The not-so-bitter pill: Effects of combined oral contraceptives on peripheral physiological indicators of emotional reactivity.

Combined oral contraceptives (COC) are used by millions of women worldwide. Although findings are not entirely consistent, COC have been found to impact on brain function and, thus, to modulate affective processes. Here, we investigated electro-physiological responses to emotional stimuli in free cycling women in both the early follicular and late luteal phase as well as in COC users. Skin conductance response (SCR), startle reflex, corrugator and zygomaticus activity were assessed. COC users showed reduced overall startle magnitude and SCR amplitude, but heightened overall zygomaticus activity, although effect sizes were small. Thus, COC users displayed reduced physiological reactions indicating negative affect and enhanced physiological responses signifying positive affect. In free cycling women, endogenous 17ß-estradiol levels were associated with fear potentiated startle in both cycle phases as well as with SCR and zygomaticus activity during the follicular phase. Testosterone was associated with corrugator and zygomaticus activity during the luteal phase, while progesterone levels correlated with corrugator activity in the follicular phase. To the contrary, in COC users, endogenous hormones were not associated with electro-physiological measures. The results further underscore the importance of considering COC use in psychophysiological studies on emotional processing.

Predictions get tougher in older individuals: a longitudinal study of optimism, pessimism and depression.

PURPOSE: To examine whether optimism/pessimism reliably predicts depression and whether such function is stable also in older age. METHOD: In a prospective study, we observed a representative sample of n = 4,046 primary care patients over 5 years. The Life Orientation Test (LOT-R, measuring optimism/pessimism) and the Depression-Screening Questionnaire were applied. Medical diagnoses were recorded by the treating physician in a structured medical interview. RESULTS: Depression could only be predicted by LOT-R scores in younger-age cohorts. In older adults, test stability and predictive accuracy of optimism/pessimism were markedly reduced, while somatic comorbidity gained importance as a predictor. CONCLUSIONS: Predictive value of screening measures for mental disorders may be specific in older age due to lower trait stability and age-specific psychometric limitations as well as age-related changes in relevant predictors.

The needs of the many: Exploring associations of personality with third-party judgments of public health-related utilitarian rule violations.

Safeguarding the rights of minorities is crucial for just societies. However, there are conceivable situations where minority rights might seriously impede the rights of the majority. Favoring the minority in such cases constitutes a violation of utilitarian principles. To explore the emotional, cognitive, and punitive responses of observers of such utilitarian rule transgressions, we conducted an online study with 1004 participants. Two moral scenarios (vaccine policy and epidemic) were rephrased in the third-party perspective. In both public health-related scenarios, the protagonist opted against the utilitarian option, which resulted in more fatalities in total, but avoided harm to a minority. Importantly, in vaccine policy, members of the minority cannot be identified beforehand and thus harm to them would have been rather accidental. Contrariwise, in epidemic, minority members are identifiable and would have needed to be deliberately selected. While the majority of participants chose not to punish the scenarios' protagonists at all, 30.1% judged that protecting the minority over the interests of the majority when only accidental harm would have occurred (vaccine policy) was worthy of punishment. In comparison, only 11.2% opted to punish a protagonist whose decision avoided deliberately selecting (and thus harming) a minority at the cost of the majority (epidemic). Emotional responses and appropriateness ratings paralleled these results. Furthermore, complex personality × situation interactions revealed the influence of personality features, i.e., trait psychopathy, empathy, altruism, authoritarianism, need for cognition and faith in intuition, on participants' responses. The results further underscore the need to consider the interaction of situational features and inter-individual differences in moral decisions and sense of justice.

The long and the short of it: 5-HTTLPR and moral judgement.

Differences in moral sentiments are widespread. Increasingly, their biological correlates are investigated to elucidate potential sources of divergent moral attitudes and choices. Serotonin is one such potential modulator. We investigated the effects of a functional serotonergic polymorphism, 5-HTTLPR, which was previously linked to moral choices albeit with inconsistent findings. N = 157 healthy young adults completed a set of congruent and incongruent moral dilemmas. In addition to the traditional moral response score, this set allows by using a process dissociation (PD) approach an estimation a deontological and a utilitarian parameter. While there was no main effect of 5-HTTLPR on any of the three moral judgement parameters, there was an interaction effect between 5-HTTLPR and endocrine status on PD parameters, which was mainly due to the deontological but not the utilitarian parameter. In men and free cycling women, LL homozygotes showed reduced deontological tendencies compared to S allele carriers. Contrariwise, in women using oral contraceptives, LL homozygotes had increased deontology parameter scores. Furthermore, LL genotypes in general reported less difficulty in making harmful choices, which were in addition associated with less negative emotions. The findings suggest that 5-HTTLPR might be involved in modulating cognitive and emotional processes contributing to moral decisions.

Similarity between brain activity at encoding and retrieval predicts successful realization of delayed intentions.

Remembering delayed intentions can be highly demanding. Accuracy in laboratory paradigms assessing prospective memory (PM) is typically well below ceiling, and failure to remember intended behaviors after a delay is a common occurrence in everyday life. However, relatively little is known of the potential differences in brain activity that distinguish successful versus unsuccessful PM. In this fMRI study, participants repeatedly encoded, stored, and then had the opportunity to retrieve intended behaviors while engaged in a distracting ongoing task. This yielded a success rate of approximately two thirds. Overall levels of brain activity distinguished successful versus unsuccessful trials at all three stages (encoding, storage, and retrieval), suggesting multiple neural determinants of PM success. In addition, the voxelwise similarity between patterns of brain activity at encoding and retrieval was greater for successful than unsuccessful trials. This was true even in posterior cingulate, which showed opposite patterns of signal change between encoding and retrieval. Thus, successful realization of delayed intentions may be associated with reinstatement of encoding context at the time of retrieval.

Prefrontal cortical mechanisms underlying individual differences in cognitive flexibility and stability.

The pFC is critical for cognitive flexibility (i.e., our ability to flexibly adjust behavior to changing environmental demands), but also for cognitive stability (i.e., our ability to follow behavioral plans in the face of distraction). Behavioral research suggests that individuals differ in their cognitive flexibility and stability, and neurocomputational theories of working memory relate this variability to the concept of attractor stability in recurrently connected neural networks. We introduce a novel task paradigm to simultaneously assess flexible switching between task rules (cognitive flexibility) and task performance in the presence of irrelevant distractors (cognitive stability) and to furthermore assess the individual "spontaneous switching rate" in response to ambiguous stimuli to quantify the individual dispositional cognitive flexibility in a theoretically motivated way (i.e., as a proxy for attractor stability). Using fMRI in healthy human participants, a common network consisting of parietal and frontal areas was found for task switching and distractor inhibition. More flexible persons showed reduced activation and reduced functional coupling in frontal areas, including the inferior frontal junction, during task switching. Most importantly, the individual spontaneous switching rate antagonistically affected the functional coupling between inferior frontal junction and the superior frontal gyrus during task switching and distractor inhibition, respectively, indicating that individual differences in cognitive flexibility and stability are indeed related to a common prefrontal neural mechanism. We suggest that the concept of attractor stability of prefrontal working memory networks is a meaningful model for individual differences in cognitive stability versus flexibility.

Children under stress - COMT genotype and stressful life events predict cortisol increase in an acute social stress paradigm.

Dopamine and norepinephrine are key regulators of cognitive and affective processes. The enzyme catechol-O-methyltransferase (COMT) catabolizes catecholamines and the COMT Val158Met polymorphism has been linked to several neuropsychiatric variables. Additionally, stressful life events (SLEs) contribute substantially to affective processes. We used the stress-induced activation of the hypothalamic-pituitary-adrenal axis to investigate the effects of COMT and SLEs on the cortisol response in 119 healthy children (8-12 yr). Saliva cortisol was measured during and after the Trier Social Stress Test for Children. SLEs were assessed with a standardized interview with one of the children's parents. Linear regression analysis revealed a significant effect for COMT, with Met allele carriers showing a higher cortisol response (ß=0.300, p=0.001). In turn, more SLEs lead to a less pronounced cortisol increase (ß=-0.192, p=0.029) probably indicating increased resilience. Our results further underscore the essential and differential role of genetic variation and environmental factors on stress responsivity.

The heart as judge: Association of heart rate variability with moral judgement-A replication study.

There is growing research into contributing processes and biological correlates of moral inclinations. Recently, a negative association between utilitarianism and resting heart rate variability (HRV) as an indicator of cardiac vagal tone/parasympathetic activity was reported. We aimed to replicate and extend these findings by additionally investigating the sympathetic parameter electro-dermal activity (EDA), but found no associations in the total sample (N = 157). However, when taking sex and the use of combined oral contraceptives (COC) into account, we found a positive association between HRV and estimated deontology in women using COC and men, while in free cycling women there was a negative association. While no direct replication, our results also point to associations between higher HRV and decreased endorsement of harmful actions that serve a greater good. Unlike HRV, EDA showed no associations with moral judgements. In addition, there were correlations between personality traits and moral judgement.

Predicting cortisol stress responses in older individuals: influence of serotonin receptor 1A gene (HTR1A) and stressful life events.

Considerable variability in the activity of the hypothalamus-pituitary-adrenal (HPA) axis in response to stress has been found in quantitative genetic studies investigating healthy individuals suggesting that at least part of this variance is due to genetic factors. Since the HPA axis is regulated by a neuronal network including amygdala, hippocampus, prefrontal cortex as well as brainstem circuits, the investigation of candidate genes that impact neurotransmitter systems related to these brain regions might further elucidate the genetic underpinnings of the stress response. However, aside from genetic risk factors, past stressful life events might also result in long-term adjustments of HPA axis reactivity. Here, we investigated the effects of the -1019 G/C polymorphism in the HTR1A gene encoding the serotonin (5-HT) receptor 1A (5-HT(1A)) and stressful life events experienced during childhood and adolescence on changes in cortisol levels in response to the Trier Social Stress Test (TSST) in a sample of healthy older adults (N=97). Regression analyses revealed a significant effect of HTR1A genotype with the G allele being associated with a less pronounced stress response. In addition, an inverse relationship between past stressful life events and cortisol release but no gene × environment interaction was detected. The results further underscore the crucial role of functional serotonergic genetic variation as well as stressful events during critical stages of development on the acute stress response later in life.

Variation in genes involved in dopamine clearance influence the startle response in older adults.

The dopamine transporter (DAT) and the enzyme catechol-O-methyltransferase (COMT) both terminate synaptic dopamine action. Here, we investigated the influence of two polymorphisms in the respective genes: DAT1 (SLC6A3) VNTR and COMT val(158)met (rs4680). Startle magnitudes to intense noise bursts as measured with the eye blink response were recorded during the presentation of pictures of three valence conditions (unpleasant, pleasant and neutral) and during baseline without additional pictorial stimulation in a sample of healthy older adults (N = 94). There was a significant Bonferroni corrected main effect of COMT genotype on the overall startle responses, with met/met homozygotes showing the highest and participants with the val/val genotype showing the lowest startle response, while participants with the val/met genotype displayed intermediate reactions. There was also a DAT1 VNTR main effect, which, after Bonferroni correction, still showed a tendency toward significance with carriers of at least one 9-repeat (R) allele showing smaller overall startle responses compared to 10R/10R homozygotes. Thus, older adult carriers of COMT variants, which result in lower enzyme activity and therefore probably enhanced dopamine signaling, showed stronger startle activity. Although the functional significance of DAT1 VNTR is less defined, our results point to a potential influence of SLC6A3 on startle magnitude.

Androgenic morality? Associations of sex, oral contraceptive use and basal testosterone levels with moral decision making.

Aside from cultural, psychological, or situational factors, differences in moral judgements might also be influenced by biological variables. Since previous studies have reported stronger utilitarian tendencies in men, the relationship between testosterone and moral judgments has gained interest. Utilitarian judgements focus on the consequences of an action in terms of a cost-benefit analysis while deontological judgements are based on rules that are independent of an action's outcome or of situational features. We investigated decisions in moral dilemma situations in N = 157 young adults using a process dissociation approach to allow an independent estimate of underlying utilitarianism and deontology. Significant effects of sex (p = .009) and endocrine status (p = .011) on utilitarianism were found with the highest levels in men and the lowest in free cycling women while oral contraceptive users fell in between. Furthermore, there were correlations of salivary testosterone with utilitarianism in free cycling women (r = .303) and with deontology in men (r = -0.263) while no significant associations between testosterone and moral choices were found in oral contraceptive users. However, the duration of contraceptive use correlated negatively with deontology (r = -.316). The findings underscore the role of sex, endocrine status as well as testosterone in moral judgements but also point to specific associations depending on sex and oral contraceptive use.

Stathmin, a gene regulating neural plasticity, affects fear and anxiety processing in humans.

The identification of biological mechanisms underlying emotional behavior is crucial for our understanding of the pathogenesis of mental disorders. Besides genes modulating neural transmission and influencing amygdala reactivity and anxiety-related temperamental traits a different plasticity regulating genes affect interindividual differences in emotional regulation. Recently it has been demonstrated that stathmin, a regulator of microtubule formation which affects long-term potentiation (LTP), controls learned and innate fear responses in rodents, but its role in human emotion regulation is unknown. We hypothesized that in humans the gene coding for stathmin (STMN1), which is highly expressed in the lateral nucleus of the amygdala and associated thalamic and cortical structures, influences behavioral responses to fear and anxiety stimuli by way of two common single nucleotide polymorphisms (rs182455, SNP1; rs213641, SNP2). These polymorphisms are located within or close to the putative transcriptional control region. We used the acoustic startle paradigm and a standardized laboratory protocol for the induction of fear and psychosocial stress in 106 healthy volunteers to investigate the impact of stathmin gene variation on two fear- and anxiety-controlling effector-systems of the amygdala. We found that STMN1 genotype interacting with individuals' gender significantly impacts fear and anxiety responses as measured with the startle and cortisol stress response. We therefore conclude that STMN1 genotype has functional relevance for the acquisition and expression of basic fear and anxiety responses also in humans.

When the killing has been done: Exploring associations of personality with third-party judgment and punishment of homicides in moral dilemma scenarios.

Killing people is universally considered reprehensible and evokes in observers a need to punish perpetrators. Here, we explored how observers' personality is associated with their cognitive, emotional, and punishing reactions towards perpetrators using data from 1,004 participants who responded to a set of fifteen third-party perspective moral dilemmas. Among those, four scenarios (architect, life boat, footbridge, smother for dollars) describing deliberate killings were compared to investigate the role of the content features "motive for killing" (selfish vs. utilitarian) and "evitability of victims' death". Participants' moral appropriateness ratings, emotions towards perpetrators, and assigned punishments revealed complex scenario-personality interactions. Trait psychopathy was associated with harsher punishments in all scenarios but also with less concern about killing in general, an increased moral appreciation of utilitarian motives for killing, and a reduced concern about the killing of avoidable victims. Need for cognition was associated with considering a utilitarian motive for killing as a mitigating factor, while intuitive/authority-obedient thinking was linked to a strong focus on avoidability of harm as an aggravating factor when assigning punishments. Other-oriented empathy, trait anxiety, and justice sensitivity did not account for differences in third-party punishments. Our explorative findings highlight the importance of inter-individual differences for moral decision making and sense of justice.

Rhythm and blues: Influence of CLOCK T3111C on peripheral electrophysiological indicators of negative affective processing.

Dysfunction in the circadian system has been linked to emotion regulation and mood disorders with genetic variation in clock genes as likely contributors. Here, we focused on endophenotypes of affective processing and investigated in two independent samples of healthy individuals (n1=99, n2=108) whether genotypes of a functional single nucleotide polymorphism (SNP) in the gene encoding CLOCK (CLOCK T3111C, rs1801260) differed in physiological responses to emotional stimuli. Both samples underwent an emotional startle paradigm with startle responses being measured via EMG. In the second sample, skin conductance responses as well as corrugator and zygomaticus activity were also assessed. In both samples, CLOCK T3111C was associated with overall startle responses to loud noise bursts with T/T homozygotes showing consistently more marked responses. However, in the all-female second sample, the effects of CLOCK on skin conductance responses to the same loud noise bursts depended on hormone status: similar to the startle results, in free-cycling women T/T homozygotes showed more pronounced skin conductance response (SCR) compared to C allele carriers. The opposite was true for women using combined oral contraceptives (COC). A further CLOCK × hormone status interaction effect was found for corrugator activity. In free-cycling women, T/T homozygotes presented with less corrugator activity to affective pictures compared to C allele carriers, while the opposite pattern emerged for COC users. The findings emphasize the potential role of CLOCK for affect and mood.

Serotonin transporter gene variation and stressful life events impact processing of fear and anxiety.

Genetic variation of the serotonin transporter (5-HTT) has been associated with fear- and anxiety-related behaviours. The amygdala is considered crucial in emotional modulation and stronger amygdala reactivity in response to fearful stimuli has been found in carriers of the short (S) allele of the 5-HTT gene in imaging studies. Additionally, reactivity of amygdala-innervated effectory systems is also of particular interest. We recently reported the impact of a functional polymorphism in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) on the acoustic startle reflex. Here, we attempted to replicate and extend these findings. Startle magnitudes to intense noise bursts as measured with the eyeblink response were recorded in 106 healthy volunteers during baseline without additional stimulation and while they viewed pictures of three valence conditions: unpleasant, pleasant and neutral. Subjects were genotyped for the tri-allelic functional polymorphism 5-HTTLPR. In replication of our previous findings we found that carriers of the low-expressing S or LG alleles exhibited stronger overall startle responses across conditions than LA/LA homozygotes, while there were no differences in emotional startle modulation between the two genetic groups. In addition, we found that the recent experience of stressful life events resulted in overall higher startle responses and less startle habituation across blocks. The results replicate and emphasize the role of 5-HTTLPR and stress on the overall startle response as a possible genetically driven endophenotype for anxiety-related behaviour.

Processing emotions: Effects of menstrual cycle phase and premenstrual symptoms on the startle reflex, facial EMG and heart rate.

Emotional reactivity varies across the menstrual cycle although physiological findings are not entirely consistent. We assessed facial EMG and heart rate (HR) changes in healthy free cycling women (N = 45) with an emotional startle paradigm both during the early follicular and the late luteal phase, verified by repeated salivary 17ß-estradiol, progesterone and testosterone assessments. Cycle phase impacted startle responses with larger magnitudes during the luteal phase. Notably, this effect was only present when premenstrual symptoms and sequence of lab sessions were included as co-variates. At rest, participants showed a tendency towards higher HR and reduced high frequency (HF) power during the luteal phase indicating reduced parasympathetic tone. HF power was also negatively associated with startle magnitudes. HR changes in response to emotional images differed between the two cycle phases. Initial HR deceleration was more marked during the follicular phase particularly when viewing negative pictures. However, cycle phase did not significantly impact corrugator and zygomaticus activity in response to emotional pictures. Among the three gonadal steroids, correlation patterns were most consistent for testosterone. During the follicular phase, testosterone was associated with zygomaticus activity while viewing neutral or positive pictures and with less pronounced HR deceleration in response to negative images. During the luteal phase, testosterone was negatively associated with fear potentiated startle. The findings underscore the importance of considering menstrual cycle phase when investigating physiological indicators of emotion. However, the modulating effect of premenstrual symptoms also emphasizes potential inter-individual differences.

Winter is coming: Seasonality and the acoustic startle reflex.

Circannual rhythms and seasonality have long been in the interest of research. In humans, seasonal changes in mood have been extensively investigated since a substantial part of the population experiences worsening of mood during winter. Questions remain regarding accompanying physiological phenomena. We report seasonal effects on the acoustic startle response in a cross-sectional (n=124) and a longitudinal sample (n=23). Startle magnitudes were larger in winter (sample 1: p=0.026; sample 2: p=0.010) compared to summer months. Although the findings need to be replicated they may have implications regarding the timing of startle experiments.

BDNF val(66)met genotype shows distinct associations with the acoustic startle reflex and the cortisol stress response in young adults and children.

Brain Derived Neurotrophic Factor (BDNF) is a crucial regulator of neuronal development, organization and function and the val(66)met polymorphism in the BDNF gene has been associated with several (endo-) phenotypes of cognitive and affective processing. The BDNF met allele is considered a risk factor for anxiety and fear related phenotypes although findings are not entirely consistent. Here, the impact of BDNF val(66)met on two parameters of anxiety and stress was investigated in a series of studies. Acoustic startle responses were assessed in three adult samples (N1=117, N2=104, N3=116) as well as a children sample (N4=123). Cortisol increase in response to the Trier Social Stress Test (TSST) was measured in one adult sample (N3) and in the children sample (N4). The BDNF met allele was associated with enhanced cortisol responses in young adults (p=0.039) and children (p=0.013). On the contrary, BDNF met allele carriers showed a reduced acoustic startle response which reached significance in most samples (N1: p=0.004; N2: p=0.045; N3: n.s., N4: p=0.043) pointing to differential effects of BDNF val(66)met on distinct endophenotypes of anxiety and stress-related responses. However, small effect sizes suggest substantial additional genetic as well as environmental contributors.

The impact of sex and menstrual cycle on the acoustic startle response.

Sex differences in fear and anxiety have been widely reported although results are not entirely consistent depending on measures used. Also, a possible influence of the menstrual cycle is often not taken into account, and effect sizes are not always discussed. In a sample of healthy young adults (n=111 women without hormonal contraceptives and n=107 men) the acoustic startle response (ASR) and emotional ASR modulation were analysed. We found no significant effect of sex on ASR (p=.269) but a significant effect of menstrual cycle (p=.027, η(2)=0.105). Compared to men, women showed increased ASR during the late luteal phase probably reflecting elevated negative emotionality, and during ovulation which, however, might be due to increased auditory sensitivity and changes in general CNS arousal. Neither sex nor menstrual cycle affected startle modulation. Thus, at least in young adults, menstrual cycle but not sex per se appears to contribute significantly to ASR variance.

Threatening shapes: the impact of simple geometric configurations on peripheral physiological markers.

The fast and reliable neuronal and behavioral responses to negative affective stimuli have been suggested to be at least partly based on the processing of simple geometric configurations within complex visual stimuli. In this context, one line of experimental and neuroimaging evidence suggests that simple V-shaped stimuli result in patterns of neuronal activation and behavioral responses akin to pictures of negative facial expressions. The present study investigated the effects of circles as well as upward and downward pointing triangles in healthy young adults on three peripheral physiological markers - skin conductance response (SCR), facial EMG, and startle reflex - in order to further narrow the gap between neuroimaging findings and behavioral data regarding the impact of geometric shapes. We found significant effects of geometric forms on the startle reflex (p≤0.001, η(2)=0.080) and the SCR (p=0.029, η(2)=0.078), but not on facial EMG. Furthermore, subjective valence and arousal ratings of geometric stimuli differed significantly, with downward pointing triangles being perceived as less pleasant and more arousing. In sum, our findings provide further evidence that simple geometric shapes convey emotional meaning. Particularly, the observed changes in SCR and startle response underscore the notion that geometric shapes lead to preparatory changes in physiological activation patterns, which are essential for facilitation of appropriate behavioral responses. However, the smaller effect sizes compared to more realistic affective pictures also highlight the organisms' ability to differentiate between real impending danger and abstract cues in order to avoid unnecessary excessive responses.