The behavioral and cognitive deficits of autism are underpinned by both structural and functional maldevelopment in the young brain. While structural abnormalities in the first few years of life have been studied, producing a wealth of information and new theories about the disorder, functional abnormalities have thus far been relatively unexplored due to the expected difficulties in imaging such a young age cohort. Preliminary work completed by this laboratory, however, demonstrates that it is possible to use sleep fMRI to study brain function in both autistic and typically developing toddlers. The results obtained thus far are consonant with both structural studies of the young brain and functional studies in older autistic subjects. In autistic toddlers hearing neutral speech, higher-order cortices display aberrant lateralization and unusual activation patterns that are similar to far younger typical toddlers, with abnormalities particularly marked in frontal, temporal and cerebellar cortices. Our cross-sectional studies of typical toddlers, meanwhile, suggest increased specialization of speech processing with a developmental shift from activation of bilateral frontal, temporal and cerebellar regions in 20 month olds to temporal cortex and right cerebellum by 3 years of age. We also show the feasibility of conducting fMRI studies of social and non-social orienting sounds in toddlers. We will conduct fMRI studies of the 30-month-old autistic toddler's neural responses to social and non- social;emotional and emotionally-neutral;and speech and non-speech sounds, as well as to basic visual stimuli. Our comparison groups will be mental age matched (18-month-old) and chronological age matched (30-month-old) typically developing toddlers. Each typically developing child will be imaged at both ages;this longitudinal design will allow us to also explore typical functional development, itself a nascent field of knowledge. Our functional findings will be correlated with behavioral, anatomical, developmental, and clinical data so as to assemble a picture of the complex interactions between brain structure, brain function, developmental trajectory, and behavior in both the autistic and typically developing brain. These pioneering studies will be among the first to pinpoint functional deficits in the autistic brain as close as possible to the onset of clinical symptoms, with implications for new models of the disorder, further study of its biological basis, the search for early diagnostic markers, and the development of novel therapies.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Child Psychopathology and Developmental Disabilities Study Section (CPDD)
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Gilotty, Lisa
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Courchesne, Eric; Pramparo, Tiziano; Gazestani, Vahid H et al. (2018) The ASD Living Biology: from cell proliferation to clinical phenotype. Mol Psychiatry :
Fingher, Noa; Dinstein, Ilan; Ben-Shachar, Michal et al. (2017) Toddlers later diagnosed with autism exhibit multiple structural abnormalities in temporal corpus callosum fibers. Cortex 97:291-305
Solso, Stephanie; Xu, Ronghui; Proudfoot, James et al. (2016) Diffusion Tensor Imaging Provides Evidence of Possible Axonal Overconnectivity in Frontal Lobes in Autism Spectrum Disorder Toddlers. Biol Psychiatry 79:676-84
Pramparo, Tiziano; Lombardo, Michael V; Campbell, Kathleen et al. (2015) Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers. Mol Syst Biol 11:841
Pramparo, Tiziano; Pierce, Karen; Lombardo, Michael V et al. (2015) Prediction of autism by translation and immune/inflammation coexpressed genes in toddlers from pediatric community practices. JAMA Psychiatry 72:386-94
Lombardo, Michael V; Pierce, Karen; Eyler, Lisa T et al. (2015) Different functional neural substrates for good and poor language outcome in autism. Neuron 86:567-77
Manning, Janessa H; Courchesne, Eric; Fox, Peter T (2013) Intrinsic connectivity network mapping in young children during natural sleep. Neuroimage 83:288-93
Eyler, Lisa T; Pierce, Karen; Courchesne, Eric (2012) A failure of left temporal cortex to specialize for language is an early emerging and fundamental property of autism. Brain 135:949-60
Dinstein, Ilan; Pierce, Karen; Eyler, Lisa et al. (2011) Disrupted neural synchronization in toddlers with autism. Neuron 70:1218-25
Courchesne, Eric; Mouton, Peter R; Calhoun, Michael E et al. (2011) Neuron number and size in prefrontal cortex of children with autism. JAMA 306:2001-10

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