Sleep-dependent Memory Processing in Schizophrenia

精神分裂症的睡眠依赖性记忆处理

• 批准号: 8292552
• 负责人: DARA S MANOACH
• 金额: $ 45.4万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292552
• 关键词: Acids; Activities of Daily Living; Aminobutyric Acids; Attention; Biological Markers; Cell Nucleus; Cognition; Cognitive deficits; Cross-Over Studies; Data; Double-Blind Method; Electroencephalography; Eszopiclone; Failure; Feedback; Fingers; Functional disorder; GABA-A Receptor; Glutamates; Goals; Impaired cognition; Impairment; Individual; Intervention; Lead; Learning; Link; Literature; Mediating; Memory; Memory impairment; Modeling; Motor; Motor Skills; N-Methylaspartate; Neurocognitive Deficit; Neuropsychological Tests; Outcome; Participant; Patients; Performance; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Play; Publishing; Quality of life; Research; Research Design; Role; Schizophrenia; Severities; Sleep; Sleep disturbances; Speed; Stage II Sleep; Symptoms; Testing; Thalamic structure; Time; Training; base; clinically relevant; cognitive function; density; disability; effective intervention; effective therapy; functional outcomes; gamma-Aminobutyric Acid; hypnotic; improved; indexing; memory process; neuropsychological; neurotransmission; novel; procedural memory; programs; receptor; restoration; therapy development

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. PUBLIC HEALTH RELEVANCE: Although sleep plays a critical role in learning and memory, 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. We will determine whether eszopiclone, a common sleep medication, can normalize sleep and restore sleep- dependent memory processing in patients with SZ, which can result in improved cognitive function and quality of life.

描述（由适用提供）：十多年来的研究确定，睡眠在记忆巩固中起着至关重要的作用，有助于其稳定，增强和整合到现有的皮质网络中。尽管睡眠在记忆和认知中的重要作用至关重要，但异常的睡眠通常被认为是导致精神分裂症（SZ）认知缺陷的潜在因素。这种监督很重要，因为缺乏认知缺陷的有效治疗方法，而且睡眠异常是潜在的治疗靶标。水龙头文献表明，睡眠会更广泛地旋转中位数睡眠依赖性记忆巩固和认知功能。同时，最近的一些研究表明，SZ中的睡眠纺锤体大大减少。我们的初步数据是第一个将睡眠主轴防御与SZ中的睡眠依赖性记忆巩固障碍联系起来的数据，我们现在已经在四项独立研究中记录了这一记忆。它们还提供了首次证明横跨皮层连贯性的相干性降低。纺锤活性减少还可以预测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暗示着纺锤体生成的丘脑皮质反馈回路，该反馈受到�-氨基丁酸（GABA）ERGIC和N-甲基 - 甲基 - d-甲酸（NMDA）受体介导的受体介导的谷氨酸氨基氨基氨基甲酸神经疗法的调节。拟议的研究的主要目的是复制和扩展我们的安慰剂对照，双盲试验研究的发现，即埃索普隆（Lunesta）（Lunesta），恢复睡眠纺锤体，并依赖睡眠依赖于SZ的运动记忆到正常水平。 Eszopiclone是一种非苯并二氮卓类药物，可作用于丘脑网状核中的GABAA受体，在那里产生睡眠纺锤体。我们还将通过检查已知会受到损害的其他类型的记忆的巩固来确定SZ中睡眠依赖性记忆是否更普遍的损害。最后，我们将通过将纺锤体活性和其他睡眠参数与基于标准神经心理学评估，SEM表现和功能能力相关的认知缺陷来建立SZ异常睡眠的临床相关性。总而言之，我们的初步数据表明，异常的纺锤体损害了精神分裂症的睡眠依赖性记忆巩固，导致阳性症状，并且是治疗精神分裂症认知缺陷的新颖目标。该项目是新颖的，并且在临床和科学上都是显着的，因为如果确认了UR假设，它将将特定的认知防御与特定机制联系起来并提供有效的干预措施。这是拟议的研究计划有可能大大扩展SZ中认知防御的当前模型，并导致干预措施可显着改善SZ患者的生活质量。 公共卫生相关性：尽管睡眠在学习和记忆中起着至关重要的作用，但异常的睡眠通常被忽略为导致精神分裂症认知缺陷（SZ）的潜在贡献者。这种监督很重要，因为缺乏认知缺陷的有效治疗方法，而且睡眠异常是潜在的治疗靶标。我们将确定Eszopiclone是一种常见的睡眠药物，可以使SZ患者的睡眠正常化并恢复依赖性睡眠记忆加工，这可能会改善认知功能和生活质量。