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 #
5R01MH081023-05
Application #
8423027
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Gilotty, Lisa
Project Start
2009-05-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$360,142
Indirect Cost
$99,643
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
Di Martino, A; Yan, C-G; Li, Q et al. (2014) The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism. Mol Psychiatry 19:659-67
Nair, Aarti; Keown, Christopher L; Datko, Michael et al. (2014) Impact of methodological variables on functional connectivity findings in autism spectrum disorders. Hum Brain Mapp 35:4035-48
Fishman, Inna; Keown, Christopher L; Lincoln, Alan J et al. (2014) Atypical cross talk between mentalizing and mirror neuron networks in autism spectrum disorder. JAMA Psychiatry 71:751-60
Keown, Christopher Lee; Shih, Patricia; Nair, Aarti et al. (2013) Local functional overconnectivity in posterior brain regions is associated with symptom severity in autism spectrum disorders. Cell Rep 5:567-72
Nair, Aarti; Treiber, Jeffrey M; Shukla, Dinesh K et al. (2013) Impaired thalamocortical connectivity in autism spectrum disorder: a study of functional and anatomical connectivity. Brain 136:1942-55
Keehn, Brandon; Muller, Ralph-Axel; Townsend, Jeanne (2013) Atypical attentional networks and the emergence of autism. Neurosci Biobehav Rev 37:164-83
Cardinale, Ryan C; Shih, Patricia; Fishman, Inna et al. (2013) Pervasive rightward asymmetry shifts of functional networks in autism spectrum disorder. JAMA Psychiatry 70:975-82
Shih, Patricia; Keehn, Brandon; Oram, Jessica K et al. (2011) Functional differentiation of posterior superior temporal sulcus in autism: a functional connectivity magnetic resonance imaging study. Biol Psychiatry 70:270-7
Shukla, Dinesh K; Keehn, Brandon; Müller, Ralph-Axel (2011) Tract-specific analyses of diffusion tensor imaging show widespread white matter compromise in autism spectrum disorder. J Child Psychol Psychiatry 52:286-95
Muller, Ralph-Axel; Shih, Patricia; Keehn, Brandon et al. (2011) Underconnected, but how? A survey of functional connectivity MRI studies in autism spectrum disorders. Cereb Cortex 21:2233-43

Showing the most recent 10 out of 14 publications