Prefrontal Function in Adolescent Limited vs Life Course Persistent SUD

描述(申请人提供)：本申请的重点是了解从青春期到成年的青春期酒精和/或大麻使用障碍(定义为DSM-IV物质滥用/依赖(SUD))持续与戒断的大脑机制。我们建议使用全面的神经心理学组件和功能磁共振成像(FMRI)扫描范式来测量前额叶和海马区的认知功能，这是一种决策-奖励不确定性任务，旨在挑战前额叶皮质(PFC)的两个主要细分：背外侧(DlPFC)和腹内侧部(VmPFC)系统。DLPFC和vmPFC分别为参与决策和奖励评估的执行职能提供不同的组成部分。SODS与这些PFC系统中的功能障碍有关。该应用程序建立在对具有代表性的儿童人群样本的独特纵向研究的基础上：大烟山研究(GSMS)。参与者(N=1,411名幸存的)于1993年首次接受轴心I障碍的评估，包括药物和酒精使用、滥用和成瘾，年龄在9-13岁之间，到目前为止平均接受了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GSM-IV Axis I诊断中心招募，该中心在26-28岁重新评估DSM-IV Axis I诊断，并在此基础上招募160人进行病例对照研究(每个细胞40人)：1)青春期限制性SUD(AL-SUD)，2)青少年持续性SUD(LCP-SUD)，3)无SUD病史且年龄、性别和社会人口学上与SUD受试者匹配的青少年SUD组(高危组)的高风险。(4)对照组，既无SUD病史，也无主轴性疾病病史。对青少年起病的SUD的神经生物学研究需要控制共发病，因为精神障碍中的PFC缺陷可能是导致SUD风险增加的原因。我们预测LCP-SUD患者与AL-SUD患者之间将存在dlPFC和vmPFC功能差异。这项建议还将使我们能够衡量青少年局限性和持续性SUD对年轻人前额叶和海马区结构和功能发育的影响。我们期望观察到AL-SUD组、LCP-SUD组、高危组和对照组在dlPFC和vmPFC活动模式、认知功能和海马体体积方面的显著差异。公共卫生相关性了解那些终生有药物和酒精问题的人与那些对公共卫生没有重要相关性的人的神经生物学基础。这种了解有助于更好地识别那些处于危险之中的人，帮助开发更好的治疗方法，并向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药物滥用至关重要。

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.