Podcast: Watershed moments in development

A Summary of Autism Discoveries in 2016 and What It Means for Families

By Alycia Halladay, PhD, Chief Science Officer of the Autism Science Foundation and the Scientific Advisory Board of the Autism Science Foundation

To listen to our year-end research summary podcast, click here.

For decades, the autism community has known that autism affects the entire family. Biological parents have been included in autism studies to examine where genetic mutations come from, but always with an eye for understanding the affected individual. This year in research saw a much bigger focus on family members of those with autism, particularly siblings.  The goal of these studies is to understand the genetic and biological nature of autism so that help can be provided not just to those with a diagnosis, but to family members as well.

Many studies focused on what is known as the “broader autism phenotype,” previously explored in biological parents. The “broader autism phenotype” refers to some behavioral features of autism, including those in emotion, language, and social skills that do not meet the level of a diagnosis of autism spectrum disorder. Rather, they have been termed anything from “intermediate” autism to “a hint of autism.” Joe Piven and James Harris hypothesized this year that Bruno Bettleheim may have tragically misinterpreted these features, in the absence of a true understanding of autism, as “refrigerator mothers.” Clinicians have urged scientists to note these symptoms in a way that does not create a new diagnostic category and noting certain social, personality and language characteristics in family members has been crucial for nailing down the underlying biology.

Importantly, significant scientific discoveries in autism were made possible by looking directly at the brains of people with autism. This type of research has been made possible through the Autism BrainNet. This summary highlights the important role of studying brain tissue from individuals with autism to better understand people with autism across the lifespan, including those with known causes and unknown causes of autism spectrum disorder (ASD). See the section below entitled “Using brain tissue to understand causes of ASD” for more details on findings from brain tissue research in 2016.

Siblings show features of autism, but not to worry

This year, four studies assessed the broader autism phenotype in siblings, and other studies went further to look at psychiatric symptoms in siblings who were not diagnosed with autism. In the past, researchers mistakenly believed that siblings showed no symptoms of autism. In fact, adolescent, school age, and adult siblings of those with autism show elevated autism symptoms [1, 2] as well as categorical features of autism similar to those seen with autism [3], compared to those with no family history. High-risk infant sibling studies have shown that siblings of toddlers with autism, while not diagnosed with autism, have a higher rate of autism spectrum disorder (ASD) symptoms [4].

This is also consistent with the broader autism phenotype, with the last study indicating that sibling symptoms are observed across the lifespan. Unfortunately, signs of the broader autism phenotype puts siblings at risk for internalizing and externalizing behaviors like depression, psychological problems, and other behavioral issues [5, 6]. In addition to anxiety and depression, research this year showed increased risk of psychiatric comorbidities including ADHD and substance abuse disorders [7-9]. On the other hand, siblings who were within the typical range of Social Responsiveness Scale (SRS) scores didn’t show elevated sensory issues [10]. The goal of studying siblings of those with autism, again, is not to look for features which pathologize them, but to help identify features, challenges, and strengths that help them. Research published previously identifies the unique nature of sibling relationships, in that siblings of a person with autism view their relationship positively across the lifespan, whereas siblings of typically developing individuals tend to report positive feelings at a decreased rate in adulthood [11].

Understanding the causes of autism by studying sex differences

In addition to understanding siblings to help develop specialized services and supports, learning about siblings can help researchers understand the causes of autism and, specifically, why females are less likely to be diagnosed compared to males. New prevalence data from the CDC showed that the prevalence of autism is again at 1:68, perhaps showing a plateau in the rates of autism in the US. However, the difference in the rates between males and females still hovers around 4:1 depending on IQ [12]. Researchers this year showed that females may be able to hide symptoms because of better social abilities [13] and because they may be protected in some way from certain symptoms [14]. For example, those studying infants at risk for autism show that baby girls with autism show increased attention to social stimuli compared to baby boys [15]. This difference may affect how they express symptoms later on. Finally, preliminary studies this year suggest a slight bias in diagnostic instruments [16] and evidence of camouflaging autism symptoms in females [17].

There are likely multiple reasons behind the male sex bias in autism, but few have received any empirical study. This year, the Autism Sisters Project began recruiting at the Icahn School of Medicine at Mount Sinai. This study is poised to understand why females are not diagnosed as often, including differences in IQ and underlying genetic factors. Of importance, the study is focusing on the undiagnosed sister of individuals with ASD. As much as studying siblings with autism may help researchers understand sex differences in autism, so will actually studying males and females with ASD. Donna Werling from USCF looked at genes expressed in the brains of males and females with and without autism to understand sex differences in gene expression, particularly in those genes associated with autism. She found that it was not ASD risk genes that show differences, but those that are involved in neural pathways associated with autism, like microglia and the immune system, that show sex differences. The male bias in this gene expression may be what modulates ASD risk [18]. A male sex bias is not unusual across neurodevelopmental disorders, and so understanding its role in autism diagnoses may be informative of disorders like ADHD and anxiety as well. Just like there are fewer females diagnosed with autism, there are fewer brains of females to study, slowing scientists’ understanding of ASD. In order to learn more about how women with ASD can participate, click here.

More to learn about genetics associated with ASD

Even more new risk genes were discovered this year, and/or replicated in different cohorts. These investigations went beyond “autism” vs. “no autism” to specific features of autism, with the goal of understanding what genes lead to what behavioral features of ASD. For example, several studies found associations between a gene called POGZ and autism, particularly autism with intellectual disability [19-23]. POGZ is a gene that makes a protein that affects the expression of other genes. Therefore, the mutation of this gene produces disruption in the expression of several genes, rather than just one. Similar specific behavioral features are found with mutations of TRIP12 or DYRK1A, which also leads to widespread, rather than specific, changes in gene expression with a particular form of autism: autism with intellectual disability [24, 25]. By further investigating individuals for whom substantial amounts of data is available, including cognitive ability and comorbid medical conditions, the causes of these features will be better understood and will hopefully lead to better treatments. Researchers have also better identified how genes seen in other disorders but cause autism are transmitted, for example via maternal [26, 27] or paternal [28] pathways, influenced by things like paternal age [29], which might aid genetic counseling. Contrary to this idea, however, is the finding that individuals with either a known genetic cause of autism or autism where there is no known cause (i.e., idiopathic) have a considerable amount of overlap in mutations in the brain which affect how genes are turned on and off – in other words “epimutations” [29, 30]. This is further evidence that beyond the way DNA is sequenced, factors that affect how genes are activated are important to autism etiology as well. Epigenetic markers are known to be sensitive to environmental exposures of different types and insight into these pathways continue to open the door to understanding gene/environment interactions in autism.

And it’s not just about pure genetics, it’s about interactions between genes and the environment.

Genetics plays a huge role in the causes of autism, but this year researchers dove even deeper into the multifactorial causes of autism, specifically the role of genetics and the environment. The environment includes, broadly speaking, anything from toxic chemicals to age of the parent. It includes sociological, pharmacological, toxicological, and medical exposures.

This year saw two epidemiological studies examining the interaction between genes and the environment, but this time the investigation expanded to include who carried the genetic mutation and how autism was defined. First, studying the genotype of mothers showed that a particular mutation of the serotonin receptor gene and a high level of stressors during pregnancy produced a higher risk for having a child with autism than those without this same mutation [31]. Rather than using these factors to understand autism risk, others are going beyond to understand symptoms within autism. For example, using the Simons Simplex Collection, scientists showed that boys with autism who had genetic markers of mutations called copy number variations, together with exposure to an environmental exposure, showed the most severe autism symptoms, marked by repetitive behaviors and cognitive challenges [32]. The study is the first to look at type and severity of symptoms following multiple risk factors rather than a diagnosis, and the idea of understanding multiple risk factors for symptoms, rather than diagnosis itself, needs further study. Animal models of autism found that paternal age, a commonly accepted risk factor for autism spectrum disorder, combined with a mutation of a gene that affects synaptic development, results in certain symptoms of ASD in this model [33]. More fine-grained analysis of autism symptoms, rather than an autism diagnosis per-se, is needed to better understand the causes of autism. It’s also important to understand environmental factors because in some cases, like those of chemical and toxicological exposures, these can be controlled through regulatory means. Many studies have linked air pollution to autism [34] and in early July a landmark consensus statement authored by over 30 scientists, physicians, and public health experts was published which calls for the reduction of toxic chemical exposures to possibly reduce the risk of many developmental disorders [35]. So far, the only established way to protect against autism has been dietary folic acid supplementation [36], so reduction of modifiable risk factors should be a focus of future public health research.

Another potentially modifiable risk factor is maternal infection during pregnancy. Of course, not all cases of maternal infection are preventable, but some of them are. This year, a study revealed that neither having the flu, nor being vaccinated against the flu during pregnancy, was shown to contribute to autism risk in children [37]. However, maternal immune response during pregnancy was linked to a specific behavioral phenotype of autism, specifically those with intellectual disabilities [38]. According to animal models, the effects of altering the immune system function early in cell formation may lead to longer lasting elevations in chemokines (which are immune chemicals associated with autism) than previously thought [39]. This may be attributed to long lasting changes in gene expression patterns, regulated via epigenetic mechanisms [40, 41], resulting in an increase of methylation of genes and producing effects across generations. These findings converge with other research that demonstrates similar methylation patterns in individuals with ASD, even without immune system challenges during early life.

For years, some autism researchers have observed the presence of antibodies to brain tissue in some mothers of children with autism. This year, researchers looking at animal models discovered that they may be acting through an autism risk gene [42]. Also, the increased risk may be particularly elevated in mothers with specific medical conditions [43]. While scientists remain cautious about translating these findings to a commercialized method of determining autism risk, they continue to provide insights into the neurobiology of autism, and especially the immune system.

Using brain tissue to understand causes of ASD

Brain tissue research will also help researchers better identify causes of different types of autism so that better treatments can be developed. For example, one of the more challenging and debilitating medical comorbidities associated with autism is seizures and epilepsy. A study of brains of individuals with both autism and autism and epilepsy show increased numbers of glial cells. These cells are not neurons, rather they provide support and protection to brain cells [44]. The glial cell numbers were highest in those with restricted and repetitive behaviors, but, interestingly enough, the number of glia go down over time in individuals with autism, but up in those without autism. This suggests that the glial cells contribute to autism severity and cause. Similar comparisons to other disorders associated with autism were made studying amyloid B precursor protein and their metabolites. These molecules are associated with Alzheimer’s disease but also have a host of other functions that are not pathogenic. For example, they can affect neuroinflammation and normal cellular activity. In autism, levels of these proteins were reduced in brain and plasma, but elevated in individuals with Fragile X syndrome [45]. This suggests that these amyloid B proteins are involved with both disorders, and may be a target of interventions in the future.

Figure found in Parikshak et al., 2016

Brain tissue research goes beyond identifying treatment targets to helping researchers understand how the brains of people with autism work on a cellular level. This year, two studies demonstrated that in addition to mutations in autism risk genes, mutations in areas of the gene that control the function of autism risk genes are also affected [30, 46]. What is also interesting is that regardless of the symptoms or causes of autism, the pattern of gene activity was similar in those with autism, validating a much smaller study from years ago [46]. These results also reiterate the importance of early intervention for treatment of debilitating autism symptoms, since both genes identified recently that control brain development peak during the first few years of life. It is important for all families, regardless of whether or not they are directly affected by autism, to learn more about brain tissue donation. You can register for more information by clicking here.

Should clinicians think in terms of autism diagnosis, or in terms of symptoms?

This year showed the shared features between autism and many other disorders like Phelan-McDermid syndrome, mutations of chromosome 16, Dup15, and even schizophrenia. In particular, disorders don’t just share autism symptoms; they show similar neurological and cognitive features as well [27, 47]. So how much is specific to autism, and how much is related to behavioral, neurological, and other medical issues that are seen without an autism diagnosis? And do these genetic findings explain certain symptoms associated with autism, but not core to autism? It has been argued that classifying individuals based on specific symptom dimensions, such as the presence of abnormal behaviors, absence of other behaviors, and cognitive ability may help clinicians better distinguish cross disorders [48, 49]. This idea is not new, with a recent movement towards a new way of thinking towards autism diagnosis [50]. New findings from the brains of individuals with a diagnosis of autism or schizophrenia show significant overlap between the gene transcription in the brains of people with either autism or schizophrenia, but not bipolar disorder [51]. The authors conclude that these two disorders share many genes associated with synapse development, and the formation of connections across different brain regions. Therefore, these disorders may not be totally different at the biological level. Rather than thinking of autism as a whole, early signs of autism can also be linked to specific genetic markers, which may explain autism symptoms, but not autism as a diagnosis. This includes mutations of the oxytocin receptor on later empathy [52] and dopamine receptors on a core feature – initiating joint attention [53]. This idea has enormous implications for autism research and treatment, as it implies a switch in the way autism is identified. It has been suggested that behavioral symptoms, combined with biological and environmental variables, should be combined to lead to categories, rather than diagnosis of disorders. This is called Research Domain Criteria, or RDOC.

Autism can also be very difficult to diagnose, but this year two new studies suggested that the process can be streamlined, at least a little bit. In school age verbal children, a new instrument called the Autism Symptom Inventory (ASI) was good at diagnosing autism in about 20 minutes [54]. Another instrument, which doesn’t have a name yet, combines three short instruments (including the ASI) and was also promising, especially in terms of studies aiming to understand the causes of autism, both genetic and environmental [55]. These studies offer hope to large scale epidemiological studies seeking to identify and characterize individuals with autism, although right now their ability to identify different subtypes which may be amenable to specialized treatments is limited.

When it comes to intervention, earlier is best, but not the only option

The most remarkable evidence of the effectiveness of early intervention has come from longitudinal studies – those that study an intervention YEARS after it was delivered. If early intervention improves brain connectivity and allows for connections to be formed to alleviate autism symptoms, the effects may not be seen right away – it may take years. They can take the form of an intervention study that follows families for a long time, or by investigating factors early on that predicted improvement at school age and beyond. This year saw both. In 2010, a gold standard randomized clinical trial study out of the UK looked at a parent-delivered intervention focusing on communication, and, while they found it showed promise, it didn’t produce improvements in symptom severity [56]. The initial findings were hopeful, but also disappointing. However, when they followed up on these children five years later, the training of the parents to deliver the intervention resulted in a reduction of autism symptoms [57]. The findings are important for many reasons. First, autism intervention is a journey, not necessarily a destination, and interventions delivered early on may alter the trajectory of symptoms [57]. Second, parents can deliver interventions in a wide variety of settings in a way that is more intensive than limited clinic time, and an intervention targeted at one set of autism symptoms like social communication may also affect others like repetitive behaviors [58]. This does not mean that trained Applied Behavioral Analysis (ABA) therapists and intervention delivered by trained professionals should be abandoned. Parent-delivered interventions are a supplement at ages when kids spend most of their time with parents rather than schools. Another important thing to remember about early intervention is that more data published this year shows that for a percentage of children, a diagnosis is not possible at two years of age. A group of children who show some symptoms but don’t meet criteria at two years of age do end up with a diagnosis by three years of age [59] despite being seen by well-trained, very experienced clinicians. Early intervention may help those who don’t have an actual autism diagnosis yet. Studying infants with autism has also been instrumental in determining not only interventions, but the nature of autism itself. For years, people assumed that the reduced eye contact in people with autism was because they were actively averting the eyes, found eye contact aversive, and didn’t want to look at the gaze of the other person. However, this isn’t the case. At least early in life, infants with autism don’t actively avert gaze, they just aren’t that interested in looking at the eyes and don’t get the same social signals from eye contact as those with autism do [60].

Parents as methods of treatment delivery

Parent-delivered interventions can be used at different times, again to supplement, rather than replace, other treatments delivered in clinical settings. Parent training, not the less intensive parent education, on behavior management techniques improved adaptive behavior and daily living in children with autism. However, these gains were mostly seen in those with average intellectual functioning [61]. This suggests that not all individuals respond to parent-delivered interventions. And it isn’t just used in isolation. It enhances the efficacy of drugs to alleviate ADHD in those with autism [62]. Parent training may seem like an easy solution, but in the real world setting of parents and trainers, it is very complicated [63].

What can predict who will respond to what treatment?

There have also been advances in pharmacological treatments of autism, but they always struggle with improving behavior or outcome, not specific to core autism symptoms. Oxytocin, a naturally occurring hormone, has shown mixed results in improving different aspects of autism-related behavior, including face recognition, social behavior, and empathy [64]. Looking at the effect of oxytocin on the brain, it improves connectivity between areas of the brain involved in reward and those involved in perception of social communication cues in children with autism [65]. However, it isn’t simple, and, as it turns out, that makes the story more promising. People with mutations of the oxytocin receptor have different types of mutations. These different types of mutations in people with autism lead to different patterns of this connectivity [66] as well as the ability to recognize faces [67]. Finally, these different mutations also predict the behavioral response to oxytocin – in other words, whether or not this hormone produces improvements in social abilities [68]. These different studies are a perfect illustration of how personalized medicine will improve autism treatment. Those with particular types of genetic differences will respond better to oxytocin treatment than others, which will speed up people receiving the right type of intervention.

In addition to genetic markers predicting treatment response, advances in other biomarkers to predict treatment response have been made as well. Individuals who were more responsive to Pivotal Response Treatment (PRT) showed a specific pattern of pre-treatment brain activity when presented with a social situation on a video [69]. In fact, it predicted response to treatment better than any baseline behavioral measures. In the future, just like looking at the genetic makeup of people with autism, understanding their underlying brain function before treatment can help get the people into the treatments that would benefit them the most.

The whole purpose of improvements in autism diagnosis and interventions is to deliver services to individuals that need them. So, how are insurance mandates doing in terms of identifying individuals with autism and providing them with the treatments they need? This year, David Mandell at the University of Pennsylvania demonstrated with data obtained through insurance companies that these mandates are increasing the number of people receiving services. That’s the good news. The bad news is that the increase is not nearly as much as it should be keeping in pace with the prevalence of autism. So, he concludes, these mandates are necessary but not sufficient to provide services to all that need them [70]. In addition, there are acknowledged gaps in what pediatricians know about non-medical treatments and services in their areas, and what parents need them to understand [71].

In summary, this year saw research that helps understand the causes of autism; includes siblings to provide better services to the entire family; showed promise of the concept of “personalized medicine” everyone has heard so much about; demonstrated the long term, not just short term effects of behavioral interventions and the importance of parents and caregivers; and emphasized the need to better understand features of individuals with autism rather than just the straight diagnosis of ASD.

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62. Smith, T., et al., Atomoxetine and Parent Training for Children With Autism and Attention-Deficit/Hyperactivity Disorder: A 24-Week Extension Study. J Am Acad Child Adolesc Psychiatry, 2016. 55(10): p. 868-876 e2.
63. McKnight, L.M., M.P. O’Malley-Keighran, and C. Carroll, ‘Just wait then and see what he does’: a speech act analysis of healthcare professionals’ interaction coaching with parents of children with autism spectrum disorders. Int J Lang Commun Disord, 2016. 51(6): p. 757-768.
64. Ooi, Y.P., et al., Oxytocin and Autism Spectrum Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pharmacopsychiatry, 2016.
65. Gordon, I., et al., Intranasal Oxytocin Enhances Connectivity in the Neural Circuitry Supporting Social Motivation and Social Perception in Children with Autism. Sci Rep, 2016. 6: p. 35054.
66. Hernandez, L.M., et al., Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism. Mol Psychiatry, 2016.
67. Westberg, L., et al., Variation in the Oxytocin Receptor Gene Is Associated with Face Recognition and its Neural Correlates. Front Behav Neurosci, 2016. 10: p. 178.
68. Watanabe, T., et al., Oxytocin receptor gene variations predict neural and behavioral response to oxytocin in autism. Soc Cogn Affect Neurosci, 2016.
69. Yang, D., et al., Brain responses to biological motion predict treatment outcome in young children with autism. Transl Psychiatry, 2016. 6(11): p. e948.
70. Mandell, D.S., et al., Effects of Autism Spectrum Disorder Insurance Mandates on the Treated Prevalence of Autism Spectrum Disorder. JAMA Pediatr, 2016. 170(9): p. 887-93.
71. Levy, S.E., et al., Shared Decision Making and Treatment Decisions for Young Children With Autism Spectrum Disorder.Acad Pediatr, 2016. 16(6): p. 571-8.

This year was filled with both challenges and encouraging signs of progress. The world continues to cope with the many hardships associated with the COVID-19 pandemic, which have negatively impacted the community, including scientists who study autism. Families and individuals continue to show individualized and specialized needs, specifically those from racially and ethnically diverse communities, females and girls, and we continue to understand the specific needs of those groups. For example, the close of the year saw the publication of a report by the Lancet Commission, which formally introduces the concept of “profound autism” representing individuals with different support needs. New CDC data released in December also show that autism rates are rising while age at diagnosis is decreasing [1]. While this is not a comprehensive summary of every single autism discovery in 2021, here we summarize many significant autism discoveries and related news of the past year:

Listen to the 2021 Year End Summary here.

Lancet Commission Endorses Use of Term “Profound Autism”

On December 6, The Lancet published an extensive report from a global team of autism researchers and stakeholders. The report, titled “The Lancet Commission on the Future of Care and Clinical Research in Autism,” recognized that effective autism assessment and care require personalized, stepped-care approaches that meet an individual’s needs throughout their lives, and that greater investment is urgently needed to develop and refine practical interventions that can improve the lives of people with autism. The Commission also formally introduced the term “profound autism” to distinguish individuals who have high dependency needs and urged policymakers to focus on the unique needs of this group, which represents approximately 30% of people with autism [2]. The goal of this label is to recognize the uniqueness of these individuals and that their support needs and outcomes are different from those of others. There is also evidence that the underlying biology of those with “profound autism” is different [3-5].

The term “profound autism” is intended to describe autistic people who are likely to need 24-hour support throughout their lives. The report states that useful categories like “profound autism” can bring attention to the different needs of different people. In fact, the goal of the new term “profound autism” is to equip parents, service providers and the public with the language necessary to ensure that each individual with autism receives the accommodations and interventions they need [2]. These can vary greatly. Some of those diagnosed with autism engage in destructive or self-injurious behavior. Some have intellectual disabilities; others are star students. Some are unable to perform basic tasks like brushing their teeth and getting dressed; others can live fully independent lives. Autism is a disorder in which no two diagnoses look the same, and terms like “profound autism” help distinguish needs

CDC Reports Autism Prevalence Continues to Rise

The CDC ADDM Network released updated autism prevalence data this year, announcing that one in 44 8-year-old children is diagnosed with autism [1]. This is an increase from the one in 54 number for 8-year-olds reported in March 2020. Using a slightly different but validated methodology from previous years [6], new CDC data confirm that autism prevalence and diagnoses have gone up steadily in the past five years. 

The CDC information makes it clear that we are getting better at diagnosing autism and identifying it earlier, which is encouraging because research has consistently shown the value of early intervention. However, more than 58% of children identified had intellectual disability or borderline intellectual disability. This cohort of children with profound autism warrants more attention from policymakers and service providers, as their needs are dramatically different from those with milder forms of autism. While the prevalence went up, the demographics across race, ethnicity and cognitive ability stayed pretty stable from the last prevalence estimate [1]. This information calls for further understanding of the nature of this rise beyond just diagnostic practices, including alerting pediatricians and supporting further and more expanded studies of gene x environment interactions [7]. One example would be the differential influence of toxic chemicals on cells with genetic mutations associated with autism, which revealed a susceptibility to toxic chemical exposures with cells with autism-related variation [8].

Reaching the Hard to Reach

Those from racially and ethnically diverse backgrounds have long been recognized as being diagnosed later, if at all. There are years and years of CDC data which show that while this trend is improving, it is still problematic in terms of equitable access to services. It also produces another problem that perpetuates the underdiagnosis and lack of access: not enough families from racially and ethnically diverse communities are being studied in research, which means most research findings apply to white communities, not the communities represented in the real world who need help [9]. A few studies this year specifically targeted those from either Hispanic [10] or Black and Hispanic families [11, 12]and found their needs were different or developed tools for their particular culture. However, in a commentary this year, researchers highlighted the need to engage diverse communities at the beginning of the research question, to ensure they have a voice at each step, and to possibly adapt the study question to their particular circumstances [9].

Unfortunately, not all of the challenges facing underserved communities are the same. For example, those who are minimally verbal and have intellectual disabilities are left out of research for logistical reasons, or, in many cases, the intellectual and verbal abilities of individuals with more profound autism are not reported at all [13]. Those with intellectual disability are usually recognized more often, but there were only four intervention studies published in PubMed in 2021 that specifically included a group of autistic people with intellectual disability.  

Understanding Autism in Females 

While females with ASD have not typically been placed in the “underdiagnosed” category, they certainly are a group that has been underserved by scientific research. Because of the 4:1 difference in prevalence for males to females, autism research studies typically include four times fewer females, which means findings are not generalizable to females [14-17].

In the last year, there have been several studies showing that the challenges faced by autistic females are different from those facing autistic males. For example, a phenomenon called “passing as autistic” (otherwise known as masking) — where someone with autism tries to hide their symptoms to pass in social situations — was found to be elevated in females [18, 19]. Comorbidities like epilepsy have been shown to be higher in females [20], and baseline brain activity in autistic youth is different based on biological sex [16]. While the female brain is clearly different from the male brain, even in autism, the lack of females included in research has also significantly impaired our understanding of brain differences between males and females with ASD for more personalized support [21].

Because of the disparity in diagnosis between males and females, there are very few studies that can examine the effects of sex and gender on diagnosis, making consistent findings across sex/gender almost impossible, but it has been done [22]. What has been learned is that the striatum (and genes controlling striatal development) may play a role in autism symptoms in females. This has not been identified as an area of interest in males [23]. Research also shows that females have a higher burden of variants in the oxytocin receptor gene, which affect them differently than males with ASD [15], and differential links between brain activity and autism features [16], supporting something called the “female protective effect.” This protective effect might be genetic or might occur through the estrogen pathway [24, 25]. Finally, while the entire autism community has a higher than expected rate of gender dysphoria, it seems to affect girls more than boys [26]. Behavioral features are also slightly different, which complicates diagnosis [17]. Together, these results demonstrate that scientific findings, including use of biomarkers for diagnosis, which are seen in males may be different than those seen in females. Scientists need to ensure that enough females are recruited into research studies and better understand the difference between females and males to ensure that scientific findings generalize to care in the community.

The Pandemic Is Still Causing Problems

Almost two years into the pandemic, scientists are still working to understand the long-term effects on people with autism. Studies focused on increases in challenging behaviors and loneliness in autistic youth and adults [27, 28], and also on understanding the mental health challenges due to prolonged social distancing guidelines, including multiple waves of lockdowns [29-32]. Additionally, studies show that families with autism are disproportionately affected by job losses and food insecurity [33, 34]. And while telehealth-based diagnosis and services are becoming more common as a result of social distancing, families of younger children who need direct behavioral supports remain the least satisfied [35, 36], a trend continuing from 2020 [37]. The challenges associated with the pandemic are not limited to those with a diagnosis and their families. Scientists who dedicate their lives to help those on the spectrum have struggled with some of the same issues that families with autism have [38], including mental health and childcare challenges. This compounds the problem of developing scientific discoveries and delivering them to the community.

New Technologies for Diagnosis and Treatment

With the pandemic came the use of remote and virtual technologies, not just to identify and diagnose autism, but also to provide supports and services. As the pandemic continues, researchers are studying what works and what doesn’t, especially in families who say that they found telehealth more accessible and beneficial [35]. Remote assessments have changed the nature of how autism is diagnosed, with scientists emphasizing the need for use of good clinical judgment rather than reliance on singular instruments [39]. Telehealth assessments have meant that diagnosis is now more accessible to those in remote areas who are traditionally underdiagnosed. Another bright spot is that the pandemic has allowed children to be observed remotely in their home environment, which may significantly enhance the ability of clinicians to observe early markers of autism [39, 40]. New technologies that enable videotaping via remote camera — for later review by clinicians — are also gaining traction. Recently, Cognoa received FDA marketing authorization for its new remote videotaping tool, CanvasDx. Duke University also published data a tool that plays different movies and visual scenes on an iPad and allows clinicians to determine the likelihood of an autism diagnosis by examining where the children looked in the scene [41], as past research has shown that children with autism are more likely to look at objects and less likely to look at social stimuli. In both cases, these recordings, together with standard early screening methods, can be analyzed to help facilitate diagnosis. A 2021 review found these mobile digital technologies to be promising in diagnosis [42].

Beyond just supporting diagnosis, mobile technology may be used to improve cognitive and social skills across the lifespan [43]. A recent systematic review indicated that these mobile interventions were particularly helpful in targeting practical skills [43, 44]. They can also be used to predict responses to stressful situations and abnormal sensory arousal [45]. Finally, robots and videogames on devices are showing promise in helping kids with autism develop social skills [46, 47]. While these technologies may have benefits beyond the pandemic and can alleviate some of the burden of traveling to multiple appointments, they will not replace the need for children to be diagnosed and/or receive therapy from trained, in-person clinicians [39, 48].

Intervention Before Diagnosis

A few years ago, scientists in the UK began studying the possibility of promoting skills in parents as a way to mitigate autism symptoms in infants [49]. By working with parents in their home and promoting social and communication skills through activities like reading and play, autism severity scores improved. This year, a group in Australia conducted its own randomized controlled study starting at 9-12 months — before a diagnosis can be made — to provide support to parents and offer video feedback on supporting language and social development in their infants. This study showed that support of infant social and communication skills measured at one year led to a reduction of autism severity scores at 24 months, with these improvements being maintained long after the end of the intervention period [50]. Factors like caregiver interaction and adjusting the environment to promote learning in these toddlers are key ingredients to changing developmental trajectory [51, 52]. New tools are also allowing earlier and earlier detection of markers of ASD, with some evidence that it can be done as early as 12 months of age [53]. These findings represent the potential benefits of decades worth of early detection work and operationalize a methodology for parents to learn to promote social and communication skills in their infants.

However, the need for earlier detection and diagnosis of autism remains a priority within autism research and the autism community. This year, researchers identified changes in the grey matter (cell bodies) and white matter (the neuron branches) in children as young as 12 months of age [54] who go on to be diagnosed with autism. Changes in brain activity, while not a diagnostic marker, can be seen in infants as young as 3 months of age [55] and can prove helpful in diagnosis at 6 months [56]. In addition, some behavioral signs can also trigger preemptive intervention. Groups led by UC Davis demonstrated both declining gaze to faces, which was replicated in two different cohorts [57], and unusual inspection of objects at 9 months, which predicts reduced social engagement at 12 months in those who later develop an autism diagnosis [58]. In addition, vocalizations (or intents to communicate) were lower in children as young as 12 months [59]. Together, while not diagnostic, some of these early markers and signs can facilitate entry into preemptive interventions, which can produce skills in caregivers and infants that change the developmental trajectory. Finally, there is an erroneous perception that parents believe that all of autism is “bad” and needs to “be eliminated.” In fact, when they were specifically asked, parents identified characteristics like love, kindness, humor, humanity and resilience that they value and appreciate in their children [60].

Autism and Aging

There has traditionally been a lack of understanding as to what happens to autistic adults as they enter their golden years. This year, Drexel University utilized Medicaid data to examine the risk of dementia in those with autism and found that those with ASD were 2.6 times more likely to be diagnosed with dementia compared to the general population [61]. This has profound impacts on planning for elderly relatives with ASD and developing interventions that may stunt the development of dementia in this population.

Understanding the Role of Genetics in Autism 

Traditionally, genetic variation association with autism has been bucketed as “rare” mutations and “common” mutations. Rare mutations on genes typically lead to deleterious effects such as seizures or intellectual disability [62]. Sometimes, like in the case of BRCA (breast cancer gene), they can be fatal. Common mutations are seen in lots of people, not just those with autism, but the human body can tolerate many common mutations with no major effects. However, if the genetic variant is found in an autism risk gene, for example, then it can dispose someone to an autism diagnosis [62]. Mutations found in autism risk genes — including those associated with cell adhesion, neuron-glia interactions and synapse formation — are most likely to be common variants involved in autism [3].

This year, sequencing of more than 800 people with an autism diagnosis revealed that 27% had evidence of a rare genetic mutation, mostly in one of the 102 genes identified in 2020 as being relevant for ASD [3, 63]. Presence of a mutation of one of these genes also results in a distinct set of behavioral features early in life that is different from those without a rare mutation [64]. Interestingly, instead of advancing the traditional “rare vs. common variation debate,” scientists this year learned that even in those who have a rare genetic mutation, there is also a high burden of common variation [63]. Scientists found that both rare and common genetic risks contribute to autism susceptibility, and that the dual risks may increase the likelihood of an autism diagnosis [63]. These findings make things complicated for genetic counselors who need to assess all the factors and communicate to families whether or not a particular rare variant is causative. In addition, sequencing technologies are revealing more and more genes that are relevant to ASD but incredibly rare; in fact, they are likely to be part of a multi-factorial cause of individual cases of ASD [65]. Finally, we’ve learned that common variation influences not only core autism symptoms, but also psychiatric comorbidities [66].

Studying Rare Genetic Syndromes Opens the Door to New Therapeutics

The use of induced pluripotent stem cells, or iPSCs, to study the brain on a cellular level has so far been focused on rare genetic diseases associated with autism, like Dup15q syndrome, CNTNAP2 and CDKL5 disorder. However, while the genetic targets may be more specific than in idiopathic autism, there are also converging mechanisms of disrupted connectivity in the brain that make these single gene disorders useful in understanding the neurobiology of ASD [67-71].

In addition to some shared (and some distinct) neurobiology across autism with a known genetic cause, there is overlap on the basic neurobiology level in terms of cortical thickness [72] and G-protein-coupled-receptors across different psychiatric disorders, including autism [73]. Some of these rare genetic syndromes have been responsive to targeted gene therapy, which opens up the door for them to be used in idiopathic autism if proven safe and effective in large groups of people with neurodevelopmental disorders.

Remember Glial Cells? They May Play a Bigger Role Than We Thought.

One brain cell type that is experiencing renewed interest in autism is glial cells, particularly with regard to sex differences in ASD. Glial cells are found in the brain, but they do not communicate with each other. Rather, they provide insulation to neurons that do communicate via electrical impulses. Traditionally, because they were not thought to be communication cells, they were not considered critical for study. But recent evidence has shown that there may be different subtypes of autism defined by the upregulation of genes that control glial cells [74]. Gene expression in these microglia may also contribute to differences in brain structure [75]. In addition, the direct study of brain tissue has shown that in certain layers of the cortex, astrocytes — a type of glial cell — are decreased [76]. Taken together, the dysregulation of glial cells may contribute to different cell processes, brain structure, functional changes and psychiatric syndromes associated with autism.

What Can We Do to Improve Outcomes of Those with Autism?

New research shared this year focused on improving outcomes. First, we learned that the presence of a brother or sister not on the autism spectrum improves adaptive behavior across the lifespan for those with an autism diagnosis [77]. On the other hand, parental stress in early life and early adverse events can make outcomes worse [78].

Research continues to show that, especially in the early years, parents and caregivers can play a critical and life-changing role in their child’s development. For young children, Naturalistic Developmental Behavioral Interventions (NDBIs), which are child-led and utilize behavioral principles delivered in the home, are most helpful [79, 80] and now may be delivered via telehealth [81]. One good thing to come out of the pandemic is the availability of remote access to video series, including but not limited to the Autism Navigator, which can help parents identify early signs and deliver these interventions to their young children from home [82]. The literature on the efficacy of these NDBIs grows greater every year.  However, not everyone has access to early interventions or even expert clinicians. To address the disparities seen across the world and across different comorbidities and other individual factors, the Lancet Commission report called for a stepped-care and personalized health model for interventions [2]. This includes provisions not just for individual and family factors, but also for accessibility and cost. These recommendations on how different groups approach care are essential to obtain a more specialized approach to helping families and individuals on the spectrum lead happy, healthy and successful lives. Unfortunately, some promising therapeutics like oxytocin failed to meet the cut of significantly helping those with ASD [83].  Other organ systems besides the brain, including the gastrointestinal system, continue to be investigated to help alleviate co-occurring medical conditions.  Many families turn to things like probiotics to help with issues like constipation and diarrhea, however, new evidence suggests that the microbiome is more influenced by diet than autism itself [84] calling into question the validity of probiotic use for GI problems.

In Memoriam

Sadly, the autism community lost three scientists this year who have made enormous contributions to the field and changed the way people think about autism. Sir Michael Rutter, known as the Father of Child Psychiatry, a professor at the Institute of Psychiatry at Kings College London, was one of the most influential psychiatric scientists of the past 50 years. He was one of the first researchers to study autism, publishing a study of autistic twins in 1977. He helped dispel the myth that parenting styles influenced an autism diagnosis and brought scientific rigor to understanding autism. He helped develop the two gold standard tools for diagnosis: the ADI-R and the ADOS. His commitment to helping children and families was not limited to autism, however; he helped families with a number of psychiatric conditions and behavioral issues.

Li-Ching Lee, who served as the Associate Director for Global Autism at the Wendy Klag Center of Johns Hopkins School of Public Health, was one of the reasons why autism is recognized as a global condition. She focused her research on identifying and helping families with autism across the world, calling it a “human rights issue” when the needs of families in under-resourced countries were ignored. She also worked tirelessly to understand autism in the US, working closely with the CDC to understand who and where people were being diagnosed and how they could be helped. Beyond being an amazing scientist, her fellow students have called her an amazing friend, mentor and teacher who went above and beyond to help her students be successful while helping families.

Finally, George C. Wagner of Rutgers University was one of the first behavioral neuroscientists to try to develop a behavioral model of ASD in rodents at a time when scientists were starting to try to understand how to recapitulate the features in model systems. His work helped define how autism should be studied in animals, and how it overlapped or was different than other psychiatric disorders. He based his models on the core features rather than particular behaviors, including delay of skill development, plateauing of skills and possible regression of skills. This helped fundamentally change the field of animal models of ASD. Many of his students (including ASF CSO Alycia Halladay) went on to help families with ASD following training.

All three of these amazing scientists will be remembered not just for their contributions to science, but for their training of early career researchers who continue to make an impact.

The Last Word

Over the last 40 years, autism has moved from a categorial (yes/no) diagnosis to a dimensional diagnosis [85], taking into account the complexity and differences of features across the lifespan. While there may be core features of ASD that are common across the spectrum, people with autism, just like people without autism, are all different and need to be recognized as such [2, 86].  

While this summary captures what happened in 2021, we urge you to read more about how science has changed the way families with autism have been perceived, treated and helped over the past 40 years. The Journal of Autism and Developmental Disorderspublished a series that you can look through here, and Dr. Giacomo Vivanti shared his long-term perspective on the November 14 ASF podcast here: https://asfpodcast.org/archives/1258. In fact, one of the best ways to keep up with changes in autism science is to subscribe to the ASF podcast on Spotify, Apple Podcasts or Google Podcasts.

You can make a difference

These research findings and important discoveries were thanks to the thousands of families and autistic individuals who participated in research studies over the past few years. As you can read from this report, your contributions make an impact. There are other research opportunities and as we continue to live in the pandemic, many more of them are available in your own home with interaction with professionals to support you. You can read more about them here. Finally, there are ways to learn about credible science outside social media, which also includes SpectrumNews and the Autism BrainNet. Just signing up for more information on the Autism BrainNet gets you regular information about what the brains of autistic people look like and how they are different from those without a diagnosis.

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43.       de Nocker, Y.L. and C.K. Toolan, Using Telehealth to Provide Interventions for Children with ASD: a Systematic Review. Rev J Autism Dev Disord, 2021: p. 1-31.

44.       Leung, P.W.S., et al., Effectiveness of Using Mobile Technology to Improve Cognitive and Social Skills Among Individuals With Autism Spectrum Disorder: Systematic Literature Review. JMIR Ment Health, 2021. 8(9): p. e20892.

45.       Nuske, H.J., et al., Evaluating commercially available wireless cardiovascular monitors for measuring and transmitting real-time physiological responses in children with autism. Autism Res, 2021.

46.       Penev, Y., et al., A Mobile Game Platform for Improving Social Communication in Children with Autism: A Feasibility Study. Appl Clin Inform, 2021. 12(5): p. 1030-1040.

47.       Riches, S., et al., Therapeutic engagement in robot-assisted psychological interventions: A systematic review. Clin Psychol Psychother, 2021.

48.       Nuske, H.J. and D.S. Mandell, Digital health should augment (not replace) autism treatment providers.Autism, 2021. 25(7): p. 1825-1827.

49.       Green, J., et al., Randomised trial of a parent-mediated intervention for infants at high risk for autism: longitudinal outcomes to age 3 years. J Child Psychol Psychiatry, 2017. 58(12): p. 1330-1340.

50.       Whitehouse, A.J.O., et al., Effect of Preemptive Intervention on Developmental Outcomes Among Infants Showing Early Signs of Autism: A Randomized Clinical Trial of Outcomes to Diagnosis. JAMA Pediatr, 2021. 175(11): p. e213298.

51.       Davis, P.H., et al., Caregiver responsiveness as a mechanism to improve social communication in toddlers: Secondary analysis of a randomized controlled trial. Autism Res, 2021.

52.       Grzadzinski, R., et al., Pre-symptomatic intervention for autism spectrum disorder (ASD): defining a research agenda. J Neurodev Disord, 2021. 13(1): p. 49.

53.       Wetherby, A.M., et al., The Early Screening for Autism and Communication Disorders: Field-testing an autism-specific screening tool for children 12 to 36 months of age. Autism, 2021. 25(7): p. 2112-2123.

54.       Godel, M., et al., Altered Gray-White Matter Boundary Contrast in Toddlers at Risk for Autism Relates to Later Diagnosis of Autism Spectrum Disorder. Front Neurosci, 2021. 15: p. 669194.

55.       Tran, X.A., et al., Functional connectivity during language processing in 3-month-old infants at familial risk for autism spectrum disorder. Eur J Neurosci, 2021. 53(5): p. 1621-1637.

56.       Peck, F.C., et al., Prediction of autism spectrum disorder diagnosis using nonlinear measures of language-related EEG at 6 and 12 months. J Neurodev Disord, 2021. 13(1): p. 57.

57.       Gangi, D.N., et al., Declining Gaze to Faces in Infants Developing Autism Spectrum Disorder: Evidence From Two Independent Cohorts. Child Dev, 2021. 92(3): p. e285-e295.

58.       Miller, M., et al., Repetitive behavior with objects in infants developing autism predicts diagnosis and later social behavior as early as 9 months. J Abnorm Psychol, 2021. 130(6): p. 665-675.

59.       Plate, S., et al., Infant vocalizing and phenotypic outcomes in autism: Evidence from the first 2 years. Child Dev, 2021.

60.       Cost, K.T., et al., “Best Things”: Parents Describe Their Children with Autism Spectrum Disorder Over Time.J Autism Dev Disord, 2021. 51(12): p. 4560-4574.

61.       Vivanti, G., et al., The prevalence and incidence of early-onset dementia among adults with autism spectrum disorder. Autism Res, 2021. 14(10): p. 2189-2199.

62.       Gaugler, T., et al., Most genetic risk for autism resides with common variation. Nat Genet, 2014. 46(8): p. 881-5.

63.       Klei, L., et al., How rare and common risk variation jointly affect liability for autism spectrum disorder. Mol Autism, 2021. 12(1): p. 66.

64.       Wickstrom, J., et al., Patterns of delay in early gross motor and expressive language milestone attainment in probands with genetic conditions versus idiopathic ASD from SFARI registries. J Child Psychol Psychiatry, 2021. 62(11): p. 1297-1307.

65.       Wilfert, A.B., et al., Recent ultra-rare inherited variants implicate new autism candidate risk genes. Nat Genet, 2021. 53(8): p. 1125-1134.

66.       Rodriguez-Gomez, D.A., et al., A systematic review of common genetic variation and biological pathways in autism spectrum disorder. BMC Neurosci, 2021. 22(1): p. 60.

67.       de Jong, J.O., et al., Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder. Nat Commun, 2021. 12(1): p. 4087.

68.       Jacot-Descombes, S., et al., Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats.Mol Autism, 2020. 11(1): p. 89.

69.       Colombo, E., et al., The K63 deubiquitinase CYLD modulates autism-like behaviors and hippocampal plasticity by regulating autophagy and mTOR signaling. Proc Natl Acad Sci U S A, 2021. 118(47).

70.       Victor, A.K., et al., Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility. Front Mol Neurosci, 2021. 14: p. 747855.

71.       Vasic, V., et al., Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment. Genes (Basel), 2021. 12(11).

72.       Writing Committee for the Attention-Deficit/Hyperactivity, D., et al., Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders. JAMA Psychiatry, 2021. 78(1): p. 47-63.

73.       Monfared, R.V., et al., Transcriptome Profiling of Dysregulated GPCRs Reveals Overlapping Patterns across Psychiatric Disorders and Age-Disease Interactions. Cells, 2021. 10(11): p. 2967.

74.       Nassir, N., et al., Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells. Hum Genomics, 2021. 15(1): p. 68.

75.       Takanezawa, Y., et al., Microglial ASD-related genes are involved in oligodendrocyte differentiation. Sci Rep, 2021. 11(1): p. 17825.

76.       Falcone, C., et al., Neuronal and glial cell number is altered in a cortical layer-specific manner in autism.Autism, 2021. 25(8): p. 2238-2253.

77.       Rosen, N.E., J.B. McCauley, and C. Lord, Influence of siblings on adaptive behavior trajectories in autism spectrum disorder. Autism, 2021: p. 13623613211024096.

78.       Hollocks, M.J., et al., The association of adverse life events and parental mental health with emotional and behavioral outcomes in young adults with autism spectrum disorder. Autism Res, 2021. 14(8): p. 1724-1735.

79.       Schuck, R.K., et al., Neurodiversity and Autism Intervention: Reconciling Perspectives Through a Naturalistic Developmental Behavioral Intervention Framework. J Autism Dev Disord, 2021.

80.       Waddington, H., et al., The effects of JASPER intervention for children with autism spectrum disorder: A systematic review. Autism, 2021. 25(8): p. 2370-2385.

81.       Dai, Y.G., et al., Development and Acceptability of a New Program for Caregivers of Children with Autism Spectrum Disorder: Online Parent Training in Early Behavioral Intervention. J Autism Dev Disord, 2021. 51(11): p. 4166-4185.

82.       Wainer, A.L., et al., Examining a stepped-care telehealth program for parents of young children with autism: a proof-of-concept trial. Mol Autism, 2021. 12(1): p. 32.

83.       Sikich, L., et al., Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder. N Engl J Med, 2021. 385(16): p. 1462-1473.

84.       Yap, C.X., et al., Autism-related dietary preferences mediate autism-gut microbiome associations. Cell, 2021. 184(24): p. 5916-5931 e17.

85.       Rosen, N.E., C. Lord, and F.R. Volkmar, The Diagnosis of Autism: From Kanner to DSM-III to DSM-5 and Beyond. J Autism Dev Disord, 2021. 51(12): p. 4253-4270.

86.       Lord, C. and S.L. Bishop, Let’s Be Clear That “Autism Spectrum Disorder Symptoms” Are Not Always Related to Autism Spectrum Disorder. Am J Psychiatry, 2021. 178(8): p. 680-682.

A Summary of Autism Research in 2017 and What It Means for Families

By Alycia Halladay, PhD, Chief Science Officer of the Autism Science Foundation and the Scientific Advisory Board of the Autism Science Foundation

Listen to the 2017 Year End Summary here.

To listen to our year-end science summary podcast, click here.

This was not the first year that understanding the different subtypes of autism became a hot topic of discussion in the autism community, but in 2017, it certainly had much higher visibility on community blogs, in public speeches, editorials, science surveys, and public forums. There was especially fierce debate on the specific needs of people on the spectrum across the lifespan, with some divergence on the priorities of research.

The US Government Makes a Plan

Generating some of this discussion was the new strategic plan of the Interagency Autism Coordinating Committee (IACC). The committee, which is authorized by the Autism Cares Act, reconvened in 2015, but began work on a strategic plan for science this year. The IACC is made up of both public and private members representing funding agencies, advocacy organizations, people with autism, service providers, parents, and researchers, all members of the autism community. The group provides advice to the Secretary of Health and Human Services, collecting information from a wide variety of audiences to identify top priorities and needs in autism research. Importantly, the IACC does not make funding decisions, but the federal government uses its recommendations as a guide for calls for funding and other funding opportunities¹.

The IACC also writes a strategic plan for autism research each year, which guides but does not mandate funding opportunities. An updated IACC strategic plan published this year, reformulated seven crucial questions of importance for the autism community. It included an entire chapter devoted to meeting the needs of individuals as they move into adulthood, clearly an understudied and underfunded topic. The revision and expansion of this chapter sparked debate on what precisely those needs are.

Different Perspectives and Priorities 

Surveys and interviews in the United Kingdom have revealed differences in the research priorities of different stakeholder groups^2,3, and this year Autism Speaks conducted an online survey of its own⁴ which showed somewhat similar findings. As a whole, self-advocates and autistic adults place less of a priority on understanding early symptoms, biological mechanisms, causes, and treatments than parents. In addition to more formal findings in scientific literature, voices expressed via the blogosphere revealed highly disparate opinions of self-advocates⁵ and parents⁶. These differences may be partially explained by the differing abilities and disabilities of adults who are able to express their needs and voice their opinions and those who rely on parents or caregivers to do so.

But what does the science say? Qualitative research has revealed that autistic adults feel that research directed at changing them is counterproductive, and that adaptation needs to occur in the world around them³. Understandably, research priorities are also driven by individual personal experiences with individuals with autism and autistic adults^7,8. While the goal of the DSM 5 was to provide a more accurate and specific diagnosis, an unintended consequence has been to lump the differently able autism groups into one definition, sometimes creating confusion and resentment when limited research money is involved.

Unfortunately, developing specific ways to distinguish the different subtypes of autism across the spectrum has proven elusive and remains one of the big challenges of autism researchers. Current large-scale research projects are focused on using biological approaches to distinguish the different subtypes. The subtypes will be used to understanding the different causes, to understand different strengths and abilities along with needs and disabilities, and to develop more focused, personalized treatments. These subtypes may be based on how individuals function in society.

This year, given new initiatives in sharing, pooling and standardizing larger data sets, researchers were able to re-examine the differences in autism phenotype, called the “autismS,” scientifically. The goal of identifying different subgroups of individuals with autism and autistic adults is to better characterize their needs and abilities toward tailoring services and supports, because the needs of each person can be so drastically different across the spectrum.

The Big Way the Ends of the Spectrum Are Different From Each Other 

One factor that discerns both those who are able to self-advocate and those who need ongoing lifetime care is cognitive ability, measured by intellectual quotient or IQ. To truly understand the variability of people across the autism spectrum, big data is going to lead scientists to more answers.

This year, scientific research articles examined the different outcomes of individuals with autism with a wide range of cognitive abilities and found that IQ was an important predictor of outcomes in children with autism^9-12. These included children involved in treatment studies as well as research cohorts. This is not necessarily a new finding, but it does replicate findings in larger cohorts that had previously only been replicated in smaller studies.

In these studies, autism severity scores, adaptive behaviors, and communication improved in individuals with higher IQs¹²; those with lower IQs typically had the highest severity symptoms¹⁰. Additionally, while stability of an autism diagnosis is high, children with autism who did ultimately move off the spectrum after diagnosis were more likely to have an average developmental quotient, reflecting higher cognitive ability¹³. Of course, early intellectual quotient does not fully explain outcome¹¹, as language ability is also crucial¹². It is also important to note that although cognition is often intact in individuals with optimal outcome, IQ alone does not always result in independent functioning. In other words, IQ is not the be-all-end-all of outcome in autism. As revealed in the Autism Speaks Autism Treatment Network, many individuals with ASD who do not have cognitive impairment exhibit significant deficits in adaptive functioning, and this gap has again been found to be larger in older versus younger individuals¹⁴. These differences can be associated with psychiatric comorbidities into adulthood¹⁵. These findings highlight the need for evaluating, monitoring, and treating adaptive behavior over time to determine whether an individual is independently applying her repertoire of cognitive skills to daily routines and activities when life demands them. The most comprehensive measure for assessing adaptive behavior is the Vineland Adaptive Behavior Scales, now in its Third Edition¹⁶, which helps clinicians better assess the role of adaptive behavior in both symptoms and a multitude of outcomes associated with autism.

Other larger scale studies to subtype children with autism have revealed that more subtle language use and language impairments do a good job of distinguishing different groups of people with autism, and that these groups also differ in non-verbal IQ¹⁷. In the Study to Explore Early Development, a project that included almost a thousand preschool children with autism, clinician scientists explored how symptoms cluster together to form groups, which may be then used to describe subtypes. Factors such as language impairments and cognitive rigidity predicted who was in what subtype¹⁸. This is the largest study so far to look at different aspects of functioning and abilities in a group of children with the intention of trying to group them into different types.

Beyond “Yes or No” as a Diagnosis 

But why look at an autism diagnosis as an either/or thing when there is so much that distinguishes people across the spectrum? Rather than considering autism a “yes or no” diagnosis, there is now more evidence from larger groups that there are different dimensions of autism symptoms in children, including language and cognitive ability¹⁸. It is less about presence or absence of intellectual disability and language, but language and cognitive abilities along a continuum of impairment. Cognitive ability may also play a large role in autism diagnosis. A recent prospective study of the DSM-5 reinforced the high sensitivity and specificity of the newer DSM-5 criteria, while also revealing that those with higher IQ who were labeled under DSM-IV may not have met the threshold for an autism diagnosis under the DSM-5¹⁹. Taken together, these studies further add to the research published this year that demonstrate different features of autism may constitute different types of autism, or new forms of autism altogether.

Efficacy of different intervention strategies also seems to be dependent on IQ of the child, as a scientific analysis of the anecdotal reports of fever improving symptoms was investigated. Parents with a child with lower non-verbal IQ and lower language levels reported more fever-related improvements in communication and repetitive behaviors²⁰. This could be explained by multiple factors, including the presence of a definable subtype that is more responsive to different interventions.

The Biology Behind Autism Subtypes 

Large-scale genetics studies of thousands of individuals with autism showed that different autism subtypes also have distinct genetic profiles. For example, those with what is known as a de novo mutation (not present in mother or father), show lower IQ scores and higher rates of epilepsy than those with what are known as common variants²¹. Therefore, different types of genetic mutations can have different influences on autism symptoms and can work together to shape different features of autism. Common variants, which can be inherited, are seen in everyone, but add together to increase risk of certain diseases like Alzheimer’s and Crohn’s. They do not seem to influence intellectual function in autism, while de novo variants do²¹. Whole genome sequencing studies also showed the diversity of different types of genetic variants in people with autism.²² While the association of de novo variants with lower IQ in individuals with autism is not a novel finding, the replication across multiple large-scale studies is an important contribution.

Adding to the complexity of the role of these de novo mutations, researchers discovered that when those with and without de novo mutations were matched based on IQ, those with de novo mutations actually have less pronounced autism symptoms²³. Therefore, these finding suggest that these mutations may not confer any more risk for autism than other types of mutations. In other words, they may be more indicative of IQ than they are of autism. In addition, those individuals with de novo mutations had a different pattern of brain activity when shown non-social vs. social video scenes, independent of cognitive ability²⁴. In fact, in some analyses, for people with autism and de novo gene mutations, intellectual disability is treated as a co-morbid symptom rather than a subtyping measure²⁵. This again shows the differential influence of de novo gene mutations and other types of mutations on autism symptoms, and the importance of taking IQ into account when understanding autism and that presence of intellectual disability, presence of de novo variants, or both, may be a distinct autism subtype.

Big data, or large sample sizes, also helped scientists understand how an autism diagnosis influences immune functioning on a genetic level²⁶ and has helped resolve discrepancies in findings in brain structure across studies. In fact, the largest study to date of people with autism at different ages illustrated that the cortex is most enlarged in adolescence, and replicated findings that other areas like the nucleus accumbens (moderating reward) and the amygdala (controlling emotion and anxiety) were smaller in those with autism²⁷. The ultimate in “big data,” whole-genome sequencing, revealed new genes of interest and greater appreciation for the role of these genes. For example, one group found that previously understood areas of the genome, previously unstudied, could be important for ~6% of autism diagnoses²².

Presence of mutations in newly identified autism risk genes were also associated with lower adaptive ability, furthering the notion of a more severe genetic phenotype, as suggested earlier²⁸.

With new datasets, it is also possible to determine the origin of when the de novo mutation occurred. As these de novo mutations occur in a small percentage of people with autism, large numbers are needed to better understand their influence and role in diagnosis. These different types of mutations can occur prior to the formation of the embryo, or in the post-zygotic period after the formation of the embryo. The timing of these mutations seems to have influence over behavioral features²⁴ and has also been linked to the development of specific brain regions, specifically the amygdala²⁹. There is also preliminary evidence to suggest that individuals with these post-zygotic mutations are less likely to be intellectually impaired²⁹, again tying genetics with intellectual function and autism diagnosis. These post-zygotic mutations are present in a significant percentage of individuals with autism³⁰, making them a potential target for new personalized medicine initiatives.

Genetics Provides More Answers 

The genetic influence on specific behaviors, particularly autism-related behaviors, was better understood this year. By looking at twins, researchers were better able to establish the genetic influence of specific autism behaviors, specifically different eye gaze, which describes how people with autism pay more attention to objects and less to social situations³¹. This behavior controls how people with autism take in information about the world around them. Under strong genetic influence, eye gaze is altered in people with autism, and this differential input of different exposures then influences brain development. As Warren Jones, an author or the study stated, the effects of genetic influence on behavior “ripple forward” to alter brain development.

Genetics have also helped explain the comorbidity of autism with psychiatric issues and disorders. While behavioral overlap is seen between autism and disorders like schizophrenia, ADHD and anxiety, there have been few studies that identify a genetic overlap. This year, a novel locus on chromosome 10 was identified through large scale collaboration of multiple genetic cohorts³². With regards to schizophrenia, the exact symptoms and the mechanisms of schizophrenia and autism are not identical. But what causes the difference? To investigate, researchers used a sample of over 5000 individuals to determine the overlap between social communication symptoms in both autism and schizophrenia. It seems as the genetic influences of social communication features in autism and schizophrenia may be based on development, with one genetic factor being more prominent in early development (autism) and the other in adolescence (schizophrenia)³³.

Beyond psychiatric comorbidities associated with autism, one of the concerns of both families and autistic adults is presence of medical comorbidities, such as epilepsy. A large percentage of people with autism have some form of epilepsy, but not everyone with epilepsy has autism. So is there something different about epilepsy in people with autism? In order to address this, scientists focused on the SCN2A gene, which codes for a sodium channel that can mediate the activity of a neuron³⁴. Research using genetic, molecular and electrophysiological data showed that very tiny variations in the way this channel works may be at the center of these differences. Some mutations in the way the sodium channel functions are associated with epilepsy in the absence of autism, another type of mutation on this same gene which controls the same sodium channel is associated with epilepsy as a comorbid disorder to autism³⁴. This opens up possibilities to both better understand autism and epilepsy, and how to treat the specific features of epilepsy in people with autism.

Other major breakthroughs were made using animal models to understand the molecular underpinnings of autism, providing new hope for novel drug treatments. For example, individuals with mutations of a specific region of chromosome 16 have a high risk of autism. A better understanding of genes on this chromosome could lead to more targeted treatments. One of these genes, KCTD13, was found to be crucial to the changes in synaptic plasticity associated with mutations of chromosome 16, and most importantly, these changes were reversed with a compound that inhibits a chemical called RhoA³⁵. In another study, behavioral features following a particular mutation in the tuberous sclerosis gene in mice was shown to be similar to those with autism. These features were controlled by a particular cerebellar circuit, one that could be turned on and off in the animal model³⁶ and rescued some of the behavioral features. Taken together, these exciting findings illustrate the capacity for new medical or pharmacological interventions to treat not all of autism, but particular symptoms determined in part, by the presence of different genetic mutations.

It’s Not All Just Genetics 

Genetics is not the entire story in autism, and scientists continue to identify environmental factors that work together with genetics to confer risk, and through that, to identify ways to preempt symptoms, especially in those most disabled.   In 2012, the first study appeared suggesting that maternal consumption of folic acid prior to pregnancy and during pregnancy reduced the probability of having a child diagnosed with autism. This year, two new large epidemiological studies in the US and Europe replicated and expanded these findings, showing a lower probability of having a child with autism after folic acid use³⁷ during pregnancy, and more specifically, a child with autism and intellectual disability³⁸. A meta-analysis of multiple studies showed this effect was not limited to one particular race or ethnicity³⁹ and is present regardless of whether there was a strong genetic or environmental component to the diagnosis^37,40. The recommendation to take folic acid prior to or during pregnancy is not unusual—it’s something that the March of Dimes has been telling women to do for decades to reduce birth defects. Also, gene/environment interactions, rather than the influence of one or the other, have again proven critical. Presence of a genetic mutation called a copy number variation, plus exposure to high levels of air pollution, showed an effect on diagnosis more than either by itself ⁴¹.

This year, the presence of gene/environment interactions was, for the first time, explored in terms of autism symptoms rather than probability of autism diagnosis. Rather than examine each genetic mutation individually, researchers examined environmental exposure with type of genetic mutation—either copy number variation or mutation—in likely autism genes. Two studies revealed that the combination, rather than each in isolation, increased autism severity scores in children with prenatal exposures and genetic factors^42,43. This approach will open the doors to new ways to understand genetic and environmental contributions together, rather than in isolation, on different autism outcomes.

Some environmental factors have been shown to increase probability of a diagnosis in the absence of genetic susceptibilities. One such risk factor, maternal immune activation in response to an infection, has been shown to raise the probability of having a child with autism up to two-fold. This year, toxoplasmosis and herpes were added to the list of possible immune events that can increase risk^44,45. More importantly, the mechanism by which maternal immune activation alters probability of diagnosis was better ascertained. While previous studies have hypothesized through animal models or epidemiological designs that circulating chemicals called cytokines, produced as a response to maternal immune activation, were the cause, newer findings in the cerebral spinal fluid in individuals with autism and autistic adults has not found this to be the case⁴⁶. Rather, transcription of genes that control how the brain is connected and shaped during development can be altered with early immune activation⁴⁷ and is thought to be more crucially involved. And it isn’t all forms of maternal immune activation, as the presence of fever specifically as part of the immune reaction is also an important component of the effect⁴⁸.

Another environmental factor, spacing of pregnancies, was also replicated as a risk factor in a large study. Too little time or a large amount of time between pregnancies increased the risk of the second child having an autism diagnosis⁴⁹. Better understanding of the mechanism by which this occurs could lead to factors that could preempt symptoms⁴⁹.

Of importance to the community, some environmental factors have been dispelled as influencing a diagnosis. For example, new and advanced statistical techniques have unraveled the role of maternal depression from maternal antidepressant use, and found that the use of antidepressants itself was not sufficient to elevate the probability of having a child diagnosed with autism⁵⁰. Also, rather than infertility treatments, infertility itself seems to be underlying the link between in vitro fertilization and autism⁵¹. Understanding of these relationships allows parents to have more informed conversations with their doctors about family planning.

Paternal and Grandparental Factors

Environmental exposures aren’t just a “mom thing,” either. Paternal exposures are also known to play a role. Both maternal and paternal prenatal exposures to asthma- causing agents have also been shown to be linked to autism⁵². Advanced paternal age, linked to autism in multiple studies previously, was also more carefully examined. The same researchers who studied the association to autism also quantified factors in older fathers that led to higher educational achievement in kids, and named them in aggregate as the “geek index⁵³.” Those fathers with a higher “geek index” were more likely to have male children who went further in school and earned more money⁵³. This outcome is clearly different from those with lower functioning autism, who may not be able to be independent. This shows that there are different pathways originating from the same place, which are associated with different outcomes. Paternal influence on outcome might possibly be explained through epigenetic mechanisms—the way environmental factors turn on and off genes during development. Exposures prior to pregnancy might affect both the sperm and egg of future generations, seen when there is a paternal effect. These changes in gene expression have been linked to a number of outcomes, including autism. They are not just observed in parental exposures, but in grand-parental exposures as well. These types of observations are incredibly hard to achieve, since outcomes need to be tracked across generations, through many decades. However, use of registry data or longitudinal studies where databases are linked on related individuals now makes this possible.

This year saw the first study of grand-parental exposure on later autism features. Grand-maternal smoking was linked to impaired scores on social communication measures and restrictive and repetitive behavior scales, which are independently predictive of an autism diagnosis⁵⁴. Not only is it the first study to look beyond mother/father exposures, because this grandmaternal exposure affects the egg or sperm of subsequent generations, these findings advance the role of epigenetic mechanisms involved in autism. These include methylation, where methyl groups that are attached to areas of the DNA turn on and off gene expression, and histone acetylation, where DNA winds on histones, which may affect gene expression. Late last year, a project that investigated the cumulative effects of genetic mutations with environmental exposures was conducted in cell lines. This study showed new methylation marks on even more autism risk genes, which may cause genetic instability in areas of the genome outside the original mutation⁵⁵. This opens up new ways to understand the role of genetic and environmental contributions to autism. However, because epigenetic marks are dependent on the tissue of interest, studying the brains of people with autism is essential to better understanding underlying causes of ASD.

It Takes Brains to Solve Autism

The Autism BrainNet provides brain tissue to researchers worldwide to not just discover the causes of autism, but also identify newer treatment targets, and pinpoint the underlying neurobiology of autism to better understand individuals with autism. The largest study to date on methylation in autism found greater levels of methylation in autism brains compared to those without autism, across the genome but also in particular patterns of DNA regions⁵⁶.   Looking more specifically at particular neurons in the cortex, areas that are more or less methylated in autism compared to those without autism were focused on the immune system and neurodevelopment⁵⁷. Taken together, differential patterns of methylation in brain tissue may explain gene / environment interaction in autism.

But the autism discoveries, which are possible thanks to brain tissue, are not limited to causation. The region called the amygdala has been linked to autism through genetic, behavioral and structural neuroimaging studies. Looking at the cells in the amygdala, researchers find that the neuron length is longer and there are more sites of contact with other neurons on them in the autism brain⁵⁸. However, these changes are age-dependent, as there are greater spine densities compared to controls in children and adolescents and less density compared to controls in adulthood, which may partially explain changes in symptoms of autism as people age⁵⁸. Another clinically relevant finding is the loss of what are known as inhibitory neurons in the cortex of brains with autism. A decrease in signals that slow down neuronal activity in the brain may contribute to the dysregulation of too much or too little activity in multiple areas brain examined by different research groups^59,60. In addition to a reduction in inhibitory neurons which help with the checks and balances of brain activity, there is evidence that cells that become neurons of the corpus callosum, the tract of fibers that connects the right and left hemisphere, do not develop properly ⁶¹. This is consistent with other studies using imaging techniques, which demonstrate that cells in the brain do not go to the right places or do not reach their final destinations accurately. These results also help explain some of the behavioral and biological signs of ASD.

The Big News This Year: Biology Before Behavior 

Some of the most highly-publicized and possibly the most impactful findings from this year were multiple studies that looked at early biological signs, or biomarkers, of autism before autism symptoms emerge. One longitudinal research study, called the Infant Brain Imaging Study, tracked brain size and shape of infant siblings of those with an autism diagnosis, who have a 15x risk of being diagnosed themselves. In this way, biological features from as young as 6 months of age were tracked in infants to 2 years when autism diagnosis could be made. This allowed scientists the unprecedented ability to detect biological features prior to when even very early warning signs emerge, with the potential for even earlier detection and, hopefully, earlier intervention.

Earlier findings from the Infant Brain Imaging Study revealed that white fiber tracts grew at a slower rate in infants with autism compared to those who did not. While interesting, those findings were also preliminary. This year, a more detailed analysis of growth in infants with autism showed that increased surface area of the cortex from 6-12 months was tied to brain overgrowth at 12-18 months, which was then associated with social deficits⁶². The researchers then took this larger data set—MRIs of brain volume, surface area, cortical thickness at 6 and 12 months of age, and gender of the infants—and used a computer program to identify a way to classify babies most likely to meet criteria for autism at 24 months of age⁶². Now scientists are even closer to finding a biological method of detecting autism even before behavioral features emerge in babies with an older sibling with autism.

This finding was followed by the discovery in the same dataset of the use of 6 months functional connectivity as an accurate predictor of autism diagnosis⁶³ and identification of the circuit that controls a key feature of autism—joint attention⁶⁴. Functional connectivity analyses at 6 months also revealed a different circuit for the emergence of repetitive behaviors and sensory sensitivities⁶⁵. Later in the year, another analysis of the data revealed an 18% increase in cerebrospinal fluid outside the brain could be detected in those with autism as early as six months of age⁶⁶.

While the Infant Brain Imaging Study was used to generate algorithms for earlier diagnosis, other investigations also revealed different interesting biological markers that need further study. For example, electroencephalographic (EEG, a measure of brain activity) markers in the frontal lobe of the brain were altered in three month-old infant siblings of those with autism, compared to those without an older sibling⁶⁷. Another research group showed that, at seven months, EEG during a gaze shifting task improved the accuracy of a commonly used instrument to detect early signs and symptoms of autism in infants, the Autism Observational Scale in Infants⁶⁸. This suggests that biological measures can enhance behavioral observation to predict ASD. At 18 months, compared to toddler siblings of those without an autism diagnosis, younger siblings of individuals with autism exhibited less synchronized activity between both sides of the brain. These infants showed higher levels of sensory seeking, which was linked to autism symptomatology⁶⁹.  This may open the door for earlier interventions focused on particular symptoms, reducing disability.

New Early Markers of Autism

Current larger scale studies are now examining the use of EEG as a biomarker for autism and how it is linked to symptoms. The convergence of data around neurological signs of autism, before even the time when symptoms are able to be detected by a trained clinician, shows the importance and power of infant siblings research design to identify the earliest biological signs. Earlier detection leads to expedition into early intervention. But it wasn’t just about biology. Another, even earlier, behavioral marker was revealed this year. This was to name which, when not present by nine months, predicts an earlier diagnosis of ASD and lower receptive language scores⁷⁰. Pediatricians should be urged to consider this as an early warning sign of ASD.

The Autism Community Takes Part

The same biological markers used to aid in early detection of autism are also helping to understand how early interventions are affecting brain function. Following very early exposure to a parent-delivered intervention for those who have a 15x higher probability of an autism diagnosis (infant sibs), some of the brain activity markers changed within months after the intervention. This shows that parent-delivered interventions help to change both behaviors and brain function. And while parent-delivered interventions don’t necessarily lead to a change in autism diagnosis as a “yes or no” concept, longer term follow up of early infant interventions have, again, resulted in positive findings with regards to attentiveness and initiation of communication⁷¹, which may lead to even greater gains with longer follow-up, or higher level of functioning in those with a diagnosis. Of great importance to advocates making the case for getting these interventions covered by insurance, the cost savings realized in the long run in early interventions was documented through an economics approach⁷². Early intervention, not surprisingly, costs more in the beginning in terms of added services, but eventually more than makes up for those upfront costs through savings in fewer services needed in adolescence and adulthood⁷².

In the past, many intervention and treatment studies have met with difficulties because accurate measures to study change over time in people with autism have not been developed or validated. In order to address this challenge, new measures have been designed and tested. One uses biosensors to collect biological data including heart rate, eye tracking and a sleep monitor, which will be used in future clinical trials to incorporate biological markers into treatment outcome⁷³. Another used a portal EEG machine to track brain activity during a variety of circumstances and settings⁷⁴. Importantly, two new behavioral instruments incorporating parental feedback into the final product were validated this year. The first was the direct result of the Patient Centered Outcome Research Institute, funded by the Affordable Care Act. This measure asks parents to nominate their top concerns for later tracking of treatment response. This measure has been shown to be valid in tracking symptoms of ADHD in children with autism⁷⁵. The other, the Autism Family Experience Questionnaire (AFEQ), was developed with consistent input of parent groups and consists of four domains relating to parental perspectives, child social functioning, family life and child symptoms⁷⁶.

How Technologies Can Enhance Interventions 

Technology has also shown to be an important adjunct to intervention protocols. For example, the smartglass (previously known as Google Glass) has been repurposed by other companies and has been shown to be well tolerated and fun for both children and adults with autism^77,78, reducing symptoms of ASD, such as challenging behaviors, and improving non-verbal communication⁷⁷. Augmentative and alternative communication (AAC) devices have also been studied in a variety of settings over the past few years, but surprisingly, they have only been investigated for a limited range of communicative gestures, like requesting^79,80. Now, they are being studied and proving helpful in conjunction with, rather than replacing, naturalistic behavioral interventions⁸¹. Further research should focus on using these devices for a wider range of communication skills.

iPads, which are used by so many families or individuals with autism, were not previously studied scientifically in terms of their use for different purposes. In a new study this year, however, a group examined if the iPad was really helpful in enhancing the effectiveness of a home-based parent-delivered intervention. In fact, use of the iPad led to short-term improvements in autism-related behaviors and an increase in certain skills; however, the amount of time kids used the iPad in conjunction with the intervention declined over time⁸². They were probably still using the device, but not for its intended use. Newer applications will need to provide additional ways to engage users for the purpose of intervention. Other therapies, such as music therapy, were shown in a randomized trial to be no better than other therapies for core autism symptoms⁸³. However, if you or your family love music, don’t drop music therapy yet – there is no evidence to say it is harmful or doesn’t work as an adjunct to more proven intervention techniques. Many parents I know who use music therapy use it in conjunction with other techniques.

More Findings About Females, But Much More Is Needed 

In 2015, this summary was titled “The Year of the Female” due to the increase in studies focused on females with autism. This year saw a continued explosion in the knowledge around females with autism and how sex differences in those without autism can help inform why females have different symptoms and different prevalence of ASD. In fact, an entire issue of the journal Autism was devoted to scientific investigations of females with ASD⁸⁴. The topics of this issue ranged from impressions from clinicians and psychometrics of current assessment instruments in females to why the prevalence of autism is different in males compared to females. This last question has intrigued and frustrated researchers, because understanding this difference might lead to a better understanding of the causes, treatment and measurement of both males and females with ASD.

What Explains the Gender Gap? 

While previously assumed to be 4:1, the M:F bias in autism might actually be less. A new review and meta-analysis of millions of people shows variability across studies and calls into questions the original 4:1 number⁸⁵. However, even at 3:1, there is a considerable difference in prevalence in autism between males and females, and several theories about what’s behind this disparity.

One theory is that females, through better innate social communication abilities, are able to camouflage their symptoms and mask their diagnosis. This has been observed in the naturalistic setting of recess in elementary schools, illustrated by females showing compensatory behaviors in social situations⁸⁶. Camouflaging was also operationalized by a research group who defined it as the difference between how someone feels on the inside (self-report measures of autism symptoms and measures of social cognition) compared to how they appear on the outside (observational measures)⁸⁷. Using this methodology revealed higher camouflaging scores in females⁸⁷, further reinforcing this as a potential mechanism for diagnostic disparity. Unfortunately, higher camouflage scores were also associated with higher markers of depression, indicating the need to recognize psychiatric issues in females with ASD.

Another hypothesis for the difference in prevalence is that females are protected against an autism diagnosis. This year, additional evidence was published that supports the concept of a female protective effect in autism. This protective effect may be seen in the siblings of autistic females. To examine this using the big data approach, the rate of autism diagnosis in families was examined when the first child was a male vs. the first child was a female. When the older sibling was a female, recurrence rate was 1.3x higher than if the older sibling was a male⁸⁸. This is consistent with other data finding that autistic females have more genetic mutations that are also seen in family members, but don’t always translate to an ASD diagnosis—hence, a protective effect in females with this shared genetic burden.

The female protective effect was also observed with regards to prenatal androgen levels. In children whose older sibling was a male, there was no association between cord blood levels of androgen and either early autism scores or social responsiveness. However, if the older sibling was a female, there was a positive association between prenatal testosterone and autism at both 12 and 36 months⁸⁹. This could mean that the shared genetic liability seen in siblings of females changes sensitivity to prenatal androgen exposure. Finally, the protective effect was observed in brain tissue of individuals with autism. Female brains showed more dysregulated RNA levels, particularly in immune system and nervous system pathways, demonstrating a greater genetic load in females despite a lower prevalence⁹⁰, consistent with other studies examining the differences in gene expression in males and females with ASD.

Let’s Talk About Sex

Possibly due in part from pressure from the self-advocacy community for more and higher quality research to help and better understand adults with autism, more scientific findings were published relating to the specific challenges faced by adults with ASD.

First, most diagnostic tools have traditionally been geared towards children with ASD. A new instrument called the 3Di-Adult takes about 40 minutes to administer and was shown to be both sensitive and specific⁹¹ to diagnosing autism in adults, providing a resource for adults who previously had not received a formal diagnosis.

Studies focused on sexuality in people with autism almost tripled this year, and many of them reinforced what the Neuroqueer movement has been saying for a while: People with autism are less likely to affiliate with an established gender or sexual orientation^92-95. Autistic females are more likely to have more sexual partners, but also more negative sexual experiences compared to males⁹³. A new sexual education program was released that has shown to help with what might be the biggest issue in sexuality in autistic adolescents and adults: poor or incomplete sexual education⁹⁶.

Autism and Employment Challenges

Another important issue affecting many autistic adults is employment. After 10 years of gathering data from vocational rehabilitation services, it appears that the only predictor of employment outcome is number, not type, of VR services, suggesting “the more the better⁹⁷”. Outside VR services, other factors predicted successful sustained employment. These included better independent living skills, receiving an inclusive education, and living in an urban environment (probably due to transportation issues)⁹⁸. The good news is that the research community is paying special attention to employment issues, supporting a policy brief for employment, and developing new types of programs.

Big Findings Come From Big Data

This was another exciting year for autism research, using big data to better understand and isolate the factors that make people with autism similar and different. Whether you are a person with autism, a family member, a service provider, or someone else affected by autism—regardless of whether you agree on the needs of people with autism, no matter the IQ or verbal ability of you or your child—progress is being made each year to make your life better.

While it may be difficult to see in the very short term, giant gains continue to be made thanks to scientific advances that can be seen after 5 years, or even a decade. It’s frustrating to be told to “just be patient,” but the “informed hope” we should all have is that science and research will continue to provide answers—answers that help everyone.

Thank You

The research and the progress in care thanks to scientific understanding of autism does not happen without families and individuals who give their time and effort for these studies. Thank you! Researchers also play an important role—it’s not an especially glamorous job and the hourly pay would be way below minimum wage. The contributions by the entire autism community make these things possible. Want to participate? Register for the Autism BrainNet at www.takesbrains.org. Answer a few questions and spit into a tube and you can become part of Spark at www.sparkforautism.org. Spark is exactly the sort of “big data” project that will help understanding of individuals across the spectrum and what makes them so different.

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