Jan Buitelaar, M.D., Ph.D., University Medical Center Utrecht (Pilot Research)
For both clinical and research reasons it is important to detect children with typical autism and with the broader phenotype of autism spectrum disorders at an age as early as possible. We have started to screen children of 14 months in the general population for possible autism, to identify these children, to perform a regular and systematic follow-up, and to establish a final diagnosis at the age of 3.5 year. Specific aims are to develop a reliable screening instrument to detect children at high-risk for autism at 14 months of age, to develop diagnostic criteria for autism under age 3 year, and to study the biologic, behavioral, cognitive and environmental correlates and predictors of development in children at high-risk for autism.
Rita Cantor, Ph.D., University of California, Los Angeles (Bridge Grant)
A statistical technician will take the AGRE family structure, phenotype and genotype data files and merge them appropriately into genetic analysis files which have very fixed formats, and make these files available to interested investigators using a request process; generate information in response to requests; conduct analyses on the AGRE database suggested by individuals with no analytic infrastructure; and conduct analyses on the AGRE database suggested by UCLA investigators.
Ved Chauhan, Ph.D., Institute for Basic Research in Developmental Disabilities (Bridge Grant)
Several reports suggest that autism is a common neurological disorder among children. However, continuous scientific neglect of this disease has resulted in very few biochemical studies. The diagnosis of the disorder is done behaviorally. A biochemical marker for this disease is urgently needed to assist the behavioral diagnosis. We analyzed erythrocyte membrane fluidity in the blood samples from 7 autistic children, their siblings and parents. Interestingly, 86% of the autistic children showed a decrease in membrane fluidity as compared to their normal siblings and parents. Fluidity of the membrane is an index of microenvironment of the membrane that controls its biological functions. Normally, membrane fluidity decreases with age, and therefore, normal children are expected to have higher membrane fluidity as compared to their parents. Our preliminary results, therefore, suggest that autistic children follow an opposite pattern for membrane fluidity as compared to normal controls. We hypothesize that erythocyte ghost membrane fluidity is decreased in patients with autism, due to an imbalance in the phospholipid/cholesterol molar ratio, and that platelets may also be altered in autism.
Mirella Dapretto, Ph.D., University of California, Los Angeles (Pilot Research)
Deficits in social communication are a hallmark feature of autism. Even in high-functioning autistic individuals, mastery of the formal aspects of language (e.g., phonology and syntax) is associated with deficits in understanding the communicative intentions of others, as conveyed in discourse and by the use of prosodic cues. Although several neuroimaging studies point to a number of structural and functional abnormalities in the autistic brain, thus far, no empirical study has focused on the brain circuitry involved in the persistent communicative deficits seen in autistic individuals, particularly in the pragmatic domain (i.e., the context-appropriate social use of language). Indeed, very little is known about the neural substrate of these high-level linguistic functions in the normal adult brain and even less about the functional and structural neural developments associated with the emergence of these communicative abilities in the normally developing brain. The proposed research will use functional and structural magnetic resonance imaging to (1) identify the networks of cortical activity associated with basic and complex linguistic functions in a sample of normally developing children; (2) examine how these neural networks change as a function of age and linguistic competence; (3) relate the developmental changes in the functional networks subserving language processing to age-related changes in brain morphometry; and (4) assess how the patterns of cortical activity, brain morphometry, and functional/structural relationships may be altered in a sample of high-functioning autistic children as compared to age- and gender-matched normal controls. First year funding partner: The Autism Coalition for Research and Education
Geraldine Dawson, Ph.D., University of Washington (Pilot Research)
Research has demonstrated that individuals with autism have difficulty perceiving and remembering faces. Furthermore, one published study and our preliminary data indicate that the fusiform gyrus, a brain region involved in face perception, is not normally activated during viewing of unfamiliar faces in individuals with autism. These data suggest that abnormal functioning of the fusiform gyrus may be a biological marker of autism. However, it is unclear whether abnormal fusiform gyrus activation and its accompanying impairments in face recognition in autism represent a stable biological marker of autism, or are the secondary result of a lack of normal attention to and experience with faces. The proposed research will begin to address this question by determining whether activity of the fusiform gyrus in persons with autism can be readily modified through increased familiarity and expertise with visual stimuli. The goals of this project will be to: (1) Confirm our pilot fMRI data showing abnormal activation of the fusiform gyrus in individuals with autism; (2) Determine whether viewing of familiar faces (e.g., parents) yields greater fusiform activation than unfamiliar faces in individuals with autism; and (3) Determine whether training in the recognition of faces or objects leads to greater fusiform activation during the viewing of these trained stimuli. If greater familiarity or training leads to greater activation of the fusiform gyrus, this will be more consistent with an experience-driven neural abnormality hypothesis. Alternatively, if increased activation is not found, this will be stronger evidence of a stable biological marker in autism.
Steward Flaschen Memorial Young Investigator Award:The role of early environment in the regulation of oxytocin receptor expression and social behavior
Darlene Francis, Ph.D., Emory University (Young Investigator)
The inability to form normal social attachments characterizes many forms of psychopathology, yet there has been little attention devoted to understanding the neural basis of social attachment and bond formation. We propose to investigate the neurobiology of social attachment and social bonding. The neuropeptide oxytocin has previously been implicated in the central mediation of attachment behaviors. It is important for the central control of social attachment behaviors as well as the expression of parental care. While cellular and molecular studies have begun to provide preliminary understanding of how oxytocinergic pathways are regulated, notably in the social prairie vole species, little attention has been devoted to the environmental regulation of this system. We will determine if within species differences in the oxytocin receptor system are related to differences in social behavior. We will then investigate the role the early postnatal environment (i.e. parental care) plays in the expression of this receptor system and the social behaviors associated with it. Conclusions: Autism, as with most other forms of psychopathology, is most likely the result of a fine interplay between our genes and our environments. The proposed experiments will allow us to begin to integrate the role of genes and gene regulation in the context of a known environment. Ultimately we wish to investigate the role of both the prenatal and postnatal environments and their relationship to genes implicated in the regulation of social attachment.
Michael Gershon, M.D. Columbia University (Bridge Grant)
Peripheral serotonin concentrations are often elevated in autistic children, and some children have benefited from treatment with exogenous secretin. This study will measure the number of secretin and serotonin-producing cells in intestinal biopsies of autistic children and normal controls, measure the content of SERT, and measure the expression of the duodenal 5-HT3 receptor. Through his rediscovery of the "second brain" nerve cells in the gut that act as a brain, Dr. Gershon has helped bring the emerging field of neurogastroenterology to the forefront of modern medicine.
Dan Gillette, Ed.M., Stanford University (Contracted Research)
For many affected by autism, verbal communication is extremely difficult. Though many children with autism learn to speak and read, their path is often not an easy one. Recently, there have been significant technological advances that make it possible to build truly useful and portable communication systems devices with off-the-shelf components. With the introduction of handheld computers and the rapid expansion of the Internet and World Wide Web, attention can now be focused on adapting technology to effectively aid verbal communication.
Elena Grigorenko, Ph.D., Yale University (Pilot Research)
Five-to-ten percent of autistic children manifest hyperlexia-an ability to read and decode single words beyond the expected level based on the level of the child's IQ. In the context of otherwise retarded cognitive functioning, this ability is rather striking and deserves thorough and detailed investigation. The potential interventional importance of hyperlexia is difficult to underestimate: the engagement of reading and fascination with a printed symbol demonstrated by children with hyperlexia suggest that printed symbols may be used as a vehicle for communicating instructions. Currently, however, very little is known about hyperlexia. The long-term objective of this project is a better understanding of the etiology of autism, in particular, autism with hyperlexia. The data we collect will make it possible to characterize more completely the nature of the relationship between autism and hyperlexia. We propose to collect a sample of 20 families of hyperlexic autistic probands, 20 families of autistic probands without hyperlexia (gender- and age-matched to the hyperlexia sample), and 20 control families of gender- and age- matched controls. Studying these families should help to clarify further the transmission of autism and enhance our understanding of the phenomenon of hyperlexia as well as the familial relationships between autism and hyperlexia. In all cases, information will be obtained by direct structured assessment of all pertinent family members. These assessments will include an extensive neuropsychological assessment, structured interviews for the assessment of autism and related conditions, and structured psychiatric interviews for the documentation of all major psychiatric disorders. First year funding partner: The Autism Coalition for Research and Education
Tarik Haydar, Ph.D., Yale University, (Bridge Grant)
Dr. Haydar, a postdoctoral fellow in Dr. Pasko Rakic's laboratory, is working on the reasonable assumption that understanding the mechanisms of neurogenesis in humans is an essential step for designing the cure or treatment for disorders such as autism.
Nancy Isenberg, M.D., Ph.D., JFK Institute Medical Center (Pilot Research)
Social cognitive deficits are a critical feature of autism. Based on animal lesion, single-cell recording, and neurological studies, a specialized neural circuit centered on the amygdala, and involving orbitofrontal cortex, anterior cingulate and superior temporal sulcus, has been proposed to underlie social cognition. In order to identify the neural systems which are disordered in the social cognitive deficits in autism, we will utilize event-related fMRI along with a probe, piloted in healthy subjects, that reliably activates an amygdala circuit, relevant for the evaluation of and response to interpersonal, linguistic threat. Linguistic threat processing is an aspect of social cognition with evolutionary significance and is therefore more likely than other cognitive tasks, such as theory of mind, to target phylogenetically older limbic structures, such as the amygdala, which have been implicated neuropathologically in autism. In addition, we will perform diffusion tensor MRI in patients with autism and matched controls to further characterize white matter abnormalities that may also result in disturbances in functional connectivity between limbic and prefrontal areas thought to be relevant for social cognition. Understanding which neural systems are involved in the social cognitive deficits in autism will allow for the development of more appropriate interventions and new treatments. Pilot data provided by this study will be used as the basis for submission of an NIH career development award.
Deborah Keil, Ph.D., Medical University of South Carolina (Environmental Factors of Autism)
Infantile autism (IA) is a neurodevelopmental syndrome found in 1-5 cases of every 10,000 children with boys acquiring this syndrome 3-5 times more than girls. The spectrum of disorders of autism includes a range of impaired development of language and communication, unusual behaviors, and mental retardation. A diversity of pathophysiological effects also exist to include hyperserotoninemia, decreased T-cell proliferative function and activation, increased soluble IL-2 levels in serum, decreased CD8+ cells, decreased NK cells, development of anti-brain autoantibodies, decreased cerebellum volume and Purkinje cell number. Several studies indicate that the etiology of IA is multi-factorial and includes exposure to environmental chemicals. In particular, mercury exposure during infant and child development has been implicated in IA, especially in the case of vaccines containing mercury. Although mercury exposure from vaccines has been implicated in autism, this association has been criticized due to a lack of supportive experimental dose-response data. Thus, the proposed study will assess the possible role of methylmercury (MeHg) and thimerosal (TH) in contributing to the pathophysiology of IA using a mouse model to assess dose-responsive effects in cognitive and physiological parameters that encompass nervous, immune and enzyme pathways. This comparative approach will permit increased understanding of deficits due to MeHg or TH after acute exposure during early developmental stages and facilitate understanding of etiological causes of autism or other neurodevelopmental diseases. Furthermore, this study will also improve our understanding of the health effects attributed to different forms of mercury and contribute to the development of toxicological risk assessment models for detecting environmental contaminants that would adversely impact children's health.
Rebecca Landa, Ph.D., Kennedy Krieger Center for Autism and Related Disorders (Bridge Grant)
Participants will be assessed at 6-, 14-, 24- and 36-month age levels. It is an important objective of this study to assess changes in the strength of association between predicators and outcomes, and hopefully document the possibility of autism diagnosis as early as 14 months of age. These findings will be critical to understanding the developmental course of autism spectrum disorders, early diagnosis, and guidelines for intervention. First year funding partner: The Autism Coalition for Research and Education
Ken Lange, Ph.D., University of California, Los Angeles (Bridge Grant)
A biomathematician will take the AGRE data and do more comprehensive check for pedigree relationship errors (this will involve comparing theoretical and empirical kinship coefficients for each pair of relatives in the data); do a gamete competition test for association of each marker with autism; do a bivariate QTL analysis of the two traits: time to first word and the obsessive-compulsive measure (this may strengthen the evidence for a QTL locus on chromosome 7); and do a nonparametric linkage analysis of the data using autism as a qualitative trait.
Dominic Massaro, Ph.D., University of California, Santa Cruz (Innovative Technology for Autism Award)
The goal of the proposed research is to evaluate the potential for computer-assisted speech and language tutors to train and develop language skills with autistic children. Our language-training program utilizes a computer-animated talking head as the conversational agent, Baldi, who guide's students through a variety of exercises designed to develop lexical and phonological awareness. We propose to develop a motivational language tutorial program capable of introducing classroom curriculum and training and developing language and listening skills. Our research is a three-part process in which we will, 1) develop the necessary applications, 2) implement the applications in the curriculum of both the Bay School and Natural Bridges Elementary, and 3) evaluate the progress of the program.
Effective programs for this population share the following elements: (a) curriculum addressing the ability to use and comprehend language, and interact socially, (b) highly supportive teaching environments and generalization strategies, and (c) classroom environments that are predictable and routine. We believe full integration of the language tutors into the curriculum will greatly enhance the language development of children with autism. We believe this program holds promise for this population, our confidence derived from the success the program has witnessed not only at TMOS, but also with our preliminary work with these children.Sensorimotor gating in autistic disordered adults
William Perry, Ph.D., University of California, San Diego (Pilot Research)
There is considerable evidence that Autistic Disorder (AD) results from abnormal brain development and yet the specific brain abnormalities that account for the social, behavioral, communication and cognitive deficits of AD remain unknown. There is evidence to suggest that some autistic symptoms can best be explained as a disorder of filtering or "gating" of sensorimotor information. Sensorimotor gating in AD can be studied using prepulse inhibition (PPI) of the human startle reflex, an operational measure of sensorimotor gating. This approach will be particularly informative because there are existing models for understanding the neural circuitry of startle gating, and startle gating deficits are associated with cognitive deficits in specific neurodevelopmental disorders.
The first objective of this proposal is to determine whether PPI deficits occur in AD adults. A second objective is to correlate PPI to behavioral, and neuropsychological measures. The final objective of this proposal is to develop the optimal PPI parameters for use in a functional neuroimaging (fMRI) setting so that the regional brain activity associated with deficient startle gating can be determined.
Twenty-five carefully diagnosed AD and 25 age and I.Q.-matched normal adults will be assessed using unimodal acoustic and tactile (air-puff) PPI paradigms. Neuropsychological tests of executive function, attention and vigilance will be administered. PPI will be assessed and correlated to behavioral (i.e., symptom) and neuropsychological performance. Based upon these results, a unimodal tactile PPI paradigm will be piloted for use in a fMRI setting.Diagnosis and treatment of attentional abnormalities in children with autism using an automated multimedia video game
Bertram Ploog, Ph.D., College of Staten Island/CUNY (Innovative Technology for Autism Award)
Stimulus overselectivity is an attentional dysfunction, common in autistic individuals, which may seriously impair their social and academic functioning. We assume that behavior analysis can make significant contributions to the brain sciences and that early behavioral intervention may impact brain development and function. This proposal is aimed at improving our understanding of the attention processes involved in stimulus overselectivity and designing a treatment which employs audio-visual computer and Internet technology. The proposed study employs an experimental paradigm (a simple concurrent schedule of reinforcement) based upon behavior analytical principles, to explore factors which are involved in stimulus overselectivity. The paradigm is used to manipulate and test a variety of stimuli that differ in modality, quantity, quality, frequency, intensity, complexity, and discriminability. By incorporating the paradigm into a video game, the training and testing procedures will be enjoyable for the children, the procedures can be fully automated (reducing the need for professional involvement), and remediation procedures can be built into the game. Since the game is based upon "off the shelf" computer technology, and will be Internet accessible, it should provide affordable opportunities for remediation for a large group of affected children.
Nicole Rinehart, Ph.D. Monash University (Victoria, Australia) (Young Investigator)
Problems with motor functioning are a well known, but poorly understood, aspect of autism and Asperger's disorder. The aim of this research is thus to provide neurobehavioural and neurophysiological measures to quantify and qualify motor disturbance in these disorder groups. Recent retrospective studies have shown that even as infants, children with autism exhibit clear features of motor disturbance, which, if detected and clearly defined, could advance early diagnosis. In addition to advancing the clinical definition of autism and Asperger's disorder, a careful examination of motor disturbance may also illuminate the neurobiological underpinnings of these disorders. For example, recent evidence has shown that individuals with autism and Asperger's disorder have problems at the planning or initiation stages of motor functioning which may signify neural disruption within the basal-ganglia thalamocortical circuitry, for example, deficiencies in basal ganglia output to the supplementary motor area (Rinehart, Bradshaw, Brereton, & Tonge, in press). This study will consist of three separate experimental paradigms. Experiment 1 will utilise a digitised tablet kinematics task to provide a comprehensive analysis of the following features of motor function in a group of young people with autism and Asperger's disorder: movement time, peak velocity, movement acceleration, and movement deceleration. Experiment 2 will use a Clinical Stride Analyser to examine cadence and stride length in young children with autism and Asperger's disorder. Finally, Experiment 3 will use a movement-related potentials (EEG) technique devised by Cunnington, Iansek, Johnson, and Bradshaw (1997) to measure brain activity during the preparatory and execution phases of movement in these disorder groups. First year funding partner: The Autism Coalition for Research and Education
Ellen Silbergeld, Ph.D., University of Maryland School of Medicine (Environmental Factors of Autism)
Methyl mercury (MeHg) is an environmental pollutant that causes profound neurotoxicity and has been associated with autism. A major toxic effect associated MeHg exposure in humans is damage to the developing nervous system, involving inhibition of cell migration. This project will test the hypothesis that methyl mercury disrupts neurodevelopment through perturbing cytokine-directed neural migration, resulting in permanent structural alterations of the CNS and behavioral and cognitive dysfunction. By defining the role of inflammatory cytokines in brain development, the results of this project may also have implications for understanding mechanisms by which maternal infections increase risks of autism and other perinatal brain disorders.
Anthony Torres, M.D., Utah State University (Contracted Research)
Numerous immune abnormalities have been noted in subjects with autism. The Reed Warren Memorial Laboratory at Utah State University has reported associations between autism and genes in the human leukoctye antigen (HLA) region on chromosome 6. Besides being the most gene rich region in the human genome, HLA genes encode many proteins with critical immune response functions. More diseases have associations with HLA genes than any other region in the human genome. Recently we have been able to link HLA-DR4 to autism by HLA-typing entire families. The transmission disequilibrium test (TDT) indicates that the probands inherit the HLA-DR4 allele more often from the fathers than would be expected. Linking HLA-DR4 to autism expands out knowledge between the immune system and autism. Our project with Cure Autism Now is very important, as research until this time has been with a limited number of probands and families mainly from Utah. Increasing the HLA database with several hundred additional families through Cure Autism Now and the Autism Genetic Resource Exchange (AGRE) will add significant power to our theory of autoimmune mechanisms in autism. First year funding partner: The Autism Coalition for Research and Education
Anthony Wynshaw-Boris, M.D., Ph.D., University of California, San Diego (Pilot Research)
Numerous studies have demonstrated a strong familial tendency in autism, but no genes important for autism have been isolated. An alternative is to study animal models containing defined genetic mutations that display characteristics of autism. Studies of such mice may provide novel insights into processes that influence behavioral variation and aspects of human neuropsychiatric disorders. We have produced mice completely deficient for Dvl1 that surprisingly exhibit reduced social interaction and abnormalities of sensorimotor gating. The novel behavioral abnormalities displayed by Dvl1-deficient mice make them a potential genetic model for aspects of several human psychiatric disorders including autism. Therefore, we propose to examine the Dvl1-deficient mice in detail to try to identify abnormalities in neuronal morphology or function. To determine whether behavioral phenotypes are due to developmental abnormalities or adult signaling defects, we are producing conditional knock-out alleles to inactivate Dvl genes in a spatially and temporally restricted pattern during development, or in the adult. To understand the pathways that mediate the effects of Dvls on behavior, we will also use the Dvl1 homozygous mice as a sensitized strain to screen for genetic suppressors of the social interaction and sensorimotor gating phenotype. We will use cDNA microarray analysis to compare regional brain patterns of gene expression in wild-type and mutant mice throughout development. Patterns of global gene expression will be compared to try to identify regulatory pathways important for the Dvl1 mutant behavioral phenotype.
Leman Yel, M.D., University of California, Irvine (Environmental Factors of Autism)
Organic mercury compounds are known to be toxic mainly to the nervous system. Recently, the similarities between the neurological findings in mercury exposure and autism have come to attention. It has been estimated that children are exposed to a quantity of mercury that exceeds the safety guidelines in the first two years of life through thimerosal (ethylmercury salicylate) in vaccines. And, a strong association between the administration of certain vaccinations and the onset of autistic manifestations has been noted. Autism is a multi-factorial disease in the pathogenesis of which genetic, immunological, and environmental factors play a role. Brain biopsies from autistic children show degeneration and a loss of neuronal cells without any evidence of inflammation that is consistent with an apoptotic (programmed cell death) process. Mercury accumulates in the mitochondria and disrupts cell energetics. It has been shown to induce apoptosis by causing mitochondrial dysfunction in lymphocytes. No study has been published on the apoptotic effect of mercury in the nervous system. We hypothesize that mercury induces apoptosis in neuronal cells and this effect is mainly via the mitochondrial pathway. This might be more pronounced in children with autism because of genetic susceptibility. Thus, apoptosis due to mercury exposure may contribute to the pathogenesis of autism. Therefore, we intend to examine the effect of thimerosal on apoptosis induction and the signaling steps of mitochondrial pathway of apoptosis in neuronal cells. The results would clarify the effect of a mercury compound in neuronal cell death and degeneration, and provide a better understanding of the potential role of mercury exposure in the pathogenesis of autism.
Andrew Zimmerman, M.D., Kennedy Krieger Institute (Pilot Research)
Salient behavioral characteristics of autism include underdeveloped communication skills, limited social interactions and repetitive activities. Clinician and parent reports suggest that fever may be associated with behavioral improvements in children with autism. The improvements may decline toward baseline when the fever subsides. The objective of this pilot study is to advance our understanding of the neurobiology of autism. The specific aims of this study are: 1) to assess if fever is associated with behavioral improvements in children with autism, and 2) to characterize the types and frequencies of these changes.
Study participants are children between the ages of six and eighteen years with a diagnosis of autism who are members of Autism Society of America chapters in the Baltimore-Washington area. Parents will take their children's temperatures each day with skin tapes and call research staff on the first day a child has a fever. Trained staff will visit the home that day and perform a behavioral test, the Autism Diagnostic Observation Schedule (ADOS). The ADOS will be performed with the child on two additional occasions: 1) one to two days later when the fever is declining, and 2) one week later when the child has not had a fever for a week. Comparison ADOS data will be collected on three days in a parallel time sequence for age- and sex-matched children with autism who do not get fevers over the study period. A second comparison group of non-autistic siblings of the "febrile" participants with autism will be studied as well.Research and design of accessibility tools for those with autism (2001-2003)
Archimedes Access Research and Technology International, Inc. (AARTI) (Contracted Research)
Research the efficacy of computer accessors in regard to computer assisted communication for the autistic by creating and testing a communicator prototype. This study will include subjects fitting a range of competencies, including the more severely impacted.