The orienting of spatial attention to backward masked fearful faces is associated with variation in the serotonin transporter gene

Threat signals facilitate spatial attention, even when awareness of these signals has been restricted through the use of backward masking. However, unrestricted/unmasked threat cues tend to delay the disengagement of attention, whereas restricted/masked threat facilitates orienting, suggesting different underlying mechanisms. Within the general population, the serotonin transporter gene polymorphism (5HTTLPR) is associated with one's allocation of attention to unmasked threat signals. However, it is unclear to what extent the 5HTTLPR gene may be involved in nonconscious biases to masked threat, and whether or not such biases are driven by facilitated orienting or delayed disengagement. Participants were genotyped and performed a dot-probe task with backward masked fearful and neutral faces. Results indicate that short-allele carriers of the 5HTTLPR gene nonconsciously orient spatial attention to masked fearful faces. On the other hand, homozygous long-allele individuals tended to direct attention away from masked fearful faces. All participants' performance was at chance in a posttask assessment of awareness for the masked faces. The results add to current literature on the 5HTTLPR and attention biases, and suggest that threat signals facilitate the orienting of attention in short-allele carriers of the 5HTTLPR gene even under restricted processing conditions.     

Genetic Gating of Human Fear Learning and Extinction: Possible Implications for Gene-Environment Interaction in Anxiety Disorder

ABSTRACT— Pavlovian fear conditioning is a widely used model of the acquisition and extinction of fear. Neural findings suggest that the amygdala is the core structure for fear acquisition, whereas prefrontal cortical areas are given pivotal roles in fear extinction. Forty-eight volunteers participated in a fear-conditioning experiment, which used fear potentiation of the startle reflex as the primary measure to investigate the effect of two genetic polymorphisms (5-HTTLPR and COMTval158met) on conditioning and extinction of fear. The 5-HTTLPR polymorphism, located in the serotonin transporter gene, is associated with amygdala reactivity and neuroticism, whereas the COMTval158met polymorphism, which is located in the gene coding for catechol-O-methyltransferase (COMT), a dopamine-degrading enzyme, affects prefrontal executive functions. Our results show that only carriers of the 5-HTTLPR s allele exhibited conditioned startle potentiation, whereas carriers of the COMT met/met genotype failed to extinguish conditioned fear. These results may have interesting implications for understanding gene-environment interactions in the development and treatment of anxiety disorders.     

COMT gene polymorphisms,cognitive performance,and physical fitness in older adults

ObjectiveIt is well known that genetic predispositions might influence cognitive performance, particularly in older adults. One gene related to executive functioning is the COMT gene with met/met carriers outperforming val/val carriers in cognitive tasks. Further, it has been shown that fitness is positively related to cognitive functioning in older adults. As both, the COMT genotype and physical exercise have been shown to influence dopamine availability and as changes in dopamine metabolism seem to play a key role in cognitive aging, the aim of this study was to analyze the association of the COMT gene polymorphisms with the relationship between fitness and cognition.DesignWe used a cross-sectional design.MethodSixty-eight healthy older adults between 62 and 79 years of age were analyzed in this study. DNA was extracted from capillary blood samples. Participants performed a modified version of the Flanker Task as an indicator of executive control and a battery of motor and physical tests as indicators of fitness.ResultsHierarchical regression analyses revealed a positive influence of overall fitness and an interactive effect of fitness and COMT polymorphisms on Flanker accuracy performance. Val/val carriers revealed the highest positive correlation between fitness and cognition.ConclusionsOur data suggest that particularly val/val allele carriers benefit from exercise by improved cognitive functioning whereas met/met carriers already perform closer at their optimum level.     

COMT genotype influences prefrontal response to emotional distraction

Early studies of genetic effects on brain activity have been conducted to investigate primarily either the influence of polymorphisms in dopaminergic genes, especially the catechol-O-methyltransferase (COMT) gene, on prefrontal cognitive processes such as working memory, or that of polymorphisms in the serotonin transporter gene on the amygdala response to threatening stimuli. Here, we address genetic influences on the neural systems underlying cognitive-affective interactions. Specifically, we assess the effect of the COMT val¹⁵⁸met polymorphism on frontal regulation of attention under emotional distraction. Healthy volunteers were scanned while performing a house-matching task with affectively negative versus neutral distractors. Effects of val allele load were examined on frontal regions associated with attentional control and emotion regulation, and on parahippocampal regions associated with perception of houses. As we predicted, val load correlated positively with activity in control- and task-related regions during performance under emotional distraction. These findings provide an initial step toward identifying genetic contributions to interindividual variability in recruitment of mechanisms that regulate affective processing.     

Suppression mediates the effect of 5‐HTTLPR by stress interaction on depression

A number of studies have shown that the presence of short (S), as opposed to long (L), allele of the serotonin transporter‐linked polymorphic region (5‐HTTLPR) is associated with a higher risk for depression following exposure to stressful life events. However, many other studies failed to confirm this association. One reason for this inconsistency might be the fact that the interaction of the 5‐HTTLPR polymorphism with stress may relate not to depression per se, but rather to adaptive or maladaptive emotion regulation strategies. Here we show that individuals homozygous for the long allele respond to stressful events by reappraising their emotional meaning, which may hamper the harmful effect of stress on mental health. In S genotype carriers, on the other hand, stress triggers the appearance of intrusive thoughts and vain attempts to suppress them, which in this group acts as a mediator between stress and depressive symptoms. These findings are in line with neuroimaging studies showing that 5‐HTTLPR polymorphism has an effect on the connectivity among key areas involved in emotion regulation.     

Cross-task individual differences in error processing: Neural,electrophysiological, and genetic components

The error-related negativity (ERN) and error positivity (Pe) are electrophysiological markers of error processing thought to originate in the medial frontal cortex. Previous studies using probabilistic reinforcement showed that individuals who learn more from negative than from positive feedback (negative learners) had larger ERNs than did positive learners. These findings support the dopamine (DA) reinforcement-learning hypothesis of the ERN and associated computational models. However, it remains unclear (1) to what extent these effects generalize to tasks outside the restricted probabilistic reinforcement-learning domain and (2) whether there is a dopaminergic source of these effects. To address these issues, we tested subjects’ reinforcement-learning biases behaviorally and recorded EEG during an unrelated recognition memory experiment. Initial recognition responses were speeded, but the subjects were subsequently allowed to self-correct their responses. We found that negative learners, as assessed via probabilistic learning, had larger ERNs in the recognition memory task, suggestive of a common underlying enhanced error-processing mechanism. Negative learners also had enhanced Pes when selfcorrecting errors than did positive learners. Moreover, the ERN and Pe components contributed independently to negative learning. We also tested for a dopaminergic genetic basis of these ERP components. We analyzed the COMT val/met polymorphism, which has been linked to frontal DA levels. The COMT genotype affected Pe (but not ERN) magnitude; met/met homozygotes showed enhanced Pes to self-corrected errors, as compared with val carriers. These results are consistent with a role for the Pe and frontal monoamines in error awareness.     

Stressful life events, perceived stress, and 12-month course of geriatric depression: direct effects and moderation by the 5-HTTLPR and COMT Val158Met polymorphisms

Although the relation between stressful life events (SLEs) and risk of major depressive disorder is well established, important questions remain about the effects of stress on the course of geriatric depression. Our objectives were (1) to examine how baseline stress and change in stress is associated with course of geriatric depression and (2) to test whether polymorphisms of serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met) genes moderate this relation. Two-hundred and sixteen depressed subjects aged 60 years or older were categorized by remission status (Montgomery-Asberg depression rating scale≤6) at 6 and 12 months. At 6 months, greater baseline numbers of self-reported negative and total SLEs and greater baseline perceived stress severity were associated with lower odds of remission. At 12 months, only baseline perceived stress predicted remission. When we examined change in stress, 12-month decrease in negative SLEs and level of perceived stress were associated with improved odds of 12-month remission. When genotype data were included, COMT Val158Met genotype did not influence these relations. However, when compared with 5-HTTLPR L/L homozygotes, S allele carriers with greater baseline numbers of negative SLEs and with greater decrease in negative SLEs were more likely to remit at 12 months. This study demonstrates that baseline SLEs and perceived stress severity may influence the 12-month course of geriatric depression. Moreover, changes in these stress measures over time correlate with depression outcomes. 5-HTTLPR S carriers appear to be more susceptible to both the effects of enduring stress and the benefit of interval stress reduction.     

Effects of social context and predictive relevance on action outcome monitoring

Outcome monitoring is crucial for subsequent adjustments in behavior and is associated with a specific electrophysiological response, the feedback-related negativity (FRN). Besides feedback generated by one's own action, the performance of others may also be relevant for oneself, and the observation of outcomes for others' actions elicits an observer FRN (oFRN). To test how these components are influenced by social setting and predictive value of feedback information, we compared event-related potentials, as well as their topographies and neural generators, for performance feedback generated by oneself and others in a cooperative versus competitive context. Our results show that (1) the predictive relevance of outcomes is crucial to elicit an FRN in both players and observers, (2) cooperation increases FRN and P300 amplitudes, especially in individuals with high traits of perspective taking, and (3) contrary to previous findings on gambling outcomes, oFRN components are generated for both cooperating and competing observers, but with smaller amplitudes in the latter. Neural source estimation revealed medial prefrontal activity for both FRN and oFRN, but with additional generators for the oFRN in the dorsolateral and ventral prefrontal cortex, as well as the temporoparietal junction. We conclude that the latter set of brain regions could mediate social influences on action monitoring by representing agency and social relevance of outcomes and are, therefore, recruited in addition to shared prediction error signals generated in medial frontal areas during action outcome observation.     

COMT val158Met and executive control: a test of the benefit of specific deficits to translational research

The role of catechol-O-methyltransferase (COMT) val158met in prefrontal cortical deficits associated with the liability to schizophrenia remains controversial. This study evaluated 464 healthy adult participants using three measures of executive functions in working memory: a 3-back version of the N-back continuous performance task (CPT) and two variants of the AX-CPT. The interpretability of N-back performance was confounded by possible generalized deficits, whereas the AX variants included internal controls for uncovering specific deficits. There was no relationship between the COMT genotype and N-back performance, whereas val/val individuals had a specific deficit on a dot-pattern version of the AX-CPT. In this case, a specific executive function known as context processing appeared to be compromised. These data suggest that the interpretability gained by including task manipulations to uncover specific deficits can enhance associations between cognitive and genetic levels of analysis.     

Maternal depressive history, teen 5HTTLPR genotype, and the processing of emotional faces: Exploring mechanisms of risk

Variations in the serotonin transporter gene (5HTTLPR) and biased processing of face-emotion displays both have been implicated in the transmission of depression risk, but little is known about developmental influences on these relationships. Within a community sample of adolescents, we examine whether 5HTTLPR genotype moderates the link between maternal depressive history and errors in face-emotion labeling. When controlling for current levels of depression and anxiety among youth, a two-way interaction between maternal depressive history and 5HTTLPR genotype was detected. Specifically, adolescents whose mothers reported a depressive history and who had a low expressing genotype made more errors in classifying emotional faces when compared with adolescents with an intermediate or high expressing genotype, with or without maternal depression history. These findings highlight the complex manner in which maternal depression and genetic risk may interact to predict individual differences in social information processing.     

How to consistently link extraversion and intelligence to the catechol-O-methyltransferase (COMT) gene: on defining and measuring psychological phenotypes in neurogenetic research

The evidence for associations between genetic polymorphisms and complex behavioral/psychological phenotypes (traits) has thus far been weak and inconsistent. Using the well-studied Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene as an example, we demonstrate that using theoretical models to guide phenotype definition and measuring the phenotypes of interest with a high degree of specificity reveals strong gene-behavior associations that are consistent with prior work and that would have otherwise gone unnoticed. Only after statistically controlling for irrelevant portions of phenotype variance did we observe strong (Cohen's d = 0.33-0.70) and significant associations between COMT Val158Met and both cognitive and affective traits in a healthy male sample (N = 201) in Study 1: Carriers of the Met allele scored higher in fluid intelligence (reasoning) but lower in both crystallized intelligence (general knowledge) and the agency facet of extraversion. In Study 2, we conceptually replicated the association of COMT Val158Met with the agency facet of extraversion after partialing irrelevant phenotype variance in a female sample (N = 565). Finally, through reanalysis of a large published data set we showed that Met allele carriers also scored higher in indicators of fluid intelligence after partialing verbal fluency. Because the Met allele codes for a less efficient variant of the enzyme COMT, resulting in higher levels of extrasynaptic prefrontal dopamine, these observations provide further support for a role for dopamine in both intelligence and extraversion. More importantly, the present findings have important implications for the definition of psychological phenotypes in neurogenetic research.     

The Dopamine D4 Receptor (DRD4) Exon 3 VNTR Contributes to Adaptive Personality Differences in an Italian Small Island Population

The search for evolutionary forces shaping the diversity of human personality traits encouraged studies that have found that islanders are relatively closed and introverted, with little interest in the external world. The ‘personality gene flow’ hypothesis was proposed to explain the mechanism underlying this difference, suggesting that the frequency of alleles that influence islander personality traits might progressively increase in the gene pools on islands because of selective emigration of individuals not displaying these alleles. We genotyped 96 individuals from the Italian mainland and 117 from Giglio Island, whose residents were previously assessed regarding their personality traits. We genotyped three polymorphisms: the dopamine D4 receptor (DRD4) exon 3 repeat region, the serotonin‐transporter SLC6A4 5‐HTTLPR indel and the dopamine transporter SLC6A3 DAT1 3′UTR repeat region. Only the DRD4 exon 3 repeat was hypothesised to show varying allele frequencies because this polymorphism could be associated with human migration and personality traits such as extraversion, openness and novelty seeking. As predicted, no differences in allele frequencies were found for the SLC6A4 and SLC6A3 polymorphisms, whereas significant differences were observed in the frequency of the DRD4 exon 3 alleles. The DRD4.2 repeat was more common in mainlanders, as expected, whereas the DRD4.7 allele was over‐represented among islanders who never emigrated. This last result contradicts the suggested association of this allele with long‐distance migrations. We suggest that emigration might have caused gene flow out the island that resulted in somewhat unpredictable changes in the frequencies of specific alleles, thus influencing islander personality traits. Copyright © 2013 European Association of Personality Psychology     

Attention biases and habituation of attention biases are associated with 5-HTTLPR and COMTval158met

Fundamental biases in affective information processing are modulated by individual differences in the emotional response to environmental stimuli that may be partly based on the individual’s genetic make-up. To extend prior dot probe studies on attention genetics, we used a visual-search paradigm (VSP) with pictures of angry and happy faces of both sexes as targets, neutral faces as distractors, and a varying set size. Participants were selected a priori depending on their 5-HTTLPR (s/s, s/l, l/l; on a constant rs25531 A-allele background) and COMTval158met (val/val, valmet, met/met) genotypes and were matched for sex and age. We demonstrate a bias towards angry male faces (as opposed to happy male faces) irrespective of 5-HTTLPR genotype in the first experimental block that was maintained during the second experimental block only in carriers of the s-allele, which implies differential habituation processes. While a bias towards angry male faces was observed irrespective of COMTval158met genotype, only individuals with the val/val genotype exhibited a bias towards a happy female face (as opposed to an angry female face). In sum, our results both replicate and extend prior findings in the field of attention genetics and add important pieces of information to the research on attentional biases in emotion processing.     

Variation in the serotonin transporter gene modulates selective attention to threat

The 5-HTTLPR is an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene. Prior research has revealed associations between the short-allele variant of this polymorphism, enhanced self-reported negative emotionality, and hypersensitivity of fear relevant neural circuits. In a sample of 50 healthy women we examined the role of 5-HTTLPR for cognitive-affective processing of phylogenetical fear-relevant stimuli (spiders) in a dot probe task. In contrast to homozygote long-allele carriers (ll), participants carrying at least 1 short allele (ss and sl) selectively shifted attention toward pictures of spiders, when these were presented for a duration of 2,000 ms. These results argue for an involvement of 5-HTTLPR in cognitive processing of threatening stimuli and thus, underpin its general role for individual differences in negative affect.     

人际合作与冲突影响博弈决策的结果评价

人际合作与冲突是人际互动的两种主要形式, 在人类社会的发展中有着重要作用。脑成像研究表明, 当个体和人类同伴进行博弈时, 选择合作与选择冲突激活脑区的强度有所不同。但目前尚不清楚, 人际合作与冲突如何影响决策选择之后的结果评价过程。本研究采用Chicken Game任务对此问题进行了探讨, 研究记录了22名健康成人被试与人类同伴进行Chicken Game任务时的脑电活动。结果表明, 反馈负波(FRN)和P300不仅受到结果效价的影响, 同时也受到人际合作与冲突的影响。相对于选择冲突, 个体选择合作时, 输钱和赢钱反馈引发的FRN以及P300波幅差异更大。相关分析表明, RA (被试和解对方进攻)反馈引发的FRN波幅与接受该反馈后下一个trials中和解的选择率(以及总的和解率)呈显著的负相关。上述结果表明, 在社会博弈中, 合作增加了个体对博弈结果的预期, 从而引发更大的FRN效应; 并且合作共赢的结果所具有的物质意义与社会意义, 使其诱发更大的P300波幅。     

The influence of self-construals on the ERP response to the rewards for self and mother

Individual self-construal (independent vs. interdependent) could be temporarily modulated by the priming effect. Our previous studies have found that when Chinese participants gambled for mother and for self, outcome feedback evoked comparable neural responses between two conditions. However, it remains unclear if the response to rewards for mother and for self would differ after independence self-construal priming. In this study, we manipulated participants’ self-construal (independent vs. interdependent) before a simple gambling task. The event-related potential (ERP) results reveal that when an interdependent self-construal was primed, the participants exhibited a comparable feedback-related negativity (FRN) elicited by outcome feedback for self and for mother. In contrast, independent self-construal priming resulted in a greater FRN elicited by outcome feedback for self than for mother. Meanwhile, the P3 component was insensitive to self-construal manipulation. These findings indicate the modulation effect of self-construal priming on the response to rewards for others.     

Warriors versus worriers: the role of COMT gene variants

Behavioral phenotypes are generally complex, reflecting the action of multiple different genes. Nevertheless, there is growing evidence that key gene variants can alter activity within specific neuronal circuits and, therefore, influence particular cognitive-affective phenomena. One example is the catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance, while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.     

社会比较对合作任务结果评价的影响：来自ERP的证据

现实生活中人们通过社会比较获得对自身的认识。前人研究探讨了金钱收入的比较对个体结果评价的影响, 而非金钱的社会比较效应的神经加工机制尚不清楚。本研究分离比较和金钱收入, 使用双人合作的投骰子任务, 先呈现“>”或“<”代表两人点数大小的比较结果, 再呈现合作任务的输赢结果, 考察非金钱的社会比较对合作任务结果加工的影响, 记录任务表现的比较结果和最终合作任务结果的ERP数据。发现在任务表现比较结果阶段, FRN和P300对代表行为表现好坏的社会比较信息敏感, 呈现无金钱输赢提示的点数大小的比较结果时, 点数小于他人比大于他人诱发更大的FRN和更小的P300; 任务表现的比较结果对合作任务最终的金钱输赢结果的影响并没有反应在FRN上。这些表明, 对非金钱的社会比较信息的加工始于结果快速评价的早期阶段。     

GABA, glutamate, dopamine and serotonin transporters expression on memory formation and amnesia

Notwithstanding several neurotransmission systems are frequently related to memory formation, amnesia and/or therapeutic targets for memory alterations, the role of transporters γ-aminobutyric acid (GABA, GAT1), glutamate (neuronal glutamate transporter excitatory amino acid carrier; EACC1), dopamine (DAT) and serotonin (SERT) is poorly understood. Hence, in this paper Western-blot analysis was used to evaluate expression changes on them during memory formation in trained and untrained rats treated with the selective serotonin transporter inhibitor fluoxetine, the amnesic drug d-methamphetamine (METH) and fluoxetine plus METH. Transporters expression was evaluated in the hippocampus, prefrontal cortex and striatum. Data indicated that in addition of memory performance other behavioral parameters (e.g., explorative behavior, food-intake, etc.) that memory formation was recorded. Thus, memory formation in a Pavlovian/instrumental autoshaping was associated to up-regulation of prefrontal cortex GAT1 and EAAC1, striatal SERT, DAT and EACC1; while, hippocampal EACC1, GAT1 and SERT were down-regulated. METH impaired short (STM) and long-term memory (LTM), at 24 or 48h. The METH-induced amnesia down-regulated SERT, DAT, EACC1 and GAT1 in hippocampus and the GAT1 in striatum; no-changes were observed in prefrontal cortex. Post-training administration of fluoxetine improved LTM (48h), which was associated to DAT, GAT1 (prefrontal cortex) up-regulation, but GAT1 (striatum) and SERT (hippocampus) down-regulation. Fluoxetine plus METH administration was able to prevent amnesia, which was associated to DAT, EACC1 and GAT1 (prefrontal cortex), SERT and DAT (hippocampus) and EACC1 or DAT (striatal) up-regulation. Together these data show that memory formation, amnesia and anti-amnesic effects are associated to specific patters of transporters expression.     

自身得失对朋友博弈结果评价的影响：来自ERPs的证据

本研究通过经典的金钱博弈任务, 以FRN和P300为反应指标, 探讨了自身获益或损失对朋友结果评价分别会产生何种影响, 以及这种影响模式是如何受到个体自我建构方式调节的。结果发现, 在自身获益条件下, 观看朋友损益之间的FRN和P300差异不再存在; 在自身损失条件下, 虽然观看朋友输赢之间的P300差异消失了, 但FRN差异依然显著。不仅如此, 无论自身得失, 独立型自我建构启动组在观看朋友损益上的FRN差异均不再显著, 但在自身获益后看到朋友损失能激发更强的P300波幅。本研究结果表明：(1) 对朋友的结果评价模式并非固定不变, 而是会随个体自身所处得失境遇的不同而有所区别; (2) 相对于互依型自我建构启动组, 独立型自我建构启动组在面对朋友的得失时表现得更为冷漠并更具竞争性。