Medial prefrontal neuroplasticity during extended-release naltrexone treatment of opioid use disorder - a longitudinal structural magnetic resonance imaging study.

Opioid use disorder (OUD) has been linked to macroscopic structural alterations in the brain. The monthly injectable, extended-release formulation of µ-opioid antagonist naltrexone (XR-NTX) is highly effective in reducing opioid craving and preventing opioid relapse. Here, we investigated the neuroanatomical effects of XR-NTX by examining changes in cortical thickness during treatment for OUD. Forty-seven OUD patients underwent structural magnetic resonance imaging and subjectively rated their opioid craving ≤1 day before (pre-treatment) and 11 ± 3 days after (on-treatment) the first XR-NTX injection. A sample of fifty-six non-OUD individuals completed a single imaging session and served as the comparison group. A publicly available [¹¹C]carfentanil positron emission tomography dataset was used to assess the relationship between changes in cortical thickness and µ-opioid receptor (MOR) binding potential across brain regions. We found that the thickness of the medial prefrontal and anterior cingulate cortices (mPFC/aCC; regions with high MOR binding potential) was comparable between the non-OUD individuals and the OUD patients at pre-treatment. However, among the OUD patients, mPFC/aCC thickness significantly decreased from pre-treatment to on-treatment. A greater reduction in mPFC/aCC thickness was associated with a greater reduction in opioid craving. Taken together, our study suggests XR-NTX-induced cortical thickness reduction in the mPFC/aCC regions in OUD patients. The reduction in thickness does not appear to indicate a restoration to the non-OUD level but rather reflects XR-NTX's distinct therapeutic impact on an MOR-rich brain structure. Our findings highlight the neuroplastic effects of XR-NTX that may inform the development of novel OUD interventions.

Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine.

OBJECTIVE: To determine whether the psychostimulant lisdexamfetamine improves subjective and objective measures of cognitive functioning among women genetically at-risk for cancer who have undergone risk-reducing salpingo-oophorectomy and report new-onset executive functioning difficulties. METHODS: 69 participants were assigned to a randomized controlled crossover trial with 6-week trials of active medication (lisdexamfetamine) and placebo, separated by a minimum 2-week washout in an intent-to-treat framework (clinical trial registration number: NCT03187353). At trial baseline, midpoint, and endpoint, participants completed a self-report measure of executive functioning (Brown Attention Deficit Disorder Scale). At study baseline and trial endpoint, participants completed sustained attention, attention/working memory, and verbal learning/memory cognitive tasks. Side effects were assessed at 2, 3, 4, and 6 weeks for each trial. RESULTS: From trial baseline to trial endpoint, lisdexamfetamine - relative to placebo - significantly improved total scores on the self-report Brown Attention Deficit Disorder Scale (and scores on four of five subdomains) as well as attention and working memory performance. Significantly more participants endorsed side effects across the lisdexamfetamine trial versus placebo; however, trial completion rates were similar, indicating that lisdexamfetamine was nonetheless well-tolerated. CONCLUSIONS: Lisdexamfetamine improved both subjective and objective measures of attention and working memory and could offer women experiencing cognitive difficulties post-risk-reducing salpingo-oophorectomy an alternative therapeutic option.

Natural vs. Surgical Postmenopause and Psychological Symptoms Confound the Effect of Menopause on Executive Functioning Domains of Cognitive Experience.

Objective: The menopause transition is associated with difficulties in executive function. However, it is unclear whether these difficulties persist past perimenopause. This study investigated whether potential confounders, including natural vs. surgical postmenopause and menopause-related psychological symptoms, influence whether executive dysfunction persists into postmenopause. Study Design: A cross-sectional sample of women aged 35-65 years (N = 1971) in one of four groups, premenopause, perimenopause, natural postmenopause, and surgical postmenopause, were surveyed. Participants self-reported executive functioning with the Brown Attention Deficit Disorder Scale (BADDS), anxiety symptom severity with the Generalized Anxiety Disorder Questionnaire (GAD-7), and depression symptom severity with the Center for Epidemiologic Studies Depression Scale (CES-D). Main Outcome Measures: We analyzed the association between group and BADDS scores using linear regression models - first, by controlling for age, education, and self-reported attention deficit hyperactivity disorder (ADHD) diagnosis (Model #1) and, second, by further controlling for current difficulty sleeping, anxiety, and depression (Model #2). Results: In both models, BADDS scores were significantly elevated (indicating more difficulties in executive function) among women in the perimenopausal and surgical postmenopausal groups compared with those in the premenopausal group. Likewise, the perimenopausal and surgical postmenopausal groups had the highest proportions of participants who reported difficulty sleeping and clinical levels of anxiety and depression. BADDS scores were significantly higher in natural postmenopausal vs. premenopausal women without controlling for difficulty sleeping, anxiety, and depression (Model #1), but not when adjusting for these variables (Model #2). Conclusions: The type of menopause and psychological symptoms are important confounders of the relationship between the menopause transition and executive dysfunction, and help explain whether executive dysfunction persists or recovers in postmenopause.Reprinted from Maturitas 2023; 170:64-73, with permission from Elsevier. Copyright © 2023.

Application of glutamate weighted CEST in brain imaging of nicotine dependent participants in vivo at 7T.

INTRODUCTION: With nicotine dependence being a significant healthcare issue worldwide there is a growing interest in developing novel therapies and diagnostic aids to assist in treating nicotine addiction. Glutamate (Glu) plays an important role in cognitive function regulation in a wide range of conditions including traumatic brain injury, aging, and addiction. Chemical exchange saturation transfer (CEST) imaging via ultra-high field MRI can image the exchange of certain saturated labile protons with the surrounding bulk water pool, making the technique a novel tool to investigate glutamate in the context of addiction. The aim of this work was to apply glutamate weighted CEST (GluCEST) imaging to study the dorsal anterior cingulate cortex (dACC) in a small population of smokers and non-smokers to determine its effectiveness as a biomarker of nicotine use. METHODS: 2D GluCEST images were acquired on 20 healthy participants: 10 smokers (ages 29-50) and 10 non-smokers (ages 25-69), using a 7T MRI system. T1-weighted images were used to segment the GluCEST images into white and gray matter tissue and further into seven gray matter regions. Wilcoxon rank-sum tests were performed, comparing mean GluCEST contrast between smokers and non-smokers across brain regions. RESULTS: GluCEST levels were similar between smokers and non-smokers; however, there was a moderate negative age dependence (R2 = 0.531) in smokers within the cingulate gyrus. CONCLUSION: Feasibility of GluCEST imaging was demonstrated for in vivo investigation of smokers and non-smokers to assess glutamate contrast differences as a potential biomarker with a moderate negative age correlation in the cingulate gyrus suggesting reward network involvement.

Delayed effects of cigarette graphic warning labels on smoking behavior.

Introduction: Graphic warning labels (GWLs) are widely employed to communicate smoking-related health risks; however, their implementation in the US has been held back by concerns about their efficacy. Most GWLs elicit a high level of emotional reaction (ER). The extent to which ER contributes to GWLs efficacy in improving smoking outcomes is a subject of debate. Our recent study showed poorer efficacy of the high-ER GWLs versus the low-ER ones during a month-long naturalistic exposure. Whether GWL effects persist after discontinuing the exposure remains unclear. Methods: We conducted a secondary analysis to investigate the delayed effects of GWLs on smoking severity in adult smokers. The number of cigarettes smoked per day (CPD) was measured immediately as well as 4 weeks after the end of a month-long exposure to high-ER versus low-ER GWLs. Participants indicated their subjective feeling of being relieved from having to see the GWLs. Results: We found a significant reduction in CPD from the immediate to the 4-week post-exposure timepoint. There was no difference in CPD reduction between the high-ER and low-ER groups.Subjective sense of relief from GWL exposure was associated with greater CPD reduction in the high-ER group, but not the low-ER group. Conclusions: Our study suggests lasting impact of GWLs on smoking behavior. The findings may be particularly important to high-arousal GWLs, which appear less effective in reducing smoking during active exposure. Implications: Whether GWLs that evoke higher ER are more effective remains inconclusive. We recently showed that high-ER GWLs are less effective than low-ER ones in reducing smoking during continuous exposure. Here, we found evidence of delayed GWL effects such that smoking decreased from immediately to four weeks after the end of GWL exposure. Feeling of relief from GWL exposure was associated greater smoking reduction in the high-ER group. We suggest that continuously exposing smokers to high-ER GWLs that have been well remembered may be unnecessary and counterproductive.

Randomized Controlled Trial of Effects of Behavioral Weight Loss Treatment on Food Cue Reactivity.

BACKGROUND: It is not known whether behavioral weight loss can attenuate blood oxygen level-dependent responses to food stimuli. OBJECTIVES: This randomized controlled trial assessed the effects of a commercially available behavioral weight loss program (WW, WeightWatchers) compared to a wait-list control on blood oxygen level-dependent response to food cues. METHODS: Females with obesity ( N = 61) were randomized to behavioral weight loss or wait-list control. At baseline and follow-up, participants completed assessments that included functional magnetic resonance imaging scans to assess response to images of high-calorie foods (HCF) or low-calorie foods (LCF), and neutral objects. RESULTS: There were no significant between-group differences in change from baseline to follow-up in any regions of the brain in response to viewing HCF or LCF. From baseline to follow-up, participants in behavioral weight loss, compared with wait-list control, reported significantly greater increases in desire for LCF. Changes in liking and palatability of LCF and liking, palatability, and desire for HCF did not differ between groups. DISCUSSION: Behavioral weight loss was associated with increased desire for LCF without changes in neural reactivity to food cues. These results suggest that alteration of neurological processes underlying responsiveness to food is difficult to achieve through behavioral weight management alone.

Brain and cortisol responses to smoking cues are linked in tobacco-smoking individuals.

Cues associated with smoking can induce relapse, which is likely driven by cue-induced neurobiological and physiological mechanisms. For instance, greater relapse vulnerability is associated with increases in cue-induced insula activation and heightened cortisol concentrations. Determining if there is a link between such cue-induced responses is critical given the need for biomarkers that can be easily measured in clinical settings and used to drive targeted treatment. Further, comprehensively characterising biological reactions to cues promises to aid in the development of therapies that address this specific relapse risk factor. To determine whether brain and cortisol responses to smoking cues are linked, this study recruited 27 nicotine-dependent tobacco-smoking individuals and acquired whole-brain functional activation during a cue reactivity task; salivary cortisol was measured before and after scanning. The results showed that increases in blood-oxygen-level-dependent activation in the right anterior insula and right dorsolateral prefrontal cortex (DLPFC) when viewing smoking versus neutral cues were positively correlated with a post-scan rise in salivary cortisol concentrations. These brain regions have been previously implicated in substance use disorders for their role in salience, interoception and executive processes. These findings show that those who have a rise in cortisol following smoking cue exposure also have a related rise in cue-induced brain reactivity, in brain regions previously linked with heightened relapse vulnerability. This is clinically relevant as measuring cue-induced cortisol responses is a more accessible proxy for assessing the engagement of cue-induced neurobiological processes associated with the maintenance of nicotine dependence.

Behavioral Economic Strategies to Improve Enrollment Rates in Clinical Research: Embedded Recruitment Pilot Trial.

BACKGROUND: Nearly 1 in 3 clinical trials end prematurely due to underenrollment. Strategies to enhance recruitment are often implemented without scientific rigor to evaluate efficacy. Evidence-based, cost-effective behavioral economic strategies designed to influence decision-making may be useful to promote clinical trial enrollment. OBJECTIVE: This study evaluated 2 behavioral economic strategies to improve enrollment and retention rates across 4 clinical trials: information provision (IP) and contingency management (CM; ie, lottery). IP targets descriptive and injunctive norms about participating in research and CM provides participants incentives to reinforce a target behavior. METHODS: A sample of 212 participants was enrolled across 4 clinical trials focused on tobacco use: 2 focused on HIV and 2 focused on neuroimaging. The CM condition included a lottery: for each study visit completed, participants received 5 "draws" from a bowl containing 500 "chips" valued at US $0, US $1, US $5, or US $100. In the IP condition, text messages that targeted injunctive norms about research (eg, "Many find it a rewarding way to advance science and be part of a community") were sent through the Way to Health platform before all study visits. Participants were randomized to 1 of 4 conditions: IP, CM, IP+CM, or standard recruitment (SR). We performed logistic regression, controlling for sex and study, with condition as a between-subject predictor. Outcomes were the percentage of participants who attended a final eligibility visit (primary), met intent-to-treat (ITT) criteria (secondary), and completed the study (secondary). Recruitment was evaluated by the percentage of participants who attended a final eligibility visit, enrollment by ITT status, and retention by the percentage of participants who completed the study. RESULTS: Rates of attending the eligibility visit and meeting ITT status were 58.9% (33/56) and 33.9% (19/56) for IP+CM; 45.5% (25/55) and 18.2% (10/55) for IP only; 41.5% (22/53) and 18.9% (10/53) for CM only; and 37.5% (18/48) and 12.5% (6/48) for SR, respectively. In the logistic regression, females were more likely to meet ITT status than males (odds ratio [OR] 2.7, 95% CI 1.2-5.7; P=.01). The IP+CM group was twice as likely to attend the final eligibility visit than the SR group (OR 2.4, 95% CI 1.1-5.2; P=.04). The IP+CM group was also significantly more likely to reach ITT status than the SR condition (OR 3.9, 95% CI 1.3-11.1; P=.01). Those who received any active intervention (IP, CM, or IP+CM) had a higher study completion rate (33/53, 63.5%) compared to those who received SR (5/12, 41.7%), but this difference was not significant (P=.26). CONCLUSIONS: Combining IP and CM strategies may motivate participants to participate in research and improve recruitment and retention rates. Evidence from this study provides preliminary support for the utility of behavioral economics strategies to improve enrollment and reduce attrition in clinical trials.

Natural vs. surgical postmenopause and psychological symptoms confound the effect of menopause on executive functioning domains of cognitive experience.

OBJECTIVE: The menopause transition is associated with difficulties in executive function. However, it is unclear whether these difficulties persist past perimenopause. This study investigated whether potential confounders, including natural vs. surgical postmenopause and menopause-related psychological symptoms, influence whether executive dysfunction persists into postmenopause. STUDY DESIGN: A cross-sectional sample of women aged 35-65 years (N = 1971) in one of four groups, premenopause, perimenopause, natural postmenopause, and surgical postmenopause, were surveyed. Participants self-reported executive functioning with the Brown Attention Deficit Disorder Scale (BADDS), anxiety symptom severity with the Generalized Anxiety Disorder Questionnaire (GAD-7), and depression symptom severity with the Center for Epidemiologic Studies Depression Scale (CESD). MAIN OUTCOME MEASURES: We analyzed the association between group and BADDS scores using linear regression models - first, by controlling for age, education, and self-reported attention deficit hyperactivity disorder (ADHD) diagnosis (Model #1) and, second, by further controlling for current difficulty sleeping, anxiety, and depression (Model #2). RESULTS: In both models, BADDS scores were significantly elevated (indicating more difficulties in executive function) among women in the perimenopausal and surgical postmenopausal groups compared with those in the premenopausal group. Likewise, the perimenopausal and surgical postmenopausal groups had the highest proportions of participants who reported difficulty sleeping and clinical levels of anxiety and depression. BADDS scores were significantly higher in natural postmenopausal vs. premenopausal women without controlling for difficulty sleeping, anxiety, and depression (Model #1), but not when adjusting for these variables (Model #2). CONCLUSIONS: The type of menopause and psychological symptoms are important confounders of the relationship between the menopause transition and executive dysfunction, and help explain whether executive dysfunction persists or recovers in postmenopause.

Effects of current smoking severity on brain gray matter volume in opioid use disorder - a voxel-based morphometry study.

Background: Cigarette smoking (CS) and opioid use disorder (OUD) significantly alter brain structure. Although OUD and cigarette smoking are highly comorbid, most prior neuroimaging research in OUD did not control for smoking severity. Specifically, the combined effect of smoking and OUD on the brain gray matter volume (GMV) remains unknown.Objectives: We used structural magnetic resonance imaging (sMRI) to examine: (1) the GMV differences between OUD and non-OUD individuals with comparable smoking severity; and (2) the differential effect of smoking severity on the brain GMV between individuals with and without OUD.Methods: We performed a secondary analysis of existing sMRI datasets of 116 individuals who smoked cigarettes daily, among whom 60 had OUD (CS-OUD; 37 male, 23 female) and 56 did not (CS; 31 male, 25 female). Brain GMV was estimated by voxel-based morphometry analysis.Results: Compared to the CS group, the CS-OUD group had a higher GMV in the occipital cortex and lower GMV in the prefrontal and temporal cortex, striatum, and pre/postcentral gyrus (whole-brain corrected-p < .05). There was a significant interaction between group and smoking severity on GMV in the medial orbitofrontal cortex (whole-brain corrected-p < .05), such that heavier smoking was associated with lower medial orbitofrontal GMV in the CS-OUD but not CS participants (r=-0.32 vs. 0.12).Conclusions: Our findings suggest a combination of independent and interactive effects of cigarette smoking and OUD on the brain gray matter. Elucidating the neuroanatomical correlates of comorbid opioid and tobacco use may shed the light on the development of novel interventions for affected individuals.

Effects of emotional arousal on the neural impact and behavioral efficacy of cigarette graphic warning labels.

BACKGROUND AND AIMS: Graphic warning labels (GWLs) on cigarette packs have been adopted by many jurisdictions world-wide. In the United States, the introduction of GWLs has been delayed by claims that their high level of negative emotional arousal unnecessarily infringed upon the tobacco manufacturers' free speech. This study aimed to provide experimental data on the contribution of emotional arousal to GWL efficacy. DESIGN: Observational study using long-term naturalistic exposure and functional magnetic resonance imaging. SETTING: Research university in Philadelphia, PA, USA. PARTICIPANTS: A total of 168 adult smokers. MEASUREMENTS: For 4 weeks, participants received cigarettes in packs that carried either high-arousal or low-arousal GWLs (n = 84 versus 84). Smoking behavior, quitting-related cognitions and GWL-induced brain response were measured before and after the 4-week exposure. The amygdala and medial prefrontal cortex served as regions of interest. FINDINGS: Compared with the high-arousal group, the low-arousal group smoked fewer cigarettes [log10 -transformed, 1.076 versus 1.019; difference = 0.056, 95% confidence interval (CI) = 0.027, 0.085, χ2 (1)  = 14.21, P < 0.001] and showed stronger intention to quit (2.527 versus 2.810; difference = -0.283, 95% CI = -0.468, -0.098, χ2 (1) = 8.921, P = 0.007) and endorsement of the GWLs' textual component (4.805 versus 5.503; difference = -0.698, 95% CI = -1.016, -0.380, χ2 (1) = 18.47, P < 0.001). High-arousal GWLs induced greater amygdala response than low-arousal GWLs (0.157 versus 0.052; difference = 0.105, 95% CI = 0.049, 0.161, χ2 (1) = 23.52, P < 0.001), although the response to high-arousal GWLs declined over time (slope = -0.087 versus 0.016; difference = -0.103, 95% CI = -0.198, -0.009, χ2 (1) = 6.370, P = 0.046). Greater baseline amygdala response was associated with more smoking at 4 weeks in the high-arousal group, but less smoking in the low-arousal group (slope = 0.179 versus -0.122; difference = 0.287, 95% CI = 0.076, 0.498, χ2 (1) = 7.086, P = 0.008). Medial prefrontal response did not differ significantly between groups. CONCLUSIONS: High-arousal cigarette graphic warning labels (GWLs) appear to be less efficacious than low-arousal GWLs. The high emotional reaction that high-arousal GWLs elicit wanes over time. Baseline amygdala response negatively predicts efficacy of high-arousal GWLs and positively predicts efficacy of low-arousal GWLs. High emotional arousal may not be required for sustained GWL efficacy.

Addicted to green: priming effect of menthol cigarette packaging on brain response to smoking cues.

INTRODUCTION: Mentholated tobacco cigarettes are believed to be more addictive than non-menthol ones. Packaging of most menthol cigarette brands includes distinctive green hues, which may act as conditioned stimuli (ie, cues) and promote menthol smoking. To examine the cue properties of menthol cigarette packaging, we used a priming paradigm to assess the effect of packaging on the neural substrates of smoking cue reactivity. We hypothesised that menthol packaging will exert a specific priming effect potentiating smoking cue reactivity in menthol compared with non-menthol smokers. METHODS: Forty-two menthol and 33 non-menthol smokers underwent functional MRI while viewing smoking and neutral cues. The cues were preceded (ie, primed) by briefly presented images of menthol or non-menthol cigarette packages. Participants reported craving for cigarettes in response to each cue. RESULTS: Menthol packaging induced greater frontostriatal and occipital smoking cue reactivity in menthol smokers than in non-menthol smokers. Menthol packaging also enhanced the mediation by neural activity of the relationship between cue exposure and cigarette craving in menthol but not non-menthol smokers. Dynamic causal modelling showed stronger frontostriatal-occipital connectivity in response to menthol packaging in menthol compared with non-menthol smokers. The effects of non-menthol packaging did not differ between categories of smokers. CONCLUSIONS: Our findings demonstrate heightened motivational and perceptual salience of the green-hued menthol cigarette packaging that may exacerbate menthol smokers' susceptibility to smoking cues. These effects could contribute to the greater addiction severity among menthol smokers and could be considered in the development of science-based regulation and legal review of tobacco product marketing practices.

Effect of progesterone administration in male and female smokers on nicotine withdrawal and neural response to smoking cues: role of progesterone conversion to allopregnanolone.

BACKGROUND: Progesterone administration has therapeutic effects in tobacco use disorder (TUD), with females benefiting more than males. Conversion of progesterone to the neurosteroid allopregnanolone is hypothesized to partly underlie the therapeutic effects of progesterone; however, this has not been investigated clinically. METHODS: Smokers (n = 18 males, n = 21 females) participated in a randomized, double-blind, placebo-controlled crossover study of 200 mg progesterone daily across 4 days of abstinence. The ratio of allopregnanolone:progesterone was analyzed in relationship to nicotine withdrawal, smoking urges, mood states, subjective nicotine effects, and neural response to smoking cues. RESULTS: Allopregnanolone:progesterone ratio interacted with sex to predict withdrawal symptoms (p = 0.047), such that females with higher allopregnanolone:progesterone ratios reported lower withdrawal severity (b = - 0.98 [- 1.95, - 0.01]; p = 0.048). In addition, allopregnanolone:progesterone ratio interacted with sex to predict confusion (p = 0.014) and fatigue (p = 0.034), such that females with higher allopregnanolone:progesterone ratios reported less confusion (b = - 0.45 [- 0.78, - 0.12]; p = 0.008) and marginally lower fatigue (b = - 0.50 [- 1.03, 0.02]; p = 0.062. Irrespective of sex, higher ratios of allopregnanolone:progesterone were associated with stronger "good effects" of nicotine (b = 8.39 [2.58, 14.20]); p = 0.005) and weaker "bad effects" of nicotine (b = - 7.13 [- 13.53, - 0.73]; p = 0.029). CONCLUSIONS: Conversion of progesterone to allopregnanolone correlated with smoking-related outcomes in both sex-dependent and sex-independent ways. Sex-dependent effects suggest that conversion of progesterone to allopregnanolone may contribute to greater therapeutic benefits in females but not males with TUD. Trial registration Clinicaltrials.gov registration, retrospectively registered: NCT01954966; https://clinicaltrials.gov/ct2/show/NCT01954966 \.

Progesterone Increases Nicotine Withdrawal and Anxiety in Male but Not Female Smokers During Brief Abstinence.

INTRODUCTION: Although exogenous progesterone may hold promise as a treatment for nicotine use disorders, it is unclear whether it is similarly effective in males and females. This study examined the effects of progesterone on nicotine use disorder comprehensively using behavioral, psychological, and neural measures in male and female smokers exposed to brief abstinence. AIMS AND METHODS: Thirty-three male and 33 female non-treatment-seeking smokers participated in a double-blind, randomized, placebo-controlled crossover study of 200 mg of progesterone or placebo daily over a four-day abstinence period. Smoking behavior and subjective effects of nicotine were assessed at baseline and after final drug administration. Nicotine withdrawal, smoking urges, mood states, and neural response to smoking cues were measured at baseline, after the first drug administration, and after the final drug administration. RESULTS: No main effect of drug (progesterone vs. placebo) emerged for any outcome. Significant sex by drug interactions emerged for nicotine withdrawal (p = .020), perceived strength of nicotine (p = .040), and perceived bad effects of nicotine (p = .029). Males receiving progesterone reported worse nicotine withdrawal (p = .046) and a trend towards decreased bad effects of nicotine (p = .070). Males on progesterone also reported greater tension and anxiety relative to placebo (p = .021). Females on progesterone perceived nicotine's effects as being stronger relative to placebo (p = .046). CONCLUSIONS: Progesterone causes sex-dependent effects on smoking-related outcomes during brief abstinence. Specifically, progesterone in males may increase rather than decrease nicotine withdrawal and negative affect during abstinence, potentially hindering efforts to quit smoking. IMPLICATIONS: In male and female smokers undergoing a brief period of abstinence, we examined the effects of progesterone on smoking outcomes. While progesterone had limited effects in female smokers, in males, it worsened nicotine withdrawal and negative affect. Our findings emphasize the importance of analyzing sex differences in future studies examining progesterone as a potential treatment and suggest that progesterone in males could potentially exacerbate aspects of nicotine dependence. CLINICALTRIALS.GOV REGISTRATION: NCT01954966. https://clinicaltrials.gov/ct2/show/NCT01954966.

Impact of childhood adversity on network reconfiguration dynamics during working memory in hypogonadal women.

Many women with no history of cognitive difficulties experience executive dysfunction during menopause. Significant adversity during childhood negatively impacts executive function into adulthood and may be an indicator of women at risk of a mid-life cognitive decline. Previous studies have indicated that alterations in functional network connectivity underlie these negative effects of childhood adversity. There is growing evidence that functional brain networks are not static during executive tasks; instead, such networks reconfigure over time. Optimal dynamics are necessary for efficient executive function; while too little reconfiguration is insufficient for peak performance, too much reconfiguration (supra-optimal reconfiguration) is also maladaptive and associated with poorer performance. Here we examined the impact of adverse childhood experiences (ACEs) on network flexibility, a measure of dynamic reconfiguration, during a letter n-back task within three networks that support executive function: frontoparietal, salience, and default mode networks. Several animal and human subject studies have suggested that childhood adversity exerts lasting effects on executive function via serotonergic mechanisms. Tryptophan depletion (TD) was used to examine whether serotonin function drives ACE effects on network flexibility. We hypothesized that ACE would be associated with higher flexibility (supra-optimal flexibility) and that TD would further increase this measure. Forty women underwent functional imaging at two time points in this double-blind, placebo controlled, crossover study. Participants also completed the Penn Conditional Exclusion Test, a task assessing abstraction and mental flexibility. The effects of ACE and TD were evaluated using generalized estimating equations. ACE was associated with higher flexibility across networks (frontoparietal ß = 0.00748, D = 2.79, p = 0.005; salience ß = 0.00679, D = 3.02, p = 0.003; and default mode ß = 0.00910, D = 3.53, p = 0.0004). While there was no interaction between ACE and TD, active TD increased network flexibility in both ACE groups in comparison to sham depletion (frontoparietal ß = 0.00489, D = 2.15, p = 0.03; salience ß = 0.00393, D = 1.91, p = 0.06; default mode ß = 0.00334, D = 1.73, p = 0.08). These results suggest that childhood adversity has lasting impacts on dynamic reconfiguration of functional brain networks supporting executive function and that decreasing serotonin levels may exacerbate these effects.

Executive function after risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: does current mood and early life adversity matter?

OBJECTIVE: Despite the fact that negative mood and executive dysfunction are common after risk-reducing salpingo-oophorectomy (RRSO), occurring in up to a third of women, little is known about risk factors predicting these negative outcomes. Adverse childhood experiences (ACE) predict poorer health in adulthood and may be a risk factor for negative outcomes after RRSO. Given the complex relationship between early life stress, affective disorders, and cognitive dysfunction, we hypothesized that ACE would be associated with poorer executive function and that mood symptoms would partially mediate this relationship. METHODS: Women who had undergone RRSO were included in the study (N = 552; age 30-73 y). We measured executive function (continuous performance task, letter n-back task, and Brown Attention Deficit Disorder Scale Score), exposure to early life stress (ACE questionnaire), and mood symptoms (Hospital Anxiety and Depression Scale). Generalized estimating equations were used to evaluate the association between ACE and executive dysfunction and the role of mood symptoms as a mediator in this relationship. RESULTS: ACE was associated with greater severity of subjective executive dysfunction (adjusted mean difference [aMD] = 7.1, P = 0.0005) and worse performance on both cognitive tasks (continuous performance task: aMD = -0.1, P = 0.03; n-back: aMD = -0.17, P = 0.007). Mood symptoms partially mediated ACE associations with sustained attention (21.3% mediated; 95% CI: 9.3%-100%) and subjective report of executive dysfunction (62.8% mediated; 95% CI: 42.3%-100%). CONCLUSIONS: The relationship between childhood adversity and executive dysfunction is partially mediated by mood symptoms. These data indicate that assessing history of childhood adversity and current anxiety and depression symptoms may play a role in treating women who report cognitive complaints after RRSO. : Video Summary:http://links.lww.com/MENO/A571.

Video Summary:http://links.lww.com/MENO/A571.

Neural cue reactivity during acute abstinence predicts short-term smoking relapse.

In smokers, neural responses to smoking cues can be sensitive to acute abstinence, but the degree to which abstinence-related cue reactivity contributes to relapse is not fully understood. This study addressed this question in a sample of 75 smokers who were motivated to quit smoking. Participants underwent blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) during presentation of visual smoking cues and neutral stimuli on two occasions: once during smoking satiety and once following 24-hour abstinence (order counterbalanced). Following the imaging sessions, participants received brief smoking cessation counseling prior to a short-term (7-day) quit attempt. The primary smoking cessation outcome was biochemically confirmed 7-day relapse. The secondary smoking cessation outcome measure was total number of self-reported days of abstinence. During abstinence (vs satiety), smoking cue reactivity was significantly increased only in the anterior cingulate cortex (ACC); other regions showing a cue (vs neutral) response did not exhibit an abstinence effect in the stringent whole-brain analysis. Participants who showed greater smoking cue reactivity in the ACC during acute abstinence (compared with smoking satiety) were more likely to relapse (OR = 2.10 per standard deviation increase in percent signal change [abstinence minus smoking satiety], 95% CI: 1.05 to 4.20, P = 0.036). Greater abstinence-induced change in ACC activation also predicted fewer total days abstinent (ß = -0.63, 95% CI = 0.43 to 0.66, P < 0.0001). This study provides the first evidence that changes in smoking cue reactivity in the ACC during acute abstinence predict smoking relapse, thereby improving our understanding of the neurobiology of smoking cessation.

Brain Marker Links Stress and Nicotine Abstinence.

BACKGROUND: Subjective stress is a well-documented predictor of early smoking relapse, yet our understanding of stress and tobacco use is limited by reliance on self-reported measures of stress. We utilized a validated functional neuroimaging paradigm to examine whether stress exposure during early abstinence alters objective measures of brain function. METHODS: Seventy-five participants underwent blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) during the Montreal Imaging Stress Task (MIST) on two occasions: once during smoking satiety and once following biochemically confirmed 24-hour abstinence (order counterbalanced). The primary outcome measure was brain response during stress (vs. control) blocks of the MIST, assessed using whole-brain analysis corrected for multiple comparisons using clusters determined by Z ≥ 3.1. RESULTS: Abstinence (vs. satiety) was associated with significantly increased activation in the left inferior frontal gyrus, a brain region associated with inhibitory control. Abstinence-induced change in brain response to stress was positively associated with change in self-reported stress. CONCLUSIONS: This study provides objective evidence that the brain response to stress is altered during the first 24 hours of a quit attempt compared to smoking satiety. IMPLICATIONS: These results point to the potential value of inoculating smokers with stress management training prior to a quit attempt.

What has sex got to do with it? The role of hormones in the transgender brain.

Sex differences and hormonal effects in presumed cisgender individuals have been well-studied and support the concept of a mosaic of both male and female "characteristics" in any given brain. Gonadal steroid increases and fluctuations during peri-puberty and across the reproductive lifespan influence the brain structure and function programmed by testosterone and estradiol exposures in utero. While it is becoming increasingly common for transgender and gender non-binary individuals to block their transition to puberty and/or use gender-affirming hormone therapy (GAHT) to obtain their desired gender phenotype, little is known about the impact of these manipulations on brain structure and function. Using sex differences and the effects of reproductive hormones in cisgender individuals as the backdrop, we summarize here the existing nascent neuroimaging and behavioral literature focusing on potential brain and cognitive differences in transgender individuals at baseline and after GAHT. Research in this area has the potential to inform our understanding of the developmental origins of gender identity and sex difference in response to gonadal steroid manipulations, but care is needed in our research questions and methods to not further stigmatize sex and gender minorities.

Tobacco Smoking, Eating Behaviors, and Body Weight: A Review.

PURPOSE OF REVIEW: This narrative review provides an overview of the relationships among tobacco smoking, eating behaviors, and body weight. The aims are to (1) examine the concurrent and longitudinal associations between tobacco smoking and body weight, (2) describe potential mechanisms underlying the relationships between smoking and body weight, with a focus on mechanisms related to eating behaviors and appetite, and (3) discuss management of concomitant tobacco smoking and obesity. RECENT FINDINGS: Adolescents who smoke tobacco tend to have body mass indexes (BMI) the same as or higher than nonsmokers. However, adult tobacco smokers tend to have lower BMIs and unhealthier diets relative to nonsmokers. Smoking cessation is associated with a mean body weight gain of 4.67 kg after 12 months of abstinence, though there is substantial variability. An emerging literature suggests that metabolic factors known to regulate food intake (e.g., ghrelin, leptin) may also play an important role in smoking-related behaviors. While the neural mechanisms underlying tobacco smoking-induced weight gain remain unclear, brain imaging studies indicate that smoking and eating cues overlap in several brain regions associated with learning, memory, motivation and reward. Behavioral and pharmacological treatments have shown short-term effects in limiting post-cessation weight gain; however, their longer-term efficacy is limited. SUMMARY: Further studies are needed to identify the exact mechanisms underlying smoking, eating behaviors, and body weight. Moreover, effective treatment options are needed to prevent long-term weight gain during smoking abstinence.