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.

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.

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.

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.

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.

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.

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.

Cardiovascular responses to energy drinks in a healthy population: The C-energy study.

BACKGROUND: Energy drink consumption has increased significantly over the past decade and is associated with greater than 20,000 emergency department visits per year. Most often these visits are due to cardiovascular complaints ranging from palpitations to cardiac arrest. OBJECTIVE: To determine if energy drinks alter; blood pressure, electrolytes, activated bleeding time (ACT), and/or cardiac responses measured with a 12-lead electrocardiographic (ECG) Holter. METHODS: Continuous ECG data was collected for five hours (30 minutes baseline and 4 hours post consumption [PC]). Subjects consumed 32 ounces of energy drink within one hour and data (vital signs and blood samples) was collected throughout the study period. Paired students t-test and a corresponding non-parametric test (Wilcoxon signed rank) were used for analysis of the data. RESULTS: Fourteen healthy young subjects were recruited (mean age 28.6 years). Systolic blood pressure (baseline=132, ±7.83; PC=151, ±11.21; P=.001); QTc interval (baseline=423, ±22.74; PC=503, ±24.56; P<.001); magnesium level (baseline 2.04, ± 0.09; PC=2.13, ±0.15; P=.05); and calcium level (baseline=9.31, ±.28; PC=9.52, ±.22; P=.018) significantly increased from baseline. While potassium and ACT fluctuated (some subjects increased their levels while others decreased) these changes were not significant. Eight of the fourteen subjects (57%) developed a QTc >500 milliseconds PC. Other T-wave changes were noted in 9/14 (64.3%) subjects PC. CONCLUSIONS: Energy drinks increased systolic blood pressure, altered electrolytes, and resulted in repolarization abnormalities. These physiological responses can lead to arrhythmias and other abnormal cardiac responses highlighting the importance that emergency room personnel assess for energy drink consumption and potential toxicity.

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.