Autism is a brain development disorder characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. The autism spectrum disorders (ASD) also include the related conditions Asperger syndrome and PDD-NOS, which have fewer signs and symptoms. Autism has a strong genetic basis, although the genetics of autism are complex and it is unclear whether ASD is explained more by multigene interactions or by rare mutations. In rare cases, autism is strongly associated with agents that cause birth defects. Controversies surround other proposed environmental causes, such as heavy metals, pesticides or childhood vaccines; the vaccine hypotheses are biologically implausible and lack any convincing scientific evidence. The prevalence of ASD is about 6 per 1,000 people, with about four times as many males as females. The number of people known to have autism has increased dramatically since the 1980s, partly due to changes in diagnostic practice; the question of whether actual prevalence has increased is unresolved. Autism affects many parts of the brain; how this occurs is not understood. Parents usually notice signs in the first two years of their child's life. Although early behavioral or cognitive intervention can help children gain self-care, social, and communication skills, there is no known cure. Not many children with autism live independently after reaching adulthood, though some become successful, and an autistic culture has developed, with some seeking a cure and others believing autism should be tolerated as a difference and not treated as a disorder.

CART Pilot Project: Genetic and Environmental Influences on Brain Overgrowth in Autism

Project summary

Autism is a spectrum of neurodevelopmental disorders that are characterized by social and communication deficits. Currently the precise causes and the degree to which genetic and environmental factors interact to produce the syndrome are unknown. Brain overgrowth is a relatively common feature in autism and can be caused by mutations in specific genes (PTEN and TSC genes) in both autistic children and in experimental animals. Therefore, we propose to study the genetic changes caused by PTEN- and TSC-deletion using whole-genome microarray analysis and we will then compare these results with human data autistic individuals with brain overgrowth collected through the Autism Speaks AGRE database. Through these studies it is hoped that we will increase our understanding of the genetic and molecular pathways that regulates brain overgrowth and that we will identify other candidate genes for study in autism. Additionally, recent studies have demonstrated that brain overgrowth can also be caused by the interaction of environmental factors such as maternal inflammatory response (MIR) with genetic susceptibility during periods of vulnerability in fetal development. Maternal inflammatory response is simply the triggering of the immune system in pregnant mothers. Immune system activation causes the production of toxic metabolites that are designed to destroy invading organisms or materials. When excessive, this response damages surrounding healthy tissues or may be detrimental to a fetus even when produced at normal levels if it occurs at a particularly vulnerable period during brain development.

One mechanism by which genes and environment might interact in maternal inflammatory response is through the regulation of the production of reactive oxygen species (ROS). While it is well known that high levels of ROS are toxic to cells, it is less known that low levels of ROS can activate cellular pathways that promote proliferation. These ROS are produced in cells, including brain cells, by the enzyme NADPH oxidase (NOX), which in turn can reversibly inactivate certain genes which are susceptible to oxidation such as PTEN. Maternal and embryonic ROS levels can be influenced by many environmental factors such as exposure to cigarette smoke, environmental pollutants such as emission from automobiles and industries, consumption of alcohol in excess, asbestos, exposure to ionizing radiation, and bacterial, fungal or viral infections. These environmental factors can generate a maternal inflammatory response. Experimental studies have demonstrated that at least some causes of MIR can produce brain overgrowth in the developing fetus.

It is our theory that environmental factors resulting in a maternal inflammatory response contribute to brain overgrowth by inducing NOX and producing levels of ROS that can reversibly inactivate PTEN. We already know that deleting the PTEN gene leads to brain overgrowth in humans and mice. Therefore, the inactivation of PTEN as a result of maternal inflammatory response could be responsible for the widespread prevalence of brain overgrowth in Autism since many environmental factors exist which can cause a maternal inflammatory response and elevated ROS levels. In addition to testing if MIR can indeed contribute to brain overgrowth and social behavior deficits in mice we will also assess whether anti-oxidant treatment or signaling pathway inhibition during pregnancy can prevent the brain overgrowth and behavior deficits caused by maternal inflammatory response.

CART Pilot Project: Neural Basis of Autistic Spectrum Disorders in 22q11.2 Deletion Syndrome

Project summary

Defined genetic syndromes with characteristic neurobehavioral phenotypes offer a rare opportunity for investigating linkages between genes, neurobiology, and behavior. The 22q11.2 deletion syndrome (Velocardiofacial/DiGeorge syndrome) is a neurogenetic syndrome characterized by multiple central nervous system anomalies, as well as extremely high rates of autistic spectrum disorders (~14-50%). Even children with 22qDS who do not meet formal criteria for autism share many characteristics of autistic disorders, including stereotypic behaviors, sensory hyperacuity, and marked social skills deficits, and almost 100% have significant receptive and expressive language delays. However, there is considerable variability in the 22qDS phenotype, suggesting that genetic variation in the intact chromosome may modify phenotypic expression. Here we will compare children with 22qDS with and without autistic spectrum diagnoses, using novel brain imaging methods. Specifically, our aims are:

  1. To clarify the nature of information-processing abnormalities in 22q-ASD, using a comprehensive cognitive battery and functional MRI paradigm of emotion-processing, and to determine the relationship of these functional measures to brain structural anomalies
  2. To elucidate the neural bases of cognitive and quantitative behavioral traits associated with the autism phenotype.

Characterizing the structural and functional brain anomalies that distinguish children with 22qDS with autistic features from those without such features can improve our understanding of the necessary and sufficient conditions for the development of autistic spectrum disorders. These neural and cognitive differences will be examined, in future studies, in relation to variability in deletion size and to hemizygous allelic variability in genes within the deletion region. This information, in turn, will provide insights into genetic mechanisms underlying the neurodevelopmental processes that lead to the development of autistic spectrum disorders, in both individuals affected with 22qDS and in the broader population.

CART Simons Simplex Collection

Project summary

UCLA researchers are involved in a multi-site research study called the Simons Simplex Collection (SSC), to gather DNA samples from 2,000 autism patients and their families over the next three years. The SSC is a coordinated effort to create a database of information about cases where there is only one family member with autism. This group, which represents the great majority of autism spectrum disorders, will lead us to new genetic factors that increase the risk of autism.

Families from Southern California are currently being recruited to participate. Families eligible to participate consist of: only one child with an autism spectrum disorder (ASD), age four or older; one or more siblings without an ASD, age four or older; and unaffected biological parents who are willing to participate. Eligible children with an ASD will receive a behavioral assessment and all family members will donate blood, a source of DNA. A small number of families with no siblings or siblings under the age of four may be eligible to participate in the study. This information will be made available to scientists around the world who are searching for clues to the causes of autism.

Effects of Rispiridone on Repetitive Behaviours

Review and Approval
IRB Flyer: 
Renewal Date: 
2009, September 3

CART ACE Project V - Treating Repetitive Behavior In Autism

Project summary

Repetitive behaviors form a core feature of autism spectrum disorders (ASD), and frequently carry substantial impairment. However, our understanding of the neural basis of stereotypy and repetitive behaviors in ASD and their treatment is limited. Follow-up studies show the remarkable persistence of repetitive behaviors as a stable component of the phenotype. No one treatment has been solidly established for this aspect of the ASD phenotype. Recently, risperidone, a second generation atypical antipsychotic, was observed to robustly reduce stereotypic behaviors in a sample of children with autism, and this improvement was maintained for up to 6 months of continued treatment. The proposed study attempts to deepen our understanding of repetitive behaviors in ASD and its treatment by examining the changes in key neural circuits associated with risperidone treatment using functional MRI. Our pilot data suggests risperidone has powerful effects on brain activation, providing clues to the underpinnings of these ASD behavioral features and one of its mechanisms of effect. Our overarching hypothesis is that prominent stereotyped and perservative behaviors in autism reflect disordered cortico-striatal function, likely influenced by autism risk genes, and that successful treatment is associated with greater normalization of ventral striatal activation.

Our Specific Aims for the project are as follows:


  • Aim 1: Examine the benefits of risperidone administration on repetitive behaviors in a sample of 52 children and adolescents with ASD and high levels of repetitive behavior assigned to risperidone or placebo in a controlled trial; 
  • Aim 2: Describe the effects of risperidone exposure on hemodynamic activation of the ventral striatum in children and adolescents with ASD using fMRI performed on a subset of subjects in the clinical trial; and 
  • Aim 3: To determine whether risperidone treatment "normalizes" brain activity in the ventral striatum in children and adolescents with ASD compared to placebo-treated ASD children and to normal controls, as measured by fMRI. 

By combining studies of pharmacologic treatment with established neuroimaging paradigms, we believe that our proposed investigation will shed light on the neural underpinnings of this important component of the ASD phenotype and a common element of other childhood neuropsychiatric disorders. Similarly, data from our proposed investigation should help to clarify key sites of action for targeted treatments and potentially serve to identify subgroups of individuals with ASD who are more likely to benefit from certain interventions. Lastly, our study may shed light on the extent to which the core domains of ASD should be approached in a modular versus a holistic fashion with regards to its neurobiology.


UCLA Early Intervention Study for Toddlers with Communications Delays

Review and Approval
Renewal Date: 
2010, January 7

CART ACE II - Project 4: Neuroimaging signatures of autism: Linking brain function to genes and behavior

Project summary

Overview: The longitudinal stuides conducted under ACE II Project 4 will lead to a better characterization of functional brain networks in individuals with Autism Spectrum Disorder (ASD) that may ultimately be useful for earlier diagnosis as well as for informing the development of targeted behavioral and pharmacological interventions and/or evaluating their effectiveness.

Project 4 Summary: Autism is characterized by tremendous phenotypic heterogeneity likely due to its complex genetic and neural underpinnings. Research from our lab and others have provided mounting evidence of decreased responsivity to social stimuli and altered patterns of brain connectivity in individuals with ASD. Moreover, we have recently shown that aberrant functional and structural connectivity is significantly related to genetic vulnerability to the disorder. Despite these significant strides, critical questions remain unanswered with regard to:

i) the underlying mechanisms that may give rise to the reduced mirroring and reward-related responses to social stimuli we have previously characterized;

ii) the relationship between the functioning of these circuits and aberrant connectivity;

iii) the extent to which the latter reflects the cause or the effect of altered developmental trajectories in ASD and, more broadly,

iv) how know genetic risk factors for ASD impact brain circuitry subserving complex social behaviors.

The current studies are designed to address these issues, while seeking to build synergy amongst competing neurobiological accounts of ASD. Given our previously characterized cohorts, we will systematically chart longitudinal changes in brain activity and connectivity in children with and without ASD and relate the observed developmental trajectories to both behavioral phenotypes and autism risk genes.

More specifically, using a cross-lagged longitudinal design, we will perform functional magnetic resonance imaging (fMRI), resting state MRI and diffusion tensor imaging (DTI) at two timepoints (3 years apart) in two previously characterized age cohorts (6-9 and 12-14 years of age at first assessment) and relate these data to behavioral phenotypes and ASD risk poplymorphisms. This integrated research will identify the earliest departures from typical development and delineate the complex interactions among genes, brain, and behavior that drive and constrain the atypical development of the social brain in ASD.

CART ACE II - Project 5: Genetic and genomic analyses to connect genes to brain to cognition in ASD

Project summary

Overview: Autism Spectrum Disorder (ASD) varies widely in both symptoms and causes and perhaps is best thought of as "the autisms".  ASD has a strong genetic component, but the mutations causing the disorder are largely unknown.  Research from several groups including our own suggests that studying cognitive or behavioral components of autism, or endophenotypes, may aid in identification of more homogeneous subgroups and hasten the identification of genetic loci underlying this condition.  We will use genetic measures to define more homogeneous subtypes of autism so as to increase power in clinical trajectory and treatment studies, identify biomarkers and integrate genetic data with measures of behavior and brain function to identify biological processes that are disrupted in ASD and thereby find early diagnostic signs and treatment targets.

Project 5 Summary: Genetic factors contribute significantly to autism susceptibility, but the heterogeneity of ASD poses a challenge for genetic studies. In our previous ACE Center project we showed how a common ASD susceptibility variant in CNTNAP2 modulates brain function, connecting gene to brain to endophenotype for the first time in ASD.  We also identified several cases of rare, large copy number variation (CNV) and smaller variants of less certain pathogenecity.  In this current ACEII Center project, we will continue to genetically characterize all ACEII probands, hypothesizing that identifying certain etiological subclasses may provide more homogeneous populations that will be more predictive of trajectory and outcome. We will integrate identification of CNV with gene expression data to identify dysregulated genes within and nearCNVs, thus improving classification of pathogenecity, and identify those with mutations currently undetectable by structural variant analysis alone.

We will take a systems approach to functionally group these genes into biological pathways, and thus to group patients by shared molecular defects. We then will relate shared molecular pathyway defects in the patient subsets to the phenotypic biomarker measurements collected in the ACEII projects 1-4. We will test the relationship between known and newly discovered genetic variants and measures of behavior, eye tracking/pupillometry, EEG, and brain imaging at both single time points and examing longitudinal trajectories, as well as their influence on response to treatment. In this way, we seek to connect genetic variation to measures of brain function as a means of unraveling the genetics and phenotypic heterogeneity observed in ASD, and to develop improved predictors of diagnosis and treatment response.