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 对于精神分裂症 (SCZ)，早期干预可以发挥作用，特别是在认知方面。 功能障碍是 SCZ 的一个核心特征，可预测较差的临床轨迹和功能结果。 SCZ 损伤与睡眠异常和睡眠特异性振荡（纺锤体和睡眠障碍）有关。 慢波——已在 SCZ 中建立，尽管主要是在慢性患者中。 将这些观察结果转化为新颖、及时的干预措施，我们的目标是确定：睡眠是否振荡和 与健康对照 (HC) 相比，早期病程 (EC-SCZ) 患者存在认知缺陷，如果这些缺陷 彼此相关；2）听觉刺激睡眠操纵是否可以改善睡眠 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。 睡眠纺锤波呈 12-16 Hz 波动，代表 NREM 第 2 阶段睡眠的标志。 慢波是振幅约为 1 Hz 的大脑振荡，是 NREM 第 3 阶段的特征。我们和其他人已经发现 睡眠纺锤波明显缺陷，并在较小程度上表现出 SCZ 慢波和纺锤波减少 密度与较差的记忆力 (MC) 相关，这是一种已知的关键认知巩固功能。 然而，大多数证据是慢性 SCZ，同时存在睡眠振荡改变和 MD。 因此，该提案的第一个目标是在疾病发作时将这些特征确立为 SCZ 的有力标记。 确定是否存在纺锤波和慢波缺陷并与 MC 减少相关 EC-SCZ 患者相对于 HC 的表现我们还将检查睡眠振荡之间的关联。 缺陷和认知控制（CC）和工作记忆（WM），认知功能与 HC 患者的纺锤波和慢波在 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措施，我们首先需要 以确定睡眠和睡眠振荡缺陷是可以操纵的脑电图闭环系统。 睡眠期间的听觉刺激持续增强 HC 的慢波和纺锤体活动。 涉及使用无线设备，可与同步多导睡眠图 (PSG) 一起使用 睡眠实验室以提高可行性和有效性然而，还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缓解。 在 EC-SCZ 患者睡眠期间使用闭环听觉刺激 (CLAS) 进行急性修改并检查 CLAS 相关的纺锤波和慢波变化是否与这些患者的认知变化相关。 我们建议进行无线/PSG 夜间睡眠记录并评估运动序列的表现 攻丝（MST），MC任务，作为CC和WM的AX-CPT中的主要认知测量和表现 70 名 EC-SCZ 和 70 名 HC 受试者还将接受听觉认知测量。 采用双盲交叉设计进行刺激和假夜，并进行睡眠、MST 和 AX-CPT 评估。