Impact of the natural hormonal milieu on ventral striatal responses to appetitive cigarette smoking cues: A prospective longitudinal study.

Background: The female sex hormones estradiol (E) and progesterone (P) galvanize the ventral striatal reward pathway. E elevates ventral striatal dopamine and accelerates drug-cued reinstatement, while P has opposing 'protective' effects on drug-related behavior. We hypothesize that women may exhibit greater ventral striatal responses to smoking cues (SCs) during the late follicular phase of the menstrual cycle (MC) when E is high and unimpeded by P, and reduced responses during the late luteal phase when P is high. Methods: To test our hypothesis, 24 naturally cycling cigarette-dependent women completed functional magnetic resonance (fMRI) sessions over the course of 3 MCs at select time points to reflect the early follicular (low E and P; LEP, control condition), late follicular (high E, low P; HE) and mid-luteal (high E, high P; HEP) MC phases. During fMRI sessions (counterbalanced by phase), women were exposed to a SC versus nonSC audio-visual clip. Ovulation was verified for each MC, and hormone levels were acquired prior to sessions. Results: Contrasts within conditions showed that ventral striatal brain responses to SCs versus nonSCs were negligible during LEP and greater during HE (p=0.009) and HP (p=0.016). Contrasts across conditions showed that HE and HEP had greater responses than LEP (p=0.005), and HE had greater responses than HEP (p=0.049). Conclusions: Results support and extend our retrospective cross-sectional study of the influence of the hormonal milieu on SC reactivity. Results are clinically relevant as they may guide novel, hormonally-informed and immediately translatable treatment strategies that can potentially reduce relapse in naturally cycling women.

Exploration of the influence of body mass index on intra-network resting-state connectivity in chronic cigarette smokers.

BACKGROUND: Obesity and cigarette smoking are two leading preventable causes of death. Previous research suggests that comorbid smoking and obesity likely share neurobehavioral underpinnings; however, the influence of body mass index (BMI) on resting-state functional connectivity (rsFC) in smokers remains unknown. In this study, we explore how BMI affects rsFC and associations between rsFC and smoking-related behavior. METHODS: Treatment-seeking cigarette smokers (N = 87; 54 % men) completed a BOLD resting-state fMRI scan session. We grouped smokers into BMI groups (N = 23 with obesity, N = 33 with overweight, N = 31 lean) and used independent components analysis (ICA) to identify the resting state networks commonly associated with cigarette smoking: salience network (SN), right and left executive control networks (ECN) and default mode network (DMN). Average rsFC values were extracted (p < 0.001, k = 100) to determine group differences in rsFC and relationship to self-reported smoking and dependence. RESULTS: Analyses revealed a significant relationship between BMI and connectivity in the SN and a significant quadratic effect of BMI on DMN connectivity. Heavier smoking was related to greater rsFC in the SN among lean and obese groups but reduced rsFC in the overweight group. CONCLUSIONS: Findings build on research suggesting an influence of BMI on the neurobiology of smokers. In particular, dysfunction of SN-DMN-ECN circuitry in smokers with overweight may lead to a failure to modulate attention and behavior and subsequent difficulty quitting smoking. Future research is needed to elucidate the mechanism underlying the interaction of BMI and smoking and its impact on treatment.

Influence of the natural hormonal milieu on brain and behavior in women who smoke cigarettes: Rationale and methodology.

Women experience more severe health consequences from smoking, have greater difficulty quitting, and respond less favorably to nicotine replacement therapy than men. The influence of fluctuating ovarian hormones, specifically estradiol (E) and progesterone (P), on brain and behavioral responses during exposure to smoking reminders (i.e., cues) may be a contributing factor. Results from our laboratory suggest that women in the late follicular phase of their menstrual cycle (MC) have enhanced smoking cue (SC) vulnerabilities and reduced functional connectivity in neurocircuitry underlying cognitive control, potentially placing them at greater risk for continued smoking and relapse. The primary aim of this study is to examine and link hormonal status with brain and behavioral responses to SCs over the course of three monthly MCs in naturally cycling women who are chronic cigarette smokers. This longitudinal, counterbalanced study collects brain and behavioral responses to SCs at three time points during a woman's MC. Participants complete psychological and physical examinations, biochemical hormonal verification visits, and at least three laboratory/neuroimaging scan visits. The scan visits include a 10-min SC task during blood oxygen level-dependent (BOLD) data acquisition and are timed to occur during the early follicular phase (low E and P), late follicular phase (high E, unopposed by P), and mid-luteal phase (high P, high E). The primary outcomes include brain responses to SCs (compared to non-SCs), subjective craving, E and P hormone levels, and behavioral responses to SCs. This study addresses a critical gap in our knowledge: namely, the impact of the natural hormonal milieu on brain and behavioral responses to SCs, a powerful relapse trigger. Additionally, this study will provide a roadmap for human sex differences researchers who are obliged to consider the often confounding cyclic hormonal fluctuations of women.

Smoking-induced craving relief relates to increased DLPFC-striatal coupling in nicotine-dependent women.

BACKGROUND: Craving is a major contributor to drug-seeking and relapse. Although the ventral striatum (VS) is a primary neural correlate of craving, strategies aimed at manipulating VS function have not resulted in efficacious treatments. This incongruity may be because the VS does not influence craving in isolation. Instead, craving is likely mediated by communication between the VS and other neural substrates. Thus, we examined how striatal functional connectivity (FC) with key nodes of networks involved in addiction affects relief of craving, which is an important step in identifying viable treatment targets. METHODS: Twenty-four nicotine-dependent non-abstinent women completed two resting-state (rs) fMRI scans, one before and one following smoking a cigarette in the scanner, and provided craving ratings before and after smoking the cigarette. A seed-based approach was used to examine rsFC between the VS, putamen and germane craving-related brain regions; the dorsolateral prefrontal cortex (dlPFC), the posterior cingulate cortex, and the anterior ventral insula. RESULTS: Smoking a cigarette was associated with a decrease in craving. Relief of craving correlated with increases in right dlPFC- bilateral VS (r = 0.57, p = 0.003, corrected) as did increased right dlPFC-left putamen coupling (r = 0.62, p = 0.001, corrected). CONCLUSIONS: Smoking-induced relief of craving is associated with enhanced rsFC between the dlPFC, a region that plays a pivotal role in decision making, and the striatum, the neural structure underlying motivated behavior. These findings are highly consistent with a burgeoning literature implicating dlPFC-striatal interactions as a neurobiological substrate of craving.

An exploration of associations between smoking motives and behavior as a function of body mass index.

Objective: Cigarette smoking and obesity are the leading causes of premature morbidity and mortality and increase the risk of all-cause mortality four-fold when comorbid. Although research suggests that smoking motives may differ based on body mass index (BMI), it is unclear how these differences translate to smoking behavior. Method: Three groups of adults who smoke cigarettes (N = 79; obese n = 25, overweight n = 30, and lean n = 24) completed measures of smoking and the Smoking Motivations Questionnaire. Groups did not differ on age, education, cigarettes per day (CPD), pack-years, or nicotine dependence, as measured by the Fagerström Test for Cigarette Dependence (FTCD). Results: Analyses revealed different associations between reasons for smoking and smoking behavior depending on lean, overweight, or obesity status. Participants (N = 37 female, average age 39.8 years) self-reported smoking was positively associated with Addictive, and Automatic subscale scores among lean participants, with only the Addictive subscale score among those with overweight, and only the Automatic subscale score among those with obesity. Post hoc MANCOVA analysis revealed a significant interaction effect of Group x Automatic Smoking on Pack-years (F(2, 79)=3.34, p = 0.04). Conclusion: Findings suggest smoking motives are differentially associated with smoking behavior in adults who smoke depending on weight status. The daily smoking rate of participants with obesity may be less related to the addictive quality of smoking, and automaticity may be less associated with smoking history in those with overweight. Additional research on the influence of BMI on cigarette smoking is necessary to fully elucidate how obesity may impact treatment outcomes to optimize smoking cessation treatment among those with excess body weight.

Baclofen-induced Changes in the Resting Brain Modulate Smoking Cue Reactivity: A Double-blind Placebo-controlled Functional Magnetic Resonance Imaging Study in Cigarette Smokers.

OBJECTIVE: Smoking cue-(SC) elicited craving can lead to relapse in SC-vulnerable individuals. Thus, identifying treatments that target SC-elicited craving is a top research priority. Reduced drug cue neural activity is associated with recovery and is marked by a profile of greater tonic (resting) activation in executive control regions, and increased connectivity between executive and salience regions. Evidence suggests the GABA-B agonist baclofen can reduce drug cue-elicited neural activity, potentially through its actions on the resting brain. Based on the literature, we hypothesize that baclofen's effects in the resting brain can predict its effects during SC exposure. METHODS: In this longitudinal, double blind, placebo-controlled neuropharmacological study 43 non-abstinent, sated treatment-seeking cigarette smokers (63% male) participated in an fMRI resting-state scan and a SC-reactivity task prior to (T1) and 3 weeks following randomization (T2; baclofen: 80 mg/day; n = 21). Subjective craving reports were acquired before and after SC exposure to explicitly examine SC-induced craving. RESULTS: Whole-brain full-factorial analysis revealed a group-by-time interaction with greater resting brain activation of the right dorsolateral prefrontal cortex (dlPFC) at T2 in the baclofen group (BAC) (pFWEcorr = 0.02), which was associated with reduced neural responses to SCs in key cue-reactive brain regions; the anterior ventral insula and ventromedial prefrontal cortex (pFWEcorr ＜ 0.01). BAC, but not the placebo group reported decreased SC-elicited craving (p = 0.02). CONCLUSION: Results suggest that baclofen mitigates the reward response to SCs through an increase in tonic activation of the dlPFC, an executive control region. Through these mechanisms, baclofen may offer SC-vulnerable smokers protection from SC-induced relapse.

Double jeopardy: Comorbid obesity and cigarette smoking are linked to neurobiological alterations in inhibitory control during smoking cue exposure.

Obesity and cigarette smoking are two of the leading preventable causes of death in the United States. Research suggests that overlapping pathophysiology may contribute to obesity and nicotine use disorder (NUD), yet no studies have investigated the effect of obesity on neural response to reward stimuli in NUD. This study used arterial spin-labeled perfusion functional magnetic resonance imaging (fMRI) to examine neural responses during exposure to smoking versus nonsmoking cues in 79 treatment-seeking participants with NUD, 26 with normal weight, 28 with overweight, and 25 with obesity. Given that deficits in behavioral inhibitory control have been associated with both obesity and NUD, participants completed an affect-congruent Go/NoGo task to assess the effect of body mass index (BMI) on this construct in NUD. Analyses revealed that BMI was negatively associated with activation in the right dorsolateral prefrontal cortex (dlPFC) in response to smoking cues, with significantly reduced response in smokers with overweight and smokers with obesity compared with normal-weight smokers. In addition, greater commission errors on the Go/NoGo task were correlated with reduced neural response to smoking cues in the right dlPFC only among those with obesity. Together, these findings provide evidence that obesity in treatment-seeking NUDs is related to neurobiological alterations in inhibitory control over cue-potentiated behaviors, suggesting that smoking cessation may be more difficult in individuals with comorbid NUD and obesity than in those without, requiring treatment strategies tailored to meet their unique needs.

Menstrual cycle phase modulates responses to smoking cues in the putamen: Preliminary evidence for a novel target.

BACKGROUND: The preclinical literature identifies the ventral striatum (VS) as a key player in drug-conditioned responses, guiding hypotheses examining neural substrates involved in human drug cue reactivity, including the study of sex differences. Men show a replicable response that includes the VS, while women's responses have been weaker and variable. New evidence suggests that the hormonal milieu modulates women's responses to drug cues in the dorsal striatum (DS), specifically, in the putamen. Here we tested the hypothesis that the hormonal milieu affects neural responses to smoking cues (SCs) in the putamen in women cigarette smokers. METHODS: We re-examined our three previous neuroimaging studies of the influence of sex and menstrual cycle (MC) phase effects on SC neuroactivity, incorporating the DS as a region of interest. RESULTS: As previously shown, men exhibited increased ventral medial prefrontal cortex (vmPFC) and VS/V pallidum responses, and women showed increased vmPFC responses that were greater in women during the follicular phase (high estradiol), compared to the luteal phase (high progesterone). Reducing the statistical threshold within luteal phase women revealed select deactivation of the putamen. CONCLUSIONS: These preliminary findings shed light upon factors that may modulate drug cue reactivity in women, specifically the influence of hormones on DS responses. Emerging literature suggests that manipulating the hormonal milieu may open a fundamental window into sex-specific treatment targets. More rigorous study of the brain substrates involved in drug cue reactivity and other reward-related behavior that may be influenced by sex and the hormonal milieu is imperative.

Classifying and characterizing nicotine use disorder with high accuracy using machine learning and resting-state fMRI.

Cigarette smoking continues to be a leading cause of preventable morbidity and mortality. Although the majority of smokers report making a quit attempt in the past year, smoking cessation rates remain modest. Thus, developing accurate, data-driven methods that can classify and characterize the neural features of nicotine use disorder (NUD) would be a powerful clinical tool that could aid in optimizing treatment development and guide treatment modifications. This investigation applied support vector machine-based classification to resting-state functional connectivity (rsFC) data from individuals diagnosed with NUD (n = 108; 63 male) and matched nonsmoking controls (n = 108; 63 male) and multi-dimensional scaling to visualize the heterogeneity of NUD in individual smokers based on rsFC measures. Machine-based learning models identified five resting-state networks that played a role in distinguishing smokers from controls: the posterior and anterior default mode networks, the sensorimotor network, the salience network and the right executive control network. The classification method constructed classifiers with an average correct classification rate of 88.1 percent and an average area under the curve of 0.93. Compared with controls, individuals with NUD had weaker functional connectivity measures within these networks (P < 0.05, false discovery rate corrected). Further, multi-dimensional scaling visualization demonstrated that controls were similar to each other whereas individuals with NUD had less similarity to controls and to other individuals with NUD. Our findings build upon previous literature demonstrating that machine learning-based approaches to classifying rsFC data offer a valuable technique to understanding network-level differences in nicotine-related neurobiology and extend previous findings by improving classification accuracy and demonstrating the heterogeneity in resting-state networks of individuals with NUD.

Brain substrates of early (4h) cigarette abstinence: Identification of treatment targets.

INTRODUCTION: Research indicates that overnight nicotine abstinence disrupts neural activity in the mesocorticolimbic reward network; however, less is known about the time course of abstinence-induced brain changes. To examine the potential neural effects of early abstinence, we used arterial spin labeling perfusion fMRI, to measure regional cerebral blood flow (rCBF) changes in the resting brain induced by 4h of nicotine abstinence. METHODS: In a repeated measures design, 5min of resting perfusion fMRI data were acquired in awake nicotine-dependent individuals (eyes open) during 'smoking as usual' (SMK) and following 4h of monitored nicotine abstinence (ABS) conditions (N=20). Conditions were compared using a paired t test in SPM8. Craving was assessed prior to each condition. RESULTS: Compared to SMK, ABS significantly increased craving and reduced rCBF in select regions, including the hippocampus and ventral striatum (cluster corr, α=0.01, 943 contiguous voxels). The magnitude of the abstinence-induced change in rCBF correlated with the magnitude of the change in craving across conditions in select regions, including the medial and lateral orbitofrontal cortices and the anterior ventral insula (r values ranging from 0.59-0.74). CONCLUSIONS: Results show that as few as 4h of abstinence can reduce resting rCBF in multiple nodes of the brain's mesocorticolimbic network, disrupting neural processing. Identifying early withdrawal treatment targets has far-reaching implications, which include thwarting relapse proclivities. Results parallel those of the extant human literature and are in agreement with an extensive preclinical literature showing compromised mesolimbic dopaminergic function and impairments in reward function during nicotine withdrawal.

Multi-site exploration of sex differences in brain reactivity to smoking cues: Consensus across sites and methodologies.

BACKGROUND: Biological sex influences cigarette smoking behavior. More men than women smoke, but women have a harder time quitting. Sex differences in smoking cue (SC) reactivity may underlie such behavioral differences. However, the influence of sex on brain reactivity to SCs has yielded inconsistent findings suggesting the need for continued study. Here, we investigated the effect of sex on SC reactivity across two sites using different imaging modalities and SC stimulus types. METHODS: Pseudo-continuous arterial spin-labeled (pCASL) perfusion functional magnetic resonance imaging (fMRI) was used to assess brain responses to SC versus non-SC videos in 40 smokers (23 females) at the University of Pennsylvania. BOLD fMRI was used to assess brain responses to SC versus non-SC still images in 32 smokers (18 females) at McLean Hospital. Brain reactivity to SCs was compared between men and women and was correlated with SC-induced craving. RESULTS: In both cohorts, males showed higher SC versus non-SC reactivity compared to females in reward-related brain regions (i.e., ventral striatum/ventral pallidum, ventral medial prefrontal cortex). Brain activation during SC versus non-SC exposure correlated positively with SC-induced subjective craving in males, but not females. CONCLUSIONS: The current work provides much needed replication and validation of sex differences in SC-reactivity. These findings also add to a body of literature showing that men have greater reward-related brain activation to drug cues across drug classes. Such sex differences confirm the need to consider sex not only when evaluating SC-reactivity but when examining nicotine dependence etiology and treatment.

Ovarian hormones, menstrual cycle phase, and smoking: a review with recommendations for future studies.

Cigarette smoking continues to be the leading cause of preventable morbidity and mortality. Similar to other addictive substances, the prevalence of cigarette smoking is greater among men than women, yet women are less successful at quitting smoking. Preclinical and clinical research suggests that ovarian hormones (i.e., estradiol and progesterone), which fluctuate over the course of the menstrual cycle, may contribute to these sex differences. Specifically, research suggests that progesterone may protect against cigarette smoking and nicotine addiction; whereas estradiol may underlie enhanced vulnerability. In this review, we discuss new research on ovarian hormone and menstrual cycle phase effects on smoking-related responses and behavior in women, including studies examining neural responses to smoking cues, hormonal influences on medication-assisted smoking cessation, and acute smoking abstinence. We highlight innovative studies with strong research methodology and provide suggestions for future research that may allow evidence-based knowledge for immediate translation to the clinic to guide novel, hormonally-informed treatment strategies. Thus, rigorous scientific study holds the potential to reduce relapse rates, thus improving the health and saving the lives of the many thousands of women who unfortunately do not respond to current treatments.

Influence of menstrual cycle phase on resting-state functional connectivity in naturally cycling, cigarette-dependent women.

BACKGROUND: Sex differences in tobacco-related morbidity and mortality exist, with women experiencing more severe health consequences and greater difficulty with smoking cessation than men. One factor that likely contributes to these sex differences is menstrual cycle phase and associated neural and cognitive changes associated with ovarian hormone fluctuations across the menstrual cycle. Previously, we showed that naturally cycling, cigarette-dependent women in the follicular phase of their menstrual cycle showed greater reward-related neural activity and greater craving during smoking cue exposure. To better understand our results and the observed sex differences in smoking behavior and relapse, we explored potential menstrual cycle phase differences in resting-state functional connectivity (rsFC) in naturally cycling, cigarette-dependent women. Understanding how menstrual cycle phase affects neural processes, cognition, and behavior is a critical step in developing more efficacious treatments and in selecting the best treatment option based on a patient's needs. METHODS: Resting-state functional connectivity analyses were used to examine connectivity strength differences between naturally cycling, premenopausal, cigarette-dependent women who were in the follicular phase (FPs; n = 22) and those in the luteal phase (LPs, n = 16) of their menstrual cycle. We also explored associations between connectivity strength and attentional bias to smoking cues. RESULTS: Compared with LPs, FPs showed decreased rsFC between the dorsal anterior cingulate cortex (dACC) and the subgenual anterior cingulate cortex, medial orbitofrontal cortex (mOFC), and ventral striatum. Among FPs, rsFC strength between the dACC and the bilateral dorsolateral prefrontal cortex (DLPFC), the bilateral dorsal striatum, and the left temporal gyrus was inversely correlated with attentional bias to smoking cues. CONCLUSIONS: This is the first study to explore menstrual cycle phase differences in rsFC among cigarette-dependent women, and results suggest that FPs show differences in rsFC underlying cognitive control, which could place them at greater risk for continued smoking and relapse. These findings provide new insights toward individualized treatment strategies.

Cannabis, Cigarettes, and Their Co-Occurring Use: Disentangling Differences in Gray Matter Volume.

BACKGROUND: Structural magnetic resonance imaging techniques are powerful tools for examining the effects of drug use on the brain. The nicotine and cannabis literature has demonstrated differences between nicotine cigarette smokers and cannabis users compared to controls in brain structure; however, less is known about the effects of co-occurring cannabis and tobacco use. METHODS: We used voxel-based morphometry to examine gray matter volume differences between four groups: (1) cannabis-dependent individuals who do not smoke tobacco (Cs); (2) cannabis-dependent individuals who smoke tobacco (CTs); (3) cannabis-naïve, nicotine-dependent individuals who smoke tobacco (Ts); and (4) healthy controls (HCs). We also explored associations between gray matter volume and measures of cannabis and tobacco use. RESULTS: A significant group effect was observed in the left putamen, thalamus, right precentral gyrus, and left cerebellum. Compared to HCs, the Cs, CTs, and Ts exhibited larger gray matter volumes in the left putamen. Cs also had larger gray matter volume than HCs in the right precentral gyrus. Cs and CTs exhibited smaller gray matter volume than HCs in the thalamus, and CTs and Ts had smaller left cerebellar gray matter volume than HCs. CONCLUSIONS: This study extends previous research that independently examined the effects of cannabis or tobacco use on brain structure by including an examination of co-occurring cannabis and tobacco use, and provides evidence that cannabis and tobacco exposure are associated with alterations in brain regions associated with addiction.

Cannabis, cigarettes, and their co-occurring use: Disentangling differences in default mode network functional connectivity.

BACKGROUND: Resting-state functional connectivity is a noninvasive, neuroimaging method for assessing neural network function. Altered functional connectivity among regions of the default-mode network have been associated with both nicotine and cannabis use; however, less is known about co-occurring cannabis and tobacco use. METHODS: We used posterior cingulate cortex (PCC) seed-based resting-state functional connectivity analyses to examine default mode network (DMN) connectivity strength differences between four groups: (1) individuals diagnosed with cannabis dependence who do not smoke tobacco (n=19; ages 20-50), (2) cannabis-dependent individuals who smoke tobacco (n=23, ages 21-52), (3) cannabis-naïve, nicotine-dependent individuals who smoke tobacco (n=24, ages 21-57), and (4) cannabis- and tobacco-naïve healthy controls (n=21, ages 21-50), controlling for age, sex, and alcohol use. We also explored associations between connectivity strength and measures of cannabis and tobacco use. RESULTS: PCC seed-based analyses identified the core nodes of the DMN (i.e., PCC, medial prefrontal cortex, inferior parietal cortex, and temporal cortex). In general, the cannabis-dependent, nicotine-dependent, and co-occurring use groups showed lower DMN connectivity strengths than controls, with unique group differences in connectivity strength between the PCC and the cerebellum, medial prefrontal cortex, parahippocampus, and anterior insula. In cannabis-dependent individuals, PCC-right anterior insula connectivity strength correlated with duration of cannabis use. CONCLUSIONS: This study extends previous research that independently examined the differences in resting-state functional connectivity among individuals who smoke cannabis and tobacco by including an examination of co-occurring cannabis and tobacco use and provides further evidence that cannabis and tobacco exposure is associated with alterations in DMN connectivity.

Influence of menstrual cycle phase on neural and craving responses to appetitive smoking cues in naturally cycling females.

INTRODUCTION: Functional magnetic resonance imaging (fMRI) has been used extensively in an attempt to understand brain vulnerabilities that mediate maladaptive responses to drug cues. Using perfusion fMRI, we have consistently shown reward-related activation (medial orbitofrontal cortex/ventral striatum) to smoking cues (SCs). Because preclinical and clinical studies generally show that progesterone may reduce reward and craving, we hypothesized that females in the follicular phase of the cycle (FPs; when progesterone levels are low) would have greater reward-related neural responses to SCs compared with females in the luteal phase (LPs). METHODS: Sated cigarette-dependent premenopausal naturally cycling females underwent pseudo-continuous arterial spin-labeled perfusion fMRI during exposure to 10-min audio visual clips of appetitive SCs and non-SCs. Brain responses to SCs relative to non-SCs were examined among females grouped according to menstrual cycle (MC) phase at the time of scanning (22 FPs, 15 LPs). Craving scores were acquired pre- and post-SC exposure. RESULTS: FPs showed increased neural responses to SCs compared with non-SCs in the medial orbitofrontal cortex (p ≤ .05 corrected), whereas LPs did not. FPs reported SC-elicited craving (p ≤ .005), whereas LPs did not. Within FPs, SC-induced craving correlated with increased neural responses in the anterior insula (r = 0.73, p < .0001). CONCLUSIONS: FPs may be more vulnerable to relapse during appetitive SC exposure than LPs. Because the influence of MC phase on drug cue neural activity has not been examined, these results contribute to our knowledge of the neurobiological underpinnings of responses to drug cues, and they highlight the importance of monitoring menstrual cycle phase in all areas of addiction research.

The effects of chronic cigarette smoking on gray matter volume: influence of sex.

Cigarette smoke contains nicotine and toxic chemicals and may cause significant neurochemical and anatomical brain changes. Voxel-based morphometry studies have examined the effects of smoking on the brain by comparing gray matter volume (GMV) in nicotine dependent individuals (NDs) to nonsmoking individuals with inconsistent results. Although sex differences in neural and behavioral features of nicotine dependence are reported, sex differences in regional GMV remain unknown. The current study examined sex differences in GMV in a large sample of 80 NDs (41 males) and 80 healthy controls (41 males) using voxel-based morphometry. Within NDs, we explored whether GMV was correlated with measures of cigarette use and nicotine dependence. High-resolution T1 structural scans were obtained from all participants. Segmentation and registration were performed in SPM8 using the optimized DARTEL approach. Covariates included age and an estimate of total global GMV. Differences were considered significant at p≤0.001, with a whole brain FWE-corrected cluster probability of p<0.025. Among NDs compared to Controls less GMV was observed in the thalamus and bilateral cerebellum and greater GMV was observed in the bilateral putamen and right parahippocampus. Lower thalamic GMV was observed in both female and male NDs compared to Controls. Female NDs also had lower GMV in the left cerebellum and in the ventral medial and orbitofrontal cortices with no areas of greater GMV. Male NDs had lower GMV in bilateral cerebellum and greater GMV in bilateral parahippocampus and left putamen. Within male NDs, GMV in the left putamen was correlated with number of pack years. This study, conducted in a large cohort, contributes to our knowledge of brain morphology in nicotine addiction and provides additional evidence of sex-specific effects on GMV in NDs. Identifying brain vulnerabilities with respect to sex provides a methodological framework for personalized therapies to improve relapse rates for both sexes.

Sex differences in resting state neural networks of nicotine-dependent cigarette smokers.

Although several sex differences in nicotine dependence have been identified, the neural mechanisms underlying these sex differences are not clear. The present study examines sex differences in resting-state brain activity using an arterial spin labeling (ASL) perfusion imaging technique. Fifty-one (31 males) sated nicotine-dependent cigarette smokers underwent perfusion functional magnetic resonance imaging during the resting state. Using functionally defined hippocampus/amygdala (HIP/AMY) seed regions, we observed sex differences in correlation strength between the HIP/AMY and the bilateral anterior insula, rostral anterior cingulate cortex, and inferior parietal lobule with females showing stronger functional coupling than males. This pattern of synchronous variations in dynamic cerebral blood flow is consistent with recent models of nicotine dependence, and as such, our findings provide a novel perspective on the neural mechanisms that may contribute to sex differences in nicotine dependence.

Neural correlates of attentional bias for smoking cues: modulation by variance in the dopamine transporter gene.

Cigarette-dependent smokers automatically and involuntarily orient attention toward smoking cues (SCs). This attentional bias is clinically significant, as it may contribute to relapse. Thus, identifying neural and genetic correlates of attentional bias is critical for improving interventions. Our previous studies show that the dopamine transporter (DAT) SLC6A3 genotype exerts profound effects on limbic responses to SCs. One potential mechanism underlying these effects is greater attentional bias for SCs. Here, we explored associations between attentional bias for SCs and neural responses to SCs among 'sated' smokers genotyped for the SLC6A3 polymorphism. Pseudo-continuous arterial spin-labeled perfusion functional magnetic resonance imaging images were acquired during SC exposure in 35 smokers genotyped for the SLC6A3 variable number of tandem repeats polymorphism (n = 16, 9-repeats; n = 19, 10/10-repeats). Participants completed a visual dot-probe attentional bias task, which contained pictures of smoking and non-smoking pictures, to examine whether genetic variation in DAT influences attentional bias and to investigate relationships between attentional bias and neural responses to SCs. Although attentional bias to smoking pictures was not significantly different between 9-repeats and 10/10-repeats, 9-repeats showed a positive correlation between attentional bias and increased SC-induced brain activity in the amygdala, whereas 10/10-repeats showed an inverse correlation in the medial orbitofrontal cortex (mOFC). In group comparisons, 9-repeats exhibited positive correlations between attentional bias and SCs in the mOFC and amygdala, relative to 10/10-repeats. Findings suggest that genetic variation in the DAT gene influences brain responses associated with attentional bias; thus, providing additional support for a SC-vulnerable endophenotype.