Nicotine withdrawal is associated with deficits in neurocognitive function including sustained attention, working memory, and response inhibition. Several convergent lines of evidence suggest that these deficits may represent a core dependence phenotype and a target for treatment development efforts. A better understanding of the mechanisms underlying withdrawal-related cognitive deficits may lead to improve nicotine dependence treatment. We begin with an overview of the neurocognitive effects of withdrawal in rodent and human models, followed by discussion of the neurobehavioral mechanisms that are thought to underlie these effects. We then review individual differences in withdrawal-related neurocognitive effects including genetics, gender, and psychiatric comorbidity. We conclude with a discussion of the implications of this research for developing improved therapies, both pharmacotherapy and behavioral treatments, that target cognitive symptoms of nicotine withdrawal.

Increased preference for immediate over delayed rewards and for risky over certain rewards has been associated with unhealthy behavioral choices. Motivated by evidence that enhanced cognitive control can shift choice behavior away from immediate and risky rewards, we tested whether training executive cognitive function could influence choice behavior and brain responses. In this randomized controlled trial, 128 young adults (71 male, 57 female) participated in 10 weeks of training with either a commercial web-based cognitive training program or web-based video games that do not specifically target executive function or adapt the level of difficulty throughout training. Pretraining and post-training, participants completed cognitive assessments and functional magnetic resonance imaging during performance of the following validated decision-making tasks: delay discounting (choices between smaller rewards now vs larger rewards in the future) and risk sensitivity (choices between larger riskier rewards vs smaller certain rewards). Contrary to our hypothesis, we found no evidence that cognitive training influences neural activity during decision-making; nor did we find effects of cognitive training on measures of delay discounting or risk sensitivity. Participants in the commercial training condition improved with practice on the specific tasks they performed during training, but participants in both conditions showed similar improvement on standardized cognitive measures over time. Moreover, the degree of improvement was comparable to that observed in individuals who were reassessed without any training whatsoever. Commercial adaptive cognitive training appears to have no benefits in healthy young adults above those of standard video games for measures of brain activity, choice behavior, or cognitive performance.

Stress and pre-frontal cognitive dysfunction have key roles in driving smoking, however, there are no therapeutics for smoking cessation which attenuate the effects of stress on smoking and enhance cognition. Central noradrenergic pathways are involved in stress-induced reinstatement to nicotine and in the prefrontal executive control of adaptive behaviors. We used a novel translational approach employing a validated laboratory analogue of stress-precipitated smoking, fMRI, and a proof-of-concept treatment period to evaluate whether the noradrenergic α2a agonist, guanfacine (3mg/day) versus placebo (0mg/day) reduced stress-precipitated smoking in the laboratory, altered cortico-striatal activation during the Stroop cognitive-control task, and reduced smoking following a quit attempt. In nicotine-deprived smokers (n=33), stress versus a neutral condition significantly decreased the latency to smoke, and increased tobacco craving, ad-libitum smoking, and systolic blood pressure in placebo-treated subjects, and these effects were absent or reduced in guanfacine-treated subjects. Following stress, placebo-treated subjects demonstrated decreased cortisol levels whereas guanfacine-treated subjects demonstrated increased levels. Guanfacine, compared to placebo, altered prefrontal activity during a cognitive control task, and reduced cigarette use but did not increase complete abstinence during treatment. These preliminary laboratory, neuroimaging and clinical outcome data were consistent and complementary and support further development of guanfacine for smoking cessation.

Outcomes of bariatric surgery, while frequently impressive, are not universal and vary between patients and across surgical procedures. Between 20-30% of patients experience suboptimal weight loss or significant weight regain within the first few postoperative years. The reasons for this are not fully understood, but likely involve both physiological processes, behavioral factors, and psychological characteristics. Evidence suggests that preoperative psychosocial status and functioning can contribute to suboptimal weight losses and/or postoperative psychosocial distress. Much of this work has focused on the presence of recognized psychiatric diagnoses and with particular emphasis on mood disorders as well as binge eating disorder (BED). Several studies have suggested that the presence of preoperative psychopathology is associated with suboptimal weight losses, postoperative complications, and less positive psychosocial outcomes. Contemporary psychological theory suggests that it may be shared features across diagnoses, rather than a discrete diagnosis, that better characterizes psychopathology. Mood and substance use disorders (SUDs), as well as BED, share common features of impulsivity, although clinicians and researchers often use complementary, yet different terms, such as emotional dysregulation or disinhibition (i.e., loss of control over eating, as applied to food intake), to describe the phenomenon. Impulse control is a central factor in eating behavior and extreme obesity. It also may contribute to the experience of suboptimal outcomes after bariatric surgery, including smallerthan-expected weight loss and psychosocial distress. This paper reviews the literature in these

Rationale Impulsivity, a multifaceted construct that includes inhibitory control and heightened preference for immediate reward, is central to models of drug use and abuse. Within a self-medication framework, abstinence from smoking may lead to an increase in impulsive behavior and the likelihood of relapse, particularly among persons with disorders (e.g., attention-deficit/hyperactivity disorder, ADHD) and personality traits (e.g., impulsivity) linked to impulsive behavior. Objectives This study aimed to examine the effects of smoking abstinence on multiple measures of impulsivity among a non-clinical sample of adult smokers selected for high and low levels of ADHD symptoms. Methods In a within-subjects design, participants selected for high or low levels of self-reported ADHD symptoms (N=56) completed sessions following overnight abstinence and when smoking as usual (order counterbalanced). Measures of impulsive behavior included response inhibition (i.e., stop signal task), interference control (i.e., attentional modification of prepulse inhibition (PPI) of startle), and impulsive choice (i.e., hypothetical delay discounting). Results As hypothesized, abstinence decreased response inhibition and PPI. Although ADHD symptoms moderated abstinence effects on impulsive choice and response inhibition, the pattern was opposite to our predictions: the low-ADHD group responded more impulsively when abstinent, whereas the high-ADHD group was relatively unaffected by abstinence. Conclusions These findings highlight the importance of utilizing multiple laboratory measures to examine a multifactorial construct such as impulsive behavior and raise questions about how best to assess symptoms of ADHD and impulsivity among non-abstinent smokers.

Background As part of the Family Smoking Prevention and Tobacco Control Act, the United States Food and Drug Administration charged the Tobacco Products Scientific Advisory Committee with developing a report and recommendations regarding the effect of menthol in cigarettes on the public health. The purpose of this study was to examine smoking behaviors, biomarkers of exposure and subjective responses when switching from a novel menthol cigarette to a non-menthol cigarette to isolate the effect of menthol and to approximate the effect a menthol ban might have on smokers. Methods Thirty two adult smokers completed this 35-day randomized, open-label, laboratory study. After a 5-day baseline period, participants were randomized to the experimental group (n=22) where they would smoke menthol Camel Crush for 15 days followed by 15 days of non-menthol Camel Crush, or the control group (n=10) where they smoked their own brand cigarette across all periods. Participants attended study visits every five days and completed measures of smoking rate, smoking topography, biomarkers of exposure, and subjective responses. Results Although total puff volume tended to increase when the experimental group switched from menthol to non-menthol (p=0.06), there were no corresponding increases in cigarette consumption or biomarkers of exposure (ps>0.1). Subjective ratings related to taste and smell decreased during the non-menthol period (ps<0.01), compared to the menthol. Conclusions Results suggest menthol has minimal impact on smoking behaviors, biomarkers of exposure and subjective ratings. Impact When controlling for all other cigarette design features, menthol in cigarettes had minimal effect on outcome measures.

Preclinical research and learning theory suggest that a longer duration of varenicline treatment prior to the target quit date (TQD) should reduce smoking rates before cessation and improve abstinence outcomes. A double-blind RCT tested this hypothesis among 60 smokers randomized to either Extended (4 weeks of pre-TQD varenicline) or standard run-in (3 weeks of placebo, 1 week of pre-TQD varenicline); everyone received 11 weeks of post-TQD varenicline and brief counseling. During the pre-quit run-in, the reduction in smoking rates was greater among the Extended group (42% vs. 24%, p<0.01) and this effect was greater among women (57% vs. 26%, p=0.001). Continuous abstinence during the final four weeks of treatment was enhanced among women in the Extended group (67% vs. 35%). While these data suggest that extending pre-quit varenicline reduces smoking during the pre-quit period and may further enhance cessation rates, confirmatory evidence is needed from larger clinical trials. Trial Registration: www.clinicaltrials.gov identifier: NCT00835900

Background The ability to exert self-control over temptation is a fundamental component of smoking behavior change. Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) has been shown to modulate cognitive control circuits. Although prior studies show that stimulation reduces cigarette craving and self-reported smoking, effects on ability to resist smoking have not been investigated directly. Objectives We assessed effects of a single 20-minute session of 1.0 mA anodal stimulation over the left DLPFC with cathodal stimulation over the right supra-orbital area (vs. sham stimulation) on ability to resist smoking in a validated smoking lapse paradigm. Methods Twenty-five participants completed two tDCS sessions (active and sham stimulation) in a within-subject, double-blind, randomized and counterbalanced order with a two-week washout period. Following overnight abstinence, participants received tDCS in the presence of smoking related cues; they had the option to smoke at any time or receive $1 for every 5 minutes they abstained. After 50 minutes, they participated in a one hour ad libitum smoking session. Primary and secondary outcomes were time to first cigarette and cigarette consumption, respectively. Results In multiple regression models, active tDCS (compared to sham) significantly increased latency to smoke (p = 0.02) and decreased the total number of cigarettes smoked (p = 0.014) during the session. Conclusion These findings suggest that acute anodal stimulation over the left DLPFC (with cathodal stimulation over the right supra-orbital area) can improve ability to resist smoking, supporting the therapeutic potential of tDCS for smoking cessation treatment.