Reactivity to smoking-related cues may be an important factor that precipitates relapse in smokers who are trying to quit. The neurobiology of smoking cue reactivity has been investigated in several fMRI studies. We combined the results of these studies using activation likelihood estimation, a meta-analytic technique for fMRI data. Results of the meta-analysis indicated that smoking cues reliably evoke larger fMRI responses than neutral cues in the extended visual system, precuneus, posterior cingulate gyrus, anterior cingulate gyrus, dorsal and medial prefrontal cortex, insula, and dorsal striatum. Subtraction meta-analyses revealed that parts of the extended visual system and dorsal prefrontal cortex are more reliably responsive to smoking cues in deprived smokers than in non-deprived smokers, and that short-duration cues presented in event-related designs produce larger responses in the extended visual system than long-duration cues presented in blocked designs. The areas that were found to be responsive to smoking cues agree with theories of the neurobiology of cue reactivity, with two exceptions. First, there was a reliable cue reactivity effect in the precuneus, which is not typically considered a brain region important to addiction. Second, we found no significant effect in the nucleus accumbens, an area that plays a critical role in addiction, but this effect may have been due to technical difficulties associated with measuring fMRI data in that region. The results of this meta-analysis suggest that the extended visual system should receive more attention in future studies of smoking cue reactivity.

No abstract

Identifying addicts with higher risk of relapse would provide the opportunity to implement individualized interventions and increase cessation success rates. Unfortunately, the ability to predict the long-term success of drug-cessation treatments continues to elude researchers. We tested whether brain responses to emotional and cigarette-related pictures were predictive of the ability to abstain from smoking. Smokers interested in quitting (n=180) participated in a smoking cessation clinical trial. Before the initiation of any treatment we recorded event-related potentials (ERPs) evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related images. Cluster analysis was used to assign smokers to two groups based on the amplitude of the late positive potential (LPP) to the experimental stimuli. While both groups showed enhanced responses to cigarette-related cues, one group (n=81) also showed blunted brain responses to intrinsically pleasant stimuli. Smokers in the latter group were significantly less likely to be abstinent at 10, 12, and 24 weeks after their quit date. In conclusion, using event-related potentials, a direct measure of brain activity, we found that smokers with blunted brain responses to intrinsically pleasant stimuli had lower rates of long-term smoking abstinence. This response offers a new biomarker for identifying smokers at higher risk of relapse and for testing the efficacy of new interventions aimed at normalizing brain reward systems’ responses to intrinsically pleasant stimuli.

The p16(INK4a) and p14(ARF) tumor suppressor genes (TSGs) are encoded within the CDKN2A locus on chromosome 9p21 and function as cell cycle regulatory proteins in the p53 and RB pathways. Inactivation of these genes by genetic and epigenetic changes has been described in some human cancers, but their importance in cutaneous squamous cell carcinoma (SCC) has not been established. Our detailed examination of 40 cutaneous SCC revealed loss of heterozygosity of 9p21 markers in 32.5% of cases. Mutational analysis confirmed five point mutations in four of 40 SCCs. These mutations changed the amino acid sequence of p16(INK4a) in four tumors and p14(ARF) in three tumors. Promoter methylation of p16(INK4a) and p14(ARF) was detected in 13 of 36 (36%) and 16 of 38 (42%) cases, respectively. Absent protein expression was confirmed by immunohistochemistry in 13 of 16 (82%) of the tumors with biallelic inactivating events. Overall, the frequency of 9p21 alterations was 76% and for both p16(INK4a) and p14(ARF), promoter methylation is the commonest mechanism of gene inactivation. Alterations at this locus were significantly more common in tumors from immunocompetent compared with immunosuppressed individuals. These data confirm the importance of inactivation of p16(INK4a) and p14(ARF) TSGs in the pathogenesis of cutaneous SCCs.

Objective-The objective of this study was to evaluate a depression-focused treatment for smoking cessation in pregnant women, versus a time and contact health education control. We hypothesized that the depression-focused treatment would lead to improved abstinence and reduced depressive symptoms among women with high levels of depressive symptomatology. No significant main effects of treatment were hypothesized.Method-Pregnant smokers (N=257) were randomly assigned to a 10-week intensive depressionfocused intervention (Cognitive Behavioral Analysis System of Psychotherapy-CBASP) or to a time and contact control focused on health and wellness (HW); both included equivalent amounts of behavioral and motivational smoking cessation counseling. Fifty-four percent of the sample was African American; 37% met DSM-IV criteria for major depression; mean age (SD) was 25 (5.9) and women averaged 19.5 (8.5) weeks gestation at study entry. Ongoing symptoms of depression were measured using the Center for Epidemiological Studies Depression scale (CES-D).Results-The results showed that at 6-months posttreatment, women with higher levels of baseline depressive symptoms treated with CBASP had a higher probability of prolonged abstinence (F(1,253) =5.61, p=.02) and more improved depression (F(1,2620)=10.49, p=.001) than those treated with HW, whereas those with low baseline depression fared better in HW. The differences in abstinence were not retained at 6-months postpartum. Conclusions-The results suggest that pregnant women with high levels of depressive symptoms may benefit from a depression-focused treatment in terms of improved abstinence and depressive symptoms, both of which could have a combined positive effect on maternal and child health.Publisher's Disclaimer: The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting, fact-checking, and proofreading required for formal publication. It is not the definitive, publisher-authenticated version. The American Psychological Association and its Council of Editors disclaim any responsibility or liabilities for errors or omissions of this manuscript version, any version derived from this manuscript by NIH, or other third parties. The published version is available at www.apa.org/pubs/journals/ccp NIH Public Access Pritchard, 1994;Solomon et al., 2006;Zhu & Valbo, 2002) as well as post-partum relapse . There is evidence that depression clusters with SES and other risk factors for persistent smoking during pregnancy, and that the clustering of such factors predicts smoking in a gradient fashion (Kahn, Certain, & Whitaker, 2002). That depression cooccurs with low SES is not surprising. Children who grow up with low SES parents are at two to three times greater risk for developing major depressive disorder (MDD) than those who grow up with parents of higher SES, even when parental MDD status is controlled (Ritsher, Warner, Johnson, & Dohrenwend, 2001;Gilman, Kawachi, Fitzmaurice, & Buka, 2002). Because persistent smoking du...

Importance: Given the actions of varenicline tartrate and bupropion hydrochloride sustained-release (SR) on neurobiological targets related to affect and reward, it is thought that the modulation of nicotine withdrawal symptoms may contribute to their effectiveness.Objective: To assess the relative efficacy of varenicline and bupropion SR plus intensive counseling on smoking cessation and emotional functioning.Design and Setting: Placebo-controlled randomized clinical trial at a university medical center.Participants: In total, 294 community volunteers who wanted to quit smoking.Interventions: Twelve weeks of varenicline, bupropion SR, or placebo plus intensive smoking cessation counseling (10 sessions, for a total of approximately 240 minutes of counseling).Main Outcome Measures: Prolonged abstinence from smoking and weekly measures of depression, negative affect, and other symptoms of nicotine withdrawal.Results: Significant differences were found in abstinence at the end of treatment and through the 3-month postquit follow-up visit, favoring both active medications compared with placebo. At the 6-month postquit follow-up visit, only the varenicline vs placebo comparison remained significant. Varenicline use was also associated with a generalized suppression of depression and reduced smoking reward compared with the other treatments, while both active medications improved concentration, reduced craving, and decreased negative affect and sadness compared with placebo, while having little effect (increase or decrease) on anxiety and anger. No differences were noted in self-reported rates of neuropsychiatric adverse events. Conclusions and Relevance:In a community sample, varenicline exerts a robust and favorable effect on smoking cessation relative to placebo and may have a favorable (suppressive) effect on symptoms of depression and other affective measures, with no clear unfavorable effect on neuropsychiatric adverse events. Trial Registration: clinicaltrials.gov Identifier: NCT00507728.

The tumor suppressor gene APC was recently identified, and the cDNA was cloned from chromosome 5q21. Point mutations affecting APC are seen in the hereditary syndrome familial adenomatous polyposis, and point mutations in APC and a closely linked gene, MCC, as well as loss of heterozygosity involving chromosome 5q have been reported in sporadic colon cancer. To our knowledge, loss of heterozygosity involving APC or MCC or both has not yet been described in any other human cancer besides lung cancer. We used the polymerase chain reaction and DNA content flow cytometric nuclear sorting to examine 30 primary human esophageal cancers for loss of heterozygosity ofAPC or MCC or both. Loss of one allele was detected in 77% of 26 informative cases. These data suggest that loss of heterozygosity of regions on Sq including the APC and MCC genetic loci is involved in the development and/or progression of most human esophageal cancers.

Addiction has been described as the pathological usurpation of the neural mechanisms normally involved in emotional processing. Event-related potentials (ERPs) can provide a noninvasive index of neural responses associated with the processing of emotionally relevant stimuli and serve as a tool for examining temporal and spatial commonalities between the processing of intrinsically motivating stimuli and drug cues. Before beginning a smoking cessation program, 116 smokers participated in a laboratory session in which dense-array ERPs (129 sensors) were recorded during the presentation of pictures with emotional (pleasant and unpleasant), neutral, and cigarette-related content. ERP differences among categories were analyzed with use of randomization tests on time regions of interest identified by temporal principal component analysis. Both emotional and cigarette-related pictures prompted significantly more positivity than did neutral pictures over central, parietal, and frontal sites in the 452-508 ms time window. During the 212-316 ms time window, both pleasant and cigarette-related pictures prompted less positivity than neutral images did. Cigarette-related pictures enhanced the amplitude of the P1 component (136-144 ms) above the levels measured in the emotional and neutral conditions. These results support the hypothesis that for smokers, cigarette-related cues are motivationally relevant stimuli that capture attentional resources early during visual processing and engage brain circuits normally involved in the processing of intrinsically emotional stimuli.