Exposure to smoking-related cues can trigger relapse in smokers attempting to maintain abstinence.
In the present study we evaluated the effect of 24-hr smoking abstinence on brain responses to smoking-related cues using functional magnetic resonance imaging (fMRI).
Eighteen adult smokers underwent fMRI scanning following smoking as usual (satiated condition) and following 24-hr abstinence (abstinent condition). During scanning they viewed blocks of photographic smoking and control cues.
Following abstinence, greater activation was found in response to smoking cues compared to control cues in parietal (BA 7/31), frontal (BA 8/9), occipital (BA 19) and central (BA 4) cortical regions and in dorsal striatum (putamen) and thalamus. In contrast, no smoking cue > control cue activations were observed following smoking as usual. Direct comparisons between conditions (satiated vs. abstinent) showed greater brain reactivity in response to smoking cues following abstinence. In addition, positive correlations between pre-scan craving in the abstinent condition and smoking cue activation were observed in right dorsomedial prefrontal cortex (dmPFC) including superior frontal gyrus (BA 6/10), anterior cingulate gyrus (BA 32) and supplementary motor area (BA 6).
The present findings indicate smoking abstinence significantly potentiates neural responses to smoking-related cues in brain regions subserving visual sensory processing, attention and action planning. Moreover, greater abstinence-induced craving was significantly correlated with increased smoking cue activation in dmPFC areas involved in action planning and decision making. These findings suggest that drug abstinence can increase the salience of conditioned cues which is consistent with incentive-motivation models of addiction.
cue-reactivity; craving; nicotine dependence; fMRI; smoking; dorsal striatum
Varenicline, an effective smoking cessation medication, functions as an α4β2 nicotinic acetylcholine receptor partial agonist. It indirectly affects the dopaminergic reward system by reducing withdrawal symptoms during abstinence and by decreasing the reinforcement received from nicotine while smoking. We hypothesize that varenicline would have a third mechanism to blunt responses to smoking cues in the reward-related ventral striatum and medial orbitofrontal cortex and would be associated with a reduction in smoking cue–elicited craving.
A laboratory model of conditioned responding and arterial spin-labeled perfusion functional magnetic resonance imaging, a biomarker of regional brain activity, was used to test our hypothesis. Perfusion functional magnetic resonance imaging is quantitative and stable across time, facilitating the measurement of medication-induced neural modifications in the brain in response to a challenge (smoking cue exposure) and in the brain in the resting condition (without provocation). Smokers were imaged during rest and during smoking cue exposure before and after a 3-week randomized placebo-controlled medication regimen. Subjects were nonabstinent to explicitly examine the effects of varenicline on cue reactivity independent of withdrawal.
Center for the Study of Addictions, University of Pennsylvania, Philadelphia.
Subjects were nicotine-dependent smokers who responded to advertisements placed on local radio and Listservs to participate in a medication-related research study that specifically stated “this is not a Quit Smoking Study” and “smokers may be contemplating but not currently considering quitting.”
Prerandomization smoking cues vs nonsmoking cues activated the ventral striatum and medial orbitofrontal cortex (t=3.77) and elicited subjective reports of craving (P=.006). Craving reports correlated with increased activity in the posterior cingulate (t=4.11). Administration of varenicline diminished smoking cue– elicited ventral striatum and medial orbitofrontal cortex responses (t values from −3.75 to −5.63) and reduced self-reported smoking cue–elicited craving, whereas placebo-treated subjects exhibited responses similar to those observed prior to randomization. Varenicline-induced activation of lateral orbitofrontal cortex in the brain at rest (t=5.63) predicted blunting of smoking cue responses in the medial orbitofrontal cortex (r=−0.74).
Varenicline’s reciprocal actions in the reward-activated medial orbitofrontal cortex and in the reward-evaluating lateral orbitofrontal cortex underlie a diminished smoking cue response, revealing a distinctive new action that likely contributes to its clinical efficacy.
Developing means to identify smokers at high risk for relapse could advance relapse prevention therapy. We hypothesized that functional magnetic resonance imaging (fMRI) reactivity to smoking-related cues, measured prior to a quit attempt, could identify smokers with heightened relapse vulnerability.
Twenty-one nicotine-dependent women underwent fMRI prior to quitting smoking, during which smoking-related and neutral images were shown. These smokers also were tested for possible attentional biases to smoking-related words using a computerized emotional Stroop (ES) task previously found to predict relapse. Smokers then made a quit attempt and were grouped based on outcomes (abstinence versus slip: smoking 1 cigarette after attaining abstinence). Pre-quit fMRI and ES measurements in these groups were compared.
Slip subjects had heightened fMRI reactivity to smoking-related images in brain regions implicated in emotion, interoceptive awareness, and motor planning and execution. Smoking cue-induced insula and dorsal anterior cingulate cortex (dACC) reactivity correlated with an attentional bias to smoking-related words. A discriminant analysis of ES and fMRI data predicted outcomes with 79% accuracy. Additionally, smokers who slipped had decreased fMRI functional connectivity between an insula-containing network and brain regions involved in cognitive control, including the dACC and dorsal lateral prefrontal cortex, possibly reflecting reduced top-down control of smoking-related cue-induced emotions.
These findings suggest that the insula and dACC are important substrates of smoking relapse vulnerability. The data also suggest that relapse-vulnerable smokers can be identified prior to quit attempts, which could enable personalized treatment, improve tobacco-dependence treatment outcomes, and reduce smoking-related morbidity and mortality.
Insula; Dorsal anterior cingulate cortex; fMRI; emotional Stroop task; tobacco; relapse
Using fMRI, we examined whether or not adolescents with low levels of nicotine exposure (light smokers) display neural activation in areas shown to be involved with addiction in response to smoking-related stimuli.
Twelve adolescent light smokers (aged 13 to17, smoked 1 to 5 cigarettes per day) and 12 non-smokers (ages 13 to 17, never smoked a cigarette) from the San Francisco Bay Area underwent fMRI scanning. During scanning they viewed blocks of photographic smoking and control cues. Smoking cues consisted of pictures of people smoking cigarettes and smoking-related objects such as lighters and ashtrays. Neutral cues consisted of everyday objects and people engaged in everyday activities.
For smokers, smoking cues elicited greater activation than neutral cues in the mesolimbic reward circuit (left anterior cingulate (T=7.88, p<.001), right hippocampus (T=6.62, p<.001) and right parahippocampal gyrus (T=4.70, p<.001)). We found activation from smoking cues versus neutral cues within both the left and right frontal medial orbital regions (T=5.09, p<.001 and T=3.94, p=.001 respectively), which may be unique to adolescents. Non-smokers showed no significant difference in activation between smoking-related cues and neutral cues.
Our finding that smoking cues produced activation in adolescent light smokers in brain regions seen in adult and heavy teen smokers suggests that even at low levels of smoking, adolescents exhibit heightened reactivity to smoking cues. This paper adds to the existing literature suggesting that nicotine dependence may begin with exposure to low levels of nicotine, underscoring the need for early intervention among adolescent smokers.
fMRI; adolescent nicotine addiction; adolescent smoking; brain imaging
While most cigarette smokers endorse a desire to quit smoking, only about 14% to 49% will achieve abstinence after 6 months or more of treatment. A greater understanding of the effects of smoking on brain function may (in conjunction with other lines of research) result in improved pharmacological (and behavioral) interventions. Many research groups have examined the effects of acute and chronic nicotine/cigarette exposure on brain activity using functional imaging; the purpose of this paper is to synthesize findings from such studies and present a coherent model of brain function in smokers. Responses to acute administration of nicotine/smoking include: a reduction in global brain activity; activation of the prefrontal cortex, thalamus, and visual system; activation of the thalamus and visual cortex during visual cognitive tasks; and increased dopamine (DA) concentration in the ventral striatum/nucleus accumbens. Responses to chronic nicotine/cigarette exposure include decreased monoamine oxidase (MAO) A and B activity in the basal ganglia and a reduction in α4β2 nicotinic acetylcholine receptor (nAChR) availability in the thalamus and putamen. Taken together, these findings indicate that smoking enhances neurotransmission through cortico-basal ganglia-thalamic circuits either by direct stimulation of nAChRs, indirect stimulation via DA release or MAO inhibition, or a combination of these factors. Activation of this circuitry may be responsible for the effects of smoking seen in tobacco dependent subjects, such as improvements in attentional performance, mood, anxiety, and irritability.
Tobacco dependence; Functional magnetic resonance imaging; Positron emission tomography; Autoradiography; Prefrontal cortex; Review
While most cigarette smokers endorse a desire to quit smoking, only 14–49% will achieve abstinence after 6 months or more of treatment. A greater understanding of the effects of smoking on brain function may result in improved pharmacological and behavioral interventions for this condition. Research groups have examined the effects of acute and chronic nicotine/cigarette exposure on brain activity using functional imaging; the purpose of this chapter is to synthesize findings from such studies and present a coherent model of brain function in smokers. Responses to acute administration of nicotine/smoking include reduced global brain activity; activation of the prefrontal cortex, thalamus, and visual system; activation of the thalamus and visual cortex during visual cognitive tasks; and increased dopamine (DA) concentration in the ventral striatum/nucleus accumbens. Responses to chronic nicotine/cigarette exposure include decreased monoamine oxidase (MAO) A and B activity in the basal ganglia and a reduction in α4β2 nicotinic acetylcholine receptor (nAChR) availability in the thalamus and putamen (accompanied by an overall upregulation of these receptors). These findings indicate that smoking enhances neurotransmission through cortico–basal ganglia–thalamic circuits by direct stimulation of nAChRs, indirect stimulation via DA release or MAO inhibition, or a combination of these and possibly other factors. Activation of this circuitry may be responsible for the effects of smoking seen in tobacco-dependent smokers, such as improvements in attentional performance, mood, anxiety, and irritability.
Modern neuroimaging techniques offer the opportunity to non-invasively study neuroanatomical and neurofunctional correlates of nicotine dependence and its treatment. In the present review, the most widely used neuroimaging techniques—magnetic resonance imaging (MRI), positron emission tomography (PET) and functional MRI (fMRI)—are briefly described and their strengths and limitations discussed. The use of these techniques has resulted in new insights into the neuropharmacology of tobacco addiction. Studies comparing smokers and nonsmokers have shown that smokers have less grey matter density in frontal brain regions and greater concentrations of nicotinic receptors. Research on the effects of smoking a cigarette confirms that smoking leads to the release of dopamine in brain reward areas and to nicotinic receptor binding. Studies of smoking abstinence have identified functional brain correlates of increased reactivity to smoking-related cues, and worsening of concentration. To date, neuroimaging studies of nicotine dependence among individuals with mental illness have focused almost exclusively on schizophrenia. A conceptual/methodological framework for studying dual diagnosis using neuroimaging measures is provided with the aim of spurring additional research in this area.
MRI; fMRI; PET; nicotine; smoking; nicotine dependence; ADHD; schizophrenia; dual diagnosis; comorbidity
Craving is a hallmark of drug dependence, including dependence on nicotine. Many studies have examined the neural substrates of cravings elicited by smoking-related cues. Less is known about the neural basis of unprovoked, abstinence-induced cravings, despite the contributions of such cravings to smoking relapse. To fill this gap, we used arterial spin labeled (ASL) perfusion MRI to characterize the neural substrates of abstinence-induced cravings to smoke. Fifteen chronic smokers were scanned during a resting state on two separate occasions: (1) smoking satiety and (2) abstinence (following ≥ 12 hours of smoking deprivation), in counterbalanced order. Smoking abstinence state (vs. satiety) was associated with increased cerebral blood flow (CBF) in anterior cingulate cortex (ACC)/medial orbitofrontal cortex (OFC) and left OFC. Abstinence-induced cravings to smoke were predicted by CBF increases (abstinence minus satiety) in: right OFC, right dorsolateral prefrontal cortex (DLPFC), occipital cortex, ACC, ventral striatum/nucleus accumbens, thalamus, amygdala, bilateral hippocampus, left caudate, and right insula. These data suggest that increased activation in the brain's visuospatial and reward circuitry underlies abstinence-induced cravings to smoke, and thereby, may be important in relapse.
Addiction; Cerebral Blood Flow; Cortex; Mesolimbic; Nicotine; Neuroimaging
Drug cues have been shown to activate brain regions involved in attention, motivation, and reward in addicted users. However, as studies have typically measured responses in only one state (ie drug abstinence), it is unclear whether observed activations represent amplification by abstinence or stable responses. Thus, the present study was designed to evaluate the stability of event-related responses to visual drug cues in dependent smokers (n = 13) using event-related functional magnetic resonance imaging measures. Imaging was conducted following smoking as usual and following overnight abstinence, and self-reported craving measures were obtained before, during, and after scanning. Analysis of hemodynamic response (HDR) amplitudes in each of 13 regions of interest revealed larger responses to smoking compared to control cues in ventral anterior cingulate gyrus (vACG) and superior frontal gyrus. Responses to smoking cues in these and all other regions revealed no effects of abstinence/satiety, thus supporting the notion that cue-elicited brain responses are relatively stable. However, while the abstinence manipulation did not alter group-level responses to smoking cues, at the individual level, abstinence-induced changes in craving (abstinence minus satiety) were positively correlated with changes in HDR amplitude to smoking cues in frontal regions including left inferior frontal gyrus, left vACG, and bilateral middle frontal gyrus. These results suggest that brain responses to smoking cues, while relatively stable at the group level following short-term abstinence, may be modulated by individual differences in craving in response to abstinence—particularly in regions subserving attention and motivation.
magnetic resonance imaging; tobacco use disorder; smoking
The presentation of drug-associated cues has been shown to elicit craving and dopamine release in the striatum of drug-dependent individuals. Similarly, exposure to tobacco-associated cues induces craving and increases the propensity to relapse in tobacco- dependent smokers. However, whether exposure to tobacco-associated cues elicits dopamine release in the striatum of smokers remains to be investigated. We hypothesized that presentation of smoking-related cues compared to neutral cues would induce craving and elevation of intrasynaptic dopamine levels in subregions of the striatum and that the magnitude of dopamine release would be correlated with subjective levels of craving in briefly abstinent tobacco smokers. Eighteen participants underwent two [11C]-(+)-PHNO positron emission tomography (PET) scans after one-hour abstinence period: one during presentation of smoking-associated images and one during presentation of neutral images. Smoking cues significantly increased craving compared to neutral cues on one, but not all, craving measures; however, this increase in craving was not associated with overall significant differences in [11C]-(+)-PHNO binding potential (BPND) (an indirect measure of dopamine release) between the two experimental conditions in any of the brain regions of interest sampled. Our findings suggest that presentation of smoking cues does not elicit detectable (by PET) overall increases in dopamine in humans after one-hour nicotine abstinence. Future research should consider studying smoking cue-induced dopamine release at a longer abstinence period, since recent findings suggest the ability of smoking-related cues to induce craving is associated with a longer duration of smoking abstinence.
Negative affect is thought to be an important factor in the maintenance of cigarette smoking, and thus it is important to further develop objective measures of smoking-related emotional responses. Nonsmokers, nonabstinent smokers, and abstinent smokers participated in a cue reactivity task where eyeblink startle amplitude and startle probe P300 (P3) suppression were measured during the presentation of emotional pictures. During unpleasant pictures, the amplitude of both measures was smaller in nonabstinent smokers than in nonsmokers or abstinent smokers. P3 suppression, but not startle amplitude, was larger in abstinent smokers than in nonsmokers. Abstinence-induced increases in cigarette craving were associated with P3 suppression during tobacco-related pictures. Results suggest that tobacco abstinence increases emotional reactivity to unpleasant stimuli, which is consistent with negative reinforcement models of tobacco addiction.
Abnormal cue reactivity is a central characteristic of addiction, associated with increased activity in motivation, attention and memory related brain circuits. In this neuroimaging study, cue reactivity in problem gamblers (PRG) was compared with cue reactivity in heavy smokers (HSM) and healthy controls (HC). A functional magnetic resonance imaging event-related cue reactivity paradigm, consisting of gambling, smoking-related and neutral pictures, was employed in 17 treatment-seeking non-smoking PRG, 18 non-gambling HSM, and 17 non-gambling and non-smoking HC. Watching gambling pictures (relative to neutral pictures) was associated with higher brain activation in occipitotemporal areas, posterior cingulate cortex, parahippocampal gyrus and amygdala in PRG compared with HC and HSM. Subjective craving in PRG correlated positively with brain activation in left ventrolateral prefrontal cortex and left insula. When comparing the HSM group with the two other groups, no significant differences in brain activity induced by smoking cues were found. In a stratified analysis, the HSM subgroup with higher Fagerström Test for Nicotine Dependence scores (FTND M = 5.4) showed higher brain activation in ventromedial prefrontal cortex, rostral anterior cingulate cortex, insula and middle/superior temporal gyrus while watching smoking-related pictures (relative to neutral pictures) than the HSM subgroup with lower FTND scores (FTND M = 2.9) and than non-smoking HC. Nicotine craving correlated with activation in left prefrontal and left amygdala when viewing smoking-related pictures in HSM. Increased regional responsiveness to gambling pictures in brain regions linked to motivation and visual processing is present in PRG, similar to neural mechanisms underlying cue reactivity in substance dependence. Increased brain activation in related fronto-limbic brain areas was present in HSM with higher FTND scores compared with HSM with lower FTND scores.
Addiction; cue reactivity; fMRI; impulse control disorder; nicotine dependence; pathological gambling
When nicotine-dependent human subjects abstain from cigarette smoking, they exhibit deficits in working memory. An understanding of the neural substrates of such impairments may help to understand how nicotine affects cognition. Our aim, therefore, was to identify abnormalities in the circuitry that mediates working memory in nicotine-dependent subjects after they initiate abstinence from smoking.
We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to study eight smokers while they performed a letter version of the N-Back working memory task under satiety (≤1.5 hours abstinence) and abstinence (≥14 hours abstinence) conditions.
Task-related activity in the left dorsal lateral prefrontal cortex (DLPFC) showed a significant interaction between test session (satiety, abstinence) and task load (1-back, 2-back, and 3-back). This interaction reflected the fact that task-related activity in the satiety condition was relatively low during performance of the 1-back task but greater at the more difficult task levels, whereas task-related activity in the abstinence condition was relatively high at the 1-back level and did not increase at the more difficult task levels.
We conclude that neural processing related to working memory in the left DLPFC is less efficient during acute abstinence from smoking than at smoking satiety.
Functional magnetic resonance imaging; tobacco; nicotine; withdrawal; brain imaging; prefrontal cortex
Smoking withdrawal is associated with significant deficits in the ability to initiate and maintain attention for extended periods of time (i.e. sustained attention; SA). However, the effects of smoking abstinence on the temporal dynamics of neurocognition during SA have not been evaluated.
Twenty adult smokers underwent functional magnetic resonance imaging scans following smoking as usual and after 24-hr abstinence. During scanning they completed a SA task with two levels of task difficulty, designed to measure both sustained (i.e. over the duration of the task) and transient (i.e. event-related) activation.
Smoking abstinence significantly decreased task accuracy regardless of task difficulty. Compared to the smoking as usual, abstinence resulted in decreased sustained activation in right inferior and middle frontal gyri but increased transient activation across disperse cortical areas including precuneus and right superior frontal gyrus. Greater task difficulty was associated with even greater transient activation during abstinence in mostly right hemisphere regions including right inferior frontal gyrus.
Smoking withdrawal shifts the temporal and spatial dynamics of neurocognition from sustained, right prefrontal activation reflecting proactive cognitive control (Braver et al., 2009) to more disperse and transient activation reflecting reactive control.
attention; fMRI; mixed-design; nicotine dependence; prefrontal cortex; smoking
Gender differences in tobacco withdrawal are of considerable clinical importance, but research findings on this topic have been mixed. Methodological variation in samples sizes, experimental design, and measures across studies may explain the inconsistent results. The current study examined whether male (n = 101) and female (n = 102) smokers (≥15 cigarettes/day) differed in abstinence-induced changes on a battery of self-report measures (withdrawal, affect, craving), cognitive performance tasks (attention, psychomotor performance), and physiological responses (heart rate, blood pressure, brain electroencephalogram). Participants attended 2 counterbalanced laboratory sessions, 1 following 12 hr of abstinence and the other following ad libitum smoking. Results showed that women reported greater abstinence-induced increases in negative affect, withdrawal-related distress, and urge to smoke to relieve withdrawal distress. In contrast, both genders reported similar abstinence-induced changes in positive affect and urge to smoke for pleasure. Men and women exhibited generally similar abstinence-induced changes in physiological and cognitive performance measures. In addition, gender did not moderate the association between withdrawal symptoms and baseline measures of smoking behavior and dependence. Abstinence-induced changes in withdrawal distress mediated the effect of gender on latency until the 1st cigarette of the day at trend levels (p < .10). These findings suggest that there are qualitative gender differences in the acute tobacco withdrawal syndrome that may underlie gender-specific smoking patterns.
gender differences; nicotine withdrawal; affect; craving; smoking
Evidence suggests that the transition from experimental to regular smoking is facilitated by the influence of tobacco on affective and attentional mechanisms. The objective of this study was to examine affective and attentional responses in young adult smokers using fear-potentiated startle and prepulse inhibition.
Participants were 56 college non smokers, non-abstinent smokers, and overnight-abstinent smokers. The fear-potentiated startle test examined phasic responses to imminent threat cues and more sustained responses to unpredictable aversive events. Prepulse inhibition investigated responses to attended and ignored prepulse stimuli.
Abstinent and non-abstinent smokers showed increased sustained potentiation of startle to contextual cues, compared to controls. Abstinent smokers showed increased fear-potentiated startle to threat cues, compared to non-smokers. PPI did not discriminate between abstinent or non-abstinent smokers and controls.
These findings suggest that negative affectivity or anxiety is associated with smoking, particularly during withdrawal. Potentiated startle may provide a valuable tool in understanding the biologic mechanisms underlying nicotine withdrawal and inform cessation and prevention efforts.
Smoking; nicotine; fear-potentiated startle; prepulse inhibition; affective; anxiety
The association between smokers’ cue-induced craving and subsequent ability to initiate abstinence is unclear. Dependent smokers (N=158) completed a single cue-reactivity session prior to participating in a larger within-subjects study, which independently examined predictors of initiating quitting during 5 days each on nicotine versus placebo patch. In the larger study, all smokers used nicotine and placebo patch (double blind) for one week each following a preceding week of ad lib smoking, in a 2x2 cross-over design. Generalized estimating equation (GEE) models determined the predictive ability of cue-induced craving (cue reactivity) on subsequent success at initiating a quit attempt (at least 24hrs quit) for each patch condition. Smokers who exhibited greater craving during exposure to smoking cues had significantly greater odds of successfully initiating abstinence during either quit attempt week (i.e., the nicotine or placebo patch week). This relationship was not statistically significant for self-reported craving in response to neutral cues. However, a greater smoking-neutral cue difference score for cue-induced craving was also a significant predictor successfully initiating abstinence, but only among those not monetarily reinforced. Implications of these seemingly counterintuitive findings are discussed.
Predictors; Relapse; Cue reactivity; Abstinence initiation; Smoking cessation
A strong link exists between cigarette smoking and alcohol use, which may be explained by the experimental observation that alcohol ingestion promotes cigarette craving and precipitates smoking. At the neuroanatomic level, it is unclear where and how alcohol exerts these effects, although the process likely involves the ventral striatum given its function in motivational salience and appetitive reinforcement. In a double-blinded, placebo-controlled, crossover study, heavy drinking nondaily social smokers (ie, light smokers or ‘chippers') were examined using functional magnetic resonance imaging after they ingested an acute dose of alcohol or placebo. We probed reactivity in the ventral striatum and other brain regions during exposure to visual smoking vs nonsmoking control cues. We found that alcohol enhanced self-reported ratings of desire to smoke, and in this context, significantly increased ventral striatum responses to smoking compared with control cues. In exploratory analyses, we observed that alcohol dampened orbitofrontal activity across both cue types, whereas dorsolateral prefrontal and anterior cingulate cortex activation to smoking cues was not affected by alcohol. This study bridges a pharmacological challenge approach to the study of brain reactivity to smoking cues, extends prior cigarette cue imaging studies to nondependent smokers, and elucidates a potential neurobiological mechanism to explain the co-consumption of alcohol and cigarettes in nondependent users.
alcohol; fMRI; ventral striatum; cues; smoking urge; nondaily smoker; Alcohol & Alcoholism; Psychopharmacology; Imaging; Clinical or Preclinical; Addiction & Substance Abuse; fMRI; ventral striatum; cues; smoking urge; nondaily smoker
Previous studies have documented the existence of signs and symptoms of the acute tobacco abstinence syndrome; however, less attention has been paid to quantifying the magnitude of these effects.
The present study quantified the relative magnitude of subjective, cognitive, and physiological manifestations of acute tobacco abstinence.
Smokers (N = 203, ≥15 cig/day) attended two counterbalanced laboratory sessions, one following 12-hr of abstinence and the other following ad-lib smoking. At both sessions, they completed an extensive battery of self-report measures (withdrawal, affect, hunger, craving, subjective attentional bias towards smoking cues), physiological assessments (heart rate, blood pressure, brain EEG), and cognitive performance tasks (psychomotor processing, sustained attention, objective attentional bias).
Abstinence effects were largest for craving, subjective attentional bias, negative affect, overall withdrawal severity, concentration difficulty, hunger, and heart rate. Effects were moderate for positive affect and EEG power. Effects were small, but reliable, for psychomotor speed, sustained attention, and somatic symptoms. Effects on performance-based indices of attentional bias towards smoking-related cues were small and reliable for some indices but not others. Effects were small and inconsistent for blood pressure and EEG frequency. Variation in internal consistency accounted for 33% of the variation in abstinence effect sizes across measures.
There was a wide range of effect sizes both across and within domains, indicating that the acute tobacco abstinence syndrome is not a monotonic phenomenon. These findings may be indicative of the relative magnitudes of signs and symptoms that the average smoker may exhibit during acute abstinence.
Tobacco Abstinence; Smoking Deprivation; Nicotine Withdrawal; Smoking; Tobacco Dependence
A strong link exists between cigarette smoking and alcohol use which may be explained by the experimental observation that alcohol ingestion promotes cigarette craving and precipitates smoking. At the neuroanatomic level, it is unclear where and how alcohol exerts these effects, although the process likely involves the ventral striatum given its role in motivational salience and appetitive reinforcement. In a double-blinded, placebo-controlled, crossover study, heavy drinking nondaily social smokers (i.e., light smokers or “chippers”) were examined using functional magnetic resonance imaging after they ingested an acute dose of alcohol or placebo. We probed reactivity in the ventral striatum and other brain regions during exposure to visual smoking versus nonsmoking control cues. We found that alcohol enhanced self-reported ratings of desire to smoke, and in this context, significantly increased ventral striatum responses to smoking compared with control cues. In exploratory analyses, we observed that alcohol dampened orbitofrontal activity across both cue types, whereas dorsolateral prefrontal and anterior cingulate cortex activation to smoking cues was not affected by alcohol. This study bridges a pharmacological challenge approach to the study of brain reactivity to smoking cues, extends prior cigarette cue imaging studies to nondependent smokers, and elucidates a potential neurobiological mechanism to explain the co-consumption of alcohol and cigarettes in nondependent users.
alcohol; fMRI; ventral striatum; cues; smoking urge; nondaily smoker
In recent years, research applying functional neuroimaging to the study of cue-elicited drug craving has emerged. This research has begun to identify a distributed system of brain activity during drug craving. A review of this literature suggested that expectations regarding the opportunity to use a drug affected the pattern of neural responses elicited by drug cues. Using functional magnetic resonance imaging (fMRI), we examined the effects of smoking expectancy on the neural response to neutral (e.g., roll of tape) and smoking-related (a cigarette) stimuli in male cigarette smokers deprived of nicotine for 8 hr. As predicted, several brain regions (e.g., the anterior cingulate cortex) exhibited differential activation during cigarette versus neutral cue exposure. Moreover, we found that subregions of the prefrontal cortex (i.e., ventromedial, ventrolateral, and dorsolateral prefrontal cortices) showed cue-elicited activation that was modulated by smoking expectancy. These results highlight the importance of perceived drug use opportunity in the neurobiological response to drug cues.
The mechanisms underlying the low smoking cessation rates among smokers with schizophrenia (SS) are unknown. In this laboratory study, we compared the responses of 21 SS and 21 non-psychiatric controls (CS) to manipulations of 5-hour smoking abstinence, transdermal nicotine replacement (0, 21 and 42 mg), and in vivo smoking cues. Results indicate that SS were more sensitive than CS to the effects of acute abstinence on CO boost, but not more sensitive to the effects of abstinence on urge levels or withdrawal symptoms. SS and CS did not differ in urge response to in vivo smoking cues, but SS were less consistent in their reactions. These findings suggest that heightened sensitivity to the effects of abstinence on smoke intake may partially account for the low cessation rates experienced by SS, but other potential mechanisms should be explored using behavioral laboratory models.
schizophrenia; smoking; nicotine dependence; comorbidity; craving; cue reactivity
Cigarette craving, one hallmark sign of nicotine dependence, is often measured in laboratory settings using cue reactivity methods. How lab measures of cue reactivity relate to real world smoking behavior is unclear, particularly among non-treatment seeking smokers. Within a larger study of hormonal effects on cue reactivity (N=78), we examined the predictive relationship of cue reactivity to smoking, each measured in several ways. Results indicated that cue-evoked craving in response to stressful imagery, and to a lesser extent, in vivo smoking cues, significantly predicted smoking behavior during the week following testing. However, this predictive relationship was absent upon controlling for reactivity to neutral cues. Nicotine dependence may moderate the relationship between cue reactivity and actual smoking, such that this predictive relationship is less robust among highly dependent smokers than among smokers low in nicotine dependence. The question of whether cue-elicited craving predicts smoking among smokers not in treatment is best answered with a qualified yes, depending on how craving is manipulated and measured. Our findings highlight important methodological and theoretical considerations for cue reactivity research.
cue reactivity; craving; dependence; smoking
Nicotine nasal spray (NNS) may be better for relieving acute cigarette cravings than other nicotine replacement and it may help smokers with schizophrenia because of its rapid onset of action.
We tested whether NNS was more effective than a nicotine patch (NP; 21 mg) in reducing cue-induced craving during a 3-day abstinence.
Twenty-five smokers with schizophrenia or schizoaffective disorder (SA) were randomized to open-label NNS or NP treatment after baseline measures of craving were assessed. NNS users were instructed to dose at a minimum of 1/hour and up to a maximum of 40/day. Averages from a 4-item visual analogue scale (need, urge, want to smoke, crave a cigarette) measured craving.
Five subjects who smoked (4 NP, 1 NNS) were excluded, leaving 21 (11 NP, 10 NNS) for analyses. No differences were detected between groups on baseline craving. On day 3, NNS users reported significantly less craving in response to smoking cues compared to NP users (mean craving scores: NNS, 7.0; NP, 20.3; p = .014). A repeated measure ANCOVA demonstrated significantly reduced craving in the NNS group compared to the NP group from baseline to day 3 (F = 5.09; p = .037). NNS users took an average of 20 doses/day, and NNS was rated as being as easy to use as NP.
The potential utility of NNS in smokers with schizophrenia supports the need for placebo-controlled studies.
Nicotine replacement; smoking cessation; craving; cue reactivity; nicotine nasal spray; schizophrenia
The behavioral mechanisms by which bupropion reduces smoking have been explored in laboratory behavioral studies, with some inconsistent results. Intention to quit smoking has been found to moderate some effects of nicotine replacement, and the degree to which that characteristic may affect responses to other smoking pharmacotherapies is unknown.
This laboratory study examined the effects of 300 mg/day bupropion, compared with placebo, on baseline and smoking cue–elicited urge to smoke and other measures in smokers who stated that they did (n = 8) or did not (n = 17) intend to quit smoking within 6 months.
Significant interactions indicated that bupropion reduced the effects of acute abstinence on smoking urges in the presence of neutral cues, only in those who intended to quit. Bupropion and intention to quit did not reduce the effects of acute abstinence on urges in the presence of smoking cues and did not reduce nicotine withdrawal symptoms or smoking behavior between sessions.
This study is one of the first placebo-controlled examinations of the effects of bupropion on cue reactivity and provides support for the idea that laboratory smoking studies may be more likely to detect effects of pharmacological treatments for smoking when they enroll smokers who intend to quit.