Testing Reinforcer Pathology: Mechanisms and Interventions to Change Alcohol Valuation

项目总结 开发新一代酒精使用障碍(AUD)干预措施构成了一项重要的科学 差距，如果得到解决，将打开创新机会。为了解决这一差距，我们建议研究一项 新兴的成瘾新框架，强化病理学。增强剂病理学规定增强剂是 在时间窗口上集成，该窗口的长度确定不同的 增强剂。当时间窗很短时，酒精等短暂、强烈和可靠的增强剂， 将会有更大的价值。相反，随着时间窗口的延长，其他时间窗口会更长 增强剂开始产生更大的影响，酒精估值将会下降。增强剂的概念 病理学识别时间窗，用延迟贴现测量(即， 作为其延迟的函数的增强剂)，作为AUD的治疗靶点，并且它允许通过 创新的干预措施(例如，插曲的未来思维；EFT)，以提供对酒精估值的新见解。这 项目使用多个分析水平(例如，行为实验室、门诊现场研究、神经成像、 和计算模型)来量化、预测和调节AUD患者的酒精估值。 在目标1中，我们将检查增加和减少时间窗口的操作，以进行机械测试 强化病理框架。在目标1a中，我们将研究增加 酒精评估伴随变化的时间窗口(EFT)(自我管理、渴望和行为 经济酒精需求)。此外，目标1a的参与者将参加一项概念验证实地研究， 将使用远程实施EFT来影响饮酒(通过远程监控 呼吸酒精)在自然环境中。在Aim1b中，我们将检查降低 酒精估值伴随变化的时间窗口(模拟经济稀缺性)。贯穿始终 目标1，还将检查与时间窗变化相关的神经活动。在目标2中，我们将 使用功能磁共振数据的多体素分析来探索与增强病理相关的两个独立的子目标 澳元。首先，在目标2a中，我们将建立fmri延迟贴现数据的多元分组回归模型。 具有澳元的参与者子集，用于在独立的参与者子集中预测折扣。第二，在目标上 2B，我们将使用实时fMRI神经反馈来增强参与者控制他们的时间窗口的能力， 因此，他们有能力调整延迟折扣和酒类估值。在目标3中，我们将对时态 通过计算量化目标1和目标2(目标3a)的结果来扩展现有文献的窗口，以及 使用计算神经科学将主观价值与大脑感兴趣区域联系起来(目标3b)。一起， 这一严谨和创新的研究项目的发现将提高我们对澳元和 突出潜在的新颖和有效的干预策略。

PROJECT SUMMARY Developing a new generation of interventions for alcohol use disorder (AUD) constitutes an important scientific gap and, if addressed, will open innovation opportunities. To address this gap, we propose to examine an emerging novel framework for addiction, reinforcer pathology. Reinforcer pathology specifies that reinforcers are integrated over a temporal window, and the length of that window determines the relative value of different reinforcers. When the temporal window is short, reinforcers such as alcohol, which are brief, intense, and reliable, will have greater value. Conversely, as the temporal window lengthens, other more temporally extended reinforcers begin to have greater influence and alcohol valuation will decrease. The concept of reinforcer pathology identifies the temporal window, measured with delay discounting (i.e., the decline in the value of a reinforcer as a function of its delay), as a therapeutic target for AUD, and it permits target engagement via innovative interventions (e.g., episodic future thinking; EFT) to provide novel insights into alcohol valuation. This project uses multiple analytical levels (e.g., the behavioral laboratory, an outpatient field study, neuroimaging, and computational modeling) to quantify, predict, and modulate alcohol valuation among individuals with AUD. In Aim 1, we will examine manipulations that increase and decrease the temporal window to mechanistically test the reinforcer pathology framework. In Aim 1a, we will examine the effects of an intervention that increases the temporal window (EFT) on concomitant changes in alcohol valuation (self-administration, craving, and behavioral economic alcohol demand). In addition, participants in Aim 1a will participate in a proof-of-concept field study, where remote implementation of EFT will be used to impact alcohol drinking (measured by remote monitoring of breath alcohol) in the natural environment. In Aim1b, we will examine the effects of a manipulation that decreases the temporal window (simulation of economic scarcity) on concomitant changes in alcohol valuation. Throughout Aim 1, neural activity associated with changes in the temporal window will also be examined. In Aim 2, we will use multi-voxel analyses of fMRI data to explore two independent sub-aims related to reinforcer pathology in AUD. First, in Aim 2a, we will build multivariate group regression models of fMRI delay discounting data in a subset of participants with AUD to predict discounting in an independent subset of participants. Second, in Aim 2b, we will use real-time fMRI neurofeedback to enhance participants' ability to control their temporal window, and hence their ability to modulate delay discounting and alcohol valuation. In Aim 3, we will model the temporal window to extend the existing literature by computationally quantifying results from Aims 1 and 2 (Aim 3a), and connecting subjective value to brain regions of interest using computational neuroscience (Aim 3b). Together, the findings from this rigorous and innovative research project will improve our understanding of AUD and highlight potential novel and efficacious intervention strategies.