The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

The Role of Perceived Stress in the Relation between Childhood Maltreatment and Severity of Alcohol Use Disorder: A Mediation Analysis.

INTRODUCTION: Experiences of Childhood Maltreatment (CM) relate to relapse and lower treatment success in Alcohol Use Disorder (AUD), one of the most prevalent substance use disorders. However, the exact mechanisms of this relationship still remain unclear. This study examines perceived stress and "drinking to cope with negative affect" (coping) as possible mediators in this relationship. Moreover, it aims at uncovering the differential effects of the subtypes of CM. METHODS: N = 96 individuals (42% women; mean age 41 ± 13 years) including healthy controls and individuals with varying severity of AUD and CM completed the Alcohol-Dependence Scale, Childhood Trauma Questionnaire, Perceived Stress Scale and German Inventory of Drinking Situations. Mediation analyses including perceived stress as a mediator between CM (and subtypes) and severity of AUD, as well as a serial mediation of the relationship between CM and AUD severity by perceived stress and coping were conducted. RESULTS: Perceived stress significantly mediated the relation between CM and AUD severity and the serial mediation by perceived stress and coping turned out significant. Subtype-specific analyses did not yield significant results. CONCLUSION: This study reinforces perceived stress as a potential mechanism in the relation between CM and AUD severity. Moreover, coping further mediated the relationship between CM and AUD severity. Our results suggest including screening for CM (subtypes) in clinical routine in order to individually emphasize interventions focusing on stress regulation, as well as on developing healthy coping mechanisms, in patients with AUD. This might prevent heightened stress sensitivity, relapse and further maintenance of AUD.

Sports participation moderates the risk of family-specific negative life events on alcohol use among adolescents: Evidence from the longitudinal MyLife study.

Negative life events (NLE) have been associated with increased alcohol use (AU) during adolescence. However, whether this risk association may be modified by leisure activities such as sports participation (SP) remains poorly understood. This study examined whether accumulated family-specific NLE in particular were associated with greater AU, and if so, whether SP moderated this association to reduce AU among high-NLE adolescents. We examined five annual assessments from a nationwide cohort of 3,422 Norwegian adolescents (13-15 year-olds; 55.3 % girls at baseline) who participated in the MyLife study. At each assessment, adolescents reported their AU on the Alcohol Use Disorders Identification Test-Concise (AUDIT-C), the number of family-specific NLE in the past 12 months, SP days in the past 30 days, and multiple sociodemographic and individual-level characteristics (covariates). Changes over time in AU as a function of NLE, SP, and their interaction (NLExSP) were examined with a set of partially nested growth curve models. AU increased non-linearly over time in all models. The fully adjusted best-fitting model showed significant NLExSP interactions (estimate = -0.013, 95% CI [-0.02, -0.006]), such that the initial AUDIT-C scores were lower for high-NLE adolescents with high SP and greater for high-NLE adolescents with low SP. Further, linear increases in AU over time were marginally steeper for high-NLE adolescents with high SP (NLExSPxTime estimate = 0.034, 95% CI [-0.0002, 0.007]). Thus, SP appeared to have a protective role in reducing AU for high-NLE youth primarily during middle school years. Prevention efforts thus may utilize organized sports for youth facing family-specific NLE as a resource early on.

Does cannabis use substitute for opioids? A preliminary exploratory survey in opioid maintenance patients.

Various studies showed that people with substance use disorder use cannabis to reduce withdrawal or dose of their main drug. Using a questionnaire about their cannabis use, 118 participants in an opioid maintenance treatment (OMT) in Germany were examined regarding this strategy. 60% reported to use cannabis. Of those, 72% were using cannabis in the suggested way. Cannabis was used to substitute for, e.g., heroin (44.8%) and benzodiazepines (16.4%). We also asked for an estimation of how good cannabis was able to substitute for several substances (in German school grades (1 till 6)); heroin average grade: 2.6 ± 1.49. Besides that we asked about the idea of cannabis as "self-medication", e.g., to reduce pain (47%) and about negative consequences from cannabis use. Our results suggest to consider the use of cannabis by patients in OMT rather as a harm reduction strategy to reduce the intake of more dangerous drugs.

Parameter Space and Potential for Biomarker Development in 25 Years of fMRI Drug Cue Reactivity: A Systematic Review.

Importance: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

[Diagnosis and admission center : Establishment and evaluation of an integrated translational infrastructure for clinical psychiatric research]. / Diagnose- und Aufnahmezentrum : Etablierung und Evaluation einer integrierten translationalen Infrastruktur für die klinisch-psychiatrische Forschung.

The routine in-depth characterization of patients with methods of clinical and scale-based examination, neuropsychology, based on biomaterials, and sensor-based information opens up transformative possibilities on the way to personalized diagnostics, treatment and prevention in psychiatry, psychotherapy, and psychosomatics. Effective integration of the additional temporal and logistical effort into everyday care as well as the acceptance by patients are critical to the success of such an approach but there is little evidence on this to date. We report here on the establishment of the Diagnosis and Admission Center (DAZ) at the Central Institute of Mental Health (ZI) in Mannheim. The DAZ is an outpatient unit upstream of other care structures for clinical and scientific phenotyping across diagnoses as a starting point for data-driven, individualized pathways to further treatment, diagnostics or research. We describe the functions, goals, and implementation of the newly created clinical scientific translational structure, provide an overview of the patient populations it has reached, and provide data on its acceptance. In this context, the close integration with downstream clinical processes enables a better coordinated and demand-oriented allocation. In addition, DAZ enables a faster start of disorder-specific diagnostics and treatment. Since its launch in April 2021 up to the end of 2022, 1021 patients underwent psychiatric evaluation at DAZ during a pilot phase. The patient sample corresponded to a representative sample from standard care and the newly established processes were regarded as helpful by patients. In summary, the DAZ uniquely combines the interests and needs of patient with the collection of scientifically relevant data.

Cue-exposure treatment influences resting-state functional connectivity-a randomized controlled fMRI study in alcohol use disorder.

RATIONALE: Cue-exposure therapy (CET) consists of exposing patients to the cause of their affliction in a controlled environment and after psychological preparation. Ever since it was conceived, it has been suggested as a treatment for different types of behavioural impairments, from anxiety disorders to substance abuse. In the field of addictive behaviour, many different findings have been shown regarding the effectiveness of this therapy. OBJECTIVES: This study aims to examine the underlying neurobiological mechanisms of the effects of CET in patients with alcohol use disorder using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: In a randomized, controlled study, we examined patients after inpatient detoxification as well as healthy controls. Patients underwent nine sessions of CET spaced over 3 weeks. Rs-fMRI was conducted before treatment and 3 weeks after treatment onset in patients, healthy controls received only one rs-fMRI measurement. The final participant sample with complete data included 35 patients in the CET group, 17 patients in the treatment-as-usual group, and 43 HCs. RESULTS: Our results show differences in the Salience Network when comparing the CET group to the treatment-as-usual group (TAU). Functional connectivity between the anterior cingulate Cortex (ACC) and the insula was increased after CET, whereas it was decreased from ACC to the putamen and globus pallidus. Further, increased connectivity with the precuneus was found in the dorsal attention network after cue exposure treatment. CONCLUSIONS: These findings suggest that cue exposure therapy changes the resting-state brain connectivity with additional effects to the standard psychotherapy treatment. Hence, our study results suggest why including CET in standard therapies might improve the preparation of patients in front of daily situations.

Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD show changes in DNA methylation and gene expression in neuroinflammation-related pathways in the brain, biological aging represents a potentially important construct for understanding the adverse effects of substance use disorders. Epigenetic clocks have shown accelerated aging in blood samples from individuals with AUD. However, no systematic evaluation of biological age measures in AUD across different tissues and brain regions has been undertaken. METHODS: As markers of biological aging (BioAge markers), we assessed Levine's and Horvath's epigenetic clocks, DNA methylation telomere length (DNAmTL), telomere length (TL), and mitochondrial DNA copy number (mtDNAcn) in postmortem brain samples from Brodmann Area 9 (BA9), caudate nucleus, and ventral striatum (N = 63-94), and in whole blood samples (N = 179) of individuals with and without AUD. To evaluate the association between AUD status and BioAge markers, we performed linear regression analyses while adjusting for covariates. RESULTS: The majority of BioAge markers were significantly associated with chronological age in all samples. Levine's epigenetic clock and DNAmTL were indicative of accelerated biological aging in AUD in BA9 and whole blood samples, while Horvath's showed the opposite effect in BA9. No significant association of AUD with TL and mtDNAcn was detected. Measured TL and DNAmTL showed only small correlations in blood and none in brain. CONCLUSIONS: The present study is the first to simultaneously investigate epigenetic clocks, telomere length, and mtDNAcn in postmortem brain and whole blood samples in individuals with AUD. We found evidence for accelerated biological aging in AUD in blood and brain, as measured by Levine's epigenetic clock, and DNAmTL. Additional studies of different tissues from the same individuals are needed to draw valid conclusions about the congruence of biological aging in blood and brain.

Alcohol does not influence trust in others or oxytocin, but increases positive affect and risk-taking: a randomized, controlled, within-subject trial.

BACKGROUND: Alcohol consumption to facilitate social interaction is an important drinking motive. Here, we tested whether alcohol influences trust in others via modulation of oxytocin and/or androgens. We also aimed at confirming previously shown alcohol effects on positive affect and risk-taking, because of their role in facilitating social interaction. METHODS: This randomized, controlled, within-subject, parallel group, alcohol-challenge experiment investigated the effects of alcohol (versus water, both mixed with orange juice) on perceived trustworthiness via salivary oxytocin (primary and secondary endpoint) as well as testosterone, dihydrotestosterone, positive affect, and risk-taking (additional endpoints). We compared 56 male participants in the alcohol condition (1.07 ± 0.18 per mille blood alcohol concentration) with 20 in the control condition. RESULTS: The group (alcohol versus control condition) × time (before [versus during] versus after drinking) interactions were not significantly associated with perceived trustworthiness (η2 < 0.001) or oxytocin (η2 = 0.003). Bayes factors provided also substantial evidence for the absence of these effects (BF01 = 3.65; BF01 = 7.53). The group × time interactions were related to dihydrotestosterone (η2 = 0.018 with an increase in the control condition) as well as positive affect and risk-taking (η2 = 0.027 and 0.007 with increases in the alcohol condition), but not significantly to testosterone. DISCUSSION: The results do not verify alcohol effects on perceived trustworthiness or oxytocin in male individuals. However, they indicate that alcohol (versus control) might inhibit an increase in dihydrotestosterone and confirm that alcohol amplifies positive affect and risk-taking. This provides novel mechanistic insight into social facilitation as an alcohol-drinking motive.

Stress-Induced Sensitization of Insula Activation Predicts Alcohol Craving and Alcohol Use in Alcohol Use Disorder.

BACKGROUND: Stress and alcohol cues trigger alcohol consumption and relapse in alcohol use disorder. However, the neurobiological processes underlying their interaction are not well understood. Thus, we conducted a randomized, controlled neuroimaging study to investigate the effects of psychosocial stress on neural cue reactivity and addictive behaviors. METHODS: Neural alcohol cue reactivity was assessed in 91 individuals with alcohol use disorder using a validated functional magnetic resonance imaging (fMRI) task. Activation patterns were measured twice, at baseline and during a second fMRI session, prior to which participants were assigned to psychosocial stress (experimental condition) or a matched control condition or physical exercise (control conditions). Together with fMRI data, alcohol craving and cortisol levels were assessed, and alcohol use data were collected during a 12-month follow-up. Analyses tested the effects of psychosocial stress on neural cue reactivity and associations with cortisol levels, craving, and alcohol use. RESULTS: Compared with both control conditions, psychosocial stress elicited higher alcohol cue-induced activation in the left anterior insula (familywise error-corrected p < .05) and a stress- and cue-specific dynamic increase in insula activation over time (F22,968 = 2.143, p = .007), which was predicted by higher cortisol levels during the experimental intervention (r = 0.310, false discovery rate-corrected p = .016). Cue-induced insula activation was positively correlated with alcohol craving during fMRI (r = 0.262, false discovery rate-corrected p = .032) and alcohol use during follow-up (r = 0.218, false discovery rate-corrected p = .046). CONCLUSIONS: Results indicate a stress-induced sensitization of cue-induced activation in the left insula as a neurobiological correlate of the effects of psychosocial stress on alcohol craving and alcohol use in alcohol use disorder, which likely reflects changes in salience attribution and goal-directed behavior.

New Approaches to Addiction Treatment Based on Learning and Memory.

Preclinical studies suggest that physiological learning processes are similar to changes observed in addiction at the molecular, neuronal and structural levels. Based on the importance of classical and instrumental conditioning in the development and maintenance of addictive disorders, many have suggested cue-exposure-based extinction training of conditioned, drug-related responses as a potential treatment of addiction. Recently, the development of virtual reality-assisted cue-exposure treatment has put forward new approaches to extinction training. Recent data indicated that it may also be possible to facilitate this extinction training through pharmacological interventions that strengthen memory consolidation during cue exposure. Another potential therapeutic intervention is based on the so-called reconsolidation theory. According to this hypothesis, already-consolidated memories return to a labile state when reactivated, allowing them to undergo another phase of consolidation - reconsolidation - which can be interfered with by pharmacological and behavioural interventions. These approaches suggest that the extinction of drug-related memories may represent a viable treatment strategy in the future treatment of addiction.

Effectiveness of Reducing Craving in Alcohol Use Disorder Using a Serious Game (SALIENCE): Randomized Controlled Trial.

BACKGROUND: Alcohol use disorder (AUD) has become a major global health problem. Therapy for this condition is still a great challenge. Recently, it has become increasingly evident that computer-based training is a valuable addition to the treatment of addictive disorders. OBJECTIVE: This study aims to evaluate the web-based serious game SALIENCE (Stop Alcohol in Everyday Life-New Choices and Evaluations) as an add-on therapy for AUD. It combines the cue-exposure therapy approach with elements of decision-making training, enhanced by interactive panoramic images. The effects of SALIENCE training on levels of craving, attention, and cognitive bias are investigated. METHODS: In a randomized controlled trial, 62 participants with AUD undergoing 3 weeks of an extended alcohol detoxification program were randomly allocated to an intervention and a control group. A total of 49 individuals (mean age 44.04 y; 17/49, 35% female) completed all sessions and were included in the analysis. Only pretreatment data were available from the other 13 patients. Participants answered questionnaires related to alcohol consumption and craving and completed neuropsychological tasks at the beginning of the study and 2 weeks later to evaluate levels of attention and cognitive biases. During the 2-week period, 27 of the participants additionally performed the SALIENCE training for 30 minutes 3 times a week, for a total of 6 sessions. RESULTS: We observed a significant decrease in craving in both groups: the control group (mean 15.59, SD 8.02 on the first examination day vs mean 13.18, SD 8.38 on the second examination day) and the intervention group (mean 15.19, SD 6.71 on the first examination day vs mean 13.30, SD 8.47 on the second examination day; F1,47=4.31; P=.04), whereas the interaction effect was not statistically significant (F1,47=0.06; P=.80). Results of the multiple linear regression controlling for individual differences between participants indicated a significantly greater decrease in craving (ß=4.12; t36=2.34; P=.03) with the SALIENCE intervention. Participants with lower drinking in negative situations reduced their craving (ß=.38; t36=3.01; P=.005) more than people with higher drinking in negative situations. CONCLUSIONS: The general effectiveness of SALIENCE training as an add-on therapy in reducing alcohol craving was not confirmed. Nevertheless, taking into account individual differences (gender, duration of dependence, stress, anxiety, and drinking behavior in different situations), it was shown that SALIENCE training resulted in a larger reduction in craving than without. Notably, individuals who rarely consume alcohol due to negative affect profited the most from SALIENCE training. In addition to the beneficial effect of SALIENCE training, these findings highlight the relevance of individualized therapy for AUD, adapted to personal circumstances such as drinking motivation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03765476; https://clinicaltrials.gov/show/NCT03765476.

Psychometric properties of the German Penn Alcohol Craving Scale.

Craving for alcohol is an important diagnostic criterion in alcohol use disorder (AUD) and an established predictor of future relapse. The 5-item Penn Alcohol Craving Scale (PACS) is one of the most widely used questionnaires to quantify craving and has been translated into different languages. It is assumed that the PACS constitutes one factor, although theoretical considerations suggest an additional second factor. We conducted stability and factor analyses (principal component and confirmatory factor analyses) of the German PACS (PACS-G) in samples of patients with AUD from the following three German study sites: Erlangen, N = 188 (mean age: 47.1 years, 43.5% female); Mannheim, N = 440 (45.5 years, 28.6% female); Hannover, N = 107 (48.1 years, 48.6% female). In our samples, the 2-factor solution of the PACS-G version is more stable than the internationally assumed 1-factor solution. The resulting two PACS-G subscores 'difficulty to resist' (items 4 and 5) and 'thoughts about alcohol' (items 1, 2, and 3) have an internal consistency (Cronbach's alpha) of 0.80 ≤ α ≤ 0.90, m = 0.86 and 0.86 ≤ α ≤ 0.91, m = 0.89 with an overlap of R2 = 62%. We found good convergent validity assessed via the Craving Automatized Scale-Alcohol and the Obsessive-Compulsive Drinking Scale, but also correlations with depression and anxiety assessed via the Beck's Depression and Anxiety Inventories. This study is the first to provide evidence for a 2-factor solution ('difficulty to resist' and 'thoughts about alcohol') underlying the PACS-G version.

Alcohol-induced damage to the fimbria/fornix reduces hippocampal-prefrontal cortex connection during early abstinence.

INTRODUCTION: Alcohol dependence is characterized by a gradual reduction in cognitive control and inflexibility to contingency changes. The neuroadaptations underlying this aberrant behavior are poorly understood. Using an animal model of alcohol use disorders (AUD) and complementing diffusion-weighted (dw)-MRI with quantitative immunohistochemistry and electrophysiological recordings, we provide causal evidence that chronic intermittent alcohol exposure affects the microstructural integrity of the fimbria/fornix, decreasing myelin basic protein content, and reducing the effective communication from the hippocampus (HC) to the prefrontal cortex (PFC). Using a simple quantitative neural network model, we show how disturbed HC-PFC communication may impede the extinction of maladaptive memories, decreasing flexibility. Finally, combining dw-MRI and psychometric data in AUD patients, we discovered an association between the magnitude of microstructural alteration in the fimbria/fornix and the reduction in cognitive flexibility. Overall, these findings highlight the vulnerability of the fimbria/fornix microstructure in AUD and its potential contribution to alcohol pathophysiology. Fimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment.

The impact of COVID-19 pandemic on mental burden and quality of life in medical students - results of an online survey.

Objectives: Changes in academic conditions due to the COVID-19 pandemic are potential stressors for medical students and can make them vulnerable for the development of psychiatric disorders.Previous pandemics had a negative impairment on well-being due to social isolation and the perceived threat, an increase in fear, anger and frustration and an increase in post-traumatic stress disorder among health professionals. Therefore, this study examines the impact of the COVID-19 pandemic on medical students' mental health and possible psychological consequences. Methods: In this anonymous online survey (online 12/01/2021-03/31/2022), we examined the impact of COVID-19 pandemic on mental health of 561 German medical students aged between 18 und 45 years. Perceived anxiety and burden were assessed retrospectively from spring 2020 to autumn 2021. Changes in symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS), quality of life was assessed using the WHO Quality of Life Questionnaire (WHOQOL BREF). Results: Anxiety and burden showed wavelike courses with higher scores in autumn, winter and spring. The scores for depression and anxiety increased after the outbreak of the COVID-19 pandemic compared to the time before (p<.001). Results of a multifactorial ANOVA showed, that previous psychiatric illness (p<.001), being in the first two years of studies (p=.006), higher burden (p=.013) and greater differences in symptoms of depression (p<.001) were associated with a decreased quality of life in medical students. Conclusion: The COVID-19 pandemic has a negative impact on mental health of medical students and their actual quality of life. Therefore, medical faculties should establish specific support to prevent the development of psychiatric sequelae probably resulting in long-term medical leaves.

The impact of COVID-19 pandemic on mental burden and quality of life in physicians: Results of an online survey.

Background: In previous pan-/epidemics such as the SARS epidemic of 2002/2003, negative effects on the wellbeing and an increase in symptoms of depression and anxiety were observed in doctors due to social isolation and the threat they experienced. Therefore, it is feared that the COVID-19 pandemic will also have a negative impact on the mental health and quality of life of doctors. Objective: The impact of the COVID-19 pandemic on the mental health of physicians. In particular, on the subjective anxiety and burden, depression and quality of life for the total sample and subsamples (work in COVID-19 units vs. no work in COVID-19 units). Materials and methods: In an online survey, 107 physicians (23-42 years) were asked about their mental health during the COVID-19 pandemic. In addition to socio-demographic data, pandemic- and work-related data were also included. For example, infection control measures, deployment on COVID-19 wards and the subjective perceived threat posed by the pandemic. The physicians were asked to rate their perceived anxiety and stress, retrospectively, at 7 different points in time during the pandemic. The Hospital Anxiety and Depression Scale (HADS) was used to retrospectively assess symptoms of anxiety and depression before and after the onset of the pandemic. The quality of life of the participants after 2 years of the pandemic was assessed using the WHO Quality of Life (WHOQOL-BREF). Results: Both subjective anxiety and burden showed wave-like patterns with higher scores in autumn, winter and spring. We observed significant differences between the seven measurement time points for anxiety [Chi2(6) = 197.05, p < 0.001] as well as for burden [Chi2(6) = 106.33, p < 0.001]. Symptoms of depression and anxiety increased significantly during the COVID-19 pandemic (M = 14.16, SD = 7.83) compared to the pre-pandemic time [M = 7.31, SD = 5.14, t (106) = -10.67, p < 0.001]. Physicians who worked at COVID-19 units showed higher scores in quality of life related to social relationships (M = 70.39, SD = 17.69) than physicians not working at COVID-19 units [M = 61.44, SD = 24.55, t (90.14) = -2.145, p = 0.035]. The multi-factorial ANOVA showed that previous psychiatric illness (p < 0.001), greater difference in depression scores (p = 0.014), higher anxiety scores (p = 0.048) and less work experience (p = 0.032) led to lower quality of life. Conclusion: Hospitals should offer specific support, such as supervision, to prevent the development of longer-term psychiatric sequelae likely to lead to sick leave and high costs for the healthcare system. Trial registration: The study has been registered at the German Clinical Trials Registry (DRKS-ID: DRKS00028984).

The Role of Unawareness, Volition, and Neural Hyperconnectivity in Alcohol Use Disorder: A Functional Magnetic Resonance Imaging Study.

BACKGROUND: Automated alcohol craving and habitual alcohol consumption characterize the later stages of alcohol use disorder (AUD). This study reanalyzed previously collected functional neuroimaging data in combination with the Craving Automated Scale for Alcohol (CAS-A) questionnaire to investigate the neural correlates and brain networks underlying automated drinking characterized by unawareness and nonvolition. METHODS: We assessed 49 abstinent male patients with AUD and 36 male healthy control participants during a functional magnetic resonance imaging-based alcohol cue-reactivity task. We performed whole-brain analyses examining the associations between CAS-A scores and other clinical instruments and neural activation patterns in the alcohol versus neutral contrast. Furthermore, we performed psychophysiological interaction analyses to assess the functional connectivity between predefined seed regions and other brain areas. RESULTS: In patients with AUD, higher CAS-A scores correlated with greater activation in dorsal striatal, pallidal, and prefrontal regions, including frontal white matter, and with lower activation in visual and motor processing regions. Between-group psychophysiological interaction analyses showed extensive connectivity between the seed regions inferior frontal gyrus and angular gyrus and several frontal, parietal, and temporal brain regions in AUD versus healthy control participants. CONCLUSIONS: The present study applied a new lens to previously acquired alcohol cue-reactivity functional magnetic resonance imaging data by correlating neural activation patterns with clinical CAS-A scores to elucidate potential neural correlates of automated alcohol craving and habitual alcohol consumption. Our results support previous findings showing that alcohol addiction is associated with hyperactivation in habit-processing regions, with hypoactivation in areas mediating motor and attention processing, and with general hyperconnectivity.

Decoding fMRI alcohol cue reactivity and its association with drinking behaviour.

BACKGROUND: Cue reactivity, the enhanced sensitivity to conditioned cues, is associated with habitual and compulsive alcohol consumption. However, most previous studies in alcohol use disorder (AUD) compared brain activity between alcohol and neutral conditions, solely as cue-triggered neural reactivity. OBJECTIVE: This study aims to find the neural subprocesses during the processing of visual alcohol cues in AUD individuals, and how these neural patterns are predictive for relapse. METHODS: Using cue reactivity and rating tasks, we separately modelled the patterns decoding the processes of visual object recognition and reward appraisal of alcohol cues with representational similarity analysis, and compared the decoding involvements (ie, distance between neural responses and hypothesised decoding models) between AUD and healthy individuals. We further explored connectivity between the identified neural systems and the whole brain and predicted relapse within 6 months using decoding involvements of the neural patterns. FINDINGS: AUD individuals, compared with healthy individuals, showed higher involvement of motor-related brain regions in decoding visual features, and their reward, habit and executive networks were more engaged in appraising reward values. Connectivity analyses showed the involved neural systems were widely connected with higher cognitive networks during alcohol cue processing in AUD individuals, and decoding involvements of frontal eye fields and dorsolateral prefrontal cortex could contribute to relapse prediction. CONCLUSIONS: These findings provide insight into how AUD individuals differently decode alcohol cues compared with healthy participants, from the componential processes of visual object recognition and reward appraisal. CLINICAL IMPLICATIONS: The identified patterns are suggested as biomarkers and potential therapeutic targets in AUD.

MRI texture-based radiomics analysis for the identification of altered functional networks in alcoholic patients and animal models.

Alcohol use disorder (AUD) is a complex condition representing a leading risk factor for death, disease and disability. Its high prevalence and severe health consequences make necessary a better understanding of the brain network alterations to improve diagnosis and treatment. The purpose of this study was to evaluate the potential of resting-state fMRI 3D texture features as a novel source of biomarkers to identify AUD brain network alterations following a radiomics approach. A longitudinal study was conducted in Marchigian Sardinian alcohol-preferring msP rats (N = 36) who underwent resting-state functional and structural MRI before and after 30 days of alcohol or water consumption. A cross-sectional human study was also conducted among 33 healthy controls and 35 AUD patients. The preprocessed functional data corresponding to control and alcohol conditions were used to perform a probabilistic independent component analysis, identifying seven independent components as resting-state networks. Forty-three radiomic features extracted from each network were compared using a Wilcoxon signed-rank test with Holm correction to identify the network most affected by alcohol consumption. Features extracted from this network were then used in the machine learning process, evaluating two feature selection methods and six predictive models within a nested cross-validation structure. The classification was evaluated by computing the area under the ROC curve. Images were quantized using different numbers of gray-levels to test their influence on the results. The influence of ageing, data preprocessing, and brain iron accumulation were also analyzed. The methodology was validated using structural scans. The striatal network in alcohol-exposed msP rats presented the most significant number of altered features. The radiomics approach supported this result achieving good classification performance in animals (AUC = 0.915 ± 0.100, with 12 features) and humans (AUC = 0.724 ± 0.117, with 9 features) using a random forest model. Using the structural scans, high accuracy was achieved with a multilayer perceptron in both species (animals: AUC > 0.95 with 2 features, humans: AUC > 0.82 with 18 features). The best results were obtained using a feature selection method based on the p-value. The proposed radiomics approach is able to identify AUD patients and alcohol-exposed rats with good accuracy, employing a subset of 3D features extracted from fMRI. Furthermore, it can help identify relevant networks in drug addiction.

Body mass index interacts with sex to predict readmission in in-patients with alcohol use disorder.

A previous highly controlled pilot study revealed that body mass index (BMI) predicts outcome of in-patients with alcohol use disorder (AUD) in a sex-specific manner. We here provide translational evidence from a daily clinical routine setting and investigated whether BMI and sex interact to predict 24-month readmission risk in four naturalistic cohorts of a specialized addiction clinic (i.e., all patients admitted to the clinic from 2016 to 2020): (i) in-patients (443 males and 197 females) and (ii) day clinic patients (241 males and 103 females) with a primary diagnosis of AUD; (iii) in-patients (175 males and 98 females) and (iv) day clinic patients (174 males and 64 females) with a primary substance use disorder (SUD) other than alcohol. In the in-patients with AUD, BMI interacted with sex to predict the 24-month readmission risks (p = 0.008; after adjustment for age and liver enzyme activities: p = 0.012); with higher BMI, the risk increases significantly in males, whereas for females, the risk tends to decrease. In the group of overweight in-patients, we found higher readmission rates in males relative to females with an odds ratio of 1.8 (p = 0.038). No such significant effects were found in the other cohorts. This study's findings support previous results, suggesting that the easily accessible BMI may serve as a predictive and sex-sensitive biomarker for outcome in in-patients with AUD. Future studies are necessary to elucidate the underlying aetiopathological mechanisms.