Background Developing means to identify smokers at high risk for relapse could advance relapse prevention therapy. We hypothesized that functional magnetic resonance imaging (fMRI) reactivity to smoking-related cues, measured prior to a quit attempt, could identify smokers with heightened relapse vulnerability. Methods Twenty-one nicotine-dependent women underwent fMRI prior to quitting smoking, during which smoking-related and neutral images were shown. These smokers also were tested for possible attentional biases to smoking-related words using a computerized emotional Stroop (ES) task previously found to predict relapse. Smokers then made a quit attempt and were grouped based on outcomes (abstinence versus slip: smoking 1 cigarette after attaining abstinence). Pre-quit fMRI and ES measurements in these groups were compared. Results Slip subjects had heightened fMRI reactivity to smoking-related images in brain regions implicated in emotion, interoceptive awareness, and motor planning and execution. Smoking cue-induced insula and dorsal anterior cingulate cortex (dACC) reactivity correlated with an attentional bias to smoking-related words. A discriminant analysis of ES and fMRI data predicted outcomes with 79% accuracy. Additionally, smokers who slipped had decreased fMRI functional connectivity between an insula-containing network and brain regions involved in cognitive control, including the dACC and dorsal lateral prefrontal cortex, possibly reflecting reduced top-down control of smoking-related cue-induced emotions. Conclusions These findings suggest that the insula and dACC are important substrates of smoking relapse vulnerability. The data also suggest that relapse-vulnerable smokers can be identified prior to quit attempts, which could enable personalized treatment, improve tobacco-dependence treatment outcomes, and reduce smoking-related morbidity and mortality.

The insula plays a critical role in maintaining nicotine dependence and reactivity to smoking cues. More broadly, the insula and the dorsal anterior cingulate cortex (dACC) are key nodes of the salience network (SN), which integrates internal and extrapersonal information to guide behavior. Thus, insula-dACC interactions may be integral in processing salient information such as smoking cues that facilitate continued nicotine use. We evaluated functional magnetic resonance imaging (fMRI) data from nicotine-dependent participants during rest, and again when they viewed smoking-related images. Greater insula-dACC coupling at rest was significantly correlated with enhanced smoking cue-reactivity in brain areas associated with attention and motor preparation, including the visual cortex, right ventral lateral prefrontal cortex, and the dorsal striatum. In an independent cohort, we found that insula-dACC connectivity was stable over 1-h delay and was not influenced by changes in subjective craving or expired carbon monoxide, suggesting that connectivity strength between these regions may be a trait associated with heightened cue-reactivity. Finally, we also showed that insula reactivity to smoking cues correlates with a rise in cue-reactivity throughout the entire SN, indicating that the insula's role in smoking cue-reactivity is not functionally independent, and may actually represent the engagement of the entire SN. Collectively, these data provide a more network-level understanding of the insula's role in nicotine dependence and shows a relationship between inherent brain organization and smoking cue-reactivity.