• What is happening early in development?
• Are there known biological differences that help explain ASD symptoms?
• Can subgroups of people with ASD help us understand the etiology of ASD symptoms?

What Do We Know?

Researchers, clinicians, and families have long posed questions about the possible biological bases of ASD. Clinicians classify ASD as a developmental brain disorder based on the behavioral features required for diagnosis. Little evidence exists, however, for a specific neurological abnormality beyond reports of an exuberant and transient pattern of brain or head growth (Akshoomoff, Pierce & Courchesne, 2002; Dawson et al., 2007; Hazlett et al., 2005). While much of the current science suggests that the behavioral features of ASD result from atypical brain structure, wiring, or connections, there is no proven neural variance associated with ASD. Nevertheless, there are some promising leads, and projects are under way that have the potential to provide biological signatures of some forms of ASD.

The development of sophisticated imaging methods has enabled researchers to accurately visualize many aspects of brain structure and functioning. For example, many children and adults with ASD perceive and analyze the visual information conveyed by facial expression differently than do other people (Spezio et al., 2007). Other researchers have employed magnetic resonance imaging (MRI) methods to investigate differences in brain anatomy between people with and without ASD, and have found differences in the density of white and gray matter, in some cases linked to specific symptoms of ASD (Craig et al., 2007).

Subsets of people with ASD have been reported to have experienced regression (i.e., the loss of previously acquired language, social, and developmental skills). The phenomenon is poorly understood and may co-occur with medical conditions common to people with ASD, such as epilepsy. Recent studies have sought to understand the relationship between regressive symptoms, co-occurring disorders such as epilepsy, and the etiology of ASD.

Regression is not unique to people with ASD, and the loss of language skills (acute language regression) can occur in people without the disorder. In one study, researchers found that children with acute language regression (who did not have ASD) were more likely to have associated seizures or epilepsy than were children with regressive autism (which includes language regression, as well as the loss of other social and developmental skills). This suggests that there are different subtypes of language regression and may help to understand the phenomenon and its relationship to ASD (McVicar et al., 2005).

Currently, the frequency of language regression is unknown in either children with ASD or the general population. Previous studies of regression have been hampered by delayed referral for evaluation after the onset of regressive symptoms (McVicar et al., 2005).

A few hypotheses regarding how disruptions of the immune system might contribute to ASD and other neurodevelopmental disorders have emerged in recent years. Some recent findings suggest that the immune system differences of parents and their children may affect early brain development and the onset and fluctuation of symptoms in some children with ASD (Pardo, Vargas & Zimmerman, 2005). For example, some research indicates that maternal autoantibodies directed at fetal brain tissue could interfere with normal brain development (Braunschweig et al., 2008). While such medical symptoms may not be entirely specific to ASD, treating them may have significant impact on quality of life, symptom severity, and level of functioning.

Better understanding of the biology of genes linked to ASD and their functions can also provide insight. Recent studies have shown that the MECP2 gene (mutations in which can cause Rett syndrome) is involved in forming connections at the synapse. Genes regulated by the fragile X syndrome gene, FMR1, also directly affect synapse function by controlling signaling of the neurotransmitter glutamate. In addition, a 2008 study found that the two genes that cause tuberous sclerosis complex (TSC) impair the formation of axons. Recently, several groups reported remarkable success with targeted therapies in animal models of these disorders, showing the ability to reverse the underlying neuroanatomical and even behavioral deficits in the adult (Dolen et al., 2007; Ehninger et al., 2008; Guy et al., 2007). Understanding how MECP2, TS1, FMR1, TSC1 and TS2/TSC2 regulate the growth and function of neurons may help scientists understand related disorders such as autism.

What Do We Need?

Exploring the biological bases of ASD requires access to biospecimens of people with and without ASD. Some progress has been made to establish the necessary infrastructure for the collection and preservation of postmortem tissue from people with ASD. Nevertheless, the tissues currently available are insufficient for the needs of researchers. Educational campaigns, through contact with health care providers and the internet, may be useful to increase public awareness. New technology is expanding biological research beyond postmortem tissue. For example, it is now possible to create pluripotent stem cells from skin fibroblasts of individual patients to create neuronal cell lines for study.

One of the greatest barriers to progress in determining the biological bases of ASD has been the heterogeneity of the spectrum. A clear need exists to advance understanding of the many phenotypes of ASD, including studies that link genotype to phenotype, investigations of natural and treated history, analyses of genetic interaction with environmental exposures, and studies of co-occurring behavioral and medical conditions. Different autism phenotypes may have different etiologies. There is a need to combine genotyping and functional analysis to better understand the contribution of specific genotypes with functional or structural subtypes. To determine the earliest discernable onset of ASD, experts have expressed the need for an intensive, multidisciplinary study starting at early ages that examines biomedical, neurodevelopmental, and behavioral trajectories of children with ASD. A parallel multidisciplinary analysis of typically developing children and children with non-ASD developmental disorders would be especially enlightening, as limited normative information is currently available. An evaluation of differences in the interplay of biology and environmental exposures for children with and without ASD is also needed. Understanding early trajectories may lead to targeted interventions aimed at mitigating behavioral and medical challenges and improving outcomes through adulthood.

Another understudied arena of ASD research is gender differences. Many studies of autism preferentially enroll males, who, due to a 4:1 increased prevalence, are easier to recruit. Without additional information about the biological features of ASD in females, it remains unclear whether the course of ASD is similar and whether currently used interventions are appropriate for females. It is critical to determine how sex is related to etiology, protective factors, diagnosis, and trajectory. In addition, many studies of autism preferentially enroll higher-functioning individuals who do not have cognitive impairment, because of their ability to cooperate and participate in study-related tasks. However, these individuals represent only a subset of all individuals with autism, and lessons learned from them may or may not be generalizable to all individuals with ASD. Priority must be made to develop studies looking at the underlying etiology of nonverbal individuals and to understand the impact of and etiology of co-occurring language and cognitive impairment.

2011 Addendum To Question 2: How Can I Understand What Is Happening?

What Is New in This Research Area, and What Have We Learned This Past Year?

Over the past year, a group of notable studies advanced what is known about the underlying biology of ASD with respect to neuropathology, symptoms, and cellular metabolism/signaling. In recent years, researchers have noted abnormalities in brain growth, structure, and connectivity in ASD, and numerous 2010 studies strengthen the idea that the brains of people with ASD develop and connect in atypical ways (Anderson et al., 2010; Groen et al., 2010; Lai et al., 2010, Qiu et al., 2010; von dem Hagen et al., 2010).

Researchers published results of the first longitudinal study of early brain growth in toddlers aged 1½ to 5 (Schumann et al., 2010). They found evidence of cerebral gray and white matter overgrowth in all regions by age 2 ½. After correcting for age and gender, they found that almost all brain regions developed at an abnormal rate in ASD and that this trend was more pronounced in girls. Other studies uncovered differences in the volume and structure of the brain's white matter, the component of the brain that carries signals from one region to another and that allows communication between the two hemispheres (Kumar et al., 2010; Zikopoulos & Barbas, 2010). It was recently discovered that such structural abnormalities are found not only in children with ASD, but their unaffected siblings as well (Barnea-Goraly, Lotspeich & Reiss, 2010). New advances in the use of magnetic resonance imaging (MRI) suggest that structural differences in the cortex of the brain could be used as a potential biomarker for ASD (Ecker, 2010).

Important research advances continue to improve the understanding of how changes in the brain might lead to unique characteristics of ASD. Researchers have recently found abnormalities in underlying neural circuits linked to characteristic traits such as atypical eye gaze and difficulties processing visual information, facial expressions, and biological motion (Akechi et al., 2010; Brieber et al., 2010; Dinstein et al., 2010; Dziobek et al., 2010; Kikuchi et al., 2010; Kliemann et al., 2010; Koh, Milne & Dobkins, 2010; Loth, Gomez & Happe, 2010; New et al., 2010). A recent study of biological motion perception suggests that the distinct brain response in ASD may provide a neural endophenotype for the disorder (Kaiser et al., 2010a; Kaiser et al., 2010b). Another notable study is the first to identify a specific gene that can be associated with a neural endophenotype of ASD (Scott-van Zeeland et al., 2010). Using brain imaging, researchers found that variations in the known risk gene CNTNAP2 are associated with differences in functional connectivity in the frontal cortex and can predict performance on a rewards task.

In addition, the Committee has noted the importance of a consensus report about evaluation, diagnosis, and treatment of gastrointestinal disorders in children with ASD in the journal Pediatrics (Buie et al., 2010b). While the panel concluded that it was too early to make evidence-based recommendations, the consensus expert opinion was that people with ASD deserve the same thoroughness and standard of care in treating gastrointestinal symptoms as all patients, and that problem behaviors in ASD may stem from gastrointestinal problems. Of note, a study conducted in Minnesota found that children with ASD did not experience any greater frequency of gastrointestinal symptoms than the general population (Ibrahim et al., 2009). The Committee has also discussed reports of ASD symptoms diminishing during periods of fever and noted that this phenomenon, described in a 2009 review article (Mehler & Purpura, 2009) and discussed at a 2010 Simons Foundation conference (Simons Foundation, 2010) warrants further study.

Committee members have pointed to the new focus on metabolic and immune system interactions in ASD through studies of immune molecules, mitochondria, oxidative stress, and viral infections. In 2010, a team of researchers examined oxidative stress in Egyptian children with autism (Mostafa, et al., 2010). They found oxidative stress in close to 90% of these children and that this was related to an index of autoimmunity. They suggest that oxidative stress may play a role in autoimmunity, and that this represents a potential treatment target. In other notable work, a literature review suggests that extant energy metabolism deficits in ASD are not systematically related to specific genetic or genomic defects (Palmieri & Persico, 2010).

Researchers also examined gray matter from postmortem brains of individuals with ASD and found increased levels of oxidized mitochondrial proteins in more than half of subjects that were related to high calcium levels (Palmieri et al., 2010). They concluded that interactions between the mitochondrial aspartate/glutamate carrier gene and altered calcium homeostasis may play a role in autism.

Researchers are continuing to study how neuroimmune abnormalities may be associated with ASD. In a 2010 study, researchers investigated activation in microglia, cells that offer the first line of immune defense in the central nervous system. Marked activation was observed in 5 of the 13 people with ASD included in the study (Morgan et al., 2010). There is also evidence that autoimmune factors may play a role. A study of 690,000 Danish children found that those with ASD were significantly more likely to have families with a history of rheumatoid arthritis, Type 1 diabetes, or celiac disease (Atladóttir et al., 2009).

Another notable study in 2010 explored how vertical viral transmission, or the transmission of a virus from mother to child just before or after birth, may play a role in the development of ASD (Lintas et al., 2010), and a study of urinary porphyrin excretion found elevated levels in children with ASD when compared to their typically developing peers, indicating a potentially unusual pattern of metabolism (Woods et al., 2010). In addition, recent progress has been made in the development of mouse models of autism (Silverman et al., 2010; Hamilton et al., 2011). These studies and others highlight the importance of continuing to investigate multiple potential pathways and develop improved model systems to better understand the complexity of ASD.

What Gap Areas Have Emerged Since Last Year?

The Committee highlighted the newly emerging area of metabolomics, which in well-controlled studies may provide a way to examine genotype-phenotype relationships. The Committee also noted the importance of staying abreast of research from other fields that may be helpful in identifying "endophenotypes" in autism. Endophenotypes are partial/constituent phenotypes that may be more highly linked to specific genetic causes, which may not be appreciated in studies that combine all symptom profiles. Endophenotypes may aggregate in families and be amenable to deep sequencing genetic studies to identify genetic underpinnings. They also can be common to multiple neurodevelopmental disorders and offer leverage for understanding similarities and differences between different forms of developmental psychopathology.

Public comment received by the Committee in the past year points to the need for continued study of regressive autism and females with ASD. In addition, new concerns were raised about the relationship between ASD and epilepsy, liver issues, and other diseases. The relationship between inflammation in expectant mothers and ASD, as well as the association of ASD with apraxia of speech, were also identified as potential issues for further examination.

Several implementation-related issues were raised by the Committee. These include the need to add rapidly emerging findings related to cell metabolism, signaling, neuroimaging, genetics, epigenetics, and co-existing medical conditions into existing databases designed to phenotype the "autisms." Finally, the Committee emphasized the urgent need to accelerate translation of research findings to clinical practice.

What Progress Is Being Made in Fulfilling Objectives?

As exemplified by the progress in the literature and funding as documented by the 2009 IACC ASD Research Portfolio Analysis, autism research is proceeding at a brisk pace (IACC, 2010 (PDF – 1.7 MB)). There are many promising studies of the neural correlates of autism-related symptoms that have yet to be classified.

Aspirational Goal: Discover How ASD Affects Development, Which Will Lead To Targeted And Personalized Interventions.

Research Opportunities

• Multidisciplinary, longitudinal, biobehavioral studies of children, youths, and adults beginning during infancy that characterize neurodevelopmental and medical developmental trajectories across the multiple axes of ASD phenotype and identify ASD risk factors, subgroups, co-occurring symptoms, and potential biological targets for intervention. Such studies could include:
  • High-risk siblings of children, youths, and adults with ASD, children without a family history of ASD, and typically developing children; and
  • Multidisciplinary assessments of brain imaging, metabolic and immunity markers, microbiomics, metabolomics, electrophysiology, and behavior. (Revised 2011)
• Research on females with ASD to better characterize clinical, biological, and protective features.
• Human and animal studies that examine immune, infectious, and environmental factors in the occurrence of ASD.
• Research on the unique strengths and abilities of people with ASD with evaluation of functional and biological mechanisms behind social, linguistic, and cognitive profiles.
• Research on individuals with ASD who are nonverbal and/or cognitively impaired.
• Research targeting the underlying biology of co-occurring syndromes and co-occurring conditions.
• Prospective research on children with autistic regression, including potential underlying genetic and other risk factors, such as seizures and epilepsy. (Revised 2011)

Short-Term Objectives

Note: Dates that appear next to the objectives indicate the year that the objective was added to the Strategic Plan. If the objective was revised in subsequent editions of the Plan, the revision date is also noted.

Dates 2009 Revised in 2011	A.	Support at least four research projects to identify mechanisms of fever, metabolic and/or immune system interactions with the central nervous system that may influence ASD during prenatal-postnatal life by 2010. IACC Recommended Budget: $9,800,000 over 4 years. (Fever studies to be started by 2012.)
Dates 2009 Revised in 2010	B.	Launch three studies that specifically focus on the neurodevelopment of females with ASD, spanning basic to clinical research on sex differences by 2011. IACC Recommended Budget: $8,900,000 over 5 years.
Dates 2009	C.	Identify ways to increase awareness among the autism spectrum community of the potential value of brain and tissue donation to further basic research by 2011. IACC Recommended Budget: $1,400,000 over 2 years.
Dates 2010	D.	Launch three studies that target improved understanding of the underlying biological pathways of genetic conditions related to autism (e.g., fragile X, Rett syndrome, tuberous sclerosis complex) and how these conditions inform risk assessment and individualized intervention by 2012. IACC Recommended Budget: $9,000,000 over 5 years.
Dates 2010 Revised in 2011	E.	Launch three studies that target the underlying biological mechanisms of co-occurring conditions with autism, including seizures/epilepsy, sleep disorders, wandering/elopement behavior, and familial autoimmune disorders, by 2012. IACC Recommended Budget: $9,000,000 over 5 years.
Dates 2010	F.	Launch two studies that focus on prospective characterization of children with reported regression to investigate potential risk factors by 2012. IACC Recommended Budget: $4,500,000 over 5 years.
Dates 2010	G.	Support five studies that associate specific genotypes with functional or structural phenotypes, including behavioral and medical phenotypes (e.g., nonverbal individuals with ASD and those with cognitive impairments) by 2015. IACC Recommended Budget: $22,600,000 over 5 years.

Long-Term Objectives

Note: Dates that appear next to the objectives indicate the year that the objective was added to the Strategic Plan. If the objective was revised in subsequent editions of the Plan, the revision date is also noted.

Dates 2009	A.	Complete a large-scale, multidisciplinary, collaborative project that longitudinally and comprehensively examines how the biological, clinical, and developmental profiles of individuals, with a special emphasis on females, youths, and adults with ASD, change over time as compared to typically developing people by 2020. IACC Recommended Budget: $126,200,000 over 12 years.
Dates 2010	B.	Launch at least three studies that evaluate the applicability of ASD phenotype and/or biological signature findings for performing diagnosis, risk assessment, or clinical intervention by 2015. IACC Recommended Budget: $7,200,000 over 5 years.