latest research on autism

Groundbreaking study connects genetic risk for autism to changes observed in the brain

A groundbreaking study led by UCLA Health has unveiled the most detailed view of the complex biological mechanisms underlying autism, showing the first link between genetic risk of the disorder to observed cellular and genetic activity across different layers of the brain.

The study is part of the second package of studies from the National Institutes of Health consortium, PsychENCODE. Launched in 2015, the initiative, chaired by UCLA neurogeneticist Dr. Daniel Geschwind, is working to create maps of gene regulation across different regions of the brain and different stages of brain development. The consortium aims to bridge the gap between studies on the genetic risk for various psychiatric disorders and the potential causal mechanisms at the molecular level.

"This collection of manuscripts from PsychENCODE, both individually and as a package, provides an unprecedented resource for understanding the relationship of disease risk to genetic mechanisms in the brain," Geschwind said.

Geschwind's study on autism, one of nine published in the May 24 issue of Science , builds on decades of his group's research profiling the genes that increase the susceptibility to autism spectrum disorder and defining the convergent molecular changes observed in the brains of individuals with autism. However, what drives these molecular changes and how they relate to genetic susceptibility in this complex condition at the cellular and circuit level are not well understood.

Gene profiling for autism spectrum disorder, with a few exceptions in smaller studies, has long been limited to using bulk tissue from brains from autistic individuals after death. These tissue studies are unable to provide detailed information such as the differences in brain layer, circuit level and cell type-specific pathways associated with autism as well as mechanisms for gene regulation.

To address this, Geschwind used advances in single-cell assays, a technique that makes it possible to extract and identify the genetic information in the nuclei of individual cells. This technique provides researchers the ability to navigate the brain's complex network of different cell types.

More than 800,000 nuclei were isolated from post-mortem brain tissue of 66 individuals from ages 2 to 60, including 33 individuals with autism spectrum disorder and 30 neurotypical individuals who acted as controls. The individuals with autism included five with a defined genetic form called 15q duplication syndrome. Each sample was matched by age, sex, and cause of death balanced across cases and controls.

Through this, Geschwind and his team were able to identify the major cortical cell types affected in autism spectrum disorder, which included both neurons and their support cells, known as glial cells. In particular, the study found the most profound changes in the neurons that connect the two hemispheres and provide long range connectivity between different brain regions and a group of interneurons, called somatostatin interneurons that are important for maturation and refinement of brain circuits.

A critical aspect of this study was the identification of specific transcription factor networks -- the web of interactions whereby proteins control when a gene is expressed or inhibited -- that drive these changes that were observed. Remarkably, these drivers were enriched in known high-confidence autism spectrum disorder risk genes and influenced large changes in differential expression across specific cell subtypes. This is the first time that a potential mechanism connects changes occurring in brain in ASD directly to the underlying genetic causes.

Identifying these complex molecular mechanisms underlying autism and other psychiatric disorders studied could work to develop new therapeutics to treat these disorders.

"These findings provide a robust and refined framework for understanding the molecular changes that occur in brains in people with ASD -- which cell types they occur in and how they relate to brain circuits," Geschwind said. "They suggest that the changes observed are downstream of known genetic causes of autism, providing insight into potential causal mechanisms of the disease."

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• Brie Wamsley, Lucy Bicks, Yuyan Cheng, Riki Kawaguchi, Diana Quintero, Michael Margolis, Jennifer Grundman, Jianyin Liu, Shaohua Xiao, Natalie Hawken, Samantha Mazariegos, Daniel H. Geschwind. Molecular cascades and cell type–specific signatures in ASD revealed by single-cell genomics . Science , 2024; 384 (6698) DOI: 10.1126/science.adh2602

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Understanding why autism symptoms sometimes improve amid fever

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Scientists are catching up to what parents and other caregivers have been reporting for many years: When some people with autism spectrum disorders experience an infection that sparks a fever, their autism-related symptoms seem to improve.

With a pair of new grants from The Marcus Foundation, scientists at MIT and Harvard Medical School hope to explain how this happens in an effort to eventually develop therapies that mimic the “fever effect” to similarly improve symptoms.

“Although it isn’t actually triggered by the fever, per se, the ‘fever effect’ is real, and it provides us with an opportunity to develop therapies to mitigate symptoms of autism spectrum disorders,” says neuroscientist Gloria Choi , associate professor in the MIT Department of Brain and Cognitive Sciences and affiliate of The Picower Institute for Learning and Memory.

Choi will collaborate on the project with Jun Huh, associate professor of immunology at Harvard Medical School. Together the grants to the two institutions provide $2.1 million over three years.

“To the best of my knowledge, the ‘fever effect’ is perhaps the only natural phenomenon in which developmentally determined autism symptoms improve significantly, albeit temporarily,” Huh says. “Our goal is to learn how and why this happens at the levels of cells and molecules, to identify immunological drivers, and produce persistent effects that benefit a broad group of individuals with autism.”

The Marcus Foundation has been involved in autism work for over 30 years, helping to develop the field and addressing everything from awareness to treatment to new diagnostic devices.

“I have long been interested in novel approaches to treating and lessening autism symptoms, and doctors Choi and Huh have honed in on a bold theory,” says Bernie Marcus, founder and chair of The Marcus Foundation. “It is my hope that this Marcus Foundation Medical Research Award helps their theory come to fruition and ultimately helps improve the lives of children with autism and their families.”

Brain-immune interplay

For a decade, Huh and Choi have been investigating the connection between infection and autism. Their studies suggest that the beneficial effects associated with fever may arise from molecular changes in the immune system during infection, rather than on the elevation of body temperature, per se.

Their work in mice has shown that maternal infection during pregnancy, modulated by the composition of the mother’s microbiome, can lead to neurodevelopmental abnormalities in the offspring that result in autism-like symptoms, such as impaired sociability. Huh’s and Choi’s labs have traced the effect to elevated maternal levels of a type of immune-signaling molecule called IL-17a, which acts on receptors in brain cells of the developing fetus, leading to hyperactivity in a region of the brain’s cortex called S1DZ. In another study , they’ve shown how maternal infection appears to prime offspring to produce more IL-17a during infection later in life.

Building on these studies, a 2020 paper clarified the fever effect in the setting of autism. This research showed that mice that developed autism symptoms as a result of maternal infection while in utero would exhibit improvements in their sociability when they had infections — a finding that mirrored observations in people. The scientists discovered that this effect depended on over-expression of IL-17a, which in this context appeared to calm affected brain circuits. When the scientists administered IL-17a directly to the brains of mice with autism-like symptoms whose mothers had not been infected during pregnancy, the treatment still produced improvements in symptoms.

New studies and samples

This work suggested that mimicking the “fever effect” by giving extra IL-17a could produce similar therapeutic effects for multiple autism-spectrum disorders, with different underlying causes. But the research also left wide-open questions that must be answered before any clinically viable therapy could be developed. How exactly does IL-17a lead to symptom relief and behavior change in the mice? Does the fever effect work in the same way in people?

In the new project, Choi and Huh hope to answer those questions in detail.

“By learning the science behind the fever effect and knowing the mechanism behind the improvement in symptoms, we can have enough knowledge to be able to mimic it, even in individuals who don’t naturally experience the fever effect,” Choi says.

Choi and Huh will continue their work in mice seeking to uncover the sequence of molecular, cellular and neural circuit effects triggered by IL-17a and similar molecules that lead to improved sociability and reduction in repetitive behaviors. They will also dig deeper into why immune cells in mice exposed to maternal infection become primed to produce IL-17a.

To study the fever effect in people, Choi and Huh plan to establish a “biobank” of samples from volunteers with autism who do or don’t experience symptoms associated with fever, as well as comparable volunteers without autism. The scientists will measure, catalog, and compare these immune system molecules and cellular responses in blood plasma and stool to determine the biological and clinical markers of the fever effect.

If the research reveals distinct cellular and molecular features of the immune response among people who experience improvements with fever, the researchers could be able to harness these insights into a therapy that mimics the benefits of fever without inducing actual fever. Detailing how the immune response acts in the brain would inform how the therapy should be crafted to produce similar effects.

"We are enormously grateful and excited to have this opportunity," Huh says. "We hope our work will ‘kick up some dust’ and make the first step toward discovering the underlying causes of fever responses. Perhaps, one day in the future, novel therapies inspired by our work will help transform the lives of many families and their children with ASD [autism spectrum disorder]."

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Autism spectrum disorders are a group of neurodevelopmental disorders that are characterized by impaired social interaction and communication skills, and are often accompanied by other behavioural symptoms such as repetitive or stereotyped behaviour and abnormal sensory processing. Individual symptoms and cognitive functioning vary across the autism spectrum disorders.

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Brain cells, interrupted: How some genes may cause autism, epilepsy and schizophrenia

Jon Hamilton

New research probes the relationship between certain genes and brain disorders like autism and schizophrenia. Jill George / NIH hide caption

New research probes the relationship between certain genes and brain disorders like autism and schizophrenia.

A team of researchers has developed a new way to study how genes may cause autism and other neurodevelopmental disorders: by growing tiny brain-like structures in the lab and tweaking their DNA.

These "assembloids," described in the journal Nature , could one day help researchers develop targeted treatments for autism spectrum disorder, intellectual disability, schizophrenia, and epilepsy.

"This really accelerates our effort to try to understand the biology of psychiatric disorders," says Dr. Sergiu Pașca , a professor of psychiatry and behavioral sciences at Stanford University and an author of the study.

The research suggests that someday "we'll be able to predict which pathways we can target to intervene" and prevent these disorders, adds Kristen Brennand , a professor of psychiatry at Yale who was not involved in the work.

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Researchers link autism to a system that insulates brain wiring.

The study comes after decades of work identifying hundreds of genes that are associated with autism and other neurodevelopmental disorders. But scientists still don't know how problems with these genes alter the brain.

"The challenge now is to figure out what they're actually doing, how disruptions in these genes are actually causing disease," Pașca says. "And that has been really difficult."

For ethical reasons, scientists can't just edit a person's genes to see what happens. They can experiment on animal brains, but lab animals like rodents don't really develop anything that looks like autism or schizophrenia.

So Pașca and a team of scientists tried a different approach, which they detailed in their new paper .

The team did a series of experiments using tiny clumps of human brain cells called brain organoids . These clumps will grow for a year or more in the lab, gradually organizing their cells much the way a developing brain would. And by exposing an organoid to certain growth factors, scientists can coax it into resembling tissue found in brain areas including the cortex and hippocampus.

"We can actually make different parts of the nervous system in a dish from stem cells ," Pașca says. When these parts are placed in the same dish, they will even form connections, much like an actual brain. The resulting structure is called an assembloid .

Pașca's team thought they could use assembloids to study how developmental disorder genes affect special brain cells called interneurons, which are thought to play a role in several psychiatric disorders.

Research News

The first wiring map of an insect's brain hints at incredible complexity.

During pregnancy and the first two years of life, these special cells must complete a remarkable journey.

"Interneurons are born in deep regions of the brain, and then they have to migrate all the way to the cortex," Pașca says. "So you can imagine that during that migration a lot of things could go awry."

Pașca's team simulated the migration of interneurons by creating assembloids containing two types of organoids. One resembled an area deep in the brain called the subpallium, where most interneurons are generated. The other organoid resembled the cerebral cortex, where interneurons are supposed to end up.

"And then we've put them together, allowing these interneurons to move towards the cerebral cortex," he says.

The process worked just the way it's supposed to in assembloids containing typical organoids. So next, the team used a gene-editing technique called CRISPR to alter the organoids.

This approach allowed the team to study the effect of more than 400 genes associated with neurodevelopmental disorders. And they found that 46 of those genes were involved in either the generation of interneurons, or with their migration. Knock out a part of those genes and interneurons no longer arrived where they were supposed to.

In the cerebral cortex, interneurons serve as inhibitory neurons, which means they act a bit like the brake in a car. The interneurons can release a neurotransmitter that tells other neurons to reduce their activity.

Meanwhile, excitatory neurons act as the accelerator, telling other cells to become more active.

Brain networks rely on a delicate balance between excitatory and inhibitory neurons. Too much acceleration and the result can be an epileptic seizure. Too much brake and vital information may get lost or delayed.

Want to understand your adolescent? Get to know their brain

The study is important because it offers a way for scientists to study the effect of many genes at the same time, and identify the ones that affect a particular type of cell or cell function during brain development, says Dr. Guo-li Ming , a professor of neuroscience at the University of Pennsylvania's Perelman School of Medicine.

The research also shows clearly how gene variants could lead to autism or some other neurodevelopmental disorder by disturbing interneurons.

"That would be a disaster" in a developing brain, Ming says. "The circuitry would be wrong and the signaling would be wrong, and ultimately the brain functioning would be wrong."

Ming, who was not connected with study, says her lab would like to use the combination of assembloids and CRISPR in their own research on schizophrenia, another psychiatric disorder with a neurodevelopmental origin.

Pașca's study could help brain scientists make the sort of advances that cancer researchers have in the past few decades, says Brennand.

"Thirty years ago, we might have thought all intestinal cancers should be treated the same way and all lung cancers should be treated the same way," she says. "Now we know a lot better."

Instead of choosing treatments according to the location of a cancer, doctors study a tumor's genes to determine which therapy is most likely to work. A similar approach could eventually help people with autism spectrum disorder, epilepsy, and schizophrenia, Brennand says.

"This improved genetic understanding will let us do better," she says, "because we'll know which pathways we can target to intervene."

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Scientists discover how dozens of genes may contribute to autism

Using a host of high-tech tools to simulate brain development in a lab dish, Stanford University researchers have discovered several dozen genes that interfere with crucial steps in the process and may lead to autism, a spectrum of disorders that affects about one in every 36 Americans , impairing their ability to communicate and interact with others.

The results of a decade of work, the findings published in the journal Nature may one day pave the way for scientists to design treatments that allow these phases of brain development to proceed unimpaired.

The study delves into a 20-year-old theory that suggests one cause of autism may be a disruption of the delicate balance between two types of nerve cells found in the brain’s cerebral cortex, the area responsible for higher-level processes such as thought, emotion, decision-making and language.

Some nerve cells in this region of the brain excite other nerve cells, encouraging them to fire; other cells, called interneurons, do the opposite. Too much excitation can impair focus in the brain and cause epilepsy, a seizure disorder that is more common in people with autism than in the general population. Scientists therefore believe a proper balance requires more of the inhibiting interneurons.

In the developing fetus, these nerve cells start out deep in the brain in a region called the subpallium, then migrate slowly to the cerebral cortex. The process begins mid-gestation and ends in the infant’s second year of life, said Sergiu Pasca, a Stanford University professor of psychiatry and behavioral sciences who led the study.

Pasca’s team, which included researchers from the University of California at San Francisco and the Icahn School of Medicine at Mount Sinai, tested 425 genes that have been linked to neurodevelopmental disorders to determine which ones interfere with the generation and migration of interneurons. Genes linked to autism were among those identified in the study.

“What’s really cool about this paper is that autism is a collection of different behaviors, but we don’t have [an] understanding of how those behaviors are connected to differences in the brain,” said James McPartland, a professor of child psychiatry and psychology at the Yale School of Medicine, who was not involved in the study.

The new work advances research into autism by “beginning to create a fundamental understanding of the building blocks of brain development,” he said.

A new way to screen for autism genes

For ethical reasons, it is not possible to view developmental processes as they take place inside a fetal brain.

Often, scientists can instead learn the role an individual gene plays by observing what happens when that gene is knocked out of cells in a lab dish. But knocking out 425 genes one by one is time-consuming.

For their study, Pasca and his colleagues used a technique they developed six years ago that allowed them to test all 425 genes at once. They engineered the cells so that only those nerve cells that inhibit others from firing would cast a green glow. They also used the gene-editing system CRISPR to create different cells, each missing one of the 425 genes.

The scientists created clumps of cells that model the structures and functions of the brain’s subpallium and cerebral cortex. Then they placed the two different clumps beside each other in a lab dish.

“We discovered that if you put them together in close proximity, they’ll fuse immediately,” Pasca said. “And the cells know exactly what to do … and they invade the cortex exactly as they would in people.”

This was all the more remarkable because in living brains, the region of the subpallium that makes interneurons is not right next to the cerebral cortex, but is inches away, Pasca said.

Pasca and his colleagues allowed time for interneurons to form and migrate to the cerebral cortex. Then they examined the genetic profiles of the various cells. This allowed them to hunt for the genes that caused two defects: the failure to generate interneurons and the failure of interneurons to journey into the cerebral cortex.

They found 13 genes whose absence prevented interneurons from forming. They identified another 33 genes that, when missing, prevented interneurons from traveling to the cerebral cortex. All told, 46 genes — 11 percent of the 425 linked to neurodevelopmental disorders — appeared to affect the nerve cells that inhibit their neighbors, leading to an imbalance.

The scientists learned that one of the genes crucial to the migration of interneurons, LNPK, has been linked to seizure disorders. This would support the idea that seizures result from too much excitation of neurons and too little inhibition.

A new, more diverse human genome offers hope for rare genetic diseases

Using the fused clumps of cells, the researchers “performed by far the largest screen for autism and [neurodevelopmental disorder] genes,” Guo-li Ming, a professor in the departments of neuroscience and psychiatry at the University of Pennsylvania, wrote in an email commenting on the study.

Ming, who was not involved in the project, described it as a “tour-de-force” that may one day lead researchers to develop treatments for autism and other disorders — therapies based on the genetic profile of an individual patient.

The autism services cliff

Experts stressed that autism is not one disease, but a group of disorders. The neuron imbalance is only one of multiple possible causes.

Many people with autism, for example, have defects of the microglia, cells that regulate brain development, injury repair and maintenance of the networks that process information.

And genes alone cannot account for autism, said Yale’s McPartland. “It’s complicated, and it’s fascinating. You can have [autism in] identical twins and they almost always will both have autism. But not always.”

Jennifer Singh, an autism expert and associate professor in the school of history and sociology at Georgia Institute of Technology, said too much money has been poured into searching for the genetic underpinnings of autism spectrum disorder. Singh pointed to a 2018 report by a federal advisory committee, which found that 60 percent of the funding for autism research addressed the biology and risk factors, but only 2 percent dealt with “life span issues” for people living with the spectrum of disorders .

“This hyper focus and massive investment obscures the real issues people with autism and their families face,” Singh wrote in an email. She cited the “autism services cliff,” which occurs when people with autism can no longer attend public school. “Services that would be useful for autistic adults do not exist or are no longer available,” she said.

Pasca said that it’s important to study “the natural history of the disease. But we also need to understand the biological basis if we want to develop effective [treatments].”

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Autism Prevalence Rises Again, Study Finds

The pandemic may have disrupted the detection of autism spectrum disorder in young children, researchers also reported.

By Emily Anthes

The prevalence of autism spectrum disorder in American children rose between 2018 and 2020, continuing a long-running trend , according to a study released by the Centers for Disease Control and Prevention on Thursday. In 2020, an estimated one in 36 8-year-olds had autism, up from one in 44 in 2018. The prevalence was roughly 4 percent in boys and 1 percent in girls.

The rise does not necessarily mean that autism has become more common among children, and it could stem from other factors, such as increased awareness and screening.

“I have a feeling that this is just more discovery,” said Catherine Lord, a professor of psychiatry at the University of California, Los Angeles medical school, who was not involved in the research. “The question is what’s happening next to these kids, and are they getting services?”

The rise was especially sharp among Black, Hispanic, and Asian or Pacific Islander children. For the first time, autism was significantly more prevalent among 8-year-olds in these groups than in white children, who have traditionally been more likely to receive autism diagnoses.

“These patterns might reflect improved screening, awareness and access to services among historically underserved groups,” the researchers wrote.

But why the prevalence in these children has surpassed that in white children is an open question that requires more investigation, Dr. Lord said.

An accompanying study, also published on Thursday, suggests that the pandemic may have disrupted or delayed the detection of autism in younger children.

For this analysis, the researchers compared the number of autism evaluations and identifications for children who were 4 years old in 2020 to the equivalent numbers from four years earlier. In the six months before the pandemic began, autism evaluations and identifications were higher among the 4-year-olds than they had been in young children four years prior.

That is good news, Dr. Lord said. “It means we’re finding kids younger.”

But after March 2020, when the World Health Organization declared Covid-19 a pandemic, autism evaluations and detections plummeted, remaining below prepandemic levels through the end of 2020, the researchers reported.

Parents may have been less likely to bring their children in for autism evaluations during the pandemic, Dr. Lord said. The closure of schools and the shift to remote learning may have also made it harder for educators to identify children who might have benefited from evaluations or services.

“Disruptions due to the pandemic in the timely evaluation of children, and delays in connecting children to the services and support they need, could have long-lasting effects,” Dr. Karen Remley, director of the C.D.C.’s National Center on Birth Defects and Developmental Disabilities, said in a statement.

Both studies are based on data from the Autism and Developmental Disabilities Monitoring Network , which has used health and education records to track autism in communities across the United States since 2000.

The network has documented an increase in autism prevalence since 2000 , when approximately one in 150 8-year-olds were estimated to have autism.

The 2020 data come from sites in 11 states and are not necessarily representative of the nation as a whole. Data from other locations could help provide a more comprehensive picture, Dr. Lord said.

Emily Anthes is a reporter for The Times, where she focuses on science and health and covers topics like the coronavirus pandemic, vaccinations, virus testing and Covid in children. More about Emily Anthes

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Autism Spectrum Disorder in 2023: A Challenge Still Open

Annio posar.

1 IRCCS Istituto delle Scienze Neurologiche di Bologna, UOSI Disturbi dello Spettro Autistico, Bologna, Italy

2 Department of Biomedical and Neuromotor Sciences, Bologna University, Bologna, Italy

Paola Visconti

In this paper, we provide an update on autism spectrum disorder (ASD), including epidemiology, etiopathogenesis, clinical presentation, instrumental investigations, early signs, onset patterns, neuropsychological hypotheses, treatments, and long-term outcome. The prevalence of this condition has increased enormously over the last few decades. This increase prompted a search for possible environmental factors whose effects would add up to a genetic predisposition leading to the development of autism. But the genetic and environmental variables involved are extremely numerous, and conclusive data regarding the etiopathogenesis are still far away. Assuming that a well-defined etiology is still found today only in a minority of cases, numerous pathogenetic mechanisms have been hypothesized. Among these, we mention oxidative stress, mitochondrial dysfunction, alteration of the intestinal microbiota, immune dysregulation, and neuroinflammation. These pathogenetic mechanisms could alter epigenetic status and gene expression, finally leading to ASD. Inherent in the term spectrum is the great clinical heterogeneity of this condition, mainly due to the frequent comorbidity that characterizes it. The earlier the diagnosis is made and the earlier psychoeducational treatment begins, the better the prognosis. In this sense, the role of pediatricians can be decisive in making children with signs suggestive of autism undergo a specialist diagnostic course. The development of increasingly advanced cognitive-behavioral educational techniques has considerably improved the prognosis of affected individuals, even though only a small minority of them come off the autistic spectrum. Pharmacological therapies are used to treat comorbidities. During childhood, the most important prognostic factor for long-term outcome seems to be intellectual functioning.

Introduction

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), autism spectrum disorder (ASD) is an early-onset, mostly lifelong condition characterized by persisting deficits in social-communication skills (including social-emotional reciprocity, nonverbal communication, and developing/maintaining relationships) and restricted, repetitive behaviors (including stereotypies, insistence on sameness, highly restricted and fixated interests, and sensory abnormalities). Symptoms are present early in development and cause significant impairments in social and occupational functioning. ASD symptoms are not better explained by intellectual disability or global developmental delay, and this is a very important concept in order to avoid confusing these conditions. However, ASD often co-occurs with intellectual disability; comorbid diagnoses of ASD and intellectual disability are possible only when social communication skills are lower than expected in relation to the general developmental level. According to DSM-5, 3 levels of severity of ASD have been established: level 1 (requiring support), level 2 (requiring substantial support), and level 3 (requiring very substantial support). 1 The choice made in the DSM-5 to cancel the subdivision into the 5 diagnostic categories established by the DSM-IV (autistic disorder, Rett’s disorder, childhood disintegrative disorder, Asperger’s disorder, and pervasive developmental disorder not otherwise specified), 2 unifying everything under the term ASD, 1 has not been without criticism, and it is hoped that it will be corrected in the next edition of the DSM. 3 Despite various attempts to find a biological marker, today, the diagnosis of ASD is still based solely on clinical criteria. 1

From a historical perspective, the first reports of children with autism have been till today attributed by most authors to Leo Kanner (1943) 4 and Hans Asperger (1944), 5 but in reality, the first to describe this condition in a scientific journal was a woman, Grunya Efimovna Sukhareva, who in 1926 reported 6 boys with autism (which today would be defined “high functioning”), providing a lot of clinical details, including sensory abnormalities, 6 , 7 which acquired their proper weight only in the DSM-5’s description of ASD. 1

As concerns ASD etiopathogenesis, while in the past the psychogenetic theories prevailed, today we know that ASD is a condition with a neurobiological basis. The etiology is multifactorial and is characterized by an interaction between genetic and environmental factors. 8

In this narrative review, we aim to provide an update about this condition, considering epidemiology, etiopathogenesis, clinical presentation, instrumental investigations, early signs and onset patterns, neuropsychological hypotheses, treatments, and long-term outcome.

Epidemiology and Etiopathogenesis of Autism Spectrum Disorder

According to the most recent epidemiological studies carried out in the United States, ASD recurs in 1 in 36 children at age 8, and it is about 4 times more frequent among males than females. 9 The prevalence of this condition has increased enormously over the last few decades; This increase would be to some extent apparent as there is now greater awareness of this condition, but it would be largely real. 10 This last aspect prompted a search for possible environmental factors whose effects would add up to a genetic predisposition leading to the development of autism. 8 Indeed, early exposure, in particular during pregnancy and in the first year of extrauterine life, to air pollutants (especially particulate matter with an aerodynamic diameter ≤2.5 μm) 11 or to agricultural pesticides 12 is associated with a higher risk for ASD.

But the genetic and environmental variables involved are extremely numerous, and conclusive data regarding the etiopathogenesis of ASD are still far away. Assuming that a well-defined etiology is still found today only in a minority of cases with ASD, numerous pathogenetic mechanisms have been hypothesized and supported by interesting data. Among these mechanisms, we mention oxidative stress, 13 , 14 mitochondrial dysfunction, 15 alteration of the gut microbiota (see the wide variety of microorganisms colonizing the human gastrointestinal tract), 16 immune dysregulation, 17 and neuroinflammation. 14 Note that these mechanisms are not mutually exclusive but could act in synergy with each other, leading to the development of ASD. 8 In reality, the true meaning of the alterations to these mechanisms has yet to be understood. Let us take the example of the gut microbiota: are the alterations found in subjects with ASD the cause of the disorder or its consequence, taking into account the food selectivity they often display and their propensity to bring inedible objects to their mouths? 18

A key to understanding how these pathogenetic mechanisms could act is given by the concept of epigenetics. Epigenetics is a crucial gene regulation system based on chemical changes in DNA and histone proteins without altering the sequence of DNA. The abovementioned pathogenic mechanisms could alter epigenetic status and gene expression, finally leading to ASD. Also, some environmental factors, including heavy metals (e.g., lead) and endocrine disrupting chemicals (e.g., pesticides), could directly or indirectly modify the epigenetic status. 19 , 20

However, the fact that, according to the most recent studies, the prevalence of ASD in males is confirmed (male-to-female ratio = 3.8) 9 suggests that, in the etiopathogenesis of the disorder, genetics still outweighs acquired factors.

We dedicate a last mention to the so-called syndromic autism. It describes the minority of individuals with ASD who present comorbid features and/or a putative genetic etiology. This concept has been deeply criticized, also because it has no single definition, and is probably destined to fall into disuse. 21 We have preferred not to use it in this review.

Heterogeneity of Autism Spectrum Disorder Clinical Presentation

Inherent in the term “spectrum” is the great clinical heterogeneity of this condition. The range of possible impairments in ASD goes from severe disability with almost complete absence of personal autonomy to a so-called high-functioning condition in which the individual can have normal or even higher-than-normal intellectual functioning and can play a role of responsibility in the social context. 3 The considerable heterogeneity of the ASD clinical picture is mainly due to the frequent comorbidity that characterizes it. Intellectual disability, attention-deficit/hyperactivity disorder (ADHD), insomnia, mood disorders, and epilepsy are just some of the possible neuropsychiatric comorbidities. Also, medical comorbidities, in particular gastroenterological ones (including celiac disease), can complicate the clinical picture of individuals with ASD. 3 , 22

Another element of clinical heterogeneity is given by the possible presence of sensory abnormalities that are very often found in subjects with ASD, especially in the first years of life, leading to a distortion of the perception of reality and representing the possible key to understanding many of their atypical behaviors (e.g., attraction to artificial lights, annoyance for crowded environments, food selectivity) and also of the so-called challenging behaviors (e.g., auto- or hetero-aggressiveness, throwing things, tantrums). 23 An impairment of multimodal integration (i.e., the ability to integrate information coming from different sensory channels: visual, auditory, somatosensory, etc.) has also been implicated. 23 In this regard, functional magnetic resonance imaging studies have highlighted elements that suggest an alteration of brain long-range connectivity in individuals with ASD, 24 which could lead precisely to an impairment of this integration capacity.

Instrumental Investigations in Individuals with Autism Spectrum Disorder

From the point of view of the etiological diagnosis, nowadays it seems essential to carry out the following investigations: hearing evaluation through behavioral audiometry or, if not possible, through an auditory brainstem response (ABR) test; genetic tests (array-based comparative genomic hybridization, or array CGH; in males, molecular search for fragile X syndrome; and in some cases, next generation sequencing); electroencephalogram possibly also during sleep, even in the absence of overt clinical seizures, in particular to rule out electroclinical conditions such as continuous spikes and waves during slow sleep (CSWS), which are potentially treatable with a drug therapy. 25 Common neuroimaging techniques, and in particular brain magnetic resonance imaging, are usually normal or at most show nonspecific findings; 26 therefore, they should be performed only in some cases, including: a clinical history characterized by marked and persisting neurocognitive deterioration; the presence of clear neurological signs (macrocrania or microcrania, cerebral palsy, dystonia, etc.); a genetic condition that notoriously predisposes to a brain malformation; epileptic seizures; an electroencephalogram showing relevant alterations such as focal paroxysmal abnormalities or asymmetries of the electrogenesis. At the conclusion of the etiological workup, genetic counseling is recommendable, even though instrumental investigations have not shown any significant results, aiming also at calculating the risk of recurrence of ASD (or other neurodevelopmental disorders) in the family.

Early Signs and Onset Patterns of Autism Spectrum Disorder

A reasonable diagnostic suspicion of ASD can usually be placed around 18 months of age, while a definitive diagnosis of ASD can commonly be made within 3 years of age. There are several tools for early screening of ASD; one of the most used is still today the Modified Checklist for Autism in Toddlers (M-CHAT). 27 To make the final diagnosis of ASD as objective as possible, standardized assessment tools are used today, such as the Autism Diagnostic Observation Schedule—Second Edition (ADOS-2), 28 and Autism Diagnostic Interview—Revised (ADI-R). 29 In this context, the time factor is very important. 27 The earlier the diagnosis is made and the earlier psychoeducational treatment begins, the better the prognosis. 30 In this sense, the role of pediatricians can be decisive in making children with signs suggestive of ASD undertake a specialist diagnostic course. Nowadays, several ASD screening tests for pediatricians are available, none of which, however, is without setbacks; they represent useful tools but should not be considered the only source of information in order to decide whether to start a diagnostic workup in a center specialized in neurodevelopmental disorders. For this purpose, it is very important to pay attention to all possible warning signs reported by parents as well as to directly observe the behavior of the child. 27 In infants, even before a possible speech delay becomes evident, the most indicative signs of ASD are strictly related to social-communication skills as follows: looking at the faces of others; orienting to name; presence of joint attention (i.e., the ability to share focus with others on 1 object); affect sharing; and imitation. 31 When some of these behaviors are lacking, a specific assessment is mandatory. Further, let us not forget that the core signs of autism are not infrequently preceded by signs of impaired motor development, 32 such as motor delay, mostly slight, 33 hypotonia, 34 walking on tiptoes, and/or clumsiness. 1 Therefore, the presence of an early motor impairment, even if mild, should be included among the first signs that could lead to a timely ASD diagnosis. 32

Several different ASD onset patterns have been reported. The most frequent are the “early-onset” pattern, characterized by social-communication deficits developing in the first year or so, and the “regressive autism”, characterized by an onset of autistic signs in the second year, mostly at 16-20 months, associated with a loss of social-communication skills. Another onset pattern is characterized by mixed features: first delay and later loss of social communication skills. There is also an onset pattern named “developmental plateau”, characterized first by normal social development and/or non-specific abnormalities (involving also feeding or sleep), and later by a lack of new acquisitions on the socio-communicative level. 31

Neuropsychological Hypotheses About Autism Spectrum Disorder

From a neuropsychological point of view, 3 main hypotheses have been developed to explain cognitive dysfunction in individuals with ASD. 35 First, failure of theory of mind refers to the inability to interpret the behaviors of others based on their feelings and beliefs and to identify their intentions and emotions, leading to social communication impairments. 36 , 37 Second, there is the hypothesis of a deficit of executive functions, which are a series of cognitive processes including attention, working memory, inhibitory control, planning, and cognitive flexibility that are crucial for adaptive behavior and social cognition skills. 38 , 39 Third, weak central coherence theory refers to the propension of individuals with ASD to use an information processing style that is excessively detail-oriented, 40 , 41 leading to an impairment of social interactions for which an adequate integration of diverse elements such as voice, mimicry, gestures, and environmental context is necessary. 41 This theory partly overlaps with what was mentioned above regarding the multimodal integration deficit and underlines once again the fact that, although visuospatial skills and attention to detail represent strengths in these subjects, when they have to integrate this type of stimuli with other types of stimuli, they may encounter great difficulty. 35

These 3 theories are not mutually exclusive. Each of them is able to explain a part of the autistic symptomatology, but none is able to give a complete explanation. 35

Treatments for Autism And Longterm Outcome

The development of increasingly advanced cognitive-behavioral educational techniques, of which the best known belong to applied behavior analysis (ABA) therapy, has considerably improved the prognosis of affected individuals. Applied behavior analysis utilizes the principles of psychological learning theory in order to modify the behaviors usually present in subjects with ASD. In the 1970s, Ole Ivar Lovaas developed a method that was based on Burrhus Frederic Skinner’s operant conditioning theory, with the aim of changing behaviors and improving social interactions in children with ASD. During the past 60 years, ABA has changed considerably, evolving into many treatment practices, with the aim of dealing with the problems of individuals with ASD in all functioning domains, such as cognition, social skills, language, daily living skills, and challenging behaviors. 42 Today, only a small minority of these subjects come off the autistic spectrum, but almost all can improve considerably by increasing their level of autonomy. 43 After the diagnosis, psychoeducational and often emotional support are very important for parents. Several other interventions are used extensively around the world for children with ASD, although the evidence for their effectiveness does not match that of ABA. Occupational therapy interventions, in particular those using new technologies such as the computer, have shown positive effects on activities of daily living and social skills. 44 In the contest of occupational therapy, sensory integration interventions, in particular when using the principles proposed by Anna Jean Ayres (e.g., tailoring challenges to assure that they are slightly beyond the current performance level of the child), showed positive effects on participation in daily-life activities and routines. 45 Floortime, a relationship-based therapy, has shown that it can improve communication, emotional functioning, and daily living skills in children with ASD. 46

A pharmacological therapy for the core symptoms of autism does not exist. However, pharmacological therapies are used to treat comorbidities: for example, melatonin or (if not effective) niaprazine for sleep disorders, antiseizure drugs for epilepsy (the choice of drugs depends mainly on the type of epilepsy and possible behavioral undesirable effects), and methylphenidate for ADHD. In addition, drug therapy is used to treat challenging behaviors when cognitive-behavioral interventions have not produced adequate results. In these situations, atypical neuroleptics (e.g., risperidone and aripiprazole) are currently the most commonly often used drugs. Indeed, based on a recent systematic review and meta-analysis of antipsychotic medications in autism, there is some evidence for favorable effects of risperidone and aripiprazole on irritability and agitation in children with ASD. 47 However, we wish to underline that the use of pharmacotherapy should be resorted to only when there is a real need and, if possible, for limited periods of time.

Based on the hypothesis that children with ASD have increased levels of systemic heavy metals interfering with their neurodevelopment and leading to autism, in many of these patients, chelation therapy has been attempted using an agent that binds to the excess heavy metal, causing its excretion. Yet, clinical trials of this therapy in ASD are lacking. Based on literature data, in ASD there is no evidence for the effectiveness of chelation therapy, which is associated with very severe and potentially lethal side effects such as cardiac arrhythmias and hypocalcaemia. 48

Interesting findings are emerging regarding diet therapy. One recent systematic review and meta-analysis suggests that diet therapies (including ketogenic diets, gluten-free diets, and gluten-free and casein-free diets), may have favorable effects even on ASD core symptoms. However, more high-quality clinical trials are needed. 49

During childhood, the most important prognostic factor for long-term outcome seems to be intellectual functioning: the higher the intelligence quotient, the better the long-term evolution. But also, the presence of verbal language (although atypical) within 5-6 years of life appears to be a favorable prognostic factor. 43 Unfortunately, approximately 25%-30% of affected individuals develop very little to no verbal skills; they are called “minimally verbal” and usually show a poor long-term outcome. The severe deficit of communication skills (verbal and nonverbal) is very often the basis of the aforementioned challenging behaviors. Also for this reason, providing early non-speaker individuals with alternative means of communication, such as augmentative and alternative communication, is of paramount importance. 50

Conclusions

For professionals who deal with ASD, it is a frustrating situation to witness the growth in the prevalence of this condition without knowing exactly the reasons and consequently without having the most suitable tools to counter it, despite all the knowledge about the neurobiology of ASD that has accumulated over the last years. Today, however, it seems clear that genetic factors alone are unable to explain this phenomenon that some have called the “autism epidemic.” Therefore, in recent years, growing attention has been paid to the environmental factors that can trigger the mechanisms leading to the development of ASD. For these factors, actions of prevention could be very useful, but they require potentially unpopular political decisions whose possible effectiveness could be evaluated only in the long term. Unfortunately, nowadays we still know too little about environmental factors to undertake fully effective prevention actions.

From the research perspective, perhaps to better understand why a child develops an ASD, it would be interesting to study not only what is possibly missing in him/her (e.g., chromosomal deletion detected by the array CGH) or what malfunctions (e.g., focal paroxysmal abnormalities on the electroencephalogram), but also the existing possible protective factors, for example, in the genetic heritage of typically developing individuals and which would be missing in subjects with ASD. This research approach could provide very useful information in the future, but it would clearly be very complicated to put into practice.

The increasing prevalence of ASD clearly has a very negative impact on the public health service, due to the large human and material resources that must be employed to address the problem on the diagnostic and therapeutic sides. However, it should be clear that what we do for today’s autistic children will inevitably affect tomorrow’s autistic adults. Spending many resources on treatments for individuals with ASD in their developmental age in order to give them as much personal autonomy as possible, for example in terms of communication skills, is an investment for the future as it reduces the risk of challenging behaviors arising in adolescence or adulthood, which in turn involve the prolonged use of large resources.

Funding Statement

This study received no funding.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept, Design, Writing, Literature Search – A.P.; Concept, Supervision, Critical Review – P.V.

Acknowledgment: The authors would like to thank Cecilia Baroncini for help in editing the text.

Declaration of Interests: The authors have no conflict of interest to declare.

What Causes Autism? Study of 100,000 Kids Reveals New Clues

From genetics to fevers, Columbia psychiatrist and epidemiologist Mady Hornig discusses the possible roots of this mysterious condition.

Autism is, for the most part, an inherited disorder: scientists estimate that up to 80 percent of a child’s risk of developing it is determined by DNA. But environmental and behavioral risk factors may also play a role, and since rates of autism in the US are at an all-time high, new and expecting parents are eager to learn more about the roots of this complex condition. 

For the past two decades, a team of researchers including  Michaeline Bresnahan ’99PH,  Mady Hornig , W. Ian Lipkin , and Ezra Susser ’74CC, ’82VPS, ’93PH, all epidemiologists at Columbia’s Mailman School of Public Health, has been searching for nongenetic clues to explain why some kids develop autism and others do not. The researchers, in collaboration with the Norwegian Institute of Public Health and other Columbia scientists, have scrutinized the medical histories of more than one hundred thousand children, as well as those of their parents. Armed with unprecedented amounts of data, the researchers are investigating dozens of hypothesized risk factors for autism — everything from parental age to maternal infections to vitamin deficiencies. Columbia Magazine recently spoke to Hornig, who is herself the mother of an adult son with autism, about the team’s research.

What are the major risk factors for autism?

Well, a father’s age, which was one of the first risk factors identified a couple of decades ago, is certainly consequential. My colleague Ezra Susser published a major study on this subject in 2006. Using data collected in Israel, he showed that men who become fathers when they’re over the age of forty are six times more likely to have a child with autism than men who father kids before turning thirty. In 2016, I coauthored a larger study , which analyzed our Norwegian data together with information from Israel and three other countries, that confirmed the impact of paternal age while adding some new twists. We discovered that women at the beginning or end of their childbearing years — those in their teens or in their forties, roughly — are also more likely to have children with autism. And the biggest risk here is when older men have children with much younger women. There may be something about the big mismatch in age that can disrupt a child’s neurodevelopment. 

Is this a reason for certain couples to avoid having children?

No, not necessarily. The thing to keep in mind is that autism is an extraordinarily complex condition that’s probably influenced by hundreds of genetic, environmental, behavioral, and dietary factors, several of which may have to co-occur and reinforce one another for the condition to arise. So even though parental age is one of the most powerful variables, it probably accounts for 5 percent or less of any child’s total risk. 

Do any other factors rise to this level of importance?

One of our more recent discoveries is quite significant: we found that if a pregnant woman experiences a high fever in her second trimester, her child’s chances of developing autism increase by 40 percent. We’re not sure why this is, but molecular evidence suggests that inflammation in the mother’s body may be associated with a delay in the formation of blood vessels in the fetal brain during a critical point in the development of the central nervous system. 

Does it matter what causes the fever?

We suspect that any number of viral or bacterial infections can probably have this effect, but we’d need to conduct even larger studies to know for sure. Influenza appears to be implicated: the mothers of many of the children diagnosed with autism in our cohort suffered a serious bout of influenza in the second trimester. But the type of infection seems to be less important than its severity, since it’s the fever itself — indicative of a systemic, full-body inflammatory reaction — that we found to be strongly associated with autism. That said, I wouldn’t want to be alarmist. A lot of women experience fevers while they’re pregnant and go on to have perfectly healthy kids. Again, the risk this poses for any particular child is quite small. 

So what’s the takeaway for pregnant women or women who plan to get pregnant?

Get a flu shot. Get vaccinated against COVID-19. Wear a mask and practice social distancing. Keep your immune system strong by exercising and eating healthy food. And if you do get sick and have a high temperature, talk to your doctor about possibly taking an anti-inflammatory medication like ibuprofen. (Acetaminophen does not counter inflammation in the same way). Physicians have traditionally cautioned against taking ibuprofen while you’re pregnant because it carries a risk of miscarriage, especially in the first trimester, or possibly deformation of the baby’s heart if given close to the time of delivery, but administration of anti-inflammatory medications for fever during the second trimester might be discussed with one’s physician. At that stage, you really want to reduce a fever as quickly as possible. 

Are any dietary factors important?

We analyzed the diets of all of the women and children who participated in our project to see if any vitamin or mineral deficiencies contribute to autism. What jumped out of the data was that women who take supplements of folic acid, or vitamin B9, early in their pregnancy are almost 40 percent less likely to have a child with autism. That wasn’t a shock because folic acid, which is found naturally in leafy vegetables, beans, and eggs, has long been known to be essential for fetal brain development. But our research revealed that folic acid supplements only protect a fetus against autism if a mother begins taking them shortly before conception and throughout the first two months of pregnancy, which is earlier than many women start on prenatal vitamins. That’s why I suggest that women who are planning a pregnancy talk to their doctors about taking prenatal supplements before they conceive. 

We’ve also found preliminary evidence that heritable differences in how the body regulates levels of vitamin D in the body may be associated with autism in certain subsets of people with the condition, but we need to do additional research to confirm that.

Other researchers have claimed that altering an autistic child’s diet, such as by removing gluten, dairy, or other potential allergens, can sometimes ameliorate symptoms. Have you found any evidence that a child’s diet might contribute to the condition’s onset?

No, though it’s possible that dietary factors play such a role and that we’d just need larger studies with more statistical power to spot them. But we’ve tended to focus our investigations on pregnant women’s health in the Norway cohort because we believe that the roots of autism are likely established in the earliest stages of brain development, in the womb, and that improving our understanding of these processes holds promise for uncovering tractable pathways for prevention.

What are you looking at next?

Our findings about the role of fever in causing autism raise all sorts of questions. For example, we’d like to know if psychosocial stressors in the mother during pregnancy may pose a risk by triggering low-grade inflammation in the body that translates into neurodevelopmental risk for the child. The use of antidepressants by expectant mothers has previously been hypothesized as a risk factor for autism, but other data suggest that antidepressants themselves are unlikely to be the culprit; we’ve considered instead that underlying or untreated depression or anxiety may be the real danger. 

Do you expect that we’ll see a spike in autism cases as a result of the COVID-19 pandemic?

Yes, sadly, I think that’s possible. And not just because many pregnant women have been getting COVID-19, but also because many people, pregnant women included, have been dealing with serious mental stress during the pandemic. It will be a few years before we know if autism rates rise in response, because the condition is usually diagnosed around age three or later. It is also quite likely that rates may rise more generally for a range of neurodevelopmental conditions, including ADHD.

Autism’s prevalence in the US has nearly tripled since 2000. Why?

Part of the explanation is certainly that doctors are more aware of the condition and are diagnosing it more frequently. But my colleagues and I suspect that other factors, like people having children later in life or environmental changes that are making our bodies more vulnerable to infections and immunological problems, are contributing to the uptick in cases.

You’ve spoken publicly about your own experiences raising a son with autism. Is there anything that you wish you’d known back when you were pregnant?

You know, it’s interesting, because I just discovered, through my own participation as a subject in an unrelated medical study, that I have a genetic mutation that’s known to interfere in the body’s absorption of folic acid. So this tells me that it’s possible I wasn’t getting enough folic acid when I was pregnant back in the late 1980s, even though I was taking the recommended four hundred micrograms per day. Now, did a lack of folic acid cause my son’s autism? That’s way too simplistic, because there were probably lots of genetic and environmental factors involved. Did it contribute? Maybe. I certainly wish that I’d known I was susceptible to folate deficiency when I was pregnant, because then I could have talked to my obstetrician about it and explored solutions. 

What is the genetic variant you have? And are pregnant women routinely tested for it today?

The gene variant, which is carried by about 15 percent of all Americans, is located in the gene MTHFR . Pregnant women aren’t routinely tested for it, and a physician might initially balk at ordering it, unless he or she is knowledgeable of cutting-edge autism research and knows how to interpret its results. But if a woman can find a doctor who thinks the test is beneficial and she has good insurance, she might get it covered.

Are there any genomic tests that can tell an adult if he or she is likely to have a child with autism?

No, because the genetics of autism are still poorly understood. Although scientists have identified more than a hundred genes linked to the condition, we can’t say precisely what many of these genes do, nor the degree to which they increase an individual’s risk. There are some geneticists who will analyze and interpret men’s and women’s DNA in an attempt to estimate this risk. However, such analyses don’t offer definitive predictions, since we still haven’t identified all of the mutations involved in autism. Further, the influence of certain gene variants on autism may also depend on whether an individual is additionally exposed to specific environmental risks that may affect the function of that gene variant during key periods of early neural development — much as the rare inherited disorder phenylketonuria (PKU), caused by genetic mutations, can be treated by reducing or eliminating the amino acid phenylalanine from a child’s diet. A good source of information on this topic is the SPARK website of the Simons Foundation, a New York–based nonprofit that supports autism research.

Eventually, we’d like to get to the point where we’re able to recommend a whole range of preventive steps parents might take to mitigate the damaging effects of specific mutations they carry. But we still have a lot more work to do, both in terms of identifying the causes of autism and in understanding how various risk factors interact. Right now, we’re still building the scientific foundation for that kind of customized clinical care. 

For more information on this research, see the following articles from Columbia's Mailman School of Public Health:

Study Identifies Biomarkers Linked to Autism Risk

Could Flu During Pregnancy Raise Risk for Autism?

Autism Risk Linked to Fever During Pregnancy

Autism Risk Linked to Herpes Infection During Pregnancy

This article appears in the Spring/Summer 2022 print edition of Columbia Magazine with the title "In search of autism's roots." 

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New Research May Change How We Think About the Autism Spectrum

Insar keynote suggests brain differences correlate with cognition—not diagnosis..

Posted May 16, 2022 | Reviewed by Davia Sills

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• Dr. Evdokia Anagnostou presented the results of neuroimaging studies at the International Society for Autism Research 2022 annual meeting.
• Of note, brain differences clustered along dimensions of cognition and hyperactivity, not diagnosis.
• These findings suggest we need to reconsider how we classify neurodivergence.

University of Toronto child neurologist Evdokia Anagnostou dropped a bombshell in her keynote Saturday at the annual meeting of the International Society of Autism Research (INSAR) in Austin, Texas, which may call into question the validity of the autism spectrum disorder (ASD) diagnosis.

What Brain Scans Tell Us About Autism Spectrum Disorder

Anagnostou and her colleagues had set out to use neuroimaging to identify brain differences unique to ASD, as compared to other neurodevelopmental differences like ADHD , OCD , and intellectual disability. And they did find that brain differences clustered into different groups—but not by diagnosis. In fact, brain scans could not distinguish children who had been diagnosed with ASD from those who had been diagnosed with ADHD or OCD.

“Dr. Anagnostou reported data from multiple papers that looked at over 3,500 children,” Dr. Alycia Halladay, Chief Science Officer at the Autism Science Foundation, explained to me. “These studies looked at multiple structural and functional features of the brain—including cortical gyrification (the way the brain folds in the cortex), connectivity of different brain regions, and the thickness of the cortical area—and found no differences based on diagnosis.”

Groupings did emerge, but they were along totally different axes. Added Halladay, “The brains themselves were more similar based on cognitive ability, hyperactivity, and adaptive behavior.” In other words, the brains of mildly affected autistic children looked much more like the brains of kids with ADHD than they did like those of severely autistic children.

Validity of the Autism Spectrum Diagnosis May Be at Stake

If replicated, these findings could have tremendous implications for our current diagnostic framework. During the question and answer period following her talk, Anagnostou described two children who both carried the diagnosis of autism; one was very mildly affected, while the other had such disordered behavior that “even their bus driver knows” he is autistic. “Should these kids have the same diagnosis?” she asked.

Right now, they do—but there has been a growing dissatisfaction among many stakeholders in the autism community with the American Psychiatric Association’s introduction of the all-encompassing ASD diagnosis in the 2013 revision of the Diagnostic and Statistical Manual (DSM-5) to replace more narrowly defined categories, including Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), and childhood disintegrative disorder.

In 2021, the Lancet Commission —a group of 32 researchers, clinicians, autistic individuals, and family members—called for the creation of a new label, “profound autism,” that would carve out those autistic individuals who also suffer from cognitive and language impairments and require round-the-clock supervision. “Anagnostou’s data converge nicely with the Lancet Commission’s proposal,” Halladay observed. “They provide biological evidence for a category that was originally defined solely by external criteria.”

At the very least. The real question is whether this work demands an even more radical re-imagining of our classification of neurodevelopmental differences. If, as Anagnostou’s data demonstrates, cognition and hyperactivity are much more correlated with brain difference than variables like social deficit that have been considered core symptoms of autism, then perhaps it’s time to scrap our current model and introduce new diagnoses based on these more salient dimensions. Aligning our diagnostic system with underlying biology is the first step in the development of targeted interventions for some of the most intractable and dangerous behaviors exhibited by the developmentally disabled, such as aggression , elopement, self-injury , and pica (the compulsion to eat inedible objects).

As Anagnostou opened her talk, “Nature doesn’t read the DSM.” But, as our understanding of the brain advances, shouldn’t the DSM reflect these divisions in nature?

Amy S.F. Lutz, Ph.D. , is a historian of medicine at the University of Pennsylvania. She is the author of We Walk: Life with Severe Autism (2020) and Each Day I Like It Better: Autism, ECT, and the Treatment of Our Most Impaired Children (2014) . She is also the Vice-President of the National Council on Severe Autism (NCSA).

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Why autistic people must be at the heart of autism research

by Gemma L. Williams, Aimee Grant and Willow Caroline Holloway, The Conversation

When the term "social model of disability" was coined by British sociologist Mike Oliver in 1983, it helped form the basis of the disability rights movement.

To mark the birth of that movement, as well as the 30th anniversary of the autistic rights movement, our new report reflects on why it is vital that autistic people are always at the center of autism research .

During the 1980s, the term "social model of disability" challenged how society largely regarded disability as a personal tragedy. Disablement was seen as something that belonged to individual disabled people, with heavily medicalized personal "impairments."

But Oliver argued that disablement came from how society treated disabled people and from the systemic lack of equitable access. The social model of disability ultimately informed disability awareness and equality training.

Not long after, in the early 1990s, as people began having access to the internet, autistic people began finding one another on chat boards and email lists.

Around the same time, autobiographical texts written by autistic people began to be published online. They helped introduce the voices of autistic people to neurotypical people for the first time. However, reflecting the perspective of that period, much of the tone of the writing conveyed the message that autism was a "tragedy" that needed to be mourned.

It was against this backdrop that the American autistic rights activist Jim Sinclair gave a seminal speech at the 1993 International Conference on Autism in Toronto, Canada. Addressing parents of autistic children, his "Don't Mourn For Us" speech called for a move away from a parental perspective that "grieves" the disabled child. Instead, Sinclair advocated for an empowered, autistic perspective. The speech helped spur the autistic rights movement.

Autism research

Historically, autism research has been conducted by non-autistic researchers. The consequence of this has been a pathologizing and often dehumanizing take on autism.

For example, in one 2019 study, autistic people were found to be more generous . But instead of seeing this as something that is advantageous to society, the researchers interpreted the findings as an example of how autistic people struggle to tell the difference between themselves and other people.

Likewise, despite the progress that has come from a shift towards a social model of disability, funding for research into autism still tends to be given to non-autistic researchers . This is often for research that doesn't address the needs of autistic people or tackle our significant health and well-being inequities.

Even when the stated aims of research appear to be about cultivating autistic well-being, there are often glaring concerns. One example of this was the Spectrum 10K project , which was launched in 2021 by researchers at the University of Cambridge, the Wellcome Sanger Institute and the University of California Los Angeles.

The project planned to generate a large autism DNA database, which was something that alarmed many autistic people. It provoked protests over the potential for it to lead to eugenics , where gene pools are altered according to which people are deemed to be superior or inferior. The study is currently paused , with a long-awaited consultation report overdue.

In recent years, there has been an increasing call for research that meaningfully involves autistic people in all stages of research, from design, through delivery to dissemination.

Collaboration

Building on this, our new report describes how we are working together as a mutually supportive, fully autistic team on the Autism: From Menstruation to Menopause project . This project was set up to address the knowledge gap about autistic reproductive experiences.

Our first task was to recruit an autistic community council. We wanted to ensure that it included people who were usually underrepresented in research. Once it had been established, the next step was for academic researchers and community council members to work together to develop accessible recruitment materials for our study's 100 autistic participants.

Although it is early days, we anticipate that our community council will have an important role in helping us interpret our findings and in preparing our reports.

We aren't suggesting that good autism research can't be done by non-autistic researchers. But autistic people should always be involved in research in a meaningful way and should be listened to at every stage of a project. By doing that, researchers can avoid inadvertently doing research that is either harmful to autistic people, or which misinterprets the findings.

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At a glance

The latest data on autism spectrum disorder (ASD) from CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network.

Prevalence of ASD

• About 1 in 36 children has been identified with autism spectrum disorder (ASD) according to estimates from CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network. [Read Article]
• ASD is reported to occur in all racial, ethnic, and socioeconomic groups. [Read Article]
• ASD is nearly 4 times more common among boys than among girls. [Read Article]
• About 1 in 6 (17%) children aged 3–17 years were diagnosed with a developmental disability, as reported by parents, during a study period of 2009–2017. These included autism, attention-deficit/hyperactivity disorder, blindness, and cerebral palsy, among others. [Read Summary]

What Is Prevalence?‎

Identified prevalence of asd, addm network 2000-2020: combining data from all sites, resource‎.

Search through a collection of information from peer-reviewed autism prevalence studies.

Autism Prevalence Studies Data Table

CDC's 2023 Community Report on Autism

Cdc's 2023 community report on autism provides summaries of the latest addm data:.

• A Snapshot of Autism Spectrum Disorder in 2020
• Progress in Early Identification Disrupted during the COVID-19 Pandemic among 4-year-old Children
• A New Pattern in Racial and Ethnic Differences Emerges in ASD Identification among 8-year-old Children
• Site Snapshots Overview

Autism Spectrum Disorder (ASD)

Autism spectrum disorder (ASD) is a developmental disability that can cause significant social, communication and behavioral challenges. CDC is committed to continuing to provide essential data on ASD and develop resources that help identify children with ASD as early as possible.

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Health care providers, public health.