Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study.

OBJECTIVE: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD. METHODS: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling. RESULTS: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively. CONCLUSIONS: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

Using computer-based habit versus chess-based cognitive remediation training as add-on therapy to modify the imbalance between habitual behavior and cognitive control in tobacco use disorder: protocol of a randomized controlled, fMRI study.

BACKGROUND: Although the vast majority of smokers are aware of the enormous preventable health hazards caused by smoking, only a small percentage of smokers manage to remain abstinent in the long term. One possible explanation for this discrepancy lies in the inflexibility of addictive behavior and associated disadvantageous decision-making. According to a dual-process theory of decision-making, two distinct decision systems can be identified. One slow deliberate system based on desirable expectations of outcome value described as goal-directed behavior and a fast reflexive system based on habitual instrumental behavior and driven by reinforcement experienced in the past. In the course of addiction development, an imbalance occurs between habitual behavior and goal-directed. The present study aims to investigate the modifiability of the balance between habitual and goal-directed behavior at the neurobiological and behavioral level in smokers using two different novel add-on therapies. We hypothesize that both interventions change the balance between goal-directed and habitual behavior, but by different mechanisms. Whereas a cognitive remediation treatment should directly improve cognitive control, in contrast an implicit priming task should affect the early processing and the emotional valence of smoking and smoking cues. METHODS: We will conduct a randomized controlled study in treatment-seeking individuals with tobacco use disorder applying either chess-based cognitive remediation training (N = 30) or implicit computer-based habit-modifying training (N = 30) as add on therapy compared to the standard smoking cessation group therapy (N = 30) only. We will address neurobiological and neuropsychological correlates associated with craving, reward devaluation, cue reactivity and attentional bias. In addition, various effects of treatment and prediction of treatment outcome will be examined using behavioral and neural measures. DISCUSSION: The present study will apply different examination methods such as functional magnetic resonance imaging, neuropsychological tests, and self-report before and after the interventions. This allows the identification of intervention-specific mechanisms and therefore potential neurobiology-based specific treatment targets for individuals with Tobacco Use Disorder. TRIAL REGISTRATION: Registered at clinicaltrials.gov/ct2/show/NCT03764969 (05 December 2018).

Association between iron accumulation in the dorsal striatum and compulsive drinking in alcohol use disorder.

RATIONALE: Brain iron accumulation has been observed in neuropsychiatric disorders and shown to be related to neurodegeneration. OBJECTIVES: In this study, we used quantitative susceptibility mapping (QSM), an emerging MRI technique developed for quantifying tissue magnetic susceptibility, to examine brain iron accumulation in individuals with alcohol use disorder (AUD) and its relation to compulsive drinking. METHODS: Based on our previous projects, QSM was performed as a secondary analysis with gradient echo sequence images, in 186 individuals with AUD and 274 healthy participants. Whole-brain susceptibility values were calculated with morphology-enabled dipole inversion and referenced to the cerebrospinal fluid. Then, the susceptibility maps were compared between AUD individuals and healthy participants. The relationship between drinking patterns and susceptibility was explored. RESULTS: Whole-brain analyses showed that the susceptibility in the dorsal striatum (putamen and caudate) among AUD individuals was higher than healthy participants and was positively related to the Obsessive Compulsive Drinking Scale (OCDS) scores and the amount of drinking in the past three months. CONCLUSIONS: Increased susceptibility suggests higher iron accumulation in the dorsal striatum in AUD. This surrogate for the brain iron level was linearly associated with the compulsive drinking pattern and the recent amount of drinking, which provides us a new clinical perspective in relation to brain iron accumulation, and also might indicate an association of AUD with neuroinflammation as a consequence of brain iron accumulation. The iron accumulation in the striatum is further relevant for functional imaging studies in AUD by potentially producing signal dropout and artefacts in fMRI images.

Effects of chess-based cognitive remediation training as therapy add-on in alcohol and tobacco use disorders: protocol of a randomised, controlled clinical fMRI trial.

BACKGROUND: Alcohol and tobacco use disorders (AUD, TUD) are frequent, both worldwide and in the German population, and cognitive impairments are known to facilitate instances of relapse. Cognitive training has been proposed for enhancing cognitive functioning and possibly improving treatment outcome in mental disorders. However, these effects and underlying neurobiological mechanisms are not yet fully understood regarding AUD and TUD. Examining the effect of chess-based cognitive remediation training (CB-CRT) on neurobiological, neuropsychological and psychosocial aspects as well as treatment outcomes will provide insights into mechanisms underlying relapse and abstinence and might help to improve health behaviour in affected individuals if used as therapy add-on. METHODS AND ANALYSIS: N=96 individuals with either AUD (N=48) or TUD (N=48) between 18 and 65 years of age will participate in a randomised, controlled clinical functional MRI (fMRI) trial. Two control groups will receive treatment as usual, that is, AUD treatment in a clinic, TUD outpatient treatment. Two therapy add-on groups will receive a 6-week CB-CRT as a therapy add-on. FMRI tasks, neurocognitive tests will be administered before and afterwards. All individuals will be followed up on monthly for 3 months. Endpoints include alterations in neural activation and neuropsychological task performance, psychosocial functioning, and relapse or substance intake. Regarding fMRI analyses, a general linear model will be applied, and t-tests, full factorial models and regression analyses will be conducted on the second level. Behavioural and psychometric data will be analysed using t-tests, regression analyses, repeated measures and one-way analyses of variance. ETHICS AND DISSEMINATION: This study has been approved by the ethics committee of the medical faculty Mannheim of the University of Heidelberg (2017-647N-MA). The findings of this study will be presented at conferences and published in peer-reviewed journals. TRIAL REGISTRATION: The study was registered in the Clinical Trials Register (trial identifier: NCT04057534 at clinicaltrials.gov).

The influence of perceived stress and self-control on efficacy of repeated transcranial direct current stimulation in non-treatment-seeking smokers.

INTRODUCTION: Transcranial direct current stimulation (tDCS) has recently been raising interest in its therapeutic impact on tobacco use disorder. This study investigates the effects of repeated frontal tDCS (anode: F3, cathode: F4) on cigarette consumption, craving and executive functions. MATERIAL AND METHODS: In a randomized sham-controlled trial, 24 individuals received active (2.0 mA) and 20 individuals received sham stimulation (0.3 mA) for 20 min on five consecutive days. The participants indicated their tobacco cravings, answered questionnaires and completed neuropsychological tasks at various time points throughout the study. Carbon monoxide (CO) levels and the daily numbers of consumed cigarettes were recorded. RESULTS: Both intervention groups experienced a significant decrease in the daily number of smoked cigarettes, CO levels, and craving after the stimulation, however, there were no improvements in executive functions. These results did not differ significantly between both intervention groups. Additionally, in the active group, a higher level of perceived stress and a lower level of self-control were linked to a lower cigarette consumption, respectively a higher reduction of the level of CO. CONCLUSION: This study does not support the hypotheses that tDCS reduces cigarette consumption, attenuates substance craving, or improves executive functions beyond the placebo effect. Our subgroup analysis suggests that high levels of perceived stress and low self-control may be predictors for a successful reduction in cigarette consumption. Furthermore, the placebo effect might be rather high for light smokers, whereas heavy smokers seem to benefit more from the specific effects of tDCS. CLINICAL TRIAL REGISTRATION NUMBER: NCT03691805.