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Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole (n = 21) or saline (n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional volumes, functional connectivity and structural integrity in the brain, respectively. After consecutive quinpirole injections, adolescent rats demonstrated clear checking behavior and repeated travelling between two open-field zones. MRI measurements revealed an increase of regional volumes within the frontostriatal circuits and an increase in fractional anisotropy (FA) in white matter areas during maturation in both experimental groups. Quinpirole-injected rats showed a larger developmental increase in FA values in the internal capsule and forceps minor compared to control rats. Our study points toward a link between development of compulsive behavior and altered white matter maturation in quinpirole-injected adolescent rats, in line with observations in pediatric patients with compulsive phenotypes. This novel animal model provides opportunities to investigate novel treatments and underlying mechanisms for patients with early-onset OCD specifically.

Contains fulltext : 193222.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Research has implicated glutamatergic projections between the various frontal subregions in the pathogenesis of compulsivity and impulsivity. Reducing striatal glutamate release, or antagonising the action of glutamate at its receptors, may therefore represent viable treatment strategies. Several glutamatergic agents with regulatory approval for other indications are available and may be of potential benefit in the treatment of compulsivity/impulsivity in psychiatric disorders in paediatric patients. METHOD: This review was performed according to PRISMA guidelines and evaluates available scientific literature concerning the use of glutamatergic agents in these patients, in order to determine their reported effectiveness/efficacy and tolerability/safety. RESULTS: Out of a total of 1,426 publications, 21 trials examining six glutamatergic substances in patients with obsessive-compulsive disorder, autism spectrum disorders, and attention deficit/hyperactivity disorder were included. CONCLUSIONS: Trial designs as well as results were heterogeneous and thus comparability was limited. Available data support the hypothesis that glutamatergic agents are of potential value in the treatment of compulsivity/impulsivity in children and adolescents. Based on the data reviewed, memantine and N-acetylcysteine suggest the best risk-benefit profile for future trials. Riluzole should primarily be further investigated in adults. Clinical research of this nature is a key element of the TACTICS Consortium project funded by the European Union (FP7).

In the HTML version of the article originally published, the author group ‘The Schizophrenia Working Group of the Psychiatric Genomics Consortium’ was displayed incorrectly. The error has been corrected in the HTML version of the article.

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to understand the genetic mechanisms of impaired brain function underlying schizophrenia. The consortium is examining the influence of genetic variation on cognitive functions and brain structural measures that are abnormal in schizophrenia using a collection of 4,125 patients, 3,644 controls, and 327 familial high-risk participants from 16 international sites. Data from each site were transferred to a central site for data harmonization and analyses. Genetic risk variants identified by previous well-powered schizophrenia GWAS, including individual SNPs, gene sets, and polygenic risk, were tested for association with cognitive functions and global/regional brain volumes that are altered in patients. Analysis of 108 SNPs from the schizophrenia PGC2 GWAS mega-analysis identified significant associations in all GENUS participants between several SNPs and general cognitive ability (Spearman’s ‘g’), visuospatial ability, and verbal learning/memory (FWE corrected p