While in the past autism research has often been dedicated to a single core deficit or localized brain defect, growing evidence suggests that autism is a """"""""distributed disorder"""""""" involving many genes and neuroanatomical loci, and many neurofunctional and behavioral systems. The resulting need for studies of network organization and brain connectivity is hampered by our lack of (i) a precise understanding of what impaired functional connectivity (""""""""underconnectivity"""""""") in autism means, and (ii) a model integrating evidence of abnormal local cortical architecture with evidence of """"""""underconnectivity"""""""". Children with autism (ages 13-17 years) and matched typically developing children will participate in neuropsychological testing, diffusion tensor imaging (DTI), and functional MRI (fMRI) experiments during performance on two simple sensory tasks (visual, auditory) and a more complex lexico-semantic language task. Event-related fMRI designs will allow us to identify activation peaks in primary visual and auditory cortices, primary motor cortex, and left inferior frontal cortex. These activation peaks will be further used for functional connectivity (fcMRI) analyses, testing for time series correlations across the brain. According to our overarching hypothesis, reduced activation concordance (reflecting compromised local cortical organization) will be associated with reduced interregional connectivity (functional, anatomical), reduced white matter integrity, and with impaired neuropsychological performance in autism.
Four specific aims will test hypotheses for the autism group of (i) reduced concordance of activity in core activation sites (fMRI), (ii) correlation between functional connectivity (fcMRI) and activation concordance, (iii) correlations of anatomical connectivity and white matter integrity (DTI) with local activation concordance and functional connectivity, and (iv) correlations between imaging (concordance, connectivity) and neuropsychological measures. Establishing links between cognitive-behavioral impairment, local cortical compromise, functional connectivity, and anatomical connectivity will have translational relevance in at least two respects. First, it promises to unite several currently separate lines of neurodevelopmental research in autism that may be the foundation for therapeutic advances;and second, it will provide an approach to characterizing neurofunctionally defined endophenotypes of autism, in support of identifying subtypes of genetic risk within the population.

Public Health Relevance

Narrative Autism is a pediatric health issue of growing urgency. Genetic approaches require the identification of biologically defined subtypes (endophenotypes), to which this project will contribute by examining links between local cortical organization, brain connectivity, and cognition in children with autism, using several types of magnetic resonance imaging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH081023-04
Application #
8211051
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Gilotty, Lisa
Project Start
2009-05-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$370,304
Indirect Cost
$99,609
Name
San Diego State University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182
Nair, Sangeeta; Jao Keehn, R Joanne; Berkebile, Michael M et al. (2018) Local resting state functional connectivity in autism: site and cohort variability and the effect of eye status. Brain Imaging Behav 12:168-179
Linke, Annika C; Jao Keehn, R Joanne; Pueschel, Ellyn B et al. (2018) Children with ASD show links between aberrant sound processing, social symptoms, and atypical auditory interhemispheric and thalamocortical functional connectivity. Dev Cogn Neurosci 29:117-126
Abbott, Angela E; Linke, Annika C; Nair, Aarti et al. (2018) Repetitive behaviors in autism are linked to imbalance of corticostriatal connectivity: a functional connectivity MRI study. Soc Cogn Affect Neurosci 13:32-42
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Dickie, Erin W; Ameis, Stephanie H; Shahab, Saba et al. (2018) Personalized Intrinsic Network Topography Mapping and Functional Connectivity Deficits in Autism Spectrum Disorder. Biol Psychiatry 84:278-286
Jao Keehn, R Joanne; Sanchez, Sandra S; Stewart, Claire R et al. (2017) Impaired downregulation of visual cortex during auditory processing is associated with autism symptomatology in children and adolescents with autism spectrum disorder. Autism Res 10:130-143
Keehn, Brandon; Westerfield, Marissa; Müller, Ralph-Axel et al. (2017) Autism, Attention, and Alpha Oscillations: An Electrophysiological Study of Attentional Capture. Biol Psychiatry Cogn Neurosci Neuroimaging 2:528-536
Di Martino, Adriana; O'Connor, David; Chen, Bosi et al. (2017) Enhancing studies of the connectome in autism using the autism brain imaging data exchange II. Sci Data 4:170010
Keown, Christopher L; Datko, Michael C; Chen, Colleen P et al. (2017) Network organization is globally atypical in autism: A graph theory study of intrinsic functional connectivity. Biol Psychiatry Cogn Neurosci Neuroimaging 2:66-75
Jahedi, Afrooz; Nasamran, Chanond A; Faires, Brian et al. (2017) Distributed Intrinsic Functional Connectivity Patterns Predict Diagnostic Status in Large Autism Cohort. Brain Connect 7:515-525

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