Sleep-dependent Memory Processing in Schizophrenia

描述(申请人提供)：十多年的研究已经证实，睡眠在巩固记忆方面起着关键作用，有助于记忆的稳定、增强和融入现有的皮质网络。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，认为它是精神分裂症(SZ)认知缺陷的潜在贡献者。这一疏忽很重要，因为缺乏对认知障碍的有效治疗，而异常睡眠是一个潜在的治疗目标。一项新兴的文献表明，睡眠纺锤波在睡眠依赖的记忆巩固和认知功能中起着更广泛的调节作用。与此同时，最近的几项研究表明，在深圳，睡眠纺锤波显著减少。我们的初步数据首次将睡眠纺锤体缺陷与SZ的睡眠依赖记忆巩固障碍联系在一起，我们现在已经在四项独立研究中记录了这一点。它们还提供了大脑皮质纺锤体连贯性降低的第一个证据。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。观察到的纺锤体异常意味着纺锤体生成丘脑皮质反馈回路的功能障碍，该回路受氨基丁酸(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的调节，所有这些都与SZ的病理生理有关。这项拟议研究的主要目标是复制和扩展我们的安慰剂对照双盲试点研究的结果，即埃索匹克隆(LUNESTA)可以将睡眠纺锤波和睡眠依赖的运动程序记忆巩固恢复到正常水平。埃索匹克隆是一种非苯二氮类催眠剂，作用于产生睡眠纺锤体的丘脑网状核中的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情况，确定SZ是否存在更普遍的睡眠依赖记忆损害。最后，我们将根据标准的神经心理评估、症状表现和功能能力，通过将纺锤活动和其他睡眠参数与认知障碍联系起来，建立SZ患者睡眠异常的临床相关性。综上所述，我们的初步数据表明，异常的纺锤波损害了精神分裂症患者睡眠依赖记忆的巩固，导致了积极的症状，是治疗精神分裂症认知缺陷的一个有前途的新靶点。这个项目是新颖的，具有临床和科学意义，因为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幅扩展目前SZ认知缺陷的模型，并导致显著改善SZ患者生活质量的干预措施。

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.