Introduction The ability to direct smoking cessation treatment based on neuroscientific findings holds incredible promise. However, there is a strong need for consistency across studies to confirm neurobiological targets. While our prior work implicated enhanced insula reactivity to smoking cues in tobacco smoking relapse vulnerability, this finding has not been confirmed. Method Using functional magnetic resonance imaging (fMRI), we evaluated the pre-cessation brain reactivity to smoking vs. neutral cues in nicotine dependent smokers who were and were not able to maintain subsequent abstinence. Results Of the 23 (7 women) individuals assessed, 13 relapsed and there were no demographic differences between those who did and did not relapse. However, smokers who relapsed showed enhanced reactivity to smoking cues in the right insula and dorsal striatum, showing significant overlap between our current and prior work despite methodological differences, including the fact that our previous work only included women. Conclusion The current work supports our prior results and builds on the concept that the insula and dorsal striatum work in concert to maintain nicotine dependence. Specifically, dorsal striatal-mediated habitual responding may be triggered both by the external drug-associated cues, and the insula-mediated internal states that provide additional context motivating drug use. This replicated finding also mirrors preclinical work that finds the same individualized distinction, as only some rodents attribute incentive salience to drug cues and are more likely to reinstate drug seeking after extinction. To effectively treat addiction, these individual characteristics and their underlying neurobiological foundations must be considered.

A developing theory is that individuals with alcohol use disorder (AUD) display exaggerated reactivity to threats that are uncertain (U-threat), which facilitates excessive drinking as a means of avoidance-based coping. There is a promising initial behavioral evidence supporting this theory; however, the neural bases of reactivity to U-threat in individuals with AUD have not been examined. The extent to which biomarkers of U-threat reactivity map onto drinking behaviors and coping motives for alcohol use is also unknown. The current study therefore examined group differences in behavioral and neural reactivity to U-threat in adults with and without AUD. The study also tested whether behavior and brain responses to U-threat correlate with problematic drinking and coping motivated drinking. Volunteers (n = 65) with and without a history of AUD (38 AUD, 27 controls) were included and completed a well-validated threat-of-shock task to probe responses to U-threat and predictable threat (P-threat) while startle eyeblink potentiation was collected. Individuals also completed a newly designed, analogous version of the task during functional magnetic resonance imaging (fMRI). Results indicated that individuals with AUD displayed greater startle magnitude during U-threat, but not P-threat, and greater right insula and dorsal anterior cingulate cortex (dACC) activation during both forms of threat compared with controls. Startle magnitude and insula activation during U-threat positively correlated with self-reported problem drinking and coping motives for alcohol use. Findings demonstrate that individuals with AUD display exaggerated sensitivity to U-threat at the behavioral and neural level and that these multimethod biomarkers tap into negative reinforcement processes of alcohol abuse.

Relapse to smoking after initial abstinence is a major clinical challenge with significant public health consequences. At the brain and behavioral level, those who relapse to tobacco smoking have both greater cue-reactivity and lower inhibitory control than those who remain abstinent. Little is known about neural activation during inhibitory control tasks in the presence of drug-related cues. In the current study, tobacco smokers (SMK; n = 22) and non-smoking controls (CON; n = 19) completed a Go/NoGo task involving smoking cues during a functional magnetic resonance imaging (fMRI) scan. Following the scan session, smokers were required to quit smoking, and maintenance of abstinence was evaluated as part of a 12-week smoking cessation trial. We evaluated pre-cessation brain activity during NoGo trials in smokers who were versus were not able to quit smoking. We then compared fMRI and inhibitory control measures between smokers and non-smokers. We did not find differences between SMK and CON in performance or activation to smoking or neutral cues. However, compared to SMK who relapsed, SMK who attained biochemically-validated abstinence at the end of the smoking cessation trial had greater neural activation in the anterior insula during NoGo trials specifically with smoking-related cues. Results indicate that within SMK, decreased inhibitory control activation during direct exposure to drug-related stimuli may be a marker of difficulty quitting and relapse vulnerability.

The greater ASRS scores in nicotine dependent individuals is in line with existent literature and the stronger dACC-AI coupling in smokers further supports the role of this network in nicotine dependence. The significant association between dACC-AI coupling and ASRS suggests that intra-SN coupling strength may impact neurocognitive functioning associated with both ADHD symptoms and nicotine dependence.

Temporally unpredictable stimuli influence behavior across species, as previously demonstrated for sequences of simple threats and rewards with fixed or variable onset. Neuroimaging studies have identified a specific frontolimbic circuit that may become engaged during the anticipation of temporally unpredictable threat (U-threat). However, the neural mechanisms underlying processing of temporally unpredictable reward (U-reward) are incompletely understood. It is also unclear whether these processes are mediated by overlapping or distinct neural systems. These knowledge gaps are noteworthy given that disruptions within these neural systems may lead to maladaptive response to uncertainty. Here, using functional magnetic resonance imaging data from a sample of 159 young adults, we showed that anticipation of both U-threat and U-reward elicited activation in the right anterior insula, right ventral anterior nucleus of the thalamus and right inferior frontal gyrus. U-threat also activated the right posterior insula and dorsal anterior cingulate cortex, relative to U-reward. In contrast, U-reward elicited activation in the right fusiform and left middle occipital gyrus, relative to U-threat. Although there is some overlap in the neural circuitry underlying anticipation of U-threat and U-reward, these processes appear to be largely mediated by distinct circuits. Future studies are needed to corroborate and extend these preliminary findings.