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Interindividual variability in the regulation of the human stress system accounts for a part of the individual's liability to stress-related diseases. These differences are influenced by environmental and genetic factors. Early childhood adversity is a well-studied environmental factor affecting an individual's stress response which has been shown to be modulated by gene environment interaction (GxE). Neuropeptide Y (NPY) plays a role in stress regulation and genetic variation in NPY may influence stress responses. In this study, we analyzed the association of a common variant in the NPY gene promoter, rs16147, with cortisol and ACTH responses to acute psychosocial stress in young adults from the Mannheim Study of Children at Risk (MARS), an ongoing epidemiological cohort study following the outcome of early adversity from birth into adulthood. We found evidence of a GxE interaction between rs16147 and early adversity significantly affecting HPA axis responses to acute psychosocial stress. These findings suggest that the neurobiological mechanisms linking early adverse experience and later neuroendocrine stress regulation are modulated by a gene variant whose functional relevance is documented by increasing convergent evidence from in vitro, animal and human studies.
Alcohol-related cues acquire incentive salience through Pavlovian conditioning and then can markedly affect instrumental behavior of alcohol-dependent patients to promote relapse. However, it is unclear whether similar effects occur with alcohol-unrelated cues. We tested 116 early-abstinent alcohol-dependent patients and 91 healthy controls who completed a delay discounting task to assess choice impulsivity, and a Pavlovian-to-instrumental transfer (PIT) paradigm employing both alcohol-unrelated and alcohol-related stimuli. To modify instrumental choice behavior, we tiled the background of the computer screen either with conditioned stimuli (CS) previously generated by pairing abstract pictures with pictures indicating monetary gains or losses, or with pictures displaying alcohol or water beverages. CS paired to money gains and losses affected instrumental choices differently. This PIT effect was significantly more pronounced in patients compared to controls, and the group difference was mainly driven by highly impulsive patients. The PIT effect was particularly strong in trials in which the instrumental stimulus required inhibition of instrumental response behavior and the background CS was associated to monetary gains. Under that condition, patients performed inappropriate approach behavior, contrary to their previously formed behavioral intention. Surprisingly, the effect of alcohol and water pictures as background stimuli resembled that of aversive and appetitive CS, respectively. These findings suggest that positively valenced background CS can provoke dysfunctional instrumental approach behavior in impulsive alcohol-dependent patients. Consequently, in real life they might be easily seduced by environmental cues to engage in actions thwarting their long-term goals. Such behaviors may include, but are not limited to, approaching alcohol.
BACKGROUND: Pavlovian-to-instrumental transfer (PIT) describes the influence of conditioned stimuli on instrumental behaviors and is discussed as a key process underlying substance abuse. Here, we tested whether neural responses during alcohol-related PIT predict future relapse in alcohol-dependent patients and future drinking behavior in adolescents. METHODS: Recently detoxified alcohol-dependent patients (n = 52) and young adults without dependence (n = 136) underwent functional magnetic resonance imaging during an alcohol-related PIT paradigm, and their drinking behavior was assessed in a 12-month follow-up. To predict future drinking behavior from PIT activation patterns, we used a multivoxel classification scheme based on linear support vector machines. RESULTS: When training and testing the classification scheme in patients, PIT activation patterns predicted future relapse with 71.2% accuracy. Feature selection revealed that classification was exclusively based on activation patterns in medial prefrontal cortex. To probe the generalizability of this functional magnetic resonance imaging-based prediction of future drinking behavior, we applied the support vector machine classifier that had been trained on patients to PIT functional magnetic resonance imaging data from adolescents. An analysis of cross-classification predictions revealed that those young social drinkers who were classified as abstainers showed a greater reduction in alcohol consumption at 12-month follow-up than those classified as relapsers (Delta = -24.4 +/- 6.0 g vs. -5.7 +/- 3.6 g; p = .019). CONCLUSIONS: These results suggest that neural responses during PIT could constitute a generalized prognostic marker for future drinking behavior in established alcohol use disorder and in at-risk states.
Behavioral choice can be characterized along two axes. One axis distinguishes reflexive, model-free systems that slowly accumulate values through experience and a model-based system that uses knowledge to reason prospectively. The second axis distinguishes Pavlovian valuation of stimuli from instrumental valuation of actions or stimulus–action pairs. This results in four values and many possible interactions between them, with important consequences for accounts of individual variation. We here explored whether individual variation along one axis was related to individual variation along the other. Specifically, we asked whether individuals' balance between model-based and model-free learning was related to their tendency to show Pavlovian interferences with instrumental decisions. In two independent samples with a total of 243 participants, Pavlovian–instrumental transfer effects were negatively correlated with the strength of model-based reasoning in a two-step task. This suggests a potential common underlying substrate predisposing individuals to both have strong Pavlovian interference and be less model-based and provides a framework within which to interpret the observation of both effects in addiction.
BACKGROUND: Addiction is supposedly characterized by a shift from goal-directed to habitual decision making, thus facilitating automatic drug intake. The two-step task allows distinguishing between these mechanisms by computationally modeling goal-directed and habitual behavior as model-based and model-free control. In addicted patients, decision making may also strongly depend upon drug-associated expectations. Therefore, we investigated model-based versus model-free decision making and its neural correlates as well as alcohol expectancies in alcohol-dependent patients and healthy controls and assessed treatment outcome in patients. METHODS: Ninety detoxified, medication-free, alcohol-dependent patients and 96 age-and gender-matched control subjects underwent functional magnetic resonance imaging during the two-step task. Alcohol expectancies were measured with the Alcohol Expectancy Questionnaire. Over a follow-up period of 48 weeks, 37 patients remained abstinent and 53 patients relapsed as indicated by the Alcohol Timeline Followback method. RESULTS: Patients who relapsed displayed reduced medial prefrontal cortex activation during model-based decision making. Furthermore, high alcohol expectancies were associated with low model-based control in relapsers, while the opposite was observed in abstainers and healthy control subjects. However, reduced model-based control per se was not associated with subsequent relapse. CONCLUSIONS: These findings suggest that poor treatment outcome in alcohol dependence does not simply result from a shift from model-based to model-free control but is instead dependent on the interaction between high drug expectancies and low model-based decision making. Reduced model-based medial prefrontal cortex signatures in those who relapse point to a neural correlate of relapse risk. These observations suggest that therapeutic interventions should target subjective alcohol expectancies.
Aims: To investigate whether concurrent alcohol and tobacco use during early adolescence characterizes a subgroup that differs from users of one substance only regarding several risk factors for later substance use problems. Methods: Participants were from a prospective longitudinal cohort study of 384 children at risk for later psychopathology, with the majority being born with obstetric complications and psychosocial adversities. Assessments of adolescent drug consumption and related intrapersonal characteristics were obtained at age 15. Results: Compared to consumers of alcohol only, 15-year-olds drinking and smoking during the same time period (past 4 weeks) had significantly higher levels of consumption and more excessive use of alcohol, started drinking at an earlier age, had higher scores on the Fagerstrom Test for Nicotine Dependence, and more cannabis use. This group could be distinguished from users of alcohol only by higher novelty seeking and more positive alcohol effect expectancies. Compared to consumers of tobacco only, concurrent users reported higher nicotine dependence and more cannabis use. No significant differences were observed regarding frequency and age at initiation of tobacco use, tobacco-related sensitivity, self- efficacy and instrumentality as well as novelty seeking. Conclusions: Concurrent alcohol and tobacco use during early adolescence is associated with characteristics that are well known as risk factors for later alcohol use problems and dependence and that should be targeted by prevention programs.
Maternal stimulation in infancy predicts hypothalamic-pituitary-adrenal axis reactivity in young men
(2013)
Evidence from animal research has demonstrated the effect of early maternal care on the offspring's endocrine and behavioral stress response in adulthood. The present prospective study investigates, in humans, the long-term impact of maternal responsiveness and stimulation during early mother-child interaction on adrenocorticotropic hormone (ACTH) and cortisol response to a psychosocial laboratory stressor in adulthood. The data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3 months, mothers and infants were videotaped during a 10-min standardized nursing and playing situation and evaluated by trained raters for maternal stimulation and infant and maternal responsiveness. At age 19 years, 270 participants (146 females, 124 males) completed the Trier Social Stress Test. The results indicated that less maternal stimulation during early interaction at age 3 months predicted diminished plasma ACTH and cortisol increase in response to acute psychosocial stress in male, but not female offspring. In contrast, maternal responsiveness was found to be unrelated to hypothalamic-pituitary-adrenal (HPA) reactivity. In accordance with the findings from animal research, the present study provides prospective evidence in humans of a long-term association between early maternal interaction behavior and the offspring's hormonal stress response in young adulthood, suggesting that poor maternal stimulation in early infancy may result in reduced HPA axis reactivity to an acute psychosocial stressor in males.
Evidence from animal research has revealed that less maternal care results in disturbed emotionality in the offspring. In the present study, the long-term impact of maternal responsiveness and stimulation during early mother child interaction on depressive psychopathology was examined until adulthood. Data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3 months, mothers and infants were videotaped during a nursing and playing situation. Maternal responsiveness and stimulation as well as infant responsiveness were evaluated by trained raters. At age 19 years, 314 participants (145 males, 169 females) were characterized on measures of depression through interview and questionnaire. In addition, measures of depression and anxiety were available from assessments in childhood. Results indicated that less maternal stimulation during early interaction was associated with a higher risk of depression in the offspring until the age of 19 years. In addition, children of less stimulating mothers showed more depressive symptoms at age 19 years and displayed more anxiety and depressive symptoms between the ages of 4.5 and 15 years. In contrast, maternal responsiveness was unrelated to children's outcome. In accordance with findings from animal research, the present study provides first longitudinal evidence in humans of a continuous and long-term influence of early maternal interaction behavior on the offspring's psychological adjustment until adulthood. The results suggest that the amount of maternally initiated contact behavior in a very early developmental stage may be crucial for children's mental health, regardless of child and maternal responsiveness.
Recent evidence suggests that heterogeneity in the age at onset could explain the inconsistent findings of association studies relating the dopamine transporter (DAT1) gene with alcohol and nicotine consumption. The aim of this study was to examine interactions between two DAT1 polymorphisms and different initiation ages with regard to alcohol and tobacco consumption levels and dependence. Two hundred and ninety-one young adults (135 males, 156 females) participating in the Mannheim Study of Children at Risk were genotyped for the 40-bp variable number of tandem repeats (VNTR) and rs27072 polymorphisms of DAT1. Age at initiation was assessed at age 15 and 19 years. Information about current alcohol and tobacco consumption was obtained at age 19 years using self-report measures and structured interviews. Results suggest that age at onset of intensive consumption moderated the association of the DAT1 gene with early adult substance use and dependence, revealing a DAT1 effect only among individuals homozygous for the 10r allele of the 40-bp VNTR who had started daily smoking or being intoxicated early in life. Equally, carriers of the T allele of the rs27072 polymorphism reporting an early age at first intoxication showed higher current alcohol consumption at age 19 years. In contrast, no interaction between rs27072 and the age at first cigarette with regard to later smoking was observed. These findings provide evidence that the DAT1 gene interacts with an early heavy or regular drug exposure of the maturing adolescent brain to predict substance (ab)use in young adulthood. Further studies are required to confirm these findings.
Theories of decision-making and its neural substrates have long assumed the existence of two distinct and competing valuation systems, variously described as goal-directed vs. habitual, or, more recently and based on statistical arguments, as model-free vs. model-based reinforcement-learning. Though both have been shown to control choices, the cognitive abilities associated with these systems are under ongoing investigation. Here we examine the link to cognitive abilities, and find that individual differences in processing speed covary with a shift from model-free to model-based choice control in the presence of above-average working memory function. This suggests shared cognitive and neural processes; provides a bridge between literatures on intelligence and valuation; and may guide the development of process models of different valuation components. Furthermore, it provides a rationale for individual differences in the tendency to deploy valuation systems, which may be important for understanding the manifold neuropsychiatric diseases associated with malfunctions of valuation.
The influence of Pavlovian conditioned stimuli on ongoing behavior may contribute to explaining how alcohol cues stimulate drug seeking and intake. Using a Pavlovian-instrumental transfer task, we investigated the effects of alcohol-related cues on approach behavior (i.e., instrumental response behavior) and its neural correlates, and related both to the relapse after detoxification in alcohol-dependent patients. Thirty-one recently detoxified alcohol-dependent patients and 24 healthy controls underwent instrumental training, where approach or non-approach towards initially neutral stimuli was reinforced by monetary incentives. Approach behavior was tested during extinction with either alcohol-related or neutral stimuli (as Pavlovian cues) presented in the background during functional magnetic resonance imaging (fMRI). Patients were subsequently followed up for 6 months. We observed that alcohol-related background stimuli inhibited the approach behavior in detoxified alcohol-dependent patients (t = -3.86, p < .001), but not in healthy controls (t = -0.92, p = .36). This behavioral inhibition was associated with neural activation in the nucleus accumbens (NAcc) (t((30)) = 2.06, p < .05). Interestingly, both the effects were only present in subsequent abstainers, but not relapsers and in those with mild but not severe dependence. Our data show that alcohol-related cues can acquire inhibitory behavioral features typical of aversive stimuli despite being accompanied by a stronger NAcc activation, suggesting salience attribution. The fact that these findings are restricted to abstinence and milder illness suggests that they may be potential resilience factors.
Background: Self-harm is highly prevalent in adolescence, often serving an emotion regulation function. Social stressors such as bullying are associated with self-harm. The neurobiological background of the relationship between social stressors and self-harm needs to be further understood to inform prevention and therapy. Methods: Participants were members of an epidemiological cohort study. 130 female participants underwent the Trier Social Stress Test (TSST) at age 19. Of them, 21 reported a history of self-harm as assessed by the Youth Self Report. Psychiatric diagnoses were recorded. Results: Participants with a history of self-harm showed significantly lower blood cortisol levels throughout the TSST. Early psychosocial adversity did not significantly differ between groups with and without self-harm, with self-harming participants reporting more childhood adversities. Conclusion: These results add to the limited field of studies showing an altered HPA axis activity in females with self-harm. Future studies need to address the causal mechanisms behind this association.
Background: The appetite-stimulating hormone ghrelin is a fundamental regulator of human energy metabolism. A series of studies support the notion that long-term appetite and weight regulation may be already programmed in early life and it could be demonstrated that the intrauterine environment affects the ghrelin system of the offspring. Animal studies have also shown that intrauterine programming of orexigenic systems persists even until adolescence/adulthood. Methods: We hypothesized that plasma ghrelin concentrations in adulthood may be associated with the intrauterine exposure to cigarette smoke. We examined this hypothesis in a sample of 19-year-olds followed up since birth in the framework of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study of the long-term outcome of early risk factors. Results: As a main finding, we found that ghrelin plasma concentrations in young adults who had been exposed to cigarette smoke in utero were significantly higher than in those without prenatal smoke exposure. Moreover, individuals with intrauterine nicotine exposure showed a significantly higher prevalence of own smoking habits and lower educational status compared to those in the group without exposure. Conclusion: Smoking during pregnancy may be considered as an adverse intrauterine influence that may alter the endocrine-metabolic status of the offspring even until early adulthood.
Drunk decisions
(2018)
Background: Studies in humans and animals suggest a shift from goal-directed to habitual decision-making in addiction. We therefore tested whether acute alcohol administration reduces goal-directed and promotes habitual decision-making, and whether these effects are moderated by self-reported drinking problems. Methods: Fifty-three socially drinking males completed the two-step task in a randomised crossover design while receiving an intravenous infusion of ethanol (blood alcohol level=80 mg%), or placebo. To minimise potential bias by long-standing heavy drinking and subsequent neuropsychological impairment, we tested 18- to 19-year-old adolescents. Results: Alcohol administration consistently reduced habitual, model-free decisions, while its effects on goal-directed, model-based behaviour varied as a function of drinking problems measured with the Alcohol Use Disorders Identification Test. While adolescents with low risk for drinking problems (scoring <8) exhibited an alcohol-induced numerical reduction in goal-directed choices, intermediate-risk drinkers showed a shift away from habitual towards goal-directed decision-making, such that alcohol possibly even improved their performance. Conclusions: We assume that alcohol disrupted basic cognitive functions underlying habitual and goal-directed decisions in low-risk drinkers, thereby enhancing hasty choices. Further, we speculate that intermediate-risk drinkers benefited from alcohol as a negative reinforcer that reduced unpleasant emotional states, possibly displaying a novel risk factor for drinking in adolescence.
Background: Evidence from animal studies supports a role for serotonin transporter gene promoter polymorphism (5-HTTLPR) gene-environment interaction (G X E) in the development of excessive alcohol intake. Few studies in humans have been conducted on this topic, yielding inconsistent results. The present study aims to further explore G x E between 5-HTTLPR and exposure to psychosocial adversity on alcohol consumption in a high-risk community sample of young adults. Methods: Data were collected as part of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study following the outcome of early risk factors from birth into young adulthood. At age 19 years, 309 participants (142 male participants, 167 female participants) were genotyped for the biallelic and triallelic 5-HTTLPR and were administered a 45-day alcohol timeline follow-back interview, providing measures of the total number of drinks and the number of binge drinking days. Psychosocial adversity was assessed at birth (family adversity) and at age 19 (negative life events). Results: In contrast to various previous reports, a significant G x E emerged, indicating that, when exposed to high psychosocial adversity, individuals with the LL genotype of 5-HTTLPR exhibited more hazardous drinking than those carrying the S allele or those without exposure to adversity. This effect, which was confined to male participants, held both for different classifications of 5-HTTLPR and different types of adversity. Conclusions: One explanation for the discrepant results might be heterogeneity in alcohol phenotypes. While the L allele relates more strongly to early-onset alcoholism, the S allele may be linked more closely to alcohol use associated with anxiety and depression.
Previous research examining gene-environment interaction (G x E) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate G x F between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort Study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This G x E replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for G x E was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.
Background: Recently, first evidence has been reported for a geneparenting interaction (G x E) with regard to adolescent alcohol use. The present investigation set out to extend this research using the catechol-O-methyltransferase (COMT) Val158Met polymorphism as a genetic susceptibility factor. Moreover, the current study examined whether a potential G x E would be consistent with one of two models of geneenvironment interplay (genetic vulnerability vs. differential susceptibility). Methods: Data were collected as part of an ongoing epidemiological cohort study following the outcome of early risk factors from birth into adulthood. Two hundred and eighty-five participants (130 males, 155 females) were genotyped for the COMT Val(158) Met polymorphism and were administered an alcohol interview, providing measures of current frequency and amount of drinking at ages 15 and 19 years. Information on three dimensions of perceived parenting behavior was obtained from the 15-year-olds. Results: Adolescents homozygous for the Met allele showed higher drinking activity at age 19 years when their parents had engaged in less supervision or were less involved, while their drinking activity was reduced under conditions of favorable parenting. No such relationship was found in individuals carrying the Val allele. Conclusions: The present findings correspond with the pattern of results predicted by the differential susceptibility hypothesis, suggesting that environmental variation would have a greater impact in individuals carrying a genetic susceptibility such that, in this group, exposure to negative environmental conditions would result in more adverse outcomes and the experience of favorable conditions would lead to more positive outcomes.