2006 Can Grants Funded

Cure Autism Now funded a variety of science programs designed to encourage innovative approaches toward identifying the causes, developing means of prevention and treatment and ultimately, finding a cure for autism and related disorders.

Field-building research grants were a core feature of Cure Autism Now's science program: Pilot Project, Young Investigator, Treatment, and Innovative Technology in Autism grants were born out of the necessity to stimulate novel research and entice investigators to join the fight to understand autism.


Treatment: Developing ways to foster learning and growth in individuals with autism


Teaching Imitation Skills to Young Children with Autism: Predicting Response to a Naturalistic Social-Communication Intervention (Treatment Grant)

Brooke Ingersoll, Ph.D., Lewis & Clark College

Children with autism have deficits in imitation skills both in structured settings and in more natural contexts such as play with others. These deficits are a barrier to learning new skills as well as socialization, and are thus an important focus of early intervention programs for children with autism. Studies have found imitation ability to be strongly correlated with other social-communication behaviors in children with autism, suggesting that targeting imitation may assist development of other behaviors such as language and joint attention. This project is designed to validate Reciprocal Imitation Training (RIT), a naturalistic, play-based imitation intervention. In addition, we are exploring which child characteristics predict response to RIT and whether teachers find the intervention to be socially valid. Children in the experimental group will receive twelve weeks of the RIT intervention targeting imitation skills while children in the control group will receive their usual treatment from community providers. Changes in performance will be compared on a series of assessments of their imitation, language, play, and social skills administered pre- and post- treatment as well as at a three month follow-up. In sum, this research will examine the role of imitation in the development of other social-communicative skills in autism, offer insights as to how these early behaviors emerge in young children with autism as a result of treatment, and allow intervention providers to determine the best method for teaching imitation skills to young children with autism

Assessment of Treatment Outcome in Preschool Children with Autism Using Behavioral and Electrophysiological Measures of Speech Processing (Treatment Grant)

Patricia K. Kuhl, Ph.D., University of Washington


This project will use measures of speech processing to assess treatment success in children with autism enrolled in an ongoing NIMH-funded Early Intervention project. The Intervention program involves 18-30 month old toddlers with Autism Spectrum Disorder (ASD), half of whom are randomly assigned to an intensive early intervention treatment program that has a strong focus on social interaction and language. The control group receives standard intervention services through the community. We will examine how the Early Intervention program affects the linguistic skills of individual children with ASD, and their social interest in speech. Measurements include assessment of children's phonetic perception skills and their social interest in speech. Both components have been shown to be important precursors to language acquisition. Measures of early phonetic skill in typically developing infants predict the speed with which the child will progress towards language mastery. Social interest in speech is important because child-directed speech exaggerates the critical phonetic information in speech. In this project, evoked electrical brain potentials (ERP) of phonetic perception skills (syllable discrimination) and word processing skills, as well as a behavioral test of listening preference for child-directed speech, will be used as outcome measures in the treatment study. The design provides a powerful test of whether early and intensive intervention focused on language and social stimulation affects brain and behavioral measures of the linguistic and social processing of speech in children with autism.

Group Cognitive Behavior Therapy for Children with Autism Spectrum Disorders and Anxiety Symptoms (Treatment Grant)

Judy A. Reaven, Ph.D. and Susan Hepburn, Ph.D., University of Colorado, Denver


Children with autism spectrum disorders are at greater risk for developing a variety of anxiety disorders than typically-developing children and those with other developmental disabilities. Anxiety symptoms interfere with participation in home, school, and community activities, narrowing opportunities for appropriate social engagement. Anxiety also significantly limits family activities, contributing to increased isolation for parents and siblings. Although many researchers and clinicians discuss the significant impact of anxiety on overall functioning of a person with autism, few intervention studies have been conducted. Research on treatment of anxiety in the general pediatric population has demonstrated that a specific intervention—cognitive-behavioral therapy—can be effective in reducing anxiety symptoms in children. The basic principles of cognitive-behavioral therapy include identification of the child's specific anxiety symptoms, as well as situations that are viewed as anxiety-provoking, and a very gradual exposure to manageable anxiety-producing situations. The present project builds upon previous research which has developed a standardized manual of family-focused cognitive-behavioral intervention. The primary purpose of the present study is to assess the effectiveness of this group-based family-focused intervention designed to reduce anxiety symptoms in children with high-functioning autism spectrum disorders

The Effectiveness of A Light on Literacy for Autism: A Case Control Study (Treatment Grant)

Agnes H. Whitaker, M.D., Columbia University


While great effort goes into teaching spoken language to children with autistic spectrum disorders (ASD), relatively little effort is directed towards teaching the other form of language that is central to human communication: namely, written language. This situation is particularly true of children in the ASD population who do not speak. Their limited speech has generally led to the view that these children are so impaired that any effort to teach written language would be futile. While few, there have been cases reported of extensive written language abilities in these individuals. If non-verbal children could be taught written language, they would then have access to the invaluable skills of language and communication that has otherwise been denied to them. The research that will be conducted will implement with non-speaking children a program entitled A Light on Literacy which has been developed by Dr. Marion Blank specifically for children with ASD. Through its use of specialized techniques that teach writing (both handwriting and keyboarding), the program provides the children with a mode for expressive language. At the completion of the program, it is expected that the children will have attained a set of skills that, in the past, have been considered beyond the reach of this population. This includes not simply word recognition and word creation, but in addition, comprehending and producing sentences connoting past, present and future, and answering questions about objects and events in the past, present and future.

Modified Cognitive Behavioral Therapy for Anxiety and Social Problems in Children with Autism (Treatment Grant)

Jeffrey J. Wood, Ph.D. and Connie Kasari, Ph.D. University of California, Los Angeles

Problems with anxiety are very common among children with ASD, and experts in the field have called for the development of treatments to address anxiety-related symptoms in this population. Anxiety can further complicate and impair the functioning of children who already face considerable challenges in development due to ASD. Recent clinical trials of cognitive behavioral therapy with neuro-typical children suggest that anxiety treatment for children with must go beyond skills training in hypothetical situations and also emphasize direct practice of new coping skills in the actual settings where problems are experienced. However, treatment protocols must be modified to accommodate ASD-specific challenges. Specifically, treatment must address social skill deficits in youth in order for optimal treatment response to occur. This project involves a clinical trial of a modified cognitive behavioral therapy treatment manual developed by the investigators to target anxiety and social skills. This includes friendship skills, peer intervention and emotion education in order to facilitate traditional cognitive behavioral treatment. Initial pilot cases have suggested this treatment can be quite effective with children with ASD, reducing their anxiety considerably with also significant gains in social functioning and self-help skills. This full study will now evaluate the overall impact on children's functioning as well as the families' satisfaction with the intervention.



Innovative Technology for Autism: Using technology to impact the lives of individuals with autism and their caregivers


Technology Support for the Early Detection of Autism


Gregory D. Abowd, D.Phil., Georgia Institute of Technology


Current screening techniques for autism are only effective for children at least as old as two years, but research suggests there are earlier signs of developmental delay. In conjunction with initiatives, such as the CDC's Learn the Signs: Act Early, we aim to produce affordable and effective solutions for proactive collection of developmental growth information from birth. Our research is aimed at collecting evidence of developmental progress in homes from birth. We will help parents to understand developmental growth of their children and to communicate that information to medical professionals more effectively. To do this, we will develop sensing and recording technologies that can be used in homes and daycare settings. We will leverage existing practices, such as the use of baby calendars, and common household items, such as baby monitors and children's toys.

Authorable Virtual Peers for Children with Autism Spectrum Disorder

Justine Cassell, Ph.D., Northwestern University


Children with Autism Spectrum Disorder (ASD) often lack the appropriate communication and reciprocal social interaction skills that lay the groundwork for academic and social achievement. However, these same children may spend hours interacting with computer games. In our previous work, we have developed a technology called virtual peers (VPs), 3D life-size animated characters that look like children and are capable of interacting, sharing real toys, and responding to children's input, and we have demonstrated that they can employ the natural activities of peer collaboration and storytelling to significantly increase children's emergent literacy and social behaviors. In the current work we propose to design and evaluate a computer system that allows children with ASD to interact with a life-size virtual peer, as well as to author interactions with that virtual peer (i.e. create and control the communication behaviors of virtual peers as a way of understanding and scaffolding their own communication and reciprocal social interaction in typical social settings). Studying the effects of the virtual peer may lead to important information about the underlying mechanisms of communication and social reciprocity in ASD, while also providing an innovative intervention for ASD.

Activity Logging Using Accelerometers (ITA Bridge Grant)

Jessica Hodgins, Ph.D., Carnegie Mellon University

Logging of activities is essential for measuring progress of children with autism and effectiveness of new interventions. However, logging is burdensome for the therapist or parent and requires time that could otherwise be spent on activities with the child. We propose to automatically log the activities of a child using accelerometers worn on the shoes and wrist. We will leverage information about human motion contained in a prerecorded and labeled database to accurately reconstruct the child's motion from low dimensional input signals (accelerations). Using this reconstruction, we will be able to create a log of labeled activities along with their duration. We envision that this log will be useful both in assessing the change induced by a particular intervention and in allowing parents or therapists to discover connections between interactions and behaviors.

Computerized Language Training Using Grammar Trainer

Felicia D. Hurewitz, Ph.D., University of Delaware


This project provides efficacy testing of a computerized speech/language intervention designed for children on the autistic spectrum. GrammarTrainer (www.autism-language-therapies.com) is a linguistically informed, multi-level curriculum that systematically encourages students to produce syntactic constructions of progressively increasing complexity. We investigate the degree to which this computer assisted intervention (CAI) can remediate syntactic, morphosyntactic and pragmatic deficits in productive speech and writing. In addition, we test the efficacy and offer further development of a production-based system, where the student must fully generate responses on the computer, as compared to commonly marketed products that only require the child to receptively interpret language.

Assessing Synchrony as a Basis for Social Connection in Autism (ITA Bridge Grant)


Kerry L. Marsh, Ph.D., University of Connecticut

One important issue in autistic spectrum disorders is understanding and ameliorating sociality deficits in individuals with autism. Forming a minimal social bond with others may require responding to others at a very basic perceptual and behavioral level. That is, it may require that one has the ability and inclination to be pulled unaware into synchrony with the movements of others. It is this issue that social psychologist Kerry Marsh (along with collaborators Robert Isenhower, Deborah Fein, Richard Schmidt, Michael Richardson and Jeffrey Kinsella-Shaw) are studying at the University of Connecticut. They propose to use cutting-edge technologies that continuously track individuals' movements over time to examine whether individuals with autism spontaneously synchronize rocking chair movements with that of another individual.

Using the tenets of human movement science, dynamical systems theory, and ecological psychology, the researchers will seek to find particular patterns of coordinated movement in autistic individuals, and they will isolate what particular processes (e.g., attentional or movement-based) might account for deficiencies that arise. Understanding the processes that generate potential deficiencies may suggest potential avenues by which researchers can redress limitations in the autistic individuals' tendencies to experience social connectedness.

Automated Data Capture In Early Childhood Classrooms (ITA Bridge Grant)

Ilene Schwartz, Ph.D., University of Washington

Collecting accurate data and using these data to make instructional decisions is an important feature of a high quality early intervention program for children with autism. Although special education teachers have a long history of talking about data collection and data-based decision making, data collection often gets ignored in the complex and fast-paced environment of inclusive early childhood classrooms. The purpose of this grant is to demonstrate the effectiveness of an automated data capture system in an early childhood classroom. This system is based on a system called Abaris which was developed to be used during discrete trial training (DTT) sessions with children with autism. The contextual differences between a DTT session and inclusive early childhood classrooms will require that major modifications are made to the system. The resulting system will have the potential to help improve data collection in special education classrooms and help pre-service teachers learn more about data collection and data-based decision making.

Generalization Support Project for the DT Trainer (ITA Bridge Grant)

Karl Smith, Accelerations Educational Software

To create DT Trainer features and components to facilitate generalization from the product to the student's environment. There are 3 aspects of this project: 1) Create a 3D to 2D set with corresponding DT Trainer content programs. 2) Create sets of laminated images from some of the DT Trainer programs. 3) Add an image printing feature to the DT Trainer.

Enhancing Social Communication Through Story-Telling Among High-Functioning Children With Autism (ITA Bridge Grant)

Patricia L. Weiss, Ph.D., University of Haifa, Israel

Children with High Functioning Autism (HFA) have the basic verbal ability for creating a story, but often lack the social understanding that is needed for such a task. Moreover, these children often prefer to play alone since they have difficulty in developing appropriate peer relationships and in interacting socially or emotionally with their peers. However, many of these children enjoy using technological devices such as computers since they provide direct and immediate feedback. We hypothesize that use of the MERL's DiamondTouch StoryTable, a very large touch screen that requires children to work together, will retain the advantages of working with a computer, yet add an important dimension, namely communication and interaction with others. In this study, the StoryTable is used with 10 pairs of boys with HFA, aged of 8-12 years who normally are associated together at school. Each pair of children will collaborate on story-telling on ten occasions over a three week period, learning how to interact with the aid of the StoryTable. We measure the children's abilities to operate the various StoryTable functions and also document their positive social interactions, negative social interactions and behaviors that are typical for children with autism. This information will enable us to determine the effectiveness of a technology-based collaboration paradigm to enhance social interaction.



Diagnosis/Assessment: Markers and tests to detect and evaluate autism symptoms earlier and more accurately



Investigation of Etiology, Determination of Prognosis and Optimization of Interventions in Autism using Metabonomics (Biomarker Initiative Bridge Grant)


Manya T. Angley, Ph.D., University of South Australia

Autism is a lifelong condition that can have profoundly negative effects on an individual and their family with respect to social, economic and emotional well-being. Typically, the later the autism diagnosis, the greater the burden exerted on the education and health care systems. Early diagnosis followed by intensive and individualized intervention mitigates the negative impact of autism and can vastly enhance quality of life for the individual and their family. In this project, metabonomics (which is a cutting edge technology that examines patterns of metabolites in biofluids) will be used to identify features in urine that are distinctive for individuals with autism. If identified, these characteristic urine profiles may potentially be used as biomarkers to confirm an autism diagnosis and subtype different groups of autistic individuals, thereby offering indications for treatment opportunities. Research Partner: Anonymous Donor

Autism-specific Impairments in the First Six Months of Infancy (Young Investigator Award)

Anjana Bhat, Ph.D., Kennedy Krieger Institute, Baltimore, MD

Impaired visual attention and affect may be early signs for autism and may impair infants' early learning abilities. Hence, the purpose of the proposed research is to conduct a prospective study to identify autism-specific impairments in visual attention, affect, and learning in infant siblings of children with autism at 3 and 6 months of age as compared to preterm and typically developing infants. Infants will be examined during a classic contingency learning paradigm known as the Mobile paradigm. The Mobile paradigm is an ideal form of assessment in multisystem disorders such as autism because it provides a multisystem assessment by taxing various developing systems such as the cognitive systems: arousal, motivation, and learning; sensory-perceptual systems: visual attention, proprioception; and motor systems: limb control and coordination. We hypothesize that infants later diagnosed with autism will specifically lack social attention and positive affect during the social interactions in the Mobile paradigm test, and that they will not display learning as compared to the typically developing infants. A better understanding of autism-specific impairments in the first six months of life will not only assist in early diagnosis but also provide a theoretical basis for developing effective early intervention programs. Research Partner: The Karma Foundation

Gaze Patterns in Autism Across the First Two Years of Life (Pilot Project Award)


Sally J. Rogers, Ph.D., M.I.N.D. Institute, University of California, Davis

During the first two years, infants develop increasingly complex social and communicative abilities. Because autism is such a devastating disorder, and because young children with autism are quite responsive to early interventions, the hunt is on for early markers of incipient autism in infancy. Abnormal gaze patterns may be one such marker. This study will use new eye tracking methodology to record infant gaze behavior during live reciprocal social interaction, and when viewing recorded social stimuli. We hypothesize that gaze abnormalities will characterize autism from an early age. The project will identify differences in gaze behavior associated with autism at 12 and 24 months in a group of toddlers who are at high risk for autism (due to the presence of a sibling with autism in the family), compared to a control group. We will examine the consistency of gaze abnormalities across the first two years of life in these children using previously gathered longitudinal data. Research Partner: The Mellanby Autism Foundation at The Giving Back Fund

Development of Motor Coordination and Anticipatory Control in Children with Autism (Pilot Project Award)

Deborah E. Thorpe, Ph.D., PT, PCS, University of North Carolina, Chapel Hill

Autism is characterized by deficits in sociability, communication and restricted behaviors. In addition to these core features, research suggests that movement abnormalities are evident in autism. Anecdotal reports often describe a variety of motor difficulties affecting functional skills such as writing, tying shoelaces, or playing sports. Although these types of difficulties may be related to dyscoordination and deficient anticipatory control mechanisms, there is a dearth of empirical research about the development of these movement abnormalities in children with autism, and how these motor patterns differ from peers. The proposed study will analyze the development of specific fine motor patterns in young children with autism disorder (2-6 years) using an experimental grasping task. We also aim to determine whether or not motor deficits (e.g., difficulty anticipating or coordinating the timing of movement) are specific to autism disorder, and how much they affect functional skills. These findings will assist in understanding the nature of autism, and have implications for earlier intervention during a period where motor skills are critical to success in educational and social situations.

The Identification of Non-Verbal Oral, Motor Speech and Phonological Impairment in Individuals with Autism Spectrum Disorder (Pilot Project Award)

Shelley L. Velleman, Ph.D. and Mary V. Andrianopoulos, Ph.D., University of Massachusetts, Amherst

Half of all children with Autism Spectrum Disorders (ASD) do not communicate by speaking. The nature of their speech problems is not understood. There are three possible causes: muscle weakness (dysarthria), poor motor programming/planning (apraxia), or limited ability to represent words as sounds in their minds (phonology). In a preliminary study, it was found that 60% of children with ASD had at least some of these factors. The purpose of this project is to test children with ASD to determine exactly what their speech problems are. We aim to develop a diagnostic measure useful for the identification and differentiation of subgroups of children with speech impairments. This will allow proper treatments to be developed and help provide specialized training for future speech-language pathologists focused on assessment and treatment of speech disorders in children with ASD.



Immune and Gastrointestinal Systems: Searching for evidence to explain the broader phenotypes


Immunological Phenotyping in Autism: A Screen for Potential Early Biomarkers of Activation (Pilot Project Award)

Paul Ashwood, Ph.D., M.I.N.D. Institute, University of California, Davis

It is thought that the interaction of genetic susceptibility and exposure to nongenetic influences during critical periods of neurodevelopment plays a part in the development of autism. Virtually the entire research literature on autism emphasizes the multiple facets of this disorder. Taken together, these data indicate that ASD is, in reality, a group of disorders that share a common behavioral profile. To make progress in identifying the causes of these disorders it will be essential to develop diagnostic markers that will lead to unequivocal differentiation of the various phenotypes. We aim to demonstrate the presence of distinct immune phenotypes in ASD based on the level of activation of their immune response. We will identify and characterize the immune response in ASD by comparing the activation status and function of lymphocyte cell populations and their cytokine/chemokine profiles, firstly in peripheral blood and secondly in isolated cell cultures that receive immunological challenge. Immunological findings will be correlated with behavioral and biomedical factors to examine the relationship between the immune responses and clinical characteristics of autism. By elucidating the medical and biological correlates of autism, we hope to contribute to a clearer understanding of the early biological processes underlying this increasingly common disorder. A better understanding of the underlying biology may contribute to earlier identification and the development of more individual-based treatment regimens. Research Partner: Peter Emch

Microglial Regulation of Cholinergic Development in the Basal Forebrain (Pilot Project Award)

G. Miller Jonakait, Ph.D., New Jersey Institute of Technology

While the neurobiological basis for autism remains poorly understood, neuropathological studies have detected structural abnormalities in certain brain regions suggesting that disruption of normal brain development may play a role in the disorder. Our work highlights one of those abnormal brain regions, the so-called cholinergic basal forebrain, that innervates important brain areas serving cognitive function. Autistic children have too many neurons in this region, but how such changes might occur in development has not been explained. Increasing evidence also suggests that fetal exposure to infectious agents or toxins with associated inflammation may play a role in the development of autism. Such infection or toxicity can extend to the embryonic brain where local inflammation might prove detrimental to the developing brain. Our own work performed on cultured rodent cells suggests that abnormal embryonic brain inflammation during development leads directly to abnormal neurodevelopmental outcomes. Specifically, it leads to the excess production of cholinergic neurons in the basal forebrain. Thus, we have shown directly that brain inflammation has important neurodevelopmental consequences. Our proposal seeks to extend those studies by investigating in vivo whether maternal infection will lead to a similar excess of cholinergic neurons in the fetal brain. We will also seek to determine whether several known inflammatory signals will act similarly in culture and what developmental mechanisms they might use to create excess numbers of these neurons. Finally, we hope to begin to identify the specific molecules that cause the basal forebrain to develop abnormally. Research Partner: The Gassin Family Foundation

Histologic, Microbiological and Molecular Analyses of Bowel Disease in ASDs (Pilot Project Award)

W. Ian Lipkin, M.D., Columbia University

Debilitating gastrointestinal (GI) dysfunction is described in some autistic children, possibly at higher frequency in individuals with a regressive phenotype. Its cause is unknown; however, some studies have implicated inflammation or infection. The significance of gastrointestinal dysfunction for brain dysfunction is controversial; some investigators have proposed that differences in GI microflora induce inflammation, influence permeability of the GI tract, or release novel neuroactive peptides that have remote effects in brain. Our project will use sensitive new assays for gene expression, microbiology and immunology to survey GI tract biopsies and blood from two groups of children: one group with GI dysfunction and autism, and one group with GI dysfunction but no neurological disturbance. The implication of an infectious agent (or agents) as factors (or cofactors) in autism or associated GI comorbidity could lead to new strategies for prophylaxis or therapeutic intervention. Discovery of distinct profiles of gene expression in GI tract or of soluble factors in peripheral blood may provide insights into pathogenesis; inform genetic analyses; and facilitate management by providing therapeutic targets and objective criteria for diagnosis and treatment response.

A Role for Immune Proteins in Early Stages of Neural Development: Possible Implications for the Pathogenesis of Autism (Pilot Project Award)

A. Kimberley McAllister, Ph.D., University of California, Davis

Proper formation of connections in the brain during childhood provides the substrate for adult perception, learning, memory, and cognition. Tragically, improper formation or function of these connections leads to many neurodevelopmental disorders, including autism. Autism spectrum disorder is a highly prevalent severe neurobehavioral syndrome with a heterogeneous phenotype. Although there is a strong genetic component to autism, the syndrome can also be caused or influenced by nongenetic factors. Specifically, maternal viral infection has been identified as the principle nongenetic cause of autism. Several studies have even indicated a genetic link between autism and immune system genes. Since immune molecules are increased following infection and are present in the developing brain, it is possible that changes in these immune molecules lead to changes in neuronal connectivity that underlie some forms of autism. This proposal will test this idea by studying the function of altered levels of a specific kind of immune molecule on the initial formation of connections and their subsequent plasticity in the developing brain. Thus, our results should reveal a mechanism for the primary nongenetic cause of autism and thereby illuminate potential preventive therapies for this devastating disease. Research Partner: The Gassin Family Foundation



Environment: The impact of our surroundings upon developing autism


Polybrominated Diphenyl Ethers as a Potential Neurodevelopmental Toxicant (Pilot Project Award)


Irva Hertz-Picciotto, Ph.D., M.P.H., University of California, Davis

Both genetic and environmental factors contribute to autism in the majority of cases, yet few specific causes have been identified. In the search for relevant environmental exposures, chemicals affecting neurodevelopment are prime suspects. One such group of chemicals is the polybrominated diphenyl ether (PBDEs). These are flame-retardants used widely in consumer products, including plastic casings for television sets and computers, construction materials, carpeting and foam cushions. Levels of PBDEs are rapidly increasing in the environment and in human tissues, with body burdens in California among the highest worldwide. Of foremost concern is the neurodevelopmental toxicity of PBDEs demonstrated in animal studies. Prenatal exposures alter spontaneous behaviors, adversely affect learning and memory, and result in a lack of ability to habituate to a novel situation. PBDEs cross the placenta, accumulate in the fetus, and disrupt thyroid hormones, which are crucial for early brain, motor, language and sensory development. Thus, we will measure PBDEs in serum collected from children participating in a large epidemiologic study of autism. The CHARGE (Childhood Autism Risk from Genetics and the Environment) Study has enrolled over 400 subjects, including children with autism, children with developmental delay, and children from the general population. Over 300 of these children gave blood samples, from which we will select 90 (30 from each group) for measurement of PBDEs. This project will provide preliminary data to determine whether children with autism have higher concentrations of PBDEs than those from the general population or those with developmental delay but not autism. Research Partner: Shirley Craven Foundation

Molecular and Environmental Influences on Autism Pathophysiology (Young Investigator Award)

Janel Le Belle, Ph.D., University of California, Los Angeles

The incidence of macrocephaly (enlarged head) in the population of autistic patients is considerably higher than in control populations and indicates that this may contribute to the development of ASD. We are interested in what genetic and environmental changes underlie the development of macrocephaly and autism. Mutations in PTEN can be found in some autistic patients with macrocephaly. We have a mouse model of macrocephaly in which the gene PTEN has been deleted, resulting in the abnormal growth of brain cells, producing animals with large heads. We have recently shown that PTEN has a role in the ability of normal brain stem cells to self-renew, proliferate, and grow. We will use a relatively new technology in the study of gene expression in the brain, called microarray, to identify genes that are changed in our macrocephalic PTEN mutant mice. These experiments may identify genes and gene networks that contribute to ASD. We will also study how PTEN activity is affected by environmental factors. One such factor is oxidative stress. Oxidative stress is a general term used to describe oxidative damage to a cell, tissue, or organ, caused by reactive oxygen species. Most reactive oxygen species come from the internal sources as byproducts of normal cellular metabolism, such as energy generation from mitochondria. External sources include 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. We and others have found that low levels of oxidative stress can enhance the self-renewal and proliferation of brain stem cells when grown in a culture dish, and this also results in decreased amounts of PTEN gene expression. We propose to look further at this potential mechanism by over-expressing pro-oxidant genes and disrupting anti-oxidant genes in cultured cells and in developing mouse embryos to determine if oxidative stress is a key environmental factor in the development of ASD with macrocephaly. The Jonathan Pettigrew Memorial Award

Contribution of Calcium Channel Mutations to Autism Risk and Mercury Susceptibility (Environmental Initiative Innovator Award)

Isaac Pessah, Ph.D., University of California, Davis

The goal of this research is to understand the genetic and environmental risk factors contributing to the incidence and severity of core symptoms and comorbidity seen in childhood autism. Dr. Pessah hypothesizes that mutations in specific types of calcium (Ca2+) channels may contribute to certain forms of autism and significantly increased susceptibility to adverse effects of environmental toxicants. This hypothesis is based on evidence from the Pessah lab that organic mercury, polychlorinated biphenyls, and flame retardants (PBDEs) can alter the intracellular Ca2+ signals generated by ryanodine receptors, an important type of calcium channel, and that these receptors are essential for normal maturation and function of both the immune and nervous systems. To attain these goals, mice that contain mutations for calcium channels will be studied for abnormal social behavior and their possible heightened susceptibility to organic mercury compounds such as thimerosal will be studied in detail. One mouse currently being developed possesses a mutation within a specific calcium channel (Cavl.2) that has been found to cause Timothy Syndrome (TS). Children with TS have a 60% rate of an autism diagnosis, with up to 80% of the children showing some signs of autism. Two additional mouse models are currently being studied that possess a mutation within the type 1 or type 2 ryanodine receptor Ca2+ channel (RyR1 and RyR2, respectively). Dr. Pessah's lab has found that mice possessing mutations in RyR channels have heightened susceptibility to chemically-induced adverse reactions of the immune and nervous systems. Together, the Cavl.2 and RyR2 receptors form a signaling unit in heart, neurons and T lymphocytes. This project will investigate whether these three lines of mice, which have an underlying genetic defect in Ca2+ signaling, will have increased behavioral and immunological problems when exposed to mercury, and will also examine whether mercury directly affects the development of nerve cells from these animals. Finally, the Pessah lab will determine whether children with autism have a higher frequency of Cavl.2 or RyR mutations. Collectively these experiments will provide important new information on the possible contribution of Cavl.2 or RyR mutations to autism risk in humans and launch studies of enhanced susceptibility of the developing nervous and immune systems to organic forms of mercury in mice carrying mutations relevant to autism. Research Partner: Sallie and Tom Bernard

Genetic Susceptibility to Mercury-induced Immune Dysfunction in Autism and Autism- Spectrum Disorders (Pilot Project Award)

Ellen K. Silbergeld, Ph.D., Johns Hopkins Bloomberg School of Public Health

The goal of this project is to examine genes that may affect responses to environmental risk factors in autism and autism spectrum disorders (ASD). These are complex diseases that are known to involve interactions between genetic susceptibility and acquired (or environmental) exposures. However, most research on autism/ASD development has not examined these interactions, but rather focused on either genetic or environmental risk factors, including mercury compounds. The failure to include gene-environment interactions may be one reason why we have not yet identified either key genes or significant environmental risk factors associated with autism/ASD. We plan to examine whether there are differences in how children with autism/ASD respond to one environmental contaminant (mercury) compared to their unaffected siblings and parents. We hypothesize that mercury does not cause autism by itself, but that individuals who carry certain variations in specific genes may have heightened responses to mercury, and that these variations will increase the likelihood that those children exposed to mercury will develop autism/ASD. In order to accomplish our goal, we will first develop and validate a panel of tests using immune cells found in human blood to quantitate immune responses to mercury in vitro by using the blood of healthy volunteers. Then we will apply this panel to cells obtained from children diagnosed with autism/ASD, their unaffected siblings, their parents, and unrelated community controls. This project will be the first study on this topic conducted in cells from human subjects. Eventually, we hope to identify variations in specific genes related to these responses to mercury for use in epidemiological studies of autism/ASD. Research Partner: Robert and Joni Bell



Physiology: Understanding how information is transmitted in the brain


The Neurophysiology of Multisensory Integration in Autism (Pilot Project Award)


John J. Foxe, Ph.D. and Hilary Gomes, Ph.D., City College of the City University of New York

It has long been speculated that children and adults with autism have difficulties in dealing with or combining information across the senses. This has become known as sensory integration theory and the predictions of this theory are far-reaching. If sensory integration is a core deficit, then a number of additional attributes of autism might very well be explained by this problem. For instance, our research has shown that normal integration of auditory (heard) and visual (seen) information is absolutely critical for speech recognition, particularly in busy or noisy environments. Clearly, this could also lead to real difficulties in the ability to recognize emotion and social cues in speech. Remarkably, despite the prominence of this theory, little direct investigation of multisensory processing has actually been conducted in autistic individuals. Work by this team has detailed a series of multisensory brain processes through electrophysiological measures and using functional imaging. Here, we propose to measure these previously established effects in autistic children. Specifically, we will 1) assess basic auditory-visual integration during a very simple detection task, 2) assess auditory-visual integration during a slightly higher-level identification task where subjects are asked to identify simple animal pictures and sounds and lastly 3) we will assess whether autistic individuals use multisensory visual information effectively when interpreting speech in noisy environments. By relating results across these three levels of investigation, we will be able to assess for the first time whether basic deficits in multisensory processing really do exist in this population and whether such deficits might be one of the root causes of higher-level deficits such as inability to recognize speech in distracting environments. We believe that it is imperative that a methodical scientific approach be finally taken to assess the well-known sensory integration theory of autism. The Frank del Olmo Memorial Award

Electrophysiological Indicators of Gating and Timing Abnormalities in Autism (Pilot Project Award)

Katherine M. Martien, M.D., Massachusetts General Hospital

Individuals with autism can have inaccurate processing of sensory information from both external environment (i.e. auditory, visual, tactile, and taste) and internal milieu (i.e. pain, proprioception and vestibular). This produces a cumulative effect on the developing brain that further undermines the way the brain matures and functions. Some researchers have proposed that the autistic brain has two particular basic abnormalities: 1) gating problems - that is, difficulty regulating how intensely the brain responds to sensory stimulation, and 2) timing problems - that is, a tendency for communication among parts of the brain to be poorly synchronized with each other. The processing and integration of sensory information in the brain can be studied at the biological level using electrophysiological techniques that measure the quality of the transduction (transformation) of environmental information into neuronal activity in the brain. In the present study we will examine the processing of auditory and visual information young autistic children using ERP and qEEG in an effort to identify the abnormalities in early and later signal processing, the relationship between early and late abnormalities, and how these signaling derangements contribute to abnormal patterns (and probably reduction) of coherence (synchronization) of brain functioning at the highest levels of information processing. We hope through our inquiries to find a level at which we can describe common features that are distinctive to autism, and also to identify subgroups with distinctive brain patterns that may also have distinctive underlying biological contributing factors. This will be helpful at many levels of autism research, diagnosis and treatment. Research Partner: The Gassin Family Foundation and Anonymous Donor

Integration of Faces and Vocalizations in the Primate Prefrontal Cortex (Pilot Project Award)

Lizabeth M. Romanski, Ph.D., and Tadashi Sugihara, Ph.D., University of Rochester

The integration of faces and voices is crucial for recognizing and remembering objects, and for communicating effectively. Some have theorized that it is this inability to synthesize information, especially during communication, which lies at the heart of autism. Although many brain regions are involved in integrating communication information, we believe that the frontal lobes are essential and may be one of the brain regions critically affected in autism. In this project, we will examine how single cells in the frontal lobes integrate face and voice information using an animal model. Specifically, we will record the neurophysiological responses of auditory and visual neurons in the frontal lobe of awake macaque monkeys who will be presented with vocalizations and corresponding facial gestures. Our preliminary data indicate that some frontal lobe neurons show an enhanced response to simultaneous presentation of matching faces and vocalizations especially when presented in naturalistic "movie" format. It is our hope that these studies will: lead to additional diagnostic tests perhaps based on our naturalistic face-vocalization paradigm, behavioral therapeutic interventions aimed at training appropriate face and vocalization matches, and treatments aimed at repairing impaired cellular mechanisms of sensory integration which may have been altered in autism.

Brain Dynamics of Multisensory Integration in Autism Spectrum Disorders (Pilot Project Award)

Clifford D. Saron, Ph.D., and Susan M. Rivera, Ph.D., University of California, Davis

Multisensory integration (MSI), the combination of various senses to form a single integrated experience of the world, is essential to everyday life. Current research shows that there are both co-operative functions of the senses as well as inhibitory effects of one sensory system upon another that contribute to our ability to form this integrated experience. Many researchers have suggested that the formation of cross-sensory associations may be deficient in children with autism. Indeed, the well-known author with autism, Temple Grandin, has repeatedly discussed sensory integration difficulties as being at the core of her autism. The current project will examine the behavioral (reaction time), electromyographic (EMG), and brain (EEG) responses to sensory processing in children with Autism Spectrum Disorders (ASD) as compared to typically developing (TD) children. Specifically, we will examine the integration of multiple sensory systems through analysis of dense-channel array event related potentials (ERPs) elicited in response to visual, auditory, and somatosensory stimuli delivered alone or in simultaneous combination. We will investigate the brain regions involved in MSI, and probable differences in their function in autism. We predict that, compared with TD children, ASD individuals will show less improvement in a reaction time test and generally smaller electrocortical activations related to MSI when multiple sensory systems are engaged.



Cellular and Molecular Deficits: Pinpointing underlying defects and their mechanisms


Alterations in Specific Subtypes of Glutamate Receptors in Autism: An Autoradiographic and Molecular Study in the Cerebella Cortex (Pilot Project Award)

Gene Blatt, Ph.D., Boston University School of Medicine

The etiology of autism has remained elusive despite an increase incidence of the disorder. Treatment has largely targeted behavioral symptoms instead of the underlying substrates which remain unknown. The present research proposal investigates a neurotransmitter system, the glutamate system, which provides excitatory input to key nerve cells throughout the brain. One area of the brain, the cerebellum has received much attention because a cell type critical to its function is decreased in number. Once considered to only modulate motor function, there is now compelling clinical and neuroanatomical evidence that the cerebellum also modulates cortical structures involved in higher thought processes. The glutamatergic systems in the cerebellum provide a delicate excitatory-inhibitory balance so that the output of the cerebellum functions properly. Identification of which specific glutamatergic receptors and receptor subunits are altered in the cerebellum in autism can lead to therapeutic intervention targeted to the defective receptors instead of just treating behavioral symptoms. It will also give valuable leads to geneticists who can locate defective candidate gene(s) to determine whether there is a high incidence in the families of autism children which can ultimately lead to screening high-risk families for the disorder. Research Partner: The
Gassin Family Foundation


Collaborative Neuropathology Workgroup: A Comprehensive Multilevel Analysis of Frontal Lobe Microstructure in Autism (Brain Development Initiative Award)


Eric Courchesne, Ph.D., University of California, San Diego; Carlos Pardo, M.D., Johns Hopkins University; Katerina Semendeferi, Ph.D., University of California, San Diego; Karoly Mirnics, M.D., University of Pittsburgh; and Dan Buxhoevden, Ph.D., University of South Carolina


To solve the mystery of what causes autistic behavior and to develop biologically-based treatments, it is necessary to discover the underlying neural defects. As a first step, brain imaging studies have begun to successfully identify which major regions of the brain have abnormal growth and function in autism. One of these pivotal regions is the frontal lobe. It is responsible for complex social, emotional cognitive and language abilities. Now that brain imaging studies have pinpointed where to look, the next step is to discover why the frontal lobe is abnormal. To do that requires detailed examination of the microscopic building blocks -the molecules and cells - that make up the frontal lobe. New scientific methods allow an unprecedented opportunity to see these microscopic building blocks in autism by studying postmortem tissue. Such quantitative neuropathological methods are the only ones able to validate and examine in detail the nature of the neuronal, neuroglial and cytoarchitectural abnormalities in autism. As such, they are the most direct path to providing answers to the myriad of questions surrounding the brain causes of autistic behavior. A collaborative neuropathology workgroup headed by Dr. Eric Courchesne and his colleagues Drs. Pardo, Semendeferi, Mirnics, and Buxhoevden will be the first to use such quantitative methods and markers to carefully measure and identify the molecular and cellular abnormalities in frontal lobe in autism. Those discoveries are expected to point to the developmental events that ultimately caused defects in these fundamental building blocks of the brain. In sum, careful examination of the brains of individuals with autism will allow us to finally determine the cellular and molecular underpinnings that generate autistic behavior, knowledge that is necessary for rationally-designed treatment strategies. Research Partners: Mr. Peter Emch and Autism Speaks

The Role of Neuroligin in Synaptic Remodeling of Neuronal Networks (Pilot Project Award)


Michael A. Colicos, Ph.D., University of Calgary, Canada

Synaptic remodeling is believed to be a fundamental mechanism of learning and memory, and the resulting connections that are made between neurons are thought to be the basis for cognition. Disorders in this process are hypothesized to contribute to cognitive dysfunction, such as observed in autism spectrum disorder (ASD). We plan to study the process of synaptic remodeling and to characterize a protein, neuroligin, which is both associated with remodeling, and found to be mutated in some autistic patients. We need to understand how the autism associated mutation affects the connectivity between neurons, as it is this connectivity that defines our cognitive function. To do so, we have developed a unique technology, non-invasive photoconductive stimulation, which allows us to visualize the entire process of synaptic remodeling in cultured mammalian neurons grown on silicon wafers. This technique also allows for the expression or functional inhibition of specific molecules in the neurons, which will allow us to determine their role in the reorganization process. Neuroligin is a synaptic cell adhesion molecule that is involved in both synaptogenesis and in regulating synaptic transmission through the N-methyl D-aspartate (NMDA) receptor. We wish to understand the role of neuroligin and NMDA currents in the process of synaptic reorganization. By learning the functional consequences of the ASD mutation on synaptic transmission and plasticity, we hope to understand how such cognitive dysfunctions occur, and then be able to directly test in vitro therapeutic strategies using the same technology.

Self-Injurious Behavior: Pharmacological Studies in a Rat Model (Pilot Project Award)

Darragh P. Devine, Ph.D., University of Florida

Self-injurious behavior is seen in a substantial number of autistic children. The behavior disorder is determined at least partly by abnormal brain chemistry, but the brain functions that contribute to self-injury are not very well understood. The severity of self-injury ranges from mild to very severe, and these behaviors constitute an extremely debilitating symptom of autism. They are also extremely destructive for families who live with self-injurers. Many autistic self-injurers respond well to behavior therapy, and this is clearly the treatment of choice. However, there is no drug that works for all self-injurers, and research to seek out and test new drugs is not well developed. We are working with a pemoline-induced model of self-injury in rats, to evaluate drugs that may be useful in clinical treatments for self-injury. We do not allow the rats to do any serious self-harm but are testing specific drugs to see if they will prevent the rats from starting to bite at themselves. We plan to work with drugs that have been used in autistic self-injurers to further evaluate the efficiency of the model to identify effective drug therapies, and we will begin to test a new drug that we think may have beneficial effects. At the same time, we will examine the brains of the rats to identify differences in brain chemistry between the rats that self-injure, and those that do not when they are treated with pemoline or the drugs that block the self-injurious effects of pemoline. These studies will help us to understand the biological basis of self-injurious behavior, so that we can better develop effective treatment strategies. These studies may also provide a mechanism to pre-screen potentially promising drugs before they go to clinical trials and reduce the risk that ineffective drugs would be tested in autistic self-injurers.

The Relationship between Autism and Cholesterol Metabolism (Pilot Project Award)

Robert D. Steiner, M.D., Oregon Health and Science University

Cholesterol production is necessary for normal cell development and functioning. Smith-Lemli-Opitz syndrome (SLOS) is a genetic metabolic condition caused by a defect in cholesterol production by the body, with physical and mental difficulties. Most people with SLOS have autistic behaviors. Because SLOS is caused by a problem with cholesterol production, we think cholesterol production may have a role in causing autism in people who do not have this genetic condition, but just have autism. Our plan is to evaluate cholesterol metabolism in people who have autism and people who do not have autism to determine if there are differences. We will look at whether there is a relationship between cholesterol production and the severity of autistic behavior. We will also see if individuals with autism are more likely to have SLOS gene mutations than those who are not autistic, and whether family members of SLOS patients (who carry the SLOS gene) have features of autism. This will involve enrolling 45 children with autism (who do not have SLOS) from our autism clinic, 45 non-autistic, non-SLOS children, and 20 SLOS carriers. The children will have blood samples taken for analysis of cholesterol metabolism. Our findings will determine if indeed cholesterol production plays a role in causing autism. If it does, this will have implications for screening, diagnosis and treatment of autism.



Genetics: Searching DNA for mutations that point to proteins and pathways that may be amenable to treatment


Genetic and Neurobiological Analysis of Sociability, an Autism Endophenotype, in a Mouse Model System (Pilot Project Award)

Edward S. Brodkin, M.D., University of Pennsylvania School of Medicine

Impairments in social interactions are among the most prominent, disabling, and treatment-resistant symptoms of autism. A major goal of autism research is to identify genes relevant to sociability (defined as a tendency to seek social interaction), and to elucidate the function of those genes in brain development and behavior, which ultimately should advance our understanding of and ability to treat autism. To accomplish these goals, it will be crucial to develop a mouse model of sociability. We have recently initiated genetic studies of sociability in mice, and have identified genetically influenced differences among inbred mouse strains in sociability. The aims of the current proposal are 1) to further develop this mouse model system for autism research; 2) to assess the effects of particular autism candidate genes on sociability in this model system by measuring the sociability of mice in which those genes have been deleted (gene "knockout" mice); and 3) to identify brain regions that are involved in sociability, and to study differences in gene expression in such a brain region in mice that differ greatly in sociability, using GeneChip technology. These proposed studies can help to elucidate the genetic and neurobiological basis of highly disabling symptoms of autism. Research Partner: Christopher Camburn

Identification of Candidate Genes for Autism Spectrum Disorders (Young Investigator Award)

Yuhei Nishimura, Ph.D., University of California, Los Angeles

Autism is a heterogeneous condition and is likely to result from the combined effects of multiple, subtle genetic changes interacting with environmental factors. We hypothesize that there are genes whose expression are deregulated in autism. We believe that a subset of these genes can be identified through whole genome expression profiling in lymphoblastoid (white blood) cells from individuals with autism and matched controls (the AGRE collection). Although lymphoblastoid cells are not neuronal cells, recent studies suggest that lymphoblastoid cells can be useful to detect biologically plausible correlations between candidate genes and disease in various neuropsychiatric disorders. Our preliminary study using lymphoblastoid cells from autistic subjects with known genetic disorders also suggests that an approach based on lymphoblast gene expression profiling could be widely used to subgroup subjects with idiopathic autism and to identify candidate genes for autism. The ultimate goal of the proposal is to identify a set of genes that are deregulated in autism and then test these candidate genes for autism on a broader cohort of children with autism and in analysis using human brain tissue. Research Partner: The Gassin Family Foundation

A Proteomics Approach to the Identification and Characterization of Protein Targets Regulated by UBE3A (Pilot Project Award)

Lawrence T. Reiter, Ph.D., University of Tennessee Medical School

The purpose of this grant is to focus on the detection of genes involved in autism. UBE3A mutations cause a mental retardation disorder known as Angelman syndrome and duplication of this gene has been implicated in as many as 2% of all cases of inherited autism. This project will take advantage of the genetic power of Drosophila melanogaster (fruit fly) as a model system to identify genes regulated at the protein level by UBE3A. In the project we propose several techniques that allow us to generate artificially high levels of normal and mutant fly dube3a proteins in flies. We will then use protein sequencing (proteomics) to identify those genes affected by changes in the level of fly dube3a protein. Genes that appear to change in this analysis will be subjected to validation using physical association studies in cell culture and a previously published mouse model of Angelman syndrome that is lacking mouse Ube3a protein. Finally, we will screen the AGRE collection to determine if any of the genes we identify are involved in genetic risk for autism. These targets may prove useful in the future as therapeutic targets for the treatment of disorders like Angelman syndrome and autism.