2005 Can Grants funded

Grants Funded by Cure Autism Now - 2005 Genetics: Searching DNA for mutations that will point to proteins and pathways that may be amenable to treatment

The Prevalence of Mutations in X-Chromosome Linked Genes (Pilot Project Award)
Jozef Gecz, Ph.D., Women's and Children's Hospital, Australia

Genes and the environment perform a delicate balancing act in the determination of the outcomes of many disorders, including autism. Research in other diseases has shown well-documented examples of patients and families where a defect in a given gene can be identified as the primary cause. Autism is a complex genetic disorder, with many genes contributing. This study will look at genes on the human X-chromosome, which has been linked to various developmental issues (including autism). Dr. Gecz will be using samples from Cure Autism Now's AGRE biomaterial bank to study two genes (ARX and STK9) his lab had previously tied to another disorder, X-linked mental retardation. Because many patients with X-linked mental retardation also have autism, Dr. Gecz will now be screening autism patients for mutations in the ARX and STK9 genes.

Identifying the Autism Gene (s) on Chromosome 17q (Genetics Initiative Award)
Dan Geschwind, M.D., Ph.D., University of California, Los Angeles

Recently Dr. Geschwind and collaborators have identified an autism locus on chromosome 17q. Strikingly, this locus appears to be specifically related to male susceptibility to autism; females do not contribute to the linkage signal. They have now used an independent sample from Cure Autism Now's AGRE biomaterial bank to confirm this locus at a level considered highly significant--a first in autism research. To find the actual gene or genes, it is necessary to interrogate all genes within this region using a process called SNP genotyping. They will use this method to test SNPs at high density in every gene in the region, allowing them to screen every single gene and hopefully, identify the causal risk gene. Dr. Geschwind's laboratory has the most efficient technology for performing this study, and by partnering with Cure Autism Now will perform this work at a significantly reduced timescale. This will provide a major advance for the field, and identify a gene or genes related to male-specific autism risk.

DLX Genes and Autism (Pilot Project Award)
John Rubenstein, M.D., Ph.D., University of California, San Francisco

Although it is known that genetics contribute to the susceptibility to develop autism, the identity of the genes that contribute to the disorder are poorly understood. A recent model of autism, co-proposed by Dr. Rubenstein, postulates that some forms of autism are caused by an excess of excitation-to-inhibition in neural circuits controlling cognitive and emotional development. This suggests that an analysis of genes that promote inhibition in the neural circuits should be conducted in people with autism. This study will analyze the DNA sequences of a series of genes (called the DLX genes) that control the development and function of forebrain inhibitory neurons. Dr. Rubenstein's preliminary evidence shows that ~5% of autistic people in the Autism Genetic Resource Exchange data set have mutations in these genes, suggesting that further analysis is warranted.

Search for an Autism Gene on the Y Chromosome (Young Investigator Award)
Marwan Shinawi, M.D., Baylor College of Medicine

This study will attempt to identify the biological and molecular basis of autism. Specifically, the intent is to try to discover the cause of autism and develop a laboratory test that would be used to diagnose patients with autism. The study will also attempt to explain the higher male predisposition to autism. The fact that the methods used till now have failed to provide strong evidence for a major causative gene for autism suggests that many genes might contribute to autism or other genetic mechanisms may be involved. Dr. Shinawi will test whether changes that do not involve nucleotide sequence such as changes in chromatin structure and nucleotide sequence methylation can alter gene expression and eventually cause autism. The heritable changes in gene function that occur without a change in the DNA sequence are called epigenetic changes. The DNA methylation is a chemical modification of the nucleotide sequence itself that can change the expression of different genes. The emphasis will be on genes that are located on the Y chromosome, an area that has been under investigated. If an epigenetic basis is identified for autism, there might be the potential for therapeutic intervention using compounds such as folic acid, which are known to alter the regulation of genes that are subject to regulation by DNA methylation. (Jonathan Pettigrew Memorial Award)

X Chromosome Inactivation and Candidate Gene Studies in Females with Autism (Young Investigator Award)
Zohreh Talebizadeh, Ph.D., Children's Mercy Hospital & University of Missouri, Kansas City

Autism occurs at a rate of 3-4 times higher in males than in females. Although this sex ratio discrepancy is unexplained, it may suggest the involvement of X chromosome genes. Males have one X chromosome while females have two Xs. Linkage analysis has suggested the involvement of genes from several chromosomes including the X. In addition to the genetic linkage data, several lines of evidence such as X chromosome rearrangements and recently reported mutations in three X-linked genes (i.e., NLGN3, NLGN4 and MECP2) indicate that the X chromosome should be further studied in autism. In a previous study, Dr. Talebizdeh identified 10 females with autism with a high degree of X inactivation irregularity ("skewness") which may allow unequal expression of X-linked genes. X inactivation is a phenomenon that should happen randomly and allows for dosage compensation of X-linked genes in both males and females. However, 33% of the females with autism compared with 11% of unaffected female siblings showed a significant X inactivation skewness. In this project, the study will be expanded to identify more females with autism and significant X inactivation skewness. In addition, three X-linked candidate genes (NLGN3, NLGN4 and MECP2) will be evaluated in the identified autistic females with significant X inactivation skewness using both direct DNA sequencing and quantitative RT-PCR. Clinical data available from these autistic subjects will also be examined to assess if differences exist at the phenotypic level between females with significant X inactivation skewness and those with the normal random X inactivation patterns. (Research Partner: The Galli Family in honor of Danielle Bernstein)

Investigation of the Involvement of the MECP2 Gene Exon 1 and the Encoded Protein MeCP2B in Autism (Pilot Project Award)
John B. Vincent, Ph.D., Center for Addiction and Mental Health

Both autism and Rett syndrome are forms of pervasive developmental disorder with a number of similarities in clinical features. Mutations in a gene called MECP2 are responsible for 80% of Rett syndrome cases. Importantly, mutations in the MECP2 gene occasionally cause symptoms that are indistinguishable from autism. Dr. Vincent has just identified a previously unknown portion of the MECP2 gene, which may help divulge more information about how this gene functions. The investigators have already found a mutation within this new region in one girl with Rett syndrome. This finding suggests that the protein made by the new version of the gene may be the disease-relevant form. This study will be exploring the link between autism and the new form of the MECP2 gene, and hopes to elucidate its role in brain development by making animal models.

Recessive Genes for Autism Spectrum Disorders (Pilot Project Award)
Christopher A. Walsh, M.D., Ph.D., Beth Israel Deconess Medical Center

Studies suggest that autism often has a genetic cause but, to date, only two possible autism genes have been identified. We do not yet know what proportion of autism is caused by the action of either of these genes. This study involves the search for additional genes that may be involved in causing autism. By taking the unique approach of focusing our research on families with equal numbers of males and females affected, as well as families in which the parents may be related to one another, we plan to identify genes that can lead to autism only when inherited from both sides of the family. Theseso-called recessive genes may be individually rare, but collectively cause a substantial proportion of autism. (Research Partner: The Galli Family in honor of David Duber)

Genome-wide Linkage Disequilibrium and Expression Analysis of Autism in a Large Isolated Pedigree (Young Investigator Award)
Tero Ylisaukko-oja, Ph.D., National Public Health Institute, Finland

Frequent failure to establish well-replicated linkage signals has been characteristic for the genome-wide linkage studies of complex neurodevelopmental disorders, including those conducted in autism. Therefore, it is evident that novel approaches are needed to reveal genetic mechanisms underlying these disorders. This study aims to identify the autism susceptibility genes by combining the advantages of the genetically isolated population of Finland with the latest techniques in molecular genetics and biocomputing. By examining the church parish records (birth registers) extending to 17th century, the investigators have been able to construct a large pedigree consisting of 21 nuclear families with autism spectrum disorders. Currently, these families are living all around Finland, indicating that it is unlikely that such genealogical links would be observed by change. Dr. Ylisaukko-oja will perform a genome-wide scan by using more than 1000 microsatellites and a set of 100,000 SNP-markers to reveal shared haplotypes among the affected individuals in this pedigree. The power of such study design has been proven by several studies of rare monogenic disorders in the Finnish population as well as those focused on familial forms of complex diseases. The gene expression profiles in the lymphocytes of autistic individuals compared with controls will be monitored.


Immune system: Looking for evidence of dysfunction in autism

Immune Genes and Abnormal Brain Development in Autism (Pilot Project Award)
Lisa Boulanger, Ph.D., University of California, San Diego

In this study Dr. Boulanger outlines the connections between autism and immunological challenges. She will study how a variety of material infections, such as influenza, may affect the development and behavior of the fetus, even when the fetus shows no signs of direct infection itself. The fetal impact appears to be the result of a relatively nonspecific aspect of the maternal immune response, but is reflected in altered cytokines in the fetal brain. This study will use mouse models and autistic children to explore whether the expression of immune genes is altered in the autistic brain, perhaps highlighting the potential for immune-based diagnostics, treatment and prevention. (Research Partner: Liz and Peter Bell)

Sex Differences in Autism: The Potential Role of Oxytocin Signaling (Pilot Project Award)
Kathryn Anne Ellerbeck, M.D., M.P.H., University of Kansas Medical Center

The effects of oxytocin on immune function may be as important as its role in social affiliation, for which it originally received attention in autism research. Oxytocin functions in conjunction with G-proteins as a signaling neuropeptide, with effects on immune function. This study will investigate whether young children with autism have aberrant oxytocin levels in blood, if their G-proteins are abnormal, and if gender differences in oxytocin expression result in varying levels of immune response. The investigators suspect that increased Oxytocin action in the limbic system may "protect" girls from autism. The study will also explore whether abnormal oxytocin levels are associated with immune activation and altered cytokines, shedding light on possible immunological mechanisms that may relate to social function and autism. (Research Partner: Ann and Richard LaGravanes)


Environment: The impact of our surroundings upon developing autism


Glutathione-dependent Synthesis of Methylcobalamin: A Target for Neurodevelopmental Toxins (Pilot Project Award)
Richard Deth, Ph.D., Northeastern University

While the exact cause of autism is not yet known, research during the past several years has focused on the possibility that many cases of autism result from exposure to the ethylmercury-containing vaccine preservative thimerosal. A subgroup of exposed individuals may be less able to detoxify and eliminate heavy metals, placing them at higher risk. Previous work from our lab has shown that thimerosal and other heavy metals potently inhibit an enzyme that uses vitamin B12, and that this inhibition could lead to developmental disorders like autism. Thimerosal interferes with the process that converts dietary B12 to its active form, known as methylB12. MethylB12 has proven to be quite helpful in treating autism, which reinforces the idea that impaired methyl B12 synthesis may be an important contributing cause. Thus this project will investigate the biochemical pathway that makes methylB12 and will elucidate the mechanism by which thimerosal causes its inhibition. It will also compare the thimerosal susceptibility of this pathway in cells from siblings who did or did not develop autism. Preliminary results suggest that the autistic children's cells show greater sensitivity. Results from this study will help to clarify what causes autism and what makes one child more likely to develop autism than another.

Do Environmental Factors Play a Role in Autism? A Test Using Natural Experiments (Pilot Project Award)
Dennis K. Kinney, Ph.D., McLean Hospital/Harvard Medical School

Whether environmental factors play an important role in causing autism is a crucial - and hotly debated - question. Many studies report unusually high rates of medical problems during the gestations and births of persons who later developed autism, suggesting that environmental factors occurring before or around the time of birth may contribute to the development of the disorder. Skeptics, however, argue that the same genes that cause autism also cause these high rates of pregnancy and birth complications. The most powerful scientific approach to deciding this issue -- an experiment in which pregnant women were randomly assigned to low vs. high stress conditions - would clearly be unethical. We use an alternative strategy that uses natural disasters as "experiments of nature" to test the hypothesis that exposure to stressful events during vulnerable weeks of gestation significantly increases risk of developing autism. Anonymous data on more than 4,000 persons with autism from three different states, as well as on 2 million general population births in these same states, will be studied to investigate whether autism rates are significantly increased among individuals who were in certain weeks of gestation at the time their mothers were exposed to natural disasters such as extremely destructive earthquakes, hurricanes, and severe blizzards. Confirmation that pre- and perinatal environmental stressors play a significant role in causing autism would have important implications for the treatment and prevention of autism.

Information processing/Cognitive ability: Determining how the autistic brain functions

Processing of Emotional Facial Expressions in Autism: The Role of the Amygdala (Pilot Project Award)
Ralph Adolphs, Ph.D., California Institute of Technology

We know that people with autism have difficulty in social functions, but we know little about the causes of this difficulty. Dr. Adolphs will study how the brains of people with autism process social information and try to associate this processing to a particular brain region called the amygdala, which has been linked to autism. The research is aimed to gain insight into how the brains of people with autism process faces. Subjects in the study will be asked to look at pictures of faces and to make judgments about the emotional state of the face, while their eye movements are being measured. Dr. Adolphs has previously shown that people who have damage to the amygdala also have difficulty in this task, but can get better at discriminating facial expressions after receiving instruction. Ultimately the researchers hope that this study will lead to earlier diagnosis, better prediction of social dysfunction and improved strategies for rehabilitation of patients with autism.

Functional Magnetic Resonance Imaging of Cerebellar Learning in Autism (Pilot Project Award)
Greg Allen, Ph.D., University of Texas, Southwestern Medical Center

The cerebellum is the most consistent site of brain abnormality in autism. For instance, over 95% of autistic cases examined at autopsy show some form of cerebellar pathology, the most common being a reduced number of Purkinje neurons, a key component of neural circuitry in the cerebellum. Functional MRI (FMRI) investigations by Dr. Allen have found that individuals with autism display an abnormally widespread pattern of cerebellar activation during simple motor tasks. This finding is consistent with several possible manifestations of Purkinje neuron reduction. The aim of the proposed project is to use FMRI to investigate one of these potential manifestations, a disruption of cerebellar learning mechanisms. The investigation will use FMRI, a non-invasive approach to examining brain function, to study cerebellar function in 18 adult individuals with autism and 18 normal controls as they perform the serial reaction time task (SRTT). The SRTT, a standard tool for studying the neural basis of learning, is known to involve the cerebellum, and individuals with autism show impaired learning on this task. Thus, the study will help determine the relationship between such impairment and cerebellar dysfunction, and more importantly, it will investigate a potential neurofunctional link between cerebellar pathology and the symptoms of autism.

Neurophysiological Investigations of Social Attention in an Animal Model (Pilot Project Award)
Michael L. Platt, Ph.D., Duke University Medical Center

Humans are fundamentally social. During even the simplest of interactions, social cues and expectations guide where we look and pay attention, and these orienting movements in turn often betray our own deepest intentions and desires. The inability to attend to social signals or to use social cues to jointly orient attention with others profoundly diminishes the ability of people with autism and related disorders to function normally in human society. Understanding the brain mechanisms supporting social attention is thus a fundamental problem for contemporary neuroscience. Unfortunately, the mechanisms responsible for guiding attention in social situations remain poorly understood. This study will determine how a crucial structure known as the parietal cortex uses social information to guide attention. We will begin by developing a new behavioral model of human social attention in monkeys. Our preliminary data show that monkeys, just like normal humans, attend to social cues, such as faces and where they are looking, and thus serve as a superb animal model of human social attention. We will then use this new animal model to probe how neurons in the parietal cortex respond during social attention. The preliminary data indicate that social cues activate attention-related neurons in the parietal cortex, suggesting that normal social attention probably depends on meaningful social signals reaching this area of the brain. These observations suggest the possibility that social attention deficits in autism may be improved by enhancing the transmission of social signals to the parietal cortex. The development of new treatments for autism and related disorders thus may benefit directly from improved understanding of social attention mechanisms in an animal model.

Crossmodal Interactions in Autism (Pilot Project Award)
Ladan Shams, Ph.D., University of California, Los Angeles

Individuals with autism suffer from social and communication deficits. In addition, many of them perform differently from non-autistic individuals in a broad range of cognitive and perceptual tasks. In an attempt to find a common underlying cause for these perceptual differences the investigators suggest that interaction between distinct brain regions is impaired in autism, even at very initial stages of perceptual processing. Key deficits at these early stages of processing can have ramifications for higher-order perceptual, cognitive, and social processes. Previous studies have shown that individuals with autism have difficulties in performing tasks that demand using information from different senses. Our investigation will focus on the integration of simple visual and auditory stimuli. We will compare the degree of a known sound-induced visual illusion and the brain activity (ERP) elicited by the illusion between adults with autism and control groups. Dr. Shams predicts that individuals with autism will show a weaker illusion and smaller increase in sound-induced visual activity. Contingent upon verification of the researcher's predictions, they will study the role of training with synchronized auditory and visual stimuli in improving multi-sensory integration mechanisms in autism. The preliminary findings with non-autistic individuals have revealed that such training does indeed lead to enhancement of auditory-visual integration processes. A similar effect should be seen in individuals with autism. (Research Partner: Ricki and Joel Robinson)

Face Processing in Autism: An Investigation at Multiple Levels (Young Investigator Award)
Kate Humphreys, Ph.D., Carnegie Mellon University & CPEA

Many people with autism experience difficulties when recognizing and perceiving faces. They also have difficulties in other areas of visual processing; in particular they tend to focus on the parts of objects or patterns, possibly at the expense of the overall whole. Dr. Humphreys thinks that the problems people with autism have with faces may be one of the end results of their more fundamental perceptual style of concentrating on details rather than seeing things as wholes. The investigators believe it is crucial to determine where the fundamental deficit lies, as this is likely to have strong implications for remediation strategies: if the primary deficit is at the level of face processing, then remediation should target face processing per se; if, however, the primary deficit is more fundamental, then remediation strategies should focus on earlier visual processing. This study will use a cognitive neuroscience approach that includes both the psychological (what is happening in autism at the level of behavior) and neural (level of brain activation) components by conducting behavioral tests and neuroimaging tests with adults with autism, focusing on both face processing and lower level perceptual processing. We will then look for links between performances on face processing and perceptual processing in each individual, with a view to uncovering where the primary difficulty lies. (Research Partner: Beth and Pasquale Miranda)

Neural Bases of Visuo-spatial Processing in High-Functioning Autism (Young Investigator Award)
Rajesh Kumar Kana, Ph.D., Carnegie Mellon University

Research studies have revealed structural and functional abnormalities in the brain in autism. While these studies are consistent with the prediction that autism is primarily a disorder of brain functioning, no single neuropathological feature as yet has been identified unambiguously and no single model of pathophysiology is currently accepted. Several research studies have indicated that many individuals with high functioning autism have superior or intact ability in certain domains of functioning. For example, many individuals with autism are good visual thinkers. This study will investigate such advantages that high functioning individuals with autism have by using magnetic resonance imaging technology to study the integration of various brain regions when individuals with autism perform problems involving visuospatial thinking. Using these images, it is possible to detect which areas in the brain are active during processing of a particular problem. These results will be compared with typical control participants' brain scans while performing the same problems. This research is important as it will provide information about the nature of visual and spatial processing in autism, and may indicate specific type of processing differences. A clearer understanding of the way that individuals with autism process information will lead to the development of enhanced interventions.

Functional Magnetic Resonance Imaging of Social Perception in Adults with and without Autism Spectrum Disorders (Young Investigator Award)
James P. Morris, Ph.D., Duke University

This study will use functional magnetic brain imaging (fMRI) techniques to study the neural basis of social perception deficits in high functioning adults with autism. fMRI is a non-invasive imaging method that can localize changes in blood oxygenation levels in the brain - an indirect measure of underlying neural activity. Throughout the past decade fMRI has been used to examine brain activation in humans related to countless sensory and cognitive processes. The tool has also been used, with great success, to characterize the neural basis of many different clinical disorders. Social perception refers to the initial stages of evaluating the intentions of others by analysis of eye gaze direction, facial expressions and body movements. Recent advances in virtual reality technology and stimulus presentation capabilities have allowed researchers to study how humans process social information. Despite these advances, little is known about the neural basis of social perception deficits that are often associated with autism. This study will combine fMRI and virtual reality technology to help identify the neural basis for social perception deficits in autism. (Research Partner: Cathy & Shawn Ryan)

Implicit Learning and Autism Spectrum Disorders (Young Investigator Award)
Christopher J. Smith, Ph.D., Mount Sinai School of Medicine

Long before the emergence of a conscious effort to learn, infants and young children are acquiring information from their environment. This information aids in the typical development of social and communication skills. Individuals with autism experience strong deficits in these areas and it is quite possible that these deficits are related to and impaired ability to acquire information from their surroundings without conscious effort. This ability is referred to as implicit learning and has been tested in a number of different populations where explicit learning ability is affected or grossly impaired. The results from these studies strongly suggest the resiliency of implicit processes when compared to explicit functioning. This study is designed to test if individuals with autism display an impaired mechanism for implicitly learning information in a social context. Two different tasks have been designed. One of the tasks will determine if a sequence can be implicitly learned through the use of very neutral images, and the other task will determine if the sequence can be learned through the use of faces with different emotional expressions (a social task). If learning is impaired on both tasks, the results may suggest general neurological impairments. If learning is impaired on the social task only, it may imply the need for a new therapeutic direction to increase the processing time of social information. (Research Partner: Wolf, Block, Schorr and Solis-Cohen)


Cellular and Molecular Deficits: Pinpointing the underlying defect(s) in autism


Biochemical and Cellular Characterization of Neuroligin-3 Mutation Associated with Autism Spectrum Disorders (Pilot Project Award)
Davide Comoletti, Ph.D., University of California, San Diego

Today, autism spectrum disorders are accepted as being complex inheritable biological disorders that interfere with the normal development of the brain. A major limitation in the study of autism has been the difficulty in identifying the altered genes. Recently, two studies reported that mutations of two genes on the X chromosome, neuroligin-3 and neuroligin-4, have been linked to autism-spectrum disorders and mental retardation. Other genetic analyses found correlations between autism and the genes for neuroligin-1 and neuroligin-2. The neuroligin genes encode for a family of proteins expressed in the brain that govern development and maintenance of synapses, the structures which allow nerve cells to communicate with each other. Dr. Comoletti has established that the mutation found in neuroligin-3 prevents the correct cellular localization of the protein and thus impairs its normal function. This project will study the function, degradation, and localization of the normal and mutated neuroligin proteins in nerve cells in order to determine their exact function in the brain. Therapeutically, mutated neuroligin proteins could be affected by intervention with directed antioxidants and reducing agents. (Research Partner: Dor Family Foundation)

Functional Studies on the New Candidate Gene for Autism (Pilot Project Award)
Jean G. Steyaert, M.D., Ph.D., Katholieke University Leuven, Belgium

A novel approach to finding candidate genes for autism has allowed this research team to identify several candidate genes for autism. The approach consists of searching for "broken" genes in rare subjects with autism and specific chromosomal anomalies where only one gene is damaged. Three of these genes, neurobeachin, amysin and CLIC4, participate in the same biological pathway(s) in brain cells: regulated secretion. This pathway plays a role in regulating how nerve cells grow and differentiate, and probably also in controlled cell pruning (apoptosis) which is a normal part of early brain development. Deregulation of nerve cell growth and pruning has been demonstrated in the brains of persons with autism. The aim of this study is to investigate Dr. Steyaert's belief that errors in the genes neurobeachin, amysin and CLIC4 lead to problems with regulated secretion, thus effecting development of brain cells and perhaps resulting in autism. Dr. Steyaert will examine where the genes are expressed in the developing brain, and what happens if their function is disrupted in a mouse model. Such understanding may eventually lead to more focused biological treatments for autism. (Research Partner: Dor Family Foundation)


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

Evaluation of Intestinal Inflammation and Carbohydrate Digestion in Children with Autistic Spectrum Disorders and the Effect of Anti-Inflammatory Therapy on their Behavior (Pilot Project Award)
Rafail I. Kushak, Ph.D., Dr. Sc., Massachusetts General Hospital

Gastrointestinal disorders such as abdominal pain, diarrhea, constipation, and flatulence may contribute to the behavioral problems observed in children with autism. The effects of intestinal inflammation on neurological disorders experienced by autistic children remain unclear. The investigators will study this problem using recently developed non-invasive tests based on the analysis of two proteins (calprotectin and lactoferrin) found in the stool of children with intestinal inflammation. Since the absorption of biologically active proteins may affect cognitive and behavioral function, these surrogate markers of inflammation will be correlated with intestinal permeability. The study will provide valuable information for understanding the association between gastrointestinal disease and behavioral problems in autistic children. (Frank del Olmo Memorial Award)


The Role of Perceptual and Attentional Disturbances in the Early Diagnosis of Autism (Pilot Project Award)
Michelle O'Riordan, Ph.D., University of Cambridge, England

Research has recently shown an unusual ability in people with autism to notice minor features or changes in the environment. Recent studies have been used to find experimental examples of this superior ability to detect hidden pictures and sounds in both children and adults with autism. The results of these studies suggest that enhanced target detection is a feature of the disorder which remains stable throughout development from at least 7 to 40 years of age. This study will assess the possibility that this ability is present in very young infants with autism. Therefore, this study will explore the use of visual and auditory search tasks as additional tools for the early diagnosis of autism. The first benefit of this study is that visual and auditory search tasks should provide more objective experimental measures than observation methods. A second advantage is that such methods can be used prior to the development of social skills and require minimal social interaction. A third reason that visual and auditory search tasks might provide an additional tool for early diagnosis is that they are aimed at assessing phenomena which have been associated selectively with the autistic disorder. (Research Partner: Stephanie and Mark Batarse)

Early Identification of Autism Spectrum Disorder in Infants and Toddlers (Bridge Grant)
Carole Samango-Sprouse, Ed.D., George Washington University

Recent research has demonstrated that increased head circumference is associated with Children with Autism Spectrum Disorder and may be an early indication of vulnerability in typically developing infants. Additionally, a neonatal reflex call the Head Tilt Test in small study was abnormal in all infants and toddlers with ASD. It has been well substantiated in the research literature that early identification of children with ASD is very valuable and assists with recovery of more than fifty percent of the children by five years of age. This study is focused on a screening typical developing infants between the ages of 4 months and 24 months using the Head Tilt test and monitoring the growth of the infants' head circumference in an effort to determine if infants at risk for ASD may be identified by 12 months of age. This study could contribute to both the early identification of infants at risk for ASD as well as assist in the identification those siblings of children with ASD at risk for this disorder.

Use of Functional Behavioral Assessments to Evaluate Stereotypy and Repetitive Behaviors in a Double-Blind, Placebo Controlled Trial of Citalopram (Pilot Project Award)
Latha Soorya, Ph.D., Mount Sinai School of Medicine

Individuals with autism spectrum disorders show marked variability in their response to interventions. The purpose of this study is to evaluate the use of functional behavioral assessments (FBA) as tools to elucidate the effects of treating autistic children with the serotonin reuptake inhibitor (SSRI), citalpram. SSRIs are a class of medications used to target stereotyped and repetitive behaviors in autism. FBAs are methods developed from the field of applied behavior analysis used to observe how a behavior changes in relation to the events that precede (i.e. antecedents) and follow its occurrence (i.e. consequences). FBAs have been valuable tools in behavioral and medication studies. In medication studies, they are used to increase our understanding of why some individuals respond to medication and why others do not show improvements. This study will focus on the use of descriptive FBAs to identify which children respond and do not respond to medication, to evaluate patterns in repetitive and stereotyped behaviors, and to evaluate the relationship between FBAs and other outcome measures used in clinical trials. The addition of FBA methods to evaluate outcome in medication studies is an important step for research methodology in treatment of individuals with autism spectrum disorders. (Research Partners: Josh Och and the Solving the Mystery of Autism Foundation)

Cognitive Assessment of Autistic Spectrum Disorders: A Comparative Neuropsychological Perspective (Bridge Grant)
Norton Milgram, Ph.D., University of Toronto at Scarborough, Ontario, Canada

New neuropsychological assessment techniques are necessary to help us better understand the various types of autism and also to help in the evaluation of interventions. The overall objective of the proposed study is to develop a non-verbal test battery based on a comparative neuropsychological strategy that can be used for both classification and as an outcome measure in clinical trials. This approach, which Dr. Milgram and his collaborators have used in both Alzheimer's patients and children affected by the Fragile-X syndrome, uses neuropsychological tasks that are linked to known brain circuitry and were originally developed for cognitive assessment of primates and dogs. The proposal seeks to extend this work by developing a standardized test battery for children with Autism Spectrum Disorders. Dr. Milgram hopes to develop a rationale basis for categorizing subtypes of children with autism based on performance on non-verbal cognitive tasks that utilize specific brain areas likely to be affected in autism. In doing so, they will develop standardized hardware and software for administering these non-verbal cognitive tasks. Finally, Dr. Milgram aims to broaden the knowledge base of autism by characterizing aspects of cognition that have not been adequately accessed in previous research.

Search for a Biomarker for Autism (Bridge Grant)
H. Vasken Aposhian, Ph.D., University of Arizona

The etiology of autism remains obscure and no biomarker indicating its presence is known. Such a biomarker is needed because most of the current diagnostic techniques are behaviorally-based. With this in mind, Dr. Aposhian will be using Differential In-Gel Electrophoresis (DIGE) to search for a plasma biomarker for autism. DIGE is a powerful technique for comparing the relative amounts of proteins from two different sources, in this case the plasma of children with autism versus the plasma from children without autism. Any proteins found to be differentially expressed in the plasma can be subsequently identified using mass spectrometry. This bridge grant will allow the laboratory of Dr. Aposhian to extend their preliminary studies to a larger group of children.

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

Formation of an Autism Clinical Trials Network (Treatment Initiative Award)
Eric Hollander, M.D., Mount Sinai School of Medicine

There are currently no approved medications for the treatment of autism despite an acceleration of new discoveries at the basic science level. Although large networks have been funded to do clinical treatment trials, there seems to be a gap between compounds found to be promising at the bench level and federally funded trials to test the effectiveness of such compounds for autism. The same is true for alternative compounds reported to be useful in some children but with no studies to prove efficacy and safety. The proposed network of clinical investigators would attempt to fill such a gap by testing novel promising compounds, new interventions and alternative compounds relatively quickly and producing well controlled pilot data for follow-up large multi-center trials.

A multi-site double-blind placebo-controlled trial of memantine vs. placebo in children with autism targeting motor skills (Treatment Initiative Award)
Evdokia Anagnostou, M.D., Mount Sinai School of Medicine

Autism is a severe developmental disorder that affects social relations and communication abilities and is associated with restricted interests/repetitive behaviors. Numerous studies have reported a variety of motor difficulties in children with autism including problems with coordination, motor planning, unstable handedness, and oromotor difficulties affecting language. There is exciting new research examining the neurobiology of such deficits. However, there have been no recent studies to develop new interventions for motor skills in children with autism. In this study, which will kick off the Clinical Trials Network, the investigators will use a relatively novel compound, memantine, to try to improve motor deficits. Children ages 5-12 years who are verbal will be recruited to this study. They will receive either memantine or placebo (a pill that has no memantine inside) and will be followed for 14 weeks. The investigators will examine the effect of memantine on motor skills and its impact on expressive language and adaptive skills.

Can Transcranial Magnetic Stimulation Alter Motor Function in Autism and Asperger's Disorder? (Treatment Award)
Nicole J. Rinehart, Ph.D., Monash University

Throughout the developmental trajectory of autism and Asperger's disorder, a variety of fine (e.g. hand writing) and gross motor functioning (e.g. walking, hopping, skipping, catching, running) movement problems have been reported. These motor deficits, which occur in addition to the core triad of symptoms, result in additional impairment in quality of life by disabling performance in the school environment and the usual physical activities of childhood. In addition, motor abnormalities, for example, unusual gait and posture, affect how an individual with autism/Asperger's disorder is perceived by his/her peers, adding to the stigmatization and bullying in the school yard, and indeed in the broader community. In addition, it has been suggested that motor deficits may sometimes masquerade as social-communicative deficits, or indeed exacerbate children's social-communicative difficulties. The aim of this research study is to evaluate whether a technology called repetitive transcranial magnetic stimulation (rTMS) alters motor functioning in individuals with autism and Asperger's disorder. TMS is a non-invasive means of stimulating nerve cells in superficial areas of the brain, providing a powerful method for the study of motor function. The overarching goal of this research is to evaluate whether the application of rTMS may play a role in augmenting gross motor functioning in individuals diagnosed with autism and Asperger's disorder. We aim to evaluate whether rTMS is able to correct or improve movement impairment in these disorders and the functional results of any such improvement.

Computer-based receptive language training for young children with autism (Treatment Award)
Laura Schreibman, Ph.D., University of California, San Diego

The focus of this proposal is to investigate the clinical efficacy of a computer-based training program for teaching word comprehension skills to young non-verbal and minimally verbal children with autism. Dr. Schreibman will assess word comprehension abilities both before and after the administration of a computer-based language training program previously shown to effectively teach word comprehension skills to typically developing infants. Outcomes will be measured behaviorally and with recordings of event-related potentials. She hypothesizes that very young children with autism will learn word labels quickly and easily through the use of this program, therefore increasing the types of strategies to enhance language skills in these children. Numerous studies have shown early word comprehension abilities to be critical for the development of appropriate vocabulary, grammar, and cognitive skills later in development. Therefore, Dr. Schreibman anticipates any gains made in receptive language will translate to pivotal gains in later language and cognitive skills. The program is being designed with very young children in mind, and therefore could be used at the first signs of risk for autism. If successful, this computer program could be easily incorporated into a variety of intervention models. Providing an affordable training solution for families is a long-term goal of the project.

Effectiveness of Neurofeedback Training on Autism Spectrum Disorders (Bridge Grant)
Jaime Pineda, Ph.D., University of California, San Diego

Figuring out how the brain produces autistic behavior has been a challenge because the manifestations vary both in severity as well as expression. However, the discovery of "mirror neurons" provides a common basis for some of the major behavioral deficits seen in autism spectrum disorder (ASD). Mirror neurons are specific brain cells that fire when we pick something up, feel the texture of a surface, smell something unpleasant, or even when we experience emotions. What is unique is that these same cells also fire when we observe someone else performing similar actions. Studies indicate that mirror neurons may underlie the ability to imitate. Some have suggested that this provides a mechanism for the development of language, or that the mirror system is required to develop a "theory of mind" (the ability to understand another's mind). Finally, studies have found that facial expressions activate the mirror system and hence empathy may depend on it. Therefore, the existence of mirror activity in the human brain provides a neural bridge between imitation learning and higher-order social cognition. ASD individuals lack many of these seemingly simple social skills and have difficulty understanding sensations or perspectives other than their own. Dr. Pineda's research group has recently published data suggesting that ASD individuals have a dysfunctional mirror neuron system. This project will examine the effectiveness of an experimental treatment for ASD known as Neurofeedback Training. Neurofeedback is a non-evasive procedure in which the brain is trained subconsciously to increase or decrease the level of specific brain rhythms. The training requires that electrodes be placed on the scalp and for an individual to relax and watch a video that either plays or stops depending on high/low mirror neuron activity. Through such training the hope is that the dysfunctional mirror system may become normalized, potentially then allowing ASD individuals to improve imitation skills and react with greater sensitivity to other people's actions.

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

Technology Support to Track the Effectiveness of Intervention Therapies for Children with Autism (ITA Award)
Gregory Abowd, D.Phil., Georgia Institute of Technology

While there are many intervention therapies proposed to help children with autism overcome their various developmental issues, there is relatively little scientific knowledge about these interventions, and many researchers declare the need for better-controlled studies. Beyond clinical evidence of effectiveness, parents and other members in the network of caregivers for autistic individuals desire the ability to communicate information regarding the ongoing progress of a child so that better-informed decisions can be made with respect to treatment. Dr. Abowd is developing a collection of automated capture technologies to assist in the collection, analysis and visualization of relevant behavioral and performance information for children with autism. He will address both structured therapies with established data collection routines, such as discrete trial training, as well as less structured observations that occur throughout the day for children with autism and help determine positive or negative trends. Dr. Abowd is interested in combining automated and manual techniques for record keeping and hope to be able to merge information extracted directly from a child with autism through wearable sensors, sensed by the environment through cameras or other means, with valuable interpretations made by human caregivers.

Spectral Analysis of Speech in Children with Autism - a Pilot Study (ITA Bridge Grant)
Yoram Bonneh, Ph.D. and Misha Tsodyks, Ph.D., The Weizmann Institute of Science

The speech of many children with autism appears abnormal and often described as machine-like or monotonic. The exact nature of this abnormality and the underlying mechanisms are currently unknown, and its understanding could give hints about the non-verbal cases. At the same time, a quantitative measure of these abnormalities could be useful for diagnosis. The current study will look for abnormalities in the speech of young (ages 4-6) children with autism, investigating the frequency (spectral) content. Preliminary results revealed significant spectral differences between children with autism and controls, but a larger sample is needed to rule out artifacts. In addition, the study will look for subtypes as well as possible correlation with other autistic properties and will investigate the possibility of "spectral diagnosis."

Ethnography of Autism Project (ITA Bridge Grant)
Olga Solomon, Ph.D., University of Southern California

Ethnography of Autism is an interdisciplinary project that provides an ethnographic perspective on autism and communication. Dr. Solomon and colleagues have collected approximately 600 hours of video- and audio - data, documenting communicative abilities of 32 three to eighteen -year -old children with levels of functioning across the autism spectrum as they interacted with family members at home and with teachers and peers at school. The results of this project provided important information about the impact of autistic children's impairments on everyday communication, elaborating and often contradicting findings derived from experimental psychological studies examining similar domains of functioning in laboratory settings. These results are immediately relevant for design of successful educational programs and innovative technological devices that support the area of strength (conversational turn-taking) for children across the autism spectrum, and especially for those children who do not communicate through the use of vocal speech. To this end, the investigators have followed a cohort of severely impacted children with autism and their families in the Los Angeles and Chicago areas. Dr. Solomon is currently examining the development of the childrens' communicative abilities, the technological tools used by their families and teachers over time, and the childrens' educational progress. The goal of the project is to provide an understanding of communicative abilities of severely-impacted children with autism in naturalistic social environments, as well as to identify the practices and technological artifacts that promote the realization and development of a child's communicative potential.

CosmoBot™: An Interactive Robot for Children with Disabilities (ITA Bridge Grant)
Corinna E. Lathan, Ph.D., AnthroTronix, Inc.

AnthroTronix has developed CosmoBot™, an interactive robot designed for integrated therapy, education, and play for children with a wide range of disabilities including ASD. Grants from The National Science Foundation (NSF) and the National Institutes of Health (NIH) have allowed Dr. Lathan to look at developmental goals related to speech and physical therapy respectively. Subjects in the past have been recruited based on the developmental goals the child is trying to achieve, not based on their clinical diagnosis. So although they have utilized a user centered design from its inception and piloted 3 generations of robots in classrooms and clinics, they have not yet focused on the needs of children with ASD specifically. This proposal is to 1) fabricate the existing design of CosmoBot™ and 2) to evaluate its functionality with children with ASD to inform future research and impact the next generation of CosmoBot™ design.

Can Computer-Scorable Vectors Provide Adequately Sensitive and Specific Measures for an Objective, Instrumented, Low-Cost Method of Tracking Change in Social Reciprocity? (ITA Bridge Grant)
Cheryl Y. Trepagnier, Ph.D., The Catholic University of America

Impaired social interaction is a core deficit of the Autism Spectrum Disorders (ASD) and an important target of intervention. While there are excellent tools for diagnosis, it is difficult to measure progress in social interaction. Clinicians and researchers make use of subjective parent and teacher questionnaires, laborious behavioral coding of videotapes, or equipment that may be impractical in terms of expense and acceptability to children with autism. In this project the goal of the investigators is to test the principle that location, orientation and direction of movement of the head in a structured play setting can provide important information for assessing social interaction. All of this is information that could be automatically acquired and scored by a low-cost computerized system. To test this principle, interactions will be simultaneously videotaped for behavioral coding and from overhead for coding of head location, orientation and movement direction. The data sets will be compared to assess their correlation and test-retest reliability. If the head position data correlates well with behavioral coding and proves reliable, the investigators propose development of the method in order to produce a very low-cost, reliable, objective, user-friendly measure of social interaction to improve measurement of treatment impact in clinical and research settings.