Understanding the Mechanistic Interrelationship between Sleep, Co-Occurring Cannabis and Alcohol Use Disorder, and Neurocircuit Dysfunction during Early Abstinence

摘要 背景：睡眠可能在戒断中起关键作用。从大麻或酒精中戒断的人 在其他客观睡眠障碍中，慢波睡眠显著减少。独立于 物质使用，客观睡眠障碍，包括慢波睡眠持续时间的损害，慢波 活动和稳态睡眠驱动与异常的额边缘系统负性情感有关 神经回路以及负面情绪症状。重要的是，这些额叶边缘回路 大麻使用障碍（CUD）和酒精使用障碍（AUD）。因此，睡眠障碍可能是一种 机制的贡献者戒断症状，与额边缘功能障碍介导这种关系。 目的：这项建议旨在描述这些客观睡眠变化的时间轨迹， 在早期戒断期间同时发生CUD + AUD的个体，并确定这些变化如何相互关联 额叶边缘功能障碍和戒断症状方法/设计：在R61阶段，我们的目标是 在一项纵向观察性研究中检查了40名符合条件的患有共同发生的大麻使用障碍的成年人， 记录睡眠、额叶边缘功能和多种负性情感戒断症状的客观测量结果。 28天停药期内的时间点。主要的睡眠指标包括慢波睡眠持续时间 （N3阶段的分钟），慢波活动（NREM期间0.5和4.0 Hz之间的相对频谱功率），以及 稳态睡眠驱动（在随后的NREM周期中慢波EEG功率的下降）。额边缘 将使用负性情感反应性的fMRI任务来评估功能。负性情感戒断症状 会关注焦虑和抑郁如果符合R61里程碑标准，在R33阶段，我们将招募 另外80名成年人参加了一项双臂随机对照机制试验，以探讨是否干预 睡眠轨迹将引起神经回路目标下游变化以及这些轨迹如何相关 戒断症状具体目标：在R61阶段，我们的目标是建立客观睡眠的程度 CUD + AUD戒断障碍及其与额边缘功能和症状的关系 根据预先规定的里程碑标准。在R33中，我们的目标是1。检查目标的可修改性 CUD + AUD戒断期间的睡眠障碍，使用经过充分验证的睡眠操作。2.评估 客观睡眠障碍的变化与额边缘功能障碍和 戒断症状3.确定治疗结果的睡眠和神经回路调节因子。影响：我们的 神经生物学结果将为新的睡眠和大脑治疗靶点提供信息，并建立它们的可修改性， 早期戒断时有CUD + AUD者。需要这些研究来了解 客观睡眠障碍与戒断相关的神经回路功能障碍和症状，因此将 告知是否有针对性的睡眠干预早期禁欲将在多物质使用的保证。

ABSTRACT Background: Sleep may play a key role in withdrawal. Individuals withdrawing from either cannabis or alcohol have significant reductions in slow-wave sleep, among other objective sleep disturbances. Independent from substance use, objective sleep disturbances, including impairments in slow-wave sleep duration, slow-wave activity, and homeostatic sleep drive, have been associated with aberrant fronto-limbic negative affect neurocircuitry as well as negative affect symptoms. Critically, these same fronto-limbic circuits are also impaired in cannabis use disorder (CUD) and alcohol use disorder (AUD). Thus, sleep disturbance may be a mechanistic contributor to withdrawal symptoms, with fronto-limbic dysfunction mediating this relationship. Objective: This proposal aims to characterize the temporal trajectory of these objective sleep changes in individuals with co-occurring CUD+AUD during early abstinence and establish how these changes interrelate with both fronto-limbic dysfunction and withdrawal symptoms. Methods/Design: In the R61 phase we aim to examine 40 eligible adults with co-occurring cannabis use disorder in a longitudinal observational study to record objective measures of sleep, fronto-limbic function, and negative affect withdrawal symptoms at multiple timepoints across a 28-day withdrawal period. Primary sleep measures include slow-wave sleep duration (minutes in stage N3), slow-wave activity (relative spectral power between 0.5 and 4.0 Hz during NREM), and homeostatic sleep drive (the declination of slow-wave EEG power in subsequent NREM cycles). Fronto-limbic function will be assessed using an fMRI task of negative affect reactivity. Negative affect withdrawal symptoms will focus on anxiety and depression. If the R61 milestone criteria are met, in the R33 phase we will enroll an additional 80 adults into a 2-arm randomized controlled mechanistic trial to address whether intervening in the sleep trajectory will induce downstream changes in neurocircuit targets as well as how these trajectories relate to withdrawal symptoms. Specific Aims: In the R61 phase we aim to establish the extent of objective sleep disturbance across CUD+AUD withdrawal and its associations with fronto-limbic function and symptoms according to pre-specified milestone criteria. In the R33 we aim to 1. Examine the modifiability of objective sleep disturbance during CUD+AUD withdrawal using a well-validated sleep manipulation. 2. Assess the relationships between the change in objective sleep disturbance with both fronto-limbic dysfunction and withdrawal symptoms. 3. Determine sleep and neurocircuit moderators of treatment outcome. Impact: Our neurobiological results will inform novel sleep and brain treatment targets and establish their modifiability in those who have CUD + AUD in early abstinence. These studies are needed to understand the contribution of objective sleep disturbance to withdrawal-related neurocircuit dysfunction and symptoms, and therefore will inform whether a targeted sleep intervention in early abstinence would be warranted in polysubstance use.