An Experimental Medicine Approach for the Mechanistic Understanding of Cocaine Use Disorder: Reinforcer Pathology

项目总结 开发针对可卡因使用障碍(Cud)的新一代干预措施是一项重要的科学 差距，如果得到解决，将打开创新机会。为了解决这一差距，我们采用了试验性的 机械检查增强剂病理学的医学方法--一种新兴的新框架 成瘾，这可能为干预发展提供一个原则性的基础。强化病理学规定 增强剂在时间窗口上集成，该窗口的长度确定相对 不同增强剂的价值。当时间窗很短时，像可卡因这样短暂的增强剂， 强烈，可靠，将会有更大的价值。相反，随着时间窗口的延长，还会有更多 临时延长的增强剂开始产生更大的影响，可卡因的估值将会下降。这个 增强病理学的概念识别用延迟折扣测量的时间窗口(即 作为CUD的治疗靶点的增强剂的价值下降)，并且它允许 通过创新干预(例如，插曲的未来思维；EFT)实现目标参与，以提供对以下方面的新见解 可卡因估价。该项目使用多个分析水平(例如，行为实验室、神经成像和 计算模型)对CUD患者的可卡因估价进行量化、预测和调整。在……里面 目标1，我们将检查同时增加和减少时间窗口的操作 对增强剂病理框架进行机械测试。在目标1a中，我们将审查连续 暴露于增加可卡因伴随变化的时间窗(EFT)的干预 估值(需求和渴望)。在目标1b中，我们将检查降低 暴露于EFT后的时间窗口(应激探头)对可卡因估值的伴随变化。 在整个目标1中，还将检查与时间窗口中的变化相关的神经活动。在AIM 2、我们将使用fmri数据的多体素分析来探索与增强剂相关的两个独立子目标。 CUD的病理学。首先，在目标2a中，我们将建立fmri延迟折扣的多变量分组回归模型。 具有CUD的参与者子集中的数据，以预测独立参与者子集中的折扣。第二, 在目标2b中，我们将使用实时功能磁共振神经反馈来增强参与者控制其颞叶的能力 窗口，因此它们有能力调节延迟折扣和可卡因估值。在目标3中，我们将对 通过计算量化来自目标1和目标2(目标3a)的结果并将主观 利用计算神经科学对大脑感兴趣区域的价值(目标3b)。总而言之，这一发现 严谨和创新的研究项目将提高我们对CUD的理解，并突出潜在的小说 有效的干预策略。

PROJECT SUMMARY Developing a new generation of interventions for cocaine use disorder (CUD) constitutes an important scientific gap and, if addressed, will open innovation opportunities. To address this gap, we employ the Experimental Medicine approach to mechanistically examine Reinforcer Pathology, an emerging novel framework for addiction, that may provide a principled foundation for intervention development. 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 cocaine, 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 cocaine 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 CUD, and it permits target engagement via innovative interventions (e.g., episodic future thinking; EFT) to provide novel insights into cocaine valuation. This project uses multiple analytical levels (e.g., the behavioral laboratory, neuroimaging, and computational modeling) to quantify, predict, and modulate cocaine valuation among individuals with CUD. In Aim 1, we will examine manipulations that increase and decrease the temporal window in parallel to mechanistically test the Reinforcer Pathology framework. In Aim 1a, we will examine the effects of successive exposure to an intervention that increases the temporal window (EFT) on concomitant changes in cocaine valuation (demand and craving). In Aim 1b, we will examine the effects of a manipulation that decreases the temporal window (stress probes) after exposure to EFT on concomitant changes in cocaine 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 CUD. First, in Aim 2a, we will build multivariate group regression models of fMRI delay discounting data in a subset of participants with CUD 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 cocaine valuation. In Aim 3, we will model the temporal window 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 CUD and highlight potential novel and efficacious intervention strategies.