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 #
5R01MH059299-13
Application #
8274329
Study Section
Special Emphasis Panel (ZRG1-BBBP-L (60))
Program Officer
Grabb, Margaret C
Project Start
1999-08-20
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
13
Fiscal Year
2012
Total Cost
$522,847
Indirect Cost
$178,869
Name
Wayne State University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Taormina, Shibany P; Galloway, Matthew P; Rosenberg, David R (2016) Treatment Efficacy of Combined Sertraline and Guanfacine in Comorbid Obsessive-Compulsive Disorder and Attention Deficit/Hyperactivity Disorder: Two Case Studies. J Dev Behav Pediatr 37:491-5
Jagtap, Pranav; Diwadkar, Vaibhav A (2016) Effective connectivity of ascending and descending frontalthalamic pathways during sustained attention: Complex brain network interactions in adolescence. Hum Brain Mapp 37:2557-70
Thomason, Moriah E; Marusak, Hilary A; Tocco, Maria A et al. (2015) Altered amygdala connectivity in urban youth exposed to trauma. Soc Cogn Affect Neurosci 10:1460-8
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
Diwadkar, Vaibhav A (2015) Critical perspectives on causality and inference in brain networks: Allusions, illusions, solutions?: Comment on: "Foundational perspectives on causality in large-scale brain networks" by M. Mannino and S.L. Bressler. Phys Life Rev 15:141-4
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
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
Fallucca, Erin; MacMaster, Frank P; Haddad, Joseph et al. (2011) Distinguishing between major depressive disorder and obsessive-compulsive disorder in children by measuring regional cortical thickness. Arch Gen Psychiatry 68:527-33
MacMaster, Frank P; Rosenberg, David R (2010) THE USE OF GLUTAMATE MODULATING DRUGS IN OBSESSIVE COMPULSIVE DISORDER. Child Adolesc Psychopharmacol News 15:1-5
Macmaster, Frank P; Rosenberg, David R (2010) Glutamate and the Treatment of Obsessive-Compulsive Disorder. Psychopharm Rev 45:33-40

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