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Congratulations to our 2012 Pre- and Postdoctoral Grant Recipients.
Dr. Inna Fishman/Dr. Ralph-Axel Muller: San Diego State University
Examining Connectivity Patterns of Brain Networks Participating in Social Cognition in ASD
Studies have shown that there is a period of extreme neural plasticity during the 0-3 year period, and these studies have been used to develop early intervention programs. Preliminary brain imaging studies have indicated a possible second period of intense plasticity during the 12-18 year old period. If correct, this would be consistent with many parent reports of rapid gain in skills during this period. It would also argue for continuing intensive intervention during this time window. This project will examine the integrity of connections among distributed brain regions in individuals 12-18 years old using both EEG and fMRI, specifically looking at whether individuals with autism have abnormal pattern of connections within and between neural networks typically associated with social cognition, and those networks which mediate imitation. These altered patterns of brain organization can interfere with, and disrupt social cognitive development. Ultimately, findings from this project may have significant implications for detection, diagnosis and intervention programs for teens with ASD and other developmental disorders affecting social behavior.
Dr. Karyn Heavner/Dr. Craig Newschaffer: Drexel University
Evaluating Epidemiological and Biostatistical Challenges in the EARLI Investigation
This project will explore ways to more accurately determine environmental causes of autism using data from the Early Autism Risk Longitudinal Investigation (EARLI), a study of pregnant mothers who already have a child with autism spectrum disorders (ASD) and studying the environmental toxicants which they have been exposed to. Studies of this type are very difficult to conduct because even small errors in measurement of the potential toxin, the type of exposure or when it occurs can make a big difference in observed associations between the exposure and autism. Further complicating these studies, biological samples are taken from mothers and children in small amounts, making multiple tests difficult. The purpose of this project is twofold. First, we will examine how sensitive observed associations may be to small changes in measurement, with the goal of choosing the measurement strategies with the least amount of error. Second, we will develop strategies to test for the effects of multiple environmental exposures using the same biological sample, so as to conserve this finite resource. By conducting this type of methodological work early in the study, we will make much better use of limited resources and have much more confidence in our results. This will also provide guideline for others to study the environmental impacts on the development of autism
Dr. Haruki Higashimori/Dr. Yongjie Yang: Tufts University
Role of Astrocytic Glutamate Transporter GLT1 in Fragile X
Co-funded by: FRAXA Research Foundation
This project will attempt to validate a new biological target for therapy for both Fragile X and autism, which is highly associated with Fragile X. Uptake of glutamate from the synaptic cleft prevents accumulation of excess glutamate and over-activation of glutamate receptors in neurons. Normally, this uptake is done by glutamate transporters on various cells, and the most abundant one, GLT1, is located on peri-synaptic astrocytes. In Fragile X mice, GLT1 expression and glutamate uptake capability is significantly decreased. This team will test if it is the loss of FMRP in knock-out mice that leads to the loss of GLT1 and whether restoratingGLT1 activity in the FX knock-out astrocytes will decrease neuronal hyperexcitability and restore normal cortical dendritic morphology. Astrocytic glutamate transporter regulation could present a new target for the restoration of normal brain development in Fragile X and autism patients and drive forth the discovery of novel treatments.
Dr. April Levin/Dr. Charles Nelson: Children’s Hospital Boston
Identifying Early Biomarkers for Autism Using EEG Connectivity
Siblings of children with autism have a likelihood of developing autism that is nearly twenty times higher than that of the general population. Studying potential biologic predictors of autism early in life before a behavioral diagnosis can be made, and then determining which of these children ultimately merit a diagnosis of autism, can therefore provide important information about early predictors of autism. EEG is an ideal test for potentially predicting autism for several reasons. First, prior studies suggest that connections between neurons in the brain are different in children with autism, and that these connections can be assessed using EEG. Additionally, EEG is noninvasive, does not require sedation, and allows evaluation of brain activity without a child’s active behavioral participation. This study will evaluate the use of EEG-based brain connectivity as a predictor of future autism diagnosis by determining if infants with certain early EEG features are more likely to go on to be diagnosed with autism at age 3. Ultimately, this study has potential to inform future development of a clinically useful, easily administered, cost effective early screening test for autism.
Dr. Klaus Libertus/Dr. Rebecca Landa: Kennedy Krieger Institute
Effects of Active Motor & Social Training on Developmental Trajectories in Infants at High Risk for ASD
There is a considerable delay between the time parents suspect their child may be developmentally delayed and the time a formal diagnosis is made, often followed by an even greater lag before treatment services are started. However, treatment and intervention programs are most effective when started as early as possible. This study will attempt to validate a non-invasive early intervention protocol for children starting at 3 months of age. Infants will participate in an in-home, parent-guided training program using “Sticky Mittens” (infant mittens with Velcro attached to the palms) and Velcro toys, which will provide infants with reaching and grasping experiences. Typically, infants engage in successful reaching and grasping around 6 months of age. Through the “Sticky Mittens” used in this study, already 3-month-old infants will be able to experience successful “grasping” before they are physically able to do so and provide them with novel experiences important for learning. The goal of this study is twofold: First, to provide infants with experiences of self-initiated, exploratory activities (a common treatment goal for older toddlers with autism). And second, to determine whether failure to benefit from the training procedure indicates a potential red flag for autism regarding the child’s ability to learn from self initiated play experiences.
Dr. Oleksandr Shcheglovitov/Dr. Ricardo Dolmetsch: Stanford University School of Medicine
Using Induced-Pluripotent Stem Cells to Study Phelan McDermid Syndrome
Co-funded by: Phelan McDermid Syndrome Foundation
Phelan-McDermid Syndrome (PMDS) is a progressive neurodevelopmental disorder, characterized by hypotonia, global developmental delay, severely impaired to absent speech, intellectual disability, and autism spectrum disorders (ASDs). PMDS is a genetic disorder caused by the micro deletions in the pretelomeric region of chromosome 22. The goal of this project is to identify cellular and molecular abnormalities associated with neurological defects in patients with PMDS and ASDs. As starting material we use skin cells collected from PMDS patients. We reprogram skin cells into induced pluripotent stem cells (iPSCs) (which are cells that have the potential to differentiate into several different types of cells,) and then iPSCs into neurons. Studying properties of iPSCs-derived neurons from patients and controls, we are aiming to find the original genetically-based source of the problems at cellular and molecular levels. Results of this research will substantially advance our current understanding of neurobiology associated with PMDS and ASDs in humans, and the role of different genes in the development of specific cellular abnormalities. In addition, this project will provide valuable information on new therapeutic targets for future pharmacological intervention to reverse neurological defects in patients with PMDS and ASDs.
Nina Leezenbaum/Dr. Jana Iverson: University of Pittsburgh
Postural and Vocal Development during the First Year of Life in Infants at Heightened Biological Risk for AS
During the first 12 months of life, infants achieve a series of milestones in postural (e.g., independent sitting) and vocal (e.g., babbling) development. Difficulties with postural control and delayed language and communication development are common among young children with ASD. Therefore, identifying disruptions in postural and vocal development in infancy may help predict later ASD diagnosis. This research has the potential to help detect indicators of risk for ASD at a significantly earlier point in development than is currently possible, which will allow for early initiation of treatment services. It is also focused on milestones that both parents and physicians can easily be trained to identify thus making it highly useful in populations less trained to recognize more subtle early warning signs of autism.
Jennifer Moriuchi/Dr. Ami Klin: Emory University Marcus Autism Center
Gender and Cognitive Profile as Predictors of Functional Outcomes in School-Aged Children with ASD
This project will examine and analyze how children with ASD pay attention to social scenes and cues in a school environment, noting the differences in children with high vs. low IQ and comparing males vs. females. The goal is to use this data to design school settings that meet the unique and specific needs of a wide range of children with autism. It will also help us understand why some children respond to certain types of treatment while others don’t. In addition, it targets the unique needs of two traditionally underrepresented groups in autism research; girls and children with severe intellectual disability.
Rebecca Simon/Dr. Karen Bales: University of California, Davis
The Role of Serotonin in Social Bonding in Animal Models
A high level of serotonin in blood is the most consistent neurochemical change seen in autism and in family members of those with autism. In addition, the neuropeptide oxytocin is increasingly being studied and utilized as a therapeutic treatment in individuals with autism as well as being an important component in mediating social behavior. While it is known that serotonin stimulates oxytocin release, the relationship between serotonin and oxytocin has been little studied with regard to its effects on social behavior. Some commonly used antidepressants such as Prozac, which typically act to increase serotonin availability, have been increasingly used during pregnancy over the past decades, and have been identified as a significant risk factor for autism, perhaps contributing to the increase in autism prevalence This study will investigate the role of serotonin-oxytocin interactions in social behavior in two monogamous animal species, the titi monkey and the prairie vole. In three experiments, we will examine the effects of prenatal exposure to antidepressants and chronic pharmacological activation of inhibitory serotonin receptors on social behavior, and differences in receptor distribution in the brain by sex and social status. By studying these processes it may be possible to define a mechanism tying in the high serotonin found in autism with the mechanism of autism brain development.