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

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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.