[Patient and quality characteristics in the treatment with disulfiram (Antabus) in the German "Network for Alcohol Aversive Pharmacotherapy"]. / Patienten- und Qualitätsmerkmale bei der Behandlung mit Disulfiram ("Antabus") im deutschsprachigen "Netzwerk alkoholaversive Pharmakotherapie".

BACKGROUND: More than a decade ago disulfiram lost its approval for use in Germany. Nonetheless, a considerable number of psychiatric hospital outpatient departments as well as practicing physicians continue to prescribe it. These professionals have formed the "Network for Alcohol Aversive Pharmacotherapy" (NAP) to maintain a high quality of this treatment approach. OBJECTIVE: To describe the current use of disulfiram with respect to patient numbers and characteristics, side effects, and use of concomitant multimodal treatment forms. MATERIAL AND METHODS: Since 2019 the NAP has conducted an annual retrospective survey among its members regarding the aforementioned parameters. RESULTS: From 2019 to 2023 a total of 1579 treatment cases were described by 33 centers, 152 patients reported a total of 241 drinking events, 26 of them resulting in hospitalization but none causing complications or permanent harm. The most frequent side effects, in descending order, were unpleasant body odor (2.5%), fatigue, male sexual dysfunction, mildly elevated liver enzymes, allergic skin reactions and polyneuropathy (0.8%). More than one quarter of the patients suffered from comorbid depression, and approximately 5% from ADHD, borderline or other personality disorders, trauma-related disorders and anxiety disorders, respectively. Of the patients 33% were treated with antidepressants and 12% with sedating antipsychotics. Various forms of concomitant group therapy were offered to 66% of the patients. CONCLUSION: Treatment with disulfiram is legally possible, generally well-tolerated and safe. It is offered in most treatment centers as part of a comprehensive treatment plan that includes multimodal treatment of comorbid psychiatric disorders.

[Family-focused treatment approaches for drug-addicted parents]. / Familienzentrierte Behandlungsansätze für drogenabhängige Eltern.

BACKGROUND: In Germany 1.5-2.75 million children live in families affected by substance use disorders. Substance abuse can impact on family interactions in many ways. If a dependent parental drug use continues over a longer period of time, this can have pronounced psychological and social consequences for the (co)affected children. Nevertheless, family-focused treatment approaches are not yet widely used in the context of addiction treatment. AIM: This review article aims to provide an overview of the prevalence of parenthood among dependent drug users in Germany, the impact of dependent drug use on families and family-focused treatment approaches. METHODS AND RESULTS: Recording parenthood is particularly difficult in the case of dependent drug users as they often do not openly discuss it with their therapists because of the fear of consequences from youth welfare services. In order to change this, a structured recording of parenthood by the treatment providers is required. This is the prerequisite for being able to offer family-focused treatment to those affected. In Germany, three evidence-based therapy programs are available for this purpose: SHIFT, SHIFT Plus and MAMADAM. Additionally, a number of programs developed in the Anglo-American region can also be used. In contrast, the evidence for web-based programs is much weaker. DISCUSSION: In order to establish family-focused treatment approaches for drug-using parents across the board, long-term, secure funding is required. The necessary framework conditions must be created at a political level.

Aberrant functional brain network organization is associated with relapse during 1-year follow-up in alcohol-dependent patients.

Alcohol dependence (AD) is a debilitating disease associated with high relapse rates even after long periods of abstinence. Thus, elucidating neurobiological substrates of relapse risk is fundamental for the development of novel targeted interventions that could promote long-lasting abstinence. In the present study, we analysed resting-state functional magnetic resonance imaging (rsfMRI) data from a sample of recently detoxified patients with AD (n = 93) who were followed up for 12 months after rsfMRI assessment. Specifically, we employed graph theoretic analyses to compare functional brain network topology and functional connectivity between future relapsers (REL, n = 59), future abstainers (ABS, n = 28) and age- and gender-matched controls (CON, n = 83). Our results suggest increased whole-brain network segregation, decreased global network integration and overall blunted connectivity strength in REL compared with CON. Conversely, we found evidence for a comparable network architecture in ABS relative to CON. At the nodal level, REL exhibited decreased integration and decoupling between multiple brain systems compared with CON, encompassing regions associated with higher-order executive functions, sensory and reward processing. Among patients with AD, increased coupling between nodes implicated in reward valuation and salience attribution constitutes a particular risk factor for future relapse. Importantly, aberrant network organization in REL was consistently associated with shorter abstinence duration during follow-up, portending to a putative neural signature of relapse risk in AD. Future research should further evaluate the potential diagnostic value of the identified changes in network topology and functional connectivity for relapse prediction at the individual subject level.

Elevated Amygdala Responses During De Novo Pavlovian Conditioning in Alcohol Use Disorder Are Associated With Pavlovian-to-Instrumental Transfer and Relapse Latency.

Background: Contemporary learning theories of drug addiction ascribe a key role to Pavlovian learning mechanisms in the development, maintenance, and relapse of addiction. In fact, cue-reactivity research has demonstrated the power of alcohol-associated cues to activate the brain's reward system, which has been linked to craving and subsequent relapse. However, whether de novo Pavlovian conditioning is altered in alcohol use disorder (AUD) has rarely been investigated. Methods: To characterize de novo Pavlovian conditioning in AUD, 62 detoxified patients with AUD and 63 matched healthy control participants completed a Pavlovian learning task as part of a Pavlovian-to-instrumental transfer paradigm during a functional magnetic resonance imaging session. Patients were followed up for 12 months to assess drinking behavior and relapse status. Results: While patients and healthy controls did not differ in their ability to explicitly acquire the contingencies between conditioned and unconditioned stimuli, patients with AUD displayed significantly stronger amygdala responses toward Pavlovian cues, an effect primarily driven by stronger blood oxygen level-dependent differentiation during learning from reward compared with punishment. Moreover, in patients compared with controls, differential amygdala responses during conditioning were positively related to the ability of Pavlovian stimuli to influence ongoing instrumental choice behavior measured during a subsequent Pavlovian-to-instrumental transfer test. Finally, patients who relapsed within the 12-month follow-up period showed an inverse association between amygdala activity during conditioning and relapse latency. Conclusions: We provide evidence of altered neural correlates of de novo Pavlovian conditioning in patients with AUD, especially for appetitive stimuli. Thus, heightened processing of Pavlovian cues might constitute a behaviorally relevant mechanism in alcohol addiction.

Alcohol Approach Bias Is Associated With Both Behavioral and Neural Pavlovian-to-Instrumental Transfer Effects in Alcohol-Dependent Patients.

Background: Even after qualified detoxification, alcohol-dependent (AD) patients may relapse to drinking alcohol despite their decision to abstain. Two mechanisms may play important roles. First, the impact of environmental cues on instrumental behavior (i.e., Pavlovian-to-instrumental transfer [PIT] effect), which was found to be stronger in prospectively relapsing AD patients than in abstaining patients. Second, an automatic approach bias toward alcohol stimuli was observed in AD patients, and interventions targeting this bias reduced the relapse risk in some studies. Previous findings suggest a potential behavioral and neurobiological overlap between these two mechanisms. Methods: In this study, we examined the association between alcohol approach bias and both behavioral and neural non-drug-related PIT effects in AD patients after detoxification. A total of 100 AD patients (17 females) performed a PIT task and an alcohol approach/avoidance task. Patients were followed for 6 months. Results: A stronger alcohol approach bias was associated with both a more pronounced behavioral PIT effect and stronger PIT-related neural activity in the right nucleus accumbens. Moreover, the association between alcohol approach bias and behavioral PIT increased with the severity of alcohol dependence and trait impulsivity and was stronger in patients who relapsed during follow-up in the exploratory analysis. Conclusions: These findings indicate partial behavioral and neurobiological overlap between alcohol approach bias and the PIT effect assessed with our tasks. The association was stronger in patients with more severe alcohol dependence.

Using naltrexone to validate a human laboratory test system to screen new medications for alcoholism (TESMA)- a randomized clinical trial.

This registered clinical trial sought to validate a laboratory test system devised to screen medications for alcoholism treatment (TESMA) under different contingencies of alcohol reinforcement. Forty-six nondependent, but at least medium-risk drinkers were given the opportunity to earn intravenous infusions of ethanol, or saline, as rewards for work in a progressive-ratio paradigm. Work demand pattern and alcohol exposure dynamics were devised to achieve a gradual shift from low-demand work for alcohol (WFA) permitting quickly increasing breath alcohol concentrations (BrAC) to high-demand WFA, which could only decelerate an inevitable decrease of the previously earned BrAC. Thereby, the reward contingency changed, modeling different drinking motivations. The experiment was repeated after at least 7 days of randomized, double-blinded treatment with naltrexone, escalated to 50 mg/d, or placebo. Subjects treated with naltrexone reduced their cumulative WFA (cWFA) slightly more than participants receiving placebo. This difference was not statistically significant in the preplanned analysis of the entire 150 min of self-administration, i.e., our primary endpoint (p = 0.471, Cohen's d = 0.215). Naltrexone serum levels correlated with change in cWFA (r = -0.53; p = 0.014). Separate exploratory analyses revealed that naltrexone significantly reduced WFA during the first, but not the second half of the experiment (Cohen's d = 0.643 and 0.14, respectively). Phase-dependent associations of WFA with changes in subjective stimulation, wellbeing and desire for alcohol suggested that the predominant reinforcement of WFA was positive during the first phase only, and might have been negative during the second. We conclude that the TESMA is a safe and practical method. It bears the potential to quickly and efficiently screen new drugs for their efficacy to attenuate positively reinforced alcohol consumption. It possibly also provides a condition of negative reinforcement, and for the first time provides experimental evidence suggesting that naltrexone's effect might depend on reward contingency.

The Association of Non-Drug-Related Pavlovian-to-Instrumental Transfer Effect in Nucleus Accumbens With Relapse in Alcohol Dependence: A Replication.

BACKGROUND: The Pavlovian-to-instrumental transfer (PIT) paradigm measures the effects of Pavlovian conditioned cues on instrumental behavior in the laboratory. A previous study conducted by our research group observed activity in the left nucleus accumbens (NAcc) elicited by a non-drug-related PIT task across patients with alcohol dependence (AD) and healthy control subjects, and the left NAcc PIT effect differentiated patients who subsequently relapsed from those who remained abstinent. In this study, we aimed to examine whether such effects were present in a larger sample collected at a later date. METHODS: A total of 129 recently detoxified patients with AD (21 females) and 74 healthy, age- and gender-matched control subjects (12 females) performing a PIT task during functional magnetic resonance imaging were examined. After task assessments, patients were followed for 6 months. Forty-seven patients relapsed and 37 remained abstinent. RESULTS: We found a significant behavioral non-drug-related PIT effect and PIT-related activity in the NAcc across all participants. Moreover, subsequent relapsers showed stronger behavioral and left NAcc PIT effects than abstainers. These findings are consistent with our previous findings. CONCLUSIONS: Behavioral non-drug-related PIT and neural PIT correlates are associated with prospective relapse risk in AD. This study replicated previous findings and provides evidence for the clinical relevance of PIT mechanisms to treatment outcome in AD. The observed difference between prospective relapsers and abstainers in the NAcc PIT effect in our study is small overall. Future studies are needed to further elucidate the mechanisms and the possible modulators of neural PIT in relapse in AD.

Binge and high-intensity drinking-Associations with intravenous alcohol self-administration and underlying risk factors.

Some styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders.

Housing Correlates in Pregnant and Parenting Women Using Methamphetamine and Accessing Psychiatric Care.

Background: Integrated care is a promising model for pregnant and parenting women with problems related to methamphetamine use. Yet more research is imperative to guide services for this vulnerable population as methamphetamine use contributes to housing instability, which is associated with heavier use and overdose death. Method: This prospective observational study analyzed how housing at discharge from psychiatric care was related to patient characteristics, program participation, and aftercare in 102 pregnant and/or parenting women. Results: Twelve of 23 women who were unstably housed at admission (three of six homeless) achieved stable housing by discharge from integrated care. Women were more likely unstably housed at discharge when unstably housed at admission, single, living apart from at least one minor, or when the other parent had a substance use disorder (p < 0.05). Unstably housed women at discharge were also more likely to have used social and inpatient services, and to transition to inpatient rehabilitation (p < 0.05). Among baseline characteristics, logistic regression identified unstable housing at admission (OR = 6.07) and being single (OR = 4.01) as the strongest unique contributors to unstable housing at discharge (p < 0.05). Conclusion: Unstably housed women and single women seem particularly at risk of remaining in precarious living conditions despite accessing integrated care for problems associated with methamphetamine use. Future work should investigate whether stronger partnerships with government and community agencies could be a way forward to help these women attain and maintain stable housing.

Integrated Care for Pregnant Women and Parents With Methamphetamine-Related Mental Disorders.

Background: Methamphetamine use is a rapidly increasing cause of morbidity and mortality. Pregnant women and new parents who consume methamphetamine are at high risk since they seldom seek health services despite having multiple needs. We addressed this care gap by implementing an easily accessible program that pools resources from psychiatric, obstetric, and pediatric departments as well as community and government agencies. Method: This real-life observational study evaluated an integrated care program in 27 expecting parents and 57 parents of minors. The outcome criteria were treatment retention, psychosocial functioning, and abstinence. We compared participant demographics according to outcome and applied ordinal logistic regression to predict treatment success. Results: Patients received integrated care for almost 7 months on average. Nearly half achieved stable abstinence and functional recovery. Only one pregnant woman dropped out before a care plan could be implemented, and all women who gave birth during treatment completed it successfully. Three-fourths of patients had psychiatric comorbidities. Patients with depressive disorders were almost 5 times less likely to succeed with treatment. Attention-deficit hyperactivity disorder (ADHD) was diagnosed in nearly 30% of patients who dropped out of a care plan, which was about 4 times more often than in the successful outcome group. Conclusion: Our program engaged pregnant women and parents in treatment and helped them recover from methamphetamine-related mental disorders. Management of comorbid ADHD and depression should be an integral part of care initiatives to counter the methamphetamine crisis that affects parents and children across the globe.

Association of the OPRM1 A118G polymorphism and Pavlovian-to-instrumental transfer: Clinical relevance for alcohol dependence.

BACKGROUND: Pavlovian-to-instrumental transfer (PIT) quantifies the extent to which a stimulus that has been associated with reward or punishment alters operant behaviour. In alcohol dependence (AD), the PIT effect serves as a paradigmatic model of cue-induced relapse. Preclinical studies have suggested a critical role of the opioid system in modulating Pavlovian-instrumental interactions. The A118G polymorphism of the OPRM1 gene affects opioid receptor availability and function. Furthermore, this polymorphism interacts with cue-induced approach behaviour and is a potential biomarker for pharmacological treatment response in AD. In this study, we tested whether the OPRM1 polymorphism is associated with the PIT effect and relapse in AD. METHODS: Using a PIT task, we examined three independent samples: young healthy subjects (N = 161), detoxified alcohol-dependent patients (N = 186) and age-matched healthy controls (N = 105). We used data from a larger study designed to assess the role of learning mechanisms in the development and maintenance of AD. Subjects were genotyped for the A118G (rs1799971) polymorphism of the OPRM1 gene. Relapse was assessed after three months. RESULTS: In all three samples, participants with the minor OPRM1 G-Allele (G+ carriers) showed increased expression of the PIT effect in the absence of learning differences. Relapse was not associated with the OPRM1 polymorphism. Instead, G+ carriers displaying increased PIT effects were particularly prone to relapse. CONCLUSION: These results support a role for the opioid system in incentive salience motivation. Furthermore, they inform a mechanistic model of aberrant salience processing and are in line with the pharmacological potential of opioid receptor targets in the treatment of AD.

Effects of moderate alcohol levels on default mode network connectivity in heavy drinkers.

BACKGROUND: It is well established that even moderate levels of alcohol affect cognitive functions such as memory, self-related information processing, and response inhibition. Nevertheless, the neural mechanisms underlying these alcohol-induced changes are still unclear, especially on the network level. The default mode network (DMN) plays an important role in memory and self-initiated mental activities; hence, studying functional interactions of the DMN may provide new insights into the neural mechanisms underlying alcohol-related changes. METHODS: We investigated resting-state functional connectivity (rsFC) of the DMN in a cohort of 37 heavy drinkers at a breath alcohol concentration of 0.8 g/kg. Alcohol and saline were infused in a single-blind crossover design. RESULTS: Intranetwork connectivity analyses revealed that participants showed significantly decreased rsFC of the right hippocampus and right middle temporal gyrus during acute alcohol exposure. Moreover, follow-up analyses revealed that these rsFC decreases were more pronounced in participants who reported stronger craving for alcohol. Exploratory internetwork connectivity analyses of the DMN with other resting-state networks showed no significant alcohol-induced changes, but suffered from low statistical power. CONCLUSIONS: Our results indicate that acute alcohol exposure affects rsFC within the DMN. Functionally, this finding may be associated with impairments in memory encoding and self-referential processes commonly observed during alcohol intoxication. Future resting-state functional magnetic resonance imaging studies might therefore also investigate memory function and test whether DMN-related connectivity changes are associated with alcohol-induced impairments or craving.

Translating preclinical models of alcohol seeking and consumption into the human laboratory using intravenous alcohol self-administration paradigms.

Preclinical models of alcohol use disorder (AUD) have advanced theoretical, mechanistic, and pharmacological study of the human condition. "Liking" and "wanting" behaviors reflect core processes underlying several models of AUD. However, the development and application of translational models of these preclinical approaches are at an incipient stage. The goal of this study was to examine how intravenous free-access and progressive-ratio, operant-response human alcohol self-administration paradigms can be used as translational human model parallels of preclinical "liking" and "wanting." Participants were 40 adults (mean age = 23.7, SD = 2.0; 45% female) of European descent who reported 12.6 drinking days (SD = 5.2) out of the previous 30 (average = 4.1 drinks per drinking day [SD = 1.7]). Individuals diverged in their alcohol self-administration behavior, such that free-access and progressive-ratio paradigm outcomes were not significantly correlated (p = 0.44). Free-access alcohol seeking was related to enjoying alcohol (p < 0.001), but not craving (p = 0.48), whereas progressive-ratio seeking at similar levels of alcohol exposure was related to craving (p = 0.02), but not enjoying (p = 0.30). Family history of alcoholism, venturesomeness traits, and disinhibition traits were unrelated (ps > 0.70) to preferred level of breath alcohol concentration (BrAC) in the free-access session, a measure of liking alcohol. Family history of alcoholism, disinhibition traits, and recent drinking history were significantly related (ps < 0.05) to alcohol seeking in the progressive-ratio paradigm, a measure of wanting alcohol. We conclude that intravenous alcohol self-administration paradigms show promise in modeling behaviors that characterize and parallel alcohol "liking" and "wanting" in preclinical models. These paradigms provide a translational link between preclinical methods and clinical trials.

Sensation seeking, impulsivity, and aggression moderate sex effects on adolescent laboratory binging.

Sex, comprising biological and gender-related distinctions, is a known risk factor for alcohol use disorders. Moreover, sensation seeking, impulsivity, and aggression have been found to predict binge drinking and to reflect behavioral disinhibition. We tested effects of these disinhibited traits on binging during intravenous alcohol self-administration (ivASA), a method that eliminates sex differences in the pharmacokinetics of alcohol. Eighty-five German social drinkers (49 men) completed 3 questionnaires assessing sensation seeking, impulsivity, and aggression, as well as an ivASA session at ages 18-19. Sixty-five of them were retested at ages 21-22. Participants reported real-life drinking problems and the number of binge days in the 45 days preceding lab testing. Analyses employed continuous data and median splits to examine associations between disinhibited traits and the portion of women and men in the sample who achieved a breath alcohol concentration of 80 mg% during ivASA ("binge fraction"). At ages 18-19, and only if scoring low on sensation seeking, impulsivity, or aggression, women had significantly lower binge fractions during ivASA than men. Further, low compared to high impulsivity or aggression predicted lower binge fractions in women but not in men. Neither first- nor second-wave disinhibited traits significantly predicted binge fractions at ages 21-22. We perceive that personality traits reflecting behavioral disinhibition might be a strong indicator of drinking problems, specifically among young women. Targeted brief interventions might therefore be used in educational or clinical settings to inform such women about their increased risk and the potential health and behavioral problems associated with binge drinking. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Subjective alcohol responses in high- and low-risk adolescents: results from the Dresden Longitudinal Study on Alcohol Use in Young Adults.

BACKGROUND AND AIMS: Research shows that sensitivity to certain alcohol responses conveys risk for problem drinking. This study aimed to determine if high-risk adolescent drinkers infuse more alcohol and experience greater alcohol-induced stimulation and wanting and less sedation than low-risk adolescent drinkers. DESIGN AND PARTICIPANTS: Ninety-two low- (n = 38) and high-risk (n = 54) adolescent drinkers, as determined by Alcohol Use Disorders Identification Test scores of < 6 or ≥ 6, respectively, participated in the Dresden Longitudinal Study on Alcohol Use in Young Adults in which intravenous alcohol self-administration was examined in a mixed within- and between-subjects design. SETTING: Technische Universität Dresden. Dresden, Germany. MEASUREMENTS: Predictors were drinking status (high- versus low-risk), time and their interactions. Outcomes were arterial blood alcohol concentration (aBAC); alcohol-induced stimulation, sedation and wanting assessed at baseline, 10 (alcohol prime), 45, 65, 85, 105, 125 and 145 minutes. Covariates were family history of alcohol use disorder, sex and aBAC. RESULTS: The alcohol prime dose produced similar sharp increases in stimulation and sedation in high- and low-risk drinkers (time P < 0.001; group × time P > 0.05). During self-administration, high-risk drinkers reached higher aBACs (P = 0.028) at a faster rate (group × time P < 0.001), and experienced further increases in stimulation (group × time P = 0.005) but with similar sedation (group × time P = 0.794) than in low-risk drinkers. High-risk drinkers also exhibited greater tonic alcohol wanting (group P = 0.003) throughout the session. CONCLUSIONS: High-risk adolescent drinkers appear to have heightened sensitivity to alcohol-induced stimulation and tonic high levels of wanting compared with low-risk adolescent drinkers.

Neurocognitive Dysfunctions and Their Therapeutic Modulation in Patients With Methamphetamine Dependence: A Pilot Study.

AIM: Methamphetamine (MA) abuse and dependence are increasing worldwide and are commonly associated with cognitive deficits. Some studies indicate that such impairments can improve if users become abstinent, but overall results remain inconclusive. Hence, we have performed a longitudinal case-control study investigating key surrogates for attention and impulsive decision-making before and after treatment. METHODS: Thirty patients with MA dependence and 24 non-substance-abusing control participants were recruited. Groups were matched on age, sex and education. All subjects performed a baseline assessment to obtain neurocognitive measures of sustained attention and delay discounting. Patients subsequently participated in an MA-specific relapse prevention program including repeated monitoring of relapse status. After 3 months, participants of both groups were reevaluated for neurocognitive performance. RESULTS: At baseline, MA patients showed a significantly higher number of omissions compared to controls, indicative of lower sustained attention. Interestingly, we observed a steep decrease of omissions in MA patients to control-group level post treatment. On the other hand, MA patients discounted delayed rewards significantly stronger than controls, indicating a more impulsive choice behavior both before and after treatment. LIMITATION: The results should be interpreted with care because of the small sample and short follow-up period. CONCLUSION: Our data support earlier findings on partial recovery of cognitive deficits in MA patients. They also strengthen the indication for recently recommended psychotherapeutic interventions and may provide a behavioral monitoring tool to inform treatment progress.

Impact of Long-Term Alcohol Consumption and Relapse on Genome-Wide DNA Methylation Changes in Alcohol-Dependent Subjects: A Longitudinal Study.

BACKGROUND: Genetic factors play an important role in the development and maintenance of alcohol use disorder (AUD). Significant and widespread differences in methylation levels of multiple regions within the genome have been reported between AUD patients and healthy controls in large epigenome-wide association studies (EWASs). Also, within patient populations, methylation changes over time (both during and after withdrawal) have been identified as sensitive indicators for disease activity. The detection of changes in methylation levels is a powerful tool to further explore and understand the biological correlates and underpinnings of AUD. Although there is strong and convincing evidence for differences in methylation of various sites between AUD patients and controls, only few studies assessed changes within patients over longer periods of time while taking into account alcohol consumption, relapse, and abstinence. So far, the longest period assessed as a within-subject design using EWASs was 4 weeks. METHODS: Here, we investigated changes in whole-genome methylation levels within a sample of 69 detoxified AUD patients over a period as long as 12 months for the first time, comparing patients that relapsed within the follow-up period to those that remained abstinent. RESULTS: Whole-genome methylation patterns of individual CpG sites over time did not differ between abstinent and relapsing patients. However, there was a negative association between global mean methylation at the 12-month follow-up and alcohol consumption within our sample. CONCLUSION: Although the present study represents the largest study of methylation levels in a sample of AUD patients with a follow-up period of 1 year and accounting for alcohol consumption and relapse to date, the sample size might still not be large enough to detect genome-wide significant effects. Therefore, large-scale, long-term studies with AUD subjects are needed to determine the utility of DNA methylation for the assessment and monitoring of persons with alcohol use disorders.

A multimodal neuroimaging classifier for alcohol dependence.

With progress in magnetic resonance imaging technology and a broader dissemination of state-of-the-art imaging facilities, the acquisition of multiple neuroimaging modalities is becoming increasingly feasible. One particular hope associated with multimodal neuroimaging is the development of reliable data-driven diagnostic classifiers for psychiatric disorders, yet previous studies have often failed to find a benefit of combining multiple modalities. As a psychiatric disorder with established neurobiological effects at several levels of description, alcohol dependence is particularly well-suited for multimodal classification. To this aim, we developed a multimodal classification scheme and applied it to a rich neuroimaging battery (structural, functional task-based and functional resting-state data) collected in a matched sample of alcohol-dependent patients (N = 119) and controls (N = 97). We found that our classification scheme yielded 79.3% diagnostic accuracy, which outperformed the strongest individual modality - grey-matter density - by 2.7%. We found that this moderate benefit of multimodal classification depended on a number of critical design choices: a procedure to select optimal modality-specific classifiers, a fine-grained ensemble prediction based on cross-modal weight matrices and continuous classifier decision values. We conclude that the combination of multiple neuroimaging modalities is able to moderately improve the accuracy of machine-learning-based diagnostic classification in alcohol dependence.

Dysfunctional approach behavior triggered by alcohol-unrelated Pavlovian cues predicts long-term relapse in alcohol dependence.

We demonstrated that alcohol-dependent patients who relapsed within 1 year after detoxification showed stronger PIT effects compared with abstainers and controls. Relapsers particularly failed to correctly perform in trials where an instrumental stimulus required inhibition while a Pavlovian background cue indicated a monetary gain. Under that condition, relapsers approached the instrumental stimulus, independent of the expected punishment. The failure of inhibiting an aversive stimulus in favor of approaching an appetitive context cue reflects dysfunctional altered learning mechanisms in relapsers.

Dissociating neural learning signals in human sign- and goal-trackers.

Individuals differ in how they learn from experience. In Pavlovian conditioning models, where cues predict reinforcer delivery at a different goal location, some animals-called sign-trackers-come to approach the cue, whereas others, called goal-trackers, approach the goal. In sign-trackers, model-free phasic dopaminergic reward-prediction errors underlie learning, which renders stimuli 'wanted'. Goal-trackers do not rely on dopamine for learning and are thought to use model-based learning. We demonstrate this double dissociation in 129 male humans using eye-tracking, pupillometry and functional magnetic resonance imaging informed by computational models of sign- and goal-tracking. We show that sign-trackers exhibit a neural reward prediction error signal that is not detectable in goal-trackers. Model-free value only guides gaze and pupil dilation in sign-trackers. Goal-trackers instead exhibit a stronger model-based neural state prediction error signal. This model-based construct determines gaze and pupil dilation more in goal-trackers.