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

描述（由申请人提供）：慢性复发性药物成瘾障碍是冲动药物使用升级为强迫性药物滥用时行为和大脑状态转变的产物。这些过渡状态通过动物模型得到了很好的信息，尽管它们的人类表征尚不清楚。在这一修订后的提案中，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：青春期的发育时期、早期生活创伤的暴露和潜在问题药物滥用的存在。提出了四个具体目标来检验项目假设。一个概念模型将被测试，在这个模型中，早期创伤对两种中间人格特征的影响，包括消极的（应激反应，目的1）和积极的（冲动性，目的2）行为强化过程，介导了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行为强化模型的核心，其中压力或不安的缓解加强了药物使用，冲动或抑制性行为控制缺陷加强了药物使用。早期的生活压力也会加剧这两种特征。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综合征标准的青春期女孩组将通过任务相关功能磁共振成像（fMRI）反应进行比较。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相同的神经关联（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（目标4）。提出的横断面研究设计将测试一个整体假设，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的大脑成熟，即压力反应性和冲动性，使受影响的个体易患药物使用障碍。

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.