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Boaz Barak/Guoping Feng: Massachusetts Institute of Technology
Characterizing and Manipulating the Social Reward Dysfunction in a Novel Mouse Model for Autism
Social behavior deficit is a central and common feature in autism, although the cause is poorly understood. One possible mechanism is that autistic patients have impaired social motivation to engage in reciprocal social interaction. The main neural system involved in mediating the effects of motivation/reinforcement is the reward system. To better define the social motivation deficit, we will study mouse model for autism to characterize the physiological and functional properties of the reward system. We will further test whether enhancing the function of the reward system could improve social interaction in mouse models of autism. Together, these studies will help us understand the role of reward system in social behavior and identify potential novel strategies for treatment of social interaction deficits in autism.
Shweta Ghai/Gordon Ramsey: Emory University, Marcus Center
Identifying Biomarkers for Early Detection of Prosody Disorders in ASD using Electroglottography
Atypical prosody is a characteristic feature of the communication deficit in autism spectrum disorders (ASD). Investigating disorders of prosody in autism is clinically important because disordered expressive prosody is an obstacle to social integration and communication for individuals with ASD and can be a life-long problem even when other areas of language improve. The goal of this project is to identify biomarkers for early detection of prosody disorders is autism. Using electroglottography (EGG), we will characterize voice quality in 2- to 3-year-old children with ASD, children with developmental delays and typically developing children. Subsequently, we will examine the relation of voice quality measures to clinical outcome measures for speech motor deficits and impairments in social interaction in ASD. This project will provide novel insights into the etiology of prosody disorders in ASD by investigating the role of physiological motor deficits and impaired social interaction in the production of disordered prosody. The results of this will project will be of benefit in developing objective measures that are successful and easy to administer for early screening and diagnosis of prosody deficits in ASD so as to expand the potential for early interventions in young children on the autism spectrum.
Katherine Kuhl Meltzoof Stavropoulos/James McPartland: Yale University
The Effects of Oxytocin on Social Reciprocity in Individuals with ASD
Improved understanding of the brain basis of social motivation in autism spectrum disorder (ASD) is needed to develop scientifically-informed treatments. Although joint attention is a key focus of interventions, the passive nature of most neuroscience research has offered little direct insight into activity in reward systems during interactions with a social partner. This project combines eye-tracking and electrophysiology to study joint attention in a simulated face-to-face interaction. This paradigm will allow us, for the first time, to identify biological markers of reward anticipation in the context of shared attention. To investigate the responsiveness of these markers to intervention, we have developed game-based paradigms designed to shape pro-social patterns of gaze. We will use these paradigms after administration of oxytocin versus placebo to test the hypothesis that administration of oxytocin facilitates social learning. This innovative research aims to shed light on the biological basis of self-motivated social behavior.
Julia Parish-Morris /Robert Schultz: University of Pennsylvania
Developing Automated Algorithms to Assess Linguistic Variation in Individuals with Autism
Individuals with autism spectrum disorder (ASD) often struggle to use conversational and flexible speech, which complicates their efforts to navigate social relationships and contributes to peer alienation. Effective treatment for communication impairments is hindered by insufficient metrics to measure change. In fact, it is sometime hard to “put your finger on” what exactly differs in the language of a person on the spectrum, even though we easily identify that there is a difference. This study will identify linguistic markers of ASD in naturalistic language samples. Certain markers (e.g., conversational turn-taking) are hypothesized to correlate with real-world social functioning, while others (e.g., contraction use) are hypothesized to correlate with cognitive flexibility (which usually goes hand in hand with issues such as insisting on sameness). The tools developed in this project can be used to establish personalized profiles of linguistic strengths and weaknesses, enhancing our ability to design effective interventions for pragmatic language, and will directly benefit individuals and families by providing quantifiable treatment goals and dimensional measures of change. We hope to expand this line of research and collect conversational language samples remotely, including from toddlers, and use this information as part of a package of tools to more efficiently make diagnoses. Because this project uses “machine learning” and auditory recordings, it is easy to scale up to collect “big data” for research on causal mechanisms and for widespread clinical applications.
Aarthi Padmanabhan/Vinod Menon: Stanford University
Social Motivations and Striatal Circuit Development in Children and Adolescents with Autism
Deficits in social communication are fundamental behavioral outcomes in children and adolescents with Autism Spectrum Disorder (ASD), and are manifested in a lack of orientation to, and engagement with, communication signals, including speech. It is possible that communication difficulties arise from impairments in the connections between areas of the brain involved in speech and those that support the processing of social reward cues and emotion; disconnection between these regions could significantly impact the basic motivation to engage in social communication. This is an important area to understand, as speech is a critical communicative tool that is essential throughout the lifespan, and a lack of motivation to pursue social communication may aversely impact the development of other key social skills. However, little is known about how the social brain develops in children and adolescents with ASD. Thus, this project seeks to map out developmental changes in brain function, as well as the formation of critical connections between speech and reward regions of the brain, during late childhood and adolescence, in both individuals with ASD and those without. Using functional magnetic resonance imaging, we will examine brain function in 40 individuals (ages 7-18 years) with high functioning autism and 40 typically-developing individuals as they listen to both their mothers’ voices and strangers’ voices. As a mother’s voice is arguably the earliest and most critical vocal source in a child’s life, we predict that the brain’s reward systems will be more engaged when participants hear these sounds relative to when they hear strangers’ voices. We also predict that the development of these critical brain areas will differ between individuals with and without ASD. The results of this study have the potential to contribute to the identification of critical developmental time periods during which brain-based treatments of social impairments may be most helpful to individuals with ASD.
Nick Goeden/Alexandre Bonnin: University of Southern California
The impact of maternal inflammation during pregnancy on placental tryptophan metabolism, and the downstream consequences on fetal brain development
There is increasing evidence that maternal infection in humans is associated with placental dysfunction and an increased risk for autism in the offspring. In animal models, maternal infection causes behavioral and molecular changes in the offspring that are consistent with those seen in autism. However, the mechanisms by which infection, leading to maternal immune activation, alters fetal brain development are poorly understood. The goal of this project is to characterize the impact of maternal infection and immune activation during pregnancy on placental function, and the downstream consequences on fetal brain development. We recently discovered that the placenta, which is a major interface between mother and fetus, converts maternal tryptophan to serotonin during early pregnancy, thereby providing a source of serotonin for the developing fetal brain. Furthermore, dysregulation of serotonin levels in the developing fetal brain has been associated with the onset of autism spectrum disorders in the offspring. Disruption of this placental tryptophan metabolism during pregnancy may constitute a molecular mechanism by which maternal immune activation contributes to the later onset of disorders like autism in the offspring. Through the use of our novel ex vivo placental perfusion system, we will test the hypothesis that maternal immune activation directly alters placental tryptophan metabolism, ultimately affecting fetal brain development, and contributing to the onset of autism spectrum disorders.
Mapping the Neurobehavioral Phenotype in Phelan McDermid Syndrome
Autism spectrum disorders (ASD) can be conceived of as having multiple distinct genetic risk genes, one of which is SHANK3 on the end of chromosome 22. The loss of one form of SHANK3 causes a form of ASD known as Phelan McDermid Syndrome (PMS), which comprises 0.5-1% of all ASD cases. PMS is characterized by ASD, as well as global developmental delay, motor skills deficits, and delayed or absent speech. To date, no studies have comprehensively described the behavioral features of PMS and few have characterized ASD symptom domains in PMS according to best-practice guidelines. The aim for this project is to use a comprehensive assessment battery to characterize the behavioral, cognitive, language, sensory, and motor deficits in PMS. This work will also establish a patient population that can be followed over time using repeated longitudinal assessments to clarify the natural history of the disorder. We expect that the knowledge gained from completing this study will aid in understanding the range of deficits in PMS and establishing a neurobiological footprint of the disorder to identify important targets for intervention. If successful, this project will help to establish the foundation for future clinical trials in PMS and in other ASD-related disorders that share its signaling pathways.
Donghui Wei/Daniele Piomelli: University of California, Irvine
Endocannabinod Enhancement of Sociability in Autism-related Mouse Models
A growing number of parents of children with autism say they are considering treating their children with medical marijuana because of anecdotal reports of medical benefits of marijuana in subjects with autism. The first step in testing this theory is to examine the effects of the active principle in marijuana, ∆9-tetrahydrocannabinol, to see how it interacts with receptors in the brain that are thought to be involved in social interactions. Preliminary studies used a safe agent that enhances a marijuana-like chemical already produced in the brain, known as anandamide, that regulates mood and cognition. These studies found that enhancing anandamide completely corrects abnormal anandamide signaling and the social deficits observed in two well-established mouse models of autism. In this ASF-funded study, the researcher aims to test: (a) whether dysfunctional anandamide signaling contributes to asocial behavior; (b) how the biochemical signaling of anandamide causes its pro-social behavioral effects. This research will have important implications for both understanding the neurobiology of social deficits as well as the development of novel therapies for autism spectrum disorders.
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.
Andrea Chu: Boston University
The goal of the research program is to understand why some people with autism spectrum disorder fail to acquire spoken language. The studies are designed to advance knowledge of who these children and adolescents are (how they interpret spoken language; how they communicate; how they process social information; other aspects of their behavior, etc.); how their brains initiate sounds and speech. Researchers are also developing novel methods for assessing the children that are individualized to the specific profiles and interests of each participant. Researchers investigate these questions in the context of a novel intervention for younger school-aged children in which they can explore behavioral and brain markers that may predict who benefits most from the intervention. The specific project that will be focus of the summer research activity involves learning more about the children and adolescents by testing and analyzing their behavioral patterns, including their processing of social videos.
Jordan Doman: University of Pittsburgh
Many individuals with autism spectrum disorder (ASD) struggle with problems with emotional control or suffer from symptoms of anxiety and depression. Despite the pervasiveness of these concerns and the marked degree to which they exacerbate impairment and distress, very little is known their underlying causes. This project will focus on understanding factors that influence neural responses to emotionally-provocative stimuli in 25 high-functioning adolescents with ASD as compared to 23 typically-developing matched controls. Identifying mechanisms underlying differences in emotional processing during this key developmental period will open the door to more targeted prevention and treatment efforts related to emotional distress and the development of co-occurring psychiatric disorders in ASD. In addition to this project, Ms. Doman will gain an understanding of what an ASD research career entails through exposure to other ongoing studies and involvement in all stages of research from grant writing to analysis and manuscript preparation.
Molly Johnson: University of Pennsylvania
The purpose of this study is to analyze baseline parent and student data, collected from 200 families of children with autism who are newly entering the preschool early intervention system, to determine the associations between parent characteristics and children’s early intervention placements. The results will have important implications for understanding disparities in placement and potentially in child outcomes. This study will also contribute to a larger study upon which the independent project is based in order to examine: 1) What are the most promising intervention practices upon which to build in the community early intervention settings? 2) Which combinations of community placements and interventions are most effective? 3) How does the effectiveness of these settings and interventions vary based on the characteristics of the child?
Veronica Kang: University of Washington
As part of my training, Ms. Kang has been working with Dr. S.J. Webb in the Autism Research Program studying brain-behavior relations in Autism. During the ASF summer research experience, she will gain a deeper understanding of language development and the brain activity in children with ASD. She will be participating in data collection for 2 studies: the NIMH sponsored ACE Network project focused on neuroimaging genetics in girls and boys with ASD and the NIMH sponsored Fast-Fail AS study on the use of EEG to predict medication response in adults with ASD. The primary project will be to examine pragmatic language in twins and siblings with ASD to better understand how the age and gender of siblings influences the language abilities of a child with ASD. This project will help Ms. Kang prepare for graduate school in clinical psychology, with a focus on individuals with ASD and their families.
Cynthia Peng: Rutgers, The State University of New Jersey
This research project focuses on the stress system of an autism related animal model, the Engrailed-2 gene deletion mutant (En2-KO). Following a controlled stressor, the activation of stress-related neurons will be assessed using immunohistochemistry, a protein staining method. The results of this study will provide insight to how an autism related gene affects stress responses in an animal model, which in turn will further our understanding of the physiology behind the symptoms of ASD.
Jonathan Raduazzo: Harvard University
As a neurodevelopmental disorder, autism is associated with atypical brain development and maturation, but the underlying causes of brain synapse dysfunction in autism remain a mystery. One important aspect of typical brain development is the removal of excess or inappropriate synapses. Our lab and others have reported that MEF2 genes play a key role in this brain development process. Interestingly, mutations and deletions of the MEF2C gene in humans result in a neurodevelopmental disorder on the autism spectrum. Since MEF2 genes regulate the pruning of excess brain synapses, we speculate that loss of MEF2 function in the brain results in too many synapses, which might consequently alter typical behaviors in individuals. We find that genetic deletion of MEF2C in the mouse brain results in behaviors reminiscent of autism in humans, including impairments in social behavior, communication and restricted/repetitive behaviors. Work supported by this grant will explore the structure and function of brain synapses and brain circuits in this new animal model of autism. Based on preliminary findings, we also plan to explore a new treatment strategy to determine if autism-related behaviors can be reduced or reversed. Ultimately, we hope to uncover potential brain mechanisms that cause autism-like behaviors in these mice with the long-term goal of developing new therapeutic treatment strategies for autism spectrum disorders.
Nicholas Ray: San Diego State University
Mr. Ray, an undergraduate student at San Diego State University, and a Research Assistant at the Brain Development Imaging Lab (BDIL), is particularly interested in the developmental trajectory of the neuroanatomical abnormalities observed in autism. Supported by this Award, Mr. Ray will be able to devote his summer months to analyzing close to a 100 anatomical brain images collected in BDIL through their ongoing brain imaging studies. The goal of these analyses is to extract measures such as brain volume or cortical thickness, which can then be used in conjunction with other, more advanced connectivity analyses of ASD brain organization currently underway in the lab. Importantly, these measures extracted from anatomical images highly depend on the quality of the image processing (such as tissue segmentation), which requires a careful and time-consuming quality assurance process. Under Dr. Fishman’s mentorship, Mr. Ray will oversee this process, with a goal of having reliable and dependable brain volume measures available for close to a 100 participants by the end of the summer. This output is essential for a complete, unbiased interpretation of the findings from the ongoing functional and structural connectivity studies in ASD, especially in the maturational trajectories of brain anatomy observed in autism.
Sam Tomlinson: Yale University
When people interact, a great deal of important information is exchanged through the eyes and the face. Processing this information and recognizing its meaning is a remarkable capacity of the human social cognitive system. For many individuals with autism spectrum disorders (ASDs), however, everyday interactions come with difficulties that point to deficits in parsing social cues. Identifying when and how these deficits emerge is a critical question with profound implications for early diagnosis and clinical intervention of ASDs. This project explores both the developmental time course and neural basis of social difficulties in ASD. Specifically, we study the brain's response to robust sources of social information, such as eye contact, facial expression, and emotional valence, to search for potential early indicators of atypical development. This project will also apply Mr. Tomlinson's background in oscillatory EEG analysis to examine resting state brain activity in children with ASD.
Michelle Won: University of Notre Dame
Although families with children with Autism Spectrum Disorder (ASD) experience heightened family stress, few programs exist to support these families. Additionally, programs are rarely adapted to the specific needs of families with ASD, and the available interventions have not been carefully evaluated. Moreover, existing programs do not focus on the whole family, often overlooking the siblings of individuals with ASD. I This project will explore whether an established intervention program (the Family Communication Project) can be adapted to reduce stress and improve communication in families of individuals with ASD. In the intervention, we will include parents, the individual with ASD, and a sibling who does not have ASD. The goals of the intervention are to reduce family stress/conflict and to build family relationships, including connectedness between siblings. The broader goal of this study is to create an affordable intervention program that can be accessed by families in the community.