The Role of Anxiety-Related Brain Circuits in Tobacco Dependence and Withdrawal

近5000万美国人吸烟，吸烟是导致过早死亡和 美国的残疾问题。尽管从烟草使用到尼古丁依赖的转变与 随着多种激励机制的持久变化，大多数神经生物学研究都集中在奖励-- 相关制度。很少有人致力于了解参与脑电活动的大脑回路 人类中与戒断相关的负面影响。这是不幸的--高度焦虑是尼古丁的标志 而且有令人信服的证据表明，这在进化上是保守的 戒断的特征极大地刺激了尼古丁依赖和复发。啮齿动物的机械工作和 我们小组的成像研究表明，戒断强化焦虑反映了大脑中 围绕终纹床核(BNST)、岛前核(AI)和中脑的神经回路。 扣带皮质(MCC)。但这一回路与人类戒断反应的相关性尚未被探索，而且仍然存在。 未知。利用我们团队独特的多学科专业知识，此提案的目标是使用 先进的fMRI分析技术与基于手机的生态瞬间的创新结合 评估(EMA)，首次了解与焦虑相关的大脑回路与慢性 戒烟者的烟草使用和急性尼古丁戒断。功能磁共振成像将被用于评估与焦虑相关的 匹配良好的24小时戒烟组和非戒烟组的激活和功能连接 吸烟者(n=36人/组，一半为女性)。EMA将用于评估应激源暴露、负面影响、吸烟 14天(5次/天)，包括24小时的 在功能磁共振成像治疗前立即停药。这些数据将使我们能够系统地了解 焦虑相关脑回路与：(1)急性尼古丁戒断和(2)临床相关特征的相关性 真实世界中的情绪和行为。这些目标与NIDA战略计划密切相关。 解决第一个目标将提供一个前所未有的机会来审查翻译 突出成瘾的神经生物学模型的相关性，指导双向发展 尼古丁依赖的翻译模型，在电路水平识别新的生物靶点，并告知 开发新型戒烟辅助设备。解决第二个目标将完善我们对病因学的理解， 为行为治疗提供新的靶点，并为基于手机的干预措施的发展提供信息。 了解与焦虑相关的大脑回路在戒断中的作用对于旨在减少 烟草依赖造成的巨大痛苦和经济负担。

Nearly 50 million Americans smoke tobacco and smoking is the leading cause of premature death and disability in the US. Although the transition from tobacco use to nicotine dependence is associated with enduring changes in multiple motivational mechanisms, most neurobiological research has focused on reward- related systems. Very little attention has been devoted to understanding the brain circuits involved in withdrawal-related negative affect in humans. This is unfortunate—heightened anxiety is a hallmark of nicotine deprivation in both rodents and humans and there is compelling evidence that this evolutionarily-conserved feature of withdrawal powerfully motivates nicotine dependence and relapse. Mechanistic work in rodents and imaging work by our group suggests the hypothesis that withdrawal-potentiated anxiety reflects alterations in a neural circuit encompassing the bed nucleus of the stria terminalis (BNST), anterior insula (AI), and mid- cingulate cortex (MCC). But the relevance of this circuitry to withdrawal in humans is unexplored and remains unknown. Leveraging our team's unique multi-disciplinary expertise, the goal of this proposal is to use an innovative combination of advanced fMRI analytic techniques and mobile phone-based ecological momentary assessment (EMA) to understand, for the first time, the relevance of anxiety-related brain circuits to chronic tobacco use and acute nicotine withdrawal in abstinent smokers. fMRI will be used to assay anxiety-related activation and functional connectivity in well matched groups of 24-hour abstinent and non-abstinent tobacco smokers (n=36/group; half female). EMA will be used to assay stressor exposure, negative affect, smoking urge/craving, alcohol/substance use, and smoking for 14 days (5x/day), including the 24-hour period of withdrawal immediately prior to the fMRI session. These data would enable us to systematically understand the relevance of anxiety-related brain circuits to: (1) acute nicotine withdrawal and (2) clinically-relevant features of mood and behavior in the real world. These objectives are closely aligned with the NIDA Strategic Plan. Addressing the first objective would afford an unprecedented opportunity to examine the translational relevance of prominent neurobiological models of addiction, guide the development of bidirectional translational models of nicotine dependence, identify new biological targets at the circuit level, and inform the develop of novel cessation aids. Addressing the second objective would refine our understanding of etiology, provide new targets for behavioral therapy, and inform the development of mobile phone-based interventions. Understanding the role of anxiety-related brain circuits in withdrawal is critical for efforts aimed at reducing the tremendous suffering and economic burden caused by tobacco dependence.