2013 Grantees

3-Year Early Career Award:

Dr. Jill Locke: University of Pennsylvania

Multi-Site, Randomized, Controlled Implementation Trial of an Evidence-Based, Adult and Peer-Mediated Social Skills Intervention for Elementary School Children with Autism Spectrum Disorder

Co-funded with the FAR Fund

With the rising cost of educational services for children with autism and fiscal challenges that school districts face, it is imperative that cost-effective autism-related interventions are easily implemented and sustained in schools. Social impairment represents the most challenging core deficit of autism and greatly affects children’s school experiences; however, few evidence-based social skills programs have been translated into and sustained in schools because of the challenges that schools face when adapting and implementing evidence-based practices. This project will identify and address school-level challenges that interfere with the implementation of a promising social skills intervention that trains school staff to work with children with autism. If successful, this project will advance our understanding of implementing evidence-based social skills interventions in public schools and provide schools with a built-in mechanism to support their students.

Treatment Grant:

Dr. Alexander Kolevzon: Icahn School of Medicine at Mount Sinai

Human Clinical Trial of IGF-1 in Children with Idiopathic ASD

A double-blind, randomized, placebo controlled, phase 2 human clinical trial of Insulin-Like Growth Factor-1 (IGF-1) in children with a genetic cause of autism (Phelan McDermid Syndrome) is currently underway at the Seaver Autism Center for Research and Treatment at Mount Sinai. That study builds on previous work in a mouse model system of Phelan McDermid Syndrome which showed that IGF-1 treatment reversed the effects of disrupted glutamate signaling associated with impaired learning and memory. This Treatment Grant will expand the current study to add a cohort of children with autism but without Phelan McDermid Syndrome. IGF-1 is a commercially available compound that is known to promote synaptic maturation and plasticity. It has already been shown to reverse behavioral and physiological deficits associated with Rett Syndrome in mouse models and preliminary results in children with Rett syndrome are promising. Results from this trial are expected to provide evidence that IGF-1 is safe, well tolerated, and efficacious in targeting core symptoms of autism in children without Phelan McDermid Syndrome because of the potential that the glutamate signaling pathway is relevant to diverse forms of autism.

Postdoctoral Fellowships:

Dr. Aimee Badeaux and Dr. Yang Shi: Boston Children’s Hospital

Molecular Characterization of Autism Gene CHD8 in Shaping the Brain Epigenome

This research is aimed at understanding how the brain is wired during development and immediately after birth, with a focus on the function of a class of genes that are mutated in a significant number of patients with ASD. We think this type of gene responds to environmental cues to shape the brain; this could help explain how autism seems to arise from both genetic and environmental alterations. The knowledge gained from this research will illuminate common abnormalities in the young brain that cause autism, and will therefore guide the next generation of therapies to reverse these events and ameliorate autism symptoms.

Results from the research award: The gene of interest, CHD8, is involved in chromatin remodeling – this is how DNA is wound up in the double helix and plays a role in “epigenetics”. That is, changes in how the gene expresses itself without specific mutations. This is a new and exciting field of genetics research and our understanding of how epigenetics affects brain development is impacting other disorders like schizophrenia and intellectual disability. In order to understand more about chromatin remodeling affects brain function, the analyses were expanded to include two additional molecules. The lab used a mouse model to show that a single gene which disrupts in how the DNA is shaped affected many proteins involved in how neurons develop. The next phase will be to generate a new mouse model which is more specific to CHD8, which has recently been demonstrated to be associated with ASD.

Dr. Sara Schaafsma and Dr. Donald Pfaff: Rockefeller University

Sex-Specific Gene-Environment Interactions Underlying ASD

This project will investigate whether a gene-environment interaction can explain why boys are much more often affected by ASD than girls. This study uses a mouse model to investigate the interaction between immunological prenatal stress, a known predisposing environmental factor, with a mutation in a gene that is linked to ASD risk and whether this interaction is different for both sexes. It is hypothesized that males who are genetically vulnerable to develop ASD are more susceptible to the detrimental effects of prenatal immunological stress than genetically vulnerable girls. Knowledge about this sex-specific gene-environment may offer new avenues of enquiry into ASD, provide unique insights into its neurobiology, and therefore impact a variety of areas in ASD research. Identifying sex-specific interacting risk factors and thereby opening the possibility to decrease the chances of high-risk children for autism of developing the disorder would considerably impact the lives of these children and their families.

Results from the research award: In a genetic knockout animal model of autism, prenatal stress affected males more than females. Specifically, males showed decreased social behavior and decreased expsression of a stress hormone in the hippocampus, where the effects in females exposed to prenatal stress were not as profound. Of course, the overall relationship between prenatal stress, sex and genotype is complex, and may partially explain the male bias in ASD.

Dr. Teresa Tavassoli and Dr. Joseph Buxbaum: Icahn School of Medicine at Mount Sinai

Developing a Sensory Reactivity Composite Score for the New DSM-5

Sensory reactivity difficulties can be challenging for children with autism spectrum disorder and their families, making everyday activities, such as a trip to the supermarket, an impossible task. This project will look at how children with single gene and idiopathic (meaning unknown origin) forms of ASD react to sensory stimuli, e.g. touch and sound. Sensory reactivity will be measured using parent reports, observations and physiological measures, such as heart rate. Our aim is to identify the most robust ways to measure sensory reactivity in children with ASD, which can be used to guide diagnosis (sensory over-reactivity and under-reactivity as proposed for DSM-5) and sensory-based treatments. In addition, by including children with single gene forms of ASD this research can help to identify potential biomarkers for sensory over-and-under-reactivity. This research will also help to better understand the sensory world of children with ASD and can be used to design sensory-friendly environments.

Results from the research award: The investigators found that a significant proportion of children with ASD (60-80%) showed sensory reactivity issues using three sensory measures. In addition they found a moderate overlap across measures when used to classify individuals as having sensory reactivity symptoms, which suggests the need for multiple approaches. These results mean that researchers may need a combination of parent-report and observational tasks to detect sensory reactivity issues in ASD.

Predoctoral Fellowships:

Alexandra Bey and Dr. Yong-hui Jiang: Duke University

The Role of Shank3 in Neocortex Versus Striatum and the Pathophysiology of Autism

There are currently very limited options for treating patients with autism spectrum disorders due to poor understanding of the way the core behavioral deficits occur. In part, this is because the brain regions controlling the abnormal behaviors are unknown. This study will use a mouse model of autism, which allows us to very precisely disrupt the function of specific brain regions, to examine which regions control each category of ASD behavioral deficits. This will inform the development of new treatments that target specific brain regions tailored to the behavioral profile of the individual.

This project will begin in 2014.

Ezzat Hashemi and Dr. Veronica Martinez-Cerdeno: University of California, Davis

Alteration of Dendrite and Spine Number and Morphology in Human Prefrontal Cortex of Autism

This project will analyze the cellular architecture of pyramidal neurons in the prefrontal cortex of postmortem human subjects with autism. Axons and dendrites transfer the electrical signals within the brain via the spines. These electrical signals, which are important in neural networks, are altered in autism. To determine the role of dendrites and spines in disrupted signaling, we will measure the length, volume and morphology of dendrites and spines using Golgi staining and Neurolucida tracing software. This study will further the understanding of micro-anatomical pathology and neural connections involved in signal transmission in autism, and therefore, it will take us a step closer to developing new treatments for autism and other neurodevelopmental disorders.

Jessie Northrup and Dr. Jana Iverson: University of Pittsburgh

Development of Vocal Coordination between Caregivers and Infants at Heightened Biological Risk for Autism Spectrum Disorder

This project will examine the timing of vocalizations in interactions between infant siblings of children with ASD and their caregivers throughout the first year of life in order to look for early warning signs of ASD and inform early interventions. From the first days of life, infant and caregiver interactions involve mutual give-and-take that is very important for infant development. One example of this is the way in which typically developing infants and their mothers adjust the timing of their vocalizations to coordinate with one another, much like two adults having a conversation. Coordination of the timing of vocal behavior with a partner involves a mix of attention, language development, and social engagement–and for that reason, it may be an ideal context in which to look for early symptoms of autism spectrum disorder. In addition, while a lot of research on ASD has focused on individual characteristics of the child, this study will help us understand infant behavior in the context of everyday social interaction, and will therefore have implications for early interventions focused on parent-child interaction.

Results from the research award: This study found a number of differences in high risk infants during the “prodromal” period. This is the period in infancy before early signs and symptoms of autism become more obvious. Between 6-9 months of age, babies who are later diagnosed with ASD show a decrease in the number of vocalizations during play than those not diagnosed with autism. Also, those infants who went on to have language delays but not autism, were making more immature sounds like growls, squeals and grunts at 9 months. At the same time, those with typical language development were starting to vocalize words and linguistic sounds. Both of these findings demonstrate very early signs and symptoms of language development and ASD which could be amenable to intervention strategies.

Russell Port and Dr. Timothy Roberts: University of Pennsylvania

GABA and Gamma-band Activity: Biomarker for ASD?

The differences in brain activity that generate the symptoms of ASD are not understood, yet it is this very activity that is targeted by treatment. This research aims to directly study brain activity by measuring the magnetic signals generated by the brain as it responds to sound. Our research suggests that a certain kind of activity in the brain (gamma-band) is disrupted in children with ASD, and differences in the inhibitory neurochemical GABA is involved. By targeting the underlying biology, this research may allow us to determine which treatments are effective earlier and on an individual basis, and guide treatment development.

Results from the research award: This project combined 2 different sets of data: those from humans and those from animals. First, state of the art imaging technology was used to isolate the source of brainwaves during tasks when a person listens to sounds and words. This revealed a specific type of brainwave which is regulated by a particular brain chemical during these tasks. In order to study this even further, they used a mouse model with a mutation of the 16p region of the chromosome. This area has been associated with ASD in genetic studies. Animals with this mutation showed less activity of this chemical in the auditory cortex.

Enhancement Mini-Grants:

Dr. Pamela Ventola: Yale University

Sex Differences in the Neural Mechanisms of Treatment Response

Because of the skewed sex ratio in autism, prior treatment studies have not permitted inference regarding differential treatment response in boys and girls. Here we study how girls respond to an empirically supported behavioral treatment approach, Pivotal Response Training (PRT), to foster development of more effective treatments for girls and boys. We will assess treatment outcome at the behavioral and brain-based level, using functional magnetic resonance imaging (fMRI), to better understand how the trreatment works and to identify possible brain-based markers that may predict magnitude of treatment response.

Results from the research award: PRT is an effective treatment in a short-duration (4 months) model. All of the children included in our study thus far have made clinically meaningful gains, but the results also highlighted the heterogeneity in ASD. Based on neuroimaging data (functional magnetic resonance imaging; fMRI) before treatment started, the children differed in how they responded, at the brain level, to social information. One subgroup of children exhibited hyperactivation in social areas of the brain, and another exhibited hypoactivation in the same regions. Both groups exhibited normalization of brain responses following treatment; after the treatment, their brain responses to social information were more similar to typically developing children, again as assessed using fMRI. The treatment seemed to exert its effect in different ways depending on the child’s baseline brain-based profile. This is the first work to demonstrate how brain-based responses to treatment may differ between groups of children with ASD.

Dr. Jessica Suhrheinrich: University of California San Diego

Use of Real Time Video Feedback to Enhance Teacher Training

Although evidence‐based practices for educating children with autism are being applied and studied in school settings, there is less information about the best ways to train teachers to use these practices. In this project, teachers of students with autism receive training and on‐going coaching in an adapted evidence‐based practice. The ASF research enhancement funding will support an investigation of the benefit of immediate video feedback, as compared to verbal and written feedback alone, during classroom coaching sessions.

Results from the research award: Pending.

Dr. Aaron Shield: Boston University

The Effects of Autism on the Sign Language Development of Deaf Children

This grant will fund additional data collection and travel to schools for deaf children around the U.S., thus expanding the control group of typically-developing deaf children to compare to deaf children with ASD. Findings from this study will inform the eventual adaptation diagnostic and screening instruments for use with deaf and hard-of-hearing children, as well as future interventions with deaf and hard-of-hearing children with ASD.

Results from the research award: This study investigated a population that has rarely been studied: children with ASD who are exposed to a sign language natively by their Deaf parents. The study has documented several characteristics of the signing of these children. First, a number of signing children with ASD showed sign echolalia (repeating the signs of others), just as hearing children with ASD sometimes show speech echolalia. Second, deaf children with ASD were more likely to refer to themselves and to others using sign names rather than pronouns, showing that difficulty with pronouns occurs in both sign and speech. Third, approximately one-quarter of children recruited for the study did not demonstrate expressive sign language, showing that some deaf children with ASD are minimally-verbal in sign, just as some hearing children with ASD are. Fourth, deaf children with ASD performed more poorly than typically-developing deaf children on measures of theory of mind and visual perspective-taking, two non-linguistic social skills that are thought to be impaired in ASD. However, children with ASD performed as well as TD children on a mental rotation task, which suggests that spatial cognition is intact in ASD. This study lays the groundwork for future work with deaf or hard-of-hearing children with ASD and sheds new light on the relationship between social skills and language.

Dr. Adam Naples: Yale University

Cross-Modal Automated Assessment of Behavior during Social Interactions in Children with ASD

This grant will enhance ongoing research exploring brain activity in children with autism during simulated social interactions. By using novel technologies to evaluate facial expression, gaze, and affect, on-screen social partners will respond to children’s behavior in real-time. For example, computerized faces will “smile back” in response to a child’s facial expressions. This study will investigate the brain mechanisms of multimodal reciprocal social interaction for the first time.

Results from the research award: The current project is underway and currently in the piloting stage. With our collaborators we have implemented the MultiSense data collection system for integrating non-verbal behaviors with EEG and eye-tracking recordings. We are piloting data collection assessing verbal and non-verbal behaviors. We are currently integrating the MultiSense data stream with EEG recording and eye-tracking, and we will soon commence data collection with children with ASD.

Dr. Haruki Higashimori: Tufts University

Role of Astrocytic Glutamate Transporter GLT1 in Fragile X Syndrome

One of the crucial functions of astrocytes in the healthy brain is to maintain very low levels of the excitatory neurotransmitter, glutamate. This is accomplished by removal of excess glutamate through specialized glutamate transporters, such as GLT1, which are specifically found on astrocytes. Recently, we discovered that Fragile X Syndrome (FXS) mice have fewer and more dysfunctional GLT1 transporters. In this mini-grant we propose to expand on our findings in the rodent brain. We propose to evaluate human brain tissue samples to assess whether there is a similar alteration in human glutamate transporter in FXS and autism patients. This study will be the first to address whether human astrocyte dysfunction contributes to the development of FXS, and may identify an important new target for restoration of normal brain development in both FXS and autism patients.

Results from the research award: Age matched tissue samples from human cortical Fragile X Syndrome (FXS, n=4) patients showed a similar decrease in excitatory amino acid transporter (EAAT2) protein expression seen in rodent model of FXS. EAAT2 is an astrocytic glutamate transporter that removes up to 95% of extracellular glutamate in the brain, which properly balances cellular excitation and inhibition and supports normal synaptic function.

Dr. Gazi Azad: University of Pennsylvania

Partners in Schools: A Program for Parents and Teachers of Children with Autism

The goal of Partners In School is to develop and test a program that will improve parent-teacher communication about interventions for diverse children with autism attending public schools. With support from this enhancement grant, I will compensate parents and teachers for their participation, hire a student for data collection and management, and receive training from the Nebraska Center for Research on Children, Youth, Families, and Schools. Successful completion of this project will result in a new culturally sensitive tool for communication improvement, which is the first step for fostering family-school partnerships for children with autism.

Results from the research award: The results of my research are currently being analyzed. Preliminary results indicated that parents and teachers generally agreed about their primary and secondary concerns for children with autism. However, when given an opportunity to communicate their concerns to each other, half of the parent-teacher dyads discussed problems that neither reported as their primary concern, and a third discussed problems that neither reported as their primary or secondary concern. These findings suggest that interventions should target parent-teacher communication, rather than agreement, to facilitate home-school collaboration.