Brain Substrates of Extinction-Based Treatment for Nicotine Dependence

描述（由申请人提供）：一种基于戒烟的治疗（EBT），吸烟者在目标戒烟日期前的几周内吸烟脱尼古丁（“denic”）香烟并佩戴尼古丁贴片，已显示出作为尼古丁依赖的新型有效治疗的前景。这种EBT预处理（EBT-PRE）打破了吸烟和尼古丁输送之间的偶然关系，从而促进吸烟行为的消除，使吸烟者更容易戒烟。EBT-PRE相对于基于临床的EBT具有潜在优势，因为消退训练可以在各种各样的环境中发生（即，在吸烟者通常吸烟的所有环境中）。因此，它可能不太容易受到“更新效应”的影响，即一种情况下的灭绝不会推广到其他情况。最近的临床试验的EBT-PREs使用denics加尼古丁贴片已报告4周连续戒烟率在30至50%的范围。在最近的一项研究中，我们观察到EBT-PRE可以减弱大脑对杏仁核中与吸烟相关的线索的反应，杏仁核是奖励学习和灭绝的关键基质。本申请的首要目标是进一步阐明EBT-PRE的神经基础。将100名（n=100）吸烟者随机分配至两个治疗组之一：戒烟治疗（EBT; n=50）组，受试者在戒烟日期前1个月佩戴21 mg/d尼古丁贴片的同时吸烟，或尼古丁替代治疗（NRT; n=50）组，受试者吸烟至戒烟日期。在戒烟日期后，两组都将接受标准尼古丁替代治疗。在这项随机试验中，将在基线[fMRI 71]、治疗前第4周[fMRI 72]和戒烟后24小时内[fMRI 73]使用fMRI测量大脑线索反应性（CR）。我们假设，与NRT相比，EBT将导致杏仁核对吸烟相关线索的反应性降低，并且基线时更大的脑CR（以及EBT对脑CR的更大衰减）将与更好的EBT结局相关。该项目建立在调查小组的早期工作和专业知识的基础上，并高度响应RFA，该RFA寻求阐明“可能指导干预措施的灭绝机制”和“确定大脑机制.”的研究。参与预防”。EBT-PRE代表了一种新的、潜在有效的和高度可传播的尼古丁依赖治疗方法，阐明其潜在的神经机制将导致这种治疗的进一步完善。 公共卫生相关性：在美国，吸烟是导致死亡和残疾的主要可预防原因。一种新的戒烟治疗方法试图打破吸烟与尼古丁向大脑输送之间的关系，使吸烟者更容易戒烟。这种“基于预防的”疗法（EBT）的临床试验表明它是安全的，而且可能有效;然而，人们对它如何改变大脑功能知之甚少。这项研究将有助于更好地了解EBT的神经基础，从而进一步完善这种有前途的新治疗方法。

DESCRIPTION (provided by applicant): An extinction-based therapy (EBT) in which smokers smoke denicotinized (`denic') cigarettes and wear a nicotine patch in the weeks leading up to a target quit date has shown promise as a novel and effective treatment for nicotine dependence. This EBT pretreatment (EBT-PRE) breaks the contingent relationship between smoking a cigarette and nicotine delivery, thus promoting extinction of smoking behavior and making it easier for the smoker to quit. EBT-PRE has a potential advantage over clinic- based EBTs in that extinction training can occur in a wide variety of contexts (i.e. in all of the contexts the smoker typically smokes). Therefore, it may not be as susceptible to the `renewal effect' in which extinction in one context does not generalize to others. Recent clinical trials of EBT-PREs using denics plus the nicotine patch have reported 4 week continuous abstinence rates in the 30 to 50% range. In a recent study, we observed EBT-PRE to attenuate brain reactivity to smoking-related cues in the amygdala-a critical substrate of reward learning and extinction. The overarching goal of the present application is to further elucidate the neural basis of EBT-PRE. One hundred (n=100) smokers will be randomly assigned to one of two treatment arms: an extinction-based therapy (EBT; n=50) arm in which participants will smoke denic cigarettes while wearing a 21 mg/d nicotine patch for one month prior to their quit date or a nicotine replacement therapy (NRT; n=50) arm in which participants will smoke their usual brand of cigarettes up to the quit date. Following the quit date, both groups will undergo standard nicotine replacement therapy. Overlaid on this randomized trial, brain cue-reactivity (CR) will be measured using fMRI at baseline [fMRI71], in the fourth week of the pretreatment period [fMRI72] and within 24 hrs of quitting smoking [fMRI73]. We hypothesize that EBT will result in decreased amygdalar reactivity to smoking-related cues compared to NRT and that greater brain CR at baseline (and greater attenuation of brain CR by EBT) will be associated with better EBT outcomes. This project builds upon the investigative team's earlier work and expertise and is highly responsive to the RFA which seeks research that elucidates the `mechanisms of extinction that might guide interventions' and `identifies brain mechanisms...involved in extinction'. EBT-PRE represents a novel, potentially effective and highly disseminable treatment for nicotine dependence and elucidating the neural mechanisms underlying it will lead to further refinement of this therapy. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading preventable cause of death and disability in the U.S. A new smoking cessation treatment seeks to break the relationship between smoking a cigarette and delivery of nicotine to the brain making it easier for smokers to quit. Clinical trials of this `extinction-based' therapy (EBT) suggest it is safe and potentially effective; however, little is known about how it changes brain function. The proposed research will lead to a better understanding of the neural basis of EBT which will lead to further refinement of this promising new treatment.