Autism Speaks, Goals, Science, Autism Speaks Funded Studies: Pilot Grant Program 2006

Autism Speaks received 279 letters of intent for its Pilot Grant Awards in Autism Research program by the stated November 1, 2005 grant deadline. Ultimately, 212 full proposals were received by the January 31, 2006 deadline, representing a 30% increase over the 163 full proposals received in the 2005 cycle. The Autism Speaks Scientific Affairs Committee, including Dr. Gary Goldstein and Drs. Joseph Coyle, Emanuel DiCicco-Bloom, Susan Hyman, Barry Gordon, CT Gordon, Eric London, Marshalyn Yeargin-Allsopp, and Susan Folstein recommended 50 projects totaling $5,610,627.12 to the Autism Speaks Board of Directors for funding consideration and approval. On June 13 all 50 projects were approved by the Autism Speaks Board of Directors. Proposals were assigned to broad categories based on the primary research objectives and methodology. There are many proposals that involve multiple disciplines and approaches. To see a breakdown by broad topic areas, click the topic name in the list below: Cognitive/Motor Processing: 6 Studies Diagnosis: 4 Studies Epidemiology: 2 Studies Genetics: 4 Studies Language + Communication: 5 Studies Neurobiology (includes molecular biology, immunology, etc.):13 Studies Neuroimaging : 10 Studies Neuropathology: 2 Studies Treatment: 4 Studies Studies on Cognitive and Motor Processing University of Montreal Jocelyn Faubert, PhD $119,000 total for two years Investigating the pathogenesis of repetitive behaviors in autism using a fully immersive virtual reality environment. Dr. Faubert and colleagues will employ fully immersive virtual reality (FIVR) technology to investigate the cause and potential treatments of repetitive behaviors in autism. Based on previous studies, it is possible that autistic individuals confronted with complex information will adopt behavioral strategies to reduce the amount of detailed information in a given scene in an attempt to limit its complexity. This can be achieved through eccentric or lateral glancing in individuals with autism – a behavior which is maintained to regulate the complexity of the visual environment and reduce discomfort. By systematically manipulating the complexity of the virtual environment using FIVR technology while measuring heart rate and skin conductance to monitor perceptual changes, the mechanism by which lateral glancing occurs can be better defined. If an association between the complexity of the perceived environment and physiological response is demonstrated, this suggests that pathogenesis of repetitive behaviors in autism may be the result of atypical information processing in autism. Significance: This group will employ a truly innovative approach and technique to assess the pathogenesis of stereotyped behavior in autism: fully immersive virtual reality (FIVR) technology. This approach is unique in that it allows for the sensory-behavioral interactions to be assessed in a non-invasive manner and in real-time. This is one of the few fully functional systems in North America that is exclusively used for investigating human behavior; and brings together scientists from complementary areas of research to use FIVR to study autism. The Groden Center June Groden $118,880 total for two years Telemetric Assessment of Movement Stereotypy in Children with ASD Movement stereotypies represent one of the most disruptive classes of stereotypical behaviors occurring in children with an ASD. Engagement in these behaviors can lead to social stigmatization, and can complicate social interaction. Unfortunately, the lack of accurate and timely measures of these behaviors has slowed the development of interventions to reduce or prevent stereotypical motor movements. The current proposal will evaluate the use of wireless accelerometers and pattern recognition software to automatically detect two of the most common, high-frequency stereotypical motor movements (body-rocking and hand-flapping) in children with an ASD in real-time. The system that will be tested uses small, noninvasive wireless and wearable sensors that can be easily suited to individuals with ASD. Significance: Obtaining detailed and accurate information on the occurrence, type of movement frequency, duration, and setting events associated with movement stereotypy is critical to understanding and treating this potentially disruptive behavior. Reliable recording of movement stereotypies will enable researchers to study what functional relations may exist between these behaviors and specific antecedents and consequences. These measures can facilitate efficacy studies of behavioral and pharmacologic interventions intended to decrease the incidence or severity of this behavior. Rutgers University, Newark Maggie Shiffrar, PhD $119,966 total for two years Do deficits in visual motion processing underlie social difficulties in autism? Little is known about the perceptual deficits associated with autism. This is surprising because the accurate perception of socially relevant information is a necessary first step in social behavior. People communicate vast amounts of rich social information, such as emotion and intention, through their actions. Given the importance of human action perception to social behavior, vision researchers have conducted numerous experiments to understand how the human visual system normally analyzes the bodily movements or actions of other people. This is done by simulating human movements using multiple points of light across a computer screen. This psychophysical measurement will be applied to individuals with high functioning autism (HFA) to determine how, and how well, adults with autism can differentiate patterns of individual points of light that mimic human movement. Significance: This proposal addresses the question of whether individuals with high functioning autism (HFA) are compromised in their ability to perceive human action. If individuals with HFA have difficulty perceiving the actions of other people, then this might account for aspects of their social deficits. Such a finding would indicate that significant changes are needed in our understanding, assessment, and treatment of HFA. The results of this study are complemented by the group at the University of Glasgow which will investigate neural activation during tasks which involve visual processing while observing biological stimuli. The MIND Institute at University of California at Davis Marjorie Solomon, PhD $120,000 total for two years Motivation and Cognitive Control in Autism While much effort has been directed at the deficits in social functioning and goal-directed behavior in individuals with autism, there has been little study of non-social forms of motivation that can cause profound problems in adaptive functioning. Research in other diseases has shown that the nucleus accumbens in the brain is underactivated in individuals with ASD, leading to disturbances in goal-directed behavior and learning. The goal of this study is to examine this brain area more carefully, and examine the utilization of this region during tasks which involve monetary, not social, rewards. The investigators will use the Monetary Incentive Delay Task, which has been used in other clinical populations such as schizophrenia. It is anticipated that an underactivity of the nucleus accumbens will be associated with impairments of this task. This experiment will also compare the activation of this brain area with measures of impairment in goal-directed behavior and with the severity of restricted and repetitive behavior symptoms. Significance: The proposed study will represent an important step forward in the way clinicians conceptualize the role of reinforcements when they deliver psychotherapeutic interventions. University of Pittsburgh Beatriz Luna, PhD $118, 364 total for two years Development of perceptual processing in autism Individuals with autism show the tendency to visually focus on individual elements in a scene, possibly at the expense of encoding the entire situation. To investigate the idea that people with autism focus on each element in a scene individually rather than processing multiple elements simultaneously, areas of the brain will be monitored during different visual processing tasks. This will be done in two ways: First, the ability to see and configure multiple, randomly located elements. Second, the ability to track multiple objects at the same time will be monitored. In addition to visual processing ability, the function of areas of the brain that contribute to this ability (specifically the occipital lobe) will be examined using fMRI technology. In order to characterize the developmental trajectory of perceptual development in autism, multiple age groups will be assessed on both tasks. This will be done to probe the integrity of neurodevelopmental processes, and to provide insight regarding the timing of intervention. Significance: A better characterization of basic visual processing in autism, including the development of these abilities and their neural substrates, has the potential to help a wide-range of people with autism spectrum disorders. This knowledge is crucial to designing useful visual interventions, providing compensatory strategies that may help people with autism spectrum disorders process visual stimuli across domains. University of California at San Diego Jeanne Townsend, PhD $119,914 total over two years Cross-Modal Integration Deficits in ASD It has been well established that the integration of auditory and visual integration is impaired in individuals with autism, however, the more specific nature and neural basis of this impairment are not known. One explanation of these deficits lies in the inability to connect basic auditory and visual information. The integration of sensory information (sight of a mother's face and hearing her voice) is a prerequisite to the formation of meaningful percepts with which children understand their environment. It is possible that different factors (including how closely they are linked in time and where they are located in space), may disrupt integration of auditory and visual information in individuals with autism. Dr. Townsend will try to identify different factors which may impair the integration of visual and auditory signals in children with autism, and monitor the electrical activity of the brain during tasks where either one, or both of these stimuli are presented. Significance: These data will be used to more specifically ascertain the nature by which sensory integration is impaired, so that better intervention strategies can be developed for individuals with ASD that will improve integration of auditory and visual information. back to top

Studies to Improve Diagnosis of Autism University of California at San Diego Karen Dobkins, PhD $60,000 for one year Neural & Behavioral Precursors to Autism The aim of this proposal is to investigate the risk factors associated with the development autism spectrum disorders (ASD), with the ultimate goals of illustrating and describing the neural basis of ASD and aiding in early diagnosis of ASD. Dr. Dobkins and her group are studying infant siblings of individuals with ASD (referred to as "at-risk" infants) longitudinally over 6–36 months. Although only ~8–15% of at-risk infants are predicted to develop ASD, the remaining at-risk infants are nonetheless expected to exhibit sub-clinical differences in neural pathway functioning. Using a variety of techniques (visual psychophysical, behavioral, and EEG), Dr. Dobkins and her colleagues will investigate different neural pathways that have been implicated in ASD. Children will be tested at 6 -18 months on tasks which monitor visual processing of motion, color, form, and facial images. While children are engaged in these tasks, the activation of specific pathways in the brain, as measured by electrical brain activity (i.e. event related potentials or ERP), will be tracked non-invasively. Over the course of this study, several additional standardized behavioral tests will be administered to assess social, communicative, and cognitive skills, including those that are used for diagnosing ASD. Significance: The data from these different assessments will be used to determine which of the measures described above correlate with, and might therefore provide early diagnostic identifiers for, ASD and other social/emotional/communicative outcomes. Yale University School of Medicine Katarzyna Chawaraska, PhD $119,989 total for two years Face and gaze processing in the second year of life: comparison between ASD, DD, and typical infants. This project will examine face scanning patterns, sensitivity to direct gaze, and the development of other visual processes in toddlers with ASD, toddlers with developmental delays (DD), and typically developing toddlers (TD). While many studies have focused on typical development of these skills in the above populations in the first year of life, there is limited evidence regarding their progression in the second year. To address this issue, the researcher will determine whether 18 to 24-month-old toddlers with ASD show impairments in any of these targeted skill areas and evaluate whether these deficits are specific to ASD by comparing them to a group of typically developing children and children with developmental delays not associated with autism. Several types of visual cognition paradigms will be employed, and visual responses will be recorded using cutting-edge eye-tracking technology. Significance: The proposed project will lead to identification of the areas of strength and impairment in toddlers with ASD and inform the development of improved ascertainment tasks suitable for detecting abnormalities in 0 to 18-month-olds. The findings of this study could also highlight key areas of visual cognition suitable for early intervention. Boston University School of Medicine Helen Tager-Flusberg, PhD $119,836 total for two years Identifying Neurobehavioral Markers of ASD in High Risk Infants This pilot project is designed to identify novel neurobehavioral risk markers for autism spectrum disorders (ASD) that may be present during the first 12 months of life, before a diagnosis of ASD is currently possible. Infants "at risk" for autism (i.e. baby siblings) will be recruited along with those younger siblings in a family with no first degree relatives diagnosed with ASD or other related disorders. The infants will be tracked from 6 months to 18 months of age and all will be evaluated for early signs of autism and language delay. Two novel measures that could be sensitive for identifying emerging problems in language/communication and social/affective behavior will be evaluated. One assesses brain activity during the presentation of verbal and auditory stimuli, which will be correlated with a parent diary to record weekly reports on developmental progress of infants. Significance: The research proposed has the potential to make significant additions to the knowledge base by detailing early behavioral, social and electrophysiological markers for ASD, and how they appear and/or change across the first year and a half. This work may well lead to the development of new screening methodologies and/or early intervention. Mark Johnson, PhD University of London $113,410 total for two years UK Infant Sibs Project: Phase One Studying high-risk groups for developing autism promises to advance our understanding of the early markers of autism and the broader phonotype of the condition. Based on the genetic basis of autism, one of the most clearly identified at-risk groups is the siblings of children with ASD. This approach have been productive and is expected to continue to provide possibility of predicting which infants are likely to develop the overt behavioral symptoms of autism based on early behavioral and brain differences during the first years. This proposal is a 2-year pilot project to establish feasibility and the core of a UK national network for studying infant siblings of children with autism. Establishing a network of labs is important due to the interdisciplinary nature of the studies required, and to increase the sample sizes. In phase 1 we will focus on (1) establishing a suitable battery of tasks for use in the first 24 months of life, and (2) piloting procedures for selecting the most high-risk sample to maximize the efficiency of future studies. This study is a natural expansion of the already successful high risk baby siblings research consortium established under the direction of Autism Speaks and the National Institute of Child Health and Human Development. Significance: The project brings into the primarily U.S.–based, Autism Speaks-supported Baby Siblings Research Consortium a number of well-established investigators in the U.K. The tasks proposed are similar to those used in other ongoing studies of infant siblings, but represent the integration of neurophysiology and developmental psychology which exists in only a few of the currently existing sites, thus enhancing the overall scientific value and opportunities of the consortium. back to top

Studies on Autism Epidemiology California Department of Health Services Gayle Windham, PhD $60,000 for one year Autism and Prenatal Hormone Markers The California Department of Health Services is currently tracking the prevalence and demographic characteristics of autism. This data will be linked to hormone and protein markers measured during pregnancy. This is made possible though the California prenatal screening program, in which several hormones or protein markers were measured in maternal blood during the second trimester. In the proposed study, the levels of these hormone/protein in nearly 2,000 pregnant women and their offspring who are later diagnosed with autism, compared to the nearly 600,000 screened births during the same two years. Although hormonal factors have been frequently suggested as contributing to the occurrence or severity of autism, few studies have investigated this hypothesis. Significance: The results will help shape further research to rigorously evaluate complex interactions between genetic factors, in utero hormonal factors, and environmental factors in relation to autism. In addition to the analyses proposed, the investigators have numerous opportunities for follow-up, including examining similar parameters in other birth years, examining other newborn screening markers, and potentially obtaining newborn blood spots for genotyping. The proposed study provides a unique and cost-effective opportunity explore important data on a very large population. University of Memphis Julie Cleary $115,330 total for two years Developmental Differences in Young African-American and Caucasian Children with Autism Spectrum Disorders (ASD) Despite many advances in biomedical and genetics research, ASD diagnoses continue to depend on subjective behavioral observations, and differences in clinician's thoughts and beliefs, which are influenced by cultural factors, may affect recognition of behavioral symptoms and later treatment. At this time, there is very little known about the presentation of autism spectrum disorders in young children from varying cultural and racial backgrounds and ambient culture. Dr. Cleary will specifically examine the cultural differences in diagnosis of autism by studying the differences in the quality of communication behaviors in young African-American and Caucasian children with autism spectrum disorders. This will be done by comparing types and frequency of communicative actions, including gestures, protests, vocalizations and words. In addition, play behavior and eye shifts will also be monitored during structured laboratory observations. Children with ASD from various cultures would be expected to exhibit deficits in social, communication, and behavior development but might differ in presentation. Significance: By examining the influences of the ambient culture on the children's communication behaviors, the proposed project should result in more culturally sensitive practices that contribute to an earlier accurate diagnosis for children from all cultures. back to top

Studies to Elucidate the Genetics of Autism University of California at Los Angeles Daniel Geschwind, MD, PhD. $119,497.50 total for two years A promising new animal model for the molecular study of Autism endophenotypes. Several converging lines of evidence, including data from the Geschwind lab, point to the possible involvement of Contactin Associated Protein-Like 2 (CNTNAP2/CASPR2) in autism. Based on these data, mice with mutations in the Cntnap2 will be generated and characterized using behavioral assays which target the core aspects of autism. These include measures of social interaction, vocal communication, and restricted/repetitive behavior. These animals will be compared to animals without this genetic mutation to determine whether specific molecules thought to be involved in disease etiology may show altered gene activity and behavior. Significance: Study of Cntnap2 mutant mice has the potential to impact not only on our understanding of autism pathogenesis, but also provide a system in which pre-clinical therapeutic strategies can be empirically investigated. University of Iowa Thomas Wassink, MD $120,000 total for two years Detecting Genomic Copy Number Variation in Autism Using cDNA Micro-Array Technology While the likelihood of an individual developing autism is largely determined by genetic factors, the specificity of these variants has remained elusive due to the fact that most autism genetic studies have tried to find disease-related genetic variants that are either very small, ranging from 1–100 nucleotides in length, or very large, such as chromosomal abnormalities that may involve millions of base pairs of DNA. This focus has existed largely because of technological limitations. The recent emergence of micro-array DNA technology has overcome this limitation and revealed that these intermediate-sized variants, also called genomic copy number variants (CNVs), has the potential to illuminate the contribution of genetic susceptibility to disease by a wide variety of mechanisms. The over-arching goal of this proposal is therefore to begin to determine the role that CNVs play in autism susceptibility. This will be accomplished using a DNA micro-array that brings together nearly 30,000 unique DNA elements from across the genome onto a small glass slide. The quantity of DNA at each of these elements will be tested in autistic individuals and comparison subjects. Confirmatory, low-cost assays will be developed to test these CNVs of interest in families with multiple autistic children to see whether the CNVs track with disease in those families. Significance: Data from this study will contribute to a more comprehensive understanding of the genetic basis of autism and suggest directions for future investigations. Oxford University Simon Fisher, D.Phil $115,050 total for two years A ChIP-on-chip system for dissecting genetic pathways involved in developmental language disorders The Fisher lab has previously reported that mutations of a gene, called FOXP2, cause a severe developmental communication disorder. FOXP2 abnormalities lead to problems with articulating speech, accompanied by impairment in many aspects of language ability. The protein made by FOXP2 controls the behavior of cells by binding to DNA and switching on and/or off other genes (so-called "downstream targets"). FOXP2 provides an exciting starting point for uncovering neural processes that may be widely relevant for language-related disorders, including autism. In particular, the downstream targets of FOXP2 in the brain represent potential candidates for other genetic risk factors that might be involved in these disorders. The investigators have developed an innovative method for purifying stretches of DNA that are directly bound by FOXP2 protein in neuronal-like cells. They will use this to identify potential targets of FOXP2 and utilize mouse models of FOXP2 mutations to help analyze the biological roles of these genes. Significance: This work represents a novel approach for uncovering genetic risk factors in ASD, offering a complement to traditional strategies for studying genetics of ASD. It could also provide important new insights into neural pathways involved in language development. University of British Columbia Suzanne Lewis, MD $120,000 total for two years Craniofacial Endophenotypes Associated with the Autism Spectrum Disorders Sibling, twin and family studies have shown that genetic changes play a major role in ASD. The estimated rates of chromosome abnormalities in persons with ASD range from 5-48%, depending on whether subjects have cognitive delay and/or physical anomalies. Small chromosomal anomalies, such as microdeletions and microduplications, might be relatively common and clinically important markers for identifying underlying genetic causes, including genes conferring susceptibility to ASD. This study will undertake DNA-based candidate gene studies with genomic microarray screening for autism-related microdeletions and microduplications in at least 200 cases from different affected families. In addition, rigorous clinical phenotyping and 3-dimensional craniofacial analysis will be performed in these individuals. This project aims to identify unique autism subgroups based on standardized behavioral and craniofacial analysis and link them to specific genetic markers. Significance: This project has the potential to improve ascertainment and diagnosis, as well as a better understanding of the relationship between genetic abnormalities and physical and behavioral attributes in ASD. back to top

Studies that Examines Autism Communication Impairments University of North Carolina Molly Losh, PhD $105,497 total for two years Characterizing the Language Endophenotype in Autism: Longitudinal, Genetic, and Neuropsychological Correlates Language impairment is perhaps the most debilitating clinical feature of autism. Findings that language-related impairments are more common among family members of autistic individuals, coupled with evidence for genetic overlap between autism and language disorders (e.g., Specific Language Impairment) suggest that that impaired language is a genetically meaningful feature of autism. Understanding the roots of autistic persons' language difficulties is therefore not only critical from a clinical/therapeutic standpoint, but also promises to inform molecular genetic studies of autism, where the identification of genetically relevant clinical features is essential. The language and social-cognitive functioning of children with autism along with their parents will be assessed by the investigators. These results will be compared to the parents' early measures of verbal functioning using scores on the Iowa Test of Basic Skills, conducted on elementary school children since 1955. This study adopts family-genetics, developmental, and neuropsychological perspectives to systematically examine language features in individuals with autism and their parents suggestive of inter-generational transmission of language impairments genetically relevant to autism. Significance: Results from the proposed studies will provide important guiding phenotypic information for efforts to dissect the genetic underpinnings of autism, and may inform preventive intervention efforts by highlighting targets for intervention across the autistic spectrum. Findings from the proposed studies will also provide a launching point for further investigation into the neural substrates (using fMRI) associated with language impairment in autism. Harvard Medical School Alvaro Pascual-Leone $59,687 for one year The Language Neural Network in Autism Several studies have measured brain activity while individuals with ASD perform language tasks and reported important differences in brain activity as compared to healthy individuals. However, these traditional studies are limited because performing the language task itself can interfere with the accuracy of the functional image. In order to solve this problem, this study will use a novel non-invasive approach combining transcranial magnetic stimulation (TMS) with real-time functional magnetic resonance (fMRI). Real-time combined TMS/fMRI can identify the level of activity between frontal and temporal language-related areas without the potential interference of behavioral activation on the images. Findings will be complemented with those of diffusion tensor imaging, which characterize the anatomy of connections between the language-related regions. Using this new methodology, functional and anatomical information about connections between language-related regions in ASD and normal subjects independent of any behavioral confounders can be assessed. Significance: TMS has been shown to be effective in modulating brain activity, guiding brain plasticity, and thus exert therapeutic utility in a variety of neuropsychiatric disorders. While the goal of this experiment is to characterize the language-related brain areas to gather information on how to modulate brain activity, the findings will be used to develop a new therapeutic strategy for improving language skills in ASD. Montreal Children's Hospital, McGill University Catherine Hambly $42,800 for one year The impact of bilingual language exposure on expressive vocabulary size in children with ASDs The overall goals of this study are to lay the foundation for studying bilingualism in children with ASDs by profiling the skills of bilingual children with ASDs as compared to those who speak only one language. This study will survey children diagnosed with ASD and describe the language environments of children at 3 centers in the Montreal English- and French-speaking communities. The results of this research will identify factors that influence language choices for families of children with an ASD, and evaluate if a difference in expressive vocabulary exists from monolingual versus bilingual environments. Finally, an additional sub-analysis of all data from bilingual children will explore the relationship between child factors and the amount of and contexts of bilingual exposure to identify conditions favoring the development of bilingual expressive vocabulary in children with an ASD. Significance: Professionals and families should evaluate the evidence from this study prior to making recommendations for changes in language environments in both children "at risk" for autism and those not at risk for developmental language deficits. Results will allow researchers across all disciplines will use this pilot work to determine how bilingualism factors into language development in future studies, and help clinicians in their diagnostic evaluations and recommendations for intervention. University of Child Health-University College London Tony Charman, PhD $118,600 total for two years Behavioral and electrophysiological responses to speech sounds and social stimuli in young children with ASD Children with delayed language onset in the absence of social impairments are diagnosed with a condition called developmental language disorder (DLD). Various theoretical accounts have been proposed to explain the differences in children with autism vs. DLD. However, understanding what underlies delayed language onset in children with ASD and DLD is important to inform psycho-educational intervention approaches and to further clarifying the relation between the two disorders. This study will use both behavioral and electrophysiological experiments to examine the behavioral and brain activity patterns in children with impaired language and social processing vs. those with DLD and typically developing children at different points during development. These studies will better describe both the behavioral responses and neural systems in children with language delay with and without autism, and importantly, follow these children for several years to determine how early language impairment predicts later function in adolescence. Significance: Although it seems very likely that early social-communicative impairments contribute to delayed language onset in many children with ASD, there are many gaps in the understanding of how sound and speech deficits lead to social impairments. A better understanding of how these impairments differ between children with ASD and DLD, on both speech function and brain activity, will lead to better therapeutic interventions and more sophisticated research on the genetic and neurological basis of speech delay. Oxford University Kate Nation $59,940 for one year Tracking cues to word learning in autism Delays and difficulties learning new words are characteristic of autism, yet the reasons for this are unclear. Typical children learn new words very quickly from the surrounding language context, for instance when watching a television program or reading a book. The proposed project will investigate whether children with autism are sensitive to these contextual cues and whether they use them to learn new words when reading or listening. Using an eye-tracking paradigm, this group at Oxford University will investigate what children choose to look at as they hear (or read) language. Eye-tracking is a naturalistic way of measuring how children attend to different stimuli (words and pictures) when learning new words. Both when and where the individual looks when reading different sentences presented together with different images will be examined. In addition to studying how children affected and not affected with autism attend to different stimuli in the environment while learning a new word, a variety of behavioral tests that assess a wide range of language and literacy processes will be administered. This will reveal individual differences within the population and help understand why some children are not as efficient at processing contextual cues to learn new words. As well as identifying the nature of word learning from linguistic context in children with autism, this study will reveal which cues they find helpful. Significance: By examining the way children with autism understand the meaning of different words, this research will help predict individual differences in word learning. This may help identify "sub-groups" of children with autism spectrum disorder. In addition, by identifying alternative mechanisms for the way children with autism learn language, a foundation for future intervention studies which focus on teaching children to use contextual cues to improve language comprehension will be established. back to top

Studies Exploring the Neurobiology of Autism (Includes molecular biology, immunology, developmental biology, neurochemistry, etc.) Yale University School of Medicine Ivana Kawikova, MD, PhD $120,000 total for two years Is autoimmunity involved in the pathogenesis of autism? Many neuropathological studies in autism have reported a reduction in numbers of cells in the brain in areas which control motor coordination and cognitive functioning. While the mechanism of this loss in cell number is unknown, a recent study demonstrated the presence of inflammation in the same brain areas. This suggests that an autoimmune process may play a role in the neuronal loss observed in autism. Autoimmunity occurs when the immune system not only protects the body against infectious microorganisms, but mounts an immune response against one's own tissue. This experiment will investigate whether the mechanisms which regulate autoimmunity are inadequate in children with autism and whether this is accompanied by signs of immune system activation. Measures of immune function will also be coupled with diagnostic instruments to shed light on whether changes in immune system activation is related to the severity of autism symptoms which is different from individual to individual. Significance: Determining the precise role of specific immune activity may elucidate an important immune mechanism leading to inflammation in CNS of autistic patients, as well as open new therapeutic possibilities for these patients. Princeton University Asif Ghazanfar, PhD $119,943 total for two years Large-scale network operations in the primate brain underlying the sensorimotor integration of social signals Autistic children fail to develop skills related to social signal processing, which may be attributed to their inability to attend to social cues mediated through eye gaze. Like humans, macaque monkeys produce unique facial expressions when producing different vocal signals and they can also perceptually match the appropriate facial posture with a vocalization. The eye movement patterns that monkeys use to process these ‘multisensory' social inputs are also identical to those used by human adults and children when they view human faces producing speech. This research seeks to shed light on the neurobiology of communication signals and deficits in autistic children using macaque monkeys as a model system. Significance: Using this animal model, the researchers will be able to better define the role of functional interactions between cortical areas during multisensory integration of faces and voices. National Institute for Medical Research, London James Briscoe, PhD $59, 948 for one year Teratogen induced ASD and brainstem development While the etiology of autism and ASD is unknown, prenatal exposure to chemical teratogens including the antiseizure medications thalidomide and valproate are associated with increased incidences of ASD. Exposure to these agents is known to produce brainstem abnormalities which are reflected in individuals with autism. While the mechanism by which these defects are caused by these chemicals is being explored, the findings do raise the possibility that they may be similar to that which contributes to autism neuropathology. This project proposes to initiate a detailed analysis of the effect of thalidomide and valproate on different species of animals, including the rat, mouse, chick and zebrafish. The investigators will examine a panel of molecular markers – genes which will identify specific structures in the developing brainstem. The identification of chemical induced brain defects in these organisms will offer the opportunity for many follow up studies to determine the exact nature of the flaws and how they cause the symptoms of ASD. Significance: Because exposure to thalidomide and valproate has been associated with symptoms of autism spectrum disorder, an understanding of the specific biochemical and molecular effects of these teratogens during early brainstem development will help better identify disease mechanism. This information is likely to have far-reaching implications for understanding and diagnosing ASD and may aid the development of therapeutic interventions to treat or ameliorate ASD symptoms. University of Massachusetts Medical School Alonzo Ross, PhD $120,000 total for two years Mutant forms of PTEN Linked to Autism Recently, it was reported that some patients with both autism and macrocephaly have mutations in the PTEN tumor suppressor gene. PTEN is a lipid phosphatase that regulates cell survival and proliferation. It also plays a critical role during development, influencing neural stem cells as well as immature and mature neurons. While previous studies have reported an interesting association with PTEN mutations and autism, Dr. Ross's lab will expand the investigations into this genetic mutation by determining whether specific PTEN mutations eliminate the expression of PTEN or reduce its stability. Significance: Understanding the genetic and biochemical bases of autism is one of the first steps to better diagnosis and therapy. This study is also intriguing since many drugs that affect PTEN signaling pathway are already available given the gene's known role in cancer, and could potentially be tested for autism if a biological connection can be established with ASD. Craig Powell, PhD University of Texas Southwestern Medical Center $120,000 total for two years The Role of Neuroligins in Cognitive Function: Implications for Autism Genetic studies have suggested an association between autism and mutation in a gene which codes for a protein called neuroligin. Neuroligins have been shown to mediate the formation of connections between brain cells and control the balance of activity between them. Preliminary studies in Dr. Powell's lab have suggested that one form of neuroligin plays a role in social learning and other autism-related behaviors in mice. These studies will be expanded to examine multiple mutations of different forms of neuroligins in an animal model, as well as investigate the functional effects of a mutation of a previously unstudied form of neuroligin (neuroligin 3). In parallel with studies which examine the behavioral function, collaborators on this project will be directly examining the molecular function of neuroligins in the brain using electrophysiology, biochemistry, and imaging techniques. These studies will provide a better understanding of how neuroligin mutations might lead to autism-like behavioral abnormalities, and lead to a better understanding of the basic neurobiological underpinnings of autism. Significance: It is anticipated that these studies will lead to one or more novel animal models of autism. Once autism-related behavioral abnormalities have been fully characterized, there will be a unique opportunity to use our knowledge of neuroligin function to test potential treatments in neuroligin-based mouse models of autism. Weizmann Institute of Science, Israel Joel Sussman, PhD $119,900 total for two years Identification of Novel Proteins Associated with Autism: Structural Studies on Neuroligins, Their Homologs and Their Partners Neuroligins are members of a family of proteins known as cholinesterase-like adhesion molecules due to their structure similarity to an enzyme found in the nervous system, acetylcholinesterase. While Dr. Powell's lab will be examining the functional and biochemical consequences of mutations of this protein, the Sussman lab will use state of the art molecular biology techniques to determine if similar proteins such as gliotactin and neurotactin interacts with neuroligin, and what effects mutations of gliotactin and neurotactin produces on neuroligin expression. By studying proteins which interact with neuroligin, additional proteins whose mutation might be involved in autism or other neurodevelopmental diseases may be discovered. Significance: The protein neuroligin has been shown to be directly involved in synapse assembly in the central nervous system. The finding that mutations in this protein are associated with familial autism, Asperger syndrome and mental retardation supports the notion that development of the disease is associated with defective formation of neuronal connections or circuits. By examining the biophysical, biochemical and structural characterization the interaction of neuroligin with other proteins, these results may assist in the development of treatment approaches to autism by identifying possible molecular targets for therapeutics. University of Oregon Philip Washbourne, PhD $119.698 total for two years The role of Neuroligin in synapse formation in vitro and in vivo Dr. Washbourne's lab will be investigating the effects of neuroligin mutation on the expression of cell adhesion molecules. Cell adhesion molecules play a key role in the generation of new synapses, stabilization of existing connections in the brain, and establishment of the proper balance of activation vs. inhibition of activation in under the appropriate conditions. This experiment will extend the other projects which target neuroligin as a protein of interest by generating a strain of mouse with a mutation of neuroligin which can be "turned on" and "turned off". In this way, the expression of the neuroligin protein can be maintained under normal conditions as well as conditions where the protein is not produced normally, and the stability and maintenance of brain connections on a cellular level can be observed. Significance: Using state of the art techniques this new animal strain represents an unprecedented model system which will help researchers gain insight into brain regions that are affected in autism and try to pinpoint a cellular and molecular basis of this devastating condition. Northwestern University Dane Chetkovich, PhD $119,995 total for two years Role of Neuroligins in Synaptic Plasticity Synapses are the site of functional connections between neurons, and neuroligins are critical for the establishment and maintenance of these critical connections underlying brain communication. This study will investigate the interaction of the neuroligin molecule with a receptor subtype in the brain associated with activating neuronal activity and target of medications used to treat autism – the NMDA receptor. The Chetkovich lab will utilize cellular and molecular biological approaches to investigate the mechanism by which neuroligins participate in the development, maintenance and function of neuronal connections. Significance: These studies will provide a better understanding the cellular processes underlying synapse development and function, in order to identify biochemical loci for therapeutic intervention in autism. Monell Chemical Senses Center Alan Gelperin, PhD $120,000 total for two years Altered processing of social signals in a mouse model of autism Strategies for developing and studying animal models of autism have focused on social and communication function using a different battery of tests. In mouse models, the olfactory (smell) system serves as a basis for investigating social interaction, thus knowledge of the proper functioning of this system is necessary to determine the mechanisms by which these behaviors are disrupted. Dr. Gelperin and colleagues will be studying the olfactory system in a mouse model which is genetically engineered to be deficient in receptors for a critical social communication peptide (pituitary adenylate cyclase activating peptide or PAC). Specifically, the processing of social signals for mating and social behavior will be measured together with neuronal activity in the olfactory centers of the mouse brain during these tasks. By investigating the cellular and physiological responses of olfactory neurons during tasks which involve social signals, the neural basis of social reciprocity will be better understood. Significance: The proposed work will test a specific hypothesis about the underlying neurological mechanism of impaired social reciprocity in PAC1-/- mice. If the proposed work indicates that social reciprocity disruption arises from abnormal timing relations of network activity in the olfactory system, it might be possible to extrapolate to human and provide neurobiological insight into one of the core deficits of autism. Duke University Medical Center Ryohei Yasuda $119,851 total for two years Regulation of spatiotemporal dynamics of Ras in neurons A signaling protein Ras is important for many processes essential for the regulation of neuronal connection such as strengthening of synaptic contacts, formation of new synapses and regulation of cellular activity. Consistent with essential roles of Ras signaling in many neuronal signaling processes, failures of Ras signaling cause diseases associated with learning and cognitive deficits including X linked mental retardation and possibly autism. Therefore, detailed analyses of Ras signaling in neurons are crucial for a better understanding of Ras-related mental diseases. To study Ras signaling in neurons, Dr. Yasuda has developed a novel technique that allows imaging Ras activity at the single synapse level in living neurons deep in brain tissue. Such analysis occurs in real-time and can be performed when neurons are subjected to different physiological conditions. Because this protein is involved in so many cellular mechanisms and processes, the function may be dependent on the location of this protein within the neuron. The Yasuda lab is set up to investigate sub-cellular localization of proteins and evaluate expression of Ras during different physiologic conditions. Significance: By dissecting the roles and mechanisms of Ras signaling using this technique, the proposed research is expected to better demonstrate how Ras signaling controls cellular function under different conditions. Such results will provide significant insights into basic pathophysiological mechanisms that underlie Ras-related diseases, possibly including autism. University of Cambridge Frederick Livesey, MD, PhD $119,914 total for two years Neocortical area formation and the pathogenesis of autistic spectrum conditions While Dr. Gilmore and colleagues at the University of North Carolina will be studying the relationship between early testosterone levels and later brain development using structural imaging techniques, Dr. Livesey at the University of Cambridge will be investigating the influence of testosterone on early brain development in an animal model. T his project will determine if testosterone can control the levels of FGF8, a protein which is necessary for the normal development of the brain. The animal study will be conducted alongside a clinical experiment which will test blood levels of FGF8 and a set of genes that FGF8 controls in a population of children with diagnosed with autism and those not affected. By combining experimental studies using mouse as a model system with a pilot study to investigate possible cellular mechanisms of altered brain development in individuals with autism spectrum disorders, this research will generate fundamental data on this promising theory for the cause and pathogenesis of autism. Significance: While the cause of autism spectrum disorders is unknown, disruption in the fetal exposure to testosterone levels is hypothesized to contribute to some of the behavioral symptoms. However, the question arises as to how increased androgens could lead to the varied neurological signs and symptoms associated with autism. Therefore, this study will investigate the possible biological mechanisms by which high levels of fetal androgens could affect forebrain development and lead to the development of autistic spectrum conditions. Northwestern University School of Medicine Anis Contractor, PhD $120,000 total for two years Synaptic Function in Mouse Models of Disorders Associated with Autism Because of autism is a complex neurobiological disorder with multiple causes, it has been useful to develop animal models that recapitulate only some of the symptoms of the disorder to isolate specific genes of interest and their influence on the spectrum of behavioral disturbances. Fragile X and Rett Syndrome are two neurodevelopmental disorders that result in mental retardation and autistic behavior. Each of these disorders is caused by the disruption of a single gene and therefore it has been possible to generate a model of the human disease by genetic mutation in mice. The mouse models for these two syndromes display many of the same traits as the human disease, including some neurobiological and neuropathological correlates. This study will record activity from individual neurons in the somatosensory region of Fragile X and Rett Syndrome mice in order to examine the precise nature of the deficits in synaptic communication and plasticity that are thought to underlie some of the cognitive dysfunctions of these two disorders. Significance: Studies which investigate the neurobiology of neurodevelomental disorders with known genetic causes provide a simple model for scientist to investigate the role of genes on brain development. The outlined research will give insight into fundamental disruptions in synaptic communication that may underlie the sensory and cognitive impairments in these mouse models and therefore enhance our understanding of the basis for the human disorders. University of California at Davis Hwai-Jong Cheng, PhD $119,990 total for two years Axon Pruning and Autism Spectrum Disorder Although what causes autism spectrum disorders is still unclear, imaging studies have demonstrated that certain brain areas are enlarged while others are reduced. This suggests that abnormalities in the control of size and shape of brain cells and the extent of their contacts – called pruning- with other brain cells play an important role in this effect. The main goal of this application is to investigate the link between molecules that are implicated in regulating developmental axon pruning and the gene that causes fragile X syndrome, a common form of inherited autism-related disorders. Dr. Cheng and colleagues have recently identified two molecules: Sema3F and its receptor, Plexin-A3, as key regulators for stereotyped axon pruning of hippocampal mossy fibers in the fragile X knockout mouse. By using the most advanced technologies, the investigators plan to determine whether the neuropathological deficit in the fragile X knockout mouse is caused by changes in expression of Sema3F and Plexin-A3. Significance: The ultimate goal of these studies is to understand the molecular and cellular mechanisms of developmental axon pruning and provide a therapeutic basis for treating human neurodevelopmental disorders including autism spectrum disorders. back to top

Studies on Autism Neuroanatomy and Neuropathology University Campus Bio-Medico, Rome Flavio Keller, MD $292,024 total for two years Comparative Analysis of Cerebellar Neuropathology in Human Autistic Patients and in Cerebellar Mouse Mutants Neuroanatomical and neuroimaging studies in autism conducted by several research groups show faulty development of neural structures, particularly in a structure at the base of the brain called the cerebellum. The cerebellum is a particularly interesting research target because its structure and function has remained consistent throughout evolution. In addition, the development of the cerebellum takes place during late pregnancy and early postnatal life, which is a period that is believed to be critical for autism. Specifically, the size of the cerebellum is reported to be smaller in individuals with autism and the number of cells which direct messages to other brain areas, Purkinje cells, are shown to be reduced in number. While the mechanism that affects Purkinje cell number and cerebellar size is not yet well described, preliminary data suggests that reelin, an autism candidate gene, interacts with gonadal sex hormones during cerebellar development. An interaction of abnormal reelin expression coupled with exposure to differing levels of testosterone during brain development may contribute to the reduced number of Purkinje cells in individuals with autism. This study will look for alterations of enzymes and receptors involved in gonadal steroid signaling in human brain tissue to determine the interaction between testosterone levels, reelin expression, and Purkinje cell development. The results of human brain tissue research will be followed by examining the effects of estrogen in a genetic strain of mouse named Reeler mice. Reeler mice lack the reelin protein which leads to a malformed cerebellum with disorganized Purkinje cells. By using this approach, the effects changes in gestational environment, including testosterone levels with genetic mutations on human pathology can be investigated in a multifaceted way. Significance:This study will investigate the interaction between genetic vulnerability and gonadal steroid hormones on Purkinje cell survival, migration, and/or differentiation, which would account for the biased sex ratio of autism. This hypothesis has not yet been tested and these researchers will examine the role of reelin, a candidate gene for autism, and 17beta-Estradiol, on mouse Purkinje cells. Dr. Keller's group will be linking animal models with human pathological studies in an interdisciplinary fashion and studying the possible protective role of estrogen on genetic susceptibility to autism spectrum disorders. University of Maryland School of Medicine Michael Vogel, PhD $118,692 total for two years Neuroinflammation, the kynurenine pathway, and autism Although the causes of autism are still unknown, there is growing evidence that genetic, environmental, and immunological factors may contribute to the development of the disorder. Many cases of autism are reported to be associated with chronic activation of the immune system. This experiment will investigate markers of chronic neuroinflammation in brain tissue from individuals affected with autism. These markers will be compared to levels of two newly studied neuroactive compounds which have been associated with cell death: kynurenic acid (KYNA) and quinolinic acid (QUIN). Dr. Vogel and his colleagues will investigate if alterations in the relative abundance of KYNA and/or QUIN affect the development and functioning of neural circuits or induce damage in the nervous system thereby contributing to the development of autism. Significance: Alterations in immune system function has been associated with autism, however, the link between immune reactivity and onset of autism spectrum disorder has not been clearly defined. Changes in KYNA and QUIN in human postmortem tissue along with other neuropathological alterations would help better define the relationship of the immune system in brain development and neurodevelopmental disorders. These results could lead to new targets, possibly those in the immune system, for the development of novel treatments for autism. back to top

Studies that Explore Novel Applications of Neuroimaging Techniques in Autism Research Face Processing: Weill Medical College of Cornell University Nim Tottenham, PhD $110,890 total for two years The Role of Visual Experience in Facial Expression Processing in Children with ASD People with autism spectrum disorders spend less time looking at faces than non-affected individuals, and when they do, they spend much more time focusing on the mouth than in the eyes. This is coupled by a reduction in activity in areas of the brain that are responsible for proper interpretation of facial features, including the fusiform gyrus. This could be caused by either an inability of the brain to process stimuli regarding facial expression, or because individuals with autism are not engaging images and averting their eyes from the face. To further elucidate this mechanism, this study will examine face processing when gaze is focused either on the eye or mouth region of a face and record activation of the fusiform gyrus using fMRI technology. The results will provide insight to the mechanism of face processing skills in individuals with autism and lead to a targeted intervention that addresses face processing skills. Significance: Given that face perception and expression processing are critical to enriching social experiences and drive our understanding of the motivations intentions of others, a deficit in face processing is a significant handicap for individuals with ASD. This study will provide further insight into the nature of face processing deficits, and generate knowledge that could better inform intervention. Duke University Kevin Pelphrey, PhD $112,200 total for two years Functional Neuroimaging of the Developing Social Brain in Children with Autism Previous studies which assess brain function in adults with autism using a technique called functional magnetic resonance imaging (fMRI) have defined the neural circuitry involved in a range of cognitive and psychological processes. These investigations have demonstrated the potential for fMRI studies to contribute to our understanding and treatment of autism. However, the volume of research to date using fMRI procedures to study children with autism has been minimal. This is unfortunate because fMRI is well suited to studying autism's developmental nature. Researchers have theorized that a common characteristic of individuals with autism is the striking abnormalities in social perception, that is, the evaluation of intentions of others by eye-gaze direction, facial expressions, body movements, speech or other kinds of motion. This is part of a domain of skills referred to as theory of mind, social cognition, mentalizing, or mindreading. This is a proposal to conduct a highly innovative combination of fMRI and eye tracking studies aimed at a more comprehensive characterization of the neural circuitry underlying the development of different aspects of social perception. Significance: This work will likely impact the development of new methods of diagnosis, treatment, and/or prevention of autism spectrum disorders by identifying neurophysiological mechanisms involved in social perception deficits. This knowledge will help inform skill-based treatment models that train teaching children with autism to monitor eye gaze, identify emotions, and infer the intentions of others. Finally, by defining functional brain phenotypes using fMRI, these studies have the potential to help differentiate subtypes of the autism spectrum, and provide clues into other causes of this disorder. MEG/EEG: Massachussets General Hospital Tal Kenet, PhD $118,611.32 total for two years Relationship between Coherence and Sensory Processing Deficits in Autism – a Whole Head MEG Study One hypothesis for some of the core deficits in autism is the inability of the cortex to organize and process sensory information. Deficit in the cortex's ability to decode and interpret sensory signals could lead to symptoms such as hypersensitivity to visual and auditory stimuli, and in some instances, higher cognitive function in certain domains of functioning. As these are both characteristics of autism spectrum disorders, Dr. Kenet and her colleagues at MGH will examine electrical activity across brain regions to determine if different areas of the cortex communicate in an organized way, or synchoronize, to different stimuli. This information about brain activity will be superimposed on an anatomical brain image using MRI techniques. These results will allow these researchers to link these changes in brain activity to alterations in brain size, differences in brain activity between brain hemispheres, as well as neuroanatomical changes previously reported such as increases in white matter density. This study is important because it integrates deficits in sensory processing, abnormal connectivity of different brain regions, and neuroanatomical differences. Significance:This novel approach will examine the functional activity individual brain areas involved in autism spectrum disorders, then investigate how these different areas work together and send messages to each other. This study is expected to contribute to advances in the neurobiology of autism, and possibly identify markers in brainwave activity that will help in earlier identification of those affected with ASD. University of Houston Bhavin Sheth, PhD $119, 647.00 total for two years Dynamic topography of somatosensory and motor systems in individuals with autism While deficits in the visual and auditory systems of individuals with autism have been well-studied, far less is known about deficits in somatosensory function and motor action. Using a technique called magnetoencephalography (MEG), this study will investigate the function of somatosensory and motor cortices in the brain of individuals with autism using tactile stimulation on the fingers, and compare the synaptic activity in brain circuits of individuals with autism to typically developing individuals. Based on computer modeling techniques, relative contributions of the somatosensory and motor cortices will be used to discriminate autistic individuals from those who are not affected. These measures will also indirectly test aspects of important theories about autistic function and has the potential to be used as a diagnostic tool on neural as well as behavioral data in the future. Significance: There is currently little knowledge about the function of the somatosensory cortex in both children and adults with autism. This area of the brain is important because sensorimotor deficits are common in ASD, yet the mechanism by which these dysfunctions occur have not been established. The response dynamics of neurons in this area will test current hypotheses of why individuals with autism show deficits in the integration of sensory processing and ultimately lead to a better understanding of the neural basis of autism. University of Tampere , Finland Jari Hietanen, PhD $35,343 for one year Psychophysiological measurements of direct eye gaze processing in children with autism spectrum disorders Avoidance of eye contact is commonly observed in individuals with autism spectrum disorders (ASD), but the cognitive and biological mechanisms underlying this avoidance are poorly understood. Research has suggested that faces in which the eyes exhibit a fearful expression may be misinterpreted as overly arousing or threatening. This study will use psychophysiological (skin conductance, heart rate, EEG) measurements to explore how children with ASD respond to exaggerated forms direct eye gaze – either by demonstrating a fearful reaction or a defensive reaction. These results will determine whether these fearful and defensive reactions are related to degree of social impairment. The findings from this study will progress the understanding of why children with ASD avoid eye contact, even with those people who are very familiar to them. Future research will explore how eye contact avoidance early in life can cause atypical development of neural specialization in face processing. Significance: By examining the factors by which children with autism respond to eye contact, data from this study will form the basis of training protocols to teach these children to respond more appropriately to facial images, possibly using other forms of complementary technology. Structural Imaging: University of North Carolina John Gilmore, PhD $85, 979 total for two years The role of prenatal and neonatal testosterone in early brain development Autism occurs significantly more often in males than in females, yet research on potential causes of the biased sex ratio is extremely limited. Multiple clues suggest that alterations in testosterone levels during development may contribute to this sex difference. However, there is a currently a major gap in research relevant to this hypothesis: no studies have directly examined whether testosterone is related to individual differences in brain development in human beings. The proposed study will fill this crucial gap by measuring early testosterone levels early in development using both salivary testosterone and the length of the fingers from 2 weeks to 2 years of life. These findings will be related to structural brain development assessed via high-resolution MRI on a 3T magnet at 2 weeks after birth, with follow-up scans and comprehensive neurocognitive assessments at 1 and 2 yr. Finally, in order examine a genetic predisposition for changes in testosterone level, the number of CAG triplets in the androgen receptor gene will also be assessed. Significance: Despite compelling evidence that testosterone plays a major role in brain development in animal models, almost nothing is know about its affect on brain development in humans. The proposed study will fill this crucial gap in our present knowledge by measuring early testosterone exposure and receptor sensitivity in a large population sample and relating them to development of regions known to be sexually dimorphic in childhood: the cerebrum, amygdala, hippocampus, and caudate. The resulting data is essential to critically evaluate the testosterone hypothesis of autism. University of Texas Southwestern Medical Center Greg Allen, PhD $119,450 total for two years Functional Connectivity of the Cerebellum in Autism The cerebellum is one of the most consistent sites of brain abnormalities in individuals with autism. There is an emerging theoretical view that autism is characterized by the abnormal development of brain connectivity, however, functional connectivity within the cerebellum and between the cerebellum and other brain regions in autism has not been studied. Because of converging cellular, molecular and behavioral evidence demonstrating a crucial role of this brain area on the pathology of autism spectrum disorders, it has been proposed that cerebellar pathology and impairments in proper functional connections both in to and out of the cerebellum may play a role in the behaviors and symptoms of autism. To investigate cerebellar connectivity in autism, the researchers will employ functional connectivity magnetic resonance imaging (FCMRI), which assesses interregional coherence of MRI signal change as an index of functional connectivity. FCMRI will be used to examine the functional integrity of cerebellar connections with limbic, thalamic, and cerebrocortical sites in children with autism spectrum disorders and in healthy controls. Significance: A crucial step toward increasing the understanding of the etiology of autism is determining the underlying neurobiology. The proposed study provides two potential indirect indices of this pathology, high-resolution measurement of cerebellar volume and cerebellar functional connectivity measured with FCMRI. FCMRI may be a particular useful tool for assessing the functional integrity of cerebellar networks, and may ultimately prove to be a means of early identification of neuro-functional defects. This information may lead to better informed treatments and contribute to knowledge on the cause of autism. Functional Imaging: Hospital for Sick Children, Toronto Margot Taylor, PhD $115,907 total for two years Neuroimaging the development of frontal lobe cognitive function in autism Functional magnetic resonance imaging (fMRI) uses the relationship between blood flow in the brain and neuronal activity to identify areas of brain activity associated with specific cognitive functions; diffusion tensor imaging (DTI) uses the movement of water molecules in the different tissues in the brain to determine the structural pathways in the brain. This project will combine these neuroimaging techniques with behavioral tasks which measure attention and executive function to the study two of the core deficits in children with ASD and to compare them to typically developing children. Functional MRI will be used to identify areas of the brain active with frontal lobe functions and DTI will be used to identify the connections between brain regions. Dr. Taylor's study will investigate the neuroanatomy and brain function of children with ASD to determine if nerve pathways between brain regions have weaker connections, and if brain activity during specific cognitive tasks is less focused than non-affected children. The results will determine if the children with ASD have atypical activation (with fMRI) with these tasks, or if the poor performance is due to less robust interconnections (with DTI) among the networks implicated. Significance: By identifying behavioral and neuroimaging patterns characteristic of the core deficits in ASD, earlier diagnosis and intervention could be attained. Furthermore, an improved understanding of the neurocognitive underpinnings of ASD will allow for the development of focused treatment strategies and accurate neuroimaging monitoring of their efficacy. University of Glasgow Frank Pollick, PhD $117,484 total for two years The processing of biological motion patterns in adults with high-functioning autism: A fMRI study Recent neuroimaging studies have suggested two major areas of interest in the brain that explains deficits in interpretation in visual motion processing and interpreting actions of others. These include the both Superior Temporal Sulcus (STS) and regions of the pre-motor and parietal cortices. This experiment will investigate the visual motion processing impairment further by studying brain activation using fMRI in conjunction with behavioral tasks which test either biological motion stimuli or geometric stimuli in individuals affected and not affected with autism. These stimuli are displays in which human actions are depicted as points of light which form either images of human motion or objects. It has already been established that autistic populations have difficulty with interpreting biological motion stimuli, as compared to simple geometrical forms. The question of interest is whether this difficulty is due to the perceptual problem of integrating motion information across space and time or the cognitive problem of interpreting the meaning of a correctly perceived motion stimulus. Significance: A variety of data and theories pertinent to the neural basis of ASD suggest that a key component of the dysfunction in understanding biological motion may be controlled by specific brain regions and their connections to each other. By probing the circuitry which connects these brain areas with a complementary series of behavioral and neuroimaging experiments, the most likely cause of these functional deficits can be determined. Princeton University Sabine Kastner, PhD $120,000 total for two years Towards a primate model of autism: Functional MRI studies on social cognition in behaving macaques Recent neuroimaging studies in individuals with ASD have shown reduced activity in areas of social cognition networks suggesting a possible neural substrate for these social impairments. However, questions regarding the activity of these different brain areas and their functional interaction have yet to be answered. Primates exhibit social complex behavior like humans, and studying their social cognitive deficits could help us gain a better understanding of the pathology of autism. Dr. Kastner's lab will take the first necessary steps towards establishing a primate model in autism by identifying brain networks that mediate functions in social cognition using functional magnetic resonance imaging (fMRI) in awake, behaving monkeys. Primate fMRI is a new cutting-edge technique that allows for the first time for a direct comparison of brain function in humans and monkeys. The goal of these experiments is to determine the cellular mechanisms underlying social cognition in different nodes of the network using single cell physiology, and also to identify the functionally critical nodes of the network, the dysfunction of which leads to impairments of social functions to gain a better understanding of the underlying cause of social interaction deficits in individuals with ASD. Significance: A primate model that exhibits complex social behavior like humans would greatly help us attain a deeper understanding of the pathobiology of autism, since it would allow a more direct study of the causal relationships of the different brain regions involved in social cognition. Following the identification of brain networks in the macaque that mediate functions in social cognition have been identified, these areas could be targeted for future invasive analysis. back to top

Studies that Have Treatment Implications Craig Powell, PhD University of Texas Southwestern Medical Center $120,000 total for two years Characterization and Treatment of Autism-related Behaviors in PTEN Conditional Knockouts: A Potential Animal Model of Autism Recent human autism studies have suggested a link between autism and mutations in a gene called PTEN. By making mice lacking the PTEN gene in certain regions of the brain, the Powell lab hopes to create a new animal model of autism and to test likely therapies in this model. Dr. Powell's group will complement the studies conducted by the Ross group at the University of Massachussets by studying the behavioral consequences of PTEN mutations. First, these investigators will test whether mice lacking proper PTEN function show normal social interaction behavior. Following functional characterization, the molecular and cellular changes due to loss of PTEN function will be investigated to assess which processes contribute to social behaviors. Finally, these animals will be treated with a compound which affects these downstream molecular changes in order to determine if behavioral abnormalities can be rescued with a pharmacological agent. Significance: These studies will provide further evidence linking abnormal regulation of protein synthesis to autism, and will likely implicate interesting new targets in the search for autism treatments. Seaside Therapeutics Randall Carpenter, MD Baylor University School of Medicine Richard Paylor, PhD $119, 833 total for two years Treating autistic-like traits in mouse models of Fragile X Syndrome Fragile X syndrome (FXS) is the most common known genetic cause of autism. Human genetic studies have revealed that fragile X syndrome (FXS) is caused by a mutation in a single gene that prevents expression of a single protein. Brain developmental in the absence of this single protein is associated with significant morbidity including impaired cognitive function, attention deficit and hyperactivity, anxiety, obsessive-compulsive and autistic behaviors. Therefore, knowledge of the function of this protein as well as therapeutic targets may potentially be helpful to discoveries in autism research. The Paylor lab has recently demonstrated that specific strains of fragile X mice display ‘autistic-like' traits including abnormalities in social interaction, compulsive behaviors and anxiety-related responses. Recent studies indicate that compounds which target the glutamate receptor can also effectively treat abnormalities in brain cell function, seizures and some abnormal behaviors in these fragile X mice. Therefore, the aim of these is to assess efficacy of mGluR5 antagonists in this animal model of autism. Significance: This proposed collaborative research program offers a unique opportunity to evaluate the impact of novel potential therapeutic agents not only in mouse models of FXS, but also mouse models of FXS that display unique autistic-like features. Mount Sinai School of Medicine Evdokia Anagnostou $119,516 total for two years Brain Glutamate Concentrations in Autistic Children by Magnetic Resonance Spectroscopy There is sufficient evidence to suggest that behavioral abnormalities observed in autism may be, in part, the result of dysregulation of glutamate neurotransmission in the brain. One method of measuring glutamate in the brain in a non-invasive measure is termed Magnetic Resonance Spectroscopy (MRS). This technique is based on the same principles as MRI but, instead of images, it provides information about the biochemical composition of the brain. In this study, the investigators will study glutamate concentrations in the brain of older children and adolescents with normal intelligence and autism. In addition, secondary analyses of MRS analysis will measure concentrations of other brain chemicals such as choline, creatine and NAA and exploring possible correlations between abnormalities in such chemicals and the symptoms of autism. Significance: Several currently used pharmacological treatments of autism spectrum disorder symptoms include targeting receptors for this neurotransmitter, and a better understanding of the role of glutamate transmission on symptoms of autism will lead to better targeted intervention strategies in the future. Indiana University School of Medicine David Posey, MD $120,000 total for two years A Placebo Controlled Trial of Memantine in Children and Adolescents with Autism Despite the recognition that autism is a common disorder with enormous public health significance, no medications have been shown to consistently improve the core social impairment of autism and available medications are most effective at reducing severe irritability and aggression. Combining two medications has proven effective in a number of other brain disorders, but has received little attention in autism. This study will investigate the hypothesis that memantine can improve certain aspects of autism including social withdrawal, inattention, and other behavioral manifestations of the disorder. We plan to test this hypothesis by treating children and adolescents who are already receiving atypical antipsychotics, and add memantine or placebo to assess the improvement of symptoms with memantine. The participants will be followed with standardized assessments and rating scales. Significance: Considering the clinical complexity of the syndrome and the well-characterized symptom domains, it may be necessary to treat individuals with one or more pharmacological and behavioral interventions. This study will be one of the first placebo-controlled trials of memantine in autism, as well as one of the first examining coactive medication treatment strategies for this difficult-to-treat disorder. back to top