Sleep-dependent Memory Processing in Schizophrenia

描述（由申请人提供）：十多年的研究已经确定，睡眠在记忆巩固中起着关键作用，有助于其稳定，增强和整合到现有的皮层网络中。尽管睡眠在记忆和认知中起着关键作用，但睡眠异常通常被忽视为精神分裂症（SZ）认知缺陷的潜在贡献者。这种疏忽很重要，因为缺乏有效的认知缺陷治疗方法，而异常睡眠是一个潜在的治疗目标。一个新兴的文献表明，睡眠纺锤波介导睡眠依赖的记忆巩固和认知功能更普遍。与此同时，最近的几项研究表明，睡眠纺锤波在SZ中显着减少。我们的初步数据是第一个联系睡眠梭形缺陷与睡眠依赖性记忆巩固的损害，我们现在已经记录在四个独立的研究。他们还首次证明了大脑皮层中纺锤波的连贯性降低。纺锤体活动减少也预示着阳性症状和神经认知缺陷的严重程度增加。所观察到的纺锤体异常涉及纺锤体生成丘脑皮质反馈回路的功能障碍，该反馈回路由γ-氨基丁酸（GABA）能和N-甲基-D-天冬氨酸（NMDA）受体介导的谷氨酸能神经传递调节，所有这些都与SZ的病理生理学有关。拟定研究的主要目的是复制和扩展我们的安慰剂对照、双盲初步研究的结果，即右佐匹克隆（Lunesta）将SZ的睡眠纺锤波和运动程序记忆的睡眠依赖性巩固恢复至正常水平。右佐匹克隆是一种非苯二氮卓类催眠药，作用于产生睡眠纺锤波的丘脑网状核中的GABAA受体。我们还将通过检查已知受损的其他类型记忆的巩固，确定SZ中是否存在更普遍的睡眠依赖性记忆受损。最后，我们将建立相关的纺锤波活动和其他睡眠参数与认知功能障碍的基础上，标准的神经心理学评估，症状表现和功能能力的SZ异常睡眠的临床相关性。总之，我们的初步数据表明，异常纺锤波损害精神分裂症的睡眠依赖性记忆巩固，有助于阳性症状，是一个有前途的新的目标，为精神分裂症的认知缺陷的治疗。这个项目是新颖的，在临床和科学上都有重要意义，如果你的假设得到证实，它将把特定的认知缺陷与特定的机制联系起来，并提供有效的干预。因此，拟议的研究计划有可能大大扩大目前的模型，在SZ的认知缺陷，并导致干预措施，显着提高个人的生活质量与SZ。

DESCRIPTION (provided by applicant): More than a decade of research has established that sleep plays a critical role in memory consolidation, contributing to its stabilization, enhancement and integration into existing cortical networks. Despite the critical role of sleep in memory and cognition, abnormal sleep has generally been overlooked as a potential contributor to cognitive deficits in schizophrenia (SZ). This oversight is important as effective treatments for cognitive deficits are lacking and abnormal sleep is a potential treatment target. A burgeoning literature suggests that sleep spindles mediate sleep-dependent memory consolidation and cognitive function more generally. At the same time, several recent studies show that sleep spindles are dramatically reduced in SZ. Our preliminary data are the first to link the sleep spindle deficit wih the impairment of sleep-dependent memory consolidation in SZ that we have now documented in four independent studies. They also provide the first demonstration of reduced coherence of spindles across the cortex. Reduced spindle activity also predicted increased severity of positive symptoms and neurocognitive deficits. The observed spindle abnormalities implicate dysfunction in the spindle-generating thalamocortical feedback loop, which is regulated by both ¿-aminobutyric acid (GABA)ergic and N-methyl-D-aspartate acid (NMDA) receptor mediated glutamatergic neurotransmission, all of which have been implicated in the pathophysiology of SZ. The primary goal of the proposed study is to replicate and extend the findings of our placebo-controlled, double-blind pilot study that eszopiclone (Lunesta), restores sleep spindles and sleep-dependent consolidation of motor procedural memory in SZ to normal levels. Eszopiclone is a non-benzodiazepine hypnotic agent that acts on GABAA receptors in the thalamic reticular nucleus where sleep spindles are generated. We will also determine whether there is more general impairment of sleep-dependent memory in SZ by examining the consolidation of other types of memory that are known to be impaired. Finally, we will establish the clinical relevance of abnormal sleep in SZ by correlating spindle activity and other sleep parameters with cognitive deficits based on standard neuropsychological assessment, symptom presentation, and functional capacity. In summary, our preliminary data suggest that abnormal spindles impair sleep-dependent memory consolidation in schizophrenia, contribute to positive symptoms, and are a promising novel target for the treatment of cognitive deficits in schizophrenia. This project is novel and both clinically and scientifically significant in that if ur hypotheses are confirmed, it will link a specific cognitive deficit to a particular mechanism and provide an effective intervention. Thus, the proposed research program has the potential to substantially expand current models of cognitive deficits in SZ and to lead to interventions that significantly improve the quality of life of individuals with SZ.