1. Converging evidence indicates that increasing activity in the left dorsolateral prefrontal cortex (DLPFC) with high frequency repetitive transcranial magnetic stimulation (HF rTMS) decreases delay discounting (DD) rates and reduces cigarette consumption. Lower DD rates are linked with higher quit rates. This project evaluated the feasibility of testing HF rTMS for the treatment of tobacco dependence. In this randomized double-blind sham-control study, smokers received 8 sessions of 20 Hz rTMS of the left DLPFC (45 20-pulse trains, inter- train interval 20 seconds, 110% of motor threshold) after a biochemically verified 24-hour quit attempt. All participants read Forever Free® relapse prevention materials during sessions. Sessions were delivered once per day, 4 sessions per week, and completed within 12 days. Feasibility, DD, and abstinence measures were administered at every session and 2, 4, 8 and 12 weeks after the quit day. Cigarettes per day (cpd) were assessed weekly for 12 weeks. Treatment engagement and acceptability, DD, and total days abstinent were compared with analysis of variance. Perceived comparability with cessation medications was evaluated with chi-square analysis. Days to relapse were compared with Cox proportional hazard modeling. Participants (N = 15; 47% male, mean age = 48 years), smoked a mean of 12 cpd. No differences were found in willingness to engage in and complete treatment, acceptability of treatment, and perceived comparability of treatment with cessation medications. The active (n = 7) group discounted the $1000 magnitude less than the sham (n = 8) group (p =.02). No difference was found in days to relapse, but the sham group relapsed in half as many days as the active group [M = 15 (SD = 21) vs M = 33 (SD = 37) days; p =.43)], and the active group reported significantly more days abstinent than the sham group [M = 40 (SD = 34) vs M = 12 (SD = 14) days; p =.05]. These preliminary findings suggest that HF rTMS of the DLPFC is practicable, feasible, and acceptable to smokers. Limited efficacy testing suggests that rTMS might improve tobacco dependence treatment outcomes. Larger studies are needed to examine efficacy. Abstract Methods High Frequency Repetitive Transcranial Magnetic Stimulation for the Treatment Of Tobacco Dependence: Feasibility and Limited Efficacy Testing Recruitment: Participants were recruited via newspaper advertisements as well as flyers posted in the community and word of mouth. Inclusion/Exclusion Criteria: Participants were required to be 21-65 years of age, right-handed, smoking 5-20 cigarettes daily, and highly motivated to quit. Participants also passed a urine test for drugs of abuse, a pregnancy test, and had no contraindications for rTMS treatment (e.g., no seizure history, no abnormal findings on an MRI of brain, etc.). Design: Randomized double-blind sham-control feasibility study Study Procedures: Baseline questionnaires administered Urine drug test, pregnancy test, and MRI of the brain administered Biochemically verified 24-hour quit the day before initiating treatment Randomized to receive 8 daily active or sham HF rTMS treatment sessions Active and sham receive 20 Hz pulses, 45 20-pulse trains, inter- train interval 20 seconds, 110% of motor threshold Participants read the 8 Forever Free® during the rTMS sessions Pre-post session acceptability, daily smoking, and comparability measures administered Cigarettes per day assessed weekly Outcome assessments 4, 8, and 12 weeks after the quit day Methods (continued) Results Participant characteristics (n=15) VariableRangeMean (SD) Age28-6348.1 (8.9) % Male-46.7 (7) Socioeconomic status † 2-105.3 (2.5) Subjective social status0-105.7 (2.1) Cigarettes per day 6-1811.6 (3.4) Motivation level*0-109.4 (0.7) FTND score0-104.3 (2.1) †Values assigned to income and educational levels were summed resulting in a discrete analogue scale (range of 2-10) FTND = Fagerström Test for Nicotine Dependence *Assessed on a scale of 0-10, where 0 = not at all, and 10= most possible Treatment engagement and acceptability Willingness to engage in treatment† Acceptability of treatment† Active (n=7) M (SD) Sham (n=8) M (SD) Active (n=7) M (SD) Sham (n=8) M (SD) Mean post- session 9.7 (0.4)9.3 (0.7)8.3 (1.4)9.1 (1.4) Week 49.8 (0.4)8.7 (1.9)9.2 (1.0)8.7 (1.5) Week 89.2 (0.8)8.8 (1.3)8.2 (1.8)8.7 (1.8) Week 128.8 (1.3)9.3 (0.8)8.6 (0.9)8.5 (1.6) Mean (SD) 9.7 (0.4)9.2 (0.9)8.4 (1.1)8.9 (1.4) †Assessed on a scale of 0-10, where 0 = not at all, and 10= most possible Perceived comparability to other tobacco medications and/or treatments† ResponseActive %(N)Sham %(N) Week 4 Worse0.0 Same20.0 (1)50.0 (2) Better80.0 (4)50.0 (2) Week 8 Worse20.0 (1)0.0 Same80.0 (4)0.0 Better0.0100.0 (1) Week 12 Worse0.0 Same80.0 (4)50.0 (1) Better20.0 (1)50.0 (1) †Assessed on a scale of 0-10, where 0 = not at all, and 10= most possible Willingness to engage in treatment: No differences found. F (1,13) = 1.7, p =.22 Acceptability of treatment: No differences found F (1,13) =.42, p =.53 Perceived comparability: Participants who previously tried other treatments generally indicated that rTMS was comparable to or better than other treatments Week 4: χ 2 (2, N = 15) = 1.94, p =.38 Week 8: χ 2 (3, N = 15) = 11.0, p =.01 Week 12: χ 2 (2, N = 15) = 5.76, p =.06 DD: The active group discounted $1000 significantly less, on average, than the sham group [M = -8.0 (SD = 2.7) vs M = -3.5 (SD = 0.5) days; p =.02)]. Conclusions Preliminary findings indicate that rTMS treatment for tobacco dependence is practicable, feasible, and acceptable to smokers. Limited efficacy testing suggests that rTMS treatment for tobacco dependence combined with a minimal relapse prevention intervention is likely to be efficacious in the treatment of tobacco dependence among cigarette smokers. No differences were found between the active and sham conditions in willingness to engage in treatment and acceptability of treatment. Most participants who had tried other treatments perceived rTMS to be the same or better than other treatments. Participants who received active rTMS discounted the $1000 magnitude less than those who received the sham suggesting a higher likelihood of achieving long-term abstinence. Although no significant difference was found in days to relapse, participants randomized to sham relapsed in half as many days as those randomized to active treatment. Participants randomized to active treatment reported significantly more total days abstinent than those randomized to sham. This is a preliminary report of an ongoing study with a targeted recruitment goal of N = 30. A greater number of subjects will provide more evidence to evaluate feasibility and limited efficacy testing. Days to Relapse M (SD) Active (n=7)33.4 (37.0) Sham (n=8)14.6 (21.2) Likelihood Ratio Chi- Square (1, n = 15) =.63, p =.43. The risk ratio for active participants relative to sham participants was.62 (95% confidence interval: (.2 – 2.1) Total Days Abstinent M (SD) Active (n=7)40.0 (34.0) Sham (n=8)11.8 (13.7) Participants in the active treatment condition were abstinent for significantly more days than participants in the sham condition (t = 2.06, DF = 7.7, p =.04). Ria Malhotra 1, Efime Popovitz 1, Luana Panissidi, MA 1, Christine E. Sheffer, PhD 1, Warren K. Bickel, PhD 2, Thomas H. Brandon, PhD 3, Jami Pittman, BS 1, Antonio Mantovani, MD, PhD 1, Christopher T. Franck, PhD 2, Syed Amir Abdali, MS 1, Lisa Flynn, MPH 4. 1 Sophie Davis School of Biomedical Education, City College of New York, 2 Virginia Tech Carilion School of Medicine and Research Institute, 3 Moffitt Cancer Center, 4 MSK. This study was funded by grants from the National Institutes of Health, National Cancer Institute R21CA178813, PI: Christine Sheffer; 20CA192993 and P20CA192991, PIs: Christine Sheffer and Jamie Ostroff; Support from NIDA 5R25DA035161 (Hien, D. & Ruglass, L. PIs) Outcome Assessment: Delay discounting (DD) of $100 and $1000: Assessed at baseline and 2, 4, 8, and 12 weeks after the quit date using a computerized delay discounting program Feasibility: Willingness to engage in treatment, acceptability of treatment, and perceived comparability of rTMS with other treatments (i.e., bupropion, varenicline, nicotine replacement, etc.) assessed after each treatment session and 4, 8, and 12 weeks after quit date on a scale of 0-10, where 0 = not at all, and 10 = most possible. Cigarettes per day: Assessed daily during treatment and weekly thereafter using a timeline follow-back procedure Days to relapse: Number of days until relapse to smoking (i.e., smoking any amount for seven consecutive days) Total days abstinent: Sum of all days in which no cigarettes were smoked Data Analysis: Differences between the active and sham conditions for: Treatment engagement and acceptability were analyzed with analysis of variance. Delay discounting were analyzed using a repeated measures analysis of variance. Perceived comparability with other tobacco treatments were analyzed with χ 2 analyses. Days to relapse were analyzed with Cox Proportional Hazard modeling. Total days abstinent were analyzed using a Welch’s two-sample t-test. Results (continued) Days Sham Active Days to Relapse by Treatment Total Days Abstinent by Treatment