five years; A 2023 meta-analysis of all previous studies pegged the increased likelihood at twofold.

Many children with CHD also have some traits that resemble autism but don’t merit a diagnosis, such as problems with theory of mind and executive function, which includes working memory, cognitive flexibility, planning and self-regulation. “There’s also the question of what do we do with everything that lies in between,” says Johanna Calderon, chair in neurodevelopment at the University of Montpellier in France and lead scientist of the Cardiac Neurodevelopmental Team at the French National Institute of Health and Medical Research.

Scientists used to think that these neurodevelopmental issues stemmed from the life-saving surgeries that infants with CHD typically undergo. Techniques such as deep hypothermia to achieve circulatory arrest and circulating the blood externally were thought to damage the brain by reducing blood flow to it or causing blood clots.

But as it turns out, factors related to heart surgery account for only 5 to 8 percent of differences in neurodevelopmental issues among people with CHD, according to a 2019 review. And milder heart defects are more strongly linked to autism than severe ones, another 2019 study showed. What’s more, many children with CHD show signs of atypical brain development before they even enter the operating room.

Instead, neurodevelopmental outcomes are more likely determined by genetic mutations that affect both the heart and the brain, and by CHD-related brain changes in utero, recent research suggests, meaning heart defects in children should not be treated in isolation. And differences in the home environment, hospital care and socio-economic factors may contribute to outcomes as well.

“The more we know, it starts to get more complicated,” Panigrahy says.

Certain genetic mutations can raise the chances of both CHD and neurodevelopmental issues, mounting evidence suggests.

Children with CHD plus another congenital defect or a neurodevelopmental condition are three times more likely than would be expected by chance to have a harmful mutation, unlike children with CHD alone, according to a 2015 paper published in Science. “We discovered that if you look at de novo changes that are damaging, they tend to be in genes that are expressed in both heart and brain,” says Bruce Gelb, dean of child health research at the Icahn School of Medicine at Mt. Sinai in New York City, who led the work. “That, I think, is just because Mother Nature reuses genes, and uses the same gene programs to do more than one function.”

This study, along with a follow-up study in 2017 in Nature Genetics, identified 19 genes with harmful de novo mutations among 2,871 people with CHD; de novo mutations in these genes had previously been linked to autism. Many of these genes modify chromatin, which determines how DNA is packaged in cells and expressed into proteins.

A 2021 study found a total of 101 genes that influence a person’s susceptibility to both autism and CHD. Five of these genes — including SCN2A — encode ion channels; none of the five had been previously linked to CHD. Disrupting SCN2A in frogs affected the development of both the heart and the brain.

More clues continue to crop up. Mice with autism-linked mutations in genes involved in the Wnt/beta-catenin pathway, which governs cell growth and cell death, have malformations in their hearts, a 2022 study showed. And according to a study published in February, mutations in the autism-linked MYT1L gene lead to the faulty expression in the brain of SCN5A, a gene that is normally only expressed in the heart and also encodes an ion channel.

In general, for CHD genetics, it is still early days, Gelb says. “If we are at 50 percent, that’s generous, so there’s still a lot of discovery to do on genetics alone,” he says. As for CHD cases that have not yet been linked to genetic mutations, “the predominant thought is that it is genetic; we just don’t understand the genetics yet.”

The Science and Nature Genetics papers used data from the Pediatric Cardiac Genomics Consortium, which has recruited more than 13,600 people with CHD, plus their parents. Now in its third year of investigation, the focus has shifted from the underlying causes of CHD to how genetic variation relates to outcomes, including neurological ones, Gelb says. “The question is, if you look at genetic variation in kids with CHD, does it help differentiate between the kids with CHD who tend to do better versus worse?” he says.

Certain genetic mutations can raise the chances of both CHD and neurodevelopmental issues, mounting evidence suggests.

Children with CHD plus another congenital defect or a neurodevelopmental condition are three times more likely than would be expected by chance to have a harmful mutation, unlike children with CHD alone, according to a 2015 paper published in Science. “We discovered that if you look at de novo changes that are damaging, they tend to be in genes that are expressed in both heart and brain,” says Bruce Gelb, dean of child health research at the Icahn School of Medicine at Mt. Sinai in New York City, who led the work. “That, I think, is just because Mother Nature reuses genes, and uses the same gene programs to do more than one function.”

This study, along with a follow-up study in 2017 in Nature Genetics, identified 19 genes with harmful de novo mutations among 2,871 people with CHD; de novo mutations in these genes had previously been linked to autism. Many of these genes modify chromatin, which determines how DNA is packaged in cells and expressed into proteins.

A 2021 study found a total of 101 genes that influence a person’s susceptibility to both autism and CHD. Five of these genes — including SCN2A — encode ion channels; none of the five had been previously linked to CHD. Disrupting SCN2A in frogs affected the development of both the heart and the brain.

More clues continue to crop up. Mice with autism-linked mutations in genes involved in the Wnt/beta-catenin pathway, which governs cell growth and cell death, have malformations in their hearts, a 2022 study showed. And according to a study published in February, mutations in the autism-linked MYT1L gene lead to the faulty expression in the brain of SCN5A, a gene that is normally only expressed in the heart and also encodes an ion channel.

In general, for CHD genetics, it is still early days, Gelb says. “If we are at 50 percent, that’s generous, so there’s still a lot of discovery to do on genetics alone,” he says. As for CHD cases that have not yet been linked to genetic mutations, “the predominant thought is that it is genetic; we just don’t understand the genetics yet.”

The Science and Nature Genetics papers used data from the Pediatric Cardiac Genomics Consortium, which has recruited more than 13,600 people with CHD, plus their parents. Now in its third year of investigation, the focus has shifted from the underlying causes of CHD to how genetic variation relates to outcomes, including neurological ones, Gelb says. “The question is, if you look at genetic variation in kids with CHD, does it help differentiate between the kids with CHD who tend to do better versus worse?” he says.

The genetic ties between CHD and autism, though preliminary, already have clinical implications. “It helps us better understand what we’re supposed to be monitoring and looking out for,” says Sonia Monteiro, associate professor of pediatrics at Baylor College of Medicine in Houston, Texas.

Understanding the interplay between the two conditions could also prevent autism traits from getting swept under the rug by both parents and physicians.

Overall, cardiac programs throughout the U.S. and Europe have increased their vigilance around neurodevelopmental difficulties. That has been demonstrated by the establishment of the Cardiac Neurodevelopmental Outcome Collaborative in 2016, a network of centers across the U.S. and in Europe whose mission is to “determine and implement best practices of neurodevelopmental services.”

Children with CHD need close observation for neurodevelopmental issues even into adolescence, Calderon says. “It’s not just caring about the heart; I think it’s about really caring about the whole child, I would say even the whole family, to improve outcomes,” she says.

With children who have difficulties that do not add up to a diagnosis of autism, the danger is that they may slip through the cracks.

Mice with a mutation that boosts the activity of the autism-linked protein UBE3A show an array of behaviors reminiscent of the condition, a new study finds. The behaviors differ depending on whether the animals inherit the mutation from their mother or their father, the work also reveals.

The results add to mounting evidence that hyperactive UBE3A leads to autism. Duplications of the chromosomal region that includes UBE3A have been associated with autism, whereas deletions and mutations that destroy the gene’s function are known to cause Angelman syndrome, which is characterized by developmental delay, seizures, lack of speech, a cheerful demeanor and, often, autism.

“UBE3A is on a lot of clinicians’ radar because it is well known to be causative for Angelman syndrome when mutated or deleted,” says lead investigator Mark Zylka, professor of cell biology and physiology at the University of North Carolina at Chapel Hill. “What our study shows is that just because you have a mutation in UBE3A, it doesn’t mean that it’s going to be Angelman syndrome.”

In the cell, UBE3A is involved in the degradation of proteins, and “gain-of-function” mutations — which send the UBE3A protein into overdrive — result in enhanced degradation of its targets, including UBE3A itself. Studying the effects of these mutations could provide insight into how they affect brain development and suggest targets for therapies, says study investigator Jason Yi, assistant professor of neuroscience at Washington University in St. Louis, Missouri.

Gain-of-function mutations in UBE3A can disrupt early brain development and may contribute to neurodevelopmental conditions that are distinct from Angelman syndrome, Yi and Zylka have shown in previous studies. One of the mutations they analyzed had been found in an autistic child, so the team used CRISPR to create mice with this mutation.

During embryonic development, the mice show increased numbers of a specific subset of inhibitory interneurons in the brain’s outer layer compared with controls. Problems with interneurons can lead to the imbalance between neuronal excitation and inhibition seen in some forms of autism, previous studies suggest.

The differences in the number of interneurons mostly disappeared after birth, Zylka’s team found. The researchers now plan to investigate whether the alterations seen during embryonic development in mutant mice have a lasting effect on the imbalance of excitatory and inhibitory brain signals.

The parent of origin of UBE3A mutations can influence the severity of behavioral traits. This is because although people inherit two copies of the gene, only the one inherited from the mother is active in neurons — the paternal copy is silent. So Zylka’s team set out to study three groups of mutant mice: one that inherited the mutated copy of UBE3A from their mother, one that inherited it from their father, and one that inherited two mutated copies of UBE3A.

Mice that inherited the mutated UBE3A from their mother and those that inherited two mutated copies, but not those that inherited the mutated UBE3A from their father, were hyperactive compared with controls. In a test that assesses sociability in mice, only animals that inherited the mutated UBE3A from their father failed to show a preference for an unfamiliar mouse versus an empty cage — a behavior indicative of social deficits.

In a test of motor coordination, in which mice are placed on a rod that spins at increasing speed, mutant mice performed similarly to controls. Mice that inherited the mutated UBE3A from their mother stayed on the rod even longer than control animals, the researchers found. This is in contrast with what has been observed in mouse models of Angelman syndrome, which fall off the rotating rod sooner than controls, Zylka says.

The researchers reported their results in Cell Reports last month.

The findings suggest that gain-of-function mutations in UBE3A result in an autism-like condition that is different from Angelman syndrome, Zylka says. “All the clinical data and this preclinical data point to this being a new syndromic disorder, with phenotypes that are going to vary by parent of origin and by the severity of the gain-of-function mutation.”

University of Haifa researchers have discovered a significant association between autism and accelerated development of neurons in embryos.

The research, led by Dr. Shani Stern from the Department of Neurobiology at the University of Haifa, focused on children with autism who had genetic mutations as the underlying cause of their condition.

By studying neurons at the embryonic stage, the team found evidence of rapid neuron development that was not observed in children without autism. Additionally, the neurons displayed signs of rapid deterioration, characterized by low connectivity.

“Neurons that develop at a normal rate typically develop defense mechanisms for their complex activities, such as handling ions and neurotransmitters, which can be toxic. The accelerated development we observed in children with autism may have caused them to be exposed to these challenges before having developed adequate protective mechanisms,” explained Stern.

The team’s study was published in Translational Psychiatry a peer-reviewed journal, earlier in July.

Traditionally, research into autism caused by genetic mutations has often relied on mouse models, focusing on post-birth stages of neuron development. However, Stern’s approach involved reprogramming mature cells from specific individuals into induced stem cells, which were then transformed into neurons. This enabled the researchers to track the development of neurons even before birth.

The study compared the development of cortical neurons in children with autism caused by various gene mutations to their unaffected siblings, forming the control group. Cortical neurons were chosen due to their known involvement in the changes observed in the brains of children with autism.

Regardless of the specific genetic mutation, all children with autism exhibited accelerated cortical neuron development during the embryonic stage and early months of life. At this early stage, the neurons were considered “mature,” displaying action potentials, strong electrical currents, and even forming active neuronal networks. In contrast, the neurons of the control group did not exhibit such advanced development at the same stage.

However, as the control group’s neurons reached the stage of producing action potentials and networks, the cortical neurons of children with autism had already begun to deteriorate, showing reduced connectivity.

Stern suggested that the early accelerated development could be responsible for the subsequent deterioration.

Stern and her team are now focused on investigating compounds and drugs that could slow down this rapid development, offering protection to the developing neurons and potentially providing new therapeutic strategies for autism.

UCLA Health researchers have published the largest-ever study of families with at least two children with autism, uncovering new risk genes and providing new insights into how genetics influence whether someone develops autism spectrum disorder.

The new study, published in the Proceedings of the National Academy of Sciences, also provides genetic evidence that language delay and dysfunction should be reconsidered as a core component of autism.

Most genetic studies of autism have focused on families with one child affected by the neurodevelopmental disorder, sometimes excluding families with multiple affected children.

As a result, few studies have examined the role of rare inherited variation or its interaction with the combined effect of multiple common genetic variations that contribute to the risk of developing autism.

“Study design is critical and not enough attention has been paid to studying families with more than one affected child,” said lead study author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology and Psychiatry at UCLA.

Autism is highly heritable: It is estimated at least 50% of genetic risk is predicted by common genetic variation and another 15%–20% is due to spontaneous mutations or predictable inheritance patterns. The remaining genetic risk is yet to be determined.

For this study, researchers performed whole genome sequencing in 4,551 individuals from 1,004 families with at least two children diagnosed with autism. This group included 1,836 children with autism and 418 children without an autism diagnosis.

The researchers found seven potential genes that are predicted to increase the risk of autism: PLEKHA8, PRR25, FBXL13, VPS54, SLFN5, SNCAIP, and TGM1.

This is remarkable because other studies have had to analyze much larger cohorts to identify a similar number of novel risk genes. This is because in this case, most of the new genes were supported by rare inherited DNA variations that were transmitted from parents to children with autism.

The researchers also examined polygenic risk, in which a combination of commonly found genetic variations can raise the likelihood of developing autism. They found children who inherit rare mutations from unaffected parents in combination with polygenic risk are more likely to have autism.

This helps explains why parents who carry a single rare mutation may not show signs of autism even if their children do. It also lends support to the liability threshold model, a concept in behavioral genetics that holds there is an additive effect of genes that influences the probability that someone develops a certain trait.

In another important finding, children who had language delay had a higher likelihood of inheriting a polygenic score associated with autism, while there was not a similar relationship for children without language delays.

This pattern was specific to autism and was not seen in other traits like educational attainment, schizophrenia or bipolar disorder, suggesting there’s a link between the genetic risk for autism and language delay.

However, the most recent edition of the professional guidebook used by mental health providers to diagnose disorders—the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)—does not consider language delay a core autism symptom, citing the variability in language ability among people with autism.

“This association of general risk for ASD that was strongest in those with language delay suggests that language is actually a core component of ASD. This finding needs to be replicated in larger cohorts, especially those recruited more recently under DSM-5,” Geschwind said.

The health conditions that tend to accompany autism in adolescence grow even more prevalent by early adulthood, according to a new longitudinal study.

The findings underscore the importance of continually screening for these conditions in autistic children as they age, especially as they transition from pediatric to adult care.

“There are many health conditions, both psychiatric as well as physical health, that are common in autism. And they don’t go away as teens become adults,” says Beth Ann Malow, professor of neurology at Vanderbilt University in Nashville, Tennessee, and lead investigator of the study.

The transition to adulthood can be difficult for everyone, but “when you overlay that with aspects of autism and/or autism-related services, it can become pretty complicated,” says Kristin Long, associate professor of psychological and brain sciences at Boston University in Massachusetts, who wasn’t involved in the study.

On top of that, adults with autism have a higher-than-average prevalence of most medical conditions, including seizures, obesity and diabetes as well as immune, gastrointestinal and sleep disorders. These also include psychiatric conditions such as depression, anxiety and bipolar disorder. This makes access to health care even more critical, Malow says.

In the new study, which was published in Autism Research in June, Malow and her colleagues analyzed the electronic health records of 1,418 autistic people and 6,029 non-autistic people aged 14 to 22 who received health care through Kaiser Permanente Northern California from 2014 to 2019. Participants who were 14 at the start of the study were followed until age 19, whereas those who were 17 at the start were followed until age 22. The data from both cohorts were combined and used to model the prevalence of each condition over time.

Malow and her team focused on health conditions that affect quality of life and for which they had sufficient sample sizes: obesity, anxiety, ADHD and depression, as well as cardiovascular, neurological and sleep disorders.

All tracked conditions were more common in autistic youth than in non-autistic youth, and the prevalence of all conditions increased with age in both groups. At age 14, obesity and ADHD were more prevalent in autistic boys than girls, but by age 22, all conditions were more prevalent in autistic women than men.

I think this paper is great because we have always looked at the prevalence of health conditions in autism at one given time point, but no one’s ever followed it over time,” says Ann Neumeyer, associate professor of neurology at Harvard Medical School, who wasn’t involved in the study. “And that's the beauty of this paper.”

The prevalence of psychiatric conditions in the non-autistic cohort may be underestimated because those people may not visit the doctor as regularly as those with autism do, says Eric Rubenstein, assistant professor of epidemiology at Boston University, who was not involved in the study. “An autistic person going in to get certain therapies might be more likely to pick up those diagnoses because they’re seeing the provider, whereas other people may not.”

Obesity and dyslipidemia, or high levels of lipids in the blood, were more abundant in autistic youth at all ages but also rose at a faster rate than in non-autistic youth.

The rates of obesity are really, really high among the autistic population,” says James McCauley, assistant professor of psychology at Saint Mary’s College of California in Moraga, who was not involved in the study. “And it’s concerning to see here and in other work, the trajectories of obesity increasing across adolescence into adulthood.”

Because the study relied on medical records, it did not include uninsured people or those who did not visit the doctor, which is a limitation of the findings, Rubenstein says. The study also did not stratify the results by intellectual ability, race or income level, which could have revealed additional disparities.

Research using three-dimensional replicas of the developing brain created in a lab dish is shedding new light on autism spectrum disorder.

Yale researchers found two paths to autism in the developing brain.

“It’s amazing that children with the same symptoms end up with two distinct forms of altered neural networks," co-senior author Dr. Flora Vaccarino said in a university news release. She is director of the program in neurodevelopment and regeneration at the Child Study Center at Yale School of Medicine in New Haven, Conn.

These abnormalities, which arise just weeks after the start of brain development, have been associated with the emergence of autism, according to the new research.

They seem to be dictated by the size of the child’s brain, the scientists said. That discovery may help to diagnose and treat autism in the future.

Researchers collected stem cells from 13 boys diagnosed with autism to create the brain organoids, which are lab-grown replicas of the developing brain that mimic neuronal growth in the fetus.

Patients were recruited from clinicians at the Yale Child Study Center.

Eight of the boys had a condition in which the head is enlarged, called macrocephaly.

About 20% of autism cases are in people with macrocephaly, in which the newborn's head size is in the 90th percentile or greater. These tend to be more severe autism cases.

Children with autism and macrocephaly exhibited excessive growth of excitatory neurons compared with their fathers, according to the study authors. The organoids of other children with autism had a deficit of the same type of neurons.

Excitatory neurons, which cause messages to be fired off in the brain, play a key role in functions like thinking, learning and memory, according to the Cleveland Clinic.

Vaccarino said these findings may help identify autism cases that would benefit from existing drugs used to reduce symptoms of other disorders that involve excessive excitatory neuron activity, such as epilepsy. While autism patients with macrocephaly might benefit from these medications, those without enlarged brains may not.

Creating biobanks of patient-derived stem cells could be key to tailoring therapeutics to specific individuals, the authors noted.

Abstract
Autism is a neurodevelopmental condition involving atypical sensory-perceptual functions together with language and socio-cognitive deficits. Previous work has reported subtle alterations in the asymmetry of brain structure and reduced laterality of functional activation in individuals with autism relative to non-autistic individuals (NAI). However, whether functional asymmetries show altered intrinsic systematic organization in autism remains unclear. Here, we examined inter- and intra-hemispheric asymmetry of intrinsic functional gradients capturing connectome organization along three axes, stretching between sensory-default, somatomotor-visual, and default-multiple demand networks, to study system-level hemispheric imbalances in autism. We observed decreased leftward functional asymmetry of language network organization in individuals with autism, relative to NAI. Whereas language network asymmetry varied across age groups in NAI, this was not the case in autism, suggesting atypical functional laterality in autism may result from altered developmental trajectories. Finally, we observed that intra- but not inter-hemispheric features were predictive of the severity of autistic traits. Our findings illustrate how regional and patterned functional lateralization is altered in autism at the system level. Such differences may be rooted in atypical developmental trajectories of functional organization asymmetry in autism.

In what they call the largest study ever done, researchers found using marijuana while pregnant may increase the risk that a child will develop autism.

“Women who used cannabis during pregnancy were 1.5 times more likely to have a child with autism,” said study author Dr. Darine El-Chaâr, a maternal fetal medicine specialist and clinical investigator at Ottawa Hospital Research Institute in Canada.

The study, published Monday in the journal Nature, reviewed data from every birth in Ontario, Canada, between 2007 and 2012, well before recreational marijuana was legalized in Canada in 2017. Of the half a million women in that data pool, researchers then narrowed the study to 2,200 women who said they used only marijuana during pregnancy, without mixing it with tobacco, alcohol or opioids.

The study did not capture the amount and type of marijuana the women used during pregnancy. Nor did the study know when during the pregnancy or how often women used it. And while the study could only show association, not cause and effect, researchers said they did their best to eliminate confounding factors.

Weed use during pregnancy growing
As weed becomes legalized and more socially acceptable, health care researchers worry that moms-to-be might think it’s fine to use to treat morning sickness or use recreationally, despite the lack of research on long-term impacts on a fetus.

Women also chose to use marijuana to avoid medications they felt were more harmful to their baby, such as anti-nausea pills, anti-psychotic medications and opioids, a small study of pregnant women by Washington State University researchers found.

Use of marijuana by pregnant women has been growing in the United States in recent decades. An analysis last year of over 450,000 pregnant American women ages 12 to 44 by the National Institute on Drug Abuse found cannabis use more than doubled between 2002 and 2017.

The vast majority of marijuana use was during the first three months of pregnancy, the study found, and was predominantly recreational rather than medical.

Yet the first trimester may be one of most sensitive times for the developing brain of a fetus, when it’s most susceptible to damage, El-Chaâr said. Studies have found receptors for cannabis in the brains of animals as early as five and six weeks of gestational age, she said.

What to do
Any woman using marijuana and discovers she is pregnant should immediately discuss her use with her doctors, experts say. Yet many young women aren’t honest, studies have shown. One study of women 24 years old and younger found they were about twice as likely to screen positive for marijuana use than they stated in self-reports.

The self-reported prevalence of marijuana use during pregnancy ranges from 2% to 5% in most studies, according to the American College of Obstetricians and Gynecologists.

“Pregnant women or women contemplating pregnancy should be encouraged to discontinue use of marijuana for medicinal purposes in favor of an alternative therapy for which there are better pregnancy-specific safety data,” ACOG states in its recommendations.

“There are insufficient data to evaluate the effects of marijuana use on infants during lactation and breastfeeding, and in the absence of such data, marijuana use is discouraged”

Abstract
Social behaviors, how individuals act cooperatively and competitively with conspecifics, are widely seen across species. Rodents display various social behaviors, and many different behavioral paradigms have been used for investigating their neural circuit bases. Social behavior is highly vulnerable to brain network dysfunction caused by neurological and neuropsychiatric conditions such as autism spectrum disorders (ASDs). Studying mouse models of ASD provides a promising avenue toward elucidating mechanisms of abnormal social behavior and potential therapeutic targets for treatment. In this review, we outline recent progress and key findings on neural circuit mechanisms underlying social behavior, with particular emphasis on rodent studies that monitor and manipulate the activity of specific circuits using modern systems neuroscience approaches. Social behavior is mediated by a distributed brain-wide network among major cortical (e.g., medial prefrontal cortex (mPFC), anterior cingulate cortex, and insular cortex (IC)) and subcortical (e.g., nucleus accumbens, basolateral amygdala (BLA), and ventral tegmental area) structures, influenced by multiple neuromodulatory systems (e.g., oxytocin, dopamine, and serotonin). We particularly draw special attention to IC as a unique cortical area that mediates multisensory integration, encoding of ongoing social interaction, social decision-making, emotion, and empathy. Additionally, a synthesis of studies investigating ASD mouse models demonstrates that dysfunctions in mPFC-BLA circuitry and neuromodulation are prominent. Pharmacological rescues by local or systemic (e.g., oral) administration of various drugs have provided valuable clues for developing new therapeutic agents for ASD. Future efforts and technological advances will push forward the next frontiers in this field, such as the elucidation of brain-wide network activity and inter-brain neural dynamics during real and virtual social interactions, and the establishment of circuit-based therapy for disorders affecting social functions.

Conclusions and future outlook
We have discussed recent findings that have elucidated critical brain circuits governing different aspects of social behavior. Studies using modern neuroscience tools that monitor and manipulate circuit activity have significantly advanced our knowledge of their function and dysfunction in normal mice and various ASD models toward a goal of a deeper understanding of human social behavior and relevant disorders. Social behavior is mediated by a distributed brain-wide network among cortical (e.g., mPFC, ACC, IC) and subcortical (e.g., NAc, BLA) structures and neuromodulatory systems (e.g., oxytocin, dopamine, serotonin). We drew particular attention to the IC as a unique cortical area in this review as it plays a vital role in multisensory processing, monitoring of social interaction, social decision-making, and empathy. Studies of ASD mouse models have shown that dysfunctions in mPFC-BLA circuitry and neuromodulatory systems are prominent. Pharmacological rescues by local or oral administration of various drugs have provided valuable clues for developing new therapeutic agents for ASD. In the future, technical advances that enable more precise tracing, recording, and manipulation of specific circuits and the introduction of new social behavioral assays will allow us to tackle important conceptual issues and make subsequent groundbreaking discoveries in this field. We here outline some major open questions regarding social behavioral mechanisms and developing potential treatments for ASD.
(1)
Each brain region, such as the mPFC, is connected with functionally diverse target regions. How does a large-scale brain-wide network operate while mice engage in social behavior? Elucidation of this problem will give us an important insight into near-whole-brain level biological principles of social behavioral mechanisms beyond a single circuit level. Besides investigating interactions between two or more defined circuits, an interplay between multiple neuromodulatory systems is another crucial point of interest. Analyses of network-level compensatory mechanisms elicited by primary circuit defects in ASD models will also substantially deepen our understanding of the dysfunction of autistic brains. Recently, simultaneous multi-site electrical recording from multiple brain regions has identified a brain-wide network that encodes individual rewarding social experiences. Optical methods that allow parallel recording from multiple areas and numerous neurons, such as mesoscopic calcium imaging, wide-field two-photon imaging, and multi-site two-photon imaging, may also be useful for this direction of research.

(2)
New technologies to monitor neural activity during social behavior enormously increased our knowledge of the underlying mechanisms within a single individual. An extension of such techniques to performing simultaneous recording of brain dynamics from two or more interacting animals opens a new avenue for exploring inter-brain neural dynamics that may serve as neural correlates for shared social variables . Recent work in bats and mice reveals inter-brain synchrony in the PFC during social interaction. How do such inter-brain dynamics emerge from the action of specific neural circuits? How are they implicated in social defects in neuropsychiatric disorders? And how do inter-brain dynamics during interaction in the real world relate to those in physical-digital social interaction? For example, the “mouse metaverse”, the amalgamation of virtual reality (VR) and physical reality that can provide an immersive three-dimensional social experience in a digital space, offers opportunities for studying novel aspects of social communication in mice. What are the inter-brain dynamics of mice like when they interact with each other via avatars of themselves in an immersive virtual environment? Combined with the use of empathy and prosocial behavior, we may be able to visualize the “mouse mind”.

(3)
To take full advantage of our knowledge about the circuit mechanisms of social behavior, it is important to pursue not only pharmaceutical interventions but also non-pharmaceutical therapies. How can we establish circuit-based cures for disorders that affect social functioning? Despite its invasiveness, deep brain stimulation through implanted electrodes that directly intervene in pathological neural circuits has been applied to treat various neurological and neuropsychiatric disorders . For the ASD population, non-invasive brain stimulation techniques such as transcranial magnetic stimulation and transcranial direct current stimulation have been used for treatment and rehabilitation, and meta-analyses of studies identify some beneficial effects on symptoms, including the social domain. However, the efficacy, specificity, and safety of the current methods still face technical challenges. Next-generation non-invasive or minimally invasive neuromodulation technologies that use electric, optical, magnetic, and acoustic signals may offer a prospect for the clinical applications of circuit-specific brain stimulation therapy.

Humans can perform the most complex level of social behavior, and the action of brain networks that support such outstanding quality is extraordinarily intricate. Insights gained from future research using rodents as a model and their extension to explore principles shared with humans will continue to advance our understanding of the biological underpinnings of social behavior and associated deleterious changes. This endeavor will eventually lead to the development of circuit-based therapies for relevant disorders.

A new study published in Scientific Reports demonstrates striking similarities in synaptic abnormalities and behavioral patterns between male and female mouse models of autism spectrum disorder (ASD). This research challenges the conventional male-centric focus in ASD studies and underscores the vital need to include both sexes in autism research.

Historically, ASD research has been skewed towards males, prompted by a higher diagnosed prevalence in males compared to females. This new study, however, suggests that the traditional approach may overlook critical aspects of the disorder, especially in females. The motivation behind this research was to bridge this gap and provide a more comprehensive understanding of ASD.

“The main goal is to test the molecular/biochemical differences or similarities between males and females in autism,” said study author Haitham Amal (@haitham_amal), an associate professor at Hebrew University. “The estimated prevalence rate of males diagnosed with ASD exceeds females by a ratio of 4:1. As a result, males remain the primary focus of ASD studies in clinical and experimental settings. Meanwhile, some studies indicate an underestimation of this disorder in females. It was therefore very important to test whether the hypothesis that males are indeed different from females at a molecular and behavioral level.”

The research involved young male and female mice with specific mutations linked to autism. The team compared these mice with regular, non-mutated mice. Two different mouse models were used, each representing a different human-based mutation. The primary objective was to analyze brain connections by examining specific proteins in the brain and the presence of tiny structures in brain cells.

To investigate synaptic development and function, the researchers employed a combination of Golgi staining and the analysis of key neuronal proteins. Golgi staining, a classical neuroanatomical technique, was used to visualize the structure of neurons, particularly the dendritic spines. In parallel, levels of specific proteins critical for synaptic function were measured.

Both male and female mice with ASD-related mutations showed a notable decrease in spine density on their neurons. Spine density is a key indicator of synaptic health and connectivity; lower spine density suggests reduced synaptic connections, which are critical for efficient neural communication.

Alongside this, there were marked reductions in levels of important synaptic proteins, including GAD1, NR1, VGAT, and Syp. These proteins are integral to synaptic transmission and plasticity. GAD1 is involved in the synthesis of the inhibitory neurotransmitter GABA, NR1 is a component of NMDA receptors crucial for synaptic plasticity, VGAT is involved in GABA transport in synaptic vesicles, and Syp is associated with the regulation of neurotransmitter release.

To connect these synaptic changes to behavior, the study employed sociability tests. These tests are designed to assess social interaction and preference for social novelty, which are often affected in individuals with ASD. In these tests, both male and female mice with ASD mutations exhibited deficits in social behavior compared to their non-mutated counterparts. This was evidenced by their reduced interaction with other mice and possibly less exploration of social stimuli.

Importantly, the researchers found a correlation between the observed synaptic changes and the behavioral patterns. The reduced spine density and altered levels of synaptic proteins suggested a disrupted neural network, which could underlie the social interaction deficits observed in the mice. Such a correlation is significant as it provides a potential explanation for the behavioral symptoms of ASD based on underlying neurobiological changes.

These results challenge the conventional approach in ASD research that has predominantly focused on male subjects, based on the higher diagnosed prevalence of ASD in males. The similarity in synaptic and behavioral patterns found in both male and female mice implies that female models of ASD should not be overlooked, as they provide essential insights into the disorder. This understanding is crucial for developing more comprehensive and effective treatment strategies that cater to both sexes.

However, the study is not without limitations. The use of animal models allowed the researchers to examine the specific biochemical changes associated with ASD. But these models may not fully replicate the complexities of human ASD. Future research could focus on validating these findings in human subjects and exploring the molecular mechanisms underlying these similarities.

The study, “Mutations associated with autism lead to similar synaptic and behavioral alterations in both sexes of male and female mouse brain“, was authored by Manish Kumar Tripathi, Shashank Kumar Ojha, Maryam Kartawy, Igor Khaliulin, Wajeha Hamoudi, and Haitham Amal.