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

描述(申请人提供)：慢性复发性药物成瘾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制药物滥用。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。在这份修订的提案中，我们建议通过表征三个可能的成瘾风险因素的影响和交互作用来定义人类向药物成瘾过渡的神经生物学机制：青春期发育期、早期生活创伤和潜在问题药物滥用的存在。为了检验项目假设，本文提出了四个具体目标。将测试一个概念模型，在该模型中，早期创伤对两种中间人格特征的影响，涉及消极(对压力的反应性，目标1)和积极(冲动，目标2)行为强化过程中介从冲动药物使用向强制药物使用转变的高风险。这两个特征是强迫性药物滥用的行为强化模型的核心，在该模型中，压力或焦虑感的缓解会加强药物的使用，而抑制行为控制的冲动或缺陷会加强药物的使用。早年的生活压力也会使这两个特征更加突出。有潜在问题药物使用史(-/+)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青春期女孩群体，将通过与任务相关的功能磁共振成像(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神经相关性(目标3)。使用功能磁共振模式分类和预测方法的多变量、个体水平的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转变风险的神经生物学解释(目标4)。拟议的横断面研究设计将检验一项总体假设，即创伤暴露通过改变与药物成瘾风险有关的两个行为强化过程的大脑成熟程度，使受影响的个人容易患上药物使用障碍：应激反应和冲动。

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.