ABSTRACT Smoking remains the leading preventable cause of death in the United States and worldwide, causing nearly one in ten deaths worldwide. The majority (70%) of smokers want to quit, yet most are unsuccessful. Therefore, new approaches to help people quit are urgently needed, and may differ in efficacy between men and women, in whom a number of brain differences have been documented. At the receptor level, smoking induces dopamine release in the ventral striatum in men, but the dorsal striatum in women, and is also linked to decreased striatal dopamine D2-type receptor availability in men, and increased midbrain dopamine D2-type receptor availability in women. At the network level, preliminary data from our laboratory has linked the relief of cigarette craving to the extent of coupling between large-scale networks in women, but not men, in whom smoking instead is linked to changes in insula connectivity. This application builds on these recent findings to test the efficacy of a novel potential smoking cessation aid, repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation technique, with special attention to sex as a biological variable. This includes two complementary objectives: To test the effect of rTMS on clinical features of smoking separately in men and women, and in so doing, provide additional training that will facilitate the transition to independence as a researcher specializing in brain differences in male and female smokers. This will be achieved through two experiments. In the first experiment (K99 phase) male and female smokers will receive rTMS stimulation targeting the dorsolateral prefrontal cortex (dlPFC), supplementary motor area (SMA), posterior parietal cortex (PPC), or sham, and the effect of rTMS to each region on craving, withdrawal, and affect will be evaluated. The best of these targets (i.e., where stimulation produced the greatest decrease in craving, withdrawal, and negative affect) will be selected for Experiment 2 (R00 phase), in which 13 sessions of rTMS will be performed. Craving, withdrawal, affect, cigarettes per day, and level of dependence will be evaluated seven days before, daily throughout, and daily for six weeks following rTMS. Resting state functional connectivity will be evaluated before and after rTMS to provide mechanistic information regarding the basis of rTMS efficacy in male and female smokers. The K99 phase will take place at UCLA with support and training from the director of the Neuromodulation Division, a collaborator on this project, and two other collaborators with expertise in smoking research. This team of collaborators will provide training with respect to rTMS and smoking research. A separate team will provide professional development feedback and guidance in addition to the faculty mentor through quarterly meetings. Together, this approach will achieve the project's specific aims to: 1. Develop expertise in rTMS as a therapeutic intervention; 2. Measure the effect of rTMS targeting the SMA, PPC, and dlPFC on craving, withdrawal, and affect; 3. Measure the effect of rTMS on RSFC with fMRI; and 4. Measure effects of rTMS on subsequent smoking and dependence.

PROJECT NARRATIVE Smoking is the leading preventable cause of death in the world, and most smokers who want to quit have trouble doing so. This project aims to effectiveness of a new therapy currently being explored as a smoking cessation therapy, repetitive transcranial magnetic stimulation, with special attention to differences between male and female smokers, who may require stimulation of different brain regions.