Relationships between brain anatomy, brain chemistry and behavior/cognition will be characterized among children with autism in comparison to children with mental retardation and normal siblings of children from the two clinical groups. These relationships will be compared at 2 time points to assess underlying brain developmental processes hypothesized to be operative among children with autism. Specifically, in reference to the well-replicated imaging findings of increased brain volum in autism, if brain hypertrophy reflects hyperplasia arising from over-proliferation of neurons and/or disruption of apoptosis during the pre or perinatal periods, then group differences in brain anatomy/brain chemistry are expected to remain stable across the two time points. If, on the other hand, structure abnormalities reflect synaptic pruning abnormalities with onset during the preschool period, or gliosis, emergance or amplification of group differences is expected at the second time point. For samples of 60 children with autism, 40 children with mental retardation, and 20 age-matched normal siblings aged 3-4 years old, measures of brain anatomy from 2-D and 3-D and 3-D MRI, regional brain chemistry from 2-D proton echo-planar spectroscopic imaging (PEPSI) and behavior/cognition will be obtained. Children with autism and those with mental retardation will be followed longitudinally and these measures reassessed at 6-7 years of age. An additional group of normal siblings will be assessed at ages 6-7 to provide normative data. As part of this proposal, addditional normative brain volumetric data will be made available by Dr. Jay Giedd at the NIMH which will be used also to assess measurement reliability between sites. Morphometric analysis using intensity-based segmentation techniques, subregion segmentation and 3-D surface rendering techniques will be used to characterize subtle differences in brain anatomy. PEPSI will be used to examine regionally-specific differences in brain chemistry; for brain anatomical regions exhibiting structural abnormalities, brain chemistry patterns of N-acetyl asparatate (NIAA), choline, and lactate levels will help to distinguish whether such abnormalities will reflect neuronal as opposed to glial processes. Additionally, patterns of NAA change will help to distinguish abnormal synaptic pruning developmental processes. We predict that brain chemical abnormalities will map both to corresponding brain structural abnormalities and impairments on neuropsychological tasks assessing those brain regions. PEPSI measurements in combination with MRI is expected to be more sensitive and specific for demarcating subpopulations of children with autism than MRI detection of anatomical differences alone.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
United States
Zip Code
Iverson, Jana M; Northrup, Jessie B; Leezenbaum, Nina B et al. (2018) Early Gesture and Vocabulary Development in Infant Siblings of Children with Autism Spectrum Disorder. J Autism Dev Disord 48:55-71
Charman, Tony; Young, Gregory S; Brian, Jessica et al. (2017) Non-ASD outcomes at 36 months in siblings at familial risk for autism spectrum disorder (ASD): A baby siblings research consortium (BSRC) study. Autism Res 10:169-178
Corrigan, Neva M; Shaw, Dennis W W; Estes, Annette M et al. (2013) Atypical developmental patterns of brain chemistry in children with autism spectrum disorder. JAMA Psychiatry 70:964-74
Sterling, Lindsey; Munson, Jeffrey; Estes, Annette et al. (2013) Fear-potentiated startle response is unrelated to social or emotional functioning in adolescents with autism spectrum disorders. Autism Res 6:320-31
Jones, E J H; Webb, S J; Estes, A et al. (2013) Rule learning in autism: the role of reward type and social context. Dev Neuropsychol 38:58-77
Corrigan, Neva M; Shaw, Dennis W W; Richards, Todd L et al. (2012) Proton magnetic resonance spectroscopy and MRI reveal no evidence for brain mitochondrial dysfunction in children with autism spectrum disorder. J Autism Dev Disord 42:105-15
Fatemi, S Hossein; Aldinger, Kimberly A; Ashwood, Paul et al. (2012) Consensus paper: pathological role of the cerebellum in autism. Cerebellum 11:777-807
Vieland, Veronica J; Hallmayer, Joachim; Huang, Yungui et al. (2011) Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism. J Neurodev Disord 3:113-23
Pinto, Dalila; Pagnamenta, Alistair T; Klei, Lambertus et al. (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368-72
Kim, Jieun E; Lyoo, In Kyoon; Estes, Annette M et al. (2010) Laterobasal amygdalar enlargement in 6- to 7-year-old children with autism spectrum disorder. Arch Gen Psychiatry 67:1187-97

Showing the most recent 10 out of 15 publications