Maggie M. Sweitzer

Delay discounting and smoking: Association with the Fagerström Test for Nicotine Dependence but not cigarettes smoked per day

Delay discounting (DD) has been shown to be related to smoking status and-less consistently-frequency of cigarette use, but its independent relationship with dependence has not been examined. In this study, we evaluated the relationship between smoking and DD as a function of both smoking quantity and level of dependence controlling for use. A sample of 710 adults completed a DD task using hypothetical monetary rewards, and participants were classified according to smoking status. Current smokers were further characterized as light, moderate, or heavy smokers on the basis of number of cigarettes smoked per day (CPD). Dependence was assessed using the Fagerström Test of Nicotine Dependence (FTND), with the CPD item removed. Current smokers discounted delayed rewards more than never, occasional, or ex-smokers; the latter three groups did not differ. DD was not related to CPD, analyzed continuously or categorically. FTND scores independently predicted DD, controlling for CPD. Analysis of individual FTND items revealed a relationship between DD and morning smoking. When analyzed categorically based on a median split, individuals high in dependence discounted delayed rewards more steeply than low dependence, never, tried-it, and ex-smokers, while these groups did not differ from each other. These results suggest that DD among smokers is not simply the result of nicotine exposure, but may be an important marker for dependence, especially urgency to smoke in the morning.

Dissociated Effects of Anticipating Smoking versus Monetary Reward in the Caudate as a Function of Smoking Abstinence

BACKGROUND Theories of addiction suggest that chronic smoking may be associated with both hypersensitivity to smoking and related cues and hyposensitivity to alternative reinforcers. However, neural responses to smoking and nonsmoking rewards are rarely evaluated within the same paradigm, leaving the extent to which both processes operate simultaneously uncertain. Behavioral evidence and theoretical models suggest that dysregulated reward processing may be more pronounced during deprivation from nicotine, but neuroimaging evidence on the effects of deprivation on reward processing is limited. The current study examined the impact of deprivation from smoking on neural processing of both smoking and monetary rewards. METHODS Two separate functional magnetic resonance imaging scans were performed in 38 daily smokers, one after smoking without restriction and one following 24 hours of abstinence. A rewarded guessing task was conducted during each scan to evaluate striatal blood oxygen level-dependent response during anticipation of both smoking and monetary rewards. RESULTS A significant reward type by abstinence interaction was observed in the bilateral caudate and medial prefrontal cortex during reward anticipation. The blood oxygen level-dependent response to anticipation of smoking reward was significantly higher and anticipation of monetary rewards was significantly lower during abstinence compared with nonabstinence. Attenuation of monetary reward-related activation during abstinence was significantly correlated with abstinence-induced increases in craving and withdrawal. CONCLUSIONS These results provide the first direct evidence of dissociated effects of smoking versus monetary rewards as a function of abstinence. The findings suggest an important neural pathway that may underlie the choice to smoke in lieu of alternative reinforcement during a quit attempt.

Imaging genetics and the neurobiological basis of individual differences in vulnerability to addiction

BACKGROUND Addictive disorders are heritable, but the search for candidate functional polymorphisms playing an etiological role in addiction is hindered by complexity of the phenotype and the variety of factors interacting to impact behavior. Advances in human genome sequencing and neuroimaging technology provide an unprecedented opportunity to explore the impact of functional genetic variants on variability in behaviorally relevant neural circuitry. Here, we present a model for merging these technologies to trace the links between genes, brain, and addictive behavior. METHODS We describe imaging genetics and discuss the utility of its application to addiction. We then review data pertaining to impulsivity and reward circuitry as an example of how genetic variation may lead to variation in behavioral phenotype. Finally, we present preliminary data relating the neural basis of reward processing to individual differences in nicotine dependence. RESULTS Complex human behaviors such as addiction can be traced to their basic genetic building blocks by identifying intermediate behavioral phenotypes, associated neural circuitry, and underlying molecular signaling pathways. Impulsivity has been linked with variation in reward-related activation in the ventral striatum (VS), altered dopamine signaling, and functional polymorphisms of DRD2 and DAT1 genes. In smokers, changes in reward-related VS activation induced by smoking abstinence may be associated with severity of nicotine dependence. CONCLUSIONS Variation in genes related to dopamine signaling may contribute to heterogeneity in VS sensitivity to reward and, ultimately, to addiction. These findings illustrate the utility of the imaging genetics approach for investigating the neurobiological basis for vulnerability to addiction.

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.

Dependence and Withdrawal-Induced Craving Predict Abstinence in an Incentive-Based Model of Smoking Relapse

INTRODUCTION Understanding factors that render some individuals more vulnerable to smoking relapse during the early stages of a quit attempt is critical to tailoring treatment efforts. Development of laboratory models of relapse can provide a framework for identifying underlying mechanisms that may contribute to vulnerability. Here, we explored predictors of abstinence in a novel incentive-based model of relapse. METHODS Fifty-six nontreatment seeking daily smokers completed several nicotine dependence measures prior to participating in a 1-week abstinence incentive test. During the abstinence procedure, participants earned monetary reinforcement for each biochemically verified day of abstinence according to a descending schedule of reinforcement. RESULTS Compliance with the procedure was excellent. All but 3 participants were able to initiate abstinence; nearly 70% lapsed as incentives were reduced. Scores on the Fagerström Test for Nicotine Dependence (FTND), number of cigarettes smoked per day, and self-reported craving on the first day of abstinence each independently predicted time to lapse. The single item of time to first cigarette in the morning on the FTND significantly predicted time to lapse, even when controlling for other significant predictors just listed. The Nicotine Dependence Syndrome Scale (NDSS) and Wisconsin Inventory of Smoking Dependence Motives did not predict lapse, but the NDSS did predict reinitiation of abstinence among those experiencing an initial lapse. CONCLUSIONS These findings partially replicate those of previous full-scale clinical trials and support the feasibility and validity of an incentive-based model of relapse. The time-limited and laboratory-based nature of this model has the potential to further investigations of underlying mechanisms contributing to relapse.

Smoking Abstinence-Induced Changes in Resting State Functional Connectivity with Ventral Striatum Predict Lapse During a Quit Attempt

The ventral and dorsal striatum are critical substrates of reward processing and motivation and have been repeatedly linked to addictive disorders, including nicotine dependence. However, little is known about how functional connectivity between these and other brain regions is modulated by smoking withdrawal and may contribute to relapse vulnerability. In the present study, 37 smokers completed resting state fMRI scans during both satiated and 24-h abstinent conditions, prior to engaging in a 3-week quit attempt supported by contingency management. We examined the effects of abstinence condition and smoking outcome (lapse vs non-lapse) on whole-brain connectivity with ventral and dorsal striatum seed regions. Results indicated a significant condition by lapse outcome interaction for both right and left ventral striatum seeds. Robust abstinence-induced increases in connectivity with bilateral ventral striatum were observed across a network of regions implicated in addictive disorders, including insula, superior temporal gyrus, and anterior/mid-cingulate cortex among non-lapsers; the opposite pattern was observed for those who later lapsed. For dorsal striatum seeds, 24-h abstinence decreased connectivity across both groups with several regions, including medial prefrontal cortex, posterior cingulate cortex, hippocampus, and supplemental motor area. These findings suggest that modulation of striatal connectivity with the cingulo-insular network during early withdrawal may be associated with smoking cessation outcomes.

Precipitated withdrawal from nicotine reduces reinforcing effects of a visual stimulus for rats.

INTRODUCTION Research has identified at least two positive reinforcement-related effects of nicotine: (a) primary reinforcement and (b) enhancement of reinforcement from concurrently available stimuli. Prior examples of the reinforcement-enhancing effects with rats showed that repeated, intermittent nicotine exposure increased responding for non-nicotine reinforcers, and this effect remained robust over several weeks. However, the effects of continuous nicotine exposure on responding for a non-nicotine reinforcer are unknown, as are the effects of abruptly withdrawing continuous nicotine on behavior maintained by the same reinforcer. METHODS Lever pressing for a visual reinforcer under a fixed ratio schedule was assessed while rats were maintained on a chronic, continuous infusion of nicotine (3.16 mg/kg/day; osmotic minipump). The effects of precipitated withdrawal on responding, following 16 days of continuous nicotine exposure, were assessed by pre-session subcutaneous injections of mecamylamine (1.0 mg/kg). RESULTS Continuous nicotine initially increased active responding for the visual reinforcer; however, continued exposure resulted in an attenuation of this effect. Precipitated withdrawal from nicotine resulted in a significant decline in active responding. CONCLUSIONS The initial increase in responding for the visual reinforcer with chronic nicotine exposure is consistent with prior research showing that intermittent exposure to nicotine acts as a reinforcement enhancer. However, the attenuation of this enhancement following prolonged nicotine exposure is in contrast with the persistent effects previously reported. Finally, the decrease in visual reinforcers below control levels (nicotine-naive animals) following nicotine withdrawal highlights a potential for affective withdrawal, which may serve as a motive for continued nicotine use.

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.

Smoking Abstinence and Neurocognition: Implications for Cessation and Relapse

In this chapter, we review the last decade of research on the effects of smoking abstinence on various forms of neurocognition, including executive function (working memory, sustained attention, response inhibition), reward processing, and cue-reactivity. In our review we identify smoking abstinence-induced deficits in executive function mediated by effects on frontal circuitry, which in turn is known to be affected by modulation of cholinergic, dopaminergic, and other neurotransmitter systems. We also review evidence that smoking abstinence blunts reactivity to non-drug reinforcers-a finding that is consistent with results in the animal literature. Finally, our review of cue-reactivity indicates that smoking abstinence does not appear to amplify cue-provoked craving, although it may increase attentional bias to smoking-related cues. Inconsistencies across findings and potential contributing factors are discussed. In addition, we review the literature on the effects of nicotine and non-nicotine factors in neurocognition. Finally, we provide a multi-factor model and an agenda for future research on the effects of smoking abstinence on neurocognition. The model includes four distinct yet interacting factors, including: Negative Reinforcement, Drug-Reward Bias, Goal and Skill Interference, and Non-Cognitive Factors. Additional research is needed to further evaluate the scope and time-course of abstinence-induced changes in neurocognition, the mechanisms that underlie these changes and the specific role of these processes in drug reinforcement, lapse, and relapse.