Insights into the molecular genetic basis of individual differences in metacognition.

There is a striking lack of studies on the molecular genetic basis of metacognition, i.e., the higher-order ability to monitor mental processes. Here, an initial step toward resolving this issue was undertaken by investigating functional polymorphisms from three genes of the dopaminergic or serotonergic systems (DRD4, COMT, and 5-HTTLPR) in relation to behaviorally assessed metacognition in six paradigms across three cognitive domains. We report evidence for a task-dependent higher average confidence level (metacognitive bias) in carriers of at least one S or LG-allele in the 5-HTTLPR genotype and integrate these findings within a differential susceptibility framework.

Effects of the glucocorticoid receptor gene (NR3C1) and subjective birth experience on the risk of postpartum depression and maternal bonding.

Postpartum depression (PPD) is a serious health care issue that affects a substantial share of women giving birth. PPD is considered a severe stress response that is likely associated with impaired HPA-axis activity. However, genetic findings regarding HPA-axis effects on PPD are scarce and inconsistent. Inconsistencies may be due to the neglect of environmental (stressful) events such as perinatal trauma or averse subjective birth experiences associated with PPD. Therefore, the present study aims to investigate whether the NR3C1 gene and subjective birth experience interact on PPD and postpartum bonding to the child. N = 277 mothers provided gene samples and self-report data on PPD and postpartum bonding. We genotyped 11 polymorphisms on the NR3C1 gene (including the prominent BCL1) and conducted haplotype analyses. A negative subjective birth experience was associated with both PPD and maternal postpartum bonding. Our results further show a significant main effect of NR3C1 haplotype (F1, 275 = 6.42, p = .012, η2 =.023) and a haplotype x birth experience interaction (F1, 274 = 4.57, p = .033, η2 =.016) on PPD. We did not find any NR3C1 haplotype effects on bonding. Our results support the assumption that the glucocorticoid receptor coding NR3C1 gene is involved in the development of PPD. These gene effects become particularly important in presence of a negative environmental event such as the subjective birth experience. This finding allows more targeted preventions in terms of being particularly sensitive to potentially harming environmental influences that may present even stronger risk factors for genetically vulnerable women.

The negative impact of xenophobia on compassion with suffering out-group members is attenuated by trait empathy.

Empathy enables human beings to understand and share the internal states of others. Studies show that empathy for pain is higher for in-group compared to out-group members. This might be driven by attitudes and biases towards out-groups. In a between subject design, N = 621 participants filled in questionnaires measuring xenophobia and trait empathy and were presented with photos of suffering individuals either from the in-group or an out-group, which had to be rated with respect to negative affect and the willingness to help the depicted persons. Results do not show more compassion with members of the in-group in general, but a negative effect of xenophobia on state empathy in the out-group condition. Additional moderation analyses show that this effect is less evident in presence of high trait empathy scores. Our results highlight the importance of empathy trainings to attenuate the effects of xenophobic attitudes on social cohabitation in our increasingly polarized and culturally diverse societies.

Additive serotonergic genetic sensitivity and cortisol reactivity to lab-based social evaluative stress: Influence of severity across two samples.

Prior work demonstrates that an additive serotonergic multilocus genetic profile score (MGPS) predicts amplified risk for depression following significant life stress, and that it interacts with elevations in the cortisol awakening response to predict depression. The serotonin system and HPA-axis have bidirectional influence, but whether this MGPS predicts acute cortisol reactivity, which might then serve as a mechanism for depression, is unknown. Our prior work suggests that depression risk factors predict blunted cortisol reactivity to explicit negative evaluative lab-based stress. Thus, we hypothesized that a 4-variant serotonergic MGPS (three SNPs from the original 5-variant version plus 5HTTLPR) would predict blunted cortisol reactivity to explicit negative evaluative stress versus a control. In Sample 1, growth curve modeling showed that the MGPS predicted heightened cortisol reactivity (p = 0.0001) in an explicitly negative evaluative Trier Social Stress Test variant (TSST) versus a control condition among non-depressed emerging adults (N = 152; 57% female). In Sample 2, 125 males completed the Socially Evaluative Cold Pressor Test (SECPT), an ambiguously negative evaluative manipulation; findings displayed a similar pattern but did not reach statistical significance (ps.075-.091). A participant-level meta-analysis of the two samples demonstrated a significant effect of negative evaluation severity, such that the MGPS effect size on reactivity increased linearly from control to SECPT to an explicitly negative evaluative TSST. Findings indicate that this MGPS contributes to sensitivity to social threat and that cortisol dysregulation in the context of social stress may be one mechanism by which this MGPS contributes to depression.

Effects of DRD2/ANKK1 and COMT Val158Met polymorphisms on stabilization against and adaptation to unexpected events.

Genetic variations affecting dopaminergic neuromodulation such as the DRD2/ANKK1 and the COMT Val158Met polymorphisms contribute to goal-directed behavior that requires a balance between stabilization and updating of current states and behaviors. Dopamine is also thought to be relevant for encoding of surprise signals to sensory input and adaptive learning. A link between goal-directed behavior and learning from surprise is therefore plausible. In the present fMRI study, we investigated whether DRD2 and COMT polymorphisms are related to behavioral responses and neural signals in the caudate nucleus and dlPFC during updating or stabilizing internal models of predictable digit sequences. To-be-detected switches between sequences and to-be-ignored digit omissions within a sequence varied by information-theoretic quantities of surprise and entropy. We found that A1 noncarriers and Val-carriers showed a lower response threshold along with increased caudate and dlPFC activation to surprising switches compared with A1-carriers and Met-homozygotes, whose dlPFC activity increased with decreasing switch surprise. In contrast, there were overall smaller differences in behavioral and neural modulation by drift surprise. Our results suggest that the impact of dopamine-relevant polymorphisms in the flexibility-stability trade-off may result in part from the role of dopamine in encoding the weight afforded to events requiring updating or stabilization.

The role of the SLC6A3 3' UTR VNTR in nicotine effects on cognitive, affective, and motor function.

RATIONALE: Nicotine has been widely studied for its pro-dopaminergic effects. However, at the behavioural level, past investigations have yielded heterogeneous results concerning effects on cognitive, affective, and motor outcomes, possibly linked to individual differences at the level of genetics. A candidate polymorphism is the 40-base-pair variable number of tandem repeats polymorphism (rs28363170) in the SLC6A3 gene coding for the dopamine transporter (DAT). The polymorphism has been associated with striatal DAT availability (9R-carriers > 10R-homozygotes), and 9R-carriers have been shown to react more strongly to dopamine agonistic pharmacological challenges than 10R-homozygotes. OBJECTIVES: In this preregistered study, we hypothesized that 9R-carriers would be more responsive to nicotine due to genotype-related differences in DAT availability and resulting dopamine activity. METHODS: N=194 non-smokers were grouped according to their genotype (9R-carriers, 10R-homozygotes) and received either 2-mg nicotine or placebo gum in a between-subject design. Spontaneous blink rate (SBR) was obtained as an indirect measure of striatal dopamine activity and smooth pursuit, stop signal, simple choice and affective processing tasks were carried out in randomized order. RESULTS: Reaction times were decreased under nicotine compared to placebo in the simple choice and stop signal tasks, but nicotine and genotype had no effects on any of the other task outcomes. Conditional process analyses testing the mediating effect of SBR on performance and how this is affected by genotype yielded no significant results. CONCLUSIONS: Overall, we could not confirm our main hypothesis. Individual differences in nicotine response could not be explained by rs28363170 genotype.

The Association Between Sexism, Self-Sexualization, and the Evaluation of Sexy Photos on Instagram.

Passive consumption of sexually objectifying content on social networking sites (SNS) has been shown to result in lowered body satisfaction and self-esteem, particularly in women. However, deliberate evaluations of sexually objectifying social media content are scarce. Furthermore, associations between self-objectification and active use of SNS in terms of posting behavior have not been shown so far. The present study asked N = 916 participants to rate 28 Instagram screenshots on three dimensions, namely, whether the given photos were perceived as sexually revealing, appropriate, and attractive. The ratings were related to sexist attitudes, enjoyment of sexualization, and posting behavior of the participants. Sexism was negatively associated with the perceived appropriateness of the presented Instagram photos in women. Furthermore, there were substantial correlations between appropriateness and attractiveness evaluations of the presented photos and the self-sexualizing posting behavior and enjoyment of sexualization of female users. Only inconsistent effects could be found in men. Greater appreciation of objectification seems to go along with self-objectifying behavior, which may be due to an altered perception of what can be considered as sexually revealing. Although effects seem to be smaller in men, future research should also focus on male enjoyment of sexualization, which unfortunately was not considered in the present study.

SLC6A4 polymorphisms modulate the efficacy of a tryptophan-enriched diet on age-related depression and social cognition.

BACKGROUND & AIMS: In a placebo controlled study we sought to determine if a four-weeks tryptophan-enriched diet is able to improve age-related depression or social cognitive impairment, depending on polymorphisms located in the promoter region of Solute Carrier Family 6 Member 4 (SLC6A4), also known as serotonin transporter (SERT1) gene. METHODS: 91 young volunteers (age: 21 ± 2 yrs) and 127 above 50 years old (58 ± 6 yrs) healthy volunteers completed the study. Participants from the placebo and tryptophan group followed the same protocol. Before starting the study blood samples, to measure serotonin-transporter-linked polymorphic region (5-HTTLPR) and rs25531 polymorphisms, were collected. In addition, before and after completing the study urine samples (to measure 5-hydroxyindolacetic acid (5-HIAA) were taken, while psychological questionnaires (to assess depression and social cognition levels), and a one week dietary record (to calculate the tryptophan (TRP) intake) were assessed. RESULTS: The triallelic approach of SLC6A4 showed that in S'S´ subjects there was a positive correlation between TRP intake and 5-HIAA levels. Age of participants, SLC6A4 genotype, and experimental condition were important factors contributing to the outcome of depression and social cognition. CONCLUSIONS: 5-HTTLPR and rs25531 polymorphisms play a key role in the response to the TRP- based nutritional intervention, improving only age-related depressive symptoms and empathy in S'S´ subjects who have a higher risk to show signs of depression during their lifetime.

Tryptophan-rich diet is negatively associated with depression and positively linked to social cognition.

The essential amino acid tryptophan (TRP) is discussed as a potential protective factor for physical and mental health. Besides positive effects via the microbiota of the gut on many physiological processes, TRP is the precursor of the neurotransmitter serotonin (5-HT), thereby playing a role for affective disorders. The present study investigated the effects of a TRP-rich diet on depressiveness and on one of its endophenotypes, impaired social cognition, in a population based sample. N = 482 subjects participated in an online study, assessing the ability to properly recognize emotional states from the eye region of faces (Reading the Mind in the Eye Test, RMET) and asking for subjective ratings of condemnability in a moral judgment task. Moreover, the habitual TRP intake was measured. It was hypothesized that a low-TRP diet is associated with higher depressiveness and worse performance in the social cognition tasks. The main hypotheses could be supported. However, contrary to the expectations, the effect of TRP on social cognition was not mediated by depressiveness. Results show that a tryptophan-rich diet is a potential protective factor against depression and is positively related to functioning in social cognition.

Genetic and epigenetic serotonergic markers predict the ability to recognize mental states.

The serotonergic (5-HT) system is related to affective and cognitive processes and explains behavioral variability in the normal and psychopathological range. For this reason, the hypothesis was put forward that genetic and epigenetic markers related to 5-HT metabolism predict individual differences in social cognitive functioning. Social cognitions are complex mental processes necessary for perceiving, interpreting and reacting to the behaviors of others. In order to test this hypothesis one of the most prominent theory of mind tasks, the reading the mind in the eye test (RMET), was administered to N = 435 participants and measures of performance were related to the functional MAO-A VNTR polymorphism (relevant for 5-HT catabolism) and to epigenetic markers in the promoter of the TPH-2 gene (relevant for 5-HT synthesis). It was postulated that genetic and epigenetic markers of high 5-HT activity are positively related to RMET performance. Results show that the MAO-A high activity allele, together with the degree of methylation at a promoter CpG site on the TPH-2 gene explain significant proportions of variance in the RMET performance even after controlling for age and sex effects. Present findings yield evidence for the importance of 5-HT for social cognition. Based on additional findings, the role of a TRP-rich diet for theory of mind functions is discussed.

Stress & executive functioning: A review considering moderating factors.

A multitude of studies investigating the effects of stress on cognition has produced an inconsistent picture on whether - and under which conditions - stress has advantageous or disadvantageous effects on executive functions (EF). This review provides a short introduction to the concept of stress and its neurobiology, before discussing the need to consider moderating factors in the association between stress and EF. Three core domains are described and discussed in relation to the interplay between stress and cognition: the influence of different paradigms on physiological stress reactivity, individual differences in demographic and biological factors, and task-related features of cognitive tasks. Although some moderating variables such as the endocrine stress response have frequently been considered in single studies, no attempt of a holistic overview has been made so far. Therefore, we propose a more nuanced and systematic framework to study the effects of stress on executive functioning, comprising a holistic overview from the induction of stress, via biological mechanisms and interactions with individual differences, to the influence of stress on cognitive performance.

Moderator Effects of Life Stress on the Association between MAOA-uVNTR, Depression, and Burnout.

BACKGROUND: The serotonergic and noradrenergic systems have a strong impact on several affective disorders and are key targets for psychopharmacological therapy. With respect to pathogenesis, there is a growing body of evidence showing an influence of a promoter repeat polymorphism (MAOA-uVNTR) altering the expression rate of monoamine oxidase A. However, only a few studies investigate its influence on depression with only 2 of them considering the moderating effects of life stress. For burnout, there are no studies so far investigating the genetic basis. OBJECTIVES: The aim of the present study was to replicate an interaction effect of MAOA-uVNTR and life stress on depression, and extend these possible findings to the burnout syndrome. Especially, the latter one might help in understanding the underlying mechanisms of burnout and its association to depression. METHOD: A total of n = 1,541 participants (n = 1,099 healthy controls, n = 442 inpatients with affective disorders) provided genetic samples and filled in self-report questionnaires measuring depression, burnout, and the extent of experienced stressful life events (SLEs). RESULTS: A life stress x MAOA-uVNTR interaction on depression and burnout was observed in women suggesting that carriers of the high expressing allele (MAO-H) with many SLEs had the highest scores in both burnout and depression. In men, there was only a weak effect of MAOA-uVNTR on depression. CONCLUSIONS: The results suggest a more pronounced reactivity to adverse environmental factors in carriers of the MAO-H allele. Especially the effect of life stress and MAOA-uVNTR on burnout should be independently replicated in the future as this is the first study showing this association.

The role of genetic variation in the glucocorticoid receptor (NR3C1) and mineralocorticoid receptor (NR3C2) in the association between cortisol response and cognition under acute stress.

Although HPA - axis reactivity has repeatedly been related to cognitive functioning, ambiguity remains regarding the direction of the effect, i.e. whether it benefits or impairs functioning. Genetic factors that contribute to HPA - axis reactivity on the one hand and to cognitive functioning on the other could therefore help clarify the association between stress and cognition. We genotyped 10 single nucleotide polymorphisms (SNPs) on the NR3C1 gene (rs10482682, rs33389, rs10482633, rs10515522, rs2963156, rs4128428, rs9324918, rs41423247, rs6189, rs10052957) coding for the glucocorticoid receptor (GR) and 4 SNPs on the NR3C2 gene (rs6810951, rs4635799, rs11099695, rs2070950) coding for the mineralocorticoid receptor (MR) and required N=126 healthy males to perform tasks assessing attention and reasoning before and after experiencing an acute laboratory stressor (the Socially Evaluated Cold Pressor Test, SECPT). Haplotype analyses revealed significant effects of NR3C1 (p=0.011) and NR3C2 (p=0.034) on cortisol stress response. NR3C2 also influenced attentional performance via an interaction with stress-induced cortisol response (p<0.001). Neither NR3C1 haplotype nor NR3C2 haplotype was associated with reasoning abilities. Results suggest that the association between stress induced cortisol reactivity and cognition strongly depends on genetic variation. The idea of an optimal arousal level depending on stress reactivity and genetic disposition is discussed.

The serotonin transporter polymorphism (5-HTTLPR) and coping strategies influence successful emotion regulation in an acute stress situation: Physiological evidence.

INTRODUCTION: Emotion regulation is an important everyday-life skill to reduce harm and stress. Consequently, research shows associations between psychopathologies and emotional dysregulation. The serotonin transporter polymorphism (5-HTTLPR) has repeatedly been associated to phenotypes and syndromes related to emotional dysregulation. However, there is no study showing any direct effects of 5-HTTLPR genotype and emotion regulation. Hence, the aim of the present study was to draw a link between 5-HTTLPR to emotion regulation. METHOD: N=91 healthy participants filled in a coping questionnaire, provided gene samples and participated in an emotion regulation experiment. In a within-subject design they viewed emotional pictures and were either instructed to suppress their emotions or not. During the emotion regulation task, skin conductance responses (SCR) were recorded. RESULTS: Emotion regulation abilities measured by SCR were influenced by 5-HTTLPR and coping strategies, together explaining 30% of variance. S-allele carriers showed increased SCRs when watching aversive stimuli in the uninstructed condition. However, when receiving an emotion regulation instruction, they were able to downregulate their arousal resulting in comparable SCRs as observed in LL-carriers. DISCUSSION: This is the first study showing an impact of 5-HTTLPR on physiological emotion regulation. Results show that S-allele carriers have the same emotional arousal as L-allele carriers, when they get a supportive instruction to suppress unwanted feelings. These findings have implications for psychotherapeutic treatments.

The impact of acute stress on cognitive functioning: a matter of cognitive demands?

INTRODUCTION: There is a controversy in the literature whether stress and related cortisol responses are beneficial or impairing for cognitive functioning. Conflicting results might be due to individual differences in stress reactivity and cognitive load of the applied tasks. METHODS: N = 48 participants underwent the Socially Evaluated Cold Pressor Test and were confronted with the Frankfurter Aufmerksamkeits-Inventar-2 (FAIR-2) which is a low-load attention task and two subscales of the Intelligenz-Struktur-Test 2000 R (I-S-T 2000R) as a high-load reasoning task before and after the stressor. Participants were post hoc divided into high (stress induced cortisol increase of ≥1.5 nmol/l) vs. low-cortisol responders. RESULTS: Cortisol responders showed an increased attentional performance in the post-stress condition (η2 > .14). However, there were neither stress or responder main effects nor an interaction effect on reasoning abilities. CONCLUSIONS: Results of the present study show that stress related changes in cognitive performance are due to individual differences in cortisol response and the cognitive load of the performed task. Future studies will show if these results are also valid for alternative cognitive tasks and if they can be replicated in female participants.

Differentiating Burnout from Depression: Personality Matters!

Stress-related affective disorders have been identified as a core health problem of the twenty-first century. In the endeavor to identify vulnerability factors, personality has been discussed as a major factor explaining and predicting disorders like depression or burnout. An unsolved question is whether there are specific personality factors allowing differentiation of burnout from depression. The present study tested the relation between one of the most prominent, biological personality theories, Cloninger's Temperament and Character Inventory, and common measures of burnout (Maslach Burnout Inventory General) and depression (Beck Depression Inventory 2) in a sample of German employees (N = 944) and a sample of inpatients (N = 425). Although the same personality traits (harm avoidance and self-directedness) were predominantly associated with burnout and depression, there was a much stronger association to depression than to burnout in both samples. Besides, we observed specific associations between personality traits and subcomponents of burnout. Our results underline differences in the association of burnout vs. depression to personality, which may mirror differences in scope. While symptoms of depression affect all aspects of life, burnout is supposed to be specifically related to the workplace and its requirements. The much stronger association of personality to depression can be important to select appropriate therapy methods and to develop a more specified treatment for burnout in comparison to depression.

The serotonin transporter polymorphism (5-HTTLPR) and personality: response style as a new endophenotype for anxiety.

Although the serotonin transporter length polymorphic region (5-HTTLPR) polymorphism is an extensively-investigated genetic marker of anxiety related personality traits (neuroticism and harm avoidance) and affective disorders, effect sizes in meta-analyses are small, if present at all, and all available primary studies to date lack mandatory statistical power. Moreover, questionnaire data is prone to confounding by variables such as social desirability. Therefore, extreme response style (ERS) is suggested as a new approach to elucidate the relationship between 5-HTTLPR and negative emotionality, as it is more implicit and of high reliability. N = 1075 healthy subjects were genotyped for 5-HTTLPR and a flanking polymorphism (rs25531) and filled out the NEO Five Factor Inventory and the Temperament Character Inventory. As dependent variable the number of extreme responses across all items was calculated. Using the common genotype or the triallelic approach (including rs25531) the meta-analytic findings could not be replicated. However, there was a significant association between 5-HTTLPR and extreme response style. Carriers of the L-allele or the L'-allele, respectively, had a significantly higher number of extreme responses than homozygous SS carriers across all items of the NEO Five Factor Inventory. This finding could be replicated in an alternative personality questionnaire (Affective Neuroscience Personality Scales, ANPS). There is a long tradition in psychological assessment indicating that ERS is an implicit measure of personality. Given the positive findings of the present study, ERS qualifies as a promising endophenotype in future genetic association studies on personality and affective disorders.

An interaction of a NR3C1 polymorphism and antenatal solar activity impacts both hippocampus volume and neuroticism in adulthood.

The investigation of the interaction of genes and environment in the context of mental health and personality yields important new insights for a better understanding of human nature. Both antenatal and postnatal environmental factors have been considered as potential modulators of genetic activity. Antenatally, especially smoking or alcohol drinking habits of the mother dramatically influence the health of the child during pregnancy and even later on in life. In the present study we would like to introduce a more "distant" factor that is not under the control of the becoming mother but that nevertheless plays a potential role for the health of the unborn child later on in adulthood. Here, we retrospectively investigate the influence of solar activity (while the child is still in the uterus of the becoming mother) on brain structure (with a focus on hippocampus and amygdala volume) and personality in adulthood. We observe an interaction of a genetic variant (rs41423247) of the glucocorticoid receptor gene (NR3C1) and solar activity in the first trimester after conception on both hippocampal volume and the personality trait neuroticism in adulthood in N = 254 participants. The NR3C1 gene is the focus of interest, because of its influence on the hypothalamic-pituitary-adrenal (HPA) axis and negative emotionality. Carriers of the CC variant of rs41423247 grown in the womb under the influence of high sun radiation (high solar activity) show both the highest hippocampal volume in the left hemisphere and lowest neuroticism scores. The present findings should encourage researchers in psychology and psychiatry to include also environmental influences such as solar activity besides genetics to better understand the etiogenesis of psychiatric disorders.

On the molecular genetics of flexibility: the case of task-switching, inhibitory control and genetic variants.

The adjustment of behavior to changing goals and environmental constraints requires the flexible switching between different task sets. Cognitive flexibility is an endophenotype of executive functioning and is highly heritable, as indicated by twin studies. Individual differences in global flexibility as assessed by reaction-time measurement in a task-switching paradigm were recently related to a single nucleotide polymorphism in the vicinity of the dopamine d2 receptor gene DRD2. In the present study, we assessed whether the DRD2 gene is related to backward inhibition, a control mechanism that contributes to cognitive flexibility by reducing proactive interference by no longer relevant task sets. We found that carriers of the DRD2 A1+ variant who have a lower striatal dopamine d2 receptor density than A1- carriers show a larger backward inhibition effect. This is in line with previous results demonstrating increased behavioral flexibility in carriers of this genetic variant. The discussion relates the present finding to those of previous studies assessing the neurogenetic foundations of inhibitory control.