Study and re-study

DETROIT, Mich.—Seeking to find a way to stem the repetitiveactions, tics and "stimming" behavior of children suffering from obsessive-compulsivedisorder (OCD), researchers from Wayne State University (WSU), the Universityof Michigan and the Hospital for Sick Children/University of Toronto willexamine the role of glutamate in a study involving 400 children.

The NationalInstitute of Mental Health (NIMH) paved the way for the initial research with agrant of nearly $2.7 million, bringing the total award for OCD research to morethan $6.1 million.

This is the first-ever study in child psychiatry to combineimaging and genetics research on obsessive-compulsive disorder (OCD), a severe,prevalent and chronically disabling disease, said David Rosenberg, professor ofpsychiatry in the School of Medicine at WSU, and principal investigator.

OCD affects approximately 1 to 3 percent of the populationnationwide, with about 50 percent of all OCD cases beginning in childhood andadolescence, said Rosenberg, considered an international expert in childhoodOCD. The key to understanding the syndrome is glutamate, he says.

"Glutamate is the brain's light switch which helps turnserotonin and other chemicals off and on," Rosenberg says. "Our research hasshown that glutamate abnormalities in OCD have significant treatmentimplications. This new study will further our research by combining imaging andgenetics, something never assessed in OCD patients."

The expertise at WSU is brain imaging, Rosenberg said. WSUhas the only pediatric center in the country with both positron emissiontomograpy (PET) and magnetic resonance imaging (MRI) in a pediatric center, soit's ideally positioned to do these studies in children.

In the pediatric center at the Children's Hospital ofMichigan, there is also a very powerful high-field MRI scanner that can look atthe brain's chemistry, structure and physiology with great precision, withoutthe need of shots, needles or radiation.

The current research is a follow-up to the initial studyshowing glutamate plays a key role in OCD in children.

This time investigators will combine brain imaging andgenetic with a more powerful MRI machine that can better discriminate brainchemicals—including glutamate and other related and relevant chemicals—alongwith more sophisticated genetics studies in glutamate genes, Rosenberg says.

"We are beginning to elevate child psychiatry to traditionalpediatric medicine and neurology, which will help defeat some of the stigmaabout mental illness, and ultimately lead to enhanced diagnosis and bettertreatment," he says. "Glutamate-modulating drugs are already being tested inchildhood and adult OCD based on these prior genetic and imaging findings ofglutamate involvement in OCD. Therefore, specific brain patterns and geneticfindings may help predict who is more or less likely to respond to a particulartreatment."

Dr. Gregory Hanna, associate professor of psychiatry anddirector of the Pediatric Anxiety and Tic Disorder Program at the University ofMichigan, will lead recruiting efforts for patients. Dr. Paul Arnold, assistantprofessor of psychiatry at the University of Toronto and SickKids, will leadthe genetic studies.

"The principal investigators in this study have a longhistory of collaboration with one another," Arnold says. "Drs. Rosenberg andHanna co-wrote a prescient review on the possibility of imaging genetic studiesin OCD almost a decade ago (published in 2000), and Drs. Hanna and Arnold havecollaborated for some time in genetic studies of OCD. We conducted a smallpilot study in which children with OCD who had previously received magneticresonance imaging (MRI) and magnetic resonance spectroscopy (MRS) scans atWayne State were genotyped for the same variants in GRIN2B and SLC1A1 that hadpreviously been associated with OCD. This work led to some exciting earlyresults, recently published in Brain Imaging and Behavior and PsychiatryResearch: Neuroimaging. The current, moreambitious project builds on this earlier work by taking advantage of cuttingedge imaging and genomic technology."

Specifically, investigators will collect a larger populationof 400 children (50 percent with OCD) and their parents, then compare the 200children with OCD and their 200 age-matched controls with regard to a muchwider array of glutamate system variants than studied previously.

"As with all genetic association studies, the first stepwould be to ensure that our findings are replicated in other independentsamples," Arnold says. "If the results consistently identify associations withspecific genes or biological pathways, then targeted re-sequencing of theimplicated genetic loci will be needed to provide a complete picture of thecommon and uncommon variants that may be influencing genetic susceptibility toOCD and related disorders. We expect that one of the eventual outcomes of ourcollaborative study will be the identification of biological pathways that leadto OCD and related disorders. Identification of specific genes and pathwayswill provide important clues regarding potential pharmacological agents not yetdeveloped or tested for this disorder. Collectively, our previous work has alreadyled to a re-thinking of OCD as being related to abnormalities in glutamateneurotransmission, and glutamatergic drugs are consequently being tested inOCD."

It is unlikely that this research will ultimately lead to a"cure" for OCD, he says. That's because OCD comprises a highly complex set ofbehaviors, many of which represents extremes on a continuum of behavior that weall exhibit from time to time.

"Therefore, it would be impractical and unwise to attempt to'cure' such behavior," Arnold says. "Instead, we hope that our research willultimately lead to more effective, safer and selective treatments that helpalleviate suffering in individuals with OCD symptoms that interfere with theirability to function and enjoy a good quality of life."

OCD still holds its secrets, he adds.

"As a scientist, I believe that obsessive-compulsivesymptoms represent something fundamental about the functioning of the humanmind, " Arnold says. "Therefore, a more refined understanding of thepathogenesis of this condition will teach us important lessons about normalbrain functioning and what can go wrong with this functioning. As a childpsychiatrist treating children with OCD, I am hopeful that our collaborativeresearch will ultimately lead to more effective treatments and improveddiagnostic methods that will help alleviate the considerable sufferingexperienced by children and adults with OCD. Because OCD overlaps to someextent with other neurodevelopmental disorders, it is possible that ourresearch will also provide a better understanding and better treatments forTourette's disorder, autistic disorder, separation anxiety disorder andtrichotillomania."