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

烟草使用仍然是美国头号可预防的死亡原因。不幸的是， 精神健康状况受到不成比例的影响。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。成功戒烟对于那些 患有创伤后应激障碍（PTSD）的人。尽管目前的循证医学 戒烟的药物治疗和心理治疗，需要替代治疗。神经影像 诸如静息态功能性磁共振成像（rs-fMRI）等技术提供了对 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回路。这 在神经系统水平上对TUD病理生理学的更好理解为使用提供了平台 非侵入性脑刺激（NIBS）技术，以调节受影响的电路和改善结果。持续增 美国食品和药物管理局（FDA）最近批准了一种形式的NIBS，重复经颅磁刺激， （rTMS），作为成人戒烟治疗。然而，绝大多数关于rTMS的临床研究试验 对平民和排除有精神健康问题的个人进行了戒烟培训。 为了改善患有创伤后应激障碍的退伍军人的戒烟治疗选择，研究新型脑刺激至关重要 rTMS等方法在这一特殊人群中。同样，神经科学技术的发展 加强rTMS在这一治疗耐药人群是必要的。应用rs-fMRI开发 个性化的rTMS靶点作为一种精确调节潜在神经回路的方法， 用于治疗重度抑郁症（MDD）。这一方法已得到成功的证明 戒烟，但在平民受试者谁没有精神疾病的戒烟尝试。它仍然是 不知道退伍军人是否会发现神经成像-脑刺激联合方法是可以接受的， 在患有PTSD的退伍军人群体中应用和研究这些技术是可行的。为了填补这些知识空白， 该研究旨在为rs-fMRI靶向rTMS的治疗应用开发可行性数据， 患有PTSD的退伍军人试图戒烟。通过一项单组、开放标签试验， 寻求戒烟的PTSD患者（n=14）将在5天的神经导航治疗前后接受rs-fMRI检查。 rTMS戒烟日期前一周，结合尼古丁替代疗法（NRT）和认知 行为疗法这项研究的科学目的是证明招募，保留和可接受性， 研究人群以及研究程序的可行性。此外，培训的目的是为候选人提供 指导临床研究培训，支持完成CDA-1研究和准备 CDA-2申请具体而言，候选人将发展rTMS治疗和基于fMRI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，分析和赠款写作技能。的 拟议的研究学习和培训计划为候选人提供了一个平台，以开发和实施试点 一项随机对照试验（RCT），旨在量化rs-fMRI引导的rTMS对戒烟的有效性， 患有创伤后应激障碍的退伍军人最终，这条研究路线将使候选人建立独立性， 医生科学家在退伍军人事务部，并追求职业生涯的发展，非侵入性 神经调节治疗与共病物质使用和精神疾病的退伍军人。

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.