Multimodal smoking cessation treatment combining transcranial magnetic stimulation, cognitive behavioral therapy, and nicotine replacement therapy in veterans with posttraumatic stress disorder: A feasibility randomized controlled trial protocol

Tobacco-related deaths exceed those resulting from homicides, suicides, motor vehicle accidence, alcohol consumption, illicit substance use, and acquired immunodeficiency syndrome (AIDS), combined. Amongst U.S. veterans, this trend is particularly concerning given that those suffering from posttraumatic stress disorder (PTSD)—about 11% of those receiving care from the Department of Veterans Affairs (VA)—have triple the risk of developing tobacco use disorder (TUD). The most efficacious strategies being used at the VA for smoking cessation only result in a 23% abstinence rate, and veterans with PTSD only achieve a 4.5% abstinence rate. Therefore, there is a critical need to develop more effective treatments for smoking cessation. Recent studies have revealed the insula as integrally involved in the neurocircuitry of TUD, specifically showing that individuals with brain lesions involving this region had drastically improved quit rates. Some of these studies show a probability of quitting up to 5 times greater compared to non-insula lesioned regions). Altered activity of the insula may be involved in the disruption of the salience network’s (SN) connectivity to the executive control network (ECN), which compromises that patient’s ability to switch between interoceptive states focused on cravings to executive and cognitive control. Thus, we propose a feasibility phase II randomized controlled trial (RCT) to study a patterned form of repetitive transcranial magnetic stimulation (rTMS), intermittent theta burst stimulation (iTBS), at 90% of the subject’s resting motor threshold (rMT) applied over a region in the right post-central gyrus most functionally connected to the right posterior insula. We hypothesize that by increasing functional connectivity between the SN with the ECN to enhance executive control and by decreasing connectivity with the default mode network (DMN) to reduce interoceptive focus on withdrawal symptoms, we will improve smoking cessation outcomes. Fifty eligible veterans with comorbid TUD and PTSD will be randomly assigned to two conditions: active-iTBS + cognitive behavioral therapy (CBT) + nicotine replacement therapy (NRT) ( n =25) or sham-iTBS + CBT + NRT ( n =25). The primary outcome, feasibility, will be determined by achieving a recruitment of 50 participants and retention rate of 80%. The success of iTBS will be evaluated through self-reported nicotine use, cravings, withdrawal symptoms, and abstinence following quit date (confirmed by bioverification) along with evaluation for target engagement through neuroimaging changes, specifically connectivity differences between the insula and other regions of interest. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT05723588 ### Funding Statement J. Young is supported by VA Career Development Awards (CDA-1, CDA-2), Clinical Science Research and Development Service (CSR&D): 1 IK1 CX002187-01A1, 1 IK2 CX002610-01 Department of Veterans Affairs (VA) Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC), Durham VA Health Care System Duke University Department of Psychiatry & Behavioral Sciences and Duke Interdisciplinary Studies Bass Connections. Z.-D. Deng and M. Dannhauer are supported by the National Institute of Mental Health (NIMH) Intramural Research Program (ZIAMH002955). J. Beckham is supported by a Senior Research Career Scientist Award (IK6BX003777) from VA Clinical Sciences Research and Development. The study sponsor did not or will not serve a significant role in study design, collection, management, analysis, or interpretation of data, writing of the report, decision to submit the report or ultimate authority over these activities. Public access of deidentified data will follow VA research standards. Trial results will be published by study team upon trial completion without restrictions or the use of professional writers. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRBs of Duke University and Durham VA Health Care System gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.