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.

中文翻译：

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BDNF Val66Met基因型和精神分裂症家族风险对人类认知控制神经功能网络的影响。

认知控制代表了一种基本的神经心理学特征，它可以通过不断重新分配认知资源来快速适应不断变化的环境。这种微调的机制在诸如精神分裂症的精神疾病中受损，并且导致认知缺陷。神经影像学强调了前扣带回皮层（ACC）和前额叶区域（PFC）对认知控制的贡献，并证明了遗传变异的影响以及精神分裂症的遗传易感性。在这项研究中，我们旨在检查可塑性相关神经营养因子基因BDNF（Val66Met）的功能性单核苷酸多态性（SNP）rs6265对认知控制的影响。有力的证据表明BDNF Val66Met与人类的神经可塑性有关。此外，几项研究表明，尽管该变异与精神分裂症的风险没有令人信服的关联，但它似乎是该疾病的临床表现和病程的改良剂。为了阐明使用功能磁共振成像（fMRI）的潜在机制，我们在85个健康个体的发现样本中研究了该SNP对ACC和PFC激活的影响以及这些区域之间的连通性，并试图在以下方面重复这种作用： 253个人的独立样本。此外，我们在58位未受影响的精神分裂症患者一级亲属的样本中测试了与精神分裂症家族风险相关的确定的显像表型。我们发现与风险相关的BDNF 66Met等位基因携带者中ACC和PFC之间的区域间连通性显着增加。此外，我们在一个独立的样本中复制了这种效果，并证明了其在结构混杂方面的独立性以及任务的特殊性。在家族性精神分裂症风险增加的个体中可检测到类似的偶联增加。我们的结果表明，用于认知控制的关键神经回路受可塑性相关遗传变异的影响，这可能使该回路特别容易受精神分裂症的遗传和环境风险因素影响。