autism spectrum disorder new research

New Autism Study Reveals 'Tantalizing Clues' About Its Development

S cientists have made a breakthrough in our understanding of the neuroscience behind autism spectrum disorders that promises to "revolutionize" the way we approach treatment, scientists say. The discovery revolves around an important chemical messenger that we tend to associate with pleasure and reward: dopamine.

Autism spectrum disorders are a diverse group of conditions characterized by some degree of difficulty with social interaction and communication. They affect roughly 1 in 100 children worldwide, according to data from the World Health Organization.

There are many potential causes of autism spectrum disorders, and both environmental and genetic factors are thought to play a role. A lot of questions still exist about the biochemical mechanisms that underlie these conditions, but recent evidence suggests that dopamine, the famous "feel-good" hormone, might play a role.

"While dopamine is commonly recognized as a neurotransmitter, its significance in the developmental aspects of autism is largely unexplored," said lead investigators Lingyan Xing and Gang Chen of China's Nantong University in a statement.

"Recent studies have highlighted the crucial roles of dopamine and serotonin in [neurotypical brain] development and their importance in the construction of neural circuits," they continued. "In addition, studies have indicated that the use of dopamine-related drugs during pregnancy is associated with an increased risk of autism in children.

"Armed with these tantalizing clues, we embarked on a mission to bridge the gap between dopamine's known functions and its potential impact on neurodevelopmental disorders, particularly autism," Lingyan and Gang said.

In a study published in The American Journal of Pathology , Lingyan, Gang and their colleagues investigated the role of dopamine signaling in autism development. "Our quest was to uncover a novel therapeutic target that could revolutionize the way we approach autism treatment," Lingyan and Gang said.

The study consisted of two parts. The first involved analyzing changes in gene expression in the brains of people with autism. The second used zebra fish models to explore how perturbations in dopamine signaling could produce autism-like behaviors.

In the first part of the study, the team found that patients with autism showed changes in the expression of genes involved in dopamine-signaling pathways and brain development. The authors say this indicated a potential link between dopamine disruption and autism development.

To explore this link further, the team re-created these disrupted dopamine pathways in the brains of zebra fish larvae and found that the larvae with signal disruption developed brain circuit abnormalities and behaviors reminiscent of human autism.

"We were surprised by the extent of the impact that dopaminergic signaling has on neuronal specification in zebrafish, potentially laying the groundwork for circuit disruption in autism-related phenotype," Gang wrote.

Lingyan added: "This research sheds light on the role of dopamine in neural circuit formation during early development, specifically in the context of autism. Understanding these mechanisms could lead to novel therapeutic interventions targeting dopaminergic signaling pathways to improve outcomes in individuals with autism and other neurodevelopmental 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.

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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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New study links autism spectrum disorder to disrupted developmental dopamine

by Eileen Leahy, Chhavi Chauhan, PhD, Elsevier

Recent evidence suggests that dopamine plays a crucial role in neural development. In a novel study, investigators demonstrated the link between disrupted developmental dopamine signaling and autism spectrum disorder (ASD).

Their findings underscore the importance of studying developmental signaling pathways to understand the etiology of ASD, paving the way for potential targeted interventions. Their findings appear in The American Journal of Pathology .

Lead investigators Lingyan Xing, Ph.D., and Gang Chen, Ph.D., Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, explain, "While dopamine is commonly recognized as a neurotransmitter, its significance in the developmental aspects of autism is largely unexplored. Recent studies have highlighted the crucial roles of dopamine and serotonin in development and their importance in the construction of neural circuits.

"In addition, studies have indicated that the use of dopamine-related drugs during pregnancy is associated with an increased risk of autism in children. Armed with these tantalizing clues, we embarked on a mission to bridge the gap between dopamine's known functions and its potential impact on neurodevelopmental disorders, particularly autism. Our quest was to uncover a novel therapeutic target that could revolutionize the way we approach autism treatment."

Investigators studied the role of disrupted dopaminergic signaling in the etiology of ASD by integrating human brain RNA sequencing transcriptome analysis and a zebrafish model, recognized for its high degree of conservation with humans.

To analyze the developmental deficits in ASD systematically, two large publicly available data sets were retrieved from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus database and RNA sequencing data from Arkinglab. Transcriptome analysis of human brains revealed significant correlations between changes in dopaminergic signaling pathways and neural developmental signaling in patients with autism. This suggests a potential link between disrupted developmental dopamine signaling and autism pathology.

To explore this link further researchers used the zebrafish model to study the effects of disrupted dopaminergic signaling on neural circuit development. They found that perturbations in developmental dopaminergic signaling led to neural circuit abnormalities and behavioral phenotypes reminiscent of autism in zebrafish larvae. The study also uncovered a potential mechanism by which dopamine impacts neuronal specification through the modulation of integrins.

Dr. Chen comments, "We were surprised by the extent of the impact that dopaminergic signaling has on neuronal specification in zebrafish, potentially laying the groundwork for circuit disruption in autism-related phenotype. Furthermore, the unexpected involvement of integrins as downstream targets of dopaminergic signaling provides new insights into the mechanisms underlying neurodevelopmental disorders."

Dr. Xing concludes, "This research sheds light on the role of dopamine in neural circuit formation during early development, specifically in the context of autism. Understanding these mechanisms could lead to novel therapeutic interventions targeting dopaminergic signaling pathways to improve outcomes in individuals with autism and other neurodevelopmental disorders."

ASD is a developmental disorder that usually manifests itself in early childhood. Although clinical outcomes vary greatly from case to case, autism is characterized by both a restricted interest in social interaction and repetitive behavior. This coincides with disruptions in brain connectivity shown by diffusion tension imaging.

Studies have shown that several neurodevelopmental processes may be affected in ASD, including neurogenesis, neural migration, axon pathfinding, and synaptic formation, all of which can lead to neural circuit disruption.

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Study identifies new metric for diagnosing autism

Autism spectrum disorder has yet to be linked to a single cause, due to the wide range of its symptoms and severity. However, a study by University of Virginia researchers suggests a promising new approach to finding answers, one that could lead to advances in the study of other neurological conditions.

Current approaches to autism research involve observing and understanding the disorder through the study of its behavioral consequences, using techniques like functional magnetic resonance imaging that map the brain's responses to input and activity, but little work has been done to understand what's causing those responses.

However, researchers with UVA's College and Graduate School of Arts & Sciences have been able to better understand the physiological differences between the brain structures of autistic and non-autistic individuals through the use of Diffusion MRI, a technique that measures molecular diffusion in biological tissue, to observe how water moves throughout the brain and interacts with cellular membranes. The approach has helped the UVA team develop mathematical models of brain microstructures that have helped identify structural differences in the brains of those with autism and those without.

"It hasn't been well understood what those differences might be," said Benjamin Newman, a postdoctoral researcher with UVA's Department of Psychology, recent graduate of UVA School of Medicine's neuroscience graduate program and lead author of a paper published this month in PLOS: One . "This new approach looks at the neuronal differences contributing to the etiology of autism spectrum disorder."

Building on the work of Alan Hodgkin and Andrew Huxley, who won the 1963 Nobel Prize in Medicine for describing the electrochemical conductivity characteristics of neurons, Newman and his co-authors applied those concepts to understand how that conductivity differs in those with autism and those without, using the latest neuroimaging data and computational methodologies. The result is a first-of-its-kind approach to calculating the conductivity of neural axons and their capacity to carry information through the brain. The study also offers evidence that those microstructural differences are directly related to participants' scores on the Social Communication Questionnaire, a common clinical tool for diagnosing autism.

"What we're seeing is that there's a difference in the diameter of the microstructural components in the brains of autistic people that can cause them to conduct electricity slower," Newman said. "It's the structure that constrains how the function of the brain works."

One of Newman's co-authors, John Darrell Van Horn, a professor of psychology and data science at UVA, said, that so often we try to understand autism through a collection of behavioral patterns which might be unusual or seem different.

"But understanding those behaviors can be a bit subjective, depending on who's doing the observing," Van Horn said. "We need greater fidelity in terms of the physiological metrics that we have so that we can better understand where those behaviors coming from. This is the first time this kind of metric has been applied in a clinical population, and it sheds some interesting light on the origins of ASD."

Van Horn said there's been a lot of work done with functional magnetic resonance imaging, looking at blood oxygen related signal changes in autistic individuals, but this research, he said "Goes a little bit deeper."

"It's asking not if there's a particular cognitive functional activation difference; it's asking how the brain actually conducts information around itself through these dynamic networks," Van Horn said. "And I think that we've been successful showing that there's something that's uniquely different about autistic-spectrum-disorder-diagnosed individuals relative to otherwise typically developing control subjects."

Newman and Van Horn, along with co-authors Jason Druzgal and Kevin Pelphrey from the UVA School of Medicine, are affiliated with the National Institute of Health's Autism Center of Excellence (ACE), an initiative that supports large-scale multidisciplinary and multi-institutional studies on ASD with the aim of determining the disorder's causes and potential treatments.

According to Pelphrey, a neuroscientist and expert on brain development and the study's principal investigator, the overarching aim of the ACE project is to lead the way in developing a precision medicine approach to autism.

"This study provides the foundation for a biological target to measure treatment response and allows us to identify avenues for future treatments to be developed," he said.

Van Horn added that study may also have implications for the examination, diagnosis, and treatment of other neurological disorders like Parkinson's and Alzheimer's.

"This is a new tool for measuring the properties of neurons which we are particularly excited about. We are still exploring what we might be able to detect with it," Van Horn said.

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Materials provided by University of Virginia College and Graduate School of Arts & Sciences . Original written by Russ Bahorsky. Note: Content may be edited for style and length.

Journal Reference :

• Benjamin T. Newman, Zachary Jacokes, Siva Venkadesh, Sara J. Webb, Natalia M. Kleinhans, James C. McPartland, T. Jason Druzgal, Kevin A. Pelphrey, John Darrell Van Horn. Conduction velocity, G-ratio, and extracellular water as microstructural characteristics of autism spectrum disorder . PLOS ONE , 2024; 19 (4): e0301964 DOI: 10.1371/journal.pone.0301964

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An Update on Psychopharmacological Treatment of Autism Spectrum Disorder

• Current Perspectives
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• Published: 14 January 2022
• Volume 19 , pages 248–262, ( 2022 )

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• Ramkumar Aishworiya 1 , 2 , 3 ,
• Tatiana Valica 1 , 4 ,
• Randi Hagerman   ORCID: orcid.org/0000-0001-5029-8448 1 , 5 &
• Bibiana Restrepo 1 , 5  

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While behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD.

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Introduction

ASD is a complex neurodevelopmental, biologically based condition with an estimated prevalence of 1 in 44 people [ 1 ] that impacts all areas of child development — from behavior, problem solving abilities and self-care skills, to complex social communication ability, language, and executive functioning skills. The range of symptoms and severity of ASD vary greatly from child to child, and clinical manifestations depend on the individual’s age, cognitive and language abilities, and co-occurring conditions. The last revision of the Diagnostic and Statistical Manual (DSM-5) defines ASD as impairments in two main domains: (1) social communication and interaction, which comprises challenges in social-emotional reciprocity, challenges in using nonverbal strategies during social interaction, and challenges developing, maintaining and understanding relationships, and (2) restricted, repetitive, and stereotyped patterns of behavior, manifested by unusual repetitive movements or behaviors, restricted interests, insistence on sameness and inflexible adherence to routines, as well as sensory challenges ranging from seeking to avoiding certain sensory stimuli [ 2 , 3 , 4 ]. However, a range of behavioral, cognitive, and emotional disturbances in ASD can also be attributed to a high rate of co-occurring mental health and medical conditions such as attention deficit hyperactivity disorder (ADHD), anxiety, depression, phobias, intellectual disability, speech/language impairment, restrictive/avoidant food intake, sleep issues, sensory processing issues, and genetic conditions. This often makes the recognition, diagnosis, and clinical management of ASD even more complex and difficult [ 5 , 6 , 7 , 8 ].

Classic medical management of medical conditions has largely revolved around pharmacological treatment. However, despite decades of research in ASD, current evidence has only established behavioral (non-pharmacological) treatments as the mainstay of management to address the core symptoms of ASD. Part of the reason for a lack of efficacy in many treatment studies stems from the heterogeneous etiology underlying the overall term of ASD. Some studies have subdivided enrolled patients either by their genetic etiology or phenotypic features to address this. The aim of this paper is to provide a current update on the pharmacological treatments available for ASD and therapeutic subtypes of ASD, covering both the established ones and upcoming/emerging treatments which have potential based on scientific evidence to become standard treatments in the next few years. A systematic literature search was completed on Medline, Scopus, and Embase with key search terms of “autism,” “autism spectrum disorder,” “targeted treatments,” “pharmacological therapy,” and “management” to identify relevant articles. Here we have highlighted the psychopharmacological treatments that have the most efficacy and are also, in most cases, available now or in the near future to clinicians. However, we also recognize the current mainstay of behavioral intervention in the management of ASD and will briefly review those which are supported by strong empirical evidence.

Non-pharmacological (Behavioral) Interventions

In 1987, Lovaas published an article which introduced a new treatment approach describing a significant improvement of IQ scores and educational functioning in almost 50% of children with ASD [ 9 ]. Also known as The Lovaas Method of Applied Behavior Analysis, and subsequently as discrete trial training (DTT), it is an intensive, highly structured, long-term, one-on-one behavior intervention designed for young children, which has a strong empirical support and has become the foundation for many of the evidence-based behavioral interventions in use today [ 10 ]. Subsequently, through decades of extensive research, a number of modifications and adaptations of the Lovaas method have since been developed. These can be used in different settings, environments, and procedures, and have been shown to be effective in addressing the core impairments of ASD in social communication, speech, behaviors, play, and learning [ 11 , 12 , 13 , 14 ].

Odom et al. [ 13 ] and Wong et al. [ 15 ] have classified behavioral evidence–based interventions into two groups: comprehensive treatment models (CTMs) and focused interventions.

Comprehensive treatment models focused on core ASD symptoms have been found to improve language, cognitive, and functional language skills in young children, using intensive and long-term multi-disciplinary strategies in naturalistic environments. Instructions can be provided at home or in a classroom setting, individually or in a group, provided by instructors or by parents. Examples of well-established CTMs include Early Behavior Intervention (EIBI) [ 16 ], Early Start Denver model (ESDM) [ 17 ], Developmental, Individual difference, relationship-based model (DIR/Floortime, or Greenspan model) [ 18 ], Pivotal Response Training (PRT) [ 19 ], and Treatment and education of autistic and related communication handicapped children (TEACCH) [ 20 ].

Focused interventions address a single skill or a specific area of developmental domain and are provided for a short time, until the skill is mastered. They can also be effective to address life-threatening or socially inappropriate behaviors that require rapid addressing. Examples include social skill training, toilet training, modeling, cognitive behavioral intervention, and behavioral strategies like prompting, ignoring, time delay, reinforcement, discrete trial teaching, and extinction. These can be implemented as a structured session or in a naturalistic setting at home, school, clinic, or community settings, with peers or parents, and have behavioral, developmental, or educational purposes. Peer-mediated Instruction and Intervention (PMII), also known as “Peer Modeling,” “Peer Initiation Training,” “Peer support” [ 21 , 22 ], and Picture Exchange Communication System (PECS) [ 23 ], are also other examples of focused interventions.

Behavioral interventions work most effectively when started at an early age and the majority cater to young children to optimize their development and learning skills. The sociocultural beliefs and economic capability of the family also moderate treatment impact and outcome [ 24 ]. However, behavioral interventions do have a role in older children, adolescents, and adults as well; the targets of these interventions change in older individuals to include social, vocational, leisure skills, and independent living. Research in behavioral interventions for adults with ASD is still limited and will need to be expanded in future.

Established Psychopharmacological Treatments

The use of psychotropic medications has markedly increased over the last decades; approximately two-thirds of autistic adolescents have been treated with psychotropic medications, especially those with challenging behaviors and co-occurring conditions like intellectual disability (ID), medical, and mental health diagnoses. Co-occurring mental health conditions have been reported in approximately 70% of autistic individuals ranging from attention deficit and hyperactivity disorder (ADHD), irritability, aggression, mood, and anxiety issues [ 8 , 25 , 26 ]. Mandell et al. reported that 56% were prescribed at least one psychotropic medication and 20% were prescribed three or more [ 27 ]. Individuals with ASD frequently are treated with multiple medications, including off-label use (e.g., use of antipsychotic medications in younger children). Studies have reported high rates of polypharmacy ranging from 12 to 35% based on the type of studies [ 28 , 29 ]. The increasing prescription rates for individuals with ASD is not completely understood. For instance, some authors have postulated that this may be influenced by improvements in diagnostic and clinician awareness of co-occurring mental health issues [ 25 ]. However, other researchers have reported demographic factors influencing pharmacological treatment. For instance, in a large study, those who were uninsured or exclusively privately insured were less likely to use more than 3 medications than were those insured by Medicaid [ 30 ]. Prescription medications may also be affected by demographic factors including race, ethnicity, and geography. Studies have reported that challenging behaviors and mental health diagnoses are influencing factors [ 29 ]. For example, polypharmacy is often necessary since one treatment for anxiety may not be helpful for another comorbid condition such as ADHD. Such polypharmacy will be more common as specific treatments for dysfunctional pathways are utilized which go hand in hand with other treatments for common comorbidities of ASD. An example is metformin which can downregulate the mTOR pathway, and this treatment works well with stimulants for ADHD and also Selective Serotonin Reuptake Inhibitors (SSRIs) for anxiety.

Prescribers must consider medications not only for symptoms of associated psychopathology but also as targeted treatments that have the potential to reverse the neurobiological abnormalities and should be considered as a part of an individualized therapeutic program with behavioral and educational interventions.

General Principles in Using Pharmacological Treatment in ASD

Frequently, identification and management of psychiatric issues can be complex, especially for those with limited language repertoire, low cognitive function, and those experiencing uncertain symptoms. Diagnostic overshadowing is common (failure to identify other conditions in the presence of a certain diagnosis). A high level of clinical suspicion for co-occurring mental health conditions is required for children and adolescents with communication challenges. Managing clinicians should obtain information from the child, when possible, family and other providers including teachers and therapists. Environmental changes and lack of skills can be the source of undesired behaviors and should be considered in the plan of care.

Pharmacological interventions are sometimes indicated and may facilitate their participation in therapy and enhance their daily functioning. The principles used for psychopharmacological management are the same for children with ASD as for those with typical development. However, prescribers should keep in mind that children with ASD tend to be more sensitive to medication effects and more likely to have adverse effects than children without ASD. Therefore, pharmacological treatment should be started at lower doses, and adjusted more slowly than in neurotypical children. Obtaining objective symptom measures from different sources before and after the intervention is key to objectively evaluate the response of treatment in different settings.

Serotoninergic Medications

Serotoninergic medications regulate the levels of serotonin which is a key messenger specially involved in the gastrointestinal, cardiovascular, and the central nervous system (CNS). The serotonin level has been reported to be elevated in the autistic population, and it has been theorized that serotonin dysregulation is associated with symptoms frequently seen in autistic individuals ranging from repetitive behaviors to anxiety. PET studies have demonstrated that young children (under 5 years old) with ASD have lower levels of serotonin in the CSF [ 31 ]. Studies of lymphoblastoid cell lines in patients with ASD compared to controls have demonstrated a deficit of enzymes that convert tryptophan to serotonin [ 32 ]. These studies suggested that those with ASD would benefit from treatment with an SSRI to stimulate neurogenesis and neuroprotection [ 33 ]. There are three different groups of medications that influence the serotonin levels: the SSRIs, SNRIs (serotonin-norepinephrine reuptake inhibitors), and tricyclic antidepressants. The SSRIs are one of the most commonly prescribed medications for autistic individuals to treat anxiety, mood issues, and irritability. However, results of available clinical trials have been inconsistent in the benefits of SSRI’s for improving aggression and the core symptoms of ASD [ 34 ].

A retrospective study of children with FXS (ages 12 to 50 months) demonstrated improvement in the trajectory of both receptive and expressive language measures on the Mullen Scales of Early Learning (MSEL) in those treated with low-dose sertraline vs those who did not receive sertraline [ 35 ]. These results led to a controlled trial for 6 months of sertraline in children ages 2 to 6 with FXS (60% also had ASD) treated clinically with low dose sertraline (2.5 to 5.0 mg/day) [ 36 ]. Those treated with sertraline demonstrated greater improvement in motor and visual subtests and the Cognitive T score on the MSEL compared to those on placebo. In the children with both FXS and ASD, there was also significant improvement on the Expressive Language subscale compared to placebo [ 36 ]. In the same controlled trial, a passive visual eye tracking measure of receptive vocabulary was also significantly improved in those treated with sertraline compared to placebo [ 37 ]. These studies suggest that young children with FXS both with and without ASD benefit from low-dose sertraline treatment. However, a similar study in young children ages 2 to 6 with idiopathic ASD (without FXS) treated with low-dose sertraline did not demonstrate a benefit of sertraline compared to placebo [ 38 ]. Therefore, the genetic subtype of ASD makes a difference in response to treatment and all children diagnosed with ASD must have genetic testing including Fragile X DNA testing and a CGH array for starters and subsequent whole exome sequencing (WES) or whole genome sequencing (WGS) if the initial studies are negative [ 39 ].

Atypical Antipsychotics

There are two medications approved by the FDA for the treatment of irritability associated with ASD: risperidone, approved for children older than 5 years of age [ 40 ], and aripiprazole, approved for children 6 to 17 years of age [ 41 ]; clinical trials found them to be effective in reducing irritability and, to a lesser degree, repetitive behaviors. These two atypical antipsychotic medications have affinity for dopamine, 5-HT, alpha-adrenergic, and histaminergic receptors in the brain. They also share similar safety profiles; the most common side effects include fatigue, increased appetite, GI symptoms, hyperprolactinemia, weight gain, and sedation, and less commonly activation including restlessness and akathisia. They are also linked to more serious side effects including dyslipidemia, hyperglycemia, metabolic syndrome, and extrapyramidal symptoms or drug-induced movement disorders. Therefore, close clinical and laboratory monitoring is recommended. Given that the efficacy and safety of these medications have not been established for the long-term treatment of irritability in autistic individuals, it is important to periodically re-evaluate the need for continuation of treatment. Since the development of atypical antipsychotics, the use of the conventional antipsychotics has been reserved for more severe cases refractory to the newer generation medications, due to the narrower safety profile and greater incidence of adverse reactions including extrapyramidal symptoms such as tardive dyskinesia with conventional antipsychotics.

Stimulant Medications

Stimulants are usually the first line of treatment to treat co-occurring attention deficit and hyperactivity disorder (ADHD) as they present with a rapid clinical effect and there is enough data supporting their use and safety. Approximately half of autistic children also meet criteria for ADHD [ 42 ], but prevalence widely varies based on samples [ 8 , 43 , 44 , 45 , 46 , 47 ]. Treating co-occurring ADHD symptoms in autistic individuals should focus on improvement in enhancing their daily function in multiple settings, including learning, and hopefully long-term functional outcomes improving associated symptoms causing impairment in the academic setting, peer relationships, and emotional regulation, which are also key predictors and mediators of functional difficulties in adulthood. Before starting a patient on a regimen, the prescribing clinician should assess the potential risks for pharmacotherapy by obtaining a complete past medical history, family history, and a physical examination with a specific focus on the cardiovascular system. It is important to obtain pretreatment baseline information and a close follow up to objectively evaluate the impact of common side effects associated with pharmacotherapy for ADHD (i.e., appetite changes, hypertension, weight loss, sleep disturbances, headaches, abdominal pain). Baseline sleep problems do not appear to predict stimulant-related sleep problems and may improve with stimulant therapy [ 48 ]. Adolescent patients should be assessed for substance use or abuse prior to starting treatment.

There are two main stimulant families: the amphetamines are usually slightly more efficacious than the methylphenidate derivates which are usually better tolerated [ 49 ]. In a systematic review and network meta-analysis that included 81 published and unpublished randomized trials in > 10,000 neurotypical children, amphetamines were slightly more efficacious than methylphenidate in reducing clinician-rated core symptoms of ADHD at approximately 12 weeks; however, amphetamines were less tolerable than placebo and methylphenidate was better tolerated than amphetamines [ 49 ]. Specific systematic review of four-crossover trials in autistic children (113 participants) age 5 to 13 years found low-quality evidence that short-term treatment with methylphenidate may improve hyperactivity and inattention in children with ASD, and the only significant adverse side effect was reduced appetite as rated by parents; however, there was no evidence of impact on core ASD symptoms or improvement in social interaction [ 50 ]. In the largest crossover trial, approximately 50% of children with ASD responded to methylphenidate based on the hyperactivity subscale of the Aberrant Behavior Checklist (ABC); the effect size ranged from 0.20 to 0.54, depending upon dose and rater, with greater improvement at higher doses; then, this modest effect supports that Methylphenidate exerts a lower effect on primary ADHD symptoms in individuals with ASD compared to those in the neurotypical population. Six of 66 children in the double-blind phase (9.1%;) discontinued treatment due to adverse effects, including irritability, repetitive behaviors, tics, insomnia, and reduced appetite [ 51 ].

Treatment failure is defined by lack of satisfactory improvement in core symptoms of ADHD at the maximum dose or the occurrence of intolerable adverse effects. At least half of the children who presented with an inadequate response or side effects to a certain medication may respond well to another one. For those children failing to respond to two different medications, the prescriber should evaluate other causes for the limited therapeutic response including (1) the presence of comorbid psychiatric diagnosis, (2) unrealistic expectations about the expected clinical response, (3) misuse or medication diversion, and (4) lack of adherence to the regimen. Children on stable maintenance dose should be followed every 6 months to monitor side effects and evaluate clinical response.

Alpha-2-adrenergic Agonists

There is also evidence about the use of alpha 2 agonists to improve core ADHD symptoms, but alpha-2-adrenergic agonists (i.e., guanfacine and clonidine) are frequently used in children under 5 year old with ADHD or hyperarousal, cases with poor response to a trial of stimulants, or selective norepinephrine reuptake inhibitors, have unacceptable side effects, or have significant co-occurring conditions (i.e., sleep issues). However, studies of alpha-2-agonists in ASD are limited and have small sample sizes. Guanfacine has been reported to be safe and effective in the treatment of hyperactivity and impulsiveness in children with ASD [ 52 , 53 ]. The most common side effects of guanfacine include sedation, constipation, irritability, and aggression. A small crossover study has also suggested positive effects of clonidine in ASD including decreased irritability, stereotypy, hyperactivity, inappropriate speech, and hyperarousal behaviors [ 54 ].

Data from randomized trials, systematic reviews, and meta-analyses show that atomoxetine and alpha-2-adrenergic agonists are more effective than placebo in reducing the core symptoms of ADHD, but as a class, they are less effective than stimulants [ 49 , 55 , 56 ]. Similarly, it is key to obtain objective targeted symptom measures at baseline and during treatment to objectively evaluate the response to treatment in different settings.

In a recent review of nine controlled trials of 430 children with ASD comparing the response between methylphenidate, atomoxetine, and guanfacine, methylphenidate and atomoxetine had superior effects than placebo in addressing ADHD symptoms; however, the response for hyperactivity symptoms was less than observed in neurotypical populations with both medications [ 57 ]. Worse treatment outcomes were associated with individuals with lower cognitive functioning.

Sleep issues are frequently reported in children with ASD potentially affecting their behavior, daily functioning, and family life. There is some evidence suggesting that low melatonin levels affect the circadian rhythm in autistic children [ 58 ]. In cases where behavioral and environmental sleep interventions have been implemented with limited response, clinicians may recommend the use of melatonin which is usually well tolerated and has a low incidence of side effects [ 59 ]. There is increasing evidence for the use of prolonged-release melatonin in autistic individuals with limited response to regular release formulations [ 60 ]. Melatonin is an over-the-counter product that is not regulated by the FDA. When parents/caregivers purchase melatonin, they should seek a formulation that contains melatonin as the only active ingredient.

N-acetylcysteine

N-acetylcysteine (NAC) is another antioxidant that can be purchased over the counter (OTC), and it can improve the imbalance of excitation: inhibition (E:I) that is seen in some forms of ASD [ 61 ]. NAC works by two mechanisms to lower the E:I imbalance; it lowers glutamatergic neurotransmission, and the cysteine leads to an increase in glutathione synthesis which is an important antioxidant. Cysteine is also oxidized to cystine, which further helps to reduce glutamatergic neurotransmission [ 62 ]. Hardan and colleagues carried out a controlled trial of escalating doses of NAC from 900 mg once a day for 4 weeks, increasing to bi-daily dosing for 4 weeks and then tri-daily dosing for the last 4 weeks compared to placebo. They randomized 33 subjects with ASD ages 3.2 to 10.7 years and after 12 weeks of treatment they found significant improvement on their primary outcome measure, irritability subscale on the ABC ( p  < 0.001) for patients treated with NAC compared to placebo. Additional improvements were seen in stereotypic behaviors with significance reached on the RBS-S Stereotypies subscale ( p  < 0.014) and the SRS Autism Mannerisms subscale ( p  < 0.045) for those treated with NAC vs placebo [ 62 ]. NAC was well tolerated although an occasional patient did not like the taste or had minimal gastrointestinal side-effects.

Dietary Supplements

Sulforaphane is a naturally occurring isothiocyanate (found in broccoli and other cruciferous vegetables) [ 63 , 64 , 65 ]. Sulforaphane is an antioxidant, anti-inflammatory, and mitochondrial protective agent that has been studied in several animal models and humans with neurodegenerative and neurodevelopmental disorders [ 66 ]. Sulforaphane is a sulfur-rich dietary phytochemical which can penetrate the blood brain barrier, and it subsequently induces the nuclear factor erythroid 2 related factor 2 ( Nrf2 ) signaling cascade that stimulates the expression of more than 200 genes that are antioxidants and involved in detoxification and neuroprotection in the CNS [ 67 ]. The effect leads to reduction of superoxide and other reactive oxygen species (ROS), upregulation of the proteozome system to digest unfolded or misfolded proteins, enhancement of autophagy, inhibition of pro-inflammatory cytokines, protection from heme toxicity, and defense of neuronal cells from Aβ 42 -mediated cytotoxicity.

There have been a few studies in patients with ASD [ 68 , 69 ] including a controlled trial of young men ages 13 to 27 with moderate to severe ASD treated with sulforaphane ( n  = 29) compared to placebo ( n  = 15) for 18 weeks. Significant improvements were seen on the Aberrant Behavior Checklist (ABC), the Clinical Global Improvement Scale (CGI-I), and the Social Responsiveness Scale 2 (SRS) [ 69 ]. This positive trial lead to a more detailed study in children with ASD, a randomized controlled trial of sulforaphane lasting 15 weeks followed by an open label trial for another 15 weeks in 57 children ages 3 to 12 years [ 70 ]. Although the primary outcome measure, the Ohio Autism Clinical Impressions Scale, did not improve significantly in those on sulforaphane, a secondary measure, the ABC, did significantly improve on sulforaphane vs placebo but the SRS did not. In addition, there were significant improvements in the biomarkers including the glutathione redox status, mitochondrial respiration, inflammatory markers, and heat shock proteins on sulforaphane vs placebo, and these improvements correlated with improvements on the ABC. They utilized a commercial product of sulforaphane called Avmacol made by Nutrimax with a tablet dose of 2 to 8 tablets per day depending on the weight of the child (equivalent to 2.2 μmol/kg/day). There were no significant adverse events and the supplement was well tolerated.

Other antioxidants have been studied in ASD including omega-3 fatty acids [ 71 , 72 ] with mixed results, and these antioxidants promote glutathione recycling by facilitating the conversion of oxidized glutathione into reduced glutathione. A more recent study was carried out by Mazahery et al. [ 73 ] in 111 children with ASD ages 2.5 to 8 years, and they were randomized to placebo, Vitamin D 2000 IU/day, or omega-3 722 mg/day or both interventions for 1 year of treatment. Seventy-three patients completed a year of therapy, and those on both treatments had a significant reduction in their primary outcome measure, irritability on the ABC subscale ( p  < 0.001) compared to placebo, and those treated with vitamin D alone also had a reduction in irritability also compared to placebo ( p  < 0.45) [ 73 ]. These studies suggest that antioxidants may be a helpful ancillary treatment in some patients with ASD, although biomarkers of oxidative stress would be helpful to assess in further studies to better identify those who would benefit from this treatment.

Emerging Targeted Treatments with a Possible Role in ASD

Oxytocin (OXT) is a neuropeptide synthesized in the hypothalamus that plays a critical role in social functioning. Extant literature has shown that OXT enhances social processing in typically developing adults (enhanced eye contact, better emotion recognition in faces) immediately after its administration [ 74 ]. There have been generally positive results of OXT in adults with ASD, with trials showing improvements in repetitive behaviors, social reciprocity, and emotion recognition [ 75 , 76 , 77 ]. However, all these trials studied only short-term benefits (within a few weeks) of OXT administration. A recent randomised, placebo-controlled, double-blind study in adults with ASD showed improvements in self-reported repetitive behaviors and positive mood at 1 year post treatment after an initial 4 weeks of oxytocin treatment [ 78 ]. However, in this same study, there were no significant treatment benefits for social responsiveness with OXT [ 78 ]. Another recent study in young adults with ASD also did not demonstrate any immediate benefits of OXT on empathy and social perception [ 79 ].

Results of OXT studies in children have overall been more equivocal with mixed results. Although 4 studies showed positive short-term results of OXT administration on social responsiveness (following 4 or 5 weeks of OXT administration) [ 80 , 81 , 82 , 83 ], another 2 studies did not demonstrate any OXT specific improvements in social responsiveness or repetitive behavior in children with ASD [ 84 , 85 ]. A recent randomized controlled trial (RCT) however did not show any significant effects between the OXT and placebo group in aberrant behavior, social communication, or cognition [ 86 ]. At the neural networks level, it has been shown that intranasal OXT leads to increased activation in the brain regions known to be involved in perceiving and thinking about social-emotional information and enhances effective connectivity between nodes of the brain’s reward and socioemotional processing systems [ 87 , 88 ]. There were no noted side effects in these studies on children with ASD, thus far, although animal studies have raised the possibility of increased basal OXT levels with long-term OXT administration; the clinical effects of this being unclear. Of pertinence, there remains a lack of conclusive evidence for the long-term beneficial effects of OXT in addressing the core symptoms of autism [ 89 ]. Given that the vast majority of studies in children utilize parent-reported outcome measures of social and behavioral symptoms, inherent limitations of bias in reporting even in placebo-controlled trials are likely to come into play. Another important consideration is whether the gains that are seen with OXT administration in the experimental setting translate to real life and this is also unclear. The role of OXT thus far has been limited to its immediate effect after administration and hence is not a single treatment option for ASD. Nonetheless, as illustrated by a recent meta-analysis, there does seem to be overall beneficial effects of OXT on social symptoms of ASD, although this review included both children and adults [ 90 ]. There is also some promising research looking at the role of OXT in combination with other treatment modalities including behavior therapy and probiotics, with clinical trials in this area ongoing [ 91 , 92 ]. It is also likely that the effects of OXT in ASD are modulated by age, gender, and possibly genetic factors [ 77 , 79 , 90 ]. As such, although it holds much promise, the use of OXT in individuals with ASD is currently not a mainstream treatment.

Bumetanide is a well-established loop diuretic that works by inhibiting sodium–potassium-chloride co-transporters, namely, NKCC1 and NKCC2. Bumetanide has been purported as a potential treatment in autism due to its inherent chloride-related antagonist effects which is linked to GABA-ergic inhibition [ 93 ]. Bumetanide has been shown to reduce broad ASD symptomatology in children following a 3-month treatment course in 2 placebo-controlled randomized controlled trials [ 94 , 95 ]. Both of these trials used outcomes that are screening tools for ASD, namely, the SRS and the Childhood Autism Rating Scale (CARS). Another open-label trial of 6 children with severe ASD and intellectual disability showed parent-reported improvement in communicative abilities of all children after 3 months of bumetanide [ 96 ]. However, a recent double-blind, placebo-controlled, phase 2 superiority trial in children with ASD without severe intellectual disability did not show any treatment benefits on the core symptoms of ASD as measured on the SRS-2 [ 97 ]. It did show treatment benefits on the repetitive behavior scale, with no major adverse effects. Another study has suggested possible combined effects of bumetanide with ABA therapy in improving ASD symptoms on the CARS, although this was not a randomized controlled trial [ 98 ]. There are 2 phase 3 clinical studies ongoing now, which may shed further information on the potential benefits of bumetanide in ASD [ 99 ]. There is some functional-MRI-based evidence suggesting that bumetanide reduces the exaggerated amygdala activation to eye contact in individuals with ASD and contributes to increased eye-gaze time with biological stimuli and better emotional face perception [ 100 , 101 ]. Regardless, based on current literature, there is inconclusive evidence for the role of bumetanide in addressing the core symptoms of ASD [ 102 , 103 ].

Targeted treatments that reverse known neurobiological abnormalities in subgroups of ASD where there is also animal data to demonstrate benefit have emerged in the last decade for subgroups of ASD. The subgroup of ASD that is leading the way in targeted treatments is FXS, the most common single gene cause of ASD. In addition, post mortem studies have shown that FMRP, the protein that is missing or deficient in FXS, is also deficient in the brain in patients with idiopathic ASD without a fragile X mutation [ 104 , 105 ]. Therefore, FXS is a model for targeted treatments in other subtypes of ASD and treatments that work well in FXS may also be beneficial for other forms of ASD. So we will describe some of the targeted treatment studies with compounds that are available currently, although not FDA approved for FXS nor ASD.

Animal studies in FXS have demonstrated a hyperactive insulin receptor and up-regulation of the mammalian target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase/extracellular signal-related kinases (MAPK/ERK) signaling pathways, as well as elevation of MMP-9 levels in the absence of FMRP, the protein produced by the FMR1 gene [ 106 , 107 , 108 ]. Metformin is a bi-guanide that is a primary treatment for type 2 diabetes, but it can also reduce the appetite in individuals with obesity. Therefore, studies of metformin were first carried out in patients with FXS who demonstrated obesity, often with the Prader-Willi-phenotype of FXS [ 109 ]. In a handful of patients with FXS treated clinically with metformin between the ages of 4 and 60 years old, there was improvement in overeating but also on the ABC subscales of irritability, aggression, and social avoidance [ 109 ]. Parents also stated that they saw improvement in the expressive language abilities in conversation. The potential language improvements are currently being studied in a controlled trial of metformin occurring over 3 sites, 2 in Canada (Edmonton and Montreal), and one site in the USA at the MIND Institute funded by the Azrieli Foundation (NCT03479476, NCT03862950). Patients ages 6 to 45 are recruited into a randomized controlled trial lasting 4 months with outcome measures including the Expressive Language Sampling as the primary outcome but also event related potentials, eye tracking, NIH toolbox, and other behavioral measures are assessed. The results will be available in 2022. Additional open label studies have been carried out with metformin including one in children ages 2 to 7 years old with FXS, and improvements were seen in behavior and development on the MSEL [ 110 ]. Individual case studies have shown that macroorchidism did not develop in boy who started metformin clinically before puberty [ 111 ] and two adults with FXS improved their IQ when using metformin for over one year [ 112 ].

Lovastatin is a commonly used statin that lowers cholesterol levels, but it does this by inhibiting 3-hydroxy-3methylglutaryl coenzyme A (3HMG-CoA) reductase, and it is FDA approved for lowering hypercholesterolemia or hyperlipidemia in children and adults. This action lowers the excessive protein production of the MEK-ERK pathway which are elevated in FXS. Studies of lovastatin treatment in the FXS knock out (KO) mouse rescued excess protein synthesis and also epilepsy [ 113 ]. These animal studies stimulated FXS patient trials. The one controlled trial included 32 children with FXS between 10 to 17 years treated in a RCT for 20 weeks with a dose of 10 to 40 mg a day as tolerated [ 114 ]. In addition, the patients all received Parent Implemented Language Intervention (PILI) [ 115 ] delivered by distance video teleconferencing over 12 weeks by a speech and language therapist with 4 sessions per week. Parents were taught a set of language facilitation techniques that were utilized with shared story telling sessions with their child. The main outcome measures were the number of utterances and new words utilized in addition to additional language scales, behavioral measures (ABC), and the CGI-I. So this study compared the combined effects of lovastatin plus PILI to PILI alone with placebo. Remarkably, there was significant improvements from baseline in both groups, but the outcomes were the same in both groups; that is, PILI alone had as much improvement as lovastatin plus PILI demonstrating the power of intensive language intervention [ 114 ].

Cannabidiol

Cannabidiol (CBD) is a phytocannabinoid found in Cannabis sativa , marijuana. Although there are hundreds of phytocannabinoids in marijuana, CBD is the second most common one after delta-9-tetrahydrocannabinol (THC) which has psychotropic properties. Marijuana has been used for 8000 years in India, China, and Middle East for fiber and medicinal properties; then introduced to Europe in early nineteenth century by Napoleon’s army returning from Egypt and then to Britain for medical use by a surgeon who served in India. CBD is the non-psychotropic component of marijuana, and there are numerous therapeutic effects of this drug including treatment of anxiety, pain, nausea, and motor deficits including the tremor in Parkinson’s disease [ 116 ]. CBD has both neuromodulatory and neuroprotective effects through a number of mechanisms including blocking neuroinflammation and potentiating anti-inflammatory pathways, improving mitochondrial function, GABA A agonist potentiation, stimulation of 5HT 1A receptors, and enhancing levels of anandamide (AEA) [ 116 , 117 , 118 , 119 ].

The endocannabinoid system has two receptors CB 1 found primarily in the CNS and CB 2 found throughout the body and the immune system. The primary endogenous ligands for CB 1 and CB 2 receptors are called endocannabinoids (ECs) and include anandamide AEA and 2-arachidonoylglycerol (2-AG). The ECs modulate synaptic transmission throughout the CNS, yielding widespread influence on cognition and behavior. The ECs are synthesized and released from post-synaptic membrane-bound phospholipids in response to neuronal signaling and act as retrograde signaling molecules across the synaptic cleft to stimulate CB 1 receptors on the presynaptic terminal, and they can inhibit neurotransmitter release from the presynaptic terminal. Enzymes that function in synthesizing 2-AG include phospholipase C and diacylglycerol lipase (DAGL).

CBD has also been shown to act as a positive allosteric modulator at GABA A receptors, and controlled trials have shown that CBD in the form of Epidiolex is an effective anticonvulsant in Dravet syndrome and Lennox-Gastaut syndrome [ 120 ]. CBD’s ability to enhance endocannabinoid levels and facilitate GABAergic transmission may serve to improve the balance in inhibitory and excitatory transmission and help restore neuronal function and synaptic plasticity in patients with ASD and FXS even when there is no epilepsy. Animal models of both FXS and ASD have shown benefits when treated with CBD [ 121 , 122 ]. Studies of individuals with ASD treated with CBD and open label trials of CBD are reviewed by Nezgovorva et al. [ 123 ]; however, the preparations studied have both CBD and variable levels of THC, although in general, benefits were seen in irritability, sleep disorders, tantrums, and anxiety. Currently, studies of cannabidavarin (CBDV) are taking place in ASD and CBDV has also been helpful in animal models of ASD [ 123 ].

Recently, the development of a topical CBD that is manufactured so that there is no THC has facilitated studies in both ASD and in FXS. The BRIGHT study was an open label study of children ages 3 to 17 with ASD lasting 14 weeks, and benefits were seen in most outcome measures including the ABC and measures of anxiety [ 124 ]. Currently, a controlled trial of this topical CBD called Zyn002 is taking place in children with ASD. Another recent randomized controlled trial (RCT) looking at an oral preparation of CBD in children and young adults with ASD demonstrated positive improvements in behavior and social communication with CBD [ 125 ].

Huessler et al. [ 126 ] carried out an open label trial of Zyn002 in Australia for children with FXS of ages 3–17 years old with doses of the transdermal CBD at doses 250 mg bi-daily for 12 weeks (ACTRN12617000150347). Both the primary outcome, the Anxiety Mood and Depression (ADAMS) scale and the secondary measures including the ABC, demonstrated efficacy. Subsequently, a multicenter controlled trial of over 200 children with FXS was carried out and efficacy was seen in only those children with > 90% methylation with FXS on the primary outcome measure of the Social Avoidance subscale of the ABC FX , a scale that has been developed for FXS modified from the ABC (Berry-Kravis et al. 2022 under review Sci Trans Medicine). Currently, the FDA has not approved Zyn002 for general use, but an additional multicenter controlled trial is now taking place to win this approval. It is very likely that the current controlled trials taking place for ASD and FXS will show efficacy for subgroups for both disorders, and subsequently, CBD will be more broadly utilized.

Arbaclofen, also called STX209, is a selective ɣ-aminobutyric acid type B receptor agonist that is the R-enantiomer of racemic baclofen. For many subtypes of ASD, there is a GABA B deficit and arbaclofen has rescued the behavioral deficits including social deficits in the mouse models of idiopathic ASD [ 127 ], deletion of 16p11.2 [ 128 ], and FXS [ 129 ]. There are 3 pathways that are improved with arbaclofen: Stimulation of presynaptic GABA B receptors inhibits glutamate release thereby lowering the mGluR5 pathway. Stimulation of GABA receptors also improves inhibition that is down-regulated in many forms of ASD and arbaclofen also enhances K channel activation which can also be down-regulated in many forms of ASD [ 130 ]. The promising mouse studies led to human trials in FXS [ 131 ] that initially showed improvements in those with ASD plus FXS leading to phase 3 trials in FXS [ 132 ]. However, the adult studies of FXS did not demonstrate efficacy and the pediatric trials did not reach significance for the primary outcome measure, but did show limited improvements in secondary measures including the Parenting Stress Index because of lowered irritability in the children [ 132 ].

Both open label studies in idiopathic ASD and in those with a 16p11.2 deletion have been carried out with positive behavioral benefits. A controlled trial with idiopathic ASD has also been started but not yet reported. Arbaclofen has been well tolerated even at higher doses up to 15 mg tri-daily so it is likely that further studies will be carried out both in ASD and in subtypes of ASD including FXS.

Trofinetide

Insulin like growth factor 1 (IGF1) is considered an emerging treatment for ASD in animal and cellular models in ASD [ 133 , 134 , 135 , 136 ]. Trofinetide is an analogue of the amino-terminal tripeptide of IGF1, and it has been studied in patient groups of ASD subtypes. Trofinetide is glycyl-L-2-methylprolyl-L-glutamic acid, and it was studied in a controlled phase 2 trial in 82 children with Rett syndrome ages 5 to 15 years, and significant benefit was found in the high-dose group (200 mg/kg/day) compared to placebo [ 137 ]. Significant benefits were seen in several measures including the Rett Syndrome Behavior Scale, the Rett Syndrome Clinician Rating Scale, and a visual analogue scale. This report led to a multicenter phase 3 controlled trial in Rett syndrome which is ongoing currently.

Trofinetide has also been studied in a 28-day controlled trial in adolescent and adult patients with FXS [ 138 ]. Patients were randomized to trofinetide 35 mg/kg/day, 70 mg/kg/day, or placebo. Results demonstrated that the 70 mg/kg/day was significantly beneficial compared to placebo with a permutation test utilizing the primary components of the Fragile X Syndrome Rating Scale, a Fragile X Specific Domain Scale on a visual analogue format, and the ABC FX.

In the fragile X knockout (KO), mouse studies trofinetide had several positive effects at a dose of 100 mg/kg/day yielding insight as to why it is beneficial in FXS [ 139 ]. The KO mouse was deficient in IGF1 in the brain, and this was normalized with trofinetide treatment for 28 days. Improvements in dendritic spine abnormalities, astrogliosis, neuroinflammation, glial activation, and downregulation of the MEK-ERK and PI3K-mTOR pathways were seen with trofinetide treatment leading to improvements in behavior and morphology of FXS [ 139 ]. Clearly, trofinetide is a treatment that improves multiple pathways that are dysregulated in more than one subtype of ASD and further studies at optimal doses will be carried out and some are currently taking place.

Phosphordiasterase 4D Inhibitors

It has been known for many years that cAMP, an important energy compound for improving synaptic connections, is down regulated in FXS [ 140 ]. Recent animal studies have shown that an inhibitor of cAMP breakdown called a phosphordiasterase 4DE inhibitor can rescue features of FXS in the KO mouse model and Drosophila model and can raise the cAMP levels to normal [ 141 , 142 ]. These studies led to patient trials of a PDE4D inhibitor called BPN14770, and an exciting study was recently published, a randomized controlled trial in 30 adult males with FXS that demonstrated improvements not only in behavior but also in the primary outcome measure, the NIH toolbox, and secondary measures after only 12 weeks of treatment [ 143 ]. This is the first treatment of FXS that demonstrated improvements in cognition, specifically in Oral Reading Recognition, Picture Vocabulary and Cognition Crystallized Composite Score in the NIH toolbox that has been modified for use in those with ID. The caregivers also used the Visual Analog Caregiver Rating Scales and demonstrated improvement in language and daily functioning. Families are excited that this is the first of hopefully many new medications that can reverse cognitive deficits and further controlled trials are in the planning stages.

Anavex 2–73

Anavex 2–73 (AV 2–73; Blarcamesine) is a sigma 1 receptor agonist that works between the endoplasmic reticulum and the mitochondrial membrane to normalize calcium dysregulation, oxidative stress, and mitochondrial dysfunction which is seen in many forms of ASD. It has demonstrated significant benefits in the KO mouse model of FXS where multiple behaviors were improved and deficient brain derived neurotropic factor (BDNF) levels were normalized [ 144 ]. In addition, Kaufman et al. [ 145 ] also reported significant benefits in the Rett syndrome mouse model with a rescue of behavior and BDNF levels and this work lead to patient studies in Rett syndrome that have demonstrated efficacy in a controlled trial (Anavex Life Sciences press release 2021). AV2-73 also has beneficial effects in neurodegenerative disorders because of improvement in proteostasis, autophagy, oxidative stress, prevention of protein aggregates, and improvement in mitochondrial function leading to benefits in Alzheimer’ disease and Parkinson’s disease dementia [ 146 , 147 , 148 ]. Significant potential exists for AV2-73 to improve symptoms in Fragile X-associated Tremor Ataxia (FXTAS), a neurodegenerative disease seen in approximately 40% of older carriers of the fragile X premutation, because calcium dysregulation, mitochondrial dysfunction, proteostasis, and aggregations of proteins causing inclusions occur in FXTAS [ 149 ].

Gene Therapy

Although this therapy is not available for clinicians to utilize in their patients, exciting research studies particularly after the advances in CRISPR/Cas9 technology have become available. The possibility of introducing a normal gene or protein into the CNS to treat ASD or other neurodevelopmental disorders where the mutation is known is exciting. Another example of gene therapy is the introduction of antisense oligonucleotides (ASOs) to silence RNA or gene products that are deleterious. In Angelman syndrome, where the maternal copy of UBE3A is mutated or absent, ASOs have been utilized to activate the paternal copy of UBE3A in the CNS to compensate for the missing maternal copy. Recently, a controlled trial of GTX-102, an ASO, was tried in 5 individuals with Angelman syndrome ages 5 to 15 years old. The protocol involved the intrathecal injection of GTX-102 at increasing doses once monthly for 4 months. However, an adverse effect of leg weakness was seen at the higher doses leading to an inability to walk in two patients. This was found to be related to inflammation at the level where the LP was carried out so these patients were treated with anti-inflammatories with resolution of this side effect. The future is bright for further gene therapy interventions in ASD and other neurodevelopmental disorders.

The current evidence-based management of ASD in children relies primarily on behavioral interventions to address the core symptoms of the condition. The role of pharmacological treatments currently is primarily to address co-morbid conditions associated with ASD and increases with age. These medications including anti-psychotic agents and stimulant medications are important in the clinical management of patients with ASD. However, the emergence of targeted treatments for subgroups of ASD where the genes responsible for the ASD are known and the neurobiology and potential targeted treatments have been studied to reverse the neurobiological abnormalities at least in the animal models has led to several recent achievements in patients as described here. Of note is that there are commonalities among disorders causing ASD that suggest that a targeted treatment for one disorder will be beneficial for other disorders. For instance, GABA deficits are seen in many forms of ASD and medications that are agonists for the GABA system such as CBD are likely to be helpful for many subtypes of ASD as described above. Mitochondrial dysfunction is associated with many forms of ASD, so medications that will improve mitochondrial dysfunction are likely to be helpful for many subtypes of ASD [ 150 ]. The promise of gene therapy is becoming a reality for many disorders such as Duchene Muscular Dystrophy, Spinal Muscular Atrophy, and even Angelman Syndrome because of CRISPR/Cas 9 technology so in the next few years, many additional forms of ASD will be treated with gene therapy. Until then, some of the treatments outlined here can be tried and more will become available in the near future.

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This research was supported by grants from the Azrieli Foundation, clinical trial funding to the MIND Institute from Zynerba for the CBD study, and the MIND Institute Intellectual and Developmental Disabilities Research Center P50 HD103526.

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Aishworiya, R., Valica, T., Hagerman, R. et al. An Update on Psychopharmacological Treatment of Autism Spectrum Disorder. Neurotherapeutics 19 , 248–262 (2022). https://doi.org/10.1007/s13311-022-01183-1

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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

• What Is Autism?
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• Dr. Evdokia Anagnostou presented the results of neuroimaging studies at the International Society for Autism Research 2022 annual meeting.
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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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ORIGINAL RESEARCH article

Autism spectrum disorder research: knowledge mapping of progress and focus between 2011 and 2022.

• 1 National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China
• 2 Translational Medicine Center of Chinese Institute for Brain Research, Beijing, China
• 3 Guangdong Key Laboratory of Mental Health and Cognitive Science, Institute for Brain Research and Rehabilitation (IBRR), South China Normal University, Guangzhou, China

Background: In recent years, a large number of studies have focused on autism spectrum disorder (ASD). The present study used bibliometric analysis to describe the state of ASD research over the past decade and identify its trends and research fronts.

Methods: Studies on ASD published from 2011 to 2022 were obtained from the Web of Science Core Collection (WoSCC). Bibliometrix, CiteSpace, and VOSviewer were used for bibliometric analysis.

Results: A total of 57,108 studies were included in the systematic search, and articles were published in more than 6,000 journals. The number of publications increased by 181.7% (2,623 in 2011 and 7,390 in 2021). The articles in the field of genetics are widely cited in immunology, clinical research, and psychological research. Keywords co-occurrence analysis revealed that “causative mechanisms,” “clinical features,” and “intervention features” were the three main clusters of ASD research. Over the past decade, genetic variants associated with ASD have gained increasing attention, and immune dysbiosis and gut microbiota are the new development frontiers after 2015.

Conclusion: This study uses a bibliometric approach to visualize and quantitatively describe autism research over the last decade. Neuroscience, genetics, brain imaging studies, and gut microbiome studies improve our understanding of autism. In addition, the microbe-gut-brain axis may be an exciting research direction for ASD in the future. Therefore, through visual analysis of autism literature, this paper shows the development process, research hotspots, and cutting-edge trends in this field to provide theoretical reference for the development of autism in the future.

Introduction

Autism spectrum disorder (ASD) refers to a group of early-onset, lifelong, heterogeneous neurodevelopmental conditions with complex mechanisms of emergence ( 1 ). The prevalence of ASD has increased from 1 in 69 by 2012 to 1 in 44 by 2018, as reported by the Centers for Disease Control and Prevention for 2012–2018 ( 2 , 3 ). Recent research estimates the male-to-female ratio is closer to 2:1 or 3:1, indicating a higher diagnostic prevalence of autism in males compared to females ( 4 – 6 ). Some studies have shown a high heritability of 80–93% in ASD and reported hundreds of risk gene loci ( 7 ).

Specific autistic characteristics usually appear before the age of 3 years, and some children on the spectrum may have limited nonverbal and verbal communication by the age of 18–24 months ( 8 , 9 ). The diagnosis of ASD is based on the core features of social communication impairment and unusual and repetitive sensory-motor behavior ( 10 ). Some autistic individuals can be definitively diagnosed with autism as early as 2–3 years of age and the mean age of diagnosis for autistic children is still 4–5 years ( 1 , 11 ). It is important to stress that more adults are getting assessed for possible autism ( 5 ). As autism is increasingly diagnosed, multidisciplinary involvement can help have a positive impact on the well-being and quality of life for both children and adults on the spectrum ( 12 ). Several mental diseases also affect autistic individuals, increasing the diagnosis complexity ( 13 ).

Over the past decade, researchers have struggled to explain the neurological etiology, and great progress has been made in the genetics, epigenetics, neuropathology, and neuroimaging of ASD ( 9 ). However, there is a lack of systematic review of field research and discussion of future research hotspots. Bibliometrics ( 14 ) belongs to interdisciplinary research, which has been widely used in science by analyzing highly cited papers, field keyword clustering, and the internal cooperation links of countries, thus providing a comprehensive interpretation of the development process of autism research field ( 15 ).

In some of the previous bibliometrics studies on ASD, a single software was used to focus on a specific field or research aspect of the autism ( 16 – 18 ), and the trend in the past decade has not yet been displayed. The present study comprehensively combines Bibliometrix package, CiteSpace, and VOSviewer to (1) dynamically assess quantitative indicators of ASD research publications and use different index indicators to measure the quality of research; (2) further identify the most contributing countries, institutions, journals, and authors; (3) analyze the citation network architecture; (4) determine the top 100 most cited papers; (5) conduct keyword analysis. Subsequently, bibliometrics was used to understand the current hotspots and trends in the field of ASD research for further in-depth investigation.

Materials and methods

Data collection and search strategies.

We comprehensively searched the Web of Science Core Collection (WoSCC) database from 2011 to 2022. WoSCC is a daily updated database covering an abstract index of multidisciplinary literature that exports complete citation data, maintained by Thomson Reuters (New York, NY, USA) ( 19 ). The articles’ data were independently searched by two researchers on May 29, 2022, to avoid bias caused by database updates. The scientometric retrieval process is illustrated in Figure 1 . A total of 68,769 original articles in English language were retrieved, excluding 11,661 irrelevant articles, such as meeting abstracts, editorial materials, corrections, and letters. A total of 57,108 documents were exported, and the retrieved documents would be exported in the form of all records and references.

Figure 1 . Flowchart of the screening process.

Grey prediction model

Grey models (GM) are used to construct differential prediction models with limited and incomplete data ( 20 ). The GM (1,1) model, with high accuracy and convenient calculations, is extensively utilized in the energy and medical industries ( 21 ). We used the standard GM (1,1) model to forecast the annual publication volume over the next 5 years. The operation of GM (1,1) model was done by using Python software.

Bibliometric analysis and visualization

The records of the retrieved publications were exported to Bibliometrix, CiteSpace, and VOSviewer for further bibliometric analysis.

Bibliometrix package (running on R4.0.3) was utilized to capture and extract the bibliographic information on selected publications, including topic, author, keywords, and country distribution ( 22 ). The productivity of authors/journals in the field was measured by the number of publications (Np) and assessing metrics, such as the number of citations, publication h-index value, and m-index value. The h-index is used to quantify the scientific output and measure the citation impact, and two people with similar h-index may have a similar impact in the scientific field, even if the total number of papers or total citations are different ( 23 ). The m-index can be used to compare the influence of scholars with different academic career years. The number of citations of a document is a measure of its scientific impact to a certain extent ( 24 ). Bibliometrix package was also used to screen the top 100 articles and explore research trends and hotspots.

VOSviewer is a free computer program to visualize bibliometric maps ( 25 ). The keyword co-occurrence network was constructed using VOSviewer. CiteSpace is based on the Java environment and uses methods, such as co-occurrence analysis and cluster analysis, for the visualization of scientific literature research data in specific disciplines. The visual knowledge maps were constructed using the procedural steps of CiteSpace ( 26 ), including time slicing, threshold, pruning, merging, and mapping; then, the contribution of countries and institutions of ASD over the past decade was assessed based on centrality scores. The co-citation network and dual-map of references were constructed by CiteSpace. A dual-map ( 27 ) overlay is a bipartite overlay analysis method by CiteSspace, which uses the distribution map cited journals in the WoS database as the base map, and the map generated by the cited literature data as the overlay map.

Annual publications

A total of 57,108 articles were included in this study, consisting of 46,574 articles, 2,643 conference papers, and 7,891 reviews. From 2011 to 2022, the number of publications maintained a steady growth rate ( Figure 2A ), and the grey prediction model predicted the trend of increasing publication volume in the next 5 years ( Figure 2B ). The main information for all publications is shown in Supplementary Table S1 .

Figure 2 . Global trends in publications of ASD research. (A) Single-year publication output over the past decade. (B) Model forecast curves for publication growth trends.

Distribution of countries and institutions

Autism-related research has been conducted by researchers from a variety of countries and institutions, and articles in this field have been cited 1,231,588 times ( Tables 1 , 2 ). CiteSpace visualizes collaborative networks between institutions and countries ( Figures 3A , B ). As shown in the international collaborations network of autism research ( Figure 3C ), the USA and UK are the leading countries working closely with other countries.

Table 1 . Publications in top 10 most productive countries.

Table 2 . Publications in top 10 most productive Institutions.

Figure 3 . The distribution of countries and institutions. Map of countries (A) and institutions (B) contributed to publications related to ASD research. (C) Network diagram showing international collaborations involved in ASD research. The nodes represent the countries and institutions; the color depth and size of the circle are positively correlated to the number of posts. The thickness of the curved connecting lines represents the strength of collaboration in the countries and institutions.

Analysis of journals

The h-index combines productivity and impact; typically, a high h-index means a high recognition. As presented in Table 3 , the Journal of Autism and Developmental Disorders, PLOS One, and Molecular Psychiatry were among the top three of the 20 journals with the highest h-index. The Journal of Autism and Developmental Disorders has the highest number of articles (3478) and cited number of publications (90308). Among the top 20, four journals with impact factors >10 include Molecular Psychiatry (IF: 13.437), Biological Psychiatry (IF: 12.810), Proceedings of the National Academy of Sciences of the United States of America (IF: 12.779), Journal of the American Academy of Child and Adolescent Psychiatry (IF: 13.113), which have been cited more than 10,000 times. In addition, 75% of journals belong to Q1 ( Table 3 ). The cited journals provided the knowledge base of the citing journals. The yellow paths illustrate that studies published in “molecular, biology, immunology” journals tended to cite journals primarily in the domains of “molecular, biology, genetics,” and “psychology, education, social.” The paths colored with grass-green paths illustrate that studies published in “medicine, medical, clinical” journals tended to cite journals primarily in the domains of “molecular, biology, and genetics.” The pale blue paths showcase that research published in “psychology, education, health” journals preferred to quote journals mostly in the domains of “molecular, biology, genetics,” “health, nursing, medicine,” and “psychology, education, social ( Figure 4 ).”

Table 3 . Top 20 journals ranked by h_index.

Figure 4 . A dual-map overlay of journals that published work related to ASD. A presentation of citation paths at a disciplinary level on a dual-map overlay. The width of the paths is proportional to the z-score-scale citation frequency. The labels on the map represent the research subjects covered by the journals, and the wavy curve connects the citing articles on the left side of the map and the cited articles on the right side of the map.

Analysis of authors

The top 10 most effective authors who have contributed to autism research are listed in Table 4 . The g-index and m-index are derivatives of the h-index, and if scientists publish at least 10 articles, of which 7 papers have been cited cumulatively 51 (>49), the g-index is 7; the m-index is related to the academic age of the scientists. The large g-index, h-index, and m-index indicate a great influence on the scholar’s academic influence and high academic achievement. Professor Catherine Lord from the USA is ranked first and has made outstanding contributions to autism research over the past 10 years. In terms of the number of publications, Simon Baron-Cohen was the most productive author ( n  = 278), followed by Tony Charman ( n  = 212) and Christopher Gillberg ( n  = 206). In terms of citations in this field, Daniel H. Geschwind was ranked first (18,127 citations), followed by Catherine Lord (14,830 citations) and Joseph D. Buxbaum (14,528 citations).

Table 4 . Top 10 most effective authors contributing to autism research.

Analysis of reference

The co-citation analysis network of 1,056,125 references ( Figure 5A ) showed that two articles appear simultaneously in the bibliography of the third cited document. The top 20 co-cited references (over the past decade) summarized in ASD studies are listed in Supplementary Table S2 . Most of this highly cited literature focuses on the genetic field, discovering genetic risk loci and associated mutations, constructing mutation networks highly associated with autism, and identifying genes associated with autism synaptic destruction. Some studies indicated that de novo mutations in ASD might partially explain the etiology. Multiple studies have revealed genetic variants associated with ASD, such as rare copy number variants (CNVs), de novo likely gene-disrupting (LGD) mutations, missense or nonsense de novo variants, and de novo duplications. In the cluster network graph, different colors represent varied clusters, and each node represents a cited paper, displaying the distribution of topics in the field ( Figure 5B ). The network is divided into 25 co-citation clusters ( Figure 5B ), primarily related to the diagnosis, etiology, and intervention of autism. The etiological studies include five clusters, de novo mutation, inflammation, gut microbiota, mitochondrial dysfunction, and mouse model. Intervention literature focuses on early intensive behavioral intervention, intranasal oxytocin, video modeling, and multisensory integration. The diagnostic aspects of ASD include neuroimaging functional connectivity and Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In addition, some of the references focus on gender/sex differences and sleep problems. Coronavirus disease 2019 (COVID-19) is a new cluster for autism research.

Figure 5 . Mapping on co-cited references. (A) A network map showing the co-cited references. (B) Co-cited clusters with cluster labels.

Co-occurrence analysis of keywords

The co-occurrence analysis of keywords in ASD research articles was performed using VOSviewer software; the keywords that occurred ≥200 times were analyzed after being grouped into four clusters of different colors ( Figure 6A ); the temporal distribution of keywords is summarized in Figure 6B . This map identifies various categories of research: Etiological mechanisms (red), Clinical features (green), Intervention features (blue), and the Asperger cluster (yellow). In the “Etiological mechanisms” cluster, the research includes brain structure and function, genetics, and neuropathology. In the “Clinical features” cluster, the common keywords were “symptoms,” “diagnosis,” “prevalence,” and its comorbidities, including “anxiety” and “sleep.” In the “Intervention features” cluster, the research population of ASD is concentrated in “young children,” “intervention,” and “communication.” These interventions improve the learning and social skills through the involvement of parents and schools.

Figure 6 . Keywords co-occurrence network. (A) Cluster analysis of keywords. There are four clusters of keywords: red indicates Cluster 1 ( n  = 145), green indicates Cluster 2 ( n  = 104), blue indicates Cluster 3 ( n  = 78), yellow indicates Cluster 4 ( n  = 80). (B) Evolution of keyword frequency. A minimum number of occurrences of a keyword = 200. Overall, 407 keywords met the threshold criteria. The yellow keywords appear later than purple keywords.

The 100 top-cited publications

The screening of the 100 most cited publications on ASD between 2011 and 2022 by Bibliometrix software package, each with >500 citations. The detailed evaluation index information for countries, institutions, journals, and authors ( Supplementary Tables S3 – S6 ).

Taken together, the results indicated that the United States is the country that publishes the most highly cited articles ( n  = 64), including single-country publications ( n  = 37) and multiple-country publications ( n  = 27); most articles are from academic institutions within the USA ( Figures 7A , B ).

Figure 7 . Analysis of the 100 top-cited publications Characteristics of 100 top-cited publications. The most relevant countries (A) , affiliations (B) , journals (C) and authors (D) . Trend topics (E) and thematic evolution (F) of 100 top-cited publication. Coupling Map (G) : the coupled analysis of the article, references and keywords is carried out, the centrality of the x -axis is displayed, the y -axis is the impact, and the confidence (conf%) is calculated.

The 100 top-cited ASD publications were published in 48 journals; 17 articles were published in Nature ( n  = 17), making it the highest h-index journal in this list ( Supplementary Table S5 ). In addition, 10 articles were published in Cell, and 7 articles were published in Nature Genetics ( Figure 7C ). When considering the individual authors’ academic contributions, Bernie Devlin provided 13 publications, followed by Kathryn Roeder and Stephan J Sanders, with 11 publications each ( Figure 7D ). The details of the top 10 top-cited papers are summarized in Table 5 . An article titled “A general framework for estimating the relative pathogenicity of human genetic variants” published by Martin Kircher in Nature Genetics, received the highest number of citations ( n  = 3,353).

Table 5 . Detail of top 10 citation paper.

The 100 top-cited ASD articles encompassed a range of keywords ( Figure 7E ) and displayed the main cluster of themes through specific periods (2011–2022) by analyzing those in the selected literature. The Sankey diagrams of thematic evolution explain the topics that evolved throughout the years ( Figure 7F ). In summary, the core topics of the ASD field in 2011–2014 consisted of the risk of childhood ASD and further developed into the field of human genetic variants, such as CNV and de novo mutations. In the subperiod 2015–2020, the further expansion of studies in this field leads to new clusters, such as “immune system,” “brain development,” and “fecal microbiota.” Genome research in the upper right quadrant, including mutations and risk, is a major and evolving theme. The coupled map showing the brain-gut axis field, including intestinal microbiota and chain fatty acids, located in the lower right corner is crucial for autism research but is not yet well-developed ( Figure 7G ). The research on autism, including animal models, schizophrenia, is a well-developed field, but that on high-functioning autism and diagnosis is a marginal field.

This study used various bibliometric tools and software to analyze the published articles on ASD based on the WoSCC database from 2011 to 2022. By 2022, the annual number of publications and citations of ASD-related research showed an overall upward trend, reflecting the sustained interest and the diversity of areas.

General information

In terms of regional distribution, researchers from different countries and regions have participated in autism research, and international cooperation has been relatively close over the past decade. The scientific research is supported by several countries and institutions, as well as by large-scale international cooperation ( 28 , 29 ). The USA has the highest collaboration performance, especially with UK, Canada, Australia and China. In addition to the limitations of financial aid, ethical, cultural, and racial issues are complex constraints that should be overcome for more diversity in autism research ( 30 , 31 ). We speculated that further collaboration between institutions and countries could promote autism research.

Among the top 20 academic journals, most of the papers were in the Journal of Autism and Developmental Disorders. The frequent publishing of ASD-related papers indicates the interest of readers and journal editors in Autism. Also, substantial studies have been carried out on ASDs, autism, and molecular autism. These journals are ascribed to the field of ASD, focusing on autism research and communication ASD science. However, the analysis of the 10 most cited publications revealed that they were published in such as Nature, Cell, Lancet; these ASD studies were all from high-impact journals.

From the perspective of authors, some of them have made outstanding contributions to global ASD research. Professor Catherine Lord, the top rank for h-index, m-index analysis conducted by the author, and who developed the two gold standards for autism diagnosis ( 32 , 33 ), are the most influencing factors in the field. ASD is a disease with complex genetic roots. Dr. Catherine Lord has conducted multiple studies using genome-wide association study (GWAS) and gene set analysis to identify variant signatures in autism ( 34 ). A recent meta-analysis showed that 74–93% of ASD risk is heritable, with an analysis of CNVs that highlights the key role of rare and de novo mutations in the etiology of ASD ( 35 ). Variation-affected gene clusters on networks associated with synaptic transmission, neuronal development, and chromatin regulation ( 36 , 37 ). The identification of the cross-disorder genetic risk factors found by assessing SNP heritability in five psychiatric disorders ( 38 ). Five of the top 10 cited papers in Table 5 focus on genetic variation, suggesting that over the past decade, research has shifted from a general concept of genetic risk to the different types of genetic variations associated with autism.

Simon Baron-Cohen of the Autism Research Center at the University of Cambridge was the most published author between 2011 and 2021. He contributed to the mind-blindness hypothesis of autism, developed the autism spectrum quotient (AQ) screening tool for autism, and focused on gender differences in autism ( 39 – 41 ). There are gender/sex differences in the volume and tissue density of brain regions, including the amygdala, hippocampus, and insula, and the heart-blind hypothesis links emotional recognition in individuals with autism to deficits in the amygdala ( 41 – 43 ). Then, Simon et al. backed up the “extreme male brain” theory of autism in a study of 36,000 autistic individuals aged 16–89 ( 44 ). Recently, an increasing number of studies from different perspectives have focused on how sex/gender differences are related to autism ( 4 , 5 , 45 ). In the future, studies of neural dimorphism in brain development in autism need to be conducted across the lifespan to reduce age-induced biases ( 41 ).

Hotspots and Frontiers

Keyword analysis was a major indicator for research trends and hotspot analysis. This study shows that keywords for autism research include etiological mechanism, clinical characteristics, and intervention characteristics. Genetic, environmental, epigenetic, brain structure, neuropathological, and immunological factors have contributed to studying its etiological mechanism ( 46 , 47 ). The studies on the abnormal cortical development in ASD have reported early brain overgrowth ( 48 ), reduced resting cerebral blood flow in the medial PFC and anterior cingulate ( 49 ), focal disruption of neuronal migration ( 50 ), and transcriptomic alterations in the cerebral cortex of autism ( 51 ). Genomics studies have identified several variants and genes that increase susceptibility to autism, affecting biological pathways related to chromatin remodeling, regulation of neuronal function, and synaptic development ( 51 – 54 ). In addition, many autism-related genes are enriched in cortical glutamatergic neurons, and mutations in the genes encoding these proteins result in neuronal excitation-inhibitory balance ( 51 , 55 ). A recent study using single-cell sequencing of the developing human cerebral cortex found strong cell-type-specific enrichment of noncoding mutations in ASD ( 56 ). Interestingly, genes interact with the environment; some studies have shown that environmental exposure during pregnancy is a risk factor for brain development ( 57 ), and there are changes in DNA methylation in the brains of ASD patients, reflecting an underlying epigenetic dysregulation.

Presently, the diagnosis of ASD is mainly based on symptoms and behaviors, but the disease has a high clinical heterogeneity, and the individual differences between patients are obvious ( 58 ). In this study, the keywords of the intervention cluster show the importance of early individualized intervention. Patient data are multidimensional, and individualized diagnoses could be made at multiple levels, such as age, gender, clinical characteristics, and genetic characteristics ( 59 ). Early individual genetic diagnosis aids clinical evaluation, ranging from chromosomal microarray (CMA) to fragile X genetic testing ( 60 ). However, the results of genetic research cannot guide the treatment. Notably, the treatment of autism is dominated by educational practices and behavioral interventions ( 61 ). Medication may address other co-occurring conditions, such as sleep disturbances, epilepsy, and gastrointestinal dysfunction ( 9 ). Professor Catherine Lord pointed out that the future of autism requires coordinated, large-scale research to develop affordable, individualized, staged assessments and interventions for people with ASD ( 62 ). Professor Baron-Cohen noted that increasing the sample size and collecting data from the same individual multiple times could reduce heterogeneity ( 58 ). In addition, screening for objective and valid biomarkers in the future would help to stratify diagnosis and reduce heterogeneity.

According to the keyword trend analysis of 100 highly cited documents, the genetic risk of autism was determined as the hot focus of research, and immune dysregulation and gut microbiome are the new development frontiers after 2015. Patients with ASD have altered immune function, microglia activation was observed in postmortem brain samples, and increased production of inflammatory cytokines and chemokines was observed in cerebrospinal fluid. The microglia are involved in synaptic pruning, and cytokines also affect neuronal migration and axonal projections ( 63 – 65 ). In addition, abnormal peripheral immune responses during pregnancy might affect the developing brain, increasing likelihood of autism ( 66 ). Several studies have pointed to abnormalities in immune-related genes in the brain and peripheral blood of autistic patients ( 51 , 67 , 68 ). Immune dysfunction is involved in the etiology of ASD and mediates the accompanying symptoms of autism. The patients have multiple immune-related diseases, asthma, allergic rhinitis, Crohn’s disease, and gastrointestinal dysfunction ( 69 – 71 ). Children with frequent gastrointestinal symptoms, such as abdominal pain, gas, constipation, or diarrhea, had pronounced social withdrawal and stereotyped behavior ( 70 – 72 ). Several studies suggested that these autism-related gastrointestinal problems might be related to intestinal microbiota composition ( 72 – 74 ). Accumulating evidence suggested that the microbiota-gut-brain axis influences human neurodevelopment, a complex system involving immune, metabolic, and vagal pathways in which bacterial metabolites directly affect the brain by disrupting the gut and blood–brain barrier ( 75 – 78 ). Fecal samples from children with autism contained high Clostridium species and low Bifidobacterium species ( 79 , 80 ). Probiotics can modulate gut microbiota structure and increase the relative abundance of Bifidobacteria , and clinical studies have shown that supplementation with probiotic strains improves attention problems in children with autism ( 81 , 82 ). Recent clinical trials have shown that microbiota transfer therapy improves gastrointestinal symptoms and autism-like behaviors in children with ASD ( 83 , 84 ).

This scientometric study comprehensively analyzes about a decade of global autism research. Research in the field of autism is increasing, with the United States making outstanding contributions, while neuroscience, genetics, brain imaging studies, or studies of the gut microbiome deepen our understanding of the disorder. The study of the brain-gut axis elucidates the mechanism of immunology in autism, and immunological research may be in the renaissance. The current data serve as a valuable resource for studying ASD. However, the future of autism needs further development. In the future, relevant research should be included for a complete representation of the entire autism population, and further collaboration between individuals, institutions, and countries is expected to accelerate the development of autism research.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary material , further inquiries can be directed to the corresponding authors.

Author contributions

MJ, DZ, JL, and LW conceived and designed the study. MJ, TL, XL, KY, and LZ contributed to data collection and data analysis. MJ wrote the original manuscript. DZ, JL, and LW revised the article and contributed to the final version of the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the Key-Area Research and Development Program of Guangdong Province (2019B030335001) and the National Natural Science Foundation of China (grant numbers 82171537, 81971283, 82071541, and 81730037).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1096769/full#supplementary-material

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Keywords: autism spectrum disorder, bibliometric study, CiteSpace, VOSviewer, research frontiers

Citation: Jiang M, Lu T, Yang K, Li X, Zhao L, Zhang D, Li J and Wang L (2023) Autism spectrum disorder research: knowledge mapping of progress and focus between 2011 and 2022. Front. Psychiatry . 14:1096769. doi: 10.3389/fpsyt.2023.1096769

Received: 16 November 2022; Accepted: 10 April 2023; Published: 25 April 2023.

Reviewed by:

Copyright © 2023 Jiang, Lu, Yang, Li, Zhao, Zhang, Li and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jun Li, [email protected] ; Lifang Wang, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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What Causes Autism? New Research Uncovers a Key Factor in Brain Development

By Texas A&M University College of Medicine July 31, 2022

The findings of this research reveal a significant component in the underlying causes of neural tube birth defects, intellectual disabilities, and autism risk.

Researchers from Texas A&M College of Medicine have provided answers to important questions concerning how the neocortex develops, providing new information about the root causes of intellectual disabilities.

A significant advancement in our understanding of how the brain develops has been accomplished by researchers at Texas A&M University College of Medicine . This new research advances our understanding of how the region of the brain that distinguishes humans from other animals develops and sheds light on what causes intellectual disabilities, such as autism spectrum disorders.

 For many years, scientists have recognized a significant relationship between mammalian intelligence and a thin layer of cells in the neocortex, the region of the brain that governs higher-order processes like cognition, perception, and language. The neocortex’s surface area reflects how highly developed an organism’s mental ability is. For instance, the human neocortex is only around three times thicker than the mouse equivalent. However, the human neocortex has a 1,000-fold larger surface area than that of mice. Autism spectrum disorders and intellectual impairments are among the developmental deficiencies caused by malformations in this region of the brain.

What is unknown is how evolutionary expansion of this section of the brain happens selectively in favor of growing the neocortex’s surface area at the cost of increasing its thickness. An important aspect of this process is how the initial populations of neural stem cells, which serve as the brain’s building blocks, distribute themselves.

“There are many, what we’ll call, individual processing units that are horizontally arranged in the neocortex. The more surface area you have, the more of these processing units you can accommodate,” said Vytas A. Bankaitis, Distinguished Professor at the College of Medicine, E.L. Wehner-Welch Foundation Chair in Chemistry, and co-author of this study, which was published in Cell Reports . “The question is, why is the neocortical surface area so much greater relative to its thickness as one climbs up the mammalian evolutionary tree? Why do neural stem cells spread themselves in a lateral direction as they proliferate and not pile on top of each other?”

This question is key because when the cells do not spread out, but instead pile up, it creates a thicker neocortex with a smaller surface area — a characteristic that has been observed in cases of intellectual disability and even autism.

“One of the most studied genetic causes of intellectual disability is a mutation in a gene that was originally called LIS1,” said Zhigang Xie, assistant professor at the College of Medicine and co-author of the study. “This genetic mutation will cause a smooth brain, which is associated with intellectual disability. And one typical observation is that the neocortex of the patient is thicker than normal. There are also very recent studies that identify common differences in the brain of autism that include abnormally thickened regions of the neocortex in those individuals.”

Scientists have known for some time that as neural stem cells divide, their nuclei move up and down within their anatomical space as a function of the cell cycle, a process called interkinetic nuclear migration. They do so by employing a cytoskeletal network that acts like train tracks with engines that move the nuclei up or down in a closely regulated manner. Although several ideas have been proposed, it remains an enigma why the nuclei move in this way, how this network of train tracks is controlled, and what role interkinetic nuclear migration plays in development of the neocortex.

In their study, Xie and Bankaitis provide answers to these questions.

As for why, Bankaitis explains that when there are so many cells so close together in the embryonic stage of neocortical development, the movement of their nuclei up and down causes opposing upward and downward forces that spreads the dividing neural stem cells out.

“Think about a tube of toothpaste,” Bankaitis said. “If you were to take that toothpaste tube, put it between your hands, push up from the bottom and push down from the top, what would happen? It would flatten and spread out. That’s essentially how this works. You have an upward force and a downward force caused by the movement of the nuclei that spreads these cells out.”

Xie and Bankaitis also demonstrate how the cells do this by linking together several distinct pathways that cooperate to “tell” the newborn neural stem cells where to go.

“I think for the first time, this really puts together molecules and signaling pathways that indicate how this process is controlled and why it would be linked or associated with neurodevelopmental deficiencies,” Bankaitis said. “We have taken a biochemical pathway, linked it to a cell biological pathway, and linked it to a signaling pathway that talks to the nucleus to promote the nuclear behavior that generates a force that develops a complicated brain. It’s now a complete circuit.”

The results of this study uncover an important factor in the underlying causes of autism risk, intellectual disabilities and neural tube birth defects. The new knowledge on the basic principles regulating the shape of the neocortex will also help the design of in vitro brain culture systems that more accurately reflect the developmental processes of interest and improve the prospects for neurological drug development.

“While there might prove to be many reasons why a neocortex thickens instead of spreads, our work provides a new perspective on why patients with autism and intellectual disabilities often display a thicker cortex,” Xie said. “The fact that the LIS1 gene product is a core regulator of nuclear migration, including the interkinetic nuclear migration that we study in this work, supports the conclusions we reach in this paper.”

Reference: “Phosphatidylinositol transfer protein/planar cell polarity axis regulates neocortical morphogenesis by supporting interkinetic nuclear migration” by Zhigang Xie and Vytas A. Bankaitis, 31 May 2022, Cell Reports. DOI: 10.1016/j.celrep.2022.110869

The study was funded by the NIH/ National Institutes of Health and the Robert A Welch Foundation.

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17 comments on "what causes autism new research uncovers a key factor in brain development".

I just wonder how does the thicker neucortex in Humans and other mammals collate to the Âûtistic and Co-morbidity genes that we Neurodiverse persons have and explain brighter hundreds of percent more almost hyperactivity in Right hemisphere, Tempora, Frontal lobes and Amygdala, compared to greyzones and work around in reduced activity left hemisphere and the thousands of Autism Genome Project Autistic, Co-morbidity and mutations in a few million Autistic and Co-morbidity confirmed participants recorded as 1 in 5.8 and 1 in 5.9 in Denmark and Sweden by cottaging of many multiple traits, Co-morbidities and coping mechanisms.

Autism isn’t a disability. If autism is a disability, thing so is womanhood.

Ok, Peter. Once you figure out what causes the disability in those identified autistic then you can make that declaration. Until then, and within the household I exist in, there are strengths in the identity, but in the same vein, there are also several disabling aspects as well. Hence it IS a disability. When people make bold statements like this, they are slowly creating a reality where supports could be taken away to those most profoundly affected since they are trying to sell the idea that “it’s not a disability.”

Tylenol is currently being called out for knowing that their drug causes autism and not releasing those findings.

While plenty of autistic people are disabled I’m not sure we can really say autism is a disability. It’s certainly not an intellectual disability. There is a high co-morbidity with other disorders, some of which are more of a disability than others but there are plenty of autistic people who are no less capable than any autistic person. Sometimes the same traits that appear to be a disability in some situations can be an advantage in others. My son is very sensitive to sound, he gets overwhelmed easily and I can see how and why that’s perceived as a disability. However, I have the same sensitivity and, while it was stressful and difficult in childhood, as an adult I have a great ear for subtle differences in sound. That’s an advantage in music and vocal impressions, it also allows me to identify what my children are doing without looking at them. I know the sound of pretty much every toy and surface. So perhaps suitability to environment varies and it’s not so clear cut as disability/not a disability. This can apply to traits that no one calls disabilities too. Some people love cold weather, I can’t function in cold weather at all but I’m not uncomfortable at 90 degrees. My lack of tolerance to the cold isn’t a disability but it does make me unsuited to a cold environment. In the same way we could say that autistic children who have meltdowns in chaotic environments are simply unsuited to noisier, more urban environments. Without a significant improvement of our understanding of what exactly autism is, how it works, where to draw the line between autism and its comorbidities, I suppose it’s open to debate. As a side note, when someone says “autism isn’t a disability”, it might be worth considering that they could be autistic and not see themselves as disabled, or the parent of an autistic child who doesn’t find the experience disabling. I am autistic and don’t consider myself disabled. I have two children who have been diagnosed with autism, one of whom is non-verbal. Those diagnoses don’t guarantee disability payments in and of themselves in my corner of the world anyway.

“plenty of autistic people who are no less capable than any allistic person.” Autocorrect doesn’t know the word allistic aparently.

How can we trust any research coming out of Texas a&m when they allow such egregious conflicts of interest in their programs?

Doing beef research and taking donations from organizations connected to the beef industry, and then not reporting it in their research?

They better get their house in order or might as well shut down the school.

Reading this make more questions, why does it affect more boys? and why is it that we are seeing so many cases? This finding is great but we need to find out the cause enviro, consumption foods products? We have 2-3% of Canadians are affected by this diagnosis.

My IQ is 135. I have hyperlexia with full reading comprehension. I have read a lot of credible medical literature which states that Autism/ASD is a neurodevelopmental disorder, not an intellectual disorder.

Autism isn’t an intellectual disability. The first paragraph says “… and sheds light on what causes intellectual disabilities, such as autism spectrum disorders”. The rest of the article uses “intellectual disabilities and autism” which accurately reflects the research findings. This needs to be edited as makes the authors appear ignorant to anyone who knows anything about autism.

Try tô find reasons of autism in vaccination.

As someone who can or at least say I am not autistic not that I have been told by a Dr so please read this as a possibly dumb by honest question anyway but my best friend has a son that is autistic or has a form of it possibly we are close and watched him as he grew up and I noticed some of the things about him seems like habits ,disliking change and not understanding sarcasm so I guess my question is was he born autistic because his sister and his brother are not was it in his genes or d.n.a.? Or can children develop autism threw outside factors?

While there may indeed be some truth to this, as I think there is, there is still much about it I am questioning. Yes, this research supposedly provides some possible answers, but there are also quite a few unanswered questions and vital missing pieces of this complicated “intellectual disability” puzzle. Which for the record, is incorrectly titled since Autism is in fact NOT technically considered an intellectual disability, but instead a neurological one. And not even a disability. It’s labeled a disorder. And many people would argue with that. But for time, sanity, and technicality sake, it’s a disorder. Regardless, I wish I had more hope in this but if the people doing this work are comparing and calling Autism the same as intellectual disabilities…well, let’s just say i have my doubts.

This was a great article. Hats off to the team finding these correlations and observations. These are the findings that lead us in directions that hold answers.

It’s so sad to read these comments. Questioning these scientific finding because of the funding channels uses as an o stitution..situation… arbitrarily saying that autism shouldn’t be considered a disability because of personal observations of qualitative factors is mind blowing. It’s as though there is an entire wave of people who are not being taught how anything on the world actually works. Or why. Clearly discernment has left the building.

If one wants to protect the status quo of autism, I just can’t begin to fathom why but thats not important, which is something alot of you could learn, but back to the issue, if you convince the world over that autism should not be looked at as a disabilty then you better take a long hard look at yourself in the mirror and ask yourself a few questions: 1. Do you have any business voicing opinions like that on platforms that are far reaching? Let me translate for the younger crowd… do you have any scientific/educational/vocational credentials that support your words as anything more than an opinion or thought? If so, pipe down. 2. If your message hits and the world over decides it is not a disabilityany more, research will cease. Do I understand the power of change? Have I performed efficacy studies that support making this change or am I only doing this for the fluffy feelings Inside me?

Honestly, I read about all these school shootings and I’m always surprised when I find out the shooter WASNT a teacher.

Good luck to those of you who are unknowingly barking for research, similar to that performed in this article, to stop. You’re the real disability in the world. You’ve convinced us all.

My son was born in 2009. Extra genetic material on line 16, tourette’s syndrome followed at age 3, ADHD, OCD, and lastly behavioral problems. No doctor out of the 20+ doctors we seen knew how to treat or help him. I am sad daily as I had to place him in his father’s care. I have 6 children under 12yo. He would look for any opportunity to get too one of his sister’s and beat them until he seen blood. He would laugh and think it was so cool. I wish I knew what went so wrong.

I am a 73 year old recently retired physician, very successful in my 45 year career. As my brain has gradually reaclimated to “normal” life after 45 years on constant “high alert”, I have noticed a reemergence of intellectual, cognitive and social patterns of function which are very suggestive of ASD, and which were evidently unlearned during my decades of acquired “normal” behavior. Throughout my life I have dealt with often awkward and cringy social abilities. Many professional, personal and romantic relationships suffered from my unique ability to sabotage them. Since I come from a family in which nearly all males of one lineage (my paternal grandfather’s) are clearly on the spectrum, I’ve realized, for the first time that I am as well. A few of these males are/were severely disabled, but much more frequently they are like me — reasonably social but with an awkwardness which is counterbalanced by savant abilities which allow us to reach high levels of mastery in fields like medicine and teaching. All of us seem to have high levels of social justice awareness, which only seems to add to our perceived level of occupational success. It is becoming clear to me, looking back on my family’s four generations of approximately 90% incidence of ASD among the men, that this persistence of a high incidence of ASD would not occur unless the autistic spectrum disorders are a normal variant of human intellectual and social development. In other words, ASD must be normal-ish, must have served some sort of social purpose during the Ice Age, for them to persist this long. It’s not hard to imagine there being an advantage for a tribe to include a member who thinks somewhat like game animals, a la Temple Grandin; or a member like myself who appears to have an ability to see connections between seemingly unrelated abstractions; or a member who sees off-kilter dream-like narrative explanations for disturbing events in the environment — proto- myths and stories. It may be that our abilities are not needed since the evolution of culture, or perhaps these functions have been assumed and performed by new agents within the culture. Whatever, it’s clear to me, at least, that the ASD are not disorders, developmental abberrations or illnesses. Our oddball abilities should be cultivated, while we are taught how to work around our cringiness.

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• v.9(Suppl 1); 2020 Feb

Autism spectrum disorder: definition, epidemiology, causes, and clinical evaluation

Holly hodges.

1 Department of Pediatrics, Baylor College of Medicine and Meyer Center for Developmental Pediatrics, Texas Children’s Hospital, Houston, TX, USA;

Casey Fealko

2 Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA;

Neelkamal Soares

3 Department of Pediatric and Adolescent Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted interests and repetitive behaviors. There have been recent concerns about increased prevalence, and this article seeks to elaborate on factors that may influence prevalence rates, including recent changes to the diagnostic criteria. The authors review evidence that ASD is a neurobiological disorder influenced by both genetic and environmental factors affecting the developing brain, and enumerate factors that correlate with ASD risk. Finally, the article describes how clinical evaluation begins with developmental screening, followed by referral for a definitive diagnosis, and provides guidance on screening for comorbid conditions.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted interests and repetitive behaviors ( 1 ). In 2013, the Diagnostic and Statistical Manual of Mental Disorders —5 th edition (DSM-5) was published, updating the diagnostic criteria for ASD from the previous 4 th edition (DSM-IV) ( Table 1 ) ( 1 , 2 ).

ASD, autism spectrum disorder; SPCD, social (pragmatic) communication disorder.

In DSM-5, the concept of a “spectrum” ASD diagnosis was created, combining the DSM-IV’s separate pervasive developmental disorder (PDD) diagnoses: autistic disorder, Asperger’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS), into one. Rett syndrome is no longer included under ASD in DSM-5 as it is considered a discrete neurological disorder. A separate social (pragmatic) communication disorder (SPCD) was established for those with disabilities in social communication, but lacking repetitive, restricted behaviors. Additionally, severity level descriptors were added to help categorize the level of support needed by an individual with ASD.

This new definition is intended to be more accurate and works toward diagnosing ASD at an earlier age ( 3 ). However, studies estimating the potential impact of moving from the DSM-IV to the DSM-5 have predicted a decrease in ASD prevalence ( 4 , 5 ) and there has been concern that children with a previous PDD-NOS diagnosis would not meet criteria for ASD diagnosis ( 5 - 7 ). There are varying reports estimating the extent of and effects of this change. One study found that with parental report of ASD symptoms alone, the DSM-5 criteria identified 91% of children with clinical DSM-IV PDD diagnoses ( 8 ). However, a systematic review suggests only 50% to 75% of individuals maintain diagnoses ( 9 ) and other studies have also suggested a decreased rate of diagnosis of individuals with ASD under the DSM-5 criteria ( 10 ). Often those who did not meet the requirements were previously classified as high functioning Asperger’s syndrome and PDD-NOS ( 11 , 12 ). Overall, most studies suggest that the DSM-5 provides increased specificity and decreased sensitivity compared to the DSM-IV ( 5 , 13 ); so while those diagnosed with ASD are more likely to have the condition, there is a higher number of children whose ASD diagnosis is missed, particularly older children, adolescents, adults, or those with a former diagnosis of Asperger’s disorder or PDD-NOS ( 14 ). Nevertheless, the number of people who would be diagnosed under the DSM-IV, but not under the new DSM-5 appears to be declining over time, likely due to increased awareness and better documentation of behaviors ( 4 ).

It has yet to be determined how the new diagnosis of SPCD will impact the prevalence of ASD. One study found the new SPCD diagnosis encompasses those individuals who possess subthreshold autistic traits and do not qualify for a diagnosis of ASD, but who still have substantial needs ( 15 ). Furthermore, children who previously met criteria for PDD-NOS under the DSM-IV might now be diagnosed with SPCD.

Epidemiology

The World Health Organization (WHO) estimates the international prevalence of ASD at 0.76%; however, this only accounts for approximately 16% of the global child population ( 16 ). The Centers for Disease Control and Prevention (CDC) estimates about 1.68% of United States (US) children aged 8 years (or 1 in 59 children) are diagnosed with ASD ( 6 , 17 ). In the US, parent-reported ASD diagnoses in 2016 averaged slightly higher at 2.5% ( 18 ). The prevalence of ASD in the US more than doubled between 2000–2002 and 2010–2012 according to Autism and Developmental Disabilities Monitoring Network (ADDM) estimates ( 6 ). Although it may be too early to comment on trends, in the US, the prevalence of ASD has appeared to stabilize with no statistically significant increase from 2014 to 2016 ( 19 ). Changing diagnostic criteria may impact prevalence and the full impact of the DSM-5 diagnostic criteria has yet to be seen ( 17 ).

Insurance mandates requiring commercial plans to cover services for ASD along with improved awareness have likely contributed to the increase in ASD prevalence estimates as well as the increased diagnosis of milder cases of ASD in the US ( 6 , 20 , 21 ). While there was only a modest increase in prevalence immediately after the mandates, there have been additional increases later as health care professionals better understood the regulatory and reimbursement process. The increase in prevalence may also be due to changes in reporting practices. One study in Denmark found the majority of increase in ASD prevalence from 1980–1991 was based on changes of diagnostic criteria and inclusion of outpatient data, rather than a true increase in ASD prevalence ( 21 ).

ASD occurs in all racial, ethnic, and socioeconomic groups, but its diagnosis is far from uniform across these groups. Caucasian children are consistently identified with ASD more often than black or Hispanic children ( 6 ). While the differences appear to be decreasing, the continued discrepancy may be due to stigma, lack of access to healthcare services, and a patient’s primary language being one other than English.

ASD is more common in males ( 22 , 23 ) but in a recent meta-analysis ( 24 ), true male-to-female ratio is closer to 3:1 than the previously reported 4:1, though this study was not done using the DSM-5 criteria. This study also suggested that girls who meet criteria for ASD are at higher risk of not receiving a clinical diagnosis. The female autism phenotype may play a role in girls being misdiagnosed, diagnosed later, or overlooked. Not only are females less likely to present with overt symptoms, they are more likely to mask their social deficits through a process called “camouflaging”, further hindering a timely diagnosis ( 25 ). Likewise, gender biases and stereotypes of ASD as a male disorder could also hamper diagnoses in girls ( 26 ).

Several genetic diagnoses have an increased rate of co-occurring ASD compared to the average population, including fragile X, tuberous sclerosis, Down syndrome, Rett syndrome, among others; however, these known genetic disorders account for a very small amount of overall ASD cases ( 27 - 30 ). Studies of children with sex chromosome aneuploidy describe a specific social functioning profile in males that suggests more vulnerability to autism ( 22 , 23 , 31 , 32 ). With the increased use of chromosomal microarray, several sites (chromosome X, 2, 3, 7, 15, 16, 17, and 22 in particular) have proven to be associated with increased ASD risk ( 28 ).

Other risk factors for ASD include increased parental age and prematurity ( 33 - 35 ). This could be due to the theory that older gametes have a higher probability of carrying mutations which could result in additional obstetrical complications, including prematurity ( 36 ).

ASD is a neurobiological disorder influenced by both genetic and environmental factors affecting the developing brain. Ongoing research continues to deepen our understanding of potential etiologic mechanisms in ASD, but currently no single unifying cause has been elucidated.

Neuropathologic studies are limited, but have revealed differences in cerebellar architecture and connectivity, limbic system abnormalities, and frontal and temporal lobe cortical alterations, along with other subtle malformations ( 28 , 37 , 38 ). A small explorative study of neocortical architecture from young children revealed focal disruption of cortical laminar architecture in the majority of subjects, suggesting problems with cortical layer formation and neuronal differentiation ( 39 ). Brain overgrowth both in terms of cortical size and additionally in terms of increased extra-axial fluid have been described in children with ASD and are areas of ongoing study both in terms of furthering our understanding of its etiology, but also as a potential biomarker ( 40 , 41 ).

Genetic factors play a role in ASD susceptibility, with siblings of patients with ASD carrying an increased risk of diagnosis when compared to population norms, and a much higher, although not absolute, concordance of autism diagnosis in monozygotic twins ( 42 - 44 ).

Genome wide association studies and whole exome sequencing methods have broadened our understanding of ASD susceptibility genes, and learning more regarding the function of these genes can shed light on potential biologic mechanisms ( 45 ). For example candidate genes in ASD include those that play a role in brain development or neurotransmitter function, or genes that affect neuronal excitability ( 46 , 47 ). Many of the genetic defects associated with ASD encode proteins that are relevant at the neuronal synapse or that are involved in activity-dependent changes in neurons, including regulatory proteins such as transcription factors ( 42 , 48 ). Potential “networks” of ASD genetic risk convergence include pathways involved in neurotransmission and neuroinflammation ( 49 ). Transcriptional and splicing dysregulation or alterations in epigenetic mechanisms such as DNA methylation or histone acetylation and modification may play a role ( 42 , 49 - 51 ). A recent study describes 16 newly identified genes associated with ASD that raise new potential mechanisms including cellular cytoskeletal structure and ion transport ( 52 ). Ultimately, ASD remains one of the most genetically heterogeneous neuropsychiatric disorders with rarer de novo and inherited variants in over 700 genes ( 53 ).

While genetics clearly play a role in ASD’s etiology, phenotypic expression of genetic susceptibility remains extremely variable within ASD ( 54 ). Genetic risk may be modulated by prenatal, perinatal, and postnatal environmental factors in some patients ( 35 ). Prenatal exposure to thalidomide and valproic acid have been reported to increase risk, while studies suggest that prenatal supplements of folic acid in patients exposed to antiepileptic drugs may reduce risk ( 55 - 57 ). Research has not confirmed if a small positive trial of folinic acid in autism can be used to recommend supplementation more broadly ( 58 ). Advanced maternal and paternal age have both been shown to have an increased risk of having a child with ASD ( 59 ). Maternal history of autoimmune disease, such as diabetes, thyroid disease, or psoriasis has been postulated, but study results remain mixed ( 60 , 61 ). Maternal infection or immune activation during pregnancy is another area of interest and may be a potential risk factor according to recent investigations ( 62 - 65 ). Both shorter and longer inter-pregnancy intervals have also been reported to increase ASD risk ( 66 ). Infants born prematurely have been demonstrated to carry a higher risk for ASD in addition to other neurodevelopmental disorders ( 34 ). In a prior epidemiologic review, obstetric factors including uterine bleeding, caesarian delivery, low birthweight, preterm delivery, and low Apgar scores were reported to be the few factors more consistently associated with autism ( 67 ). A recent meta-analysis reported several pre, peri and postnatal risk factors that resulted in an elevated relative risk of ASD in offspring ( 35 ), but also revealed significant heterogeneity, resulting in an inability to make true determination regarding the importance of these factors.

Despite the hysteria surrounding the now retracted Lancet article first published in 1998, there is no evidence that vaccines, thimerosal, or mercury is associated with ASD ( 68 - 70 ). In the largest single study to date, there was not an increased risk after measles/mumps/rubella (MMR) vaccination in a nationwide cohort study of Danish children ( 70 ).

Ultimately, research continues to reveal factors that correlate with ASD risk, but no causal determinations have been made. This leaves much room for discovery with investigators continuing to elucidate new variants conveying genetic risk, or new environmental correlates that require further study ( 52 ).

Evaluation in ASD begins with screening of the general pediatric population to identify children at-risk or demonstrating signs suggestive of ASD, following which a diagnostic evaluation is recommended. The American Academy of Pediatrics (AAP) guidelines recommend developmental surveillance at 9, 15 and 30 months well child visits and autism specific screening at 18 months and again at 24 or 30 months ( 28 , 71 ). Early red flags for ASD include poor eye contact, poor response to name, lack of showing and sharing, no gesturing by 12 months, and loss of language or social skills. Screening tools for ASD in this population include the Modified Checklist for Autism in Toddlers, Revised, with Follow-up (M-CHAT-R/F) and Survey of Wellbeing of Young Children (SWYC) ( 72 , 73 ). Red flags in preschoolers may include limited pretend play, odd or intensely focused interests, and rigidity. School age children may demonstrate concrete or literal thinking, have trouble understanding emotions, and may even show an interest in peers but lack conversational skills or appropriate social approach. If there is suspicion of ASD in these groups, screening tools available include the Social Communication Questionnaire (SCQ), Social Responsiveness Scale (SRS), and Autism Spectrum Screening Questionnaire (ASSQ) ( 74 - 76 ).

If concerns are raised at screening, primary care clinicians are recommended to refer the child to early intervention if less than 3 years of age or to the public school system for psychoeducational evaluation in order to establish an individual education program (IEP) if the child is three years of age or older. Clinicians should additionally refer the child to a specialist (pediatric neurologist, developmental-behavioral pediatrician, child psychiatrist, licensed child psychologist) for a definitive diagnosis and comprehensive assessment ( 71 ). A comprehensive assessment should include a complete physical exam, including assessment for dysmorphic features, a full neurologic examination with head circumference, and a Wood’s lamp examination of the skin. A parent interview, collection of any outside informant observations, and a direct clinician observation of the child’s current cognitive, language, and adaptive functioning by a clinician experienced with ASD should be components of this comprehensive assessment. ( 28 , 71 , 77 , 78 ).

Additionally, primary care clinicians need to be aware of (and evaluate for) potential co-occurring conditions in children with ASD. According to a surveillance study of over 2,000 children with ASD, 83% had an additional developmental diagnosis, 10% had at least one psychiatric diagnosis, and 16% at least one neurologic diagnosis ( 79 ). In the past, rates of co-morbid intellectual disability (ID) in patients with ASD were reported from 50% to 70%, with the most recent CDC estimate reported at 31.0% (26.7% to 39.4%) with ID defined as intelligence quotient (IQ) ≤70 ( 6 , 80 ). Other common co-occurring medical conditions include gastrointestinal (GI) disorders, including dietary restrictions and food selectivity, sleep disorders, obesity, and seizures ( 81 - 84 ). Studies using electronic health record (EHR) analysis revealed prevalence of epilepsy ~20% and GI disorders [without inflammatory bowel disease (IBD)] at 10–12% ( 82 ). Epilepsy has been shown to have higher prevalence rates in ASD with comorbid ID and medical disorders of increased risk such as tuberous sclerosis complex (TSC) ( 85 - 87 ). GI disorders or GI symptomatology, including diarrhea, constipation, restrictive eating, or reflux, have been shown to be prominent in ASD across multiple studies ( 81 , 82 , 88 , 89 ). Sleep problems have been reported to occur in anywhere from 50% to 73% of patients with ASD with variation in prevalence dependent on the definition of sleep symptoms or the measurement tool used ( 90 - 92 ). Rates of overweight and obesity in ASD are reported to be roughly 33% and 18% respectively, higher than rates in typically developing children ( 81 - 84 , 93 ).

Other behavioral or psychiatric co-occurring conditions in ASD include anxiety, attention deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder, and mood disorders or other disruptive behavior disorders ( 81 ). Rates of co-occurring ADHD are reported anywhere from 25% to 81% ( 81 , 94 ). A recent meta-analysis of 30 studies measuring rates of anxiety and 29 studies measuring rates of depression reported a high degree of heterogeneity from the current literature, but stated pooled lifetime prevalence for adults with ASD to be 42% for any anxiety disorder and 37% for any depressive disorder, though the use of self-report measures and the presence of ID could influence estimates ( 95 ). In children with ASD seeking treatment, the rate of any anxiety disorder was found to be similar at 42% and in addition this study reported co-morbid oppositional defiant disorder at a rate of 46% and mood disorders at 8%, with 66% of the sample of over 600 patients having more than one co-occurring condition ( 94 ).

Currently no clear ASD biomarkers or diagnostic measures exist, and the diagnosis is made based on fulfillment of descriptive criteria. In light of a relatively high yield in patients with ASD, clinical genetic testing is recommended and can provide information regarding medical interventions or work up that might be necessary and help with family planning ( 96 ). The American College of Medical Genetics and Genomics (ACMGG) guidelines currently recommend chromosomal microarray for all children, fragile X testing in males, and additional gene sequencing, including PTEN and MECP2 , in certain patients as first tier genetic testing in the work up of ASD ( 97 ). High resolution G-banded karyotype, once recommended for all patients with ASD, is no longer routinely indicated based on recent consensus recommendations, but might still be performed in patients with a family or reproductive history suggestive of chromosomal rearrangements or specific syndromes such as sex chromosome anomalies or Trisomy 21 ( 96 - 98 ). Several professional societies recommend genetic testing for ASD, including the American Academy of Neurology, the AAP, ACMGG, and the American Academy of Child and Adolescent Psychiatry, and a child may require further referral to a geneticist and/or genetic counselor, depending on results of testing ( 25 , 28 , 97 , 99 ). As the field of genetics continues to advance rapidly, recent publications suggest whole exome sequencing may become the preferred method for clinical genetic testing in individuals with ASD ( 100 , 101 ).

Aside from genetic testing, no other laboratory work up is routinely recommended for every patient with a diagnosis of ASD. However, further evaluation may be appropriate for patients with particular findings or risk factors. Metabolic work-up should be considered in patients with any of the following concerning symptoms or signs: a history of clear developmental regression including loss or plateau of motor skills; hypotonia; recurrent episodes of vomiting, lethargy or hypoglycemia; microcephaly or poor growth; concern for other organ involvement; coarse features; or concern for seizures or ataxia. Based on the patient’s history and presentation, components of a metabolic laboratory evaluation could include complete blood count (CBC), liver and renal function tests, lactate, pyruvate, carnitine, amino acids, an acylcarnitine profile, urine organic acids and/or urine glycosaminoglycans ( 97 , 102 ). Children with a history of pica should have a lead level measured ( 28 , 103 ). In a child with significantly restricted food intake, one should consider a laboratory evaluation of nutritional status. Sleep symptoms may warrant a referral for a possible sleep study, and if restless sleep symptoms are present, an evaluation for iron deficiency is not unreasonable, particularly if dietary rigidity limits iron intake ( 104 ).

Neuroimaging is not routinely recommended for every patient with ASD ( 28 , 99 ), but may be appropriate in patients with a suspicion for TSC or other neurocutaneous disorders, microcephaly, or an abnormal neurologic exam (spasticity, severe hypotonia, unilateral findings). Patients with suspected seizures should have an electroencephalography (EEG) obtained ( 102 ). If accessible, it might be appropriate to immediately refer children with concern for further genetic, metabolic or neurologic conditions to a specialist who can then obtain and interpret the aforementioned testing. At this time there is inadequate evidence to recommend routine testing for celiac disease, immunologic or neurochemical markers, mitochondrial disorders, allergy testing, hair analysis, intestinal permeability studies, erythrocyte glutathione peroxidase studies, stool analysis, urinary peptides or vitamin and mineral deficiencies without a history of severe food selectivity.

ASD is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted interests and repetitive behaviors. Recent changes to the diagnostic criteria occurred with the transition to the new diagnostic manual (DSM-5) and will likely impact prevalence, which currently stands at 1 in 59 children in the US. ASD is a neurobiological disorder influenced by both genetic and environmental factors affecting the developing brain. Research continues to reveal factors that correlate with ASD risk and these findings may guide further etiologic investigation, but no final causal pathway has been elucidated. Clinical evaluation begins with developmental screening of the general pediatric population to identify at-risk children, followed by referral to a specialist for a definitive diagnosis and comprehensive neuropsychological assessment. Children with ASD should also be screened for common co-morbid diagnoses. While no clear biomarkers or diagnostic measures exist, clinical genetic testing is recommended as part of the initial medical evaluation. Further medical work up or subspecialist referrals may be pursued based on specific patient characteristics.

Acknowledgments

Funding: None.

Ethical Statement : The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflicts of Interest : The authors have no conflicts of interest to declare.

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• Published: 16 January 2020

Autism spectrum disorder

• Catherine Lord 1 ,
• Traolach S. Brugha 2 ,
• Tony Charman 3 ,
• James Cusack 4 ,
• Guillaume Dumas 5 ,
• Thomas Frazier 6 ,
• Emily J. H. Jones 7 ,
• Rebecca M. Jones 8 , 9 ,
• Andrew Pickles 3 ,
• Matthew W. State 10 ,
• Julie Lounds Taylor 11 &
• Jeremy Veenstra-VanderWeele 12  

Nature Reviews Disease Primers volume  6 , Article number:  5 ( 2020 ) Cite this article

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• Autism spectrum disorders
• Cognitive neuroscience
• Paediatrics

Autism spectrum disorder is a construct used to describe individuals with a specific combination of impairments in social communication and repetitive behaviours, highly restricted interests and/or sensory behaviours beginning early in life. The worldwide prevalence of autism is just under 1%, but estimates are higher in high-income countries. Although gross brain pathology is not characteristic of autism, subtle anatomical and functional differences have been observed in post-mortem, neuroimaging and electrophysiological studies. Initially, it was hoped that accurate measurement of behavioural phenotypes would lead to specific genetic subtypes, but genetic findings have mainly applied to heterogeneous groups that are not specific to autism. Psychosocial interventions in children can improve specific behaviours, such as joint attention, language and social engagement, that may affect further development and could reduce symptom severity. However, further research is necessary to identify the long-term needs of people with autism, and treatments and the mechanisms behind them that could result in improved independence and quality of life over time. Families are often the major source of support for people with autism throughout much of life and need to be considered, along with the perspectives of autistic individuals, in both research and practice.

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Acknowledgements

The authors thank J. McCauley, S. Gaspar, K. Byrne and A. Holbrook from UCLA for help with manuscript preparation. S. Tromans is thanked for his updated review of the epidemiology literature. We recognize the many investigators who contributed research that we cannot cite due to space limitations. C.L. is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHHD; R01 HD081199), the National Institute of Mental Health (NIMH; R01MH081873-01A1) and the Simons Foundation. T.S.B. is supported by grants from the Health and Social Care Information Centre, Leeds, and the National Institute for Health Research (NIHR HTA; grant ref. NIHR127337). T.C. is supported by grants from Innovative Medicines Initiative 2 (no. 777394), the Medical Research Council (MRC; grants MR/K021389/1) and the NIHR (grant 13/119/18). J.C. is funded by Autistica. G.D. is supported by the Institut Pasteur. T.F. is supported by the Autism Speaks Foundation. E.J.H.J. is supported by grants from the Economic and Social Research Council (ESRC; ES/R009368/1), the Innovative Medicines Initiative 2 (no. 777394), the MRC (MR/K021389/1) and the Simons Foundation (609081). R.M.J. acknowledges the Mortimer D. Sackler Family and the NIMH (R01MH114999). J.L.T. is supported by grants from the FAR fund and the NIMH (R34 MH104428, R03 MH 112783 and R01 MH116058). A.P. is partially supported by the Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London and the NIHR (NF-SI-0617-10120). M.W.S. is supported by the National Institutes of Health (NIH; MH106934, MH109901, MH110928, MH116487 MH102342, MH111662, MH105575 and MH115747), the Overlook International Foundation and the Simons Foundation. J.V.-V. is supported by the NIH (MH016434 and MH094604), the Simons Foundation and the New York State Psychiatric Institute. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.

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Catherine Lord

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Traolach S. Brugha

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Tony Charman & Andrew Pickles

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All authors read and edited the full document. Introduction (C.L.), Epidemiology (T.S.B.), Mechanisms/pathophysiology (M.W.S., G.D., R.M.J., T.C. and E.J.H.J.), Diagnosis, screening and prevention (T.C., E.J.H.J. and T.S.B.), Management (T.S.B., T.C., E.J.H.J., J.L.T. and J.V.-V.), Quality of life (J.L.T., J.C. and T.F.), Outlook (C.L. and A.P.), Overview of Primer (C.L.).

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C.L. acknowledges the receipt of royalties from Western Psychological Services for the sale of the Autism Diagnostic Interview-Revised (ADIR), the Autism Diagnostic Observation Schedule (ADOS) and the Social Communication Questionnaire (SCQ). T.S.B. has received royalties from Cambridge University Press and Oxford University Press. T.C. has served as a consultant to F. Hoffmann-La Roche. and has received royalties from Guilford Publications and Sage Publications. T.F. has received federal funding research support from, acted as a consultant to, received travel support from, and/or received a speaker’s honorarium from the Brain and Behaviour Research Foundation, Bristol-Myers Squibb, the Cole Family Research Fund, EcoEos, Forest Laboratories, Ingalls Foundation, IntegraGen, Kugona LLC, the National Institutes of Health, Roche Pharma, Shire Development and the Simons Foundation. J.L.T. receives compensation from Sage Publishers for editorial work. A.P. receives royalties from Imperial College Press, Oxford University Press and Western Psychological Services. M.W.S. serves on the scientific advisory boards and has stock or stock options for Arett Pharmaceuticals and BlackThorn Therapeutics. J.V.-V. has consulted or served on an advisory board for Novartis, Roche Pharmaceuticals and SynapDx, has received research funding from Forest, Novartis, Roche Pharmaceuticals, Seaside Therapeutics, SynapDx, and has received an editorial stipend from Springer and Wiley. All other authors declare no competing interests.

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Lord, C., Brugha, T.S., Charman, T. et al. Autism spectrum disorder. Nat Rev Dis Primers 6 , 5 (2020). https://doi.org/10.1038/s41572-019-0138-4

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• Signs and Symptoms
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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.

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Autism Spectrum Disorder

What is asd.

Autism spectrum disorder (ASD) is a neurological and developmental disorder that affects how people interact with others, communicate, learn, and behave. Although autism can be diagnosed at any age, it is described as a “developmental disorder” because symptoms generally appear in the first 2 years of life.

According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) , a guide created by the American Psychiatric Association that health care providers use to diagnose mental disorders, people with ASD often have:

• Difficulty with communication and interaction with other people
• Restricted interests and repetitive behaviors
• Symptoms that affect their ability to function in school, work, and other areas of life

Autism is known as a “spectrum” disorder because there is wide variation in the type and severity of symptoms people experience.

People of all genders, races, ethnicities, and economic backgrounds can be diagnosed with ASD. Although ASD can be a lifelong disorder, treatments and services can improve a person’s symptoms and daily functioning. The American Academy of Pediatrics recommends that all children receive screening for autism. Caregivers should talk to their child’s health care provider about ASD screening or evaluation.

What are the signs and symptoms of ASD?

The list below gives some examples of common types of behaviors in people diagnosed with ASD. Not all people with ASD will have all behaviors, but most will have several of the behaviors listed below.

Social communication / interaction behaviors may include:

• Making little or inconsistent eye contact
• Appearing not to look at or listen to people who are talking
• Infrequently sharing interest, emotion, or enjoyment of objects or activities (including infrequent pointing at or showing things to others)
• Not responding or being slow to respond to one’s name or to other verbal bids for attention
• Having difficulties with the back and forth of conversation
• Often talking at length about a favorite subject without noticing that others are not interested or without giving others a chance to respond
• Displaying facial expressions, movements, and gestures that do not match what is being said
• Having an unusual tone of voice that may sound sing-song or flat and robot-like
• Having trouble understanding another person’s point of view or being unable to predict or understand other people’s actions
• Difficulties adjusting behaviors to social situations
• Difficulties sharing in imaginative play or in making friends

Restrictive / repetitive behaviors may include:

• Repeating certain behaviors or having unusual behaviors, such as repeating words or phrases (a behavior called echolalia)
• Having a lasting intense interest in specific topics, such as numbers, details, or facts
• Showing overly focused interests, such as with moving objects or parts of objects
• Becoming upset by slight changes in a routine and having difficulty with transitions
• Being more sensitive or less sensitive than other people to sensory input, such as light, sound, clothing, or temperature

People with ASD may also experience sleep problems and irritability.

People on the autism spectrum also may have many strengths, including:

• Being able to learn things in detail and remember information for long periods of time
• Being strong visual and auditory learners
• Excelling in math, science, music, or art

What are the causes and risk factors for ASD?

Researchers don’t know the primary causes of ASD, but studies suggest that a person’s genes can act together with aspects of their environment to affect development in ways that lead to ASD. Some factors that are associated with an increased likelihood of developing ASD include:

• Having a sibling with ASD
• Having older parents
• Having certain genetic conditions (such as Down syndrome or Fragile X syndrome)
• Having a very low birth weight

How is ASD diagnosed?

Health care providers diagnose ASD by evaluating a person’s behavior and development. ASD can usually be reliably diagnosed by age 2. It is important to seek an evaluation as soon as possible. The earlier ASD is diagnosed, the sooner treatments and services can begin.

Diagnosis in young children

Diagnosis in young children is often a two-stage process.

Stage 1: General developmental screening during well-child checkups

Every child should receive well-child check-ups with a pediatrician or an early childhood health care provider. The American Academy of Pediatrics recommends that all children receive screening for developmental delays at their 9-, 18-, and 24- or 30-month well-child visits, with specific autism screenings at their 18- and 24-month well-child visits. A child may receive additional screening if they have a higher likelihood of ASD or developmental problems. Children with a higher likelihood of ASD include those who have a family member with ASD, show some behaviors that are typical of ASD, have older parents, have certain genetic conditions, or who had a very low birth weight.

Considering caregivers’ experiences and concerns is an important part of the screening process for young children. The health care provider may ask questions about the child’s behaviors and evaluate those answers in combination with information from ASD screening tools and clinical observations of the child. Read more about screening instruments   on the Centers for Disease Control and Prevention (CDC) website.

If a child shows developmental differences in behavior or functioning during this screening process, the health care provider may refer the child for additional evaluation.

Stage 2: Additional diagnostic evaluation

It is important to accurately detect and diagnose children with ASD as early as possible, as this will shed light on their unique strengths and challenges. Early detection also can help caregivers determine which services, educational programs, and behavioral therapies are most likely to be helpful for their child.

A team of health care providers who have experience diagnosing ASD will conduct the diagnostic evaluation. This team may include child neurologists, developmental pediatricians, speech-language pathologists, child psychologists and psychiatrists, educational specialists, and occupational therapists.

The diagnostic evaluation is likely to include:

• Medical and neurological examinations
• Assessment of the child’s cognitive abilities
• Assessment of the child’s language abilities
• Observation of the child’s behavior
• An in-depth conversation with the child’s caregivers about the child’s behavior and development
• Assessment of age-appropriate skills needed to complete daily activities independently, such as eating, dressing, and toileting

Because ASD is a complex disorder that sometimes occurs with other illnesses or learning disorders, the comprehensive evaluation may include:

• Blood tests
• Hearing test

The evaluation may lead to a formal diagnosis and recommendations for treatment.

Diagnosis in older children and adolescents

Caregivers and teachers are often the first to recognize ASD symptoms in older children and adolescents who attend school. The school’s special education team may perform an initial evaluation and then recommend that a child undergo additional evaluation with their primary health care provider or a health care provider who specialize in ASD.

A child’s caregivers may talk with these health care providers about their child’s social difficulties, including problems with subtle communication. For example, some children may have problems understanding tone of voice, facial expressions, or body language. Older children and adolescents may have trouble understanding figures of speech, humor, or sarcasm. They also may have trouble forming friendships with peers.

Diagnosis in adults

Diagnosing ASD in adults is often more difficult than diagnosing ASD in children. In adults, some ASD symptoms can overlap with symptoms of other mental health disorders, such as anxiety disorder or attention-deficit/hyperactivity disorder (ADHD).

Adults who notice signs of ASD should talk with a health care provider and ask for a referral for an ASD evaluation. Although evaluation for ASD in adults is still being refined, adults may be referred to a neuropsychologist, psychologist, or psychiatrist who has experience with ASD. The expert will ask about:

• Social interaction and communication challenges
• Sensory issues
• Repetitive behaviors
• Restricted interests

The evaluation also may include a conversation with caregivers or other family members to learn about the person’s early developmental history, which can help ensure an accurate diagnosis.

Receiving a correct diagnosis of ASD as an adult can help a person understand past challenges, identify personal strengths, and find the right kind of help. Studies are underway to determine the types of services and supports that are most helpful for improving the functioning and community integration of autistic transition-age youth and adults.

What treatment options are available for ASD?

Treatment for ASD should begin as soon as possible after diagnosis. Early treatment for ASD is important as proper care and services can reduce individuals’ difficulties while helping them build on their strengths and learn new skills.

People with ASD may face a wide range of issues, which means that there is no single best treatment for ASD. Working closely with a health care provider is an important part of finding the right combination of treatment and services.

A health care provider may prescribe medication to treat specific symptoms. With medication, a person with ASD may have fewer problems with:

• Irritability
• Repetitive behavior
• Hyperactivity
• Attention problems
• Anxiety and depression

Read more about the latest medication warnings, patient medication guides, and information on newly approved medications at the Food and Drug Administration (FDA) website  .

Behavioral, psychological, and educational interventions

People with ASD may be referred to a health care provider who specializes in providing behavioral, psychological, educational, or skill-building interventions. These programs are often highly structured and intensive, and they may involve caregivers, siblings, and other family members. These programs may help people with ASD:

• Learn social, communication, and language skills
• Reduce behaviors that interfere with daily functioning
• Increase or build upon strengths
• Learn life skills for living independently

Other resources

Many services, programs, and other resources are available to help people with ASD. Here are some tips for finding these additional services:

• Contact your health care provider, local health department, school, or autism advocacy group to learn about special programs or local resources.
• Find an autism support group. Sharing information and experiences can help people with ASD and their caregivers learn about treatment options and ASD-related programs.
• Record conversations and meetings with health care providers and teachers. This information may help when it’s time to decide which programs and services are appropriate.
• Keep copies of health care reports and evaluations. This information may help people with ASD qualify for special programs.

How can I find a clinical trial for ASD?

Clinical trials are research studies that look at new ways to prevent, detect, or treat diseases and conditions. The goal of clinical trials is to determine if a new test or treatment works and is safe. Although individuals may benefit from being part of a clinical trial, participants should be aware that the primary purpose of a clinical trial is to gain new scientific knowledge so that others may be better helped in the future.

Researchers at NIMH and around the country conduct many studies with patients and healthy volunteers. We have new and better treatment options today because of what clinical trials uncovered years ago. Be part of tomorrow’s medical breakthroughs. Talk to your health care provider about clinical trials, their benefits and risks, and whether one is right for you.

To learn more or find a study, visit:

• NIMH’s Clinical Trials webpage : Information about participating in clinical trials
• Clinicaltrials.gov: Current Studies on ASD  : List of clinical trials funded by the National Institutes of Health (NIH) being conducted across the country

Where can I learn more about ASD?

Free brochures and shareable resources.

• Autism Spectrum Disorder : This brochure provides information about the symptoms, diagnosis, and treatment of ASD. Also available  en español .
• Digital Shareables on Autism Spectrum Disorder : Help support ASD awareness and education in your community. Use these digital resources, including graphics and messages, to spread the word about ASD.

Federal resources

• Eunice Kennedy Shriver National Institute of Child Health and Human Development  
• National Institute of Neurological Disorders and Stroke  
• National Institute on Deafness and Other Communication Disorders  
• Centers for Disease Control and Prevention   (CDC)
• Interagency Autism Coordinating Committee  
• MedlinePlus   (also available en español  )

Research and statistics

• Science News About Autism Spectrum Disorder : This NIMH webpage provides press releases and announcements about ASD.
• Research Program on Autism Spectrum Disorders : This NIMH program supports research focused on the characterization, pathophysiology, treatment, and outcomes of ASD and related disorders.
• Statistics: Autism Spectrum Disorder : This NIMH webpage provides information on the prevalence of ASD in the U.S.
• Data & Statistics on Autism Spectrum Disorder   : This CDC webpage provides data, statistics, and tools about prevalence and demographic characteristics of ASD.
• Autism and Developmental Disabilities Monitoring (ADDM) Network   : This CDC-funded program collects data to better understand the population of children with ASD.
• Biomarkers Consortium - The Autism Biomarkers Consortium for Clinical Trials (ABC-CT)   : This Foundation for the National Institutes of Health project seeks to establish biomarkers to improve treatments for children with ASD.

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What are the treatments for autism?

There is currently no one standard treatment for autism spectrum disorder (ASD).

But there are many ways to help minimize the symptoms and maximize abilities. People who have ASD have the best chance of using all of their abilities and skills if they receive appropriate therapies and interventions.

The most effective therapies and interventions are often different for each person. However, most people with ASD respond best to highly structured and specialized programs. 1 In some cases, treatment can greatly reduce symptoms and help people with autism with daily activities.

Research shows that early diagnosis and interventions, such as during preschool or before, are more likely to have major positive effects on symptoms and later skills. Read more about early interventions for autism.

Because there can be overlap in symptoms between ASD and other disorders, such as attention deficit hyperactivity disorder (ADHD), 2 it's important that treatment focus on a person's specific needs, rather than the diagnostic label.

Select the links for more information on each type of treatment for ASD.

• Behavioral management therapy
• Cognitive behavior therapy
• Early intervention
• Educational and school-based therapies
• Joint attention therapy
• Medication treatment
• Nutritional therapy
• Occupational therapy
• Parent-mediated therapy
• Physical therapy
• Social skills training
• Speech-language therapy

If you have a question about treatment, talk to a health care provider who specializes in caring for people with ASD. These resources have more information about treatments for autism:

• The Centers for Disease Control and Prevention describes some treatment options. http://www.cdc.gov/ncbddd/autism/treatment.html
• National Institute of Mental Health. (2011). A parent's guide to autism spectrum disorder. Retrieved March 8, 2012, from http://www.nimh.nih.gov/health/publications/a-parents-guide-to-autism-spectrum-disorder/index.shtml
• Kotte, A., Joshi, G., Fried, R., Uchida, M., Spencer, A., Woodworth, K. Y., et al. (2013). Autistic traits in children with and without ADHD. Pediatrics, 132 (3), e612–e622.