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2012 Grant Outcomes Report
2012 Grant Outcomes Report
The following posters have been presented at scientific conferences regarding research conducted with 2012 grants:
Higashimori H., Morel L., Yang Y. (2012) Loss of Astroglial FMRP Induces GLT1 dysregulation and Enhanced Neuronal Excitability in Fragile X Syndrome (FXS). Fragile X and Autism-related Disorders Gordon Research Conference June 2012. Recipient of “Best Poster Award”
Higashimori H., Morel L., Bedor T., Yang Y. (2011) Dysfunctional astrocyte neuron communication in genetic model of Fragile X Syndrome (FXS). Society of Neuroscience Abstracts 2011
Levin A.R., Vogel-Farley, V., Tager-Flusberg, H., Nelson, C.A. (2013, May). Resting State Quantitative EEG Differences At 3 Years of Age by Risk Status and Diagnostic Outcome for Autism Spectrum Disorders. Poster presented at the International Meeting for Autism Research (IMFAR), San Sebastian, Spain.
Levin A.R., Vogel-Farley, V., Tager-Flusberg, H., Nelson, C.A. Resting state alpha power differences in adults with autism spectrum disorders are not present in toddlers. Abstract accepted for poster presentation at the Child Neurology Society Annual Meeting, Austin, Tx in October 2013.
Moriuchi, J. M., Klin, A., & Jones, W. (2013, April). Sex differences in dynamic visual scanning patterns in school-age children with autism spectrum disorders. Oral presentation given at the International Meeting for Autism Research, San Sebastien, Spain.
Moriuchi, J. M., Klin, A., & Jones, W. (2013, May). Sex differences in visual fixation patterns in school-age children with autism spectrum disorders. Poster presented at the biennial meeting of the Society for Research in Child Development, Seattle, WA.
The following presentations have been given on research conducted with 2012 grants:
Levin, A.R. (2013, May) Neural Rhythms in Autism Spectrum Disorders. Invited presentation given for the Cognitive Rhythms Collaborative (CRC), Boston, MA.
Additional funding obtained by pre- and postdoctoral fellows as a result of 2012 ASF grants:
A 2013 American Brain Foundation Clinical Research Training Fellowship. This fellowship provides two years of salary and tuition support to expand upon the findings described above, using advanced signal processing techniques to move from assessing risk for autism at the level of the group to assessing risk at the level of the individual.
Successful renewal of Fragile X Foundation post-doctoral training award for 2013-2014 period.
Preliminary findings from research conducted with 2012 grants:
Grantee Name: Haruki Higashimori
Mentor Name: Yang Yongjie
Grant Title: Role of astrocytic glutamate transporter GLT1 in Fragile X Syndrome
Sponsoring University: Tufts university
Grant period dates: July 1st 2012 to June 30 2013
The brain contains not only neurons, but also support cells called glia. The developmental role of glial cells in the brain is not well understood, but one crucial function that glial cells called astrocytes perform is to maintain low levels of the excitatory neurotransmitter glutamate. This prevents over-activation of glutamate receptors, which could lead to epileptic activity or neuronal cell death.
Glutamate uptake is done by an abundant glutamate transporter, GLT1 (EAAT2 in humans), located on astrocytes that surround synapses. We have found that GLT1 transporter dysfunction can diminish glutamate uptake in the mouse model of Fragile X Syndrome (FXS). The cortical astrocytes in these animals have fewer GLT1 transporters and subsequently show cortical neuron hyper-excitability. The number of GLT1 transporters, as well as their function, normally increases in response to neuronal activity that stimulates metabolic glutamate receptors (mGluR5) on astrocytes. To determine the cause of GLT1 dysfunction in FXS, we first confirmed that astrocytes express the Fragile X Mental Retardation Protein (FMRP) during development, and then discovered that astrocytic FMRP is responsible for regulating astrocytic mGluR5 protein translation and function. Using genetically modified mice that have a 50% reduction in GLT1 expression (similar to levels observed in FXS mice), we found that GLT1 reduction reproduces the dendritic spine abnormalities and hyper-excitability seen in fragile X. We further tested our hypothesis by restoring normal GLT1 function with the available drug, ceftriaxone. Rescuing GLT1 function in FXS animals resulted in restoration of neuronal excitability and spine density comparable to normal animals.
Preliminary findings from research conducted with 2012 grants: (continued)
Grantee Name: April R. Levin M.D.
Mentor Name: Charles A. Nelson Ph.D.
Grant Title: Identifying Early Biomarkers for Autism Using EEG Connectivity
Sponsoring University: Boston Children’s Hospital
Grant period dates: 7/1/12 – 6/30/13
Given the promising preliminary findings described in the interim progress report, we have continued to evaluate resting EEG data for differences in findings between infants at high and low risk for autism spectrum disorders, and between infants who do and do not later receive a diagnosis of ASD. These evaluations have resulted in the following findings:
Previous studies1 in adults have demonstrated higher resting-state EEG alpha power in adults with autism spectrum disorders (ASD) than in typically developing (TD) adults, in multiple regions. We replicated this study in our sample, but found that children who developed ASD showed no differences in alpha power compared to TD children from either the HRA or LRC groups, in any of the regions previously shown to demonstrate between-group differences in adults (left and right frontal and posterior), at any of the ages tested. Thus EEG-based differences in the alpha band of the power spectrum seen in ASD versus TD adults are not present in children at or prior to the time when ASD is frequently diagnosed. This suggests that electrophysiological differences between ASD and TD groups change over the course of development. Because of these changes over time, EEG analysis techniques that differentiate children who will and will not develop ASD may be different from EEG analysis techniques that differentiate adults with and without ASD.
At 36 months, children who develop autism trend towards more frontal EEG asymmetry in the high alpha band than both high and low risk children who do not develop autism.
At 12 months, children who develop autism have higher alpha power at the C3 and C4 electrodes (over sensorimotor cortex) than both high and low risk children who do not develop autism. Because our resting EEG was in fact collected while infants watched another person perform a motor activity (blowing bubbles), it is possible that this finding represents a lack of mu suppression in 12 month olds who develop ASD. This is of interest because the mu rhythm has been hypothesized to reflect mirror neuron activity 2 and has been shown to be altered in older children with ASD 3
1. Mathewson KJ, Jetha MK, Drmic IE, Bryson SE, Goldberg JO, Schmidt L a. Regional EEG alpha power, coherence, and behavioral symptomatology in autism spectrum disorder. Clin Neurophysiol International Federation of Clinical Neurophysiology; 2012;123:1798–809.
2. Nyström P, Ljunghammar T, Rosander K, Von Hofsten C. Using mu rhythm desynchronization to measure mirror neuron activity in infants. Developmental Science 2010;2:no–no.
3. Oberman LM, Ramachandran VS, Pineda J a. Modulation of mu suppression in children with autism spectrum disorders in response to familiar or unfamiliar stimuli: the mirror neuron hypothesis. Neuropsychologia 2008;46:1558–65.
Preliminary findings from research conducted with 2012 grants: (continued)
Grantee Name: Jennifer Moriuchi
Mentor Name: Ami Klin, PhD
Grant Title: Gender and cognitive profile as predictors of functional outcomes in school-aged children with ASD
Sponsoring University: Emory University
Grant period dates: 7/1/2012 – 6/30/2013
To help promote individualized interventions tailored to a child’s specific strengths and weaknesses, our project sought to better understand factors associated with positive functional outcomes in school-age children with autism spectrum disorders (ASD). In order to parse apart the broad phenotypic heterogeneity observed in ASD, we are identifying social learning strategies associated with positive outcomes in specific subgroups stratified by sex and cognitive profile. In particular, we sought to focus on girls with ASD and children with intellectual disability, two populations generally underrepresented in ASD research. To describe social learning strategies and gain a deeper understanding of how children are parsing their surrounding social world, we are using quantitative methods to analyze eye-tracking data and examine how children attend to naturalistic social scenes on a moment-by-moment basis.
Our current sample includes 159 children with ASD and 43 typically-developing (TD) children. In addition to children previously evaluated at the Yale Child Study Center, twenty-four newly recruited participants, including 16 children with ASD, 6 TD children, and 2 children with non-ASD developmental disabilities, completed the study protocol at the Marcus Autism Center within the past year. To aid our experimental success in collecting eye-tracking data, we collaborated with clinicians at Marcus to develop an eye-tracking desensitization protocol for school-age children, similar to protocols used to promote successful MRI data collection. To date, we have an overall 87% success rate in collecting usable eye-tracking data with school-age children, and with the help of the desensitization protocol, we were able to collect viewing data with several children who may previously have been excluded due to difficult behaviors.
Within our full current sample, we have found that our measures of visual scanning collected during viewing of naturalistic social scenes serve both as a categorical diagnostic marker and as a dimensional index of social disability. The degree of convergence with normative patterns of visual scanning predicted diagnostic group with 92% sensitivity and 88% specificity. In addition, the degree of convergence was associated with both level of social disability and level of everyday social adaptive skills; more convergent visual scanning predicted less social disability and better adaptive social skills in children with ASD. The result suggests that our visual scanning measure may help to serve as a performance-based measure with diagnostic and prognostic implications in school-age children across a broad range of functioning. We are continuing to recruit participants to attempt to validate these findings in an independent sample of children with ASD.
In addition, we found that sex and cognitive profile appear to interact in determining predictors of positive outcomes in school-age children with ASD. Within our sample of boys and girls matched on age, sex and cognitive profile interacted to moderate the social adaptive value of fixation on eyes regions during viewing of social scenes. There was a significant sex difference in the proportion of participants with a large discrepancy between their verbal and nonverbal abilities, and among those with an even cognitive profile, sex significantly moderated the association between the amount of eyes fixation and level of social disability. Whereas more eyes fixation predicted less social disability in boys, more eyes fixation predicted greater social disability in girls. Similarly, whereas increased convergence with normative visual scanning patterns was associated with less social disability in boys, the same was not true in girls. Most striking was that we observed these differences in social adaptive value in boys and girls with ASD in the absence of broader differences in the distribution of visual fixations and, contrary to our initial hypothesis, in the absence of difference in the timing of divergence from normative visual scanning patterns. The results indicate that although we might see the same manifest behavior in boys and girls with ASD, those behaviors may be serving very different underlying functions. Consequently, interventions may not have the same efficacy for boys and girls with ASD. We are continuing to finalize our analyses to better understand these identified differences, in particular to measure differences in engagement when both boys and girls with ASD are looking at others’ eyes, but our current results highlight the fact that girls with ASD need to continue to be studied in their own right, since conclusions drawn from boys with ASD may not hold true for girls with the disorder.
The following information has been disseminated to the public in the form of press releases, interviews and other forms of media by young investigators who received ASF grants in 2012:
Autism Speaks. (2013, May 3). Boys and girls with autism use gaze differently in social situations [Press release]. Retrieved from http://www.autismspeaks.org/science/science-news/boys-and-girls-autism-use-gaze-differently-social-situations
Gordon, S. (2013, May 1). Girls with autism may need different treatments than boys. HealthDay. Retrieved from http://health.usnews.com/health-news/news/articles/2013/05/01/girls-with-autism-may-need-different-treatments-than-boys
Singer, E. (2013, May 4). Gender differences take center stage at autism conference. Simons Foundation Autism Research Initiative. Retrieved from http://sfari.org/news-and-opinion/conference-news/2013/international-meeting-for-autism-research-2013/gender-differences-take-center-stage-at-autism-conference
Wang, S. S. (2013, May 7). How autism is different in girls vs. boys. The Wall Street Journal. Retrieved from http://online.wsj.com/article/SB10001424127887324326504578466920841542396.html