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，替代疗法是迫切需要的。 诸如静息状态功能磁共振成像(rs-fmri)等神经成像技术已经提供了 深入了解烟草使用障碍(TUD)的神经回路和成功的戒烟尝试。干预措施 调节TUD潜在的神经系统，如重复的经颅磁刺激(RTMS)，可能是 对改善临床结果至关重要。事实上，美国食品和药物管理局(FDA)最近批准了一份表格 将rTMS作为成人的短期戒烟治疗。然而，大多数rTMS用于吸烟的临床试验 已经在平民样本中进行了戒烟，并排除了有精神疾病的个人。至 为患有创伤后应激障碍的退伍军人改进戒烟治疗方案，评估新大脑至关重要 在这一弱势群体中使用rTMS等刺激方法。此外，神经科学的发展-- 增强rtms的知情技术，如基于rs-fmri的神经导航，是使rtms个体化的关键。 用于戒烟和了解作用机制。神经影像在显影中的应用 用于精确调节靶向潜在神经回路的个性化rTMS靶点已成功应用 用于治疗严重抑郁障碍(MDD)。类似的方法已经成功地在 候选人的导师戒烟，但这项工作是在平民参与者的样本中完成的 尝试戒烟的人没有精神疾病。为了填补这些知识空白，拟议的研究 旨在为退伍军人个体化神经导航rTMS的治疗应用提供可行性数据 创伤后应激障碍试图戒烟。采用可行性随机对照试验(RCT)设计，合格 患有创伤后应激障碍(n=50)寻求戒烟的退伍军人将在为期5天的疗程前后接受rs-fmri检查。 戒烟日期前一周的神经导航rTMS，结合尼古丁替代疗法(NRT)和 认知行为疗法(CBT)。这项研究的科学目的是评估提供治疗的可行性。 程序，制定初步效果大小估计，并展示干预的目标参与度 在对TUD至关重要的神经网络中。此外，补充的培训和指导计划将提供 有指导临床研究培训的候选人，支持完成CDA-2研究研究和 准备功绩评审奖励申请。具体地说，应聘者应熟练掌握rtms技术。 治疗和基于功能磁共振成像的神经导航，精通临床试验、培训和临床研究经验 与退伍军人健康相关的领域，包括创伤后应激障碍和戒烟，以及行政、分析和 授予写作技巧。拟议的研究性学习和培训计划为候选人提供了一个发展的平台 和实施一项全面的随机对照试验，旨在量化RS-fMRI引导的rTMS在 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，并追求关于非 共患药物使用和精神障碍的退伍军人的侵入性神经调节治疗。

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 critically needed. Neuroimaging techniques such as resting-state functional magnetic resonance imaging (rs-fMRI) have provided insight into the neurocircuitry of tobacco use disorder (TUD) and successful quit attempts. Interventions that modulate the neural systems underlying TUD, such as repetitive transcranial magnetic stimulation (rTMS), may be critical to improving clinical outcomes. Indeed, the US Food and Drug Administration (FDA) recently cleared a form of rTMS as a short-term smoking cessation treatment in adults. However, most clinical trials on rTMS for smoking cessation have been conducted in civilian samples and have excluded individuals with psychiatric conditions. To improve smoking cessation treatment options for Veterans with PTSD, it is critical to evaluate novel brain stimulation methods such as rTMS in this vulnerable population. Furthermore, the development of neuroscience- informed techniques to enhance rTMS such as neuronavigation based on rs-fMRI is critical to individualizing rTMS for smoking cessation and understanding mechanisms of action. The application of neuroimaging to develop personalized rTMS targets to precisely modulate targeted underlying neurocircuitry has been successfully applied to the treatment of major depressive disorder (MDD). Similar methodology has been demonstrated successfully for smoking cessation by the candidate’s mentors, but this work was completed in a sample of civilian participants making a quit attempt who did not have psychiatric illness. To fill these knowledge gaps, the proposed research aims to develop feasibility data for the therapeutic application individualized neuronavigated rTMS for Veterans with PTSD attempting to quit smoking. Using a feasibility randomized controlled trial (RCT) design, eligible Veterans with PTSD (n=50) 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 (CBT). The scientific aims of the study are to evaluate feasibility of treatment delivery procedures, develop preliminary effect size estimates, and demonstrate target engagement of the intervention within neural networks critical to TUD. In addition, complementary training and mentoring plans will provide the candidate with mentored clinical research training that supports the completion of the CDA-2 research study and preparation a Merit Review award application. Specifically, the candidate will develop technical proficiency in rTMS therapy and fMRI-based neuronavigation, proficiency in clinical trials, training, and experience in clinical research domains relevant to Veteran health including PTSD and smoking cessation, and administrative, analytical and grant writing skills. The proposed research study and training plan provide a platform for the candidate to develop and implement a full 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.