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.

The proposed project aims to develop a more effective, neuroscience-informed smoking cessation treatment for Veterans with posttraumatic stress disorder (PTSD). Veterans with PTSD are at increased risk of smoking-related health consequences due to difficulty quitting and to current smoking cessation interventions. Thus, more effective treatment options are needed. The US Food and Drug Administration recently cleared a form of non-invasive brain stimulation, repetitive transcranial magnetic stimulation (rTMS), as a smoking cessation treatment for adults. However, it is unclear whether rTMS would be effective for Veterans, especially those with PTSD. The proposed research aims to advance VA healthcare by studying rTMS in Veterans with PTSD who desire to quit smoking and to personalizing rTMS therapy with the use of functional magnetic resonance imaging (fMRI). This line of research may not only develop a more effective treatment for smoking cessation for Veterans with PTSD but may also lead to improved treatment options for Veterans with other substance use disorders and co-occurring mental illness.