Individual differences in amygdala reactivity following nicotinic receptor stimulation in abstinent smokers

Abstract

Hyperactive amygdala functioning may underlie emotional dysregulation during smoking abstinence and represents one neurobiological target for pharmacological cessation aids. Available pharmacotherapies (e.g., nicotine replacement and varenicline) aid only a subset of individuals with smoking cessation and therefore elucidating the neurobiological impact of these medications is critical to expedite improved interventions. In a fMRI study employing a within-subject, double-blind, placebo-controlled design, we assessed task performance and amygdala functioning during an emotional face matching paradigm following administration of nicotine and varenicline to 24 abstinent smokers and 20 nonsmokers. All participants underwent ~17 days of varenicline and placebo pill administration and were scanned, on different days under each condition, wearing a transdermal nicotine or placebo patch. During the amygdala reactivity paradigm, nicotinic acetylcholine receptor (nAChR) stimulation by nicotine and varenicline decreased reaction time (RT) in abstinent smokers but not in nonsmokers. When considering all smokers as a single homogenous group, no drug-induced effects on amygdala reactivity were detected. However, in an exploratory analysis we parsed participants into subgroups according to individual differences in the propensity to demonstrate stable performance augmentation following nAChR stimulation (stable RT-improvers [SI] vs. variable RT-improvers [VI]). Using this exploratory approach, drugs appeared to modulate amygdala reactivity in only one smoker subgroup but not in either nonsmoker subgroup. Specifically, in the SI-smoker cohort abstinence-induced elevated amygdala reactivity was down-regulated by nAChR stimulation. In contrast, varenicline and nicotine did not modulate amygdala functioning in the VI-smoker cohort who displayed moderate levels of amygdala reactivity in the absence of drug administration. These results suggest that pharmacotherapies most robustly dampened amygdala functioning in smokers appearing susceptible to abstinence-induced effects. Such findings provide a step towards fractionating the smoker phenotype by discrete neurobiological characteristics.

Cigarette Exposure, Dependence, and Craving Are Related to Insula Thickness in Young Adult Smokers

“…Overall experience of these subjective feeling states and the severity of the urge to smoke were negatively correlated with the thickness of the right ventral anterior insula, a brain region that integrates primary interoceptive information with emotional information and that is believed to generate conscious awareness of feeling states (Craig, 2002;Gray and Critchley, 2007). Although this is the first report to link cigarette dependence and craving to insula thickness, studies of adult smokers have found that craving is negatively correlated with restingstate functional connectivity between the right anterior insula and the ventromedial prefrontal cortex (Sutherland et al, 2013). More work is necessary to determine whether individual differences in gray-matter thickness influence the circuit-level interactions of the insula with other brain regions implicated in craving.…”

“…Although lesions to both the right and left insula disrupt smoking behavior, a greater proportion of those with right insula lesions experience a disruption in smoking behavior (Naqvi et al, 2007). Another study found that rsFC connectivity between the right (but not left) anterior insula and ventromedial prefrontal cortex was related to tobacco craving and alexithymia (Sutherland et al, 2013). Given the importance of the anterior cingulate in smoking behavior (Azizian et al, 2010;Sharma and Brody, 2009;Sutherland et al, 2012), it is also of interest that the right ventral anterior insula shows greater rsFC with anterior cingulate cortex than left ventral anterior insula (Cauda et al, 2011).…”

Down-Regulation of Amygdala and Insula Functional Circuits by Varenicline and Nicotine in Abstinent Cigarette Smokers

“…This was a within-subject, double-blind, placebo-controlled study involving 6 fMRI assessments (43). At three points during a varenicline administration regime (PILL: pre-pill, placebo, varenicline), participants were scanned twice, once each wearing a nicotine or placebo patch (PATCH).…”

Insula’s functional connectivity with ventromedial prefrontal cortex mediates the impact of trait alexithymia on state tobacco craving

“…Assessment of smokers in both the absence and presence of these drug manipulations allowed us to determine if the relations between alexithymia, craving, and rsFC were specific to the withdrawn state. In this secondary analysis of data from a larger study (Sutherland et al 2013b), we addressed three questions: (1) Does alexithymia predict individual differences in the functional coupling of the insula/ACC with other brain regions in smokers and/or nonsmokers, particularly the aI. (2) Does alexithymia predict tobacco craving severity in smokers, particularly during withdrawal.…”