Decision Neuroscience of Craving

项目概要/摘要 目前的阿片类药物流行是一场紧迫的公共卫生危机。重复使用和复发的一个关键诱发因素 在阿片类药物使用障碍（OUD）患者中，对药物的渴望或强烈的特定欲望。而 渴望已被广泛研究，并被称为预测药物使用，我们仍然缺乏一个解释， 算法精确的模型，可以直接将渴望神经生物学与其观察到的后果联系起来： 决定追求毒品而不是其他有价值的替代品。鉴于OUD的典型治疗方法不 充分解决渴望，并未能防止许多患者重复使用，澄清了精确的，决策相关的， 渴望的机制可能会为治疗渴望和改善临床结果提供更有针对性的方法。 为了解决这些重要的问题，我们开发了一个实验范式来研究渴望， 决策神经科学中广泛使用的方法，以评估基于价值的决策。决策神经科学 (or神经经济学）整合了心理学、经济学和神经科学的概念和方法， 了解决策的神经结构，并已越来越多地应用于机械 包括成瘾在内的精神疾病的研究。我们的范例构成了一个新的应用， 通过量化受试者的当下（即，状态依赖）的决策过程中的渴望15. 在健康和阿片类药物成瘾受试者的试点行为研究中，我们发现这种范式捕获了1）如何 价值-决定追求一个特定的选择与另一个的关键决定因素-变化下 渴望，以及2）这种效应对渴望对象的选择性。它还3）提供了一个算法特定的 这种变化的过程（数学描述），可用于将行为与其神经基质联系起来。在 本研究旨在通过识别特定的神经计算来阐明这种神经基质 通过这种方式，渴望调节药物和非药物替代品的价值，从而调节药物使用决策， 人OUD。我们建议在N=89例OUD患者中确定阿片类药物渴求的神经底物， 在短暂的渴望诱导后，在fMRI中以受试者内交叉设计完成我们的范式， 控制操作16.由于决策电路以奖励身份特定的方式编码值， 设计将使我们能够将与药物相关的计算与非药物相关的计算隔离开来。 值我们的研究将首次确定实验性诱发的渴望是否以及如何动态地 转移这种与药物相关的价值的“身份特异性”神经编码（目标1），以及假定的“渴望”的部分 在这个转变中涉及的“电路”（目标2）。为了测试这种机制是否是唯一的和特定于奖励身份的，我们 还将测量与实验诱导的食物渴望和特定食物价值相关的大脑活动， 相同的患者和N=89名健康对照（目标3）。如果成功，这种综合方法将揭示 有选择地减轻由渴望引起的药物价值增加的精确目标，这种增加会促进阿片类药物的重复使用， 为精确干预奠定基础，以治疗对治疗无反应的人的渴望。

Project Summary/Abstract The current opioid epidemic is a pressing public health crisis. A key precipitating factor of reuse and relapse among people with opioid use disorders (OUD) is craving, or the intense, specific desire for the drug. While craving has been extensively studied, and is known to predict drug use, we still lack an explanatory and algorithmically-precise model that can directly link craving neurobiology to its observed consequences: the decision to pursue drugs over other valuable alternatives. Given that typical treatments for OUD do not adequately address craving and fail to prevent reuse in many patients, clarifying the precise, decision-relevant, mechanism of craving may critically inform more targeted ways to treat craving and improve clinical outcome. To address these important questions, we developed an experimental paradigm to study craving based on methods widely used in decision neuroscience to assess value-based decision-making. Decision neuroscience (or neuroeconomics) integrates concepts and methods from psychology, economics, and neuroscience to understand the neural architecture for decision-making, and has been increasingly applied in mechanistic studies of psychiatric disorders including addiction. Our paradigm constitutes a novel application of this framework by quantifying a subject’s in-the-moment (i.e., state-dependent) decision process during craving15. In pilot behavioral studies in healthy and opioid addicted subjects, we find that this paradigm captures 1) how value—the key determinant of the decision to pursue a particular option versus another—changes under craving, and 2) the selectivity of this effect to the object of craving. It also 3) provides an algorithmically-specific process (a mathematical description) of this change that can be used to tie behavior to its neural substrate. In the present study we aim to elucidate this neural substrate by identifying the specific neural computations through which craving modulates the value of drug and nondrug alternatives and thereby drug use decisions in human OUD. We propose to identify the neural substrate of opioid craving in N=89 OUD patients who will complete our paradigm during fMRI in a within-subjects cross-over design following a brief craving induction or a control manipulation16. Because decision circuits encode value in a reward-identity specific manner, our design will enable us to isolate the computations associated with drug-related value from those of nondrug value. Our study will for the first time determine whether and how experimentally-induced craving dynamically shifts such “identity-specific” neural encoding of drug-related value (Aim 1), and the parts of a putative ‘craving circuit’ involved in this shift (Aim 2). To test whether this mechanism is unique and reward-identity specific, we will also measure brain activity associated with experimentally-induced food craving and specific food-value in the same patients and N=89 healthy controls (Aim 3). If successful, this integrative approach will uncover precise targets for selectively mitigating craving-induced increases in drug-value that promote opioid reuse, laying the groundwork for precision interventions to treat craving in treatment unresponsive individuals.