Sleep-dependent Memory Processing in Schizophrenia

描述（由申请人提供）：十多年的研究已经证实，睡眠在记忆巩固中起着至关重要的作用，有助于记忆的稳定、增强和融入现有的皮层网络。尽管睡眠在记忆和认知中起着至关重要的作用，但睡眠异常通常被忽视为精神分裂症认知缺陷的潜在因素。这种疏忽很重要，因为缺乏有效的治疗认知缺陷的方法，而异常睡眠是一个潜在的治疗目标。新兴的文献表明，睡眠纺锤波更普遍地调节睡眠依赖的记忆巩固和认知功能。与此同时，最近的几项研究表明，睡眠纺锤波在SZ显著减少。我们的初步数据是第一个将睡眠纺锤体缺陷与睡眠依赖性记忆巩固障碍联系起来的数据，目前我们已经在四项独立研究中记录了这一数据。他们还首次证明了大脑皮层中纺锤波的相干性降低。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。观察到的纺锤体异常与纺锤体产生的丘脑皮质反馈回路功能障碍有关，该回路由氨基丁酸（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的病理生理有关。该研究的主要目标是复制和扩展我们的安慰剂对照双盲先导研究的发现，即eszopiclone （Lunesta）可将睡眠纺锤波和睡眠依赖性运动程序记忆巩固恢复到正常水平。艾索匹克隆是一种非苯二氮卓类催眠药物，作用于丘脑网状核中产生睡眠纺锤波的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来确定SZ中是否存在更普遍的睡眠依赖性记忆损伤。最后，我们将根据标准的神经心理学评估、症状表现和功能能力，通过将纺锤体活动和其他睡眠参数与认知缺陷联系起来，建立SZ睡眠异常的临床相关性。总之，我们的初步数据表明，异常纺锤波损害精神分裂症患者睡眠依赖性记忆巩固，导致阳性症状，是治疗精神分裂症认知缺陷的一个有希望的新靶点。该项目新颖，具有临床和科学意义，因为如果我们的假设得到证实，它将把特定的认知缺陷与特定的机制联系起来，并提供有效的干预措施。因此，拟议的研究项目有可能极大地扩展SZ认知缺陷的现有模型，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.