F. Joseph McClernon

Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization

RationaleNicotine has been shown in a variety of studies in humans and experimental animals to improve cognitive function. Nicotinic treatments are being developed as therapeutic treatments for cognitive dysfunction.ObjectivesCritical for the development of nicotinic therapeutics is an understanding of the neurobehavioral bases for nicotinic involvement in cognitive function.MethodsSpecific and diverse cognitive functions affected by nicotinic treatments are reviewed, including attention, learning, and memory. The neural substrates for these behavioral actions involve the identification of the critical pharmacologic receptor targets, in particular brain locations, and how those incipient targets integrate with broader neural systems involved with cognitive function.ResultsNicotine and nicotinic agonists can improve working memory function, learning, and attention. Both α4β2 and α7 nicotinic receptors appear to be critical for memory function. The hippocampus and the amygdala in particular have been found to be important for memory, with decreased nicotinic activity in these areas impairing memory. Nicotine and nicotinic analogs have shown promise for inducing cognitive improvement. Positive therapeutic effects have been seen in initial studies with a variety of cognitive dysfunctions, including Alzheimers disease, age-associated memory impairment, schizophrenia, and attention deficit hyperactivity disorder.ConclusionsDiscovery of the behavioral, pharmacological, and anatomic specificity of nicotinic effects on learning, memory, and attention not only aids the understanding of nicotinic involvement in the basis of cognitive function, but also helps in the development of novel nicotinic treatments for cognitive dysfunction. Nicotinic treatments directed at specific receptor subtypes and nicotinic cotreatments with drugs affecting interacting transmitter systems may provide cognitive benefits most relevant to different syndromes of cognitive impairment such as Alzheimers disease, schizophrenia, and attention deficit hyperactivity disorder. Further research is necessary in order to determine the efficacy and safety of nicotinic treatments of these cognitive disorders.

24-h smoking abstinence potentiates fMRI-BOLD activation to smoking cues in cerebral cortex and dorsal striatum.

RationaleExposure to smoking-related cues can trigger relapse in smokers attempting to maintain abstinence.ObjectivesIn the present study, we evaluated the effect of 24-h smoking abstinence on brain responses to smoking-related cues using functional magnetic resonance imaging (fMRI).Materials and methodsEighteen adult smokers underwent fMRI scanning following smoking as usual (satiated condition) and following 24-h abstinence (abstinent condition). During scanning, they viewed blocks of photographic smoking and control cues.ResultsFollowing 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 greater than 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).ConclusionsThe present findings indicate that 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.

Abstinence-induced changes in self-report craving correlate with event-related FMRI responses to smoking cues.

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.

Randomized Trial of Reduced-Nicotine Standards for Cigarettes

BACKGROUND The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes. METHODS We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6. RESULTS A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups. CONCLUSIONS In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; ClinicalTrials.gov number, NCT01681875.).

Proximal Versus Distal Cues to Smoke: The Effects of Environments on Smokers' Cue-Reactivity

Smokers are highly reactive to smoking-related cues that are directly linked, or most proximal, to actual smoking behavior (e.g., lit cigarettes). However, over the course of smoking, proximal cues may not be the only stimuli to become strongly associated with smoking. Distal cues, such as the environments in which smoking occurs (e.g., bar) might also gain associative properties and come to evoke robust reactivity from smokers. To test this, a pilot study was first conducted to develop standard pictorial stimuli of smoking and nonsmoking environments, all of which were completely devoid of proximal smoking cues. A comparison set of smoking and nonsmoking proximal cues was then created. Using the 12 total pictorial cues developed, 62 adult smokers participated in a cue-reactivity study during which they viewed and rated pictorial smoking and nonsmoking environment and proximal cues. Results demonstrate that, similar to proximal cues, environments associated with smoking can alone function as stimuli capable of evoking strong subjective reactivity from smokers. This work supports a broader conceptualization of drug-related cues in cue-based research and treatment development that includes proximal and distal cues as distinct categories. (PsycINFO Database Record (c) 2008 APA, all rights reserved).

Remitted major depression is characterized by reward network hyperactivation during reward anticipation and hypoactivation during reward outcomes

BACKGROUND Although functional brain imaging has established that individuals with unipolar major depressive disorder (MDD) are characterized by frontostriatal dysfunction during reward processing, no research to date has examined the chronometry of neural responses to rewards in euthymic individuals with a history of MDD. METHOD A monetary incentive delay task was used during fMRI scanning to assess neural responses in frontostriatal reward regions during reward anticipation and outcomes in 19 participants with remitted major depressive disorder (rMDD) and in 19 matched control participants. RESULTS During the anticipation phase of the task, the rMDD group was characterized by relatively greater activation in bilateral anterior cingulate gyrus, in right midfrontal gyrus, and in the right cerebellum. During the outcome phase of the task, the rMDD group was characterized by relatively decreased activation in bilateral orbital frontal cortex, right frontal pole, left insular cortex, and left thalamus. Exploratory analyses indicated that activation within a right frontal pole cluster that differentiated groups during reward anticipation predicted the number of lifetime depressive episodes within the rMDD group. LIMITATIONS Replication with larger samples is needed. CONCLUSIONS Results suggest a double dissociation between reward network reactivity and temporal phase of the reward response in rMDD, such that rMDD is generally characterized by reward network hyperactivation during reward anticipation and reward network hypoactivation during reward outcomes. More broadly, these data suggest that aberrant frontostriatal response to rewards may potentially represent a trait marker for MDD, though future research is needed to evaluate the prospective utility of this functional neural endophenotype as a marker of MDD risk.

Mood disturbance fails to resolve across 31 days of cigarette abstinence in women.

Smoking abstinence responses were characterized in 96 female smokers. Participants completed subjective state measures twice per week for 5 weeks and were then randomly assigned to a group required to abstain for 31 days or a control group that continued to smoke. Financial incentives for biochemically verified abstinence resulted in an 81% completion rate. Abstinence-related increases in depression, tension, anger, irritability, and appetite showed little tendency to return to prequit levels and remained significantly elevated above smoke-group levels. In contrast to psychological components of anxiety, physical components decreased to smoke group levels by the 2nd week of abstinence. Trait depression and neuroticism predicted larger increased abstinence-associated negative affect. The Big Five personality dimensions predicted variance not associated with depressive traits.

Selectively reduced responses to smoking cues in amygdala following extinction-based smoking cessation: results of a preliminary functional magnetic resonance imaging study.

Preliminary studies suggest an extinction‐based smoking cessation treatment using reduced nicotine content (RNC) cigarettes decreases self‐report craving for cigarettes prior to quitting and may be an effective smoking cessation treatment. The aims of this study was to evaluate the effect of an extinction‐based smoking cessation treatment on brain responses to smoking cues using blood‐oxygen level‐dependent (BOLD) functional magnetic resonance imaging (fMRI). Sixteen (n = 16) dependent smokers were scanned using BOLD fMRI at baseline, following 2–4 weeks of smoking RNC cigarettes while wearing a 21‐mg nicotine patch, and 2–4 weeks following quitting smoking. During scanning, participants viewed smoking‐related pictures (e.g. lit cigarette) and pictures of people engaged in everyday activities (e.g. using a stapler). Event‐related BOLD responses to smoking and control cues were analyzed in regions of interest (ROIs) known to subserve reward, attention, motivation and emotion. The extinction‐based treatment simultaneously attenuated responses to smoking cues in amygdala while potentiating responses to control cues. Exploratory analysis indicated that this pattern was also observed in the thalamus of future abstinent but not relapsing smokers. The results of this preliminary study suggest that an extinction‐based treatment for smoking cessation alters brain responses to smoking and control cues in amygdala—a region previously associated with drug cue reactivity and extinction.

Repetitive transcranial magnetic stimulation of the superior frontal gyrus modulates craving for cigarettes.

BACKGROUND Previous functional magnetic resonance imaging studies have shown strong correlations between cue-elicited craving for cigarettes and activation of the superior frontal gyrus (SFG). Repetitive transcranial magnetic stimulation (rTMS) offers a noninvasive means to reversibly affect brain cortical activity, which can be applied to testing hypotheses about the causal role of SFG in modulating craving. METHODS Fifteen volunteer smokers were recruited to investigate the effects of rTMS on subjective responses to smoking versus neutral cues and to controlled presentations of cigarette smoke. On different days, participants were exposed to three conditions: 1) high-frequency (10 Hz) rTMS directed at the SFG; 2) low-frequency (1 Hz) rTMS directed at the SFG; and 3) low-frequency (1 Hz) rTMS directed at the motor cortex (control condition). RESULTS Craving ratings in response to smoking versus neutral cues were differentially affected by the 10-Hz versus 1-Hz SFG condition. Craving after smoking cue presentations was elevated in the 10-Hz SFG condition, whereas craving after neutral cue presentations was reduced. Upon smoking in the 10-Hz SFG condition, ratings of immediate craving reduction as well as the intensity of interoceptive airway sensations were also attenuated. CONCLUSIONS These results support the view that the SFG plays a role in modulating craving reactivity; moreover, the results suggest that the SFG plays a role in both excitatory and inhibitory influences on craving, consistent with prior research demonstrating the role of the prefrontal cortex in the elicitation as well as inhibition of drug-seeking behaviors.

Effects of smoking abstinence on mood and craving in men : influences of negative-affect-related personality traits, habitual nicotine intake and repeated measurements

Abstract A two-factor model of individual differences in smoking abstinence response was assessed. The two factors were nicotine bioadaptation (nicotine exposure and self-reported tolerance/dependence) and self-medication for negative affect/psychopathology. Bioadaptation was expected to promote transient increases in smoking abstinence-related negative affect, while self-medication was expected to be related to relatively permanent increases in negative affect. Of 56 male smokers starting, 50 completed the study, 30 of whom were randomly assigned to an immediate cessation group and 20 to a continuing-to-smoke control group. Mood and craving were repeatedly measured with the Profile of Mood States (POMS) and the Shiffman Withdrawal Questionnaire, administered twice per week during a three-week pre-quit baseline period and every 48 h during the 30-day abstinence phase. POMS negative moods decreased significantly across the six pre-quit baseline days even though there was no smoking cessation-related intervention during this time, a finding with implications for the question of whether quitters return to pre-quit levels of negative affect. Support for the two-factor model was provided by three of our findings. First, POMS Depression, Tension and Anger increased in the quit group after quitting and never returned to levels corresponding to the continuingto-smoke controls even after 30 days of abstinence. Second, trait depression assessed prior to smoking abstinence correlated with abstinence-related increases in POMS state depressive affect score shortly after quitting and during the last eight days of the study. Third, pre-quit cotinine concentration correlated with increases in negative affect during the first 48 h of abstinence. The findings suggest that previous studies should be interpreted with caution because of their failure to take into account the repeated-measures effect and selective attrition.