Menstrual cycle phase at quit date predicts smoking status in an NRT treatment trial: a retrospective analysis.

BACKGROUND AND OBJECTIVE: The deleterious health consequences of smoking are even more severe for women, yet ironically, they have more difficulty quitting than men. Identifying relapse predictors for women and implementing strategies to increase their chances of successfully quitting and remaining abstinent are important goals. Clinicians and researchers suggest that women could achieve greater success in smoking cessation interventions if the initial quit attempt coincided with the follicular phase (i.e., preovulatory phase) of their menstrual cycle (MC) rather than the luteal phase (i.e., premenstrual). However, no experimental data have been published to support this claim. Our objective was to determine whether MC phase affected smoking status in premenopausal female smokers participating in a smoking cessation treatment trial. METHODS: Data from 102 treatment-seeking smokers who participated in an 8-week nicotine replacement therapy (NRT) plus behavioral intervention smoking cessation study were examined retrospectively. NRT began the day subjects attempted to quit smoking (quit date). For analyses, smokers were grouped according to sex, and women were subdivided by MC phase at quit date into follicular (FF, days 1-14, n = 16) and luteal (LF, days 15-30, n = 21) groups. RESULTS: Smoking status was examined on the third day after the quit date (day 3) and at 1 week posttreatment (week 9). On day 3, 52% of LFs reported smoking compared with 19% of FFs (p < 0.04), and at week 9, 71% of LFs reported smoking compared with 31% of FFs (p < 0.02). In a comparison group of men (n = 65), 25% were smoking at day 3 and 68% at week 9. Self-report at week 9 was verified by urine cotinine levels. CONCLUSIONS: These data support the supposition that better treatment outcomes can be achieved by scheduling quit dates to coincide with the follicular phase of the MC in female smokers.

Limbic activation to cigarette smoking cues independent of nicotine withdrawal: a perfusion fMRI study.

Exposure to cigarette smoking cues can trigger physiological arousal and desire to smoke. The brain substrates of smoking cue-induced craving (CIC) are beginning to be elucidated; however, it has been difficult to study this state independent of the potential contributions of pharmacological withdrawal from nicotine. Pharmacological withdrawal itself may have substantial effects on brain activation to cues, either by obscuring or enhancing it, and as CIC is not reduced by nicotine replacement strategies, its neuro-anatomical substrates may differ. Thus, characterizing CIC is critical for developing effective interventions. This study used arterial spin-labeled (ASL) perfusion fMRI, and newly developed and highly appetitive, explicit smoking stimuli, to examine neural activity to cigarette CIC in an original experimental design that strongly minimizes contributions from pharmacological withdrawal. Twenty-one smokers (12 females) completed smoking and nonsmoking cue fMRI sessions. Craving self-reports were collected before and after each session. SPM2 software was employed to analyze data. Blood flow (perfusion) in a priori-selected regions was greater during exposure to smoking stimuli compared to nonsmoking stimuli (p<0.01; corrected) in ventral striatum, amygdala, orbitofrontal cortex, hippocampus, medial thalamus, and left insula. Perfusion positively correlated with intensity of cigarette CIC in both the dorsolateral prefrontal cortex (r2=0.54) and posterior cingulate (r2=0.53). This pattern of activation that includes the ventral striatum, a critical reward substrate, and the interconnected amygdala, cingulate and OFC, is consistent with decades of animal research on the neural correlates of conditioned drug reward.

Modulation of resting brain cerebral blood flow by the GABA B agonist, baclofen: a longitudinal perfusion fMRI study.

BACKGROUND: Preclinical studies confirm that the GABA B agonist, baclofen blocks dopamine release in the reward-responsive ventral striatum (VS) and medial prefrontal cortex, and consequently, blocks drug motivated behavior. Its mechanism in humans is unknown. Here, we used continuous arterial spin labeled (CASL) perfusion fMRI to examine baclofen's effects on blood flow in the human brain. METHODS: Twenty-one subjects (all smokers, 12 females) were randomized to receive either baclofen (80 mg/day; N=10) or placebo (N=11). A five minute quantitative perfusion fMRI resting baseline (RB) scan was acquired at two time points; prior to the dosing regimen (Time 1) and on the last day of 21 days of drug administration (Time 2). SPM2 was employed to compare changes in RB from Time 1 to 2. RESULTS: Baclofen diminished cerebral blood flow (CBF) in the VS and mOFC and increased it in the lateral OFC, a region involved in suppressing previously rewarded behavior. CBF in bilateral insula was also blunted by baclofen (T values ranged from -11.29 to 15.3 at p=0.001, 20 contiguous voxels). CBF at Time 2 was unchanged in placebo subjects. There were no differences between groups in side effects or cigarettes smoked per day (at either time point). CONCLUSIONS: Baclofen's modulatory actions on regions involved in motivated behavior in humans are reflected in the resting state and provide insight into the underlying mechanism behind its potential to block drug-motivated behavior, in preclinical studies, and its putative effectiveness as an anti-craving/anti-relapse agent in humans.

DAT genotype modulates brain and behavioral responses elicited by cigarette cues.

We previously demonstrated differential activation of the mesocorticolimbic reward circuitry in response to cigarette cues independent of withdrawal. Despite robust effects, we noted considerable individual variability in brain and subjective responses. As dopamine (DA) is critical for reward and its predictive signals, genetically driven variation in DA transmission may account for the observed differences. Evidence suggests that a variable number of tandem repeats (VNTRs) polymorphism in the DA transporter (DAT) SLC6A3 gene may influence DA transport. Brain and behavioral responses may be enhanced in probands carrying the 9-repeat allele. To test this hypothesis, perfusion fMR images were acquired during cue exposure in 19 smokers genotyped for the 40 bp VNTR polymorphism in the SLC6A3 gene. Contrasts between groups revealed that 9-repeat (9-repeats) had a greater response to smoking (vs nonsmoking) cues than smokers homozygous for the 10-repeat allele (10/10-repeats) bilaterally in the interconnected ventral striatal/pallidal/orbitofrontal cortex regions (VS/VP/OFC). Activity was increased in 9-repeats and decreased in 10/10-repeats in the VS/VP/OFC (p<0.001 for all analyses). Brain activity and craving was strongly correlated in 10/10-repeats in these regions and others (anterior cingulate, parahippocampal gyrus, and insula; r(2)=0.79-0.86, p<0.001 in all regions). Alternatively, there were no significant correlations between brain and behavior in 9-repeats. There were no differences in cigarette dependence, demographics, or resting baseline neural activity between groups. These results provide evidence that genetic variation in the DAT gene contributes to the neural and behavioral responses elicited by smoking cues.

Prelude to passion: limbic activation by "unseen" drug and sexual cues.

BACKGROUND: The human brain responds to recognizable signals for sex and for rewarding drugs of abuse by activation of limbic reward circuitry. Does the brain respond in similar way to such reward signals even when they are "unseen", i.e., presented in a way that prevents their conscious recognition? Can the brain response to "unseen" reward cues predict the future affective response to recognizable versions of such cues, revealing a link between affective/motivational processes inside and outside awareness? METHODOLOGY/PRINCIPAL FINDINGS: We exploited the fast temporal resolution of event-related functional magnetic resonance imaging (fMRI) to test the brain response to "unseen" (backward-masked) cocaine, sexual, aversive and neutral cues of 33 milliseconds duration in male cocaine patients (n = 22). Two days after scanning, the affective valence for visible versions of each cue type was determined using an affective bias (priming) task. We demonstrate, for the first time, limbic brain activation by "unseen" drug and sexual cues of only 33 msec duration. Importantly, increased activity in an large interconnected ventral pallidum/amygdala cluster to the "unseen" cocaine cues strongly predicted future positive affect to visible versions of the same cues in subsequent off-magnet testing, pointing both to the functional significance of the rapid brain response, and to shared brain substrates for appetitive motivation within and outside awareness. CONCLUSIONS/SIGNIFICANCE: These findings represent the first evidence that brain reward circuitry responds to drug and sexual cues presented outside awareness. The results underscore the sensitivity of the brain to "unseen" reward signals and may represent the brain's primordial signature for desire. The limbic brain response to reward cues outside awareness may represent a potential vulnerability in disorders (e.g., the addictions) for whom poorly-controlled appetitive motivation is a central feature.