Rebecca L. Ashare

A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation.

Stress and prefrontal cognitive dysfunction have key roles in driving smoking; however, there are no therapeutics for smoking cessation that 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, functional magnetic resonance imaging (fMRI), and a proof-of-concept treatment period to evaluate whether the noradrenergic α2a agonist guanfacine (3 mg/day) versus placebo (0 mg/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 with 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.

The effect of filter vent blocking and smoking topography on carbon monoxide levels in smokers

Two studies were conducted to examine the effect of filter vent blocking and smoking topography on carbon monoxide (CO) levels in smokers. In Study 1, 12 participants smoked two types of cigarettes (Marlboro Light and Carlton 100) under two types of blocking conditions (unblocked and half-blocked) while using a smoking topography device. Participants were restricted to 8 puffs, separated by 45 s. Significant main effects of CO boost for cigarette type and blocking condition replicated previous findings. A significant increase in CO boost for the Marlboro Light blocked condition is a novel finding for this best-selling brand. That result and the finding that topography measures did not predict CO boost made us question the reliability of CO boost. In Study 2, we examined the reliability of CO boost by recruiting 12 participants to smoke three unblocked Carlton 100 cigarettes in one session and three half-blocked in another. CO boost was significantly greater for the blocked sessions compared to the unblocked and CO boost did not differ within session, thus supporting the reliability of the measure. When participants do not switch brands within a session, smoking topography measures are predictive of CO boost.

Reward and Affective Regulation in Depression-Prone Smokers

BACKGROUND There is a disproportionately high smoking prevalence among individuals who are prone to depression. While depression has been conceptualized as a disorder of dysregulated positive affect and disrupted reward processing, little research has been conducted to determine the role of smoking in these processes among depression-prone smokers. METHODS Depression-prone smokers (DP+; n = 34) and smokers not depression-prone (DP-; n = 49) underwent two laboratory sessions, one while smoking abstinent and one while smoking ad libitum, to assess the relative reinforcing value of smoking and reward sensitivity. Using experience sampling methods, participants completed self-report measures of subjective reward, positive affect, and negative affect across 3 days while smoking as usual and 3 days while smoking abstinent. RESULTS DP+ were two times more likely to work for cigarette puffs versus money in a progressive ratio, choice task (odds ratio 2.05; 95% confidence interval 1.04 to 4.06, p = .039) compared with DP-. Reward sensitivity as measured by the signal detection task did not yield any significant findings. Mixed models regressions revealed a three-way interaction (depression group, smoking phase, and time) for subjective reward, negative affect, and positive affect. For all three of these outcomes, the slopes for DP- and DP+ differed significantly from each other (ps < .05) and the effect of smoking (versus abstinence) over time was greater for DP+ than DP- smokers (ps < .05). CONCLUSIONS These findings indicate that the effects of smoking on reward and positive affect regulation are specific to DP+ smokers and highlight novel targets for smoking cessation treatment in this population.

The Effect of Menthol on Cigarette Smoking Behaviors, Biomarkers and Subjective Responses

Background: As part of the Family Smoking Prevention and Tobacco Control Act, the U.S. Food and Drug Administration charged the Tobacco Products Scientific Advisory Committee with developing a report and recommendations about 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 5 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 (P > 0.1). Subjective ratings related to taste and smell decreased during the non-menthol period (P < 0.01), compared with 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. Cancer Epidemiol Biomarkers Prev; 22(3); 382–9. ©2013 AACR.

Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal.

Introduction: Current FDA-approved smoking cessation pharmacotherapies have limited efficacy and are associated with high rates of relapse. Therefore, there is a clear need to develop novel antismoking medications. Nicotine withdrawal is associated with cognitive impairments that predict smoking relapse. It has been proposed that these cognitive deficits are a hallmark of nicotine withdrawal that could be targeted in order to prevent smoking relapse. Thus, pharmacotherapies that increase cognitive performance during nicotine withdrawal may represent potential smoking cessation agents. Areas covered: The authors review the clinical literature demonstrating that nicotine withdrawal is associated with deficits in working memory, attention and response inhibition. They then briefly summarize different classes of compounds and strategies to increase cognitive performance during nicotine withdrawal. Particular emphasis has been placed on translational research in order to highlight areas for which there is strong rationale for pilot clinical trials of potential smoking cessation medications. Expert opinion: There is emerging evidence that supports deficits in cognitive function as a plausible nicotine withdrawal phenotype. The authors furthermore believe that the translational paradigms presented here may represent efficient and valid means for the evaluation of cognitive-enhancing medications as possible treatments for nicotine dependence.

Effects of 21 days of varenicline versus placebo on smoking behaviors and urges among non-treatment seeking smokers.

Varenicline promotes smoking cessation and reduces urges to smoke. However, the mechanisms associated with these effects and their time course are not well characterized. One mechanism may be extinction, but the duration of the current dosing protocol may not be sufficient. We examined the effect of extended pre-treatment with varenicline on smoking behavior among 17 non-treatment seeking adult smokers. Using a within-subjects, double-blind, placebo-controlled crossover design, participants received standard dosing of varenicline for 21 days, followed by a 14-day washout period and 21 days of placebo; order counterbalanced. Cigarettes per day (CPD), smoking topography, smoking urges (QSU), and side effects were assessed every three days. Biomarkers (e.g. nicotine metabolites) were collected on days 1, 7, and 21. There was a significant drug by time interaction indicating a reduction in CPD during varenicline phase (between days 10–21), but no reduction during placebo. Varenicline also led to reductions in nicotine metabolites and urges to smoke. Among this sample of non-treatment seeking smokers, varenicline significantly reduced smoking behavior. Results have important treatment implications because changes in CPD and craving did not occur until after the typical one-week run-up period. This suggests that a longer duration of pre-treatment may be beneficial for some smokers.

Risk Factors for Alcohol-Related Problems Among Victims of Partner Violence

Despite the high prevalence of alcohol-related problems and disorders among women who experience intimate partner violence (IPV), factors related to current alcohol use are understudied. We examined current risk factors for alcohol-related problems among 143 substance-using, IPV-exposed women recruited from an urban community from 2007 to 2010. Posttraumatic stress disorder (PTSD) symptom severity was associated with alcohol-related problems and a positive alcohol screen; physical IPV severity was related to alcohol dependence. Post hoc analyses revealed that PTSD symptom severity mediated relationships between physical IPV severity and hazardous, harmful, and dependent drinking. Focusing on managing PTSD symptoms and physical IPV in community-based interventions may halt the progression from alcohol use to dependence.

Transcranial Direct Current Brain Stimulation Increases Ability to Resist Smoking

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 2-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

No Effect of Commercial Cognitive Training on Brain Activity, Choice Behavior, or Cognitive Performance

1 for every 5 minutes they abstained. After 50 minutes, they participated in a 1 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.

Does Extended Pre Quit Bupropion Aid in Extinguishing Smoking Behavior

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. SIGNIFICANCE STATEMENT Engagement of neural regions and circuits important in executive cognitive function can bias behavioral choices away from immediate rewards. Activity in these regions may be enhanced through adaptive cognitive training. Commercial brain training programs claim to improve a broad range of mental processes; however, evidence for transfer beyond trained tasks is mixed. We undertook the first randomized controlled trial of the effects of commercial adaptive cognitive training (Lumosity) on neural activity and decision-making in young adults (N = 128) compared with an active control (playing on-line video games). We found no evidence for relative benefits of cognitive training with respect to changes in decision-making behavior or brain response, or for cognitive task performance beyond those specifically trained.