What a difference timing makes: Cortisol effects on neural underpinnings of emotion regulation.

The ability of emotion regulation under stress is of crucial importance to psychosocial health. Yet, the dynamic function of stress hormones for the cognitive control of emotions over time via non-genomic and genomic cortisol effects remains to be elucidated. In this randomized, double-blind, placebo-controlled neuroimaging experiment, 105 participants (54 men, 51 women) received 20 mg hydrocortisone (cortisol) or a placebo either 30min (rapid, non-genomic cortisol effects) or 90min (slow, genomic cortisol effects) prior to a cognitive reappraisal task including different regulatory goals (i.e., downregulate vs. upregulate negative emotions). On the behavioral level, cortisol rapidly reduced and slowly enhanced emotional responsivity to negative pictures. However, only slow cortisol effects improved downregulation of negative emotions. On the neural level, cortisol rapidly enhanced, but slowly reduced amygdala and dorsolateral prefrontal activation as well as functional connectivity between both structures in the down- minus upregulate contrast. This interaction speaks for an effortful but ineffective regulation of negative emotions during rapid cortisol effects and improved emotion regulation capacities during slow cortisol effects. Taken together, these results indicate a functional shift of cortisol effects on emotion regulation processes over time which may foster successful adaptation to and recovery from stressful life events.

Rapid effects of acute stress on cognitive emotion regulation.

Acute stress has been shown to either enhance or impair emotion regulation (ER) performances. Besides sex, strategy use and stimulus intensity, another moderating factor appears to be timing of the ER task relative to stress exposure. Whereas somewhat delayed increases in the stress hormone cortisol have been shown to improve ER performances, rapid sympathetic nervous system (SNS) actions might oppose such effects via cognitive regulatory impairments. Here, we thus investigated rapid effects of acute stress on two ER strategies: reappraisal and distraction. N = 80 healthy participants (40 men & 40 women) were exposed to the Socially Evaluated Cold-Pressor Test or a control condition immediately prior to an ER paradigm which required them to deliberately downregulate emotional responses towards high intensity negative pictures. Subjective ratings and pupil dilation served as ER outcomes measures. Increases in salivary cortisol and cardiovascular activity (index of SNS activation) verified successful induction of acute stress. Unexpectedly, stress reduced subjective emotional arousal when distracting from negative pictures in men indicating regulatory improvements. However, this beneficial effect was particularly pronounced in the second half of the ER paradigm and fully mediated by already rising cortisol levels. In contrast, cardiovascular responses to stress were linked to decreased subjective regulatory performances of reappraisal and distraction in women. However, no detrimental effects of stress on ER occurred at the group level. Yet, our findings provide initial evidence for rapid, opposing effects of the two stress systems on the cognitive control of negative emotions that are critically moderated by sex.

[Evaluation of the Effectiveness of the Clarification-Oriented Psychotherapy in Persons with a Narcissistic Personality Disorder According to DSM-IV - A Naturalistic Longitudinal Study with Pre-Post Design]. / Evaluation der Wirksamkeit der klärungsorientierten Psychotherapie bei Personen mit einer narzisstischen Persönlichkeitsstörung nach DSM-IV ­ eine naturalistische Längsschnittstudie mit prä-post Design.

BACKGROUND: The treatment of patients diagnosed with a narcissistic personality disorder (NPS) is considered to be extra challenging. Well-controlled studies on the effectiveness of psychotherapy in NPS patients are not available; so many interventions are based on theoretical constructs. The clarification-oriented psychotherapy (COP) is a psychotherapeutic approach, which emerged from concepts of the cognitive behavioral therapy, client-centered psychotherapy and various process-oriented procedures. The present ambulatory therapy-evaluation of COP aimed to evaluate the effectiveness of a psychotherapeutic treatment for patients suffering from NPS. METHODS AND RESULTS: Retrospective cohort-study including 173 treatment-seeking NPS-patients. Via pre-post per-protocol-analysis, significant improvements mostly with medium effect sizes were found in all relevant parameters after completion of the COP (58.6±10.5 sessions). In particular, the ambitious/narcissistic personality style in the "Personality Style and Disorders Inventory (PSSI)" (primary outcome) was improved (medium effect size: d=-0.49 [-0.67; -0.31], p<0.001). Analyses revealed even high effect sizes in terms of the improvement of depressive "states" and "traits", neuroticism as well as self-acceptance. The lowest effect sizes however were found for improvements in self-regulation (d=0.2 [0.03; 0.36], p=0.02). DISCUSSION: As no intention-to-treat analysis has been carried out, the effect sizes of COP in the treatment of NPS might be overestimated. Nevertheless, our findings support the use of COP for the treatment of NPS. In light of evidence-based medicine, the present so far most comprehensive study on this topic warranted an increase of the evidence of COP in the treatment of NPS from level IV to level III.

Acute stress influences strategy preference when dealing with high intensity emotions in men.

Stress has been shown to initiate a shift from flexible to rigid, less demanding cognitive processes. Reappraisal and distraction are two emotion regulation strategies varying in their cognitive demands. Previous studies indicate that stress improves regulatory performances of high arousal stimuli. We thus investigated whether acute stress alters the preference for reappraisal or distraction when downregulating emotions of different intensities and further explored its influence on regulatory outcomes. Eighty males were either socially stressed (n = 40) or exposed to a control condition (n = 40) prior to an emotion regulation choice paradigm. Stress increased the probability to prefer distraction for downregulating high intensity emotions. Stressed (vs. control) participants reported to be generally more successful in regulating high intensity emotions, which was positively associated with cortisol but not alpha-amylase increases. Our findings provide initial evidence that stress fosters a preference for less demanding regulatory options, suggesting favorable strategy choices in response to acute stressors.

Cortisol promotes the cognitive regulation of high intensive emotions independent of timing.

Failures to cognitively downregulate negative emotions are a crucial risk factor for mental disorders. Previous studies provide evidence for a stress-induced improvement of cognitive emotion regulation possibly mediated via glucocorticoid actions. Cortisol can initialize immediate non-genomic as well as delayed genomic effects on cognitive control functioning, but its distinct effects on emotion regulation processes remain to be shown. Here, we sought to characterize time-dependent effects of oral cortisol administration on cognitive emotion regulation outcomes. We expected cortisol to improve emotion regulation success. Possible interactions with the delay between cortisol treatment and emotion regulation, strategy use and intensity of the emotional stimuli were examined. Eighty-five healthy men received either 10 mg hydrocortisone or a placebo in a double-blind, randomized design 30 or 90 min prior to an emotion regulation paradigm, in which they were asked to downregulate their emotional responses towards low and high intensive negative pictures via reappraisal or distraction. Affective ratings and pupil dilation served as outcome measures. Reduced arousal, enhanced valence ratings as well as increases in pupil dilations indexing the cognitive regulatory effort indicated successful downregulation of negative emotions evoked by high intensive but not low intensive negative pictures. Cortisol significantly reduced arousal ratings when downregulating high intensive negative emotions via distraction and (at a trend level) via reappraisal, independent of timing, demonstrating a beneficial effect of cortisol on subjective regulatory outcomes. Taken together, this study provides initial evidence suggesting that cortisol promotes the cognitive control of high intensive negative emotions both, 30 and 90 min after treatment.

Delayed effects of acute stress on cognitive emotion regulation.

Acute stress has been shown to modulate cognitive emotion regulation. Besides interactions with strategy use or sex, another critical modulating factor appears to be stress timing. Exposure to acute stress initiates immediate and delayed glucocorticoid effects on cognitive control functions. Previous studies indicated a delayed increase in prefrontal activity after stress and cortisol elevations, which might also improve the ability to cognitively regulate emotions when the acute stress state has subsided. In this study, we investigated the delayed impact of acute stress on the two emotion regulation strategies reappraisal and distraction. Eighty-one healthy males and free-cycling females were exposed to the Trier Social Stress Test or a control condition 90 min before they were tested in an emotion regulation paradigm, which required them to up- and downregulate their emotional responses towards negative pictures. Affective ratings served to measure emotion regulation success, whereas pupil dilation was included to additionally assess the cognitive effort required to deliberately regulate emotions. Stress affected neither arousal, valence or success ratings nor pupil dilation. However, cortisol increases were significantly associated with reduced arousal and enhanced valence ratings when regulating negative emotions via distraction. Exploratory mediation analyses revealed an indirect effect of stress on arousal and valence ratings for distraction that was mediated by cortisol increase. Our findings thereby provide further evidence that cortisol is positively related to emotion regulation success, which might be driven by a glucocorticoid-mediated mechanism facilitating attentional shifting.

Acute stress improves the effectivity of cognitive emotion regulation in men.

Emotion regulation is crucial for coping with stressors but in turn can also be influenced by stress. Initial studies provided mixed evidence showing either beneficial or impairing stress effects on cognitive emotion regulation depending on stress timing, sex or the regulatory strategy. Here, we investigated the impact of acute stress on different emotion regulation strategies in men and women. N = 118 healthy participants were subjected to the Trier Social Stress Test or a control condition after which they completed an emotion regulation paradigm, requiring them to regulate their emotions in response to negative pictures using reappraisal or distraction. Cortisol levels were repeatedly measured to quantify changes in HPA axis activity. Affective ratings and pupil dilation served to measure emotion regulation success and the cognitive effort to regulate emotions. Stress reduced arousal and increased valence and success ratings for reappraisal in men, whereas no significant stress effects were found in women. Moreover, stressed men displayed a significant expansion of pupil diameter during reappraisal suggesting enhanced cognitive regulatory engagement, which ultimately may have led to better emotion regulation outcomes. Cortisol secretion positively correlated with subjective reappraisal success in men, suggesting a glucocorticoid-driven mechanism that may promote emotion regulatory performance in the aftermath of stress.

Cortisol modulates the engagement of multiple memory systems: Exploration of a common NR3C2 polymorphism.

Exposure to acute stress has been shown to result in a shift from declarative toward non-declarative learning, presumably mediated by brain mineralocorticoid receptors (MRs). In this study, we aimed to replicate and extend these findings by investigating the role of stress-associated cortisol secretion on learning behavior. Furthermore, we explored the influence of a well-characterized common single nucleotide polymorphism of the MR gene (rs2070951; minor allele frequency: 49.3%) previously shown to influence MR expression and HPA axis activity. Healthy males (n = 74) were exposed to the Trier Social Stress Test or a control condition prior to performing a probabilistic classification task (Weather Prediction Task). The use of a non-declarative learning strategy continuously increased over the course of the learning task after stress exposure, but leveled in the control condition. The shift toward a non-declarative strategy in the stress group was associated with better learning performance. Higher pre-stress cortisol levels favored the adoption of a non-declarative learning strategy. rs2070951 C/C-carriers in contrast to G-allele carriers exhibited a larger secretion of cortisol under stress. Furthermore, control participants homozygous for the C-allele adopted a non-declarative learning strategy less often than stressed participants, whereas the choice of strategy was independent of stress in G-allele carriers. The failure to switch strategies resulted in poorer performance, suggesting a beneficial effect of stress in dependence of MR variation. Consistent with previous findings, the results provide further support for cortisol as a driving force in coordinating the competition between multiple memory systems under stress.

Polymorphisms within the C3 gene are associated with specific IgE levels to common allergens and super-antigens among atopic dermatitis patients.

Atopic dermatitis (AD) is a chronic inflammatory skin disease. Twin and family studies suggest a strong genetic component of the disease. The keratinocytes secrete high amounts of C3 after stimulation with pro-inflammatory cytokines, which may play a functional role in skin inflammation. In this study, we genotyped four different single nucleotide polymorphisms (SNPs) by melting curve analysis using sequence specific hybridization probes in a well-characterized cohort of AD patients. Among four SNPs within C3 gene, higher frequencies of rs10410674 (23.5% vs 12.2%) and rs366510 (13.8% vs 6.5%) were observed in AD patients as compared with control group. None of the tested polymorphisms showed significant association with the risk of the disease phenotype. Analysis of rs10402876 SNP revealed its association with less severe AD disease expression (low SCORAD). Total serum IgE levels were not different among AD patients having any of the four SNPs. However, we observed significantly less serum-specific IgE levels to common allergens (Dermatophagoides pteronyssinus and birch pollens) and Staphylococcal enterotoxin B in AD patients having rs366510 SNP. Thus, associations of polymorphism within C3 gene with less severe AD disease expression and a weaker sensitization to common allergens suggest the role of these SNPs in the development of AD.

Staphylococcus aureus-derived enterotoxins enhance house dust mite-induced patch test reactions in atopic dermatitis.

BACKGROUND: Up to 65% of Staphylococcus aureus strains isolated from the skin of patients with atopic dermatitis (AD) produce exotoxins with superantigenic properties that may also act as allergens leading to an induction of exotoxin-specific IgE antibodies. Staphylococcal enterotoxin B (SEB) applied epicutaneously in a concentration of 10 micro g/cm(2), i.e. 200 micro g/ml, under occlusion induces cutaneous inflammation in patients with AD and healthy individuals. METHODS: We performed patch tests in 32 adult patients with AD using different concentrations (i.e. 2-200 micro g/ml) of SEA, SEB and house dust mite (HDM) extract (500 micro g/ml). Furthermore, the respective enterotoxins and HDM extract were applied simultaneously to the same patch test site. Specific IgE levels to SEA, SEB and HDM were measured with the CAP FEIA. RESULTS: The rates of patch test reactions to SEA and SEB increased with rising enterotoxin concentrations. There were no differences in the rates of patch test reactions to SEA and SEB between patients sensitized to the corresponding enterotoxin and non-IgE-sensitized patients. The number of patch test reactions to the mixture of enterotoxin and HDM extract was higher than the number of patch test reactions to either the enterotoxins or HDM extract. We identified 11 patients with AD who reacted neither to the enterotoxins nor to HDM extract, but who showed patch test reactions to the mixture. These reactions were not predicted by the presence of enterotoxin- or HDM-specific IgE. CONCLUSIONS: Colonization with exotoxin-producing S. aureus may influence the outcome of patch tests in patients with AD.

Human dendritic cells express the IL-18R and are chemoattracted to IL-18.

IL-18 is secreted by a variety of cells such as epithelial cells, macrophages, and dendritic cells (DC), in particular, in areas of chronic inflammation. The effects of IL-18 are complex and not fully understood thus far. We sought to explore human DC as a new target for IL-18, since IL-18R expression has been described on myeloid cells such as macrophages and DC are likely to get in contact with IL-18 at sites of inflammatory reactions. We demonstrate the expression of the IL-18R on human DC in peripheral blood and epidermis, as well as monocyte-derived dendritic cells (MoDC). On MoDC, IL-18R expression is up-regulated by IFN-gamma. IL-18 strongly up-regulated CD54 on MoDC, whereas the effect on MHC class II, CD83, and CD86 was only moderate and the expression of CD40 and CD80 was not affected. MoDC primed with IL-18 did not increase their capacity to stimulate the proliferation or IFN-gamma production of autologous T cells. However, IL-18 had a direct migratory effect on MoDC as indicated by induction of filamentous actin polymerization and migration in Boyden chamber experiments. In epidermal DC, IL-18 was also able to induce filamentous actin polymerization. Therefore, IL-18 might represent a novel mechanism to recruit DC to areas of inflammation, in particular under Th1 cytokine conditions where IFN-gamma is increased such as psoriasis or inflammatory bowel diseases.

Up-regulation of C5a receptor expression and function on human monocyte derived dendritic cells by prostaglandin E2.

The expression of the C5a-receptor (C5aR) on dendritic cells, its regulation and function have not been well established thus far. We show that the C5aR is expressed on human monocyte-derived dendritic cells (DC) and can be down-regulated by maturation stimuli such as tumour necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS) or CD40L and by the T helper 1-cytokine interferon-gamma (INF-gamma). Prostaglandin E2 (PGE2), a proinflammatory mediator supporting dendritic cell activation and necessary for adequate DC migration, leads to the up-regulation of C5aR expression when incubated alone and prevents down-regulation when given in combination with TNF-alpha or LPS. Stimulation of C5aR on DC triggered F-actin polymerization, indicating the chemotactic potential of DC elicited by C5a. C5a induced F-actin polymerization was increased when C5aR was up-regulated by PGE2. Stimulation of DC with C5a resulted in interleukin-10 production which was significantly increased after C5aR up-regulation with TNF-alpha and PGE2. Therefore, up-regulation of the C5aR on human DC alters their chemotactic and immunologic response to C5a.

Expression and function of histamine receptors 1 and 2 on human monocyte-derived dendritic cells.

BACKGROUND: Histamine is a well-known mediator of inflammatory and allergic reactions and has immunomodulatory capacities. There is increasing evidence that dendritic cells as professional antigen-presenting cells play a major role in the development of allergic reactions. However, a possible link between histamine and dendritic cells has not been investigated thus far. OBJECTIVE: We investigated the effect of histamine on human monocyte-derived dendritic cells (MoDCs). METHODS: Expression of histamine H1 and H2 receptors (H1R and H2R) on MoDCs was assessed by means of RT-PCR and flow cytometry. Functional exploration of these receptors was performed by monitoring the increase of intracellular calcium levels (H1R), cyclic adenosine monophosphate formation (H2R), F-actin polymerization, and IL-12p70 production. RESULTS: MoDCs express both H1R and H2R. Stimulation of dendritic cells with histamine resulted in F-actin polymerization and cyclic adenosine monophosphate production through H2R. Influx of calcium could not be detected after stimulation of dendritic cells with histamine under conditions in which histamine induced calcium influx in monocytes. Histamine and H1R and H2R agonists downregulated IL-12p70 production of prestimulated MoDCs. CONCLUSION: MoDCs express histamine H1 and H2 receptors. Our results indicate chemotactic (F-actin polymerization) and immunomodulatory (inhibition of IL-12p70 production) effects of histamine on MoDCs. Therefore histamine might represent a link between immediate-type hypersensitivity reactions and cellular inflammation in allergic disease (eg, in atopic dermatitis).