A risk factor analysis of human brain states related to development of addiction

描述（由申请人提供）：药物成瘾的慢性复发性障碍是行为和大脑状态转变的产物，因为冲动性药物使用升级为强迫性药物滥用。这些过渡状态是由动物模型很好地告知，虽然他们的人类代表是未知的。在这个修订后的提案中，我们建议通过描述三个假定的成瘾风险因素的影响和相互作用效应来定义人类向药物成瘾过渡的神经生物学机制：青春期的发育期，暴露于早期生活创伤，以及存在潜在的问题药物滥用。提出了四个具体目标来检验项目假设。一个概念模型将进行测试，其中早期创伤对两个中间人格特质的影响，涉及消极（压力反应，目标1）和积极（冲动性，目标2）行为强化过程介导从冲动到强迫性药物使用过渡的高风险。这两个特征是强迫性药物滥用的行为强化模型的核心，其中压力或烦躁的缓解会强化药物使用，冲动或抑制性行为控制的缺陷会强化药物使用。这两种特征也会因早年生活压力而加剧。通过任务相关的功能性磁共振成像（fMRI）反应，比较具有潜在问题药物使用（-/+）或创伤暴露史（-/+）但不符合药物依赖、创伤后应激障碍或抑郁症的综合征标准的青春期女孩组。进一步的横断面比较将确定成瘾发展的风险是否与药物依赖成人的成瘾过程具有神经相关性（目的3）。使用fMRI模式分类和预测方法的多变量、个体水平分析将以候选强化过程的神经信息处理网络的功能组织改变的形式寻求成瘾过渡风险的神经生物学解释（目的4）。拟议的横断面研究设计将测试一个总体假设，即创伤暴露通过改变与药物成瘾风险相关的两个行为强化过程（应激反应性和冲动性）的大脑成熟度，使受影响的个体倾向于药物使用障碍。

DESCRIPTION (provided by applicant): The chronically relapsing disorder of drug addiction is the product of behavior and brain state transitions as impulsive drug use escalates to compulsive drug abuse. These transition states are well informed by animal models though their human representations are not known. In this revised proposal, we propose to define the human neurobiological mechanisms of transition to drug addiction by characterizing the impact and interaction effects for three putative addiction risk factors: the developmental period of adolescence, exposure to early life trauma, and the presence of potentially problematic drug abuse. Four specific aims are proposed to test project hypotheses. A conceptual model would be tested in which the impact of early trauma on two intermediate personality traits involving negative (reactivity to stress, Aim 1) and positive (impulsivity, Aim 2) behavioral reinforcement processes mediates the heightened risk for transition from impulsive to compulsive drug use. These two traits are central to behavioral reinforcement models of compulsive drug abuse in which relief of stress or dysphoria reinforces drug use and impulsivity or deficits in inhibitory behavioral control reinforces drug use. Both traits are also heightened by early life stress. Groups of adolescent girls differing in having potentially problematic drug use (-/+) or trauma exposure histories (-/+), but not fulfilling syndromal criteria for drug dependence, PTSD or depression, would be compared by task- related functional magnetic resonance imaging (fMRI) responses. Further cross-sectional comparisons would determine whether risk for development of addiction shares a neural correlate of addiction processes with drug-dependent adults (Aim 3). Multivariate, individual-level analyses using fMRI pattern classification and prediction approaches would seek neurobiological explanations of addiction transition risk in the form of altered functional organization of neural information processing networks for the candidate reinforcement processes (Aim 4). The proposed cross-sectional study design would test an overall hypothesis that trauma exposure predisposes affected individuals towards drug use disorders by altering the brain maturation of two behavioral reinforcement processes linked to drug addiction risk: stress reactivity and impulsivity.