Differential dysfunctions related to alcohol and cannabis use disorder symptoms in reward and error-processing neuro-circuitries in adolescents

Alcohol and cannabis are two of the most commonly used substances by adolescents and are associated with adverse medical and psychiatric outcomes. These adverse psychiatric outcomes may reflect the negative impact of alcohol and/or cannabis abuse on neural systems mediating reward and/or error detection. However, work indicative of this has mostly been conducted in adults with Alcohol and/or Cannabis Use Disorder (i.e., AUD and CUD), with relatively little work in adolescent patients. Furthermore, of the work that has been conducted in adolescents, groups were based on categorical diagnoses of AUD and/or CUD, so the relationship between AUD and/or CUD symptom severity in adolescents and neural dysfunction is unclear. We used a Monetary Incentive Delay (MID) task to examine the relationship between AUDIT and/or CUDIT scores and functional integrity of neuro-circuitries mediating reward processing and error detection within 150 adolescents. Our findings indicate that AUDIT score is negatively related to activity in reward processing neuro-circuitry in adolescents. However, CUDIT score is negatively related to activity in brain regions involved in error detection. Each of these relationships reflected a medium effect size (Partial-η² 0.09-0.14). These data suggest differential impacts of AUD and CUD on reward versus error detection neuro-circuitries within the adolescent brain.     

Neural activation to loss and reward among alcohol naive adolescents who later initiate alcohol use

Adolescent alcohol use is associated with adverse psychosocial outcomes, including an increased risk of alcohol use disorder in adulthood. It is therefore important to identify risk factors of alcohol initiation in adolescence. Research to date has shown that altered neural activation to reward is associated with alcohol use in adolescence; however, few studies have focused on neural activation to loss and alcohol use. The current study examined neural activation to loss and reward among 64 alcohol naive 12−14 year olds that did (n = 20) and did not initiate alcohol use by a three year follow-up period. Results showed that compared to adolescents that did not initiate alcohol use, adolescents that did initiate alcohol use by the three year follow-up period had increased activation to loss in the left striatum (i.e., putamen), right precuneus, and the brainstem/pons when they were alcohol naive at baseline. By contrast, alcohol initiation was not associated with neural activation to winning a reward. These results suggest that increased activation in brain regions implicated in salience, error detection/self-referential processing, and sensorimotor function, especially to negative outcomes, may represent an initial vulnerability factor for alcohol use in adolescence.     

Individual differences and the neural representations of reward expectation and reward prediction error

Reward expectation and reward prediction errors are thoughtto be critical for dynamic adjustments in decision-making andreward-seeking behavior, but little is known about their representationin the brain during uncertainty and risk-taking. Furthermore,little is known about what role individual differences mightplay in such reinforcement processes. In this study, it is shownbehavioral and neural responses during a decision-making taskcan be characterized by a computational reinforcement learningmodel and that individual differences in learning parametersin the model are critical for elucidating these processes. Inthe fMRI experiment, subjects chose between high- and low-riskrewards. A computational reinforcement learning model computedexpected values and prediction errors that each subject mightexperience on each trial. These outputs predicted subjects’trial-to-trial choice strategies and neural activity in severallimbic and prefrontal regions during the task. Individual differencesin estimated reinforcement learning parameters proved criticalfor characterizing these processes, because models that incorporatedindividual learning parameters explained significantly morevariance in the fMRI data than did a model using fixed learningparameters. These findings suggest that the brain engages areinforcement learning process during risk-taking and that individualdifferences play a crucial role in modeling this process.     

Time to rehospitalization of clozapine versus risperidone in the naturalistic treatment of comorbid alcohol use disorder and schizophrenia

Clozapine is known to be effective in treating schizophrenia patients with comorbid alcohol use disorders (AUD). However, few prospective studies have examined the effect of clozapine on community survival of the patient, which is one of the most important indicators of success for patients with schizophrenia. In this prospective, naturalistic, observational, community-survival-analysis study, we compared the effect of clozapine and risperidone on two-year psychiatric hospitalization rate and time to hospitalization in the treatment of patients with schizophrenia and comorbid AUD. We found that the clozapine treated patients were readmitted to hospital significantly later (mean survival = 526.5 days, n = 25 patients) than the risperidone treated patients (mean survival = 420.4 days, n = 36 patients). The survival curve for the clozapine-treated patients was significantly different from that of the risperidone treated patients (log-rank test, df = 1, p = .045). At the end of the two-year study period, 75% of the risperidone treated patients had been admitted to the hospital, compared to only 48% of the clozapine treated patients. These findings suggest that clozapine should be considered for the treatment of schizophrenia patients with comorbid AUD. However, due to the limitations of this study, further studies will be required to confirm these findings.     

酒精使用障碍共病抑郁障碍机制研究进展

本文对近年来国内外关于酒精使用障碍与抑郁障碍共病的相关机制研究的最新进展进行综述,从遗传基础、神经生化、神经免疫及神经内分泌等方面阐述其共病机制,指出当前研究的不足,并预测未来的研究方向,为酒精使用障碍共病抑郁障碍的临床治疗提供新的思路。     

Altered neural reward and loss processing and prediction error signalling in depression

Dysfunctional processing of reward and punishment may play an important role in depression. However, functional magnetic resonance imaging (fMRI) studies have shown heterogeneous results for reward processing in fronto-striatal regions. We examined neural responsivity associated with the processing of reward and loss during anticipation and receipt of incentives and related prediction error (PE) signalling in depressed individuals. Thirty medication-free depressed persons and 28 healthy controls performed an fMRI reward paradigm. Regions of interest analyses focused on neural responses during anticipation and receipt of gains and losses and related PE-signals. Additionally, we assessed the relationship between neural responsivity during gain/loss processing and hedonic capacity. When compared with healthy controls, depressed individuals showed reduced fronto-striatal activity during anticipation of gains and losses. The groups did not significantly differ in response to reward and loss outcomes. In depressed individuals, activity increases in the orbitofrontal cortex and nucleus accumbens during reward anticipation were associated with hedonic capacity. Depressed individuals showed an absence of reward-related PEs but encoded loss-related PEs in the ventral striatum. Depression seems to be linked to blunted responsivity in fronto-striatal regions associated with limited motivational responses for rewards and losses. Alterations in PE encoding might mirror blunted reward- and enhanced loss-related associative learning in depression.     

Concurrent tracking of alcohol use and bipolar disorder symptoms

OBJECTIVES: Alcohol use disorders (AUDs) are common co-occurring conditions in patients with bipolar disorder (BD), but it is unclear whether or not AUD and BD symptoms are temporally correlated. The primary aim of this analysis was to examine concurrent symptom tracking and how the relative onsets of AUD and BD influence the concurrent tracking of symptoms. METHODS: Participants met DSM-IV criteria for bipolar I disorder, manic or mixed, with no prior hospitalizations and minimal treatment. Patients were rated for alcohol use and bipolar symptom severity on a weekly basis for up to 7 years. For analysis purposes, patients were placed into groups with no AUD (BD Only; n = 21), onset of AUD either concurrent with or after the onset of bipolar symptoms (BD First; n = 32), and onset of AUD at least 1 year before the onset of bipolar symptoms (AUD First; n = 18). RESULTS: None of the patient groups demonstrate consistent positive or negative temporal correlations between alcohol use and affective symptoms. However, there were significant between-group differences on the relationship of symptom tracking and age of BD onset. For the AUD First group, the correlation between age of BD onset and symptom tracking was positive 0.41. However, for the BD First and BD Only groups the correlations were negative (-0.32 and -0.41, respectively). Moreover, for patients whose BD onset was < or =18 years old, the correlation between age of onset and tracking was -0.47. CONCLUSIONS: These findings suggest that although there is no direct temporal correlation of AUD and BD symptoms in subgroups of BD patients, age at illness onset contributes to the complex relationship between BD and AUD. For younger patients there may be a greater likelihood that alcohol use and bipolar symptoms increase or decrease in unison.     

The risk of offspring developing substance use disorders when exposed to one versus two parent(s) with alcohol use disorder: A nationwide,register-based cohort study

AimFew population-based, family studies have examined associations between exposure to one vs. two parent(s) with alcohol use disorder (AUD) and the risk of offspring developing substance use disorder (SUD). Moreover, these studies have focused solely on the development of AUD, and not SUD, in offspring. The purpose of this study was to investigate whether exposure to one vs. two parent(s) with AUD increases the risk of offspring developing SUD.MethodsA population-based, cohort study was conducted in which offspring born in Denmark between 1983 and 1989 were followed through national registries until 2011. Register-based data were obtained from the: Psychiatric Central Research Register, National Patient Registry, Civil Registration System, Fertility Database, and Cause of Death Register. Adjusted hazard ratios were calculated using multivariate Cox-regression models.FindingsA total of 398,881 offspring were included in this study. Of these, 3.9% had at least one parent with AUD. Parental AUD was significantly associated with the development of SUD in offspring. Having one parent with AUD was linked to a 1.44-fold increased risk (95% CL, 1.29–1.61), while having two parents with AUD was linked to a 2.29-fold increased risk (95% CI, 1.64–3.20). No significant differences were found in relation to either parental or offspring gender.ConclusionsExposure to parental AUD is linked to an increased risk of offspring developing SUD. This risk is additive for offspring exposed to double parental AUD. The findings have important implications for clinical assessment and intervention strategies, as well as the management of offspring exposed to parental AUD.     

创伤后应激障碍合并酒精使用障碍的访谈与治疗

本文目的是通过报道病例诊疗全过程,呈现创伤后应激障碍(PTSD)合并酒精使用障碍的临床诊疗思路及治疗方案。咨客,男性,55岁。12岁时目睹母亲自杀的全过程,随后出现恐惧、孤独、失眠、回避谈论创伤相关话题、反复出现与创伤相关的梦境、易激惹、疼痛及酗酒等一系列情绪、认知、躯体及行为改变,并持续至今。社会功能明显受损,近1年和妻子离婚后症状加重而前来咨询。经过本次咨询,被诊断为PTSD合并酒精使用障碍。建议采用生物-心理-社会的综合干预方法,鼓励咨客进行规律运动,使用选择性5-羟色胺和去甲肾上腺素再摄取抑制剂(SNRI)及第二代抗精神病药物改善情绪、缓解疼痛;心理治疗方面,推荐延迟暴露疗法和认知调整;社会资源方面,在症状缓解后,鼓励咨客积极寻找工作,创造挽回其前妻的可能性。     

Family history of alcohol use disorders among adults with panic disorder in the community

Objective

Clinical studies suggest a familial association between panic disorder and alcohol use disorders but this relationship has not been examined in a representative community sample. The objective of this study is to examine the familial association between panic disorder and alcohol use disorders among adults in the community.

Method

Data were drawn from the NESARC, a nationally representative sample of over 43,000 adults in the United States. Rates of alcohol use disorders were examined using the family history method in first-degree relatives (FDRs) of adults with panic disorder. Analyses were adjusted for demographics, alcohol use disorders in the proband, and anxiety disorders in the FDRs.

Results

First-degree relatives of adults with panic disorder have significantly higher odds of alcohol use disorders, compared with FDRs of adults without panic disorder. These associations persist after adjusting for demographic characteristics, alcohol use disorders in the proband, and anxiety disorders in the FDR’s.

Conclusions

Consistent with findings from clinical studies, this is the first population-based study to show a familial link between panic disorder and alcohol use disorders. This association appears independent of the influence of comorbidity of alcohol use disorders and anxiety disorders, suggesting a potential familial and/or genetic pathway. Future longitudinal studies will be needed to further understand the mechanism of this observed association.     

Cigarette smoking and its relationship to mood disorder symptoms and co-occurring alcohol and cannabis use disorders following first hospitalization for bipolar disorder

Heffner JL, DelBello MP, Anthenelli RM, Fleck DE, Adler CM, Strakowski SM. Cigarette smoking and its relationship to mood disorder symptoms and co‐occurring alcohol and cannabis use disorders following first hospitalization for bipolar disorder. Bipolar Disord 2012: 14: 99–108. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Cigarette smoking is highly prevalent among individuals with bipolar disorder (BD) and may adversely affect symptoms of the disorder, as well as the co‐occurrence of other substance use disorders. However, anecdotal reports suggesting that smoking cessation caused a worsening of mood in smokers with BD have raised concerns about quitting. In the present study, we prospectively evaluated the course of BD, alcohol use disorders, and cannabis use disorders in relation to smoking and examined the relationship between smoking abstinence and changes in mood. Methods: Participants (N = 161) were adolescents (n = 80) and adults (n = 81) with bipolar I disorder who were hospitalized for their initial mixed or manic episode. Participants were followed up to eight years post‐hospitalization (median follow‐up = 122 weeks) as part of a naturalistic, observational study of the longitudinal course of BD and substance use. Results: The course of BD symptoms in the 12 months following index hospitalization did not differ by smoking status in either the adolescent or the adult subsample. Among adolescents, smoking was associated with an increased risk of having a cannabis or alcohol use disorder, almost all of which were new‐onset disorders, in the year following first hospitalization. Neither adolescents nor adults who were abstinent from smoking for at least two months experienced significant increases in depressive or manic symptoms. Conclusions: Although cigarette smoking did not predict a worse course of BD, smoking was associated with an increased risk of developing alcohol and cannabis use disorders in adolescents with BD. Importantly, these data provide no evidence to suggest that abstinence from smoking is associated with worsening symptoms of depression or mania in the short term.     

酒精使用障碍的潜在关键基因生物信息学分析

背景 酒精使用障碍（AUD）是一类慢性复发性脑病,遗传因素在AUD的发病过程中起重要作用。明确AUD的关键分子标志物对于进一步阐明疾病的发病机制,探索新的治疗靶点和预防复发具有重要意义。目的 应用生物信息学方法,筛选AUD的核心基因和信号通路,为AUD的防治提供新的方向。方法 从基因表达综合数据库（GEO）下载基因表达数据集GSE161986。应用R软件的limma包筛选差异表达基因（DEGs）。使用DAVID数据库进行基因富集分析（GSEA）。使用STRING数据库和Cytoscape软件构建蛋白-蛋白互作网络（PPI）并寻找网络核心基因。使用GSE44456验证筛选潜在核心基因。结果 共筛选出114个DEGs。富集分析表明,差异基因主要参与信号转导、蛋白结合、细胞膜以及MAPK信号通路等功能的调控。PPI及验证分析显示,GAD1、TIMP1和CD44可能是AUD发病的潜在关键基因。结论 GAD1和TIMP1表达异常以及MAPK信号通路可能在AUD的发病过程中起关键作用,并可能作为AUD诊断和治疗的潜在分子靶点。     

Effects of rapid eye movement sleep deprivation on fear extinction recall and prediction error signaling

In a temporal difference learning approach of classical conditioning, a theoretical error signal shifts from outcome deliverance to the onset of the conditioned stimulus. Omission of an expected outcome results in a negative prediction error signal, which is the initial step towards successful extinction and may therefore be relevant for fear extinction recall. As studies in rodents have observed a bidirectional relationship between fear extinction and rapid eye movement (REM) sleep, we aimed to test the hypothesis that REM sleep deprivation impairs recall of fear extinction through prediction error signaling in humans. In a three-day design with polysomnographically controlled REM sleep deprivation, 18 young, healthy subjects performed a fear conditioning, extinction and recall of extinction task with visual stimuli, and mild electrical shocks during combined functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. Compared to the control group, the REM sleep deprivation group had increased SCR scores to a previously extinguished stimulus at early recall of extinction trials, which was associated with an altered fMRI time-course in the left middle temporal gyrus. Post-hoc contrasts corrected for measures of NREM sleep variability also revealed between-group differences primarily in the temporal lobe. Our results demonstrate altered prediction error signaling during recall of fear extinction after REM sleep deprivation, which may further our understanding of anxiety disorders in which disturbed sleep and impaired fear extinction learning coincide. Moreover, our findings are indicative of REM sleep related plasticity in regions that also show an increase in activity during REM sleep.     

Executive functioning before and after onset of alcohol use disorder in adolescence. A TRAILS study

IntroductionThe aim of the present study was to investigate whether executive functioning (EF) in early adolescence predicted alcohol use disorder (AUD) in late adolescence and whether adolescents with AUD differed in maturation of EF from controls without a diagnosis.MethodsWe used the data from the Tracking Adolescents’ Individual Lives Survey (TRAILS), a cohort of 2230 Dutch adolescents. Working memory, inhibition, and attention were measured at ages 11 and 19. At age 19, lifetime DSM-IV diagnoses were determined, resulting in a control group (n = 1111) and two AUD groups, i.e., alcohol abusers (n = 381) and alcohol dependents (n = 51). Regression analyses assessed whether EF at age 11 predicted the transition to AUD in late adolescence and whether AUD affected maturation of EF from age 11 to 19.ResultsEF in early adolescence did not predict AUD in late adolescence. A significant interaction effect emerged between gender and alcohol dependence for shift attention (β = 0.12, SE=0.36), with girls showing smaller maturational rates. This effect remained significant after controlling for alcohol intake (ages 16 and 19) and comorbid psychiatric disorders.DiscussionOur results do not replicate the finding that EF in early adolescence is a significant predictor of AUD in late adolescence. Furthermore, for the majority of tasks, adolescents with AUD do not differ in EF maturation over the course of adolescence. Alcohol dependent girls however, show less maturation of shift attention. This is independent of the quantity of alcohol intake, which could suggest that non-normative maturation of EF is associated with the behavioural components of AUD.     

Effect of baseline cannabis use and working‐memory network function on changes in cannabis use in heavy cannabis users: A prospective fMRI study

Theoretical models of addiction suggest that a substance use disorder represents an imbalance between hypersensitive motivational processes and deficient regulatory executive functions. Working‐memory (a central executive function) may be a powerful predictor of the course of drug use and drug‐related problems. Goal of the current functional magnetic resonance imaging study was to assess the predictive power of working‐memory network function for future cannabis use and cannabis‐related problem severity in heavy cannabis users. Tensor independent component analysis was used to investigate differences in working‐memory network function between 32 heavy cannabis users and 41 nonusing controls during an N‐back working‐memory task. In addition, associations were examined between working‐memory network function and cannabis use and problem severity at baseline and at 6‐month follow‐up. Behavioral performance and working‐memory network function did not significantly differ between heavy cannabis users and controls. However, among heavy cannabis users, individual differences in working‐memory network response had an independent effect on change in weekly cannabis use 6 months later (ΔR² = 0.11, P = 0.006, f² = 0.37) beyond baseline cannabis use (ΔR² = 0.41) and a behavioral measure of approach bias (ΔR² = 0.18): a stronger network response during the N‐back task was related to an increase in weekly cannabis use. These findings imply that heavy cannabis users requiring greater effort to accurately complete an N‐back working‐memory task have a higher probability of escalating cannabis use. Working‐memory network function may be a biomarker for the prediction of course and treatment outcome in cannabis users. Hum Brain Mapp 35:2470–2482, 2014. © 2013 Wiley Periodicals, Inc .     

Neurobiological signatures associated with alcohol and drug use in the human adolescent brain

Magnetic resonance (MR) techniques provide opportunities to non-invasively characterize neurobiological milestones of adolescent brain development. Juxtaposed to the critical finalization of brain development is initiation of alcohol and substance use, and increased frequency and quantity of use, patterns that can lead to abuse and addiction. This review provides a comprehensive overview of existing MR studies of adolescent alcohol and drug users. The most common alterations reported across substance used and MR modalities are in the frontal lobe (63% of published studies). This is not surprising, given that this is the last region to reach neurobiological adulthood. Comparatively, evidence is less consistent regarding alterations in regions that mature earlier (e.g., amygdala, hippocampus), however newer techniques now permit investigations beyond regional approaches that are uncovering network-level vulnerabilities. Regardless of whether neurobiological signatures exist prior to the initiation of use, this body of work provides important direction for ongoing prospective investigations of adolescent brain development, and the significant impact of alcohol and substance use on the brain during the second decade of life.     

Longitudinal relationships of sleep and inhibitory control deficits to early adolescent cigarette and alcohol use

Research in older adolescents suggests insufficient sleep may increase substance use initiation risk. This study tested whether sleep duration and dysregulation of sleep-wake patterns in late-elementary school youth were prospectively associated with cigarette and alcohol use initiation and how sleep-related changes in inhibitory control mediate these relationships. Average sleep duration at 4th grade predicted 6th grade cigarette but not alcohol use, however indirect effects were identified through 5th grade inhibitory control to both cigarette and alcohol use. Indirect effects were also identified through inhibitory control for relationships between 4th grade weekend bed-time delay and 6th grade cigarette or alcohol use, and for relationships between 4th grade weekend wake-time delay and 6th grade cigarette or alcohol use. Reductions in nightly sleep increased risk of cigarette use. Findings suggest a pathway linking both reduced sleep duration and greater weekend shifting of sleep patterns to future substance use through sleep-related inhibitory control deficits.     

Nucleus accumbens response to rewards and testosterone levels are related to alcohol use in adolescents and young adults

During adolescence there is a normative increase in risk-taking behavior, which is reflected in, for example, increases in alcohol consumption. Prior research has demonstrated a link between testosterone and alcohol consumption, and between testosterone and neural responses to rewards. Yet, no study to date tested how testosterone levels and neural responses to rewards relate to and predict individual differences in alcohol use. The current study aimed to investigate this by assessing alcohol use, testosterone levels and neural responses to rewards in adolescents (12–17 years old) and young adults (18–26 years old). Participants were measured twice with a two-year interval between testing sessions. Cross-sectional analysis showed that at the second time point higher neural activity to rewards, but not testosterone levels, explained significant variance above age in reported alcohol use. Predictive analyses showed that, higher testosterone level at the first time point, but not neural activity to rewards at the first time point, was predictive of more alcohol use at the second time point. These results suggest that neural responses to rewards are correlated with current alcohol consumption, and that testosterone level is predictive of future alcohol consumption. These results are interpreted in the context of trajectory models of adolescent development.