Sleep-dependent negative overgeneralization in peri-pubertal anxiety

围青春期焦虑中睡眠依赖性消极过度概括

基本信息

批准号：
10580966
负责人：
DANA L MCMAKIN
金额：
$ 5.26万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10580966
关键词：
Address Adolescence Affect Age Amygdaloid structure Anxiety Arousal Basic Science Behavior Behavioral Behavioral Mechanisms Binding Biological Markers Clinical Cues Depression and Suicide Development Dimensions Emotional Enrollment Etiology Event Exhibits Fire - disasters Functional disorder Future Goals Health Hippocampus (Brain)Hour Individual Intervention Knowledge Lead Learning Magnetic Resonance Imaging Mediating Mediator of activation protein Memory Mental Depression Methods Modeling National Institute of Mental Health Neurosciences Organism Participant Pattern Physiology Play Polysomnography Process Protocols documentation Psychopathology Randomized Risk Role Sampling Shapes Sleep Sleep disturbances Stimulus Strategic Planning Substance abuse problem Symptoms Testing Wakefulness Youth anxiety symptoms anxious classical conditioning design experience high risk improved indexing long term memory memory consolidation memory process memory recall memory trace reactivation neurodevelopment neuroimaging neuromechanism neurophysiology non rapid eye movement novel randomized trial recruit relating to nervous system response sleep abnormalities sound suicidal risk

项目摘要

PROJECT SUMMARY Up to 50% of peripubertal youth with anxiety have unmet clinical needs, leaving these youth at high risk for suicide, depression and substance abuse across adolescence. In accord with the NIMH strategic plan, we aim to deepen mechanistic understanding of anxiety during the sensitive period of peripuberty to inform novel treatments and reduce health risks. This proposal focuses on negative overgeneralization, which is a core dimension of anxiety that is poorly understood, and refers to the tendency to generalize aversive responses from one context (house fire) to other contexts (camp-fire) that share features. Amygdala activity, induced by heightened emotional arousal, enhances plasticity in associative learning mechanisms, facilitating the binding of contextual features in memory that are only loosely related. We posit that sleep plays a critical role in negative overgeneralization. Specifically, we draw from basic neuroscience to propose a model by which heightened amygdala reactivity during wakefulness, induced by increased emotional arousal, facilitates replay of negative memories during sleep. This facilitated replay leads to the stabilization and integration (consolidation) of negative memories into long-term memory networks via slow wave oscillatory events during NREM sleep. We further propose that facilitated replay of negative memories during sleep promotes generalization by influencing underlying neurocomputational mechanisms (i.e., pattern completion – a computational process that makes neural representations similar). Finally, we propose that sleep-dependent consolidation is malleable, such that Targeted Memory Reactivation (TMR) of positive memories during sleep can competitively displace consolidation of negative memories, and reduce negative overgeneralization. The current proposal tests this model using a novel multi-method approach combining neuroimaging, polysomnography, and a memory task that captures behavioral generalization and its underlying neural mechanisms (i.e. pattern completion). Aim 1 examines 200 peripubertal youth (ages 10-13 years) across a full continuum of anxious symptoms in a randomized sleep (n=140) versus wake (n=60) design to demonstrate sleep-dependent effects on behavioral and neural mechanisms of negative overgeneralization. Aim 2 focuses on the 140 youth in the sleep condition to evaluate amygdala reactivity at encoding and sleep neurophysiology during post-encoding sleep as mediators between anxiety and negative overgeneralization. Aim 3 uses the same design as the sleep condition but recruits a new sample of youth with elevated anxiety (n=60) to enroll in a randomized trial in which positive memories are cued during sleep (TMR, n=30), or sham cues are presented during sleep (n=30), to examine malleability of sleep-dependent mechanisms of negative overgeneralization. This project will set the stage for the long-term goal of developing novel interventions that manipulate sleep (e.g. via TMR) not only to improve existing symptoms, but also to positively shape neurodevelopment and reduce risk in the sensitive period of peripuberty.

项目概要高达 50% 患有焦虑症的青春期青少年的临床需求未得到满足，使这些青少年面临高风险整个青春期的自杀、抑郁和药物滥用根据 NIMH 战略计划，我们的目标是。加深对青春期敏感期焦虑的机制理解，为小说提供信息该提案的核心是消极的过度概括。人们对焦虑的维度知之甚少，指的是普遍化厌恶反应的倾向从一种环境（房屋火灾）到其他具有共享特征的杏仁核活动的环境（篝火）。情感情绪唤醒，增强联想学习机制的可塑性，促进结合我们认为睡眠在记忆中起着关键作用。具体来说，我们从基础神经科学中提出了一个模型，通过该模型清醒时杏仁核的充分反应，由情绪唤醒增加引起，有助于重放这促进了睡眠期间负面记忆的重播，从而导致稳定和整合。通过慢波振荡事件将负面记忆（巩固）成长期记忆网络我们进一步提出，在睡眠期间促进负面记忆的重放可以促进 NREM 睡眠。通过影响潜在的神经计算机制（即模式完成 – 最后，我们提出依赖于睡眠的计算过程。巩固是可塑的，因此睡眠期间积极记忆的目标记忆重新激活（TMR）可以竞争性地取代负面记忆的巩固，并减少负面的过度概括。目前的提案使用一种新颖的多方法结合神经影像学来测试该模型，多导睡眠图，以及捕捉行为泛化及其潜在神经元的记忆任务机制（即模式完成）对 200 名青春期前青少年（10-13 岁）进行了全面检查。随机睡眠 (n=140) 与清醒 (n=60) 设计中焦虑症状的连续性，以证明睡眠依赖性对消极过度概括的行为和神经机制的影响。对 140 名处于睡眠状态的青少年进行研究，以评估杏仁核在编码和睡眠神经生理学方面的反应性在编码后睡眠期间作为焦虑和消极过度概括之间的中介。与睡眠条件相同的设计，但招募了一个新的焦虑程度较高的青少年样本（n = 60）来参加一项随机试验，其中在睡眠期间提示积极记忆（TMR，n = 30），或提出虚假提示在睡眠期间（n = 30），检查消极过度概括的睡眠依赖性机制的可塑性。该项目将为开发操纵睡眠的新颖干预措施的长期目标奠定基础（例如通过 TMR）不仅可以改善现有症状，还可以积极塑造神经发育和降低青春期敏感期的风险。