Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.

BACKGROUND: The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far. METHODS: This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status. RESULTS: We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability. CONCLUSIONS: The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.

Distinct dynamic behavioural response to social exclusion in male patients with a history of alcohol dependence.

Social exclusion contributes to alcohol consumption, whereas the development of alcohol dependence (AD) can in turn lead to the social exclusion of people with AD. Previous research observed altered neural responses to experimentally induced social exclusion (i.e., Cyberball game) in patients with AD. In addition, inflammation has been associated with both social behaviours and AD. Our study aimed to investigate the dynamic behavioural response and the inflammatory effects of social exclusion in male patients with a history of AD. To this end, we analysed dynamic changes in ball tossing during a partial exclusion Cyberball game and the cytokine interleukin (IL)-1b in saliva in 31 male patients who had a history of AD and 29 gender-matched healthy controls without AD. Participants were included in the first 2 min of the Cyberball game and then excluded by one of the two co-players in the proceeding 5 min. Saliva was collected three times: one before and two after the Cyberball game. Across groups, participants passed the ball more often to the excluder during the partial exclusion period. Analysis using piece-wise linear mixed models showed that patients rapidly increased ball tosses to the excluder upon exclusion, which lasted to the late response phase, whereas the early behavioural response to exclusion took longer for controls. There was no significant change of salivary IL-1b level to exclusion in either patients or controls. The results indicate a distinct dynamic behavioural response to social exclusion in male patients with a history of AD.

Measuring self-regulation in everyday life: Reliability and validity of smartphone-based experiments in alcohol use disorder.

Self-regulation, the ability to guide behavior according to one's goals, plays an integral role in understanding loss of control over unwanted behaviors, for example in alcohol use disorder (AUD). Yet, experimental tasks that measure processes underlying self-regulation are not easy to deploy in contexts where such behaviors usually occur, namely outside the laboratory, and in clinical populations such as people with AUD. Moreover, lab-based tasks have been criticized for poor test-retest reliability and lack of construct validity. Smartphones can be used to deploy tasks in the field, but often require shorter versions of tasks, which may further decrease reliability. Here, we show that combining smartphone-based tasks with joint hierarchical modeling of longitudinal data can overcome at least some of these shortcomings. We test four short smartphone-based tasks outside the laboratory in a large sample (N = 488) of participants with AUD. Although task measures indeed have low reliability when data are analyzed traditionally by modeling each session separately, joint modeling of longitudinal data increases reliability to good and oftentimes excellent levels. We next test the measures' construct validity and show that extracted latent factors are indeed in line with theoretical accounts of cognitive control and decision-making. Finally, we demonstrate that a resulting cognitive control factor relates to a real-life measure of drinking behavior and yields stronger correlations than single measures based on traditional analyses. Our findings demonstrate how short, smartphone-based task measures, when analyzed with joint hierarchical modeling and latent factor analysis, can overcome frequently reported shortcomings of experimental tasks.

The Treatment of Substance Use Disorders: Recent Developments and New Perspectives.

Substance-related disorders are complex psychiatric disorders that are characterized by continued consumption in spite of harmful consequences. Addiction affects various brain networks critically involved in learning, reward, and motivation, as well as inhibitory control. Currently applied therapeutic approaches aim at modification of behavior that ultimately leads to decrease of consumption or abstinence in individuals with substance use disorders. However, traditional treatment methods might benefit from recent neurobiological and cognitive neuroscientific research findings. Novel cognitive-behavioral approaches in the treatment of addictive behavior aim at enhancement of strategies to cope with stressful conditions as well as craving-inducing cues and target erroneous learning mechanisms, including cognitive bias modification, reconsolidation-based interventions, mindfulness-based interventions, virtual-reality-based cue exposure therapy as well as pharmacological augmentation strategies. This review discusses therapeutic strategies that target dysregulated neurocognitive processes associated with the development and maintenance of disordered substance use and may hold promise as effective treatments for substance-related disorders.

The IMAGEN study: a decade of imaging genetics in adolescents.

Imaging genetics offers the possibility of detecting associations between genotype and brain structure as well as function, with effect sizes potentially exceeding correlations between genotype and behavior. However, study results are often limited due to small sample sizes and methodological differences, thus reducing the reliability of findings. The IMAGEN cohort with 2000 young adolescents assessed from the age of 14 onwards tries to eliminate some of these limitations by offering a longitudinal approach and sufficient sample size for analyzing gene-environment interactions on brain structure and function. Here, we give a systematic review of IMAGEN publications since the start of the consortium. We then focus on the specific phenotype 'drug use' to illustrate the potential of the IMAGEN approach. We describe findings with respect to frontocortical, limbic and striatal brain volume, functional activation elicited by reward anticipation, behavioral inhibition, and affective faces, and their respective associations with drug intake. In addition to describing its strengths, we also discuss limitations of the IMAGEN study. Because of the longitudinal design and related attrition, analyses are underpowered for (epi-) genome-wide approaches due to the limited sample size. Estimating the generalizability of results requires replications in independent samples. However, such densely phenotyped longitudinal studies are still rare and alternative internal cross-validation methods (e.g., leave-one out, split-half) are also warranted. In conclusion, the IMAGEN cohort is a unique, very well characterized longitudinal sample, which helped to elucidate neurobiological mechanisms involved in complex behavior and offers the possibility to further disentangle genotype × phenotype interactions.

Volumetric Prefrontal Cortex Alterations in Patients With Alcohol Dependence and the Involvement of Self-Control.

BACKGROUND: Aspects of self-control such as sensation seeking and impaired impulse control have been implicated in alcohol dependence (ALC). Conversely, sensation seeking has been ascribed a possible protective role in stress-related psychopathologies. We therefore examined gray matter (GM) morphology in individuals with ALC, focusing on differences in prefrontal regions that have been associated with self-control. Additionally, we accounted for differences in lifetime alcohol intake regarding self-control measures and cortical structures in ALC patients. METHODS: With voxel-based morphometry (VBM) focusing on prefrontal a priori defined regions of interest, we assessed a group of 62 detoxified ALC patients and 62 healthy controls (HC). ALC patients were subsequently divided into high (n = 9) and low consumers (n = 53). Self-control was assessed by use of the Barratt Impulsiveness Scale and the Sensation Seeking Scale. RESULTS: Compared to HC, ALC had significantly less GM volume in bilateral middle frontal gyrus (MFG) and right medial prefrontal cortex as well as in the right anterior cingulate. High-consuming ALC showed smaller GM in right orbitofrontal cortex as well as lower sensation seeking scores than low consumers. In low-consuming ALC, right MFG-GM was positively associated with magnitude of sensation seeking; particularly, larger MFG-GM correlated with greater thrill and adventure seeking. CONCLUSION: Thus, our findings (i) indicate deficient GM volume in prefrontal areas related to self-control and (ii) might accentuate the phenotypic divergence of ALC patients and emphasize the importance of the development of individual treatment options.

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.

Effects of a brief mindfulness meditation practice on Pavlovian-to-instrumental transfer in alcohol use disorder - a pilot study.

Introduction: Pavlovian conditioned contextual cues have been suggested to modulate instrumental action and might explain maladaptive behavior such as relapse in participants suffering from alcohol use disorder (AUD). Pavlovian-to-Instrumental transfer (PIT) experimentally assesses the magnitude of this context-dependent effect and studies have shown a larger PIT effect in AUD populations. Taken this into account, a reduction of the influence of cues on behavior seems warranted and one approach that could alter such cue reactivity is mindfulness. Mindfulness-based interventions have been shown to be efficient in the treatment of AUD, but underlying mechanisms are yet to be elucidated. Therefore, we aim at investigating the effect of a brief mindful body scan meditation on the magnitude of the PIT effect in AUD subjects and matched controls. Methods: Using a randomized within-subjects design, we compared the effect of a short audio guided body scan meditation against a control condition (audio of nature sounds) on PIT in healthy (n = 35) and AUD (n = 27) participants. Results: We found no differences in PIT effect between healthy and AUD participants as well as between conditions. However, a significant interaction effect points to a decreased PIT effect after body scan meditation in AUD subjects only. Discussion: These pilot results suggest that AUD might be susceptible to mindfulness-induced changes in PIT, with these findings contributing to entangling the underlying mechanisms of the efficacy of mindfulness-based interventions in AUD. However, further investigation should confirm these preliminary results and the efficacy of mindfulness meditation practice in decreasing the PIT effect.

Modifying Pavlovian-to-instrumental transfer by approach avoidance training in healthy subjects: a proof of concept study.

The modulation of instrumental action by conditioned Pavlovian cues is hypothesized to play a role in the emergence and maintenance of maladaptive behavior. The Pavlovian to Instrumental transfer task (PIT) is designed to examine the magnitude of the influence of cues on behavior and we aim to manipulate the motivational value of Pavlovian cues to reduce their effect on instrumental responding. To this end, we utilized a joystick-based modification of approach and avoidance propensities that has shown success in clinical populations. To examine changes in PIT, we subjected 35 healthy participants to a series of experimental procedures: (1) Instrumental training was followed by (2) Pavlovian conditioning of neutral stimuli that were associated with monetary reward or loss. (3) In a subsequent joystick task, approach and avoidance tendencies toward conditioned cues were assessed. (4) In a transfer test, the PIT effect as the impact of conditioned cues on instrumental behavior was measured. (5) The explicit knowledge of cue-reward contingencies was assessed in a forced-choice phase. (6, 7) systematic joystick training was followed by a posttest (8) the transfer task and forced-choice test were repeated. We found no effect of training on approach-avoidance propensities in the context of this proof of concept study. A higher response rate towards negative stimuli during PIT after systematic training compared to sham training was seen. On the other hand, we saw an increased PIT effect after sham training. These results contribute to the understanding of the strength of the influence of cues on instrumental behavior. Our findings further stress the importance of context, instructions and operationalization of instrumental behavior in the framework of transfer effects.

The Dopamine System in Mediating Alcohol Effects in Humans.

Brain-imaging studies show that the development and maintenance of alcohol use disorder (AUD) is determined by a complex interaction of different neurotransmitter systems and multiple psychological factors. In this context, the dopaminergic reinforcement system appears to be of fundamental importance. We focus on the excitatory and depressant effects of acute versus chronic alcohol intake and its impact on dopaminergic neurotransmission. Furthermore, we describe alterations in dopaminergic neurotransmission as associated with symptoms of alcohol dependence. We specifically focus on neuroadaptations to chronic alcohol consumption and their effect on central processing of alcohol-associated and reward-related stimuli. Altered reward processing, complex conditioning processes, impaired reinforcement learning, and increased salience attribution to alcohol-associated stimuli enable alcohol cues to drive alcohol seeking and consumption. Finally, we will discuss how the neurobiological and neurochemical mechanisms of alcohol-associated alterations in reward processing and learning can interact with stress, cognition, and emotion processing.

Reward Processing in Alcohol-Dependent Patients and First-Degree Relatives: Functional Brain Activity During Anticipation of Monetary Gains and Losses.

BACKGROUND: According to the reward deficiency syndrome and allostatic hypotheses, hyposensitivity of mesocorticolimbic regions to non-alcohol-related stimuli predisposes to dependence or is long-lastingly enhanced by chronic substance use. To date, no study has directly compared mesocorticolimbic brain activity during non-drug reward anticipation between alcohol-dependent, at risk, and healthy subjects. METHODS: Seventy-five abstinent alcohol-dependent human subjects (mean abstinence duration 957.66 days), 62 healthy first-degree relatives of alcohol-dependent individuals, and 76 healthy control subjects without family history of alcohol dependence performed a monetary incentive delay task. Functional magnetic resonance imaging data of the anticipation phase were analyzed, during which visual cues predicted that fast response to a target would result in monetary gain, avoidance of monetary loss, or a neutral outcome. RESULTS: During gain anticipation, there were no significant group differences. During loss anticipation, abstinent alcohol-dependent subjects showed lower activity in the left anterior insula compared with healthy control subjects without family history of alcohol dependence only (Montreal Neurological Institute [MNI] -25 19 -5; t206 = 4.17, familywise error corrected p = .009). However, this effect was no longer significant when age was included as a covariate. There were no group differences between abstinent alcohol-dependent subjects and healthy first-degree relatives or between healthy first-degree relatives and healthy control subjects during loss anticipation, respectively. CONCLUSIONS: Neither the neural reward deficiency syndrome nor the allostatic hypotheses are supported by the results. Future studies should investigate whether the incentive salience hypothesis allows for more accurate predictions regarding mesocorticolimbic brain activity of subjects with alcohol dependence and healthy individuals during reward and loss anticipation and further examine the neural substrates underlying a predisposition to dependence.

Patterns of Alcohol Consumption Among Individuals With Alcohol Use Disorder During the COVID-19 Pandemic and Lockdowns in Germany.

Importance: Alcohol consumption (AC) leads to death and disability worldwide. Ongoing discussions on potential negative effects of the COVID-19 pandemic on AC need to be informed by real-world evidence. Objective: To examine whether lockdown measures are associated with AC and consumption-related temporal and psychological within-person mechanisms. Design, Setting, and Participants: This quantitative, intensive, longitudinal cohort study recruited 1743 participants from 3 sites from February 20, 2020, to February 28, 2021. Data were provided before and within the second lockdown of the COVID-19 pandemic in Germany: before lockdown (October 2 to November 1, 2020); light lockdown (November 2 to December 15, 2020); and hard lockdown (December 16, 2020, to February 28, 2021). Main Outcomes and Measures: Daily ratings of AC (main outcome) captured during 3 lockdown phases (main variable) and temporal (weekends and holidays) and psychological (social isolation and drinking intention) correlates. Results: Of the 1743 screened participants, 189 (119 [63.0%] male; median [IQR] age, 37 [27.5-52.0] years) with at least 2 alcohol use disorder (AUD) criteria according to the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) yet without the need for medically supervised alcohol withdrawal were included. These individuals provided 14 694 smartphone ratings from October 2020 through February 2021. Multilevel modeling revealed significantly higher AC (grams of alcohol per day) on weekend days vs weekdays (ß = 11.39; 95% CI, 10.00-12.77; P < .001). Alcohol consumption was above the overall average on Christmas (ß = 26.82; 95% CI, 21.87-31.77; P < .001) and New Year's Eve (ß = 66.88; 95% CI, 59.22-74.54; P < .001). During the hard lockdown, perceived social isolation was significantly higher (ß = 0.12; 95% CI, 0.06-0.15; P < .001), but AC was significantly lower (ß = -5.45; 95% CI, -8.00 to -2.90; P = .001). Independent of lockdown, intention to drink less alcohol was associated with lower AC (ß = -11.10; 95% CI, -13.63 to -8.58; P < .001). Notably, differences in AC between weekend and weekdays decreased both during the hard lockdown (ß = -6.14; 95% CI, -9.96 to -2.31; P = .002) and in participants with severe AUD (ß = -6.26; 95% CI, -10.18 to -2.34; P = .002). Conclusions and Relevance: This 5-month cohort study found no immediate negative associations of lockdown measures with overall AC. Rather, weekend-weekday and holiday AC patterns exceeded lockdown effects. Differences in AC between weekend days and weekdays evinced that weekend drinking cycles decreased as a function of AUD severity and lockdown measures, indicating a potential mechanism of losing and regaining control. This finding suggests that temporal patterns and drinking intention constitute promising targets for prevention and intervention, even in high-risk individuals.

Are psychotic-like experiences related to a discontinuation of cannabis consumption in young adults?

OBJECTIVE: To assess changes in cannabis use in young adults as a function of psychotic-like experiences. METHOD: Participants were initially recruited at age 14 in high schools for the longitudinal IMAGEN study. All measures presented here were assessed at follow-ups at age 19 and at age 22, respectively. Perceived stress was only assessed once at age 22. Ever users of cannabis (N = 552) gave qualitative and quantitative information on cannabis use and psychotic-like experiences using the Community Assessment of Psychic Experiences (CAPE). Of those, nearly all n = 549 reported to have experienced at least one psychotic experience of any form at age 19. RESULTS: Mean cannabis use increased from age 19 to 22 and age of first use of cannabis was positively associated with a change in cannabis use between the two time points. Change in cannabis use was not significantly associated with psychotic-like experiences at age 19 or 22. In exploratory analysis, we observed a positive association between perceived stress and the experience of psychotic experiences at age 22. CONCLUSION: Age of first use of cannabis influenced trajectories of young cannabis users with later onset leading to higher increase, whereas the frequency of psychotic-like experiences was not associated with a change in cannabis use. The observed association between perceived stress and psychotic-like experiences at age 22 emphasizes the importance of stress experiences in developing psychosis independent of cannabis use.

Imaging resilience and recovery in alcohol dependence.

BACKGROUND AND AIMS: Resilience and recovery are of increasing importance in the field of alcohol dependence (AD). This paper describes how imaging studies in man can be used to assess the neurobiological correlates of resilience and, if longitudinal, of disease trajectories, progression rates and markers for recovery to inform treatment and prevention options. METHODS: Original papers on recovery and resilience in alcohol addiction and its neurobiological correlates were identified from PubMed and have been analyzed and condensed within a systematic literature review. RESULTS: Findings deriving from functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies have identified links between increased resilience and less task-elicited neural activation within the basal ganglia, and benefits of heightened neural pre-frontal cortex (PFC) engagement regarding resilience in a broader sense; namely, resilience against relapse in early abstinence of AD. Furthermore, findings consistently propose at least partial recovery of brain glucose metabolism and executive and general cognitive functioning, as well as structural plasticity effects throughout the brain of alcohol-dependent patients during the course of short-, medium- and long-term abstinence, even when patients only lowered their alcohol consumption to a moderate level. Additionally, specific factors were found that appear to influence these observed brain recovery processes in AD, e.g. genotype-dependent neuronal (re)growth, gender-specific neural recovery effects, critical interfering effects of psychiatric comorbidities, additional smoking or marijuana influences or adolescent alcohol abuse. CONCLUSIONS: Neuroimaging research has uncovered neurobiological markers that appear to be linked to resilience and improved recovery capacities that are furthermore influenced by various factors such as gender or genetics. Consequently, future system-oriented approaches may help to establish a broad neuroscience-based research framework for alcohol dependence.