Obsessive-compulsive (OC) behaviors are common in youth. They are the core features of obsessive- compulsive disorder (OCD) and are often associated in youth with tic and grooming disorders, generalized anxiety disorder, and autistic spectrum disorder. This proposal is submitted in response to RFA-MH-13-080, Dimensional Approaches to Research Classification in Psychiatric Disorders, since it will examine OC behaviors and the error-related negativity (ERN) as a measure of performance monitoring - a cognitive control construct in the cognitive systems domain of the Research Domain Criteria (RDoC) matrix - in child psychiatric outpatients. The overall goal of this project - which combines our expertise in child psychopathology, psychophysiology, and genetics - is to use the ERN as an index of a neural circuit involving the anterior cingulate cortex (ACC) and pre-supplementary motor area, as well as recent advances in exome arrays and whole genome sequencing (WGS), to identify risk factors for OC behaviors characterized by the Child Behavior Checklist OC Scale (CBCL-OCS). Both the CBCL-OCS and ERN show substantial heritability in pediatric twin studies. Although progress has been made in identifying electrophysiological and genetic factors associated with OC behaviors, little of the genetic variance has been explained and the neurobiological consequences of those variants are poorly understood. As with other complex traits, there is a growing consensus that gene discovery can be facilitated by using endophenotypes, which lie on the causal pathway between genetic risk factors and symptoms. Numerous studies have demonstrated that an enlarged ERN is a state-independent trait found in patients with OC behaviors and their unaffected relatives at a higher rate than in the general population, providing strong support for the ERN as a candidate endophenotype for OC behaviors. Consistent with the RDoC project, the ERN will be examined first in 150 child psychiatric outpatients with prominent OC behaviors, 150 child psychiatric outpatients with negligible OC behaviors, and 150 matched healthy controls ages 8-18 years to delineate the relationship of the ERN to OC behaviors in youth, using tic history and depression severity as covariates. Second, common and rare exonic variants associated with ERN amplitude will be identified in a sample of 550 subjects (including 100 subjects already collected), using an exome array with extensive coverage of exonic markers. Third, WGS will be done in subjects with ERN amplitudes in the highest 5% of the distribution to identify rare and novel variants of possible clinical significance. Fourth, the role of the ERN as an endophenotype will be clarified by assessing whether the ERN mediates the effects of genetic variants on OC behaviors. This study will examine multiple variants in an important neural circuit for goal-directed behavior in a spectrum of common but understudied disorders in youth. Our work will provide a better understanding of ACC dysregulation in the pathogenesis of childhood OC behaviors and lead to new prevention and treatment strategies.
Obsessive-compulsive (OC) behaviors are common in youth and are often associated with severe forms of childhood psychopathology. There is a pressing need for studies that shed light on the pathogenesis of these behaviors and that improve our ability to diagnose, treat, and prevent the disorders associated with them. By combining electrophysiology and genetics, we can better understand the vulnerability to OC behaviors and, in turn, develop more effective treatments for these severe forms of childhood psychopathology.
|Diwadkar, Vaibhav A; Burgess, Ashley; Hong, Ella et al. (2015) Dysfunctional Activation and Brain Network Profiles in Youth with Obsessive-Compulsive Disorder: A Focus on the Dorsal Anterior Cingulate during Working Memory. Front Hum Neurosci 9:149|