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，早期干预可以起到作用，特别是对认知能力 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的损害与睡眠异常和睡眠特有的振荡有关-纺锤波和 慢波--这种波已在SCZ建立，但主要见于慢性患者。作为迈向 将这些观察转化为新的、及时的干预措施，我们的目标是确定：睡眠振荡和 早期病程(EC-SCZ)患者与健康对照组(HC)相比存在认知缺陷，如果这些缺陷 2)听觉刺激下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。 睡眠纺锤波是一种时好时坏的12-16赫兹振荡，代表着NREM第二阶段睡眠的特征。 慢波是大幅度、~1赫兹的大脑振荡，是NREM阶段3的特征。我们和其他人有 睡眠纺锤波明显不足，SCZ出现慢波，纺锤波减少 密度与较差的记忆巩固(MC)有关，MC是已知会改变的一种关键认知功能 SCZ.然而，大多数证据是在慢性SCZ中，而睡眠振荡和MD的改变的存在 在疾病开始时，这些特征将被确立为SCZ的可靠标志。因此，这项提议的第一个目标是 确定纺锤波和慢波缺陷是否存在，并与MC降低相关 EC-SCZ患者的表现相对于HC。我们还将研究睡眠振荡之间的联系 与认知控制(CC)和工作记忆(WM)相关的认知功能缺陷 在EC-SCZ患者中，HC的纺锤波和慢波受损。 为了确定改善睡眠改变是否有助于新的治疗干预措施，我们首先需要 以确定睡眠和睡眠振荡缺陷是可以被操纵的。一种脑电闭环系统， 在睡眠期间传递听觉刺激，持续增强HC的慢波和纺锤波活动。这个系统， 其涉及使用无线设备，可以与同步多导睡眠图(PSG)一起在 提高睡眠实验室建设的可行性和有效性。然而，还没有研究在以下方面使用这种闭环方法 SCZ.这项提议的第二个目标是证明睡眠纺锤波和慢波缺陷可以 急性改良闭环式听觉刺激(CLAS)在EC-SCZ患者睡眠中的应用 这些患者是否与Clas相关的纺锤波和慢波改变与认知改变有关。 我们建议进行无线/PSG夜间睡眠记录，并评估运动序列中的性能 作为一项主要的认知测量任务，在认知测试中，主体性任务(MST)作为认知测验的主要工具，在认知测验中被试作为认知测验的主要工具 二次认知测验，对70名EC-SCZ和70名HC受试者进行测试。EC-SCZ患者还将接受听力检查 采用双盲交叉设计，包括睡眠、MST和AX-CPT评估的刺激和假夜晚。