Autism Updates: ASF Goes to INSAR

Written by staff and the SAB of the Autism Science Foundation

COVID Recovery Was Slow, But Scientific Progress Continues

After two grueling pandemic years, 2022 saw a return to quasi-normalcy in both the world at large and in the world of autism research. Although the pandemic was incredibly challenging for autism families and researchers, the pivot to telehealth led to advances in online autism diagnoses, mental health supports, and interventions that will likely benefit autistic people across the globe for years to come.

Autism scientists working in diverse areas of research made important strides this year and continued to gain valuable insights into every facet of autism. They also identified more effective ways to support people on the spectrum. Researchers developed a better understanding of the unique needs and priorities of specific groups of autistic people, better-defined links between biological mechanisms and behavior, and disparities in autism diagnosis and treatment.

This work was only possible because of families like yours: You actively participated in important research studies. You agreed to have your data shared with others. You donated. You advocated. Your U.S. tax dollars supported $100 million of NIH grants funded in 2022. 

Autism science simply cannot progress without your continued partnership. Earlier this year, ASF launched a “Participate in Research” directory to match families with research studies that meet your needs and interests. Many of these studies offer compensation, and can also provide valuable information and resources to aid your family member. The goal is to use the information gleaned from research to improve the real lives of real people, both now and in the future.

Here’s a little bit of what 2022 taught us.

Early identification leads to earlier diagnosis, but diagnosis happens at all ages

• Developmental milestones are skills that most children reach at a certain age and are used by healthcare providers to track progress. This year, the CDC updated these milestones to track what 75% of children can do by certain ages, rather than 50%, causing some pushback. In addition, the CDC added new time points as well as markers that might predict an autism diagnosis.¹
• In autism, reaching developmental milestones can be delayed from months to years. Delays are often more severe and variable in those with co-occurring intellectual disability and a rare genetic variant. New research reinforced the need to focus on milestones and the importance of early intervention.: If you notice your infant is struggling with new skills, tell your healthcare provider.²
• Language skills in infants are an important predictor of an ASD diagnosis. Recent work from the ASF-supported Baby Siblings Research Consortium (BSRC) showed that maternal education levels and early gestures are important predictors of these language skills, suggesting markers for intervention.³
• Researchers have suggested that early behaviors that are predictive of a later diagnosis may be part of a larger “developmental cascade,” where, for example, the trajectory from laying to sitting to language may be disrupted. These are intertwined behavioral and neurobiological networks that affect how a person with autism functions.⁴
• There are now multiple biomarkers under investigation. Some are better than others at not just autism diagnosis, but the response to intervention.⁵ In the future, they can be used to promote earlier diagnosis and more objective measures of the effectiveness of interventions.

Key takeaways: Parents and clinicians should monitor developmental milestones early in life. Early signs are not a substitute for a diagnosis, but some supports and interventions can be provided that allow for an improvement of trajectories across the lifespan.

Parent-mediated interventions and training – they work!

• A review of 30 studies showed promising results from parent-mediated interventions, but improvements in studies are still needed.⁶
• Parent-mediated interventions can be used for teaching everything from core autism symptoms to self-care like tooth brushing.⁷
• Autism interventions can and should be customized to culture and race.^8,9
• Some parent-mediated interventions have been tested successfully in a hybrid format, leading the way for others to investigate their effect on parent and child outcomes.¹⁰
• While some have suggested parents only recognize the weaknesses in their children, recent research strongly notes that parents know their child’s strengths and use those strengths to help support their family.  Educators also note these strengths in the classroom.^11,12
• Siblings play an important role in the outcome of autistic individuals, while they also experience unique challenges themselves.^13,14

Key takeaways: Parents and caregivers often feel helpless when they are concerned about their child’s development and are facing long waiting lists for services. New research shows that providing support is beneficial for both the parents and the child outcome, and elevates strengths while mitigating support challenges. Further research should continue to explore the role of sibling relationships and support.

The brain has a distinct “signature” and sensory issues are on the front line

• One type of immune cell of the brain called the microglia has been known to affect cell communication, shape, and number. Researchers have now determined when and where these cells are expressed during development, laying the foundation for research into a critical brain cell type.¹⁷

• The greatest differences in gene expression in the brain are in sensory areas like the visual cortex.¹⁵ This may explain the almost universal problems in sensory processing that autistic individuals experience, and why sensory problems are so common in ASD.¹⁸
• The visual area, specifically the occipital cortex, was also enlarged at young ages, more so in kids who have siblings with a diagnosis, demonstrating that genetic heritability plays a role in brain activity involved in sensory processing in families.¹⁹
• A new marker of sensory processing was detected: differences in the activity of a neurotransmitter called GABA. GABA commonly slows down the activity of brain cells, which is important when they are too active, indicating this neurotransmitter is critical for sensory processing. Changing the activity of GABA neurons can alleviate sensory problems in autistic individuals.²⁰
• In addition, changes in the thickness of different cortical regions may influence sensory responses, depending on whether there is overstimulation or understimulation.²¹
• Another brain region called the amygdala may relate to anxiety in autistic people. Certain areas of the amygdala are different in size,²² and can explain variability in anxiety.²³  There is also disruption in connectivity from the amygdala to outside regions,²⁴ which may also explain how anxiety interacts with autism features.
• Rather than examining one autism feature at a time, it seems that ability to make gains or show potential for change over time is correlated to differences in brain structure. Markers of change over time are also linked to genes associated with ASD.²⁵ Targets of intervention based on biological markers may need to focus on sensitivity to change rather than a specific number on an instrument per se.
• The use of biological tools has increased this year. These tools include induced pluripotent stem cells (IPSCs) and organoids that are based on cells from individuals with different forms of ASD. Studies have looked at different types of autism (idiopathic and genetically-based) and identified creation of new brain cells as a common biological mechanism.²⁶ New studies also used novel tools to improve the validity of these cell-based systems.²⁷
• Animal models can be used to identify mechanisms by which genes and environmental factors exert their influence over behavior. Right now, there are hundreds of animal models of ASD, but not all of them are used appropriately to understand ASD. The ability of the model to recapitulate both the biology and behavior involved in ASD is essential.²⁸

Key takeaways: While different brain regions are specialized in their function, they interconnect and turn on and off in synchrony. Researchers need better models of human neurobiology, including better animal models, to understand the core and associated autism features, from sensory dysfunction to GI issues. If you want to learn more about research involving the brains of people with autism, sign up for more information at Autism BrainNet.

Genetic markers start to explain phenotype

• The presence of rare genetic variants and common variants tend to funnel people into groups defined by intellectual disability (ID) or high educational attainment.^29,30 Scientists have identified and characterized two major types of genetic variation associated with ASD. Rare genetic variants are commonly associated with lower cognitive function and profound autism, but that is not always the case.³¹  Even with hundreds of thousands of samples, scientists have still not found a direct gene – outcome linkage.  However, genetics are still important.  Genetic findings can help identify specific needs leading to appropriate supports.
• Certain types of gene mutations can explain associations with features like psychosis,³² as well as obesity and depression.³³
• Five new variants were identified that are not linked to intellectual or developmental disability (IDD), but are linked to other neuropsychiatric issues besides ASD.^31,34 Therefore, rare ASD or DD gene mutations usually lead to some sort of deleterious outcome.
• There is a significant overlap between ASD genes and genes associated with developmental disorders in general. Researchers suggest that autism specificity may be the result of when the gene is expressed. For example, in developmental disorders, genes are expressed in progenitor cells while in ASD they may be expressed in developing neurons.³⁵ 
• Other studies have not found any ASD-specific gene, they show linkage to neurodevelopmental problems in general, and can be grouped based on what cells are affected.³⁵
• There are shared pathways between ASD and other neuropsychiatric disorders.³⁶ 
• Studies have shown linkages between epilepsy, ASD and ADHD.³⁷

Key takeaways: Genetic markers associated with ASD are also associated with other developmental conditions like ADHD and intellectual disability, as well as comorbid conditions like obesity. Two major types of genetic markers, rare and common variations, may represent biomarkers of two different phenotypes, but there is overlap, and rare and common variants are likely mixed in most people. Genetic research is important for a better understanding of ASD and the development of individualized approaches for supports.

But genetics doesn’t tell it all

• Parental genetics and environmental factors are intertwined on a biological level. Genes associated with depression in parents are also linked to ASD.³⁸
• Maternal immune infections are an established risk factor for ASD. However, the genetics of children with and without maternal immune challenges during pregnancy are different.³⁹
• Studies in Norway offer a unique perspective of gestational exposures by banking blood taken mid-pregnancy during usual obstetrical visits. One study has shown that certain cytokines, or markers of immune activity, are elevated during pregnancy in both boys and girls with autism, particularly in girls. It’s unclear what role these cytokines play collectively or individually, or where they came from in the first place.⁴⁰
• Where you live can affect the role of genes vs. environment, evidenced by environmental factors playing a bigger role in heritability in certain areas of Sweden and the U.K.⁴¹
• Genetics and the environment clearly interact when it comes to the influence of an ASD diagnosis. For example, pesticide exposure exacerbated the effects of the autism CHD8 gene on rodent behavior.⁴²
• The role of environmental factors may depend not just on a diagnosis but on specific autism traits.⁴³
• Given that autism is likely part of a larger developmental disorder spectrum, regulation of toxic chemicals which are harmful to development must be expanded.⁴⁴

Key takeaways: The role of environmental factors in ASD has often been disassociated with genetics when it should be integrated into the understanding of autism’s causes, behavioral features, and interventions.

Biological sex plays a role

• Studies replicated this year showed that females with autism have a higher burden of rare genetic mutations. In addition, research is demonstrating that females with an autism diagnosis also show a higher level of “common” variations.^29,45
• The effect of higher levels of common variation in females extends to even undiagnosed members of ASD-impacted families, demonstrating that females carrying ASD genetic variation are resilient.⁴⁵
• The two above studies implicate an important role of the female protective effect but do not explain all of the differences in diagnosis.⁴⁶
• Some scientists have wondered if biases in instruments used to inform a diagnosis play a role in the sex difference. One study used a mathematical algorithm to eliminate the difference in M:F diagnostic differences, but still, females show different behavioral profiles. This further reiterates that instruments should be used to inform, not make a diagnosis, and that autism is more than a yes or no diagnosis. ⁴⁷
• Clinicians may miss an autism diagnosis in females because of camouflage. Females are also more likely to camouflage, which means they (consciously or unconsciously) pretend to fit in as a typically-developing girl. This leads to lower quality of life.⁴⁸
•  Intellectual disability plays a bigger role in autism features in girls vs. boys.⁴⁹
•  New genetic mutations involving the X chromosome were identified – and these mutations are more likely to occur in females.³⁵
• Sex differences in brain region size can be attributed to gene expression patterns. In other words, brain differences in males and females with ASD are due, in part, to underlying genetics.⁵⁰

Key takeaways: Females with ASD show different biological and behavioral profiles and are understudied in research and underserved in the community. Future research should aim to include more females to better understand their unique needs and provide targeted support.

It’s still not over, but families are in a better place than a year ago

• Despite a rocky start at the height of the pandemic in 2020 and 2021, opportunities to receive autism diagnoses, mental health supports, and interventions via telehealth have been improved, and polished, and are not only acceptable to families and clinicians but are effective.^51-57
• Families and clinicians were happier with remote diagnosis and evaluation when the diagnosis was clear; in cases where there was some ambiguity, it caused frustration.^58,59
• While many families and individuals experienced a mental health decline during the pandemic, some exhibited resiliency under social distancing guidelines.⁶⁰ The differences could be due to the degree to which services were lost, coping styles, and pre-existing mental health attributes.⁶¹

Key takeaways: Autism families suffered during the pandemic, but it also allowed for new approaches to be developed that may ultimately improve practice – including hybrid clinical services, holistic family support, and more comprehensive diagnostic practices.

It’s not all about the ASD

• Individuals with ASD experience higher levels of anxiety, GI issues, epilepsy, and other developmental disorders like ADHD compared to those without a diagnosis.
• While not a core autism symptom, anxiety is linked to insistence on sameness in toddlers with ASD, which indicates a similar underlying mechanism.⁶²
• Gastrointestinal issues plague people with autism, and there are few options for treatment. The gastrointestinal microbiome has been a target for intervention for autism symptoms, although studies are still ongoing.⁶³ GI issues were the focus of a major NIH-funded meeting this year.
• Suicide risk is higher in ASD. ⁶⁴
• Sleep problems, while mostly studied in children, are now shown to follow kids into adolescence and adulthood.⁶⁵
• There is a high degree of overlap in the brain activity profiles between ADHD and ASD kids. Differences are mostly seen when symptom severity is accounted for. ADHD and ASD show more similarities in the brain than differences.⁶⁶
• Behavioral profiles between ADHD and ASD are also similar.⁶⁷
• Mental health concerns are present in adolescents and adults with ASD with cognitive inflexibility strongly linked to compromised mental health.^68,69 Cognitive inflexibility, which is different than cognitive ability, is how someone shifts their attention from one thing to another based on what is going on around them. This may be a focus for future mental health interventions.
• Unfortunately there are no strong individual-level predictors in childhood of mental health issues in adults, but some factors that may lead to better mental health are better living skills and higher IQ.⁷⁰

Key takeaways: Outside the core features of autism listed in the DSM5, individuals experience a wide range of associated features, ranging from psychiatric issues to medical comorbidities. For many individuals, these associated features are highly debilitating.

Biases in underserved communities are getting more attention

• A recent analysis showed a reduction of the disparities in the age of ASD diagnosis for Black and Hispanic children over the last four years, but a difference still exists.⁷¹
• This is likely due to provider bias, but not necessarily diagnostic instrument biases. The standard diagnostic tools are not biased toward race or sex.⁷²
•  Lessons learned from the pandemic reiterate the need for intense community engagement, flexibility, and an understanding that a holistic approach – rather than one focused on ASD – is necessary for working with underserved communities^73,74.
• A culturally-adapted parent training program delivered by Black providers was effective in the Black community and could be a model for future engagement efforts.⁸
• Only 25% of intervention studies report the ethnic and racial makeup of their participants,⁷⁵ indicating that researchers need to do a better job of deliberately including racial and ethnic minorities, recruiting them as research leads and coordinators, and including them on boards for scientific review.⁷⁶
• Low socioeconomic status contributes to social and communication deficits in young children with ASD.⁷⁷

Key takeaways: Racial and ethnic biases are still pervasive in autism research and diagnosis, and we need a holistic approach to support families in all aspects of their lives beyond just autism symptoms. Scientists must continue to focus on the deliberate inclusion of these groups in both research and career training to better serve all individuals with autism.

On a final note, there has been a lot of debate this year about the language used to describe autism. ^78-81 There is a diversity of experiences with autism and likely to be a diversity of perspectives. Families and scientists should use scientifically accurate terms to best describe the wide range of autistic people and their symptoms.⁸²  What that is may differ from person to person, and situation to situation, which means context and preference need to be considered as well.

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