ABSTRACT
Cognitive control represents an essential neuropsychological characteristic that allows for the rapid adaption of a changing environment by constant re-allocation of cognitive resources. This finely tuned mechanism is impaired in psychiatric disorders such as schizophrenia and contributes to cognitive deficits. Neuroimaging has highlighted the contribution of the anterior cingulate cortex (ACC) and prefrontal regions (PFC) on cognitive control and demonstrated the impact of genetic variation, as well as genetic liability for schizophrenia. In this study, we aimed to examine the influence of the functional single-nucleotide polymorphism (SNP) rs6265 of a plasticity-related neurotrophic factor gene, BDNF (Val66Met), on cognitive control. Strong evidence implicates BDNF Val66Met in neural plasticity in humans. Furthermore, several studies suggest that although the variant is not convincingly associated with schizophrenia risk, it seems to be a modifier of the clinical presentation and course of the disease. In order to clarify the underlying mechanisms using functional magnetic resonance imaging (fMRI), we studied the effects of this SNP on ACC and PFC activation, and the connectivity between these regions in a discovery sample of 85 healthy individuals and sought to replicate this effect in an independent sample of 253 individuals. Additionally, we tested the identified imaging phenotype in relation to schizophrenia familial risk in a sample of 58 unaffected first-degree relatives of schizophrenia patients. We found a significant increase in interregional connectivity between ACC and PFC in the risk-associated BDNF 66Met allele carriers. Furthermore, we replicated this effect in an independent sample and demonstrated its independence of structural confounds, as well as task specificity. A similar coupling increase was detectable in individuals with increased familial risk for schizophrenia. Our results show that a key neural circuit for cognitive control is influenced by a plasticity-related genetic variant, which may render this circuit particular susceptible to genetic and environmental risk factors for schizophrenia.
Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Connectome , Executive Function/physiology , Gyrus Cinguli/physiopathology , Nerve Net/physiopathology , Neuronal Plasticity/genetics , Prefrontal Cortex/physiopathology , Schizophrenia/genetics , Adult , Female , Genetic Predisposition to Disease , Gyrus Cinguli/diagnostic imaging , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Polymorphism, Single Nucleotide , Prefrontal Cortex/diagnostic imaging , Young AdultABSTRACT
Species-conserved (intermediate) phenotypes that can be quantified and compared across species offer important advantages for translational research and drug discovery. Here, we investigate the utility of network science methods to assess the pharmacological alterations of the large-scale architecture of brain networks in rats and humans. In a double-blind, placebo-controlled, cross-over study in humans and a placebo-controlled two-group study in rats, we demonstrate that the application of ketamine leads to a topological reconfiguration of large-scale brain networks towards less-integrated and more-segregated information processing in both the species. As these alterations are opposed to those commonly observed in patients suffering from depression, they might indicate systems-level correlates of the antidepressant effect of ketamine.
