Establishing that sleep spindle and slow wave deficits are present, are associated with cognitive dysfunction, and can be acutely manipulated in early course schizophrenia

确定睡眠纺锤波和慢波缺陷的存在，与认知功能障碍相关，并且可以在早期精神分裂症中进行急性控制

• 批准号: 10733615
• 负责人: Fabio Ferrarelli
• 金额: $ 75.93万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733615
• 关键词: Acoustic Stimulation; Acute; Affect; Brain; Chronic; Chronic Schizophrenia; Clinical; Cognition; Cognitive; Cognitive deficits; Correlative Study; Crossover Design; Data; Diagnosis; Disease; Double-Blind Method; Early Intervention; Early treatment; Electroencephalography; Goals; Health Care Costs; Impaired cognition; Impairment; Individual; Intervention; Laboratories; Link; Measures; Motor; Napping; Neurobiology; Onset of illness; Participant; Patients; Performance; Research; Role; Schizophrenia; Short-Term Memory; Sleep; Stage II Sleep; System; Task Performances; Translating; Waxes; Work; auditory stimulus; cognitive change; cognitive control; cognitive function; cognitive performance; comparison group; density; disability; functional outcomes; improved; improvement on sleep; memory consolidation; non rapid eye movement; novel; sleep spindle; wireless; wireless electronic

Project Summary. In Schizophrenia (SCZ), early interventions can make a difference, particularly for cognitive dysfunction, a core feature of SCZ that predicts poorer clinical trajectories and functional outcomes. Cognitive impairments in SCZ have been linked to abnormalities in sleep and sleep-specific oscillations—spindles and slow waves— which have been established in SCZ, although mostly in chronic patients. As first steps towards translating these observations into novel, timely interventions, we aim to establish: whether sleep oscillatory and cognitive deficits are present in early course (EC-SCZ) patients vs. healthy controls (HC), and if these deficits are related to each other; and 2) whether sleep manipulation with auditory stimulation can improve sleep oscillation deficits in EC-SCZ, and if sleep oscillatory changes are related to cognitive changes in these patients. Sleep spindles are waxing and waning, 12-16 Hz oscillations that represent the hallmark of NREM stage 2 sleep. Slow waves are large amplitude, ~1 Hz brain oscillations that characterize NREM stage 3. We and others have demonstrated marked deficits in sleep spindles, and to a lesser extent, slow waves in SCZ and reduced spindle density is associated with worse memory consolidation (MC), a key cognitive function known to be altered in SCZ. However, most of the evidence is in chronic SCZ, while the presence of altered sleep oscillations and MD at illness onset would establish these features as robust markers of SCZ. Thus, the first goal of this proposal is to establish whether spindle and slow wave deficits are present and are associated with reduced MC performance in EC-SCZ patients relative to HC. We will also examine the association between sleep oscillatory deficits and cognitive controls (CC) and working memory (WM), cognitive functions that have been linked to spindles and slow waves in HC and are impaired in EC-SCZ patients. To establish whether ameliorating sleep alterations may contribute to novel treatment interventions, we first need to ascertain that sleep and sleep oscillatory deficits can be manipulated. An EEG closed-loop system, which delivers auditory stimuli during sleep, consistently enhances slow wave and spindle activity in HC. This system, which involves using a wireless device, can be employed with a simultaneous polysomnogram (PSG) in the sleep laboratory to enhance feasibility and validity. However, no study has used this closed-loop approach in SCZ. The second goal of this proposal is to demonstrate that sleep spindles and slow waves deficits can be acutely modified with closed-loop auditory stimulation (CLAS) during sleep in EC-SCZ patients and to examine whether CLAS-related spindle and slow wave changes are associated with cognitive changes in these patients. We propose to perform wireless/PSG overnight sleep recordings and assess performance in the motor sequence tapping (MST), a MC task, as the main cognitive measure and performance in the AX-CPT for CC and WM as a secondary cognitive measure, in 70 EC-SCZ and 70 HC subjects. EC-SCZ patients will also undergo auditory stimulation and sham nights in a double-blind, cross-over design with sleep, MST, and AX-CPT assessments.

项目摘要。在精神分裂症（SCZ）中，早期干预可以发挥作用，特别是在认知方面。 功能障碍，SCZ的核心特征，预测较差的临床轨迹和功能结果。认知 SCZ的损伤与睡眠异常和睡眠特异性振荡-纺锤波有关， 慢波-已经在SCZ中建立，尽管主要是在慢性患者中。作为迈向 将这些观察转化为新颖的，及时的干预措施，我们的目标是建立：睡眠是否振荡， 与健康对照（HC）相比，早期（EC-SCZ）患者存在认知缺陷，如果这些缺陷 听觉刺激的睡眠操作是否能改善睡眠 EC-SCZ的振荡缺陷，以及睡眠振荡变化是否与这些患者的认知变化有关。 睡眠纺锤波有增有减，12-16 Hz的振荡代表了NREM第2阶段睡眠的标志。 慢波是表征NREM阶段3的大振幅、~ 1Hz脑振荡。我们和其他人已经 在睡眠纺锤波中表现出明显的缺陷，在较小程度上，SCZ中的慢波和减少的纺锤波 密度与更差的记忆巩固（MC）有关，MC是一种已知会改变的关键认知功能， SCZ。然而，大多数证据是在慢性SCZ，而存在改变睡眠振荡和MD 将这些特征确定为SCZ的可靠标志物。因此，本提案的第一个目标是 确定是否存在纺锤波和慢波缺陷，以及是否与MC减少相关 EC-SCZ患者相对于HC的性能。我们还将研究睡眠振荡与睡眠质量之间的关系。 缺陷和认知控制（CC）和工作记忆（WM），认知功能已被链接到 在HC中的纺锤波和慢波，在EC-SCZ患者中受损。 为了确定改善睡眠改变是否有助于新的治疗干预，我们首先需要 以确定睡眠和睡眠振荡缺陷可以被操纵。一种脑电闭环系统， 在睡眠期间提供听觉刺激，持续增强HC中的慢波和纺锤波活动。这个系统， 包括使用无线设备，可以与同步多导睡眠图（PSG）一起使用， 睡眠实验室，以提高可行性和有效性。然而，没有研究使用这种闭环方法， SCZ。该提案的第二个目标是证明睡眠纺锤波和慢波缺陷可以被 在EC-SCZ患者睡眠期间用闭环听觉刺激（CLAS）进行急性修改，并检查 CLAS相关的纺锤波和慢波改变是否与这些患者的认知改变相关。 我们建议进行无线/PSG夜间睡眠记录，并评估运动序列中的表现 敲击（MST），一个MC任务，作为主要的认知测量和表现，在AX-CPT CC和WM作为一个 在70例EC-SCZ和70例HC受试者中进行了次要认知测量。EC-SCZ患者还将接受听觉 刺激和假夜，采用双盲、交叉设计，进行睡眠、MST和AX-CPT评估。