Background

Tobacco use is the leading cause of preventable death in the United States⁴. The majority of cigarette smokers relapse within the first year of treatment^5-9. Acute stress and smoking cues are often precipitating factors of smoking relapse^10-15. Indeed, experimental studies reliably demonstrate both acute stress^16-18 and smoking cues^17,19,20, separately, increase nicotine seeking/self-administration, a direct measure of nicotine motivation. However, few human studies have examined their potentially additive effects^21,22. The goal of this study was to isolate the effects of acute stress on cigarette cue-evoked neural activation during a simple attention-control task.

Methods

Non-treatment-seeking cigarette smokers (expired carbon monoxide ≥5ppm, ≥10 cigarettes/day, and Fagerstrom²³ score ≥4) without psychiatric comorbidities or cardiovascular/magnetic resonance imaging [MRI] contraindications were eligible. Subjects (N=21) completed two placebo-controlled, double-blind, random cross-over oral-dosing sessions: acute stress (yohimbine 54mg + hydrocortisone 10mg; YOH+HYD) and placebo (0mg, 0mg). Each subject served as his/her own control. Experimental sessions occurred on non-consecutive weekdays between 11am-4pm (Figure 1). Subjects only smoked at designated times during each session (ad libitum before/after sessions). From 1-2pm, participants completed an MRI scan with T1-weighted (MPRAGE) and gradient echo planar imaging (TE=36ms, TR=2.83s, matrix=80x80, 40 interleaved slices, voxel=2.9mm isotropic). Two tasks were administered: N-back and cerebrovascular reactivity (Figure 2). Raw fMRI data were slice-time corrected, motion-corrected, high-pass filtered (128Hz), coregistered to MNI space, smoothed (6mm Gaussian kernel), and resliced (1.5mm isotropic) in SPM8. Within each subject and session, first-level contrast maps (smoking>neutral images for 0- and 1-back, separately) were submitted to group-level, random-effects analyses (cluster-level corrected; AFNI 3dClustSim; p<.05). Mean cluster extents were extracted from first-level contrast maps (smoking>neutral images; 0- and 1-back) for regions of interest (ROIs): medial orbitofrontal cortex (mOFC), insula, and nucleus accumbens (NAcc). Cerebrovascular reactivity (CVR) maps (breath-hold>paced breathing) were contrasted by session (stress>placebo) using a liberal threshold (voxel-level; p<.05) and subtracted from N-back maps to remove potential vascular (non-neural) confounds. Finally, the choice progressive ratio task consisted of 11 independent choice trials during which subjects could earn (via computer ‘mouse’ clicks) either: one cigarette puff or money ($0.25). After the task, subjects smoked the exact number of puffs earned (preferred cigarette brand; live video-verified).

Results

Relative to placebo, YOH+HYD significantly increased heart rate, blood pressure, and saliva cortisol (Figure 3). N-back response accuracy was generally high (85%-100%) and did not differ by session (p=.22) or image type (p=.40). After scanning, self-reported appetitive craving, relief-motivated craving, and withdrawal severity was moderate, and did not differ between sessions (p’s=.54, .71, and .84, respectively). Relative to placebo, acute stress significantly increased nicotine seeking/self-administration (p<.05; partial η²=0.24; moderate-to-large effect), controlling for nicotine dependence level (Fagerstrom score). Acute stress suppressed activation: especially in the mOFC, parietal, and prefrontal cortices (Figure 4). Acute stress effects were isolated by calculating difference scores (stress minus placebo) for ROI cluster extents and subjective effects. Exploratory Pearson correlations indicated mOFC and NAcc activation were both inversely correlated with withdrawal severity (Pearson=-.58 and -.50; Figure 5). Controlling for nicotine dependence level and past-week smoking frequency, linear regressions confirmed activation relationships with withdrawal and relief-motivated craving, but not appetitive craving (R2=.49 and .47, respectively). No significant relationships were observed for craving.

Discussion

Our findings support the predictive validity of this pharmacological stress-induction approach: YOH+HYD induced a physiological stress response and increased nicotine seeking/self-administration, relative to placebo. Acute stress suppressed activation throughout the cortex, but did not modulate overall nicotine withdrawal severity or cigarette craving levels. However, bivariate correlations, and follow-up linear regressions, indicated the effect of stress on mOFC and NAcc activation was inversely related to withdrawal severity. These findings illustrate the heterogeneous effect of acute stress on important subjective constructs (craving and withdrawal), but the cooperative effects on neural signals in brains regions associated with cue processing (mOFC) and appetitive craving (NAcc)^24,25. We speculate that subjects who experienced greater withdrawal severity may have actively suppressed cigarette cue salience/appraisal (mOFC activation) in order to minimize appetitive craving (NAcc activation) which could not be sated during MRI scanning. Importantly, these relationships remained significant after controlling for potential confounds (nicotine dependence level and recent smoking frequency). It must be noted that YOH+HYD is vasoconstrictive (Figure 3), yet CVR difference maps (Figure 4) indicate greater activation during stress (>placebo; especially in the cortex). Thus, we believe stress-induced activation suppression was not an artifact of vasoconstrictive effects. This study examined two factors (stress, cues) known to precipitate smoking relapse, and found the effects of acute stress on craving/withdrawal were specific to the individual, but exhibited strong relationships with neural signals.

Acknowledgements

The authors thank Caroline Zajac-Benitez, Muzamil Arshad, Chaitali Anand, Jonathan Lynn, Andrew Neff, Lisa Sulkowski, and Paul Burghardt for their assistance.

References

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