This revised competitive renewal of a longitudinal study of brain and behavioral development in young boys with Fragile X Syndrome (FXS), entitled "Longitudinal MRI Study of Brain Development in Fragile X (RO1 MH64708)", proposes continuation of a highly successful, collaborative study conducted by research teams at Stanford University (PI: Allan Reiss) and the University of North Carolina (PI: Joe Piven). FXS is an etiologically homogeneous developmental disorder and the most common single gene disorder associated with autistic behavior. Data from the initial grant cycle reveal a pattern of behaviors in FXS that differ from that seen in idiopathic autism (iAUT), with (a) prominent lower-order restricted, repetitive behaviors (RRB) such as perseveration, motor stereotypies and repetitive language;(b) less severe (than in iAUT) higher order RRB such as compulsions and rituals, and (c) less severe social and other communication deficits. Contrasting the pattern seen in iAUT, RRB show increasing severity over time and is significant association with functional impairment in individuals with FXS. This prominence of RRB in FXS is accompanied by parallel findings from MRI/DTI showing striking developmental abnormalities in striato-frontal and thalamo-frontal neural circuitry. Taken together these findings suggest that the emergence of abnormalities in striato-frontal and thalamo- frontal neural circuitry underlie the development of abnormalities in lower-order repetitive behaviors that have a prominent, negative impact on the function of children with FXS as they reach the school-age period. Clarification of the nature and timing of emergence of these brain and behavior abnormalities will be of critical importance in designing novel therapeutics for FXS and related disorders, and in measuring the efficacy of such interventions. We therefore propose a comprehensive battery to characterize RRB and striato- frontal/thalamo-frontal neuroanatomy (employing state-of-the-art MRI and diffusion tensor imaging), in 50 school-aged boys with FXS, 50 school-aged boys with iAut, 30 developmentally-delayed (non-syndromic, non- autistic) and 35 typically-developing boys at 7 - 12 years of age. These children received longitudinal brain and behavior assessments at 1-3 and, 24 months later at 3-5 years of age during the initial grant period. Perseverative, repetitive behaviors are typically cited as being among the most disruptive aspects of FXS and are commonly a primary focus of treatment in both iAUT and FXS. However, the phenomenology and neurobiology of RRB in FXS is an area that has received little research attention. This study thus provides a unique opportunity to elucidate the neurobiological basis and development of RRB in FXS and related disorders, and promises to generate results that will impact studies of pathogenesis and treatment as well as provide insights into the neurobiological basis of autistic behavior.

Public Health Relevance

"A Longitudinal MRI Study of Brain Development in Fragile X" is a proposal to study restricted, repetitive behaviors (RRB) in 7-12 year old boys with fragile X syndrome (FXS), using magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and a battery of assessments designed to evaluate repetitive behaviors (such as perseveration, motor stereotypes, and repetitive language). These repetitive behaviors are typically reported by families as being among the most disruptive aspects of FXS and are commonly a primary focus of treatment in both FXS and autism. This study will provide a unique opportunity to understand the neurobiological basis and development of RRB in FXS and related disorders, which will have important implications for treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH064708-06A1
Application #
8237612
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Gilotty, Lisa
Project Start
2001-12-01
Project End
2017-06-30
Budget Start
2012-07-05
Budget End
2013-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$901,844
Indirect Cost
$218,306
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Saggar, Manish; Vrticka, Pascal; Reiss, Allan L (2016) Understanding the influence of personality on dynamic social gesture processing: An fMRI study. Neuropsychologia 80:71-8
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Saggar, Manish; Shelly, Elizabeth Walter; Lepage, Jean-Francois et al. (2014) Revealing the neural networks associated with processing of natural social interaction and the related effects of actor-orientation and face-visibility. Neuroimage 84:648-56
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Kenna, Heather A; Tartter, Molly; Hall, Scott S et al. (2013) High rates of comorbid depressive and anxiety disorders among women with premutation of the FMR1 gene. Am J Med Genet B Neuropsychiatr Genet 162B:872-8

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