This is a competitive renewal application of the Wayne State Principal Investigator's (Rosenberg) grant award, R01MH59299. Obsessive compulsive disorder (OCD) is a severe, prevalent, and chronically disabling disorder that emerges during childhood in as many as 50% of all cases. The overall goal of this project, which combines the unique clinical assessment, magnetic resonance imaging, and genetics expertise of three performance sites - Wayne State (neuroimaging of pediatric OCD), University of Michigan (family and molecular genetic studies of early-onset OCD) and University of Toronto (extensive genetic studies of glutamate receptor and transporter genes in OCD) - is to exploit the emerging field of imaging genetics in a critical test of the glutamate hypothesis of OCD. Preliminary studies from Rosenberg's group (R01MH59299, K24MH02037) suggest that a glutamatergically-mediated thalamocortical-striatal dysfunction may serve as a pathophysiological marker in pediatric OCD. Independent findings by the Hanna (R01MH53876, K20MH01065) and the Arnold and Kennedy groups demonstrate a significant association of the glutamate transporter gene, SLC1A1, and glutamate receptor gene, GRIN2B, with early-onset OCD. Building on long-standing existing collaborations among the three sites, exciting new pilot data in pediatric OCD patients demonstrates a significant association between regional brain glutamatergic concentrations, particularly in the anterior cingulate and the GRIN2B-rs1019385 polymorphism. Significant associations between increased left, but not right orbital frontal and increased anterior cingulate volume (R>L) with the rs1805476 variant of GRIN2B were identified in OCD patients. The GRIN2B-rs1019385 variant exhibited a non-significant trend towards association with decreased left but not right caudate volume. The SLC1A1 rs3056-AA genotype was significantly associated with increased right and left thalamic volume. Thus, GRIN2B and SLC1A1 sequence variations may be associated with differences in volume and glutamatergic concentrations within brain regions implicated in the pathogenesis of OCD. High field (3 Tesla) proton magnetic resonance spectroscopy (1H MRS) can uniquely distinguish the subcomponents of the glutamatergic resonance (glutamate and glutamine), as well as measure other compounds including the putative neuronal marker, N-acetyl-aspartate, choline compounds and creatine. Targeted 1H MRS and volumetric imaging at 3T at the Children's Hospital of Michigan at Wayne State will be combined with genotyping of 37 polymorphisms in the genes encoding GRIN2B and SLC1A1 (University of Toronto) to examine the effects of these variants on thalamocortical-striatal circuitry in 200 pediatric OCD patients, 7-19 years, and 200 age and sex-matched healthy controls. The combined study of biological, genetic and behavioral/symptom variables enacts the call for translational approaches to mental illness outlined in PA-07- 092, Collaborative R01s for Clinical and Services Studies of Mental Disorders, which may lead to a better understanding of pediatric OCD and, in turn, to new diagnostic and treatment approaches.

Public Health Relevance

Obsessive-compulsive disorder (OCD) is a chronic and disabling disorder that costs the economy over $2 billion annually and affects approximately one million children and adolescents in the United States, making it a significant public health problem. There is a pressing need for studies that shed light on the biology of the disorder in order to improve our ability to diagnose, treat, and prevent the disorder. By combining brain imaging and genetics, as we do in this proposal, we can better understand the biology of pediatric OCD and, in turn, develop more effective treatments for this severe form of childhood psychopathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085321-04
Application #
8278047
Study Section
Special Emphasis Panel (ZRG1-BBBP-L (60))
Program Officer
Grabb, Margaret C
Project Start
2009-09-11
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$385,001
Indirect Cost
$132,614
Name
University of Michigan Ann Arbor
Department
Psychiatry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Kujawa, Autumn; Swain, James E; Hanna, Gregory L et al. (2016) Prefrontal Reactivity to Social Signals of Threat as a Predictor of Treatment Response in Anxious Youth. Neuropsychopharmacology 41:1983-90
Hanna, Gregory L; Gehring, William J (2016) The NIMH Research Domain Criteria initiative and error-related brain activity. Psychophysiology 53:386-8
Yu, Dongmei; Mathews, Carol A; Scharf, Jeremiah M et al. (2015) Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD. Am J Psychiatry 172:82-93
Sampaio, Aline Santos; Hounie, Ana Gabriela; Petribú, Kátia et al. (2015) COMT and MAO-A polymorphisms and obsessive-compulsive disorder: a family-based association study. PLoS One 10:e0119592
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
Hanna, Gregory L (2015) Comorbid tics have no effect on response to cognitive-behavioral therapy in youth with obsessive-compulsive disorder. Evid Based Ment Health 18:85
Carrasco, Melisa; Hong, Christina; Nienhuis, Jenna K et al. (2013) Increased error-related brain activity in youth with obsessive-compulsive disorder and other anxiety disorders. Neurosci Lett 541:214-8
Wu, Ke; Hanna, Gregory L; Easter, Philip et al. (2013) Glutamate system genes and brain volume alterations in pediatric obsessive-compulsive disorder: a preliminary study. Psychiatry Res 211:214-20
Hanna, Gregory L; Carrasco, Melisa; Harbin, Shannon M et al. (2012) Error-related negativity and tic history in pediatric obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 51:902-10
Wu, Ke; Hanna, Gregory L; Rosenberg, David R et al. (2012) The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder. Pharmacol Biochem Behav 100:726-35

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