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

项目摘要 开发新一代可卡因使用障碍（CUD）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。为了解决这一差距，我们采用了实验 医学方法机械地检查强化病理学，一个新兴的新框架， 成瘾，这可能为干预发展提供原则基础。强化病理学规定 在时间窗口上积分，并且该窗口的长度决定相对的 不同的价值观。当时间窗较短时，可卡因等短暂的兴奋剂， 强烈的，可靠的，将有更大的价值。相反，随着时间窗口的延长， 暂时延长的麻醉品开始产生更大的影响，可卡因的价值将下降。的 强化病理学的概念识别了时间窗，用延迟折扣（即，的 作为其延迟的函数，作为CUD的治疗靶点，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）， 可卡因估值该项目使用多个分析级别（例如，行为实验室，神经成像， 计算建模）来量化、预测和调节患有CUD的个体中的可卡因评价。在 目标1，我们将检查增加和减少时间窗口的操作， 机械地测试强化病理学框架。在目标1a中，我们将研究连续 暴露于增加可卡因伴随变化的时间窗（EFT）的干预 价值（需求和渴望）。在目标1b中，我们将研究一种操纵的效果， 暴露于EFT后的时间窗（压力探针）对可卡因评价的伴随变化。 在整个目标1中，还将检查与时间窗变化相关的神经活动。在Aim中 2、我们将利用fMRI数据的多体素分析来探索与Reinforcer相关的两个独立的子目标 病理学在CUD。首先，在目标2a中，我们将建立fMRI延迟折扣的多变量组回归模型 使用CUD来预测参与者的独立子集中的折扣。第二、 在目标2b中，我们将使用实时fMRI神经反馈来增强参与者控制其颞叶的能力。 窗口，因此他们的能力，以调节延迟折扣和可卡因的估值。在目标3中，我们将对 通过计算量化目标1和2（目标3a）的结果，并将主观 使用计算神经科学对大脑感兴趣区域的价值（目标3b）。总之，这项研究的结果 严谨和创新的研究项目将提高我们对CUD的理解，并突出潜在的新颖性 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.