Autism Spectrum Disorder (ASD) is characterized by pervasive socio-emotional and cognitive deficits even in children with high intellectual function. Its neuropathophysiology involves executive dysfunction mediated by prefrontal cortex but is not well-understood, due to high phenotypic heterogeneity and comorbidity with attention and anxiety disorders and a lack of resolution in affected component processes of executive function. We postulate that symptom expression varies among ASD children due to the influence of traits that characterize comorbid disorders (impulsivity, anxiety). Examining differences in functional brain organization of executive control due to anxiety and impulsivity with sensitive fMRI probes will elucidate phenotypic heterogeneity in ASD children. Guided by developmental neuroanatomical models, we will examine multiple top-down control processes and bottom-up perceptual processes that function in adaptive balance to serve goal-directed behavior. We will test the hypothesis that specific prefrontal-striato- limbic circuits, which mediate that adaptive balance, are atypical in ASD. We will manipulate component operations of top-down (voluntary, involuntary) and bottom-up (attention bias to salience) processing in 9-12 year-old high-functioning ASD children and age, Verbal IQ, and gender matched controls. Group differences and individual variation by anxiety, impulsivity, and symptom severity will be examined with confirmatory (hypothesis-driven) and exploratory (data-driven) analysis of functional networks and underlying white-matter microstructure.
Aim I examines whether voluntary and involuntary control of attention is modulated by stimulus saliency (i.e., perceptual novelty, emotion) atypically in ASD. Exp 1 will examine incidental (involuntary) and intentional (voluntary) encoding of salient (novel/infrequent vs. familiar/repeated) distracters in the context of an ongoing task. Exp 2 will examine exogenous (involuntary) and endogenous (voluntary) attentional bias to salient faces (angry vs. neutral) in the Dot-probe task.
Aim 2 examines whether voluntary and involuntary control of responses is modulated by stimulus domain (social-emotional or non- social) atypically in ASD. Exp 3 will examine voluntary response control (response inhibition and interference suppression) and involuntary context adaptation during a Flanker task with symbolic (non-social) stimuli. Exp 4 will examine voluntary response control during conflict varying in socio-emotional significance in a Stroop-like task.
Aim 3 will examine whether intrinsic resting-state connectivity is atypical in ASD. Current research shows parallel functional organization during behavioral and resting states. We will search for resting-state correlates of component operations of executive control pooled by voluntary and involuntary conditions and domains (non-social, socio-emotional) from Exps 1-4 and determine whether they are atypical in ASD and vary by anxiety, impulsivity, and symptom severity. New knowledge from this proposal will refine models of ASD neuropathophysiology and provide targets for pharmacological and behavioral intervention.

Public Health Relevance

This project aims to elucidate individual differences in functional brain organization of higher cognition in 9-12 year old children with Autism Spectrum Disorders with normal intellectual function. It will use brain imaging to examine whether functional brain organization of executive function varies by anxiety and impulsivity that are reflected in symptoms of the disorder. Knowledge gained from proposed studies will refine clinical characterization and reveal new targets for pharmacological and behavioral treatment for Autism Spectrum Disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH084961-05
Application #
8447542
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Gilotty, Lisa
Project Start
2009-07-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$371,791
Indirect Cost
$98,743
Name
Georgetown University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Tasker, Robert C; Goodkin, Howard P; Sánchez Fernández, Iván et al. (2016) Refractory Status Epilepticus in Children: Intention to Treat With Continuous Infusions of Midazolam and Pentobarbital. Pediatr Crit Care Med 17:968-975
Murphy, Eric R; Norr, Megan; Strang, John F et al. (2016) Neural Basis of Visual Attentional Orienting in Childhood Autism Spectrum Disorders. J Autism Dev Disord :
Yerys, Benjamin E; Gordon, Evan M; Abrams, Danielle N et al. (2015) Default mode network segregation and social deficits in autism spectrum disorder: Evidence from non-medicated children. Neuroimage Clin 9:223-32
Yerys, Benjamin E; Antezana, Ligia; Weinblatt, Rachel et al. (2015) Neural Correlates of Set-Shifting in Children With Autism. Autism Res 8:386-97
Sepeta, Leigh N; Croft, Louise J; Zimmaro, Lauren A et al. (2015) Reduced language connectivity in pediatric epilepsy. Epilepsia 56:273-82
Wilmshurst, Jo M; Gaillard, William D; Vinayan, Kollencheri Puthenveettil et al. (2015) Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia 56:1185-97
Gordon, Evan M; Breeden, Andrew L; Bean, Stephanie E et al. (2014) Working memory-related changes in functional connectivity persist beyond task disengagement. Hum Brain Mapp 35:1004-17
Sanchez Fernandez, Ivan; Abend, Nicholas S; Agadi, Satish et al. (2014) Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG). Seizure 23:87-97
Supekar, Kaustubh; Uddin, Lucina Q; Khouzam, Amirah et al. (2013) Brain hyperconnectivity in children with autism and its links to social deficits. Cell Rep 5:738-47
Yerys, Benjamin E; Ruiz, Ericka; Strang, John et al. (2013) Modulation of attentional blink with emotional faces in typical development and in autism spectrum disorders. J Child Psychol Psychiatry 54:636-43

Showing the most recent 10 out of 15 publications