Francis Joseph McClernon

Individual Differences in Nicotine Dependence, Withdrawal Symptoms, and Sex Predict Transient fMRI-BOLD Responses to Smoking Cues

Exposure to smoking cues increases craving for cigarettes and can precipitate relapse. Whereas brain imaging studies have identified a distinct network of brain regions subserving the processing of smoking cues, little is known about the influence of individual difference factors and withdrawal symptoms on brain cue reactivity. Multiple regression analysis was used to evaluate relations between individual difference factors and withdrawal symptoms and event-related blood oxygen level–dependent responses to visual smoking cues in a sample of 30 smokers. Predictors were self-report nicotine dependence (Fagerström test of nicotine dependence, FTND), prescan withdrawal symptoms (craving and negative affect), and sex. The unique variance of each predictor was examined after controlling for each of the others. Positive associations were observed between FTND and reactivity to cues in right anterior cingulate and orbitofrontal cortex (OFC) whereas negative associations were observed between prescan craving and reactivity in ventral striatum. Higher negative affect or being male was associated with greater reactivity in left hippocampus and left OFC. Women exhibited greater cue reactivity than men in regions including the cuneus and left superior temporal gyrus. Individual difference factors and withdrawal symptoms were uniquely associated with brain reactivity to smoking cues in regions subserving reward, affect, attention, motivation, and memory. These findings provide further evidence that reactivity to conditioned drug cues is multiply determined and suggest that smoking cessation treatments designed to reduce cue reactivity focus on each of these variables.

ADHD and Smoking: From Genes to Brain to Behavior

Attention‐deficit/hyperactivity disorder (ADHD) and tobacco smoking are among the most common and costly psychiatric and behavioral problems. The rates of co‐occurrence of these two common problems are larger than expected by chance. Despite progress in identifying the neural and genetic substrates of each, the mechanisms underlying the high rates of comorbidity between ADHD and smoking remain largely unknown. We propose that ADHD and smoking involve dysregulation of dopaminergic and nicotinic‐acetylcholinergic circuits and that these aberrations are likely to arise, at least in part, from genetic variations. This review describes an integrative model of the ADHD–smoking comorbidity, with an emphasis on shared neuropharmacological mechanisms. We first describe the prevalence of smoking among ADHD patients. We then describe how ADHD influences stages of smoking behavior (e.g., initiation, maintenance, and relapse). We review common potential genetic substrates of ADHD and smoking, focusing on genes that regulate monoaminergic neurotransmission. We review the behavioral and neuropharmacological bases of smoking and ADHD, focusing on the modulatory roles of nicotine on attention and behavioral control. Finally, we discuss the implications of this model for prevention and clinical outcomes.

Association between attention-deficit/hyperactivity disorder symptoms and obesity and hypertension in early adulthood: a population-based study

Objective:To examine the associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, obesity and hypertension in young adults in a large population-based cohort.Design, Setting and Participants:The study population consisted of 15 197 respondents from the National Longitudinal Study of Adolescent Health, a nationally representative sample of adolescents followed from 1995 to 2009 in the United States. Multinomial logistic and logistic models examined the odds of overweight, obesity and hypertension in adulthood in relation to retrospectively reported ADHD symptoms. Latent curve modeling was used to assess the association between symptoms and naturally occurring changes in body mass index (BMI) from adolescence to adulthood.Results:Linear association was identified between the number of inattentive (IN) and hyperactive/impulsive (HI) symptoms and waist circumference, BMI, diastolic blood pressure and systolic blood pressure (all P-values for trend <0.05). Controlling for demographic variables, physical activity, alcohol use, smoking and depressive symptoms, those with three or more HI or IN symptoms had the highest odds of obesity (HI 3+, odds ratio (OR)=1.50, 95% confidence interval (CI)=1.22−2.83; IN 3+, OR=1.21, 95% CI=1.02−1.44) compared with those with no HI or IN symptoms. HI symptoms at the 3+ level were significantly associated with a higher OR of hypertension (HI 3+, OR=1.24, 95% CI=1.01−1.51; HI continuous, OR=1.04, 95% CI=1.00−1.09), but associations were nonsignificant when models were adjusted for BMI. Latent growth modeling results indicated that compared with those reporting no HI or IN symptoms, those reporting 3 or more symptoms had higher initial levels of BMI during adolescence. Only HI symptoms were associated with change in BMI.Conclusion:Self-reported ADHD symptoms were associated with adult BMI and change in BMI from adolescence to adulthood, providing further evidence of a link between ADHD symptoms and obesity.

Biomarkers for Smoking Cessation

One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development. Promising biomarkers are presented across a range of approaches including metabolism, genetics, and neuroimaging. A preclinical viewpoint is also offered, as are analytical considerations and a regulatory perspective summarizing a pathway toward biomarker qualification.

Smoking Withdrawal in Smokers With and Without Posttraumatic Stress Disorder

INTRODUCTION Previous research on smoking withdrawal in posttraumatic stress disorder (PTSD) has been limited by the use of retrospective and observational methods and has lacked repeated assessments on the first day of abstinence and evaluation of the conditioned effects of smoking. METHODS Smokers with (n = 17; 59% female) and without (n = 30; 17% female) PTSD completed 3 randomly ordered experimental sessions using a 2 (group: PTSD vs. non-PTSD) × 3 (smoking condition: usual brand vs. nicotine free vs. no smoking) design. Before the smoking manipulation, participants completed self-report measures of smoking urges and withdrawal, followed by withdrawal assessment after the smoking manipulation. RESULTS Compared with smokers without PTSD, smokers with PTSD exhibited higher craving (χ₁² = 16.60, p < .001) and habit withdrawal (χ₁² = 10.38, p = .001) following overnight abstinence. PTSD smokers also exhibited worsening negative affect throughout the morning when not smoking a cigarette (χ₁² = 11.30, p = .004). After smoking, smokers with PTSD reported diminished relief from craving (χ₁² = 6.49, p = .011), negative affect (χ₁² = 4.51, p = .034), arousal (χ₁² = 6.46, p = .011), and habit withdrawal (χ₁² = 7.22, p = .007), relative to smokers without PTSD. CONCLUSIONS Results of this preliminary investigation suggested that after overnight abstinence, PTSD smokers experienced worse withdrawal symptoms and greater urges to smoke for both positive and negative reinforcement. Research on smoking withdrawal early in the course of smoking abstinence in PTSD could inform interventions targeting abstinence early in the quit attempt.

Increased Functional Connectivity in an Insula-Based Network is Associated with Improved Smoking Cessation Outcomes

Little is known regarding the underlying neurobiology of smoking cessation. Neuroimaging studies indicate a role for the insula in connecting the interoceptive awareness of tobacco craving with a larger brain network that motivates smoking. We investigated differences in insula-based functional connectivity between smokers who did not relapse during a quit attempt vs those who relapsed. Smokers (n=85) underwent a resting-state functional connectivity scan and were then randomized into two groups (either smoking usual brand cigarettes or smoking very low nicotine cigarettes plus nicotine replacement therapy) for 30 days before their target quit date. Following the quit date, all participants received nicotine replacement therapy and their smoking behavior was observed for 10 weeks. Participants were subsequently classified as nonrelapsed (n=44) or relapsed (i.e., seven consecutive days of smoking ⩾1 cigarette/day; n=41). The right and left insula, as well as insula subdivisions (posterior, ventroanterior, and dorsoanterior) were used as seed regions of interest in the connectivity analysis. Using the right and left whole-insula seed regions, the nonrelapsed group had greater functional connectivity than the relapsed group with the bilateral pre- and postcentral gyri. This effect was isolated to the right and left posterior insula seed regions. Our results suggest that relapse vulnerability is associated with weaker connectivity between the posterior insula and primary sensorimotor cortices. Perhaps greater connectivity in this network improves the ability to inhibit a motor response to cigarette cravings when those cravings conflict with a goal to remain abstinent. These results are consistent with recent studies demonstrating a positive relationship between insula-related functional connectivity and cessation likelihood among neurologically intact smokers.

Association between the oxytocin receptor ( OXTR ) gene and mesolimbic responses to rewards

BackgroundThere has been significant progress in identifying genes that confer risk for autism spectrum disorders (ASDs). However, the heterogeneity of symptom presentation in ASDs impedes the detection of ASD risk genes. One approach to understanding genetic influences on ASD symptom expression is to evaluate relations between variants of ASD candidate genes and neural endophenotypes in unaffected samples. Allelic variations in the oxytocin receptor (OXTR) gene confer small but significant risk for ASDs for which the underlying mechanisms may involve associations between variability in oxytocin signaling pathways and neural response to rewards. The purpose of this preliminary study was to investigate the influence of allelic variability in the OXTR gene on neural responses to monetary rewards in healthy adults using functional magnetic resonance imaging (fMRI).MethodsThe moderating effects of three single nucleotide polymorphisms (SNPs) (rs1042778, rs2268493 and rs237887) of the OXTR gene on mesolimbic responses to rewards were evaluated using a monetary incentive delay fMRI task.ResultsT homozygotes of the rs2268493 SNP demonstrated relatively decreased activation in mesolimbic reward circuitry (including the nucleus accumbens, amygdala, insula, thalamus and prefrontal cortical regions) during the anticipation of rewards but not during the outcome phase of the task. Allelic variation of the rs1042778 and rs237887 SNPs did not moderate mesolimbic activation during either reward anticipation or outcomes.ConclusionsThis preliminary study suggests that the OXTR SNP rs2268493, which has been previously identified as an ASD risk gene, moderates mesolimbic responses during reward anticipation. Given previous findings of decreased mesolimbic activation during reward anticipation in ASD, the present results suggest that OXTR may confer ASD risk via influences on the neural systems that support reward anticipation.

Nicotine and Non-Nicotine Smoking Factors Differentially Modulate Craving, Withdrawal and Cerebral Blood Flow as Measured with Arterial Spin Labeling

Smoking cessation results in withdrawal symptoms such as craving and negative mood that may contribute to lapse and relapse. Little is known regarding whether these symptoms are associated with the nicotine or non-nicotine components of cigarette smoke. Using arterial spin labeling, we measured resting-state cerebral blood flow (CBF) in 29 adult smokers across four conditions: (1) nicotine patch+denicotinized cigarette smoking, (2) nicotine patch+abstinence from smoking, (3) placebo patch+denicotinized cigarette smoking, and (4) placebo patch+abstinence from smoking. We found that changes in self-reported craving positively correlated with changes in CBF from the denicotinized cigarette smoking conditions to the abstinent conditions. These correlations were found in several regions throughout the brain. Self-reported craving also increased from the nicotine to the placebo conditions, but had a minimal relationship with changes in CBF. The results of this study suggest that the non-nicotine components of cigarette smoke significantly impact withdrawal symptoms and associated brain areas, independently of the effects of nicotine. As such, the effects of non-nicotine factors are important to consider in the design and development of smoking cessation interventions and tobacco regulation.

Blunted striatal response to monetary reward anticipation during smoking abstinence predicts lapse during a contingency-managed quit attempt

RationaleTobacco smoking is associated with dysregulated reward processing within the striatum, characterized by hypersensitivity to smoking rewards and hyposensitivity to non-smoking rewards. This bias toward smoking reward at the expense of alternative rewards is further exacerbated by deprivation from smoking, which may contribute to difficulty maintaining abstinence during a quit attempt.ObjectiveWe examined whether abstinence-induced changes in striatal processing of rewards predicted lapse likelihood during a quit attempt supported by contingency management (CM), in which abstinence from smoking was reinforced with money.MethodsThirty-six non-treatment-seeking smokers participated in two functional MRI (fMRI) sessions, one following 24-h abstinence and one following smoking as usual. During each scan, participants completed a rewarded guessing task designed to elicit striatal activation in which they could earn smoking and monetary rewards delivered after the scan. Participants then engaged in a 3-week CM-supported quit attempt.ResultsAs previously reported, 24-h abstinence was associated with increased striatal activation in anticipation of smoking reward and decreased activation in anticipation of monetary reward. Individuals exhibiting greater decrements in right striatal activation to monetary reward during abstinence (controlling for activation during non-abstinence) were more likely to lapse during CM (p < 0.025), even when controlling for other predictors of lapse outcome (e.g., craving); no association was seen for smoking reward.ConclusionsThese results are consistent with a growing number of studies indicating the specific importance of disrupted striatal processing of non-drug reward in nicotine dependence and highlight the importance of individual differences in abstinence-induced deficits in striatal function for smoking cessation.

The effects of nicotine and non-nicotine smoking factors on working memory and associated brain function

Smoking abstinence impairs executive function, which may promote continued smoking behavior and relapse. The differential influence of nicotine and non‐nicotine (i.e. sensory, motor) smoking factors and related neural substrates is not known. In a fully factorial, within‐subjects design, 33 smokers underwent fMRI scanning following 24 hours of wearing a nicotine or placebo patch while smoking very low nicotine content cigarettes or remaining abstinent from smoking. During scanning, blood oxygenation level‐dependent (BOLD) signal was acquired while participants performed a verbal N‐back task. Following 24‐hour placebo (versus nicotine) administration, accuracy on the N‐back task was significantly worse and task‐related BOLD signal lower in dorsomedial frontal cortex. These effects were observed irrespective of smoking. Our data provide novel evidence that abstinence‐induced deficits in working memory and changes in underlying brain function are due in large part to abstinence from nicotine compared with non‐nicotine factors. This work has implications both for designing interventions that target abstinence‐induced cognitive deficits and for nicotine‐reduction policy.