Sustained threat and phasic fear in the laboratory and cognitive-emotional processes of anxiety in everyday life - An ambulatory assessment study.

Fear is a phasic state of apprehension to an imminent threat, whereas anxiety is a more sustained state of expecting a potential threat leading to tension and worry. The NPU-threat test is a laboratory startle paradigm allowing a reliable and valid assessment of both, fear- and anxiety-potentiated reactions. It is suggested to differentiate between anxiety disorders, but little is known on associations with everyday life experiences of cognitive-emotional processes regarding anxiety in non-clinical samples. In the present project, the NPU-threat test was applied in three studies with (1) unselected healthy individuals, (2) participants with extreme manifestations of trait anxiety (low vs. high) and (3) individuals preparing for a high-stakes exam. Self-reported states of emotionality and worry were assessed during a four-day ambulatory assessment (AA). Overall, NPU-threat test measures did not significantly differ between studies, while the AA dependent measures were sufficiently sensitive to capture differences between groups. However, there was no significant association between psychophysiological measures of the NPU-threat test and AA state measures across participants. In participants recruited for low vs. high trait anxiety we found an association with AA worry and emotionality, but no interaction with potentiated startle. The present findings do not support the idea of a link between our laboratory biomarker and adaptive regulation of cognitive-emotional states in everyday life in healthy individuals. We speculate that an association between laboratory physiological measures and everyday experience of anxious states may be detectable in clinical samples.

Challenges on the conservation of traditional orchards: Tree damage as an indicator of sustainable grazing.

Traditional orchard meadows are among the most valuable cultural and agricultural systems for nature conservation in Europe. They comprise scattered fruit trees over a highly diverse herbaceous layer and provide a wide range of ecosystem services. However, they are strongly endangered due to farmland intensification and abandonment. Livestock grazing is known to promote grassland diversity but it may also cause tree damage through debarking. In this study, we evaluated the effect of different grazers (cattle, horse and sheep) on fruit trees in 42 traditional orchards of the Rhenish uplands (Germany). Overall, we found that 70% of the study trees showed debarking damage, although most of them (40%) were slightly damaged (1-10% of the trunk debarked). Most debarked trees showed accumulated damage over time, and only 8% of the study trees were damaged during the last year. The probability of strong debarking (>50% of the trunk damaged) was higher in orchards grazed by cattle and horses than on those grazed by sheep (5.3 and 3.7-fold difference, respectively). Importantly, unsustainable levels of cumulative debarking caused a decay of crown development, which may strongly affect fruit production. Additionally, lower tree densities favored higher levels of debarking intensity but did not affect the probability of occurrence. Individual tree-protection was an effective practice in decreasing trunk debarking (95% reduction in tree damage occurrence). The impact of grazing animals on trees might represent a useful indicator to assess the sustainability of each grazing system and should be taken into account in future agriculture and conservation policies.

Don't fear 'fear conditioning': Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear.

The so-called 'replicability crisis' has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe. This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence-based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning.

Developmental investigation of fear-potentiated startle across puberty.

The goal of this study was to examine the association between affective development, puberty, and gender using the startle reflex as a marker of defensive mechanisms. Thirty-one male and thirty-five female adolescents aged ten to thirteen participated in a prospective study with up to five assessments. Longitudinal analyses revealed a significant effect of sex, with girls showing stronger fear-potentiation at all pubertal stages. Post hoc tests revealed that fear-potentiation increased in girls but not boys over the course of puberty. Furthermore, baseline startle decreased over the course of puberty. Because age was included as a covariate in all analyses, the puberty effect cannot be accounted for by age. To the best of our knowledge, this study provides the first evidence for a significant increase in fear-potentiated startle across the pubertal transition. Attribution of these changes to pubertal status rather than age has important implications for our understanding of the neurobiology of anxiety and affect regulation.

The Strengths and Difficulties Questionnaire (SDQ): the factor structure and scale validation in U.S. adolescents.

The Strengths and Difficulties Questionnaire (SDQ) is one of the most commonly used instruments for screening psychopathology in children and adolescents. This study evaluated the hypothesized five-factor structure of the SDQ and examined its convergent validity against comprehensive clinical diagnostic assessments. Data were derived from the National Comorbidity Survey - Adolescent Supplement (NCS-A), a nationally representative sample of U.S. adolescents aged 13 to 18 years. Parents/parent surrogates (n=6,483) was asked to complete a self-administered questionnaire including the SDQ and DSM-IV comprehensive diagnostic information on the participating adolescents. Confirmatory factor analysis (CFA) was conducted to assess the factor structure of the SDQ. The five-factor solution of the SDQ (including emotional, conduct, hyperactivity-inattention, peer relationship, and prosocial) provided a satisfactory fit to the data, and was invariant across sex, age, race/ethnicity and income subgroups. SDQ scores predicted a significantly increased probability of meeting criteria for a DSM-IV disorder, with better prediction for behavior disorders than for mood disorders. Decreasing the SDQ cutoffs to the 80th percentile significantly increased the sensitivity from 39% to 63% for the SDQ Total Difficulties Score, with an expected decrease in specificity from 93% to 87%. This work confirms the five-factor structure of the SDQ in an ethnically and sociodemogrpahically diverse community sample of adolescents. Our findings strengthen empirical evidence for the use of the parent-reported SDQ as a screening tool for DSM-IV behavioral and emotional disorders in adolescents identified in the general population.

Specific phobia among U.S. adolescents: phenomenology and typology.

BACKGROUND: Investigators have proposed the diagnostic value of a generalized subtype of specific phobia, with classification based upon the number of phobic fears. However, current and future typologies of specific phobia classify the condition by the nature of phobic fears. This study investigated the clinical relevance of these alternative typologies by: (1) presenting the prevalence and correlates of specific phobia separately by the number and nature of phobia types; and (2) examining the clinical and psychiatric correlates of specific phobia according to these alternative typologies. METHODS: The National Comorbidity Survey Replication-Adolescent Supplement (NCS-A) is a nationally representative face-to-face survey of 10,123 adolescents aged 13-18 years in the continental United States. RESULTS: Most adolescents with specific phobia met criteria for more than one type of phobia in their lifetime, however rates were fairly similar across DSM-IV/5 subtypes. Sex differences were consistent across DSM-IV/5 subtypes, but varied by the number of phobic types, with a female predominance observed among those with multiple types of phobias. Adolescents with multiple types of phobias exhibited an early age of onset, elevated severity and impairment, and among the highest rates of other psychiatric disorders. However, certain DSM-IV/5 subtypes (i.e. blood-injection-injury and situational) were also uniquely associated with severity and psychiatric comorbidity. CONCLUSIONS: Results indicate that both quantitative and DSM-IV/5 typologies of specific phobia demonstrate diagnostic value. Moreover, in addition to certain DSM-IV/5 subtypes, a generalized subtype based on the number of phobias may also characterize youth who are at greatest risk for future difficulties.

Functional gene polymorphisms in the serotonin system and traumatic life events modulate the neural basis of fear acquisition and extinction.

Fear acquisition and extinction are crucial mechanisms in the etiology and maintenance of anxiety disorders. Moreover, they might play a pivotal role in conveying the influence of genetic and environmental factors on the development of a (more or less) stronger proneness for, or resilience against psychopathology. There are only few insights in the neurobiology of genetically and environmentally based individual differences in fear learning and extinction. In this functional magnetic resonance imaging study, 74 healthy subjects were investigated. These were invited according to 5-HTTLPR/rs25531 (S+ vs. L(A)L(A); triallelic classification) and TPH2 (G(-703)T) (T+ vs. T-) genotype. The aim was to investigate the influence of genetic factors and traumatic life events on skin conductance responses (SCRs) and neural responses (amygdala, insula, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC)) during acquisition and extinction learning in a differential fear conditioning paradigm. Fear acquisition was characterized by stronger late conditioned and unconditioned responses in the right insula in 5-HTTLPR S-allele carriers. During extinction traumatic life events were associated with reduced amygdala activation in S-allele carriers vs. non-carriers. Beyond that, T-allele carriers of the TPH2 (G(-703)T) polymorphism with a higher number of traumatic life events showed enhanced responsiveness in the amygdala during acquisition and in the vmPFC during extinction learning compared with non-carriers. Finally, a combined effect of the two polymorphisms with higher responses in S- and T-allele carriers was found in the dACC during extinction. The results indicate an increased expression of conditioned, but also unconditioned fear responses in the insula in 5-HTTLPR S-allele carriers. A combined effect of the two polymorphisms on dACC activation during extinction might be associated with prolonged fear expression. Gene-by-environment interactions in amygdala and vmPFC activation may reflect a neural endophenotype translating genetic and adverse environmental influences into vulnerability for or resilience against developing affective psychopathology.

Assessing fear and anxiety in humans using the threat of predictable and unpredictable aversive events (the NPU-threat test).

The threat of predictable and unpredictable aversive events was developed to assess short-duration (fear) and long-duration (anxiety) aversive states in humans. A typical experiment consists of three conditions: a safe condition (neutral (N)), during which participants are safe from aversive stimuli, and two threat conditions-one in which aversive events are administered predictably (P) (i.e., signaled by a threat cue), and one in which aversive stimuli are administered unpredictably (U). During the so-called NPU-threat test, ongoing change in aversive states is measured with the startle reflex. The NPU-threat test has been validated in pharmacological and clinical studies and can be implemented in children and adults. Similar procedures have been applied in animal models, making the NPU-threat test an ideal tool for translational research. The procedure is relatively short (35 min), simple to implement and generates consistent results with large effect sizes.

Measuring anxious responses to predictable and unpredictable threat in children and adolescents.

Research has highlighted the need for new methods to assess emotions in children on multiple levels to gain better insight into the complex processes of emotional development. The startle reflex is a unique translational tool that has been used to study physiological processes during fear and anxiety in rodents and in human participants. However, it has been challenging to implement developmentally appropriate startle experiments in children. This article describes a procedure that uses predictable and unpredictable aversive events to distinguish between phasic fear and sustained anxiety in children and adolescents. We investigated anxious responses, as measured with the startle reflex, in youths (N=36, mean age=12.63 years, range=7-17) across three conditions: no aversive events (N), predictable aversive events (P), and unpredictable aversive events (U). Short-duration cues were presented several times in each condition. Aversive events were signaled by the cues in the P condition but were presented randomly in the U condition. Participants showed fear-potentiated startle to the threat cue in the P condition. Startle responses were also elevated between cues in the U condition compared with the N condition, suggesting that unpredictable aversive events can evoke a sustained state of anxiety in youths. This latter effect was influenced by sex, being greater in girls than in boys. These findings indicate the feasibility of this experimental induction of the startle reflex in response to predictable and unpredictable events in children and adolescents, enabling future research on interindividual differences in fear and anxiety and their development in youths.

Genetic variants within the dopaminergic system interact to modulate endocrine stress reactivity and recovery.

Catecholamines modulate endocrine stress reactivity by affecting regulatory influences of extra-hypothalamic brain structures on hypothalamus-pituitary-adrenal (HPA)-axis. Therefore, we aimed to investigate combined effects of functional allelic variations that affect dopamine availability in both cortical (COMT Val¹58Met polymorphism) and subcortical (DAT1 VNTR) brain regions on HPA-axis reactivity to psychosocial stress. By using a standardized laboratory stress task (public speaking) we obtained saliva cortisol samples during stress exposure and an extended recovery period in 100 healthy male adults. We report for the first time significant epistasis between COMT Val¹58Met and DAT1 VNTR on cortisol response patterns. Subjects homozygous for both the Met¹58 and the 10-repeat allele of DAT1 VNTR were characterized by markedly elevated cortisol reactivity and impaired stress recovery compared to all other groups. Our results indicate a crucial role of functional genetic variants within the dopaminergic system in the modulation of HPA-axis response patterns and highlight the need to investigate combined effects of specific candidate genes on stress-related endophenotypes.

Beyond revenge: neural and genetic bases of altruistic punishment.

It is still debated how altruistic punishment as one form of strong reciprocity has established during evolution and which motives may underlie such behavior. Recent neuroscientific evidence on the activation of brain reward regions during altruistic punishment in two-person one-shot exchange games suggests satisfaction through the punishment of norm violations as one underlying motive. In order to address this issue in more detail, we used fMRI during a one-shot economic exchange game that warrants strong reciprocity by introducing a third party punishment condition wherein revenge is unlikely to play a role. We report here that indeed, reward regions such as the nucleus accumbens showed punishment-related activation. Moreover, we provide preliminary evidence that genetic variation of dopamine turnover impacts similarly on punishment-related nucleus accumbens activation during both first person and third party punishment. The overall pattern of results suggests a common cognitive-affective-motivational network as the driving force for altruistic punishment, with only quantitative differences between first person and third party perspectives.

The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress.

BACKGROUND: Growing evidence suggests that individual differences in HPA-axis reactivity to psychosocial stress are partly due to heritable influences. However, knowledge about the role of specific genetic variants remains very limited to date. Since brain-derived neurotrophic factor (BDNF) not only exhibits neurotrophic actions but is also involved in the regulation of hypothalamic neuropeptides, we investigated the role of a common functional polymorphism within the BDNF gene (BDNF Val66Met) in the context of endocrine and cardiovascular stress reactivity. METHODS: Healthy male adults (N=100) were genotyped and exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol and self-reported mood levels were obtained at 6 time points prior to the stressor and during an extended recovery period. Furthermore, heart rate reactivity as an indicator of sympathetic activation was monitored continuously during the experimental procedure. RESULTS: We report a small, but significant effect of the BDNF Val66Met polymorphism on stress reactivity. More precisely, carriers of the met-allele showed a significantly attenuated HPA-axis and cardiovascular reactivity to the psychosocial stressor compared to subjects with the val/val genotype. Furthermore, the diminished physiological response in met-allele carriers was also attended by significantly lower self-reported ratings of perceived stress and nervousness. CONCLUSION: Our findings of a diminished endocrine and cardiovascular stress response in healthy male adults is consistent with a previously published study and adds further evidence for a crucial role of the BDNF Val66Met polymorphism in the modulation of stress reactivity.

Aggression--interactions of serotonin and testosterone in healthy men and women.

Serotonin (5-HT) and testosterone (T) have both been implicated in the regulation of aggression. Findings in humans however are very inconclusive, with respect to main effects of either system. Animal models implicate T to modulate 5-HT system activity, and furthermore have shown behaviorally relevant interactions of T and 5-HT with respect to aggression. We tested for associations between habitual T-level and 5-HT system activity, as well as behaviorally relevant interactions of T and 5-HT with respect to trait aggression in 48 healthy male and female subjects. 5-HT activity was measured by means of neuroendocrine challenge paradigm with S-citalopram. T-levels were measured in saliva samples. Trait aggression was assessed by self-report measures. T-levels were not associated with indices of central 5-HT activity. Results showed significant interaction effects between 5-HT and T for trait aggression in men only (p<0.05). Trait aggression was significantly higher in the combinations "high T+high cortisol responses" (indicating decreased 5-HT availability), and "low T+low cortisol responses" (indicating increased 5-HT availability), after S-citalopram. Results support the notion of behaviorally relevant interactions between T and 5-HT, with respect to aggression in humans, but also indicate the need for further studies.

Gene-environment interactions predict cortisol responses after acute stress: implications for the etiology of depression.

BACKGROUND: Growing evidence suggests that the serotonin transporter polymorphism (5-HTTLPR) interacts with adverse environmental influences to produce an increased risk for the development of depression while the underlying mechanisms of this association remain largely unexplored. As one potential intermediate phenotype, we investigated alterations of hypothalamic-pituitary-adrenal (HPA) axis responses to stress in individuals with no history of psychopathology depending on both 5-HTTLPR and stressful life events. METHODS: Healthy male adults (N=100) were genotyped and completed a questionnaire on severe stressful life events (Life Events Checklist). To test for gene-by-environment interactions on endocrine stress reactivity, subjects were exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol levels were obtained at 6 time points prior to the stressor and during an extended recovery period. RESULTS: Subjects homozygous for the s-allele with a significant history of stressful life events exhibited markedly elevated cortisol secretions in response to the stressor compared to all other groups, indicating a significant gene-by-environment interaction on endocrine stress reactivity. No main effect of either 5-HTTLPR (biallelic and triallelic) or stressful life events on cortisol secretion patterns appeared. CONCLUSION: This is the first study reporting that 5-HTTLPR and stressful life events interact to predict endocrine stress reactivity in a non-clinical sample. Our results underpin the potential moderating role of HPA-axis hyper-reactivity as a premorbid risk factor to increase the vulnerability for depression in subjects with low serotonin transporter efficiency and a history of severe life events.

The 5-HT1A C(-1019)G polymorphism, personality and electrodermal reactivity in a reward/punishment paradigm.

During past years the 5-HT(1A) C(-1019)G polymorphism has been associated with vulnerability to depression, anxiety-disorder and personality traits related to negative emotionality (e.g. neuroticism). Many of these studies focused on case-control comparisons or associations between genetic markers and personality traits assessed by the use of questionnaires. In contrast, overt behaviour and physiological measures in experimental paradigms, although very promising, have seldom been the focus of studies investigating the role of the 5-HT(1A) polymorphism for behaviour and psychopathology. To fill this gap, we examined the relationship between the 5-HT(1A) C(-1019)G polymorphism and reaction times (in a reward/punishment paradigm) as well as electrodermal activity, as a marker of autonomic arousal, in 123 healthy subjects. This paradigm seems very promising, as sensitivity to punishment in particular, is strongly associated to traits related to negative emotionality. Carriers of the GG genotype, which is related to increased expression of 5-HT(1A) autoreceptors, exhibited increased reaction times when they were able to win money (reward condition). In direct contrast to the reward condition, these subjects show faster reaction times in the punishment condition (losing money). Moreover, GG carriers are characterized by an enhanced electrodermal activity in all experimental conditions (win, lose and verbal feedback). Finally, the reaction-time pattern mentioned was related to higher scores on negative emotionality as revealed by self-reports. These findings demonstrate for the first time that the 5-HT(1A) polymorphism is related to personality on the level of a triadic approach including behaviour, physiology and self-reports.

TPH2 gene variation and conflict processing in a cognitive and an emotional Stroop task.

Evidence suggests that a promoter polymorphism of the tryptophan-hydroxylase 2 gene (TPH2 -703 G/T) is associated with executive control functions. The current study aimed to clarify whether this relation is restricted to a purely cognitive domain or whether such an effect can also be observed in the processing of emotional material. In a sample of 89 student subjects, a 'cognitive' and an 'emotional' Stroop paradigm were applied to measure processing of cognitive and affective conflicts. Our results suggest an impact of the TPH2 -703 G/T polymorphism on executive control in both, the cognitive as well as the emotional task. In detail, homozygous carriers of the T allele showed decelerated responses in low-conflict conditions, pointing to a rather abnormal functioning of higher-order control mechanisms. Thus, the present investigation is consistent with previous behavioural studies and adds further evidence for the impact of serotonin at the interface of cognition and emotion.

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.

Molecular genetics support Gray's personality theory: the interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system.

The present study provides the first direct molecular genetics support for Gray's Reinforcement Sensitivity Theory (RST), which is one of the most influential biologically oriented personality theories. It was investigated whether the DRD2 TaqIA and the COMT polymorphisms were related to the dimensions of Gray's personality theory, as measured by the Carver and White BIS/BAS scales. In a sample of 295 healthy subjects results revealed significant DRD2xCOMT interactions (i.e. epistasis) for the total BAS scale (related to positive emotionality) and for the subscales Drive (D) and Fun Seeking (FS). High BAS scores were observed if the catabolic enzyme activity and the D2 receptor density as indicated by the two polymorphisms were in disequilibrium, i.e. in the presence of the Val-/A1- (low enzyme activity/high receptor density) or the Val+/A1+ (high enzyme activity/low receptor density) alleles. In a random subsample (n=48), it could be demonstrated that those allele combinations of COMT and DRD2 associated with high BAS scores also had significantly lower prolactin levels under resting conditions, indicating high dopamine activity, compared to those allele combinations with low BAS scores. Furthermore, two-way interactions of DRD2 TaqIAxsmoking status and of the Met allele of COMTxsmoking status on FS and Metxgender on BIS could be shown.

[An assessment of patient education programmes for patients with type 1 and 2 diabetes, asthma and COPD, coronary heart disease, hypertension, congestive heart failure, and breast cancer in Germany]. / Erhebung und Bewertung von Schulungs- programmen für Patienten mit Diabetes mellitus Typ 1 und Typ 2, Asthma und COPD, KHK, Hypertonie, Herzinsuffizienz und Brustkrebs in Deutschland.

BACKGROUND: Patient education programmes will be a mandatory part of the new legislation on disease management programmes for chronic diseases in Germany. Today, only little is known about the number, variety and effectiveness of implemented patient education programmes in Germany. METHODS: 176 potential providers of patient education programmes were identified by literature search, Internet search, and interviews with health education experts. We developed a semi-structured questionnaire. Assessment of content and quality was conducted in two steps by using defined criteria of the Co-ordinating Committee, the Head Association of the statutory health insurances and the respective Medical Associations: the first step was to check whether the programme had a structured teaching concept and whether all requirements for education with respect to a given disease had been taken into account. In the second step, we used balance sheets for reviewing the strengths and weaknesses of the programmes. RESULTS: 49 providers handed in 95 pa tient education programmes for assess ment. Due to formal mistakes only 91 programmes could be analysed. 49 programmes failed the criteria of the first assessment step. For the remaining 42 patient education programmes balance sheets were prepared. Areas of the most frequent deficiencies included: lack of scientific evaluation of the effectiveness of the programme, lack of transparency of cost data, and quality improvement activities. CONCLUSIONS: For the purpose of a nation-wide implementation of disease management programmes the existing patient education programmes in Germany need to be further improved. Single examples demonstrated that the accessible criteria of self-management are not sufficient for the evaluation of already established patient education programmes.