Enhancing Relapse Prevention with rTMS: Dose-Response Parameters for Smoking Cessation

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Project Summary / Abstract. Tobacco use remains a significant cause of death and disease. Most smokers want to quit. Over half make a quit attempt every year, but over 90% relapse within 12 months, choosing the immediate reinforcement of smoking over the long-term benefits of quitting. Innovative methods for preventing relapse are needed. The Competing Neurobehavioral Decision Systems (CNDS) model posits that decisions are driven by interactions between the executive function network, located in the prefrontal cortex (PFC); and the impulsive network, located in limbic and paralimbic brain regions. Behavioral economic, neuroimaging, neurobiological, and neurobehavioral studies support this conceptualization. Greater PFC activity is linked with more self-control, more prudent choices, decreased delay discounting rates, and increased abstinence rates. The dorsolateral prefrontal cortex (DLPFC), a functional node in the PFC, has a significant role in executive function network. We propose that increasing activity in the DLPFC will reduce relapse to smoking. High frequency repetitive transcranial magnetic stimulation (rTMS) selectively modulates neuronal activity. In a randomized, double-blind, sham-controlled trial, we found 8 sessions (1/day), active or sham 20Hz rTMS (900 pulses) of the left DLPFC combined with a cognitive-behavioral intervention (CBI) to increase latency to relapse, short-term abstinence rates, and delay discounting The mean/median latency to relapse for active rTMS was n=45.2 and n=33.5 days compared with n=20.5 and n=8 days for sham. Active rTMS reduced the relative risk of relapse 3-fold (RR 0.29, CI 0.10-0.76, p =.01). Active rTMS also increased 12-week abstinence rates (50% vs. 15.4%, p=.05), decreased delay discounting rates, and increased the uptake of the CBI. While this evidence is compelling, an optimal dosing strategy must be determined before a long-term efficacy trial can be conducted. The goal of this project is to determine a dosing strategy for 20Hz rTMS that will produce the best long-term abstinence outcomes with the fewest undesirable effects. We will use a fully crossed, double-blinded, randomized factorial design with three factors: duration (stimulation days: 8, 12, and 16), intensity (900 or 1800 pulses per day), and a sham control for each condition. The sham control will allow for a comparison group to calculate effect sizes and account for non-specific treatment-related effects. Outcomes will include latency to relapse, 12 and 24-week point prevalence abstinence rates, delay discounting rates, cognitive-behavioral skills acquisition, and potential undesirable effects (e.g., non- compliance due to participant burden). Aim One will examine the effects of stimulation duration and intensity on all outcomes among motivated smokers (n=258). Aim Two will identify the most promising dosing strategy by systematically balancing effect sizes and undesirable effects. Establishing a dose-response relationship is critical to developing rTMS as a potential treatment for tobacco dependence. This innovative project will significantly advance research in the clinical application of rTMS in the treatment for tobacco dependence.