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

摘要 慢性复发性毒瘾障碍是行为和大脑状态转变的产物，如 冲动吸毒升级为强迫性吸毒。这些过渡状态是由动物很好地了解的 模型，尽管他们的人类表现是未知的。在这项修订建议中，我们建议界定 人类转化为药物成瘾的神经生物学机制通过表征影响和 三个假定成瘾危险因素的交互作用：青春期发育期， 暴露于早期生活创伤，以及存在潜在的有问题的药物滥用。四个具体目标是 建议对项目假设进行检验。将测试一个概念性模型，在该模型中，早期创伤的影响 关于两种中间人格特征，包括消极的(对压力的反应，目标1)和积极的(冲动， 目的2)行为强化过程调节从冲动到冲动转变的高风险 强迫性药物使用。这两个特征是强迫性药物行为强化模型的核心。 一种滥用，缓解压力或烦躁不安会加剧药物使用和冲动或抑制缺陷 行为控制强化了药物的使用。早年的生活压力也会使这两个特征更加突出。几组人 青春期女孩不同于有潜在问题的药物使用(-/+)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症状标准的人，将按任务进行比较- 相关功能磁共振成像(FMRI)反应。进一步的横断面比较将 确定成瘾发展的风险是否与成瘾过程的神经相关 药物依赖成人(目标3)。使用fMRI模式分类的多变量、个体水平分析和 预测方法将以以下形式寻求成瘾转移风险的神经生物学解释 用于候选加固的神经信息处理网络的改变的功能组织 进程(目标4)。拟议的横断面研究设计将检验创伤的总体假设 暴露使受影响的人容易患上药物使用障碍，因为它改变了两个人的大脑成熟。 与药物成瘾风险相关的行为强化过程：应激反应和冲动。

Abstract 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.