This Mentored Patient-Oriented Research Career Development Award is designed to provide specialized training in the skills necessary to become an independent investigator in the emerging field of translational developmental neuroscience focusing on the neurobiology of autism. The candidate is a child and adolescent psychiatrist and pediatric neurologist experienced in the assessment and treatment of children with autism. The need for novel specific treatments to address the profound impairments of individuals with autism requires an understanding of the underlying pathophysiology and motivates the proposed training plan to (1) develop expertise in functional brain imaging techniques optimized to examine developmentally relevant questions in children and adolescents;(2) become knowledgeable regarding developmental science methods applied in (a) longitudinal follow-up studies of autism spectrum disorder;(b) typical and atypical social development in non- human primates;and (c) in-depth quantitative analyses of typical developmental trajectories;and (3) gain expertise in general statistical methods and research design. In conjunction with pertinent formal coursework, individualized mentoring, and active participation in scientific conferences, this training program will be complemented by conducting the proposed research plan which is grounded in the overarching thesis that autism represents a neurodevelopmental dysconnection syndrome characterized by reduced long-range and increased short-range connectivity. Cortico-cortical functional connectivity (FC), defined as the temporal correlations between remote neurophysiological events, has not been systematically studied in children and adolescents with autism. Our lab has developed a method for quantifying FC from fMRI data obtained without a task (at rest) that is exquisitely sensitive to developmental differences. As a first step towards delineating the maturational trajectories of brain FC in autism, we propose to examine the cross-sectional development of FC of the pregenual anterior cingulate cortex (pgACC) in children and adolescents. We selected the pgACC network because of its involvement in social processes, preliminary reports of structural and functional abnormalities in autism, and its prolonged maturational course. These considerations inform the hypothesis of this proposal that the derangements in FC within the pgACC network in autism reflect a fundamental failure of brain maturation. Further, we posit that social impairment in autism can be directly related to abnormal pgACC connectivity. Thus, we propose to examine brain FC in 40 male children and adolescents with high-functioning full autism (HFA) compared to equal numbers of age-, sex-, handedness-, and IQ-matched healthy controls.
Our aims are to (1) use resting state fMRI to examine differences in short- and long-range FC in the pgACC network between individuals with HFA and controls, from ages 8.0-17.9 years;(2) test the relationship between social impairment, as indexed by Autism Diagnostic Observation Scale Social Interaction Total Score and measures of short- and long-range FC in the pgACC network in the HFA group;and (3) examine the rates of age-related decreases in short-range FC and age- related increases in long-range FC in the pgACC network in controls and HFA. The performance of the proposed research plan combined with the extensive resources of the institutional environment and the strong institutional support for the candidate's continued professional development will provide the basis for future longitudinal proposals that will increasingly inform our understanding of the pathophysiology of autism and related disorders of neurodevelopment.

Public Health Relevance

This is a Mentored Patient-Oriented Research Career Development Award designed to provide specialized training in the skills needed to become an independent investigator in the new field of developmental neuroscience with a focus on identifying and understanding the neuronal circuits that are abnormal in autism. The proposed research project introduces novel techniques for studying brain circuits involved in social functioning in children and adolescents with autism in comparison to typically developing children. This project has the potential to inform our understanding of the neural bases of autism, which is needed to improve early identification, refine diagnostic assessments, and yield novel treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23MH087770-04
Application #
8373888
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Gilotty, Lisa
Project Start
2010-01-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$167,187
Indirect Cost
$12,384
Name
New York University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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
Adamo, Nicoletta; Huo, Lan; Adelsberg, Samantha et al. (2014) Response time intra-subject variability: commonalities between children with autism spectrum disorders and children with ADHD. Eur Child Adolesc Psychiatry 23:69-79
Hulvershorn, Leslie A; Mennes, Maarten; Castellanos, F Xavier et al. (2014) Abnormal amygdala functional connectivity associated with emotional lability in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 53:351-61.e1
Alaerts, Kaat; Woolley, Daniel G; Steyaert, Jean et al. (2014) Underconnectivity of the superior temporal sulcus predicts emotion recognition deficits in autism. Soc Cogn Affect Neurosci 9:1589-600
Craddock, R Cameron; Jbabdi, Saad; Yan, Chao-Gan et al. (2013) Imaging human connectomes at the macroscale. Nat Methods 10:524-39
Castellanos, F Xavier; Di Martino, Adriana; Craddock, R Cameron et al. (2013) Clinical applications of the functional connectome. Neuroimage 80:527-40
Yan, Chao-Gan; Cheung, Brian; Kelly, Clare et al. (2013) A comprehensive assessment of regional variation in the impact of head micromovements on functional connectomics. Neuroimage 76:183-201
Di Martino, Adriana; Zuo, Xi-Nian; Kelly, Clare et al. (2013) Shared and distinct intrinsic functional network centrality in autism and attention-deficit/hyperactivity disorder. Biol Psychiatry 74:623-32
Chabernaud, Camille; Mennes, Maarten; Kelly, Clare et al. (2012) Dimensional brain-behavior relationships in children with attention-deficit/hyperactivity disorder. Biol Psychiatry 71:434-42
Mennes, Maarten; Zuo, Xi-Nian; Kelly, Clare et al. (2011) Linking inter-individual differences in neural activation and behavior to intrinsic brain dynamics. Neuroimage 54:2950-9

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