Prefrontal Function in Adolescent Limited vs Life Course Persistent SUD

描述（由申请人提供）：本申请的重点是了解从青春期到青年期青少年发作的酒精和/或大麻使用障碍（定义为DSM-IV物质滥用/依赖（SUD））的持续性与停止性的大脑机制。我们建议测量前额叶和海马的认知功能与一个全面的神经心理电池和功能磁共振成像（fMRI）扫描范式，决策奖励不确定性任务，旨在挑战前额叶皮层（PFC），背外侧（dlPFC）和腹内侧（vmPFC）系统的两个主要细分。DLPFC和VMPFC分别服务于决策和奖励评估中涉及的执行功能的不同组成部分。SUD与这些PFC系统的功能障碍有关。该应用程序建立在一个独特的纵向研究的代表性人口样本的儿童：大烟山研究（GSMS）。参与者（N= 1，411名幸存者）于1993年在9-13岁时首次评估了轴I障碍，包括药物和酒精使用，滥用和成瘾，迄今为止平均接受了6次评估。一半的参与者是女性，25%的样本是美国印第安人。参与者将从GSMS中招募，GSMS重新评估26-28岁时DSM-IV轴I诊断，并在此基础上招募160人进入病例对照研究（每个牢房40人）：1）活动受限性SUD（AL-SUD），2）青少年持续性SUD，也称为生命过程持续性SUD（LCP-SUD），3）青年SUD组的高风险（高危组）有青少年精神疾病史，无SUD史，且年龄、性别和社会人口统计学与SUD受试者匹配，和4）没有SUD或主要轴I障碍史的对照组。青少年发作SUD的神经生物学研究需要控制共病，因为在精神障碍中观察到的PFC缺陷可能是SUD风险增加的原因。我们预测LCP-SUD与AL-SUD受试者的dlPFC和vmPFC功能差异。这一建议也将使我们能够测量青少年有限与持续SUD对年轻成人前额叶和海马结构和功能发育的影响。我们预计，我们将观察到AL-SUD、LCP SUD、高风险组和对照组之间dlPFC和vmPFC活动模式、认知功能和海马体积的显著差异。公共卫生相关性了解那些继续与药物和酒精有终身问题的人的神经生物学基础，而那些没有与公共卫生有重要相关性的人。这种理解可以帮助更好地识别那些处于风险中的人，并帮助开发更好的治疗方法，为这些脆弱的个人提供资源和干预措施。了解成瘾的脑功能障碍对于更有效地治疗青少年物质滥用至关重要。

DESCRIPTION (provided by applicant): The focus of this application is to understand the brain mechanisms of persistence versus desistence of adolescent onset alcohol and/or marijuana use disorder (defined as DSM-IV substance abuse/dependence (SUD)) from adolescence into young adulthood. We propose to measure prefrontal and hippocampal cognitive function with a comprehensive neuropsychological battery and a functional MRI (fMRI) scan paradigm, the Decision-Reward Uncertainty Task, designed to challenge the two major subdivisions of prefrontal cortex (PFC), the dorsolateral (dlPFC) and ventromedial (vmPFC) systems. DlPFC and vmPFC serve distinct components of executive functions involved in decision making and reward evaluation, respectively. SUDs are associated with dysfunction in these PFC systems. The application builds on a unique longitudinal study of a representative population sample of children: the Great Smoky Mountains Study (GSMS). Participants (N=1,411 surviving) were first assessed for Axis I disorders including drug and alcohol use, abuse, and addiction in 1993 at ages 9-13, and have received an average of 6 assessments so far. Half the participants are female, and 25% of the sample is American Indian. Participants will be recruited from the GSMS, which re-assesses DSM-IV Axis I diagnosis at ages 26-28, and on the basis of which 160 will be recruited into a case-control study (40 in each cell): 1) adolescence-limited SUD (AL- SUD), 2) adolescent persistent also called life course persistent SUD (LCP -SUD), 3) a high risk for SUD group of young adults (high risk group) with a history of adolescent psychiatric disorders who do not have a history of SUDs and are age, sex, and sociodemographically matched to the SUD subjects, and 4) a control group with no history of SUD or major Axis I disorders. Neurobiological studies of an adolescent onset SUD need to control for co-morbidity since the PFC deficits seen in mental disorders may be responsible for the increased risk for SUD. We predict that there will be dlPFC and vmPFC functional differences in subjects with LCP-SUD vs. AL-SUD. This proposal will also allow us to measure the effects of an adolescent limited vs persistent SUD on young adult prefrontal and hippocampal structural and functional development. We expect that we will observe significant differences in the patterns of dlPFC and vmPFC activity, cognitive function, and hippocampal volumes between AL-SUD, LCP SUD, high risk, and control groups. PUBLIC HEALTH RELEVANCE Understanding the neurobiological underpinnings of individuals who go on to have lifelong problems with drugs and alcohol versus those who do not has important relevance to public health. This understanding can help to better identify those at risk and to help develop better treatments and deliver resources and interventions to these vulnerable individuals. Understanding of brain dysfunction of addiction is critical for more effective treatments of adolescent substance abuse.