1. Greater externalizing personality traits predict less error-related insula and anterior cingulate cortex activity in acutely abstinent cigarette smokers. Attenuated activity in performance-monitoring brain regions following erroneous actions may contribute to the repetition of maladaptive behaviors such as continued drug use. Externalizing is a broad personality construct characterized by deficient impulse control, vulnerability to addiction and reduced neurobiological indices of error processing. The insula and dorsal anterior cingulate cortex (dACC) are regions critically linked with error processing as well as the perpetuation of cigarette smoking. As such, we examined the interrelations between externalizing tendencies, erroneous task performance, and error-related insula and dACC activity in overnight-deprived smokers (n = 24) and non-smokers (n = 20). Participants completed a self-report measure assessing externalizing tendencies (Externalizing Spectrum Inventory) and a speeded Flanker task during functional magnetic resonance imaging scanning. We observed that higher externalizing tendencies correlated with the occurrence of more performance errors among smokers but not non-smokers. Suggesting a neurobiological contribution to such suboptimal performance among smokers, higher externalizing also predicted less recruitment of the right insula and dACC following error commission. Critically, this error-related activity fully mediated the relationship between externalizing traits and error rates. That is, higher externalizing scores predicted less error-related right insula and dACC activity and, in turn, less error-related activity predicted more errors. Relating such regional activity with a clinically relevant construct, less error-related right insula and dACC responses correlated with higher tobacco craving during abstinence. Given that inadequate error-related neuronal responses may contribute to continued drug use despite negative consequences, these results suggest that externalizing tendencies and/or compromised error processing among subsets of smokers may be relevant factors for smoking cessation success. 2. Neurobiological Impact of Nicotinic Acetylcholine Receptor Agonists: An Activation Likelihood Estimation Meta-Analysis of Pharmacologic Neuroimaging Studies. Nicotinic acetylcholine receptor (nAChR) agonists augment cognition among cigarette smokers and nonsmokers, yet the systems-level neurobiological mechanisms underlying such improvements are not fully understood. Aggregating neuroimaging results regarding nAChR agonists provides a means to identify common functional brain changes that may be related to procognitive drug effects. We conducted a meta-analysis of pharmacologic neuroimaging studies within the activation likelihood estimation framework. We identified published studies contrasting a nAChR drug condition versus a baseline and coded each contrast by activity change direction (decrease or increase), participant characteristics (smokers or nonsmokers), and drug manipulation employed (pharmacologic administration or cigarette smoking). When considering all studies, nAChR agonist administration was associated with activity decreases in multiple regions, including the ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), parahippocampus, insula, and the parietal and precentral cortices. Conversely, activity increases were observed in lateral frontoparietal cortices, the anterior cingulate cortex, thalamus, and cuneus. Exploratory analyses indicated that both smokers and nonsmokers showed activity decreases in the vmPFC and PCC, and increases in lateral frontoparietal regions. Among smokers, both pharmacologic administration and cigarette smoking were associated with activity decreases in the vmPFC, PCC, and insula and increases in the lateral PFC, dorsal anterior cingulate cortex, thalamus, and cuneus. CONCLUSIONS: These results provide support for the systems-level perspective that nAChR agonists suppress activity in default-mode network regions and enhance activity in executive control network regions in addition to reducing activation of some task-related regions. We speculate these are potential mechanisms by which nAChR agonists enhance cognition. 3. Reward Anticipation Is Differentially Modulated by Varenicline and Nicotine in Smokers. Recidivism rates for cigarette smokers following treatment often exceed 80%. Varenicline is the most efficacious pharmacotherapy currently available with cessation rates of 25-35% following a year of treatment. Although the in vivo binding properties are well known, varenicline's neurobiological mechanisms of action are still poorly understood. Varenicline acts as a nicotinic receptor partial agonist or antagonist depending on the presence or absence of nicotine and has been implicated in the reduction of reward signaling more broadly. The current study probed anticipatory reward processing using a revised monetary incentive delay task during fMRI in cohorts of smokers and non-smokers who completed a two-drug, placebo-controlled, double-blind crossover study. All participants underwent 17 days of order-balanced varenicline and placebo pill administration and were scanned under each condition wearing a transdermal nicotine or placebo patch. Consistent with nicotine's ability to enhance the rewarding properties of nondrug stimuli, acute nicotine administration enhanced activation in response to reward-predicting monetary cues in both smokers and non-smokers. In contrast, varenicline reduced gain magnitude processing, but did so only in smokers. These results suggest that varenicline's downregulation of anticipatory reward processing in smokers, in addition to its previously demonstrated reduction in the negative affect associated with withdrawal, independently and additively alter distinct brain circuits. These effects likely contribute to varenicline's efficacy as a pharmacotherapy for smoking cessation.
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