Cognitive remediation (CR) is predicated on principles of neuroplasticity, but the actual molecular and neurocircuitry changes underlying cognitive change in individuals with impaired neuroplastic processes is poorly understood. The present study examined epigenetic-neurocircuitry-behavioral outcome measures in schizophrenia, before and after participating in a CR program that targeted higher-order cognitive functions. Outcome measures included DNA methylation of genes central to synaptic plasticity (CpG sites of Reelin promoter and BDNF promoter) from buccal swabs, resting-state functional brain connectivity and topological network efficiency, and global scores of a cognitive battery from 35 inpatients in a rehabilitative ward (18 CR, 17 non-CR) with similar premorbid IQ to 15 healthy controls. Baseline group differences between healthy controls and schizophrenia, group-by-time effects of CR in schizophrenia, and associations between the outcome measures were tested. Baseline functional connectivity abnormalities within the frontal, fronto-temporal and fronto-parietal regions, and trending decreases in global efficiency, but not DNA methylation, were found in schizophrenia; the frontal and fronto-temporal connectivity, and global efficiency correlated with global cognitive performance across all individuals. Notably, CR resulted in differential changes in Reelin promoter CpG methylation levels, altered within-frontal and fronto-temporal functional connectivity, increasing global efficiency and improving cognitive performance in schizophrenia, when compared to non-CR. In the CR inpatients, positive associations between the micro to macro measures: Reelin methylation changes, higher global efficiency and improving global cognitive performance were found. Present findings provide a neurobiological insight into potential CR-led epigenetics-neurocircuitry modifications driving cognitive plasticity.

中文翻译：

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DNA甲基化的可塑性，功能性脑连通性和精神分裂症认知修复的效率。

认知矫治（CR）是以神经可塑性为基础的，但是对于神经塑性过程受损的个体，其认知变化背后的实际分子和神经回路变化知之甚少。本研究在参加针对高阶认知功能的CR计划之前和之后，检查了精神分裂症的表观遗传-神经回路行为表现指标。结果测量包括口腔拭子突触可塑性（Reelin启动子和BDNF启动子的CpG位点）关键基因的DNA甲基化，静息状态的大脑连接性和拓扑网络效率以及康复病房中35位住院病人的认知电池总体得分（18 CR，17非CR）的病前智商与15个健康对照者相似。测试了健康对照组和精神分裂症之间的基线组差异，精神分裂症中CR的逐组效应以及结局指标之间的相关性。在精神分裂症中发现额叶，额颞叶和额叶顶区域的基线功能连接异常，以及总体效率呈下降趋势，但未发现DNA甲基化。额叶和额颞连接性以及整体效率与所有个体的整体认知表现相关。值得注意的是，与非CR相比，CR导致Reelin启动子CpG甲基化水平的差异变化，额叶内和额颞功能连接性改变，增加了整体效率并改善了精神分裂症的认知表现。在CR住院病人中 从微观到宏观之间的积极联系：发现Reelin甲基化变化，更高的整体效率和改善的整体认知能力。目前的发现提供了神经生物学的见解，以潜在的CR主导的表观遗传学-神经回路修饰驱动认知可塑性。