Neuroimaging correlates and feasibility of transcranial magnetic stimulation (TMS) to improve smoking cessation outcomes in veterans with comorbid PTSD

在美国，烟草使用仍然是头号可预防的死亡原因。不幸的是，个人 有精神健康问题的人受到的影响不成比例。美国退伍军人的烟草使用率也很高， 那些经历过创伤的人更有可能吸烟。成功戒烟对于 患有创伤后应激障碍(PTSD)的个人。尽管目前循证医学的有效性 对于戒烟的药物疗法和心理疗法，需要替代疗法。神经成像 静息状态功能磁共振成像(rs-fmri)等技术为我们提供了对 烟草使用障碍(TUD)和成功戒烟尝试的神经生物学基础的神经电路。这 在神经系统水平上对TUD病理生理学的更好的理解为使用 非侵入性脑刺激(NIBS)技术，以调节受影响的电路和改善结果。事实上， 美国食品和药物管理局(FDA)最近批准了一种形式的NIBS，即重复的经颅磁刺激 (RTMS)，作为成人的戒烟治疗。然而，绝大多数关于rTMS的临床研究试验 已经在平民和有精神健康问题的被排除在外的个人中开展了戒烟活动。 为了改善患有创伤后应激障碍的退伍军人的戒烟治疗方案，研究新的脑刺激是至关重要的 在这一特殊人群中使用rTMS等方法。同样，神经科学知情技术的发展 在这一耐药人群中提高rTMS是必要的。RS-fMRI的应用研究进展 个性化的rTMS靶点作为精确调节潜在神经回路的一种方式已经成功 应用于治疗重度抑郁障碍(MDD)。这一方法论已经得到了成功的论证。 用于戒烟，但用于没有精神疾病的尝试戒烟的平民受试者。它仍然存在 不知道退伍军人是否会认为神经成像和脑刺激相结合的方法是可以接受的，还是可以接受的 在患有创伤后应激障碍的退伍军人人群中应用和研究这些技术是可行的。为了填补这些知识空白， 这项拟议的研究旨在为rs-fmri靶向rTMS在治疗方面的应用开发可行性数据。 患有创伤后应激障碍的退伍军人试图戒烟。通过单组开放标签试验，符合条件的退伍军人 14名寻求戒烟的创伤后应激障碍患者将在5天的神经导航疗程前后接受rs-fmri检查。 戒烟日期前一周的rTMS，结合尼古丁替代疗法(NRT)和认知疗法 行为疗法。这项研究的科学目标是证明招聘、保留和可接受性 研究人群，以及研究程序的可行性。此外，培训的目标是为应聘者提供 有指导的临床研究培训，支持完成CDA-1研究研究和准备 一份CDA-2申请。具体地说，候选人将提高rTMS治疗和基于功能磁共振成像的技术熟练程度。 神经导航，临床试验知识，与退伍军人相关的临床研究领域的培训和经验 健康，包括创伤后应激障碍和戒烟，以及行政、分析和赠款撰写技能。这个 建议的研究性学习和培训计划为候选人提供了开发和实施试点的平台 旨在量化RS-fMRI引导rTMS戒烟效果的随机对照试验(RCT) 患有创伤后应激障碍的退伍军人。最终，这条研究路线将允许候选人将独立性确立为一种 退伍军人事务部的内科科学家和追求非侵入性发展的职业 退伍军人合并药物使用和精神障碍的神经调节治疗。

Tobacco use remains the number one preventable cause of death in the United States. Unfortunately, individuals with mental health conditions are disproportionately affected. Tobacco use is also high among US Veterans, and those who have experienced trauma are even more likely to smoke. Successful quitting is especially difficult for individuals who develop posttraumatic stress disorder (PTSD). Despite the efficacy of current evidence-based pharmacotherapies and psychotherapies for smoking cessation, alternative treatments are needed. Neuroimaging techniques such as resting-state functional magnetic resonance imaging (rs-fMRI) have provided insight into the neurocircuitry underlying the neurobiology of tobacco use disorder (TUD) and successful quit attempts. This improved understanding of the TUD pathophysiology at the neural systems-level provides a platform for the use of non-invasive brain stimulation (NIBS) techniques to modulate affected circuitry and improve outcomes. Indeed, the US Food and Drug Administration (FDA) recently cleared a form of NIBS, repetitive transcranial magnetic stimulation (rTMS), as a smoking cessation treatment in adults. However, the vast majority of clinical research trials on rTMS for smoking cessation have been conducted with civilians and excluded individuals with mental health conditions. To improve smoking cessation treatment options for Veterans with PTSD, it is critical to study novel brain stimulation methods such as rTMS in this special population. Similarly, the development of neuroscience-informed techniques to enhance rTMS in this treatment-resistant population are necessary. The application rs-fMRI to develop personalized rTMS targets as a way to precisely modulate the underlying neurocircuitry has been successfully applied to the treatment of major depressive disorder (MDD). This methodology has been demonstrated successfully for smoking cessation, but in civilian subjects making a quit attempt who did not have psychiatric illness. It remains unknown whether Veterans would find a combined neuroimaging-brain stimulation approach acceptable or if it is feasible to apply and study these techniques in a population of Veterans with PTSD. To fill these knowledge gaps, the proposed research aims to develop feasibility data for the therapeutic application of rs-fMRI-targeted rTMS for Veterans with PTSD attempting to quit smoking. Through a single-group, open-label trial, eligible Veterans with PTSD (n=14) seeking smoking cessation will receive rs-fMRI before and after a 5-day course of neuronavigated rTMS the week prior to their quit date, in conjunction with nicotine replacement therapy (NRT) and cognitive behavioral therapy. The scientific aims of the study are to demonstrate recruitment, retention, and acceptability in the study population, as well as feasibility of study procedures. In addition, the training aim is to provide the candidate with mentored clinical research training that supports the completion of the CDA-1 research study and preparation a CDA-2 application. Specifically, the candidate will develop technical proficiency in rTMS therapy and fMRI-based neuronavigation, knowledge of clinical trials, training and experience in clinical research domains relevant to Veteran health including PTSD and smoking cessation, as well as administrative, analytical and grant writing skills. The proposed research study and training plan provide a platform for the candidate to develop and implement a pilot randomized controlled trial (RCT) aimed at quantifying the efficacy of rs-fMRI-guided rTMS for smoking cessation in Veterans with PTSD. Ultimately, this line of research will allow the candidate to establish independence as a physician scientist at the Department of Veterans Affairs and to pursue a career on the development of non-invasive neuromodulation treatments for Veterans with comorbid substance use and psychiatric disorders.