Neural Signatures of Cognitive Flexibility and Reward Sensitivity Following Nicotinic Receptor Stimulation in Dependent Smokers: A Randomized Trial

Abstract

Importance: Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment.

Objective: To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task.

Design, setting, and participants: Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016.

Main outcome and measures: A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility.

Results: The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P < .05). Conversely, neural signatures of decreased reward sensitivity in smokers (vs nonsmokers; familywise error-corrected P < .05) in the dorsal striatum and anterior cingulate cortex were not mitigated by nicotine or varenicline.

Conclusions and relevance: There was a double dissociation between the effects of chronic nicotine dependence on neural representations of reward sensitivity and acute effects of stimulation of nicotinic acetylcholine receptors on behavioral and neural signatures of cognitive flexibility in smokers. These chronic and acute pharmacologic effects were observed in overlapping mesocorticolimbic regions, suggesting that available pharmacotherapies may alleviate deficits in the same circuitry for certain mental computations but not for others.

Trial registration: clinicaltrials.gov Identifier: NCT00830739.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Performance on the Probabilistic Reversal Learning Task as a Function of Smoking Group and Nicotinic Manipulation (Nicotine and Varenicline Tartrate)

A, Acutely abstinent smokers were more likely to shift responses following a loss (lose-shift choice) compared with smokers who receive nicotine or varenicline, while neither drug affected lose-shift behavior in nonsmokers. B, Smokers receiving nicotine or varenicline repeated responses after a win (win-stay choices) more than acutely abstinent smokers. Nonsmokers receiving varenicline showed a decrease in win-stay choices. C, Smokers receiving varenicline required fewer trials to reach criterion than smokers not receiving varenicline. Nicotine did not affect trials to criterion in smokers, and neither drug had an effect in nonsmokers. D, Acutely abstinent smokers made fewer perseverative errors than smokers receiving either nicotine or varenicline. Neither nicotine nor varenicline affected perseverative errors in nonsmokers. Varenicline was given as varenicline tartrate. For an explanation of lose-shift and win-stay, see the Behavioral Measures subsection of the Methods section. Error bars indicate SEM. aP < .05. bP < .01.

Figure 2.. Model Parameters for the Hidden Markov Model as a Function of Smoking Group and Nicotinic Receptor Manipulation (Nicotine and Varenicline Tartrate)

A, Acutely abstinent smokers were biased toward shifting responses (alpha aP < .05. bP < .01. cP < .001.

Figure 3.. Whole-Brain Activation to Reward Sensitivity and Cognitive Flexibility Contrasts Across Groups and Conditions

A, Increased activation to positive vs negative outcomes in the ventromedial prefrontal cortex, posterior cingulate cortex, and ventral and dorsal striatum, as well as the superior frontal gyrus and left cerebellum. Activity decreases in anterior insula (AI), and the dorsal anterior cingulate cortex (dACC; warm colors [positive t values]: reward > punishment; cool colors [negative t values]: punishment > reward). B, Activation was greater preceding a shift than a stay in the AI, dACC, dorsal striatum, dorsolateral prefrontal cortex, posterior parietal cortex, occipital cortex, and cerebellum. Radiologic convention: left side of the image is the right side of the brain. Threshold levels have been increased to P < .00001 (A) and P < .0001 (B) with a cluster size of 70 voxels to allow for a better visualization of the results (see eFigure 9A and 9B in Supplement 2 for results corrected at familywise error–corrected P < .05). The x and y refer to the location of the slices in the Talairach coordinate system; and the t refers to the t value.

Figure 4.. Lower Reward Sensitivity Activity in Smokers Than in Nonsmokers

A, Group differences (smokers vs nonsmokers) in reward sensitivity in the bilateral dorsal striatum and dorsal anterior cingulate cortex (dACC) within the a priori volume of interest (familywise error–corrected P < .05). Radiologic convention: left side of the image is the right side of the brain. B, Regression weights extracted from the clusters identified in the imaging analysis; error bars indicate the SEM (plotted to aid interpretation only—no statistical inference should be drawn), and the shaded region indicates 95% CI. See eFigure 10 in Supplement 2 for regression weights separating out wins and losses. C, Reward sensitivity contrast weight in the absence of nicotine and varenicline tartrate was associated with severity of nicotine dependence (Fägerstrom Test for Nicotine Dependence [FTND] score). PUN indicates punishment, and REW, reward.

Figure 5.. Nicotine Effects on Cognitive Flexibility Contrast in Smokers

A, Acute nicotine administration in smokers increases neural signatures of cognitive flexibility in the bilateral striatum, anterior insula (AI), dorsal anterior cingulate cortex (dACC), and ventromedial prefrontal cortex (vmPFC) within a priori masked regions of interest (familywise error–corrected P < .05). Radiologic convention: left side of the image is the right side of the brain. B, Regression weights extracted from the clusters in part A show that activity is reduced in acute abstinence and restored to the level of nonsmokers (shaded band) when nicotine is administered. Although no significant varenicline tartrate main effects or interactions were identified in the imaging contrast, patterns are in line with the interaction of nicotine and varenicline at the receptor level. Error bars indicate SEM (plotted to aid interpretation only—no statistical inference should be drawn). Shaded regions indicate the mean [SEM] of the nonsmokers’ bold responses averaged across conditions. LST indicates lose-stay; LSW, lose-switch; and rACC, rostral anterior cingulate cortex.