rTMS for Tobacco Use in Veterans

Cigarette smoking rates are high, and quitting rates are lower in the Veteran population in the United States compared to the nonveteran population. In addition, Veterans report being more likely to have smoking- related illnesses and morbidity. Despite the efficacy of current evidence-based pharmacotherapies and psychotherapies for smoking cessation, alternative treatments are critically needed. Repetitive transcranial magnetic stimulation (rTMS), has already displayed remarkable potential for producing novel, non- pharmacological interventions for neuropsychiatric disorders, including tobacco use disorder (TUD). The group's studies demonstrate that 10 Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) reduced cue craving and cigarette consumption and increased quit rate. Instead of stimulating the superficial cortex, deep TMS (DTMS) has been permitted to target deep brain structures such as the insula. DTMS has also been approved to reduce cigarette consumption and increase quit rate and was FDA-approved as a treatment option for TUD. Neuroimaging techniques such as functional magnetic resonance imaging (fMRI) have provided insight into the neurocircuitry of TUD and its therapeutic effect for smoking cessation. Recently, the investigators' team completed an image-guided randomized controlled trial (RCT) study to compare 10 Hz rTMS over the left DLPFC to 1 Hz over the medial orbitofrontal cortex (mOFC) and sham in healthy smokers. The results showed that 10 Hz over DLPFC rTMS reduced cigarette consumption more than 1 Hz mOFC and sham. In addition, 10 Hz DLPFC rTMS increased brain activity in DLPFC and decreased brain activity in mOFC. The findings suggested that the effect of rTMS depended on the different brain regions of stimulation. To date, the efficacy of rTMS for smoking cessation has not yet been evaluated in Veterans. In this protocol, the investigators propose comparing the two rTMS protocols (DTMS vs. image-guided TMS) to find a better treatment parameter for smoking cessation in Veterans. Targeting two candidate brain regions (DLPFC vs. insula) with two different TMS treatment parameters will be performed. This application aims to identify a better rTMS treatment for smoking cessation and further develop a circuit-based precision rTMS therapy for TUDs in Veterans. The investigators hypothesize that image-guided DLPFC TMS (precision TMS) treatment will produce superior effects than insula DTMS (standard TMS) in reducing cigarette consumption. The investigators will also determine that image-guided DLPFC increases the connectivity between DLPFC, mOFC, and nucleus accumbens (NAc). In the 4-year study, the investigators will recruit 56 treatment-seeking TUDs. Participants will be randomized into two groups: The first arm is 10Hz rTMS (1800 pulses/session) over the bilateral insula with FDA-cleared DTMS (H4-coil). The other arm is image-targeted 10 Hz rTMS over the left DLPFC with figure 8 coil (3000 pulses/session). Both rTMS treatments will include 15 daily rTMS treatments for 3 weeks and 3 weeks of once- weekly rTMS. The primary endpoint will be the reduction of cigarette consumption at the end of the 3-week rTMS treatment. Aim 1: Determine whether precision image-guided TMS over the left DLPFC results in a larger reduction in cigarette consumption compared to standard DTMS targeting the insula. The primary outcome will be cigarettes per day during the treatment course. The investigators will compare the reduction of cigarette compensation between two treatment groups at the end of the 3-week rTMS treatment. Aim 2: Determine whether precision image-guided TMS increases activity in the DLPFC and modulates connectivity among the DLPFC, mOFC, and NAc and whether standard DTMS increases activity in the insula, [mOFC] and modulates connectivity among the insula, [mOFC] and NAc. The investigators will compare precision TMS to standard TMS using whole-brain imaging and network connectivity analyses. Aim 3 (exploratory): Determine whether the reductions in cigarette consumption are associated with the modulated connectivity among DLPFC, [mOFC] and NAc after precision TMS and the modulated connectivity among insula, [mOFC] and NAc after standard TMS. The investigators will test if brain connectivity can be used to predict the clinical effects of rTMS.

Inclusion criteria

• Veteran
• Males and females between the ages of 18 and 70
• Individuals who smoke 10 or more cigarettes per day and have a CO level > 10 ppm indicative of recent smoking
• Those who have not received substance abuse treatment within the previous 30 days
• Those who have been stable on psychotropic medications for at least three months
• For females, those who test non-pregnant and use adequate birth control
• Those who are willing to provide informed consent
• Those who can comply with protocol requirements and likely complete all study procedures
• Those who are motivated to quit smoking (based on responses of "very likely" or "somewhat likely" in the motivation questionnaire

Exclusion criteria

• Current moderate to severe substance use of any psychoactive substances other than nicotine or caffeine, as defined by DSM-V criteria
• Contraindications to MRI (e.g., metal in the skull, orbital or intracranial cavity, or claustrophobia)
• Contraindications to rTMS (history of a seizure or epilepsy)
• A history of autoimmune, endocrine, viral, or vascular disorders affecting the brain
• History or MRI evidence of neurological disorder that would lead to local or diffuse brain lesions or significant physical impairment
• Unstable cardiac disease, uncontrolled hypertension, severe renal or liver insufficiency, or sleep apnea
• Major Axis I disorders diagnosed according to DSM-V criteria, such as bipolar affective disorder, schizophrenia, dementia, or major depression

• Regarding the Veteran population, we will enroll smokers who have PTSD
• Current use of other forms of nicotine delivery, such as nicotine patches or electronic cigarettes
• Currently prescribed bupropion and/or varenicline