Neuropsychobiology in Polysubstance Abusers during Abstinence

 描述(由申请人提供)：多物质使用障碍(PSUD)在寻求治疗的人中比单一物质使用障碍更常见。长期吸烟在接受治疗的物质使用者中比在普通人群中更普遍，在多物质使用者(PSU)中比单一物质使用者更普遍。然而，人们对PSUD和共病吸烟的神经生物学效应、它们与神经认知和相关物质使用行为的潜在关系以及PSUD的有效治疗知之甚少。广泛的大脑成像和认知研究表明，单一替代品的使用与促进持续滥用的大脑生物学和功能异常有关；其中一些大脑异常在戒酒后部分恢复。此外，吸烟对单一物质使用者(酒精、甲基苯丙胺)的大脑生物学和功能有明显的有害影响，即使在其他健康的对照组中也是如此。值得注意的是，我们的初步研究表明，PSU患者的大脑异常在程度、性质以及对认知和行为的影响方面与有相似酒精和烟草使用史的“纯”酒精依赖样本不同，并且PSU患者在戒酒3个月后神经生物学和认知能力都有所改善。PSU治疗队列的种族和社会人口学构成也与“纯”酒精依赖队列明显不同，这表明他们构成了不同的人群。我们建议在戒断1-3周时用精选的脑磁共振(MR)、认知和自我调节措施来研究一组定义明确、特征明确的PSU，在3个月后重新研究戒除PSU，并将横断面和纵向变化措施与基线后6-9个月后评估的复发和药物使用情况联系起来。我们的区域重点是额叶-纹状体大脑，这对实现和维持成瘾障碍的长期戒断至关重要。我们的神经心理学关注的是传统的认知领域，以及冲动行为和认知控制的衡量标准。我们的主要神经生物学重点是氧化应激(OXS)，假设氧化应激是PSUD和慢性吸烟的基础，以及OXS的神经生物学和全身相关性。我们进一步假设，特定的认知和区域MR异常随着戒酒的改善而改善，并且在早期缓解期间的纵向变化措施比相应的横断面措施更好地预测随后的复发。其他MR措施将探查治疗前后与认知、自我调节以及物质和烟草使用有关的额纹状体神经元损伤、胶质增生、谷氨酸和GABA能效应以及灌流缺陷。将对同时患有酒精和可卡因使用障碍(中度到重度)、有或没有烟草和轻度大麻使用障碍的寻求治疗者进行研究。这一假设驱动的建议旨在确定持续物质滥用或戒断的多方面决定因素，作为PSU药物和行为治疗的潜在新靶点。通过禁欲表现出神经生物学和功能的改善，也将有助于将公众舆论引导到一种更有帮助的心态上，这种心态被描述为“你的大脑正在恢复中”。

 DESCRIPTION (provided by applicant): Polysubstance use disorder (PSUD) is more common among treatment seekers today than monosubstance use disorders. Chronic cigarette smoking is more prevalent among treated substance users than in the general population, and it is more prevalent in polysubstance users (PSU) than monosubstance users. Yet, very little is known about the neurobiological effects of PSUD and comorbid smoking, their potential relationships to neuro- cognition and related substance use behavior, or about effective treatment of PSUD. Extensive brain imaging and cognitive research indicate that monosubstance use is associated with abnormal brain biology and function that facilitate continued misuse; some of these brain abnormalities partially recover with abstinence. Further, smoking has clear detrimental effects on brain biology and function in monosubstance users (alcohol, methamphetamines), even in otherwise healthy controls. Notably, our preliminary studies show that brain abnormalities in PSU are different in extent, nature, and impact on cognition and behavior than in `pure' alcohol dependent samples with similar alcohol and tobacco use histories, and that both neurobiology and cognition improve in PSU over 3 months of abstinence. The ethnic and sociodemographic composition of PSU treatment cohorts is also distinctly different from that of `pure' alcohol dependent cohorts, altogether suggesting that they constitute different populations. We propose to study a well-defined and well-characterized group of PSU at 1- 3 weeks of abstinence with select brain magnetic resonance (MR), cognition, and self-regulation measures, to re-study abstinent PSU 3 months later, and to relate cross-sectional and longitudinal change measures to relapse and substance use assessed 6-9 months after baseline. Our regional focus is on fronto-striatal brain critical for achieving and maintaining long-term abstinence in addictive disorders. Our neuro-psychological focus is on traditional cognitive domains and measures of impulsive behavior and cognitive control. Our main neurobiological focus is on oxidative stress (OxS), hypothesized to underlie both PSUD and chronic smoking, and the neurobiological and systemic correlates of OxS. We further hypothesize that specific cognitive and regional MR abnormalities improve with abstinence and that longitudinal change measures during early remission predict subsequent relapse better than the corresponding cross-sectional measures. Additional MR measures will probe fronto-striatal neuronal injury, gliosis, glutamatergic and GABA-ergic effects, and perfusion deficits as they relate to cognition, self-regulation, and substance and tobacco use pre- and post-treatment. Studies will be conducted in treatment seekers with comorbid alcohol and cocaine use disorders (moderate to severe), with or without tobacco and mild cannabis use disorder. This hypotheses-driven proposal is aimed at identifying multifaceted determinants of continued substance misuse or abstinence as potential new targets for pharmacological and behavioral treatment of PSU. Showing neurobiological and functional improvements with abstinence will also help move public opinion to a mindset more helpfully described as `your brain in recovery'.