Optimizing sleep spindle measurements as translational assays of memory consolidation

这项研究提案解决了药物开发的一个关键挑战：揭示 在出发前，干预是否会在动物和人类的早期阶段影响被牵连的大脑电路 进行漫长而昂贵的临床试验。对人类和啮齿动物的研究已经建立了睡眠纺锤波，定义了 第二阶段非快速眼动(NREM)睡眠的脑电振荡，作为记忆巩固的机制。 越来越多的研究表明睡眠纺锤体异常与神经发育和神经退行性变有关 以记忆力受损为特征的疾病。在精神分裂症患者中，睡眠纺锤体缺陷预示着睡眠受损- 从属记忆巩固。研究发现，通过药物或听觉或经颅脑增加纺锤波 睡眠中的刺激可改善健康人的记忆力，为靶向纺锤波的改善提供动力 记忆障碍。但瞄准纺锤波并不一定能改善记忆。互补的啮齿动物和 人类研究提供了一个解释：睡眠依赖的记忆巩固不仅依赖于纺锤波，而且 关于它们与另外两种主要NREM睡眠振荡的精确时间协调：大脑皮层慢 振荡(SOS)和海马尖波纹。这些发现清楚地表明，尽管纺锤体是 改善记忆的有希望的目标：(I)有效的治疗需要增加纺锤波并保存或 增强它们与SOS和涟漪的耦合，以及(Ii)为了评估疗效，我们需要新的分析方法来识别纺锤体 这与SOS和涟漪结合在一起来调节记忆，而不是那些没有这样做的。我们建议：(I)确定 最强大的睡眠纺锤波转换测量作为睡眠依赖记忆巩固的测试 (UG3)，以及(Ii)非侵入性地操纵它们，以比较它们在健康人和啮齿动物身上的反应 (UH3)。利用癫痫患者的有创记录和大鼠的局部场电位，我们将首先 演示同时具有SOS和涟漪的磁盘轴(TriCS：三重耦合磁盘轴)相关联 通过记忆巩固，从而确认TriCS是记忆的翻译生物标记物。然后我们将使用 机器学习开发一种分类器，仅根据头皮脑电特征识别TriCS。我们会 通过将其应用于来自健康人的数据集来验证EEG纺锤形分类器，以证明TriCS， 但不是非偶联的纺锤体，与记忆巩固相关。在这两个物种中，我们将确定哪一个 纺锤体分析TriCS、SoC或总纺锤体预测记忆效果最好。最后，我们会 非侵入性地操纵人和大鼠的纺锤体分析。基因研究正在牵涉到特定的 精神分裂症和自闭症纺锤体缺陷的病理生理机制及识别新靶点和 治疗。我们将开发的啮齿动物和人类纺锤体分析将促进这些基因的翻译 通过允许在治疗早期对潜在干预措施进行有效评估而向临床推进 开发流水线和确定最有希望进行临床试验的候选者。

This research proposal addresses a key challenge to drug development: the paucity of biomarkers that reveal whether interventions affect implicated brain circuitry at early stages, in animals and humans, before embarking on lengthy and expensive clinical trials. Studies of humans and rodents have established sleep spindles, defining EEG oscillations of stage 2 non-rapid eye movement (NREM) sleep, as a mechanism of memory consolidation. A growing body of work implicates sleep spindle abnormalities in neurodevelopmental and neurodegenerative disorders characterized by memory impairment. In schizophrenia, sleep spindle deficits predict impaired sleep- dependent memory consolidation. Findings that increasing spindles via drugs or auditory or transcranial brain stimulation during sleep improves memory in healthy people, provides the impetus to target spindles to improve memory in disorders. But targeting spindles does not inevitably improve memory. Complementary rodent and human studies provide an explanation: sleep-dependent memory consolidation relies not on spindles alone, but on their precise temporal coordination with the other two cardinal NREM sleep oscillations: cortical slow oscillations (SOs) and hippocampal sharp-wave ripples. These findings make it clear that while spindles are promising targets for improving memory, (i) effective therapies need to increase spindles AND preserve or enhance their coupling with SOs and ripples, and (ii) to evaluate efficacy, we need new assays to identify spindles that couple with SOs and ripples to mediate memory versus those that do not. We propose to: (i) identify the most powerful translational measures of sleep spindles as assays of sleep-dependent memory consolidation (UG3), and (ii) to noninvasively manipulate them to compare their responses in healthy humans and rodents (UH3). Using invasive recordings in epilepsy patients and local field potentials (LFPs) in rats, we will first demonstrate that spindles that couple with both SOs and ripples (TriCS: triple-coupled spindles) are associated with memory consolidation, thereby validating TriCS as a translational biomarker of memory. We will then use machine learning to develop a classifier that identifies TriCS based solely on their scalp EEG features. We will validate the EEG spindle classifier by applying it to a dataset from healthy humans to demonstrate that TriCS, but not non-coupled spindles, correlate with memory consolidation. In both species, we will determine which spindle assay TriCS, SO-coupled spindles (SOCS) or total spindles predicts memory best. Finally, we will noninvasively manipulate the spindle assays in humans and rats. Genetic studies are implicating specific pathophysiologic mechanisms of spindle deficits in schizophrenia and autism and identifying novel targets and treatments. The rodent and human spindle assays that we will develop will facilitate the translation of these advances to the clinic by allowing the efficient evaluation of potential interventions early in the treatment development pipeline and the identification of the most promising candidates for clinical trials.