2007 Mentor Based Fellowships

2007 Mentor Based Fellowships
2007 Augmentation Grants
2007 Innovative Technology for Autism (ITA) Grants
2007 Opportunity and Bridge Grants
2007 Physician/Investigator Beginning Autism Research (PIBAR)
2007 Special Co-Funding with the Dana Foundation

Mentor: Helen Barbas, Ph.D.
Boston University
Post-doctoral fellow: Basilis Zikopoulos, Ph.D.
$108,000 for 2 years

Architecture of myelinated axons linking frontal cortical areas

The brains of people with autism are marked by several structural abnormalities. One prominent feature is an enlargement of the axon pathways (“white matter”) that connect neurons in different parts of the brain, allowing them to communicate. The pathways in prefrontal cortex, an area involved in executive control, are especially affected in autism: these frontal pathways are disorganized and the volume of white matter is enlarged. These abnormalities disrupt the brain's communication system for thought, emotion, and action.

This research project will pinpoint the structural factors that contribute to the enlargement of white matter in the prefrontal cortex in autism. Dr. Barbas' fellow will examine post-mortem tissue from autistic and control individuals for differences in axon density, axon size, myelination, and number of non-neuronal cells that surround axons ("glia"). A second goal of this project is to develop the use of non-invasive imaging of white matter so that future studies will not have to rely on post-mortem tissue. As a first step, the prefrontal pathways in rhesus monkeys will be mapped. These pathways will initially be scanned using non-invasive diffusion tensor imaging (DTI); subsequently, these pathways will be labeled via injections of tracers into the same brains. Information from both DTI and tracer injections will then be compared to help optimize non-invasive scanning and image analysis protocols for future use in humans.

What this means for people with autism: Finding the structural factors behind the white matter enlargement may finally reveal the relevant dysfunctional neural processes in autism. These experiments also begin the development of non-invasive imaging methods that will eventually allow more finely-scaled white matter pathway scanning in humans. These techniques will be essential for finding what underlies the neuropathology in autism, which is prerequisite to developing treatments.

Mentor: Amy Bastian, Ph.D.
Kennedy Krieger Institute
Pre-doctoral fellow: Christina Fuentes
$64,000 for 2 years

Understanding perception and action in autism

Research has shown that people with autism have a perceptual bias during sensory processing that results in a focus on details, or “local” features, often at the expense of the whole, or “global” features. That is, they often “cannot see the forest for the trees.” In contrast, typically developing populations are aware of global features in a sensory stimulus, and are able to see the idiomatic “forest.” The effect of this perceptual bias on multiple sensory systems is unknown.

Dr. Bastian's fellow will explore local versus global processing of shapes in two sensory systems: vision and touch. The perceptual bias in vision will be compared to the bias in touch using analogous stimuli. Motion perception will also be examined, and the bias in processing dynamic stimuli will be compared to the bias for static stimuli. To understand how these perceptual biases may ultimately affect behavior, the scientists will also analyze how participating subjects draw different shapes.

What this means for people with autism: This research will increase understanding of perceptual abnormalities in autism, which may be at the root of some of the symptoms of this disorder. This understanding may also lead to better behavioral treatment strategies.

Mentor: Arthur Beaudet, M.D.
Baylor College of Medicine
Post-doctoral fellow: Soeun Kim, Ph.D.
$58,000 for 2 years

DNA methylation and other epigenetic studies of autism brain

Autism may be caused by an interaction between genetic and environmental factors. This interaction may take place at the level of gene expression, which is the process by which genes are turned on and made into proteins. While much research into the genetic basis of autism has focused on finding mutations within genes, researchers also appreciate that even normal genes can play a role in causing autism if they are inappropriately turned on or off. Gene expression is tightly controlled within a cell, and disruption of this process can lead to pathological conditions. Thus, it is crucial to understand the “epigenetic” mechanisms controlling gene expression and how they may be influenced by environmental factors.

This study is looking for abnormal gene expression patterns in the brains of individuals with autism. One way that genes are turned off is through DNA methylation: an enzyme places a methyl group onto certain sequences of DNA, thus flagging those genes for silencing. Thus, by examining the methylation status of genes, one can tell whether the gene is turned off or not. Dr. Beaudet's fellow will examine the methylation patterns of genes taken from post-mortem brain tissue of autistic individuals, and compare them to tissue from controls. The primary tool for analysis will be DNA microarrays (“gene chips”), which allow a genome-wide scan.

What this means for people with autism: Finding genes that are abnormally expressed in autism will advance understanding of the genetic basis of autism, and may indicate a role for gene-environment interactions in the cause of autism.

Mentor: Loisa Bennetto, Ph.D.
University of Rochester
Pre-doctoral fellow: Susan Lee
$60,000 for 2 years

Neural basis of audiovisual integration during language comprehension in autism

People with autism have communication difficulties that may result, in part, from difficulties in processing the nonverbal cues that accompany speech. Nonverbal facial and body gestures provide crucial information for understanding language and for early language development. Dr. Bennetto's lab has found that typically developing children benefit from this added nonverbal information, but children with autism do not. In fact, language comprehension is slowed for children with autism when gestures co-occur with speech.

This study tests the hypothesis that children with autism do not automatically process nonverbal cues. Additionally, their difficulty in integrating verbal and nonverbal information may reflect differences in how individuals with autism integrate auditory and visual information. Dr. Bennetto and her pre-doctoral fellow will use functional magnetic resonance imaging (fMRI) to examine how the brains of children with high-functioning autism process gesture (communicative hand and arm movements) and speech. They will also determine whether the difficulties in integrating visual and auditory cues in autism are limited to speech signals, or if they extend to non-social situations as well.

What this means for people with autism: Finding out how and where the brain integrates visual and auditory information related to speech is essential for understanding the communication deficits in people with autism. The results from this study will also inform the development of effective language interventions.

Mentor: Patrick Bolton, Ph.D., FRCPsych
The Institute of Psychiatry, King's College, London, England
Post-doctoral fellow: Fiona McEwen, Ph.D.
$122,000 for 2 years

Imitation in autism

The discovery of “mirror neurons” and the idea that they may be essential for imitation and understanding others' minds suggests a new way to understand the cognitive nature of ASD, offers the potential for imitation-based interventions, and may help define subgroups within ASD to aid in the search for biological causes of autism.

Dr. Bolton's fellow will carry out two studies of imitation impairments. The first study will examine a sample of children who were followed from age two years to adolescence to determine if two-year-olds with ASD who do not imitate differ over time from children with ASD who show typical imitation abilities. This could potentially identify a new subtype of autism and aid in a more accurate prognosis. The second study will attempt to establish whether adults and children with ASD show impairments in the automatic imitation of hand, mouth, or eye region movements. The relationship between imitative behaviors, the understanding of self and others, and real-life functioning will be explored.

What this means for people with autism: If children with ASD who show imitation impairments differ significantly from those without impairments in that area, autism treatments can be tailored and fine-tuned accordingly.

Mentor: Dermot Bowler, Ph.D.
City University, London
Post-doctoral fellow: Sophie Lind, Ph.D.
$122,000 for 2 years

Past, present, and future-oriented thinking about the self in children with Autism Spectrum Disorder

Parents often note that children with ASD struggle to tell them what happened during their day, and research has confirmed that people with ASD do have difficulties in recalling specific personally experienced events. The ability to recall the past is crucial because it enables one to anticipate and plan for the future, and to develop behavioral flexibility and adaptability. The inability to do so could account for the lack of flexibility and anxiety typical of those with ASD.

Dr. Bowler and colleagues will assess the ability of children and adults with ASD to think about themselves in the past, present and future in order to determine how these skills impact the severity of restricted and stereotyped patterns of behavior. If difficulties in this arena do contribute to greater behavioral impairment, new interventions can be developed and employed to target this deficit.

What this means for people with autism: With a better ability to learn from the past and prepare for the future, people with ASD can adapt more easily to the world around them and shed many rigid, nonproductive coping behaviors.

Mentor: Susan Bryson, Ph.D.
IWK Health Center/Dalhousie University
Post-doctoral fellow: Nancy Garon, Ph.D.
$122,000 for 2 years

The early identification of temperament endophenotypes in ASD

The extensive clinical heterogeneity of autism complicates the search for its causes. Current research is trying to minimize this heterogeneity by identifying meaningful subcategories within autism, or “endophenotypes.” These endophenotypes can be based on different characteristics, such as morphology, physiology or behavior, and individuals in the same endophenotype may share the same cause for their autism. New research is suggesting an endophenotype based on temperament, in which members of this subgroup share the traits of flat affect, high anxiety, and poor control of attention.

Previous research from Dr. Bryson's lab has found that high-risk infants (siblings of children with autism) who fit this temperament profile go on to develop autism. In some cases, autism was diagnosed as early as 6-12 months of age. In this new study Dr. Bryson's post-doctoral fellow will test the reliability of this endophenotype by following this same group of high-risk children into preschool. Their temperament will be measured by parent reports, direct observations of behavior, and physiological measures such as heart rate and brain activity.

What this means for people with autism: Most importantly, a temperament endophenotype can potentially allow earlier detection of autism and a more tailed intervention. Identifying reliable endophenotypes in autism can also simplify the search for autism's causes.

Mentor: Linda Brzustowicz, M.D.
Rutgers University
Post-doctoral fellow
$100,476 for 2 years

Genetic studies of autism susceptibility

Although there is strong evidence of an important genetic contribution to the cause of autism, the isolation of specific genetic defects that cause autism has been difficult. This is due to the genetic heterogeneity among people with autism. A new statistical analysis method designed specifically to deal with data from genetically heterogeneous populations has been applied to an autistic population. This method located previously unidentified regions of the human genome that are likely to harbor autism susceptibility genes.

Dr. Brzustowicz's fellow will now look for autism susceptibility genes within these newly discovered regions. The regions will be evaluated by conducting high-density single nucleotide polymorphism (SNP) genotyping and linkage disequilibrium analysis using a large set of DNA samples from the Autism Genetics Resource Exchange (AGRE) collection. These techniques are powerful because they can actually make use of genetic heterogeneity to help find disease-related genes. Any candidate genes found by this analysis will then be re-sequenced using DNA from individuals with autism to identify mutations that potentially cause autism susceptibility.

What this means for people with autism: This study examines a region of the human genome that has recently been implicated in autism. Finding autism susceptibility genes in this new region will increase understanding of the genetic basis of this disorder.

Mentor: Roberta Colman, Ph.D.
University of Delaware
Pre-doctoral fellow
$60,000 for 2 years

Molecular basis of autism associated with human adenylosuccinate lyase gene defects

Adenylosuccinate lyase deficiency is a rare metabolic disorder that results in autistic features. It is caused by mutations that decrease activity of the adenylosuccinate lyase enzyme (ASL), which is essential for nucleotide synthesis. Numerous disease-related ASL mutations have been identified, but their effects are unknown because the instability of human ASL has made experimentation difficult.

Dr. Coleman's lab has recently found a solution for stabilizing human ASL, and her research program is now poised to characterize normal and mutant ASL. Dr. Coleman's fellow will conduct experiments to compare the functions of normal and mutant ASLs. The mutant forms of the enzyme will be engineered to mimic six of those found in human ASL deficiency. The enzymes will be characterized by catalytic activity, binding studies, and biophysical measurements to evaluate their size, shape and stability. The researchers expect to find that mutant forms of ASL have altered binding sites or structures, both of which would hinder the enzyme's function. The hope is that understanding the differences in function between the various ASL forms can illuminate the biological pathways that, when disrupted, will generate autism.

What this means for people with autism: Because ASL deficiency shares features with autism, these findings will have relevance to autism pathology. In addition, this project may lead to the development of novel drugs that bind to mutant enzymes, change their unstable structures, and potentially treat adenylosuccinate lyase deficiency diseases.

Mentor: John Constantino, M.D.
Washington University School of Medicine
Post-doctoral fellow: Claudia Hilton, Ph.D., OTR/L, SROT
$122,000 for 2 years

Ethnicity and the elucidation of autism endophenotypes

Research has focused on identifying subgroups of people with autism, or “endophenotypes,” in order to accelerate the discovery of autism's genetic basis. People with the same endophenotype share certain traits, which may include morphological, physiological or behavioral features. By studying subgroups of people with autism, scientists may more effectively find the genes involved in this disorder.

This research project explores a candidate endophenotype based on motor ability. Dr. Constantino's fellow will evaluate the coordination of movement in school-aged children with autism and their siblings. The subjects will come from a well-characterized sample of sibling pairs that either share autism (concordant) or do not share autism (discordant), and this sample includes both Caucasian and African-American families. By analyzing how motor abilities vary among autistic and non-autistic siblings, this work will test the reliability of this candidate endophenotype. In addition, the early development of motor abilities will be studied in a different sample of high-risk infant siblings of individuals with autism.

What this means for people with autism: Characterizing the development of motor abilities in children at risk for autism may identify subtle motor impairments that could be used to diagnose autism at earlier ages. Identifying an endophenotype based on motor abilities may also fast-track research into one type of autism.

Mentor: Deborah Fein, Ph.D.
University of Connecticut
Pre-doctoral fellow: Molly Helt
$63,370 for 2 years

Mimicry and imitation in Autism Spectrum Disorders

Many researchers believe that a deficit in mimicry (the tendency to copy gestures and facial expressions of others) and thus an inability to learn that the self and others are similarly emotional beings, may be central to the development of autism. But to date, only one published study directly demonstrates that people with autism have a specific deficit in mimicry.

This research will better establish a link between mimicry deficits and ASD symptoms. The study will also document whether people with autism also lack the biological process resulting from mimicry called facial feedback. Facial feedback is the process by which our inner emotions are affected by our facial gestures, causing us to literally feel what others are feeling through the mimicry of their faces. Such “emotional contagion” enables the typical person to bond more closely and to better interpret others' intentions and state of mind. If impairments in mimicry, facial feedback, and emotional contagion are consistently found in people with ASD, the impairments could suggest a pathway for the development of the disorder.

What this means for people with autism: If interventions can aid in the ability to mimic the faces and feel the same emotions as others, then one of the most crippling elements of autism—the lack of ability to understand and relate well to others—might be greatly alleviated.

Mentor: Marcel Just, Ph.D.
Carnegie Mellon University
Pre-doctoral fellow: Saudamini Roy
$60,000 for 2 years

Visuospatial processing in adults and children with autism

Despite impaired function in social and language domains, individuals with high-functioning autism sometimes exhibit intact or superior performance on visuospatial tasks. For example, autistic subjects show a better ability than controls in the embedded figures task (EFT), in which they detect a target object that is part of a larger figure. This task requires suppression of global processing of the larger, embedding figure in order to locate the target object. Understanding the neural mechanisms behind this ability may be revealing about how the brains of people with autism process visual stimuli.

This project will study the neural basis of the EFT abilities in high-functioning autism. Neural connectivity between different brain regions will be examined during the task, with the expectation that global connectivity will be diminished and local connectivity emphasized in autism, thus increasing performance on the task. The project will also extend this research to children with autism in order to investigate the development of visuospatial processing in this disorder. To accomplish these goals, Dr. Just's fellow will use a combination of techniques: behavioral methods to detect differences in task performance, functional imaging (fMRI) to locate brain activations during the task, and diffusion tensor imaging (DTI) to visualize the pathways that connect different brain regions.

What this means for people with autism: Understanding how the brain processes visual stimuli in this task will reveal more about the way the brain is wired together in autism, especially with respect to long- vs. short-range connectivity. Knowing the neural mechanisms responsible for the behaviors seen in autism will allow more directed treatments to be designed.

Mentor: Connie Kasari, Ph.D.
University of California, Los Angeles
Post-doctoral fellow
$102,000 for 2 years

Joint attention intervention for caregivers and their children with autism

With roughly 500,000 children meeting the criteria for ASD in the U.S., and many of them remaining severely impaired despite treatment, services for autism are a significant public health issue. Dr. Kasari is currently conducting two randomized controlled trials to test new interventions for young children with autism. One is evaluating peer interaction interventions in the highly-diverse Los Angeles public schools. The other is beginning to evaluate interventions designed for toddlers and their mothers.

The diversity of these settings will allow Dr. Kasari's fellow to develop a more nuanced understanding of ASD and the science of intervention research. The fellow will be involved in developing and implementing the randomized controlled trial of toddlers with ASD and their mothers, providing invaluable training for developing future high quality trials. Finally, access to already completed data sets will allow the fellow to begin analyzing, writing, and publishing new findings immediately.

What this means for people with autism: The quick education and training of intervention science researchers will allow novel and more effective treatments for autism to be put into use sooner rather than later.

Mentor: Janet Lainhart, M.D.
University of Utah
Post-doctoral fellow: Tom Fletcher, Ph.D.
$122,000 for 2 years

Quantifying white matter connectivity in autism

Research suggests that abnormalities of brain connectivity underlie the deficits and impairments in autism. One powerful method to measure brain connectivity is to image the pathways that carry neural signals between brain regions (“white matter”) using diffusion tensor imaging (DTI). DTI is a relatively new and non-invasive technique, and new analysis methods need to be developed to accurately visualize the full architecture of these pathways.

Dr. Lainhart's post-doctoral fellow will apply a new statistical analysis to DTI images in order to describe quantitatively the white matter tracts in brains of people with autism. The approach is unique because it will map the connectivity along the entire length of the white matter tracts. This new method will be compared to current methods, and will also be used to study the tracts involved in language development in people with autism.

What this means for people with autism: This study develops neuroimaging methods that could eventually be used for biological diagnosis and early detection of autism, and may expedite biological monitoring of the effects of treatment on brain development. Equally as important, an understanding of the brain connectivity in autism will ultimately guide the development of novel treatment interventions.

Mentor: Suzanne Lewis, M.D.
University of British Columbia
Post-doctoral fellow
$122,000 for 2 years

Gene signatures of Autism Spectrum Disorders

Research has shown that genetic changes play a major role in autism. Reports estimate that 5-28% of individuals with autism have chromosome anomalies, and this wide range depends on whether subjects have physical abnormalities and/or cognitive delay. Thus, the collection of specific chromosomal anomalies in any one individual may correlate with their particular form of autism. For this reason, it is essential to identify subgroups within autism in order to put into context the inventory of autism-related chromosome defects. By applying a new screening method to people with complex forms of autism that include physical deformities with or without intellectual disability, Dr. Lewis and colleagues have found previously unknown genomic changes in autism.

Dr. Lewis' post-doctoral fellow will apply this screening method to additional subjects with both complex and simple forms of autism, in collaboration with the Genetics Team of the Autism Spectrum Disorders Canadian-American Research Consortium (ASD-CARC). This study will characterize chromosomal anomalies with respect to their parent of origin, size, breakpoints, association with flanking sequence variations, selected candidate genes, and their presence in controls and the broader autism population. More refined phenotype information will also be collected, including measurements of craniofacial morphology, in order to associate genetic findings with specific autism subgroups.

What this means for people with autism: This study will help make sense of the large number of chromosomal anomalies related to autism by sorting out how these genetic changes segregate according to complex or simple forms of autism. These specific genetic profiles will eventually allow earlier and more accurate diagnosis.

Mentor: Kathleen Millen, Ph.D.
University of Chicago
Pre-doctoral fellow: Kimberly Aldinger
$63,500 for 2 years

The genetic link between autism and structural cerebellar malformations

Autism has been consistently associated with abnormalities in the cerebellum, a brain structure important for motor coordination and sensory integration. Specifically, the cerebellum in autism has a smaller posterior portion and fewer Purkinje cells, which control its output. These abnormalities arise from disruptions in development, and this project hypothesizes that genes regulating cerebellar development may also cause autism. Notably, "autistic-like features" are often described for patients with cerebellar malformations. Dr. Millen's lab has been systematically searching the human genome for cerebellar malformation genes. So far they have identified 21 locations, all of which have some association with autism. Thus, although not all autism-related genes are involved in cerebellar development, every cerebellar malformation gene may be related to autism.

In this research project Dr. Millen's fellow will test whether genes known to cause human cerebellar malformations also cause autism. The study will determine whether patients recruited for cerebellar malformations caused by specific genetic mutations meet the diagnostic criteria for autism. Patients recruited for their autism diagnosis and subsequently also diagnosed with a small posterior cerebellum will be examined for genetic mutations, namely changes in gene copy number, at defined cerebellar malformation genes. Mice with mutations in these cerebellar malformation genes will also be analyzed for evidence of behavioral changes relevant to autism.

What this means for people with autism: These experiments will determine whether genes that cause cerebellar malformations also cause primary autism. If so, these genetic mutations could be used as diagnostic markers for this form of autism, and could lead to therapies aimed at reversing these disruptions of cerebellar development.

Mentor: Michael Murias, Ph.D.
University Of Washington
Pre-doctoral fellow: Lindsey Sterling
$52,000 for 2 years

Psychophysiological approaches to the study of autism

The high rate of associated psychiatric symptoms (e.g., anxiety) in autism is a growing focus of interest and concern. It is unclear whether such symptoms exist as part of the core disorder of autism itself or as separate, co-morbid psychiatric conditions. Disentangling the source of such symptoms will have a tremendous impact on our understanding of autism, especially as it relates to treatment strategies. Psychophysiology methods that provide a non-verbal means of measuring psychiatric symptoms can reveal correlates of social, cognitive, and emotional processes in autism. These methods include event-related potentials (ERPs), electroencephalography (EEG), eye-tracking, galvanic skin response, and fear potentiated startle response.

Dr. Murias' fellow will use these techniques to test whether anxiety-related symptoms in autism are associated with atypical physiological responses. These responses will be compared across four groups of adolescents: those with autism and anxiety, those with autism without anxiety, those that are typically-developing but with anxiety, and those that are typically-developing without anxiety. The study will also examine individual differences in anxiety severity to see if they correlate with individual differences in these psychophysiological responses. This design will allow the detection of anxiety-related signals, and determine if they are shared between autistic and typically-developing subjects.

What this means for people with autism: These results will distinguish whether anxiety is a core autism symptom or a coexisting psychiatric condition, which will inform pharmaceutical and behavioral treatment strategies for autism.

Mentor: David Oppenheim, Ph.D.
University Of Haifa, Israel
Post-doctoral fellow
$122,000 for 2 years

Interactions between mothers and young children with ASD: Associations with maternal and child characteristics

The accumulation of research evidence suggests meaningful differences in the quality of parent-child interactions in the realm of autism, with a considerable number of children developing secure attachments to their mothers. As is the case for typical children, it is widely believed that secure and supportive relationships help children with autism to maximize their potential. An important research goal is to understand parental and child characteristics that contribute to secure attachments, and the long-term implications of such attachments.

In this project, Dr. Oppenheim's fellow will study associations between parent-child interactions and attachment and the social and emotional development of young children with autism. The new study will be based on an earlier one that made associations between mother-child interactions and the attachments formed but used only global ratings. Dr. Oppenheim's fellow will advance the research by conducting a more detailed, in-depth analysis of which maternal and child behaviors contribute to more optimal interactions. For example, prior research points to the importance of maternal synchronous and non-demanding behaviors in positive interactions; therefore, this study now will carefully code these behaviors. The study will then examine the contribution of child attachment to the level of children's symbolic play, a significant challenge for most children with ASD. Finally, a follow-up study evaluating the same sample of children in middle school will determine how significantly preschool parent-child bonds relate to children's later development.

What this means for people with autism: The knowledge of specific behaviors that promote close bonds with their autistic children can help parents create the type of supportive relationship that helps autistic children to better flourish.

Mentor: Nicholas Ponzio, Ph.D.
University of Medicine and Dentistry of New Jersey
Pre-doctoral fellow: Mili Mandai
$64,000 for 2 years

Influence of maternal cytokines on activation of the innate immune system as a factor in the development of autism

Clinical and basic studies indicate a role for the immune system in autism. One idea is that a maternal immune response during pregnancy can influence embryonic development in such a way as to increase autism risk. Dr. Ponzio's research team has studied this possibility in mice, with a focus on the effect of cytokines on prenatal development. Cytokines are immune system compounds that signal other immune cells to the site of infection. Dr. Ponzio's research found that when one type of cytokine called interleukin-2 (IL-2) was injected into pregnant mice, their offspring had altered immune profiles and behavioral abnormalities that might be related to autism.

Dr. Ponzio's pre-doctoral fellow will further explore the link between this experimental paradigm and autism. Specifically, the study will test whether IL-2 injections in pregnant mice results in offspring with nervous system inflammation, similar to that sometimes found in autism. Brains of the offspring of IL-2-injected pregnant mice will be inspected for microglia, which produce neural inflammatory responses and thus can be used as markers for neuroinflammation. The fellow will further investigate lasting effects of these IL-2 injections on the innate immune systems of offspring by measuring the activated cells, such as natural killer cells and antigen presenting cells. These measures will be compared to offspring of saline-injected control mice.

What this means for people with autism: This study may specify how the immune system has a role in autism, which will be invaluable for future treatment, and perhaps prevention, strategies.

Mentor: Mustafa Sahin, Ph.D.
Children's Hospital Boston
Post-doctoral fellow: Du-yu Nie, M.D., Ph.D.
$82,000 for 2 years

Visual system connectivity in a high-risk model of autism

While it is clear that there is a strong genetic contribution to the cause of autism spectrum disorders (ASD), classical genetic mapping techniques have yet to yield a robust model for ASD. Meanwhile, studies of Tuberous Sclerosis Complex (TSC) can provide clues to autism's etiology because 50% of TSC patients are diagnosed with autism and because the genetic causes of TSC are known. TSC stems from mutations in one of two genes (TSC1 or TSC2) and in mouse models of TSC, Dr. Sahin's lab has found aberrant axon growth, targeting and myelination in the brain, which would result in miswiring between neurons. This fits with the growing evidence for disrupted neuronal connectivity in autism.

In this research project Dr. Sahin's post-doctoral fellow will investigate how TSC1/2 gene products regulate axon guidance, myelination and circuit formation in the brain. Specifically, the molecular mechanisms of axon guidance, which involves interactions between TSC proteins and Eph receptors, will be analyzed. The study will also characterize the effect TSC1/2 expression has on the myelin-making cells (“oligodendrocytes”). Finally, the study will investigate the full complement of axonal proteins whose expression is controlled by TSC1/2.

What this means for people with autism:This study will elucidate the cellular and molecular mechanisms behind the disrupted connectivity in the brain in autism, and potentially identify molecules that can serve as targets for new therapies.

Mentor: Susan Santangelo, Sc.D.
Harvard Medical School
Pre-doctoral fellow: Kristen Lyall
$64,000 for 2 years

Maternal dietary factors and risk of autism spectrum disorders

Research suggests that autism may result from environmental factors that act during prenatal development. One idea is that a pregnant woman's diet could influence prenatal brain development, perhaps in a way that increases autism risk. Relatively little research has been dedicated to understanding how maternal dietary factors could influence brain development in offspring. One interesting dietary factor is intake of omega-3 fatty acids, which are found in fish and nut oils; these fatty acids may act in the brain to promote neural growth.

Dr. Santagelo's fellow will determine whether women with low intakes of omega-3 fatty acids during pregnancy have increased risk of having a child with autism. The women studied will be from The Nurses' Health Study II cohort, a large cohort of over 100,000 female United States nurses who have been followed prospectively since 1989. The information collected on this group includes medical, obstetrical, and prospectively collected dietary factors, including omega-3 fatty acid intake. In 2005, over 800 women in the cohort reported having had a child with an autism diagnosis. This study will compare omega-3 fatty acid intakes in women with children with autism to the intake of women without children with autism in order to characterize the relationship between maternal diet and risk of autism.

What this means for people with autism: This study may specify a prenatal environmental factor that influences autism risk, help prevent new cases, and define new treatment approaches.

Mentor: Stephen Scherer, Ph.D.
Hospital for Sick Children
Post-doctoral fellow: M.M. Ghahramani Seno, D.V.M., Ph.D.
$87,700 for 2 years

The impact of autism specific genomic variations on microRNA gene expression profile

Autism is a highly heritable but complex disorder that probably involves numerous genetic factors. While many genetic studies of autism seek abnormalities in protein-coding genes that result in dysfunctional proteins, it is also important to consider mutations that affect whether a normal gene is turned on or off in the first place. If it is inappropriately turned on or off (“expressed”), even a normal gene may contribute to autism's pathology. Gene expression can be controlled by microRNAs (miRNAs), which also lie within the genome but are not protein-coding; instead, miRNAs bind to and silence genes. Thus, abnormalities in miRNAs can lead to inappropriate gene expression and neural dysfunction.

This project hypothesizes that miRNAs are as important as protein-coding genes in pathways of nervous system development that are involved in autism, and Dr. Scherer's post-doctoral fellow will look for miRNA abnormalities in a systematic way. Previous research in Dr.Scherer's lab has identified autism-associated mutations that are copy number variants (CNVs), and these variants can affect whether there is too much or too little of a particular genetic sequence, including miRNAs. The fellow will use these autism-associated CNVs as a starting point for looking for miRNAs abnormalities. The study will also include a screen of RNA samples prepared from a subset of carefully selected families (mother-father-offspring "trios") using both miRNA and gene expression arrays. Subsequently, he will use functional analyses to confirm the results.

What this means for people with autism: This project can clarify the genetic basis of autism, and takes a novel approach by looking for autism-associated mutations in parts of the genome that do not code for proteins, but which are critical for controlling gene expression. Understanding gene regulation in autism will pinpoint the dysfunctional molecular pathways and suggest therapeutic targets.

Mentor: Laura Schreibman, Ph.D.
University of California, San Diego
Pre-doctoral fellow: Sarah Dufek
$60,000 for 2 years

Translation of evidence-based treatment in classrooms

The treatment of autism is complicated by the fact that each child with autism has a unique combination of characteristics that may require a specific mix of therapeutic interventions. To date, very few empirically-based indicators of which children are most likely to respond to a particular treatment exist. This leaves parents and practitioners to try various approaches without knowledge of how effective they will be. One reliable assessment, the Predictive Pivotal Response Training Profile Assessment (PPPA), does accurately determine which children are most likely to respond well to this evidence-based, naturalistic behavior intervention. But to date, the training required to administer the PPPA has been so time-consuming as to limit its use in clinical settings.

A modified version of the original PPPA, designed specifically for autism service providers in community settings, is currently being developed. In this project, Dr. Schreibman's fellow will systematically evaluate the validity of the modified PPPA. Once validated, the modified version would allow service providers to quickly and efficiently determine if Pivotal Response Training should be included in the intervention program of a particular child. This experience will also give Dr. Schreibman's fellow a foundation to develop future clinician-friendly assessments of other interventions' usefulness to specific children diagnosed with ASD.

What this means for people with autism: Armed with accurate and easily-administered evaluations of which treatments are most likely to help an individual child with autism, parents and service providers can save enormous amounts of time and resources, and efficiently and confidently choose interventions for each child.

Mentor: Mary Stewart, Ph.D.
Heriot-Watt University, Scotland
Pre-doctoral fellow
$64,000 for 2 years

Phonological processing in the autism spectrum

One possible source of communication problems in individuals with autism is their failure to put the individual sounds of spoken language in context. For instance, in conversation people frequently mispronounce words, and previous research by Dr. Stewart and colleagues has shown that individuals with “autistic traits” are less likely to put the word into context to correctly perceive the intended word.

In this study, Dr. Stewart's fellow will assess whether this lack of “ability to infer when listening to others” is apparent in individuals with autism and Asperger Syndrome, and to explore the factors that can affect the perception of spoken language. Factors such as the frequency of the word in a language, its phonetic similarity to the mispronounced word, and its social and emotional meaning, will all be examined for their ability to enhance correct perception of an intended message.

What this means to people with autism:A more exact understanding of the specific problems with processing spoken language in those with ASD will help to develop better interventions that will in turn make for more successful and satisfying communication.

Mentor: Mark Strauss, Ph.D.
University of Pittsburgh
Pre-doctoral fellow: Desiree Wilkinson
$62,000 for 2 years

Development of categorization and facial knowledge in infants at-risk for autism

Research in Dr. Strauss' lab has shown that people with autism may have difficulty with categorization. Categorization is an important cognitive skill that significantly reduces demands on memory. It is also critical to language development, and most theories assume an ability to categorize is a prerequisite for learning words. Deficient categorization skills would have a profound effect on how one learns about the world and ultimately acquires expertise about objects, social information such as people and faces, and language. Thus, deficits or differences in categorization may underlie the symptoms of autism.

This project will examine the categorization abilities of infants at-risk for autism. Dr. Strauss' fellow will study infants that have an older sibling with autism. Specifically, the fellow will focus on the attentional, perceptual, and memory abilities of these infants especially as they relate to categorical knowledge of objects and people. The study will also track the development of these skills by following the same infants for the first two years of life.

What this means for people with autism: Deficits in categorization skills may be a sign of autism, and they might be present as early as infancy. If so, this deficit could be used as an early diagnosis tool, and suggests new behavioral treatments geared toward enhancing categorization skills.

Mentor: Judy Van de Water, Ph.D.
University of California, Davis
Pre-doctoral fellow: Daniel Braunschweig
$64,000 for 2 years

Immunobiology in autism

Growing evidence points to a role for the immune system in autism. One possibility is that certain antibodies made by a pregnant mother can target her developing fetus in such a way as to increase autism risk. By this hypothesis, the antibodies are autoantibodies, which mistake the developing fetus as a foreign pathogen. Research from Dr. Van de Water's lab has found evidence for maternal autoantibodies that target fetal brain tissue in mothers of children with autism.

Dr. Van de Water's fellow will further explore the role of these antibodies in autism, and will begin to characterize the specific targets of these antibodies. First, the protein targets of antibodies from mothers of multiple children with autism (“multiplex”) will be compared to those from mothers of one child with autism (“simplex”). This will reveal whether these are different types of autism that are associated with different maternal autoantibodies. Second, the location of the targeted proteins in the brain will be determined via immunohistochemistry. This technique will use the autoantibodies as markers; once bound to their targeted proteins in the brain, they will be visualized to reveal where in the brain the targeted proteins reside.

What this means for people with autism: These results will provide insight into the potential pathological role for maternal antibodies in autism, leading to a potential way to diagnose whether a pregnancy is at high-risk or not. It will also allow identification of biological processes that are central to the development of autism, which will lead to opportunities to design novel targeted treatments. (Co-sponsor: The Emch Foundation)

Mentor: Samuel Wang, Ph.D.
Princeton University
Post-doctoral fellow: Eugene Civillico, Ph.D.
$97,224 for 2 years

Optical analysis of circuit-level sensory processing in the cerebellum

Autism spectrum disorders are associated with abnormalities in the cerebellum. Cerebellum function is involved in movement coordination and sensory processing, both of which are dysfunctional in autism. One idea is that abnormalities in the cerebellum in autism affect coordination in both the motor domain and cognitive domain, producing uncoordinated movements and thoughts. Dr. Wang hypothesizes that proper coordination may require the ability to make predictions based on incoming stimuli, but how the cerebellum would do this is unclear.

This research project aims to elucidate basic cerebellum function in mice, and ultimately its role in coordination. Spontaneous and sensory-evoked activity in populations of cerebellar neurons in anesthetized and alert mice will be recorded using an optical technique that detects neural activity with excellent spatial and temporal resolution. This research will clarify how the basic repeating circuit within the cerebellum processes sensory stimuli, and may be relevant to understanding how predictions based on incoming stimuli are stored and represented in the brains of normal and autistic people.

What this means for people with autism: It has been suspected that the cerebellum is involved in autism, but the cerebellum-related dysfunctions have yet to be uncovered. This project may allow us to understand the basic reason for why individuals with autism appear uncoordinated, leading to more targeted and earlier interventions.

Mentor: Sara Webb, Ph.D.
University of Washington
Post-doctoral fellow: Emily Jones, Ph.D.
$102,600 for 2 years

Neurophysiological indices of risk and outcome in autism

Electrophysiological methods offer a window into the neural signals within the brains of people with autism. Dr. Webb's lab has been using two such methods: event-related potentials (ERPs) to describe cognitive and perceptual processes, and electroencephalography (EEG) to describe neural connectivity. These non-invasive methods are sensitive to the moment-to-moment changes in neural activity, and some of the neural activity patterns obtained may serve as signatures of autism by revealing how the brains in people with autism process social and linguistic signals and integrate sensory stimuli.

This project tests whether these methods can reveal risk for autism in infants, with the goal of improving early detection. Dr. Webb's post-doctoral fellow will obtain ERP and EEG measures in 200 infant siblings of children with autism at 6 and 12 months of age. Then they will be followed to 2 years of age, when it will be determined which children developed autism. The ERP and EEG signals will then be compared between those who developed autism and those who did not, to see if there were differences in activity patterns when they were infants. Specifically, infant ERP signals to social stimuli (faces and facial expressions) will be compared between those who developed autism, those who did not, and in non-risk infants. Similar comparisons will be made for EEG signal synchronization, which reflects connectivity across different brain areas.

What this means for people with autism: These studies may identify neural signatures of autism risk in infants, thus improving early detection methods. These methods also hold promise for identifying endophenotypes based on neural activity patterns that will be useful in genetic studies of autism.

Mentor: Robert Wozniak, Ph.D.
Bryn Mawr College
Pre-doctoral fellow: Breanna Winder
$59,000 for 2 years

Temperament, emotional expression, and emotional self-regulation in relation to later ASD diagnosis

Infants with an older brother or sister with autism are at increased biological risk for an autism spectrum disorder. To date, there has been no reliable way to predict which of these younger siblings will later be diagnosed with ASD.

This large, prospective study will attempt to identify variations in vocal, motor, communicative, emotional, and related areas of development in infants that can serve as predictors of a future diagnosis of autism. The many facets of temperament and emotional expression of these high risk children will be compared to infants with no known risk in search of differences that discriminate between infants who will receive a positive screen for an autism spectrum disorder at 24 months and those who will not. Extensive coding and analysis of videotapes will be used to assess behaviors such as social avoidance, social referencing, strategies for emotional self-regulation, startle responses, use of gestures and vocalizations, and manifestations of distress.

What this means for people with autism: The knowledge that younger siblings of autistic children are at increased risk can be incredibly stressful for parents. The presence of risk factors could help parents take action sooner, and their absence could put parents' minds at ease. Moreover, the study could lead to earlier ASD screening for all infants and allow for even earlier treatment than is currently possible.

Mentor: Larry Young, Ph.D.
Emory University
Pre-doctoral fellow: Meera Modi
$62,773 for 2 years

Neural mechanisms of social cognition and bonding

Research on the neural mechanisms of social behavior has particular relevance for autism. These mechanisms are now being revealed in voles, which constitute a promising model for understanding social cognition because of differences between vole species. For example, prairie voles are highly social and are socially monogamous, while meadow voles and montane voles are polygamous and solitary. Understanding the differences between these species can eventually pinpoint the neural circuits and mechanisms governing social behavior. Previous research in Dr. Young's lab using this model has shown that certain hormones and neuropeptides help to promote social bond formation.

This project is based on the hypothesis that the neuropeptide oxytocin facilitates social learning through interactions with the neurotransmitters dopamine and glutamate. Together they may impact the molecular pathways involved in synaptic plasticity and learning and memory. Dr. Young's fellow will conduct experiments designed to understand the interaction between oxytocin and glutamate, which will include testing whether clinically available glutamatergic compounds can enhance social cognition in the prairie vole. Behavioral pharmacology and molecular biology techniques will be used, and these two approaches promise to elucidate molecular mechanisms of social learning.

What this means for people with autism: Understanding the neural mechanisms of social cognition will help identify new therapeutic strategies for improving social behavior in people with autism. Oxytocin and pharmaceuticals that target glutamate are currently under investigation as possible therapeutic agents in autism, so these studies are important to clarify how they may be operating in the brain.