Compounded Neuronal Damage in Comorbid Cigarette Smoking and Addiction

摘要 吸烟对健康的负面影响是无可争辩的：广泛的心脏和肺脏 对多种癌症的损害和重大风险。同样，CS的成瘾特性也很好- 有记录在案。流行病学研究一再表明，吸烟成瘾与 酒精和其他物质使用障碍(澳大利亚、澳大利亚、南非)。对这些数据的讨论通常集中在 关注吸烟对周围健康造成的严重后果和/或澳州/南加州复发的风险。 虽然这些都是值得研究的话题，但目前的文献状况未能解决几个关键问题 要点：首先，尽管美国普通人群的吸烟率正在下降，但澳元/南澳地区的吸烟率仍然很高。 第二，虽然我们知道可燃烟草产品中的有毒化合物极有可能导致 大脑损伤，我们还不了解吸烟史可能的剂量-反应函数 以及神经损伤标志物上的CS现状。第三，还不知道终生接触CS如何相互作用 在大脑结构和生化水平上的其他成瘾导致的行为：这可能是 发现共病成瘾的循环是如何持续的，因此对推进治疗至关重要 并预测结果。最近，大量的神经成像研究已经出现，这些研究检查了大脑 慢性吸烟者的结构。然而，这些研究中的大多数只关注单一的结果变量， 考虑了吸烟成瘾，并没有从大脑损伤的角度设计研究 假设。缺少的是来自全面的、多模式研究的信息，这些研究试图 了解CS对大脑的腐蚀性影响，以及告诉我们CS暴露如何合成化合物的数据 CS合并AUD/SUD的影响及复杂转归。缺乏这样的知识是一个重要的， 与临床相关的问题，因为它阻碍了我们开发有针对性的、机制驱动的疗法 促进戒烟和戒酒戒毒，并减轻或修复因 CS.我们建议通过应用最先进的神经成像技术来解决这一关键的知识鸿沟 为了确定CS的终生剂量反应函数如何对大脑产生负面影响 澳元。我们将在印第安纳大学医学院和斯坦福大学进行平行研究。两个站点 将招募以下样本：从不吸烟控制，目前吸烟控制，从不吸烟AUD， 以前吸烟的澳元，以及现在吸烟的澳元。所有AUD患者都将是不寻求治疗和积极活动的 酒鬼。我们将测试终生接触CS对脑代谢物(目标1)、白质束的影响 完整性(目标2)和脑网络功能(目标3)。探索性目标4将开发一个预测性有效的模型 CS介导的脑损伤对神经认知和饮酒行为的相对贡献。这个 双点设计通过抽样两个地理上不同的人群来最大化研究的力量，以及 有一个内置的复制组件，这是至关重要的，但在人类神经成像研究中往往没有实现。

Abstract The negative health consequences of cigarette smoking (CS) are indisputable: extensive heart and lung damage and significant risk for multiple types of cancer. Similarly, the addictive properties of CS are also well- documented. Epidemiological studies have repeatedly shown that cigarette addiction is highly comorbid with alcohol and other substance use disorders (AUD, SUD). Discussions of these data typically center around concern for the serious peripheral health consequences of smoking and/or risk for relapse for AUD/SUD. While these are worthy topics of inquiry, the current state of the literature has failed to address several critical points: first, while smoking rates are decreasing in the general U.S. population, they remain high in AUD/SUD. Second, while we know that the toxic compounds in combustible tobacco products are highly likely to induce brain damage, we do not yet have an understanding of putative dose-response functions of smoking history and current CS status on markers of neural damage. Third, it is not known how lifetime CS exposure interacts with other addictions at the level of brain structure and biochemistry to produce behavior: this could be key for discovering how the cycle of comorbid addictions is perpetuated, and thus is crucial for advancing treatment and predicting outcomes. Recently, a wealth of neuroimaging studies have emerged that have examined brain structure in chronic smokers. However, the majority of these studies looked at single outcome variables, only considered cigarette addiction, and did not design the studies from a perspective of a brain damage hypothesis. What are missing is information derived from comprehensive, multi-modal studies that attempt to understand the caustic effects of CS on the brain, and data that inform us of how CS exposure may compound effects of and complicate outcomes in CS comorbid with AUD/SUD. Lack of such knowledge is an important, clinically relevant problem, as it prevents us from developing targeted, mechanism-driven therapies designed to promote both smoking cessation and alcohol/drug abstinence, and to mitigate or repair brain damage from CS. We propose to address this critical knowledge gap by applying state-of-the art neuroimaging technologies to determine how the lifetime dose response function of CS exerts negative consequences on the brain in AUD. We will conduct parallel studies at the Indiana University School of Medicine and Stanford. Both sites will recruit the following samples: never-smoking controls, currently-smoking controls, never-smoking AUD, former-smoking AUD, and currently-smoking AUD. All AUD subjects will be nontreatment-seeking and active drinkers. We will test the effects of lifetime CS exposure on brain metabolites (Aim 1), white matter tract integrity (Aim 2), and brain network function (Aim 3). Exploratory Aim 4 will develop a predictively valid model of the relative contributions of CS-mediated brain damage on neurocognition and drinking behaviors. The dual-site design maximizes the power of the study by sampling two geographically distinct populations, and has a built-in replication component that is crucial, but often not realized in human neuroimaging studies.