Multimodal Imaging of Reward Brain Centers in Tobacco Smoking Veterans

描述（由申请人提供）： 烟草成瘾是美国最大的单一公共卫生问题。在退伍军人中，吸烟特别普遍，并与几个问题有关，包括癌症风险，抑郁症和其他成瘾合并症，以及心脏病等。虽然大多数吸烟者，包括那些在军队表达戒烟的愿望，大多数戒烟试验后几天内恢复吸烟，主要是因为戒断症状。我们和其他人已经表明，缰核，一个小的和未充分研究的大脑区域可能是烟草成瘾和尼古丁戒断症状的关键。缰核整合了几种类型的输入，并调节了几个中脑区域（腹侧被盖区/黑质腹侧核、中缝核、蓝斑和脚间核）的活动。在负面信息时，缰核的活动增加可能会引起负面情绪，抑郁情绪以及增强的觉醒和焦虑。这个系统存在于甚至更低级的动物形式中，因为它是允许从行为错误中学习的必要条件。我们建议使用多模态成像策略在老烟民和非吸烟者研究缰系统。根据我们自己的初步数据，我们假设吸烟者与不吸烟者相比，缰纤维减少。此外，我们假设，戒烟的老烟民将显示增强缰活动后，令人失望的事件。这可能有助于解释烟草成瘾的几个方面：如果缰在戒烟期间更加活跃，这就可以解释为什么人们会复发：试图戒烟可能类似于持续的失望状态，这种状态会因再次吸烟而消退。重要的是，烟草烟雾具有遗传成分。我们的数据显示，一种增加成为吸烟者风险的变异也与在禁欲情况下令人失望的事件中增加的缰活动有关。因此，我们假设，在戒烟试验后，大多数人会重新吸烟，以抑制源于缰核的负面影响。这种影响在具有高遗传风险的人中会更强，成为吸烟者。我们建议研究缰活动（使用功能性MRI），缰功能连接（使用静息状态功能性MRI）和缰白色物质的完整性（使用扩散张量成像）在非吸烟者和满足和戒烟的吸烟退伍军人。此外，我们还将对与烟草滥用相关的单核苷酸多态性rs 16969968进行基因分型，初步研究表明，rs 16969968也与戒烟期间缰核活动增加相关。这项研究的创新之处很明显：没有人研究过成瘾退伍军人的缰核。相关性可能很大：如果我们的假设是正确的，并且烟草依赖退伍军人的缰核异常，这将意味着成瘾大脑整合有关奖励，决策，运动和其他模式的信息的方式受到损害，并且可能依赖于饱腹感状态。这可能对该领域产生巨大影响。虽然不能立即应用，但如果我们的假设是正确的，反烟草疗法的发展应该会发生根本性的变化。在未来，我们希望能够使用遗传和机械信息定制反烟草疗法。

DESCRIPTION (provided by applicant): Abstract Tobacco addiction is the largest single public health issue in America. In veterans, smoking is particularly prevalent and is associated with several problems including cancer risk, depression and other addiction comorbidities, and heart disease, among others. Although most smokers, including those in the military express a desire to quit, most return to smoking within days of cessation trials, mainly because of withdrawal symptoms. We and others have shown that the habenula, a small and understudied brain region may be critical for tobacco addiction and nicotine withdrawal symptoms. The habenula integrates several types of input and modulates the activity of several midbrain areas (ventral tegmental area/substantia nigra compacta, raphe nucleus, locus coeruleus and interpeduncular nucleus). Upon negative information, increased activity in the habenula may elicit negative feelings, depressed mood and enhanced arousal and anxiety. This system is present in even lower animal forms because it is necessary to allow learning from behavioral mistakes. We propose to use a multimodal imaging strategy in veteran smokers and non-smokers to study the habenular system. Based on our own preliminary data, we postulate that smokers will show decreased habenular fibers when compared to non-smokers. In addition, we postulate that abstinent veteran smokers will show enhanced habenular activity upon disappointing events. That could help explain several aspects of tobacco addiction: if the habenula is more active during abstinence, that would explain why people relapse: trying to quit could be similar to a continuous state of disappointment that would subside by smoking again. Importantly, tobacco smoke has a genetic component. Our data shows that a variant that increases the risk to become a smoker is also associated with increased habenular activity during disappointing events under abstinence. Thus, we postulate that upon cessation trials, most people return to smoke to suppress the negative affect originated in the habenula. This effect would be stronger in people with high genetic risk to become a smoker. We propose to study habenular activity (using functional MRI), habenular functional connectivity (using resting state functional MRI) and habenular white matter integrity (using diffusion tensor imaging) in non-smokers and in sated and abstinent tobacco smoking veterans. In addition, we will genotype the single nucleotide polymorphism rs16969968, which is associated to tobacco abuse, and which have preliminary shown that is also associated to increased habenular activity during abstinence. The innovative aspect of this research is clear: no one has studied the habenula in addicted veterans. The relevance is potentially large: if our hypothesis is correct and the habenula is abnormal in tobacco dependent veterans, that would imply that the way the addicted brain integrates information about reward, decision making, movement, and other modalities is impaired, and likely dependent on satiety status. This may have enormous implications for the field. Although not immediately applicable, if our hypotheses are correct, the development of anti-tobacco therapies should radically change. In the future, we hope to be able to customize anti-tobacco therapies using genetic and mechanistic information.