Testing Reinforcer Pathology: Mechanisms and Interventions to Change Alcohol Valuation

项目摘要 开发新一代酒精使用障碍（AUD）干预措施是一项重要的科学研究， 这一差距如果得到解决，将带来创新机会。为了弥补这一差距，我们建议研究一个 新出现的成瘾新框架，成瘾病理学。强化病理学规定， 在时间窗口上积分，并且该窗口的长度确定不同的相对值。 咖啡机。当时间窗很短时，酒精等短暂、强烈和可靠的刺激物， 会有更大的价值。相反地，随着时间窗口变长，其它时间上更延长的时间窗口变长。 酿酒商开始有更大的影响力，酒精的价值将下降。概念设计 病理学识别时间窗，用延迟折扣（delaydiscounting）测量（即，a值的下降 作为其延迟的函数），作为AUD的治疗靶点，并且它允许通过 创新的干预措施（例如，情景式未来思维（episodic future thinking，EFT），为酒精估值提供新的见解。这 项目使用多个分析级别（例如，行为实验室，门诊实地研究，神经成像， 和计算建模）来量化、预测和调节AUD患者的酒精价值。 在目标1中，我们将研究增加和减少时间窗口的操作，以机械地测试 癌症病理学框架。在目标1a中，我们将研究增加 时间窗（EFT）对酒精评价（自我管理，渴望和行为）的伴随变化 酒精的需求）。此外，目标1a的参与者将参加一项概念验证实地研究， 其中EFT的远程实施将用于影响饮酒（通过远程监控 酒精在自然环境中。在Aim1b中，我们将研究降低 酒精估值伴随变化的时间窗口（模拟经济稀缺）。在整个 目的1，与时间窗变化相关的神经活动也将被检查。在目标2中，我们将 使用功能磁共振成像数据的多体素分析来探索与肿瘤病理学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延迟折扣数据的多元组回归模型， 参与者的一个子集与澳元预测折扣的独立子集的参与者。第二，在Aim 2b，我们将使用实时功能磁共振成像神经反馈来增强参与者控制他们的时间窗的能力， 因此他们有能力调节延迟折扣和酒精价值。在目标3中，我们将建模时间 通过计算量化目标1和2（目标3a）的结果，扩展现有文献的窗口，以及 使用计算神经科学将主观值与感兴趣的大脑区域连接起来（目标3b）。在一起， 这个严谨而创新的研究项目的结果将提高我们对澳元的理解， 强调潜在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.