Kathy Z. Tang

Effect of abstinence challenge on brain function and cognition in smokers differs by COMT genotype

The val allele of the catechol-O-methyltransferase (COMT) val158met polymorphism has been linked with nicotine dependence and with cognitive performance in healthy volunteers. We tested the hypothesis that the val allele is a risk factor for altered brain function and cognition during nicotine abstinence as compared with the normal smoking state. Chronic smokers (n=33) were genotyped prospectively for the COMT polymorphism for balanced selection of met/met, val/met and val/val groups. A visual N-back working memory task was performed during two separate blood oxygen level-dependent (BOLD) functional magnetic resonance imaging sessions in counterbalanced order: (1) smoking as usual, and (2)⩾14 h confirmed abstinence. Significant genotype by session interactions were observed for BOLD signal in right dorsolateral prefrontal cortex (DLPFC; (P=0.0005), left DLPFC (P=0.02) and dorsal cingulate/medial prefrontal cortex (P=0.01) as well as for task reaction time (P=0.03). Smokers with val/val genotypes were more sensitive to the abstinence challenge than carriers of the met allele, with the greatest effects on BOLD signal and performance speed at the highest working memory load. These data suggest a novel brain–behavior mechanism that may underlie the increased susceptibility to nicotine dependence and smoking relapse associated with the COMT val allele. Exploration of the effects of COMT inhibitors as a possible smoking cessation aid in this group may be warranted.

Continuous ASL perfusion fMRI investigation of higher cognition: Quantification of tonic CBF changes during sustained attention and working memory tasks

Arterial spin labeling (ASL) perfusion fMRI is an emerging method in clinical neuroimaging. Its non-invasiveness, absence of low frequency noise, and ability to quantify the absolute level of cerebral blood flow (CBF) make the method ideal for longitudinal designs or low frequency paradigms. Despite the usefulness in the study of cognitive dysfunctions in clinical populations, perfusion activation studies to date have been conducted for simple sensorimotor paradigms or with single-slice acquisition, mainly due to technical challenges. Using our recently developed amplitude-modulated continuous ASL (CASL) perfusion fMRI protocol, we assessed the feasibility of a higher level cognitive activation study in twelve healthy subjects. Taking advantage of the ASL noise properties, we were able to study tonic CBF changes during uninterrupted 6-min continuous performance of working memory and sustained attention tasks. For the visual sustained attention task, regional CBF increases (6-12 ml/100 g/min) were detected in the right middle frontal gyrus, the bilateral occipital gyri, and the anterior cingulate/medial frontal gyri. During the 2-back working memory task, significantly increased activations (7-11 ml/100 g/min) were found in the left inferior frontal/precentral gyri, the left inferior parietal lobule, the anterior cingulate/medial frontal gyri, and the left occipital gyrus. Locations of activated and deactivated areas largely concur with previous PET and BOLD fMRI studies utilizing similar paradigms. These results demonstrate that CASL perfusion fMRI can be successfully utilized for the investigation of the tonic CBF changes associated with high level cognitive operations. Increased applications of the method to the investigation of cognitively impaired populations are expected to follow.

Nicotine Metabolite Ratio Predicts Smoking Topography and Carcinogen Biomarker Level

Background: Variability in smoking behavior is partly attributable to heritable individual differences in nicotine clearance rates. This can be assessed as the ratio of the metabolites cotinine and 3′-hydroxycotinine (referred to as the nicotine metabolism ratio; NMR). We hypothesized that faster NMR would be associated with greater cigarette puff volume and higher levels of total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a carcinogen biomarker. Methods: Current smokers (n = 109) smoked one of their preferred brand cigarettes through a smoking topography device and provided specimens for NMR and total NNAL assays. Results: Faster nicotine metabolizers (third and fourth quartiles versus first quartile) based on the NMR exhibited significantly greater total puff volume and total NNAL; the total puff volume by daily cigarette consumption interaction was a significant predictor of total NNAL level. Conclusion: A heritable biomarker of nicotine clearance predicts total cigarette puff volume and total NNAL. Impact: If validated, the NMR could contribute to smoking risk assessment in epidemiologic studies and potentially in clinical practice. Cancer Epidemiol Biomarkers Prev; 20(2); 234–8. 2011 AACR.

Experimental evaluation of antitobacco PSAs: Effects of message content and format on physiological and behavioral outcomes

INTRODUCTION Antitobacco media campaigns using public service announcements (PSAs) have shown promise in reducing smoking initiation and increasing intentions to quit. Research on what makes an effective PSA has had mixed outcomes. The present study tested the effects of specific message features in antitobacco PSAs, using theory-based physiological and self-report outcomes. METHODS PSAs were categorized as high or low in message sensation value (MSV) and strength of argument and presented to 200 current smokers in a 2 x 2 factorial design. Physiological responses-specifically, heart rate, skin conductance, zygomaticus major, and corrugator supercilii-were assessed while participants viewed the PSAs. Beliefs, attitudes, efficacy, norms, and intentions to quit were assessed immediately following viewing. RESULTS Corrugator activity was significantly greater in the high MSV condition. Among those low in sensation seeking, low MSV PSAs elicited higher self-efficacy, whereas the reverse was true for high sensation seekers. High MSV PSAs elicited higher negative beliefs in low sensation seekers. Adding physiological measures to a model predicting intention to quit did not improve the explained variance. DISCUSSION The present study represents the first comprehensive theory-based experimental investigation of the effects of different features of antitobacco PSAs and provides a framework for future research in identifying effective features of such PSAs. Results illustrate the importance of considering individual differences, characterizing both PSA content and format, and outcome and response measures when evaluating antitobacco PSAs.

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.

Hippocampus-Specific fMRI Group Activation Analysis Using the Continuous Medial Representation

We present a new shape-based approach for regional group activation analysis in fMRI studies. The method restricts anatomical normalization, spatial smoothing and random effects statistical analysis to the space inside and around a structure of interest. Normalization involves finding intersubject correspondences between manually outlined masks, and it leverages the continuous medial representation, which makes it possible to extend surface-based shape correspondences to the space inside and outside of structures. Our approach is an alternative to whole-brain normalization in cases where the latter may fail due to anatomical variability or pathology. It also provides an opportunity to analyze the shape and thickness of structures concurrently with functional activation. We apply the technique to the hippocampus and evaluate it using data from a visual scene encoding fMRI study, where activation in the hippocampus is expected. We produce detailed statistical maps of hippocampal activation, as well as maps comparing activation inside and outside of the hippocampus. We find that random effects statistics computed by the new approach are more significant than those produced using the Statistical Parametric Mapping framework (Friston, K.J., Holmes, A.P., Worsley, K.J., Poline, J.-P., Firth, C.D., Frackowiak, R.S.J. 1994, Statistical parametric maps in functional imaging: a general linear approach. Human Brain Mapping, 2(4): 189-210) at low levels of smoothing, suggesting that greater specificity can be achieved by the new method without a severe tradeoff in sensitivity.

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.

Experimental design for functional MRI of scene memory encoding

The use of functional imaging to identify encoding-related areas in the medial temporal lobe has previously been explored for presurgical evaluation in patients with temporal lobe epilepsy. Optimizing sensitivity in such paradigms is critical for the reliable detection of regions most closely engaged in memory encoding. A variety of experimental designs have been used to detect encoding-related activity, including blocked, sparse event-related, and rapid event-related designs. Although blocked designs are generally more sensitive than event-related designs, design and analysis advantages could potentially overcome this difference. In the present study, we directly contrast different experimental designs in terms of the intensity, extent, and lateralization of activation detected in healthy subjects. Our results suggest that although improved design augments the sensitivity of event-related designs, these benefits are not sufficient to overcome the sensitivity advantages of traditional blocked designs.

A randomized controlled trial of progressively reduced nicotine content cigarettes on smoking behaviors, biomarkers of exposure, and subjective ratings

Background: The U.S. FDA has the authority to reduce cigarette nicotine content if found to benefit public health. Reduced nicotine content (RNC) cigarette use does not appear to increase harm exposure, but studies have not rigorously assessed smoking behavior or used a comprehensive panel of biomarkers. This study examined the effects of progressively decreasing RNC cigarettes on smoking behaviors, biomarkers of exposure, and subjective ratings. Methods: One hundred and fifty-eight daily, non–treatment-seeking smokers participated in a 35-day randomized, unblinded, parallel study. After a 5-day baseline period, participants were randomly assigned to an experimental group (n = 80) that smoked progressively decreasing RNC cigarettes during three 10-day periods, or control group (n = 78) that smoked their own brand throughout the study. Results: Daily cigarette consumption significantly increased for the intermediate RNCs (Ps < 0.001) but approached baseline rate for the lowest RNC (P = 0.686); in contrast, puffing behavior significantly decreased at intermediate levels and increased for the lowest RNC (Ps < 0.001). Cotinine and NNAL significantly decreased by RNC period (Ps ≤ 0.001–0.02), whereas CO boost initially increased (Ps = 0.001–0.005). 1-HOP did not change by period (P = 0.109). Conclusions: Smoking behaviors changed by RNC period via CPD and puffing behavior. Biomarkers of exposure generally decreased with nicotine content. Impact: Findings suggest that RNC use does not ubiquitously reduce smoking behaviors or biomarkers, yet the lowest RNC level tested may reduce harm exposure. This emphasizes the importance of using multiple behavioral and biologic measures to address the impact of RNC cigarette smoking. Cancer Epidemiol Biomarkers Prev; 25(7); 1125–33. ©2016 AACR.

Behavioral Filter Vent Blocking on the First Cigarette of the Day Predicts Which Smokers of Light Cigarettes Will Increase Smoke Exposure From Blocked Vents

Filter vent blocking on best-selling light cigarettes increases smoke yield during standard machine testing but not in clinical investigations of smokers. The purpose of the study was to investigate the effect of (a) manipulating cigarette filter vent blocking and (b) blocking status of first cigarette of the day on carbon monoxide (CO) boost. Participants (n = 25; Marlboro Lights nonmenthol cigarette smokers, age range 21-60 years, minimum 15 daily cigarettes, and daily smoking for a minimum 5 years) completed the laboratory-based, within-subject, double-blind, cross-over design of 2 smoking sessions, one utilizing a smoking topography device, one without. Each session consisted of smoking 4 cigarettes; 2 with filter vents blocked and 2 with filter vents unblocked. Spent first daily cigarette filters collected between sessions were scored for evidence of filter vent blocking. Smoking cigarettes with blocked filter vents significantly increased CO boost in both laboratory sessions (p < .001). Those who blocked their first cigarette of the day (n = 10) had significantly greater CO boost when smoking a blocked cigarette, in relation to smoking an unblocked cigarette and in comparison with nonblockers (p = .04). Total puff volume was a significant predictor of CO boost when smoking unblocked and blocked cigarettes (ps < .04). Blocking filter vents significantly increased smoke exposure in relation to when filter vents are not blocked, particularly for those who block filter vents on their first cigarette of the day. Total puff volume predicted CO boost, and results suggest that smokers adjust their smoking behavior by cigarette blocking status. Those smokers who block filter vents may be increasing their exposure by 30%.