Neural and cortisol responses to acute psychosocial stress in work-related burnout: The Regensburg Burnout Project.

BACKGROUND: While several attempts have been made to elucidate the pathophysiology of burnout, neural stress responses have not yet been investigated. Therefore, the aim of this study was to examine salivary cortisol and - for the first time - neural responses to acute psychosocial stress within a strictly specified sample consisting of individuals suffering from burnout (BO group) and a healthy comparison group (HC group). METHODS: After a multi-stage recruitment procedure based on burnout symptomatology and pathogenesis, 55 individuals suffering from burnout (25 women) and 61 individuals serving as HC group (31 women) out of an initial sample of 1022 volunteers were exposed to acute psychosocial stress during functional magnetic resonance imaging (fMRI) applying ScanSTRESS. RESULTS: No differences were found between the BO and the HC group with respect to cortisol and mean neural stress responses. However, an exploratory comparison of neural stress responses of the first and second run of ScanSTRESS (exposure-time effect) revealed group-specific response patterns in one cluster peaking in the left dorsal anterior cingulate cortex (dACC). While the neural activation of the HC group was higher in the first compared to the second run of ScanSTRESS (i.e., decreasing activation), this pattern was reversed in the BO group (i.e., increasing activation). CONCLUSIONS: Our analysis mainly did not provide evidence for altered acute cortisol and mean neural stress responses in burnout. However, the BO group was characterized by a limited capacity to show decreasing activation over stress exposure-time and exhibited instead increasing activation. Importantly, this group difference manifested in the left dACC which is both involved in neural stress processing and affected in individuals suffering from burnout. Given the present results, it seems promising to further examining temporal dynamics of neural stress responses in (sub-) clinical conditions such as burnout.

Neural responses to acute stress predict chronic stress perception in daily life over 13 months.

The importance of amygdala, hippocampus, and medial prefrontal cortex (mPFC) for the integration of neural, endocrine, and affective stress processing was shown in healthy participants and patients with stress-related disorders. The present manuscript which reports on one study-arm of the LawSTRESS project, aimed at investigating the predictive value of acute stress responses in these regions for biopsychological consequences of chronic stress in daily life. The LawSTRESS project examined law students either in preparation for their first state examination (stress group [SG]) or in the mid-phase of their study program (control group [CG]) over 13 months. Ambulatory assessments comprising perceived stress measurements and the cortisol awakening response (CAR) were administered on six sampling points (t1 = - 1 year, t2 = - 3 months, t3 = - 1 week, t4 = exam, t5 = + 1 week, t6 = + 1 month). In a subsample of 124 participants (SG: 61; CG: 63), ScanSTRESS was applied at baseline. In the SG but not in the CG, amygdala, hippocampus, and (post-hoc analyzed) right mPFC activation changes during ScanSTRESS were significantly associated with the trajectory of perceived stress but not with the CAR. Consistent with our finding in the total LawSTRESS sample, a significant increase in perceived stress and a blunted CAR over time could be detected in the SG only. Our findings suggest that more pronounced activation decreases of amygdala, hippocampus, and mPFC in response to acute psychosocial stress at baseline were related to a more pronounced increase of stress in daily life over the following year.

Association of polygenic scores for depression and neuroticism with perceived stress in daily life during a long-lasting stress period.

Genetic factors contribute significantly to interindividual differences in the susceptibility to stress-related disorders. As stress can also be conceptualized as environmental exposure, controlled gene-environment interaction (GxE) studies with an in-depth phenotyping may help to unravel mechanisms underlying the interplay between genetic factors and stress. In a prospective-longitudinal quasi-experimental study, we investigated whether polygenic scores (PGS) for depression (DEP-PGS) and neuroticism (NEU-PGS), respectively, were associated with responses to chronic stress in daily life. We examined law students (n = 432) over 13 months. Participants in the stress group experienced a long-lasting stress phase, namely the preparation for the first state examination for law students. The control group consisted of law students without particular stress exposure. In the present manuscript, we analyzed perceived stress levels assessed at high frequency and in an ecologically valid manner by ambulatory assessments as well as depression symptoms and two parameters of the cortisol awakening response. The latter was only assessed in a subsample (n = 196). No associations between the DEP-PGS and stress-related variables were found. However, for the NEU-PGS we found a significant GxE effect. Only in individuals experiencing academic stress a higher PGS for neuroticism predicted stronger increases of perceived stress levels until the exam. At baseline, a higher NEU-PGS was associated with higher perceived stress levels in both groups. Despite the small sample size, we provide preliminary evidence that the genetic disposition for neuroticism is associated with stress level increases in daily life during a long-lasting stress period.

Associations between cortisol stress responses and limbic volume and thickness in young adults: An exploratory study.

The investigation of the relationship between neural measures of limbic structures and hypothalamic pituitary adrenal axis responses to acute stress exposure in healthy young adults has so far focused in particular on task-based and resting state functional connectivity studies. Thus, the present study examined the association between limbic volume and thickness measures and acute cortisol responses to the psychosocial stress paradigm ScanSTRESS. Using Permutation Analysis of Linear Models controlling for sex, age and total brain volume, the associations between (sex-specific) cortisol increases and human connectome project style anatomical variables of limbic structures (i.e. volume and thickness) were investigated in 66 healthy and young (18-33 years) subjects (35 men, 31 women taking oral contraceptives). In addition, exploratory (sex-specific) bivariate correlations between cortisol increases and structural measures were conducted. The present data provide interesting new insights into the involvement of striato-limbic structures in psychosocial stress processing, suggesting that acute cortisol stress responses are also associated with mere structural measures of the human brain. Thus, our preliminary findings suggest that not only situation- and context-dependent reactions of the limbic system (i.e. blood oxygenation level-dependent reactions) are related to acute (sex-specific) cortisol stress responses but also basal and somewhat more constant structural measures. Our study hereby paves the way for further analyses in this context and highlights the relevance of the topic.

Investigation of cross-sectional and longitudinal associations between work-related burnout and hair cortisol: The Regensburg Burnout Project.

BACKGROUND: Burnout is characterized by feelings of exhaustion, depersonalization as well as reduced personal accomplishment and is linked to various negative health effects. Previous studies on biological correlates of burnout have focused on the hypothalamic-pituitary-adrenal (HPA) axis. However, especially studies on hair cortisol concentrations (HCC) were often based on cross-sectional data and yielded inconsistent results, probably due to the heterogeneity of the selected samples. Accordingly, the aim of the present study was to investigate cross-sectional as well as longitudinal associations between burnout and HCC within a sample consisting of a strictly specified group of individuals suffering from burnout (BO group) and a healthy comparison group (HC group). METHODS: After a multi-stage recruitment procedure based on burnout symptoms and pathogenesis, eligible subjects (out of an initial sample of 1022 volunteers) were assigned either to a BO (n = 55) or HC group (n = 59), as described in detail in Bärtl et al. (2022). Burnout symptoms as well as HCC (1 cm hair samples) were measured repeatedly at two sampling time points t1 (n = 114) and t2 (n = 100) with an interval of M = 7.20 months (SD = 1.16) between assessments. RESULTS: In the total study sample, no cross-sectional associations between burnout and HCC were found either at t1 or at t2. When the analysis was restricted to the BO group, HCC was positively related to burnout symptomatology at t1 but not t2. In the longitudinal analysis, burnout symptoms at t1 were significant negative predictors of HCC at t2. However, the change in HCC from t1 to t2 was not associated with the change in burnout symptoms. CONCLUSIONS: In the present study, we investigated the association between HCC and burnout in a strictly defined sample of subjects suffering from burnout and healthy controls. Our findings mainly do not support our hypotheses. At least, the positive association between HCC and burnout symptoms only within the BO group supports the idea that HPA axis alterations in burnout might only become apparent once a certain threshold of burnout symptomatology has been exceeded, while the longitudinal data provide some empirical evidence for the potential long-term development of hypocortisolism in burnout. However, respective results remain relatively inconclusive.

Comparing two psychosocial stress paradigms for imaging environments - ScanSTRESS and fNIRS-TSST: Correlation structures between stress responses.

The present post-hoc analysis of two independent studies conducted in different laboratories aimed at comparing reactions of stress activation systems in response to two different psychosocial stress induction paradigms. Both paradigms are based on the Trier Social Stress Test (TSST) and suited for neuroimaging environments. In an in-depth analysis, data from 67 participants (36 men, 31 women) from a functional magnetic resonance imaging study implementing ScanSTRESS were compared with data from a functional near-infrared spectroscopy (fNIRS) study implementing the so-called 'fNIRS-TSST' including 45 participants (8 men, 37 women). We tested the equivalence of correlation patterns between the stress response measures cortisol, heart rate, affect, and neural responses in the two samples. Moreover, direct comparisons of affective and neural responses were made. Similar correlation structures were identified for all stress activation systems, except for neural contrasts of paradigm conditions (stress vs. control) showing significant differences in association with cortisol, heart rate, and affective variables between the two samples. Furthermore, both stress paradigms elicited comparable affective and cortical stress responses. Apart from methodological differences (e.g., procedure, timing of the paradigms) the present analysis suggests that both paradigms are capable of inducing moderate acute psychosocial stress to a comparable extent with regard to affective and cortical stress responses. Moreover, similar association structures between different stress response systems were found in both studies. Thus, depending on the study objective and the respective advantages of each imaging approach, both paradigms have demonstrated their usefulness for future studies.

The association between genetic variability in the NPS/NPSR1 system and chronic stress responses: A gene-environment-(quasi-) experiment.

The neuropeptide S (NPS) and its receptor (NPSR1) have been implicated in stress regulation and stress-related disorders. The present study aimed at investigating the association between overall genetic variability in the NPS/NPSR1 system and psychological and cortisol stress regulation in everyday life. Our study was conceptualized as a gene-environment-(quasi-) experiment, a design that facilitates the detection of true GxE interactions. As environmental variable, we used the preparation for the first state examination for law students. In the prospective and longitudinal LawSTRESS project, students were examined at six sampling points over a 13-months period. While students who prepared for the exam and experienced long-lasting and significant stress, formed the stress group, law students experiencing usual study-related workload were assigned to the control group. As phenotypes we assessed changes over time in the cortisol awakening response (CAR; n = 176), perceived stress levels (n = 401), and anxiety symptoms (n = 397). The CAR was assessed at each sampling point immediately upon awakening and 30 as well as 45 min later. Perceived stress levels in daily life were measured by repeated ambulatory assessments and anxiety symptoms were repeatedly assessed with the anxiety subscale of the Hospital Anxiety and Depression Scale. With gene-set analyses we examined the joint association of 936 NPS/NPSR1 single nucleotide polymorphisms with the phenotypes to overcome well known limitations of candidate gene studies. As previously reported, we found a blunted CAR during the exam as well as significant increases in perceived stress levels and anxiety symptoms until the exam in the stress group, compared to the control group. The gene-set analysis did not confirm associations between genetic variability in the NPS/NPSR1 system and changes in perceived stress levels and anxiety symptoms. Regarding the CAR, we found a significant GxE interaction for the area under the curve with respect to the ground (p = .050) and a trend towards a significant effect for the area under the curve with respect to the increase (p = .054). When the analysis was restricted to the SG, associations for both CAR parameters were significant (ps < .050). This finding suggests that the association between genetic variability in the NPS/NPSR1 system and the CAR becomes visible under the environmental condition 'chronic stress exposure'. We conclude that the present study complements findings from animal models and that it provides novel evidence for a modulatory influence of the NPS/NPSR1 system on cortisol regulation in humans.

Higher allostatic load in work-related burnout: The Regensburg Burnout Project.

BACKGROUND: Burnout and chronic work stress have been linked to various negative health outcomes. While the mechanisms underlying this interplay are still unclear, the allostatic load (AL) model was suggested to demonstrate a possible biological pathway. However, previous studies provided divergent results regarding the association between burnout and AL, probably also due to the heterogeneity of selected samples. Therefore, the aim of the present study was to examine differences in AL between a conceptually strictly specified group of individuals suffering from burnout (BO group) and a healthy comparison group (HC group). METHODS: After a multi-stage recruitment procedure with strict inclusion criteria based on burnout symptomatology and pathogenesis, the BO group (n = 56) was compared to the HC group (n = 65) regarding an index of AL. The AL-index included 14 parameters: high-sensitivity c-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), fibrinogen, d-dimer, plasminogen activator inhibitor 1 (PAI-1), glycosylated hemoglobin (HbA1c), high-density lipoprotein (HDL) cholesterol, total cholesterol to HDL cholesterol ratio (TC/HDL), dehydroepiandrosterone-sulphate (DHEA-S), systolic blood pressure (SBP), diastolic blood pressure (DBP), waist-hip ratio (WHR), and body fat percentage. RESULTS: The BO group showed significantly higher AL-scores in comparison to the HC group. This effect remained significant after adjusting for sex, age, and smoking status. Additionally, burnout symptoms (assessed with the Maslach Burnout Inventory; MBI), MBI-subscales emotional exhaustion and depersonalization as well as chronic work stress (assessed with the effort-reward imbalance questionnaire) were significantly associated with higher AL-scores. CONCLUSIONS: Consistent with our hypothesis, we detected higher AL-scores in the BO compared to the HC group, indicating a greater cumulative physiological burden in individuals suffering from burnout. Given the high heterogeneity in individuals experiencing burnout symptoms, future studies may focus on well-specified subgroups, when examining the association between burnout and psychophysiological dysregulations.

Daily life stress and the cortisol awakening response over a 13-months stress period - Findings from the LawSTRESS project.

The LawSTRESS project is a controlled prospective-longitudinal study on psychological, endocrine, central nervous and genetic predictors of responses to long-lasting academic stress in a homogenous cohort. In this first project report, we focused on the association between daily life stress and the cortisol awakening response (CAR). The CAR, a distinct cortisol rise in the first 30-45 min after morning awakening, is a well-established marker of cortisol regulation in psychoneuroendocrinology. Law students from Bavarian universities (total n = 452) have been studied over a 13-months period at six sampling points starting 12 months prior exam. The stress group (SG) consisted of students experiencing a long-lasting and significant stress period, namely the preparation for the first state examination for law students. Law students assigned to the control group (CG) were studied over an equally long period without particular and sustained stress exposure. To investigate stress related alterations in the CAR, we examined a subsample of the LawSTRESS project consisting of 204 students with 97 participants from the SG (69.1% female, mean age = 22.84 ± 1.82) and 107 from the CG (78.5% female, mean age = 20.95 ± 1.93). At each sampling point, saliva samples for cortisol assessment were collected immediately upon awakening and 30 as well as 45 min later. Perceived stress in daily life was measured by repeated ambulatory assessments (about 100 queries over six sampling points). The time course of perceived stress levels in the two groups differed significantly, with the SG showing an increase in perceived stress until the exam and a decrease thereafter. Stress levels in the CG were relatively stable. The CAR was not significantly different between groups at baseline. However, a blunted CAR in the SG compared to the baseline measure and to the CG developed over the measurement timepoints and reached significance during the exam. Remarkably, this effect was neither associated with the increase in perceived stress nor with anxiety and depression symptoms, test anxiety and chronic stress at baseline. The present study successfully assessed multidimensional stress trajectories over 13 months and it documented the significant burden, law students preparing for the first state examination are exposed to. This period was related to a blunted CAR with presumed physiological consequences (e.g., on energy metabolism and immune function). Mean psychological stress levels as well as the CAR returned to baseline levels after the exam, suggesting a fast recovery in the majority of the participants.

Dissociation of behavioral and neural responses to provocation during reactive aggression in healthy adults with high versus low externalization.

The externalizing spectrum describes a range of heterogeneous personality traits and behavioral patterns, primarily characterized by antisocial behavior, disinhibition, and substance (mis)use. In psychopathology, abnormalities in neural threat, reward responses and the impulse-control system may be responsible for these externalizing symptoms. Within the non-clinical range, mechanisms remain still unclear. In this fMRI-study, 61 healthy participants (31 men) from the higher versus lower range of the non-clinical variation in externalization (31 participants with high externalization) as assessed by the subscales disinhibition and meanness of the Triarchic-Psychopathy-Measure (TriPM) performed a monetary modified Taylor-Aggression-Paradigm (mTAP). This paradigm consisted of a mock competitive-reaction-time-task played against a fictional opponent with preprogrammed win- and lose-trials. In lose-trials, participants were provoked by subtraction of an amount of money between 0 and 90 cents. As a manipulation check, provocation induced a significant rise in behavioral aggression levels linked with an increased activation in the anterior cingulate cortex (ACC). High externalization predicted reduced ACC responses to provocation. However, high externalizing participants did not behave more aggressively than the low externalization group. Additionally, the high externalizing group showed a significantly lower positive affect while no group differences emerged for negative affect. In conclusion, high externalization in the non-clinical range was related to neural alterations in regions involved in affective decision-making as well as to changes in affect but did not lead to higher behavioral aggression levels in response to the mTAP. This is in line with previous findings suggesting that aberrations at multiple levels are essential for developing externalizing disorders.

Sex-specific interaction between cortisol and striato-limbic responses to psychosocial stress.

Although women and men differ in psychological and endocrine stress responses as well as in the prevalence rates of stress-related disorders, knowledge on sex differences regarding stress regulation in the brain is scarce. Therefore, we performed an in-depth analysis of data from 67 healthy participants (31 women, taking oral contraceptives), who were exposed to the ScanSTRESS paradigm in a functional magnetic resonance imaging study. Changes in cortisol, affect, heart rate and neural activation in response to psychosocial stress were examined in women and men as well as potential sex-specific interactions between stress response domains. Stress exposure led to significant cortisol increases, with men exhibiting higher levels than women. Depending on sex, cortisol elevations were differently associated with stress-related responses in striato-limbic structures: higher increases were associated with activations in men but with deactivations in women. Regarding affect or heart rate responses, no sex differences emerged. Although women and men differ in their overall stress reactivity, our findings do not support the idea of distinct neural networks as the base of this difference. Instead, we found differential stress reactions for women and men in identical structures. We propose considering quantitative predictors such as sex-specific cortisol increases when exploring neural response differences of women and men.

Increasing Deactivation of Limbic Structures Over Psychosocial Stress Exposure Time.

BACKGROUND: Understanding the interplay between central nervous system and hypothalamic-pituitary-adrenal axis responses to stress in humans is assumed to be essential to contribute to the central question of stress research, namely how stress can increase disease risk. Therefore, the present study used a neuroimaging stress paradigm to investigate the interplay of 3 stress response domains. Furthermore, we asked if the brain's stress response changes over exposure time. METHODS: In a functional magnetic resonance imaging study, changes in brain activation, cortisol levels, affect, and heart rate in response to an improved ScanSTRESS protocol were assessed in 67 young, healthy participants (31 females). RESULTS: Stress exposure led to significant increases in cortisol levels, heart rate, and negative affect ratings as well as to activations and deactivations in (pre)limbic regions. When cortisol increase was used as a covariate, stronger responses in the hippocampus, amygdala, medial prefrontal cortex, and cingulate gyrus were observed. Responses within the same regions predicted negative affect ratings. Remarkably, an increasing deactivation over the two ScanSTRESS runs was found, again, in the same structures. A reanalysis of an independent sample confirmed this finding. CONCLUSIONS: For the first time, reactions in a cluster of (pre)limbic structures was consistently found to be associated with changes in cortisol and negative affect. The same neural structures showed increasing deactivations over stress exposure time. We speculate that investigating possible associations between exposure-time effects in neural stress responses and stress-related interindividual differences (e.g., chronic stress) might be a promising new avenue in stress research.

Decision-making in everyday moral conflict situations: Development and validation of a new measure.

In everyday life, we are often confronted with morally conflicting social interaction situations. Therefore, the main objective of the present set of studies was the development and validation of a new measure to assess decision-making in everyday moral conflict situations. All vignettes required a decision between an altruistic versus an egoistic behavioral response alternative. In three independent surveys (N = 200), we developed a 40-items measure with preferable mean rates of altruistic decisions (Study 1), clear representation of altruistic and egoistic response classes (Study 2), unambiguousness of social closeness classifications (socially close vs. socially distant protagonists; Studies 1 and 2), and high similarity to reality ratings (Studies 1 and 2). Additionally, we developed two parallelized item sets for future use in within-subjects design studies and investigated the measurement properties of our new scale (Studies 1 and 3). Results of Rasch model analyses and classical test theory fit indices showed unidimensionality and confirmed the appropriateness of the fragmentation into two parallelized item sets. Notably, in our data, there were neither effects of social closeness nor gender on the percentage of altruistic decisions. In sum, we propose the Everyday Moral Conflict Situations (EMCS) Scale as a promising new measurement tool that may facilitate further research in different research areas due to its broad applicability.

Measuring the reliability of picture story exercises like the TAT.

As frequently reported, psychometric assessments on Picture Story Exercises, especially variations of the Thematic Apperception Test, mostly reveal inadequate scores for internal consistency. We demonstrate that the reason for this apparent shortcoming is not caused by the coding system itself but from the incorrect use of internal consistency coefficients, especially Cronbach's α. This problem could be eliminated by using the category-scores as items instead of the picture-scores. In addition to a theoretical explanation we prove mathematically why the use of category-scores produces an adequate internal consistency estimation and examine our idea empirically with the origin data set of the Thematic Apperception Test by Heckhausen and two additional data sets. We found generally higher values when using the category-scores as items instead of picture-scores. From an empirical and theoretical point of view, the estimated reliability is also superior to each category within a picture as item measuring. When comparing our suggestion with a multifaceted Rasch-model we provide evidence that our procedure better fits the underlying principles of PSE.

The a(d) coefficient as a descriptive measure of the within-group agreement of ratings.

The a(d) coefficient was developed to measure the within-group agreement of ratings. The underlying theory as well as the construction of the coefficient are explained. The a(d) coefficient ranges from 0 to 1, regardless of the number of scale points, raters, or items. With some limitations the measure of the within-group agreement of different groups and groups from different studies is directly comparable. For statistical significance testing, the binomial distribution is introduced as a model of the ratings' random distribution given the true score of a group construct. This method enables a decision about essential agreement and not only about a significant difference from 0 or a chosen critical value. The a(d) coefficient identifies a single true score within a group. It is not provided for multiple true score settings. The comparison of the a(d) coefficient with other agreement indices shows that the new coefficient is in line with their outcomes, but does not result in infinite or inappropriate values.