Sustained brain response to repeated drug cues is associated with poor drug-use outcomes.

A threefold increase in fatal cocaine overdoses during the past decade highlights the critical lack of medications for cocaine use disorders. The brain response to drug cues can predict future drug use; however, results have been mixed. We present preliminary evidence that a sustained response to repeated cocaine cues within a single task is a significant predictor of drug-use outcomes. Seventy-three cocaine inpatients were administered a passive-viewing fMRI task, featuring 500 ms novel evocative (cocaine, sexual, aversive) and neutral comparator cues in the first half (Half1), which were then repeated in the second half (Half2). After the baseline scan, patients received eight outpatient treatment weeks with twice-weekly drug screens. Drug-use outcome groups were empirically defined based on cocaine-positive or missing urines averaged across the outpatient phase: GOOD (<40%), POOR (>85%), and Intermediate (INT, between 40% and 85%) outcomes. Differences of response to initial (Half1) and repeated (Half2) cues in a priori (cue-reactive) regions were tested between outcome groups (3 [Group] × 2 [Halves] ANOVA). An interaction was found in the brain response to drug (but not sex or aversive) cues, with a significant difference between the GOOD and POOR outcome groups in Half2, driven by a significant decrease in brain response by the GOOD outcome group and a sustained brain response by the POOR outcome group, to repeated cocaine cues. The brain response to repeated drug cues may be a useful predictor of future drug use, encouraging future intervention studies to restore a "healthy" (decreasing) response to the repeated presentation of drug cues.

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.

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.

Emotional, physical and sexual abuse are associated with a heightened limbic response to cocaine cues.

Drug-reward cues trigger motivational circuitry, a response linked to drug-seeking in animals and in humans. Adverse life events have been reported to increase sensitivity to drug rewards and to bolster drug reward signaling. Therefore, we hypothesized that cocaine-dependent individuals with prior emotional, physical and sexual abuse might have a heightened mesolimbic brain response to cues for drug reward in a new brief-cue probe. Cocaine-dependent human individuals (N = 68) were stabilized in an inpatient setting and then completed an event-related blood-oxygen-level dependent functional magnetic resonance imaging task featuring 500-ms evocative (cocaine, sexual, aversive) and comparator (neutral) cues. Responses to three questions about emotional, physical and sexual abuse from the Addiction Severity Index were used to divide the patients into subgroups (history of Abuse [n = 40] versus No Abuse [n = 28]). When subjects were grouped by the historical presence or absence of emotional, physical or sexual abuse, the Abuse group showed a heightened midbrain, thalamic, caudate, and caudal orbitofrontal cortex response to cocaine cues; a similar result was found in other evocative cues, as well. These findings are the first reported for a 500-ms cocaine-cue probe, and they highlight the ability of very brief evocative cues to activate the brain's motivational circuitry. Although all participants had severe cocaine use disorders, individuals reporting prior abuse had a heightened mesolimbic response to evocative cues. To our knowledge, this is the first study in humans linking a history of abuse to a brain vulnerability (heightened mesolimbic response to drug cues) previously shown to contribute to drug-seeking.

Nipping cue reactivity in the bud: baclofen prevents limbic activation elicited by subliminal drug cues.

Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e., subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role in relapse prevention, we examined whether baclofen-a GABAB receptor agonist that reduces mesolimbic dopamine release and conditioned drug responses in laboratory animals-could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo. Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p < 0.005; cluster corrected at p < 0.05). These results suggest that baclofen may inhibit the earliest type of drug cue-induced motivational processing-that which occurs outside of awareness-before it evolves into a less manageable state.

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.

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.

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.

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.

Trauma exposure among cannabis use disorder individuals was associated with a craving-correlated non-habituating amygdala response to aversive cues.

The relationship of cannabis-use disorder and trauma exposure at the level of the brain is not well-understood. Cue-reactivity paradigms have largely focused on characterizing aberrant subcortical function by averaging across the entire task. However, changes across the task, including a non-habituating amygdala response (NHAR), may be a useful biomarker for relapse vulnerability and other pathology. This secondary analysis utilized existing fMRI data from a CUD population with (TR-Y, n = 18) or without trauma (TR-N, n = 15). Amygdala reactivity to novel and repeated aversive cues was examined between TR-Y vs. TR-N groups, using a repeated measures ANOVA. Analysis revealed a significant interaction between TR-Y vs. TR-N and amygdala response to novel vs. repeated cues in the amygdala (right: F (1,31) = 5.31, p = 0.028; left: F (1,31) = 7.42, p = 0.011). In the TR-Y group, a NHAR was evident, while the TR-N group exhibited amygdala habituation, resulting in a significant difference between groups of amygdala reactivity to repeated cues (right: p = 0.002; left: p < 0.001). The NHAR in the TR-Y (but not TR-N) group was significantly correlated with higher cannabis craving scores, yielding a significant group difference (z = 2.1, p = 0.018). Results suggest trauma interacts with the brain's sensitivity to aversive cues, offering a neural explanation for the relationship between trauma and CUD vulnerability. These findings suggest the importance of considering the temporal dynamics of cue reactivity and trauma history in future studies and treatment planning, as this distinction may help decrease relapse vulnerability.

Dopamine transporter genotype modulation of neural responses to smoking cues: confirmation in a new cohort.

Previously we demonstrated profound effects of dopamine transporter (DAT) SLC6A3 genotype on limbic responses to smoking cues (SCs). Probands carrying at least one copy of the 9-repeat allele (9-repeat carriers) had greater neural responses to SCs in the anatomically interconnected rostral ventral striatum/medial orbitofrontal cortex (VS/mOFC), compared with homozygotes for the 10-repeat allele (10/10-repeats). To test the reliability of the initial findings, we examined perfusion functional magnetic resonance images acquired during SC exposure in a new cohort of smokers (N=26) who were genotyped for the SLC6A3 polymorphism. In smokers overall, activity was enhanced in the VS/mOFC (t=3.77). Contrasts between allelic groups revealed that 9-repeat carriers had a greater response to SCs in the VS (t=3.12) and mOFC (t=3.19). In separate groups, 9-repeat carriers showed increased activity in the VS (t=5.47) and mOFC (T=4.96), while no increases were observed in 10-repeats. Subjective reports of craving correlated with increased activity in reward-related structures including the extended amygdala, insula and post-central gyrus, and decreased activity in the dorsolateral prefrontal cortex, and were DAT-genotype dependent (r=0.63-0.96). In secondary analyses, we found that The Fagerström Test for Nicotine Dependence scores correlated with enhanced SC-induced perfusion in 10/10-repeats in the insula, mOFC, medial temporal and superior frontal gyri (r=0.50-0.82), while correlations were absent in 9-repeat carriers. Despite heterogeneity introduced by a host of factors, including variance in other genes involved in smoking behavior, we confirm that DAT genotype predicts the direction and location of neural responses to SCs.

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.

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.

Effects of topiramate on neural responses to alcohol cues in treatment-seeking individuals with alcohol use disorder: preliminary findings from a randomized, placebo-controlled trial.

Topiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200 mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n = 12) and placebo (n = 8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward-the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate's attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug's neurobiological mechanism of action in reducing heavy drinking.

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.

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.

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.

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.