Smoking-related illness causes over 440,000 deaths in the U.S. and over 5 million deaths worldwide annually, and this figure is increasing. Although effective existing therapies double to triple cessation rates, relapse rates remain high. Up to 90 percent of people who quit smoking relapse within the first year, even with the best treatment available. Thus, we face a critical need to develop a better understanding of the neurobiological underpinnings of addictive processes, and of relapse in particular, in order to develop targeted relapse prevention therapies that help people to maintain abstinence. Most relapse occurs following smoking cue exposure. We recently demonstrated that functional magnetic resonance imaging (fMRI) measures of heightened cue-reactivity prior to a smoking cessation attempt identified smokers who would relapse on nicotine replacement therapy (NRT);greater brain reactivity to smoking-related cues was associated with relapse and was not ameliorated by NRT. Tools now exist to evaluate individual patterns of abnormal cortical and subcortical brain reactivity to smoking cues in relapse prone smokers and to train people to modulate this abnormal smoking-related cue-associated brain reactivity with the aim of ameliorating disease-associated craving and compulsive urges. This resubmitted Exploratory / Developmental Research project will test such a tool, real-time fMRI used with emotion regulation strategies, as a novel approach to understanding and potentially modulating the neurobiology of addiction and of relapse in particular. This study is made possible by an ongoing collaboration between Drs. Evins and Stoeckel, at the Massachusetts General Hospital (MGH) Center for Addiction Medicine, who have a track record of study of novel treatments for nicotine dependence, and Drs. Gabrieli, Whitfield-Gabrieli and Graybiel, a highly innovative and productive team of cognitive neuroscientists at the Massachusetts Institute of Technology (MIT), who have pioneered this novel imaging technique. The proposed work has the potential to produce improved understanding of brain mechanisms underlying relapse and potentially, a novel therapy that could reduce the enormous morbidity and mortality caused by chronic, relapsing addiction to smoked tobacco, and also offers the potential for improved understanding and treatment of related disorders such as OCD that involve compulsive urges and failure of inhibitory control. PUBLIC HEALTH RELEVANCE: Addiction to smoked tobacco remains the largest preventable cause of morbidity and premature mortality in the developed world. This study will test neuromodulation with real-time fMRI to determine whether people can gain voluntary control of brain activity associated with craving and whether such control is associated with reduced craving and reduced smoking. If our aims are achieved, we will further our understanding of the neurobiological mechanisms of relapse to nicotine dependence, and we will discover what may become an entirely novel therapy that may improve cessation rates and reduce relapse rates. This technique may also have applications to other addictions, depression, OCD, and ADHD.