Faculty Bibliography

Some people develop symptoms of posttraumatic stress disorder (PTSD) after having experienced a traumatic event, whereas others do not. Intrusive memories are a cardinal symptom of PTSD and a better understanding of encoding and consolidation of intrusive memory may yield important insights on differences in the response to trauma. The primary aim of this study is to investigate whether psychosocial stress induction (Trier Social Stress Test) versus active control (placebo version) leading to respective biological stress responses during the encoding and consolidation of a film-elicited analogue trauma influences the development of intrusive memories over the course of 7 consecutive days. We hypothesized that the activation of the biological stress system increases the number of intrusive memories over the course of 7 days. This single-blind randomized placebo-controlled study examined 122 young healthy women. Biological stress response was measured by salivary cortisol, salivary α-amylase activity, and heart rate variability. Generalized linear mixed models were used to analyze longitudinal effects of activation of biological stress response on self-reported number of intrusive memories. Cross-validated regularized regression (least absolute shrinkage and selection operator) was applied for data-driven feature selection including known biological and psychological predictors. Corroborating our hypothesis, biological stress-responders to the Trier Social Stress Test reported significantly more intrusive memories after trauma film. A priori designed post hoc tests point at significantly more intrusions on Day 1 and 2 in biological stress responders. Least absolute shrinkage and selection operator regression revealed salivary cortisol, salivary α-amylase activity, heart rate variability, subjectively rated distress, fear, and (on trend level) dissociation during the trauma film as relevant predictors of intrusive memories. A heightened biological stress response in young women is associated with more intrusive memories the first days after experiencing a trauma analogue. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

In a previous study, we found that - in contrast to healthy individuals - patients with borderline personality disorder (BPD) and post-traumatic stress disorder (PTSD) showed better memory retrieval performance after hydrocortisone administration compared to placebo. As these results suggest an altered function of corticosteroid receptors in the brain in PTSD and BPD, we examined the effect of hydrocortisone on brain activation in both disorders. We recruited 40 female healthy controls, 20 female unmedicated patients with PTSD and 18 female unmedicated patients with BPD. We conducted a placebo-controlled cross-over study, in which all participants underwent two resting state MRI measurements after they received either a placebo or 10 mg hydrocortisone orally and in randomized order. There was a time interval of one week between the measurements. We analysed resting state functional connectivity (RSFC) with the hippocampus and the amygdala as seed regions. Compared to healthy controls, both patient groups showed reduced hippocampus RSFC to dorsomedial prefrontal cortex (dmPFC). Positive hippocampus dmPFC RSFC correlated negatively with childhood trauma (r = -0.47) and with severity of clinical symptoms, measured with the Borderline Symptom List (r = -0.44) and the Posttraumatic Stress Diagnostic Scale (r = -0.45). We found neither differences in amygdala RSFC nor an effect of hydrocortisone administration. Childhood trauma might lead to decreased positive hippocampus dmPFC RSFC. This might explain symptoms of PTSD and BPD that are characterized by dysfunctional fear regulation.

Several studies found that acute stress leads to increased risk taking in humans. However, this effect appears to be time-dependent because the few studies that examined delayed (>40 min after stress onset) stress effects show in fact a decrease in risk taking. In 32 young healthy women, we intra-individually examined whether psychosocial stress decreases risk taking 80 min after stress induction. All participants performed the Balloon Analog Risk Task (BART) twice: once after exposure to the Trier social stress test (TSST) and once after a control condition Placebo-TSST (P-TSST). The experimental order was randomized across participants. The psychophysiological stress response increased after the TSST compared to the P-TSST, indicated by elevated cortisol concentrations, elevated alpha-amylase activity, and elevated blood pressure. We found a significant interaction of stress condition and experimental order. Compared to the control condition psychosocial stress decreased risk taking in novel decision situations but not when participants were already familiar with the BART from the prior condition. Delayed effects of psychosocial stress lead to a decrease in risk taking in unfamiliar but not familiar conditions 80 min after stress exposure. Lay summary It has been suggested that stress exerts delayed effects on risk taking propensity. We found that individuals who are exposed to psychosocial stress take less risk when confronted with novel decisions even 80 min after the stressor compared to individuals who are not stressed.

The steroid hormone cortisol is released in response to stress and exerts its effects in the brain via two different receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). This review - dedicated to Dirk Hellhammer - focusses on the role of MR on cognitive and emotional function in healthy individuals and in stress-associated disorders such as major depressive disorder (MDD) or borderline personality disorder (BPD). Animal data and studies from healthy individuals converge such that MR play an important role in the appraisal of new situations and the following response selection. Decision-making and empathy are important determinants of this response selection and both are affected by MR function. Furthermore, MR are crucially involved in visuospatial navigation and memory in young and elderly healthy individuals whereas the exact physiological role of MR in verbal learning and verbal memory needs to be further characterized. In contrast to studies in healthy participants, age played a moderating role on the effects of MR stimulation on cognition in depressed patients. In young depressed patients, MR stimulation exerted beneficial effects on verbal memory and executive function, whereas in elderly depressed patients MR stimulation led to impaired verbal learning and visuospatial memory. Similar to healthy controls, BPD patients showed enhanced emotional empathy but not cognitive empathy after MR stimulation. Accordingly, this make MR an interesting target for potential pharmacological augmentation of psychotherapy in BPD. Given the important role MR play in cognitive and emotional function in health and disease, further studies should examine whether MR modulation can alleviate cognitive and emotional problems in patients with stress-associated disorders.

BACKGROUND:Many depressed patients do not achieve response or remission despite adequate treatment. Identifying predictors of outcome can contribute to developing therapeutic algorithms for difficult-to-treat depression. Therefore, we examined clinical predictors of response and remission in a naturalistic inpatient sample undergoing multimodal treatment for depression. METHODS:Three hundred and fifty-one consecutive inpatients admitted to a tertiary care university hospital (specialized psychiatry unit for treatment of unipolar and bipolar depression) between January 2014 and December 2016 were characterized by a set of sociodemographic and clinical variables. The predictive value of these variables for response (≥ 50% decrease from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score) and remission (MADRS score at discharge < 10) were explored using bivariate analysis and logistic regression. RESULTS:Greater symptom severity and fewer psychotropic medications at the time of admission predicted response. Remission rates were higher for patients with non-chronic depression, higher number of previous depressive episodes, fewer psychotropic medications and less severe depression at admission. LIMITATIONS:This was a retrospective study without a control group. The sample was drawn from a single inpatient ward specialized for difficult-to-treat depression. CONCLUSIONS:Greater baseline depression severity might be a proxy for a less chronic course of depression thereby explaining its association with greater response rates. Fewer episodes in the past and polypharmacy could indicate treatment-resistance and chronicity, contributing to lower remission rates. Therefore, preventing chronicity should be a central aim of depression treatment.

Converging evidence suggests that a single sub-anesthetic dose of ketamine can produce strong and rapid antidepressant effects in patients that do not respond to standard treatment. Despite a considerable amount of research investigating ketamine's mechanisms of action, the exact neuronal targets conveying the antidepressant effects have not been identified yet. Preclinical studies suggest that molecular changes induced by ketamine bring forward large-scale network reconfigurations that might relate to ketamine's antidepressant properties. In this prospective two-site study we measured resting state fMRI in 24 depressed patients prior to, and 24 h after a single sub-anesthetic dose of ketamine. We analyzed functional connectivity (FC) at baseline and after ketamine and focused our analysis on baseline FC and FC changes directly linked to symptom reduction in order to identify neuronal targets that predict individual clinical responses to ketamine. Our results show that FC increases after ketamine between right lateral prefrontal cortex (PFC) and subgenual anterior cingulate cortex (sgACC) are positively linked to treatment response. Furthermore, low baseline FC between these regions predicts treatment outcome. We conclude that PFC-sgACC connectivity may represent a promising biomarker with both predictive and explanatory power.

About 20 to 30 percent of patients with Major Depressive Disorder (MDD) do not respond to standard treatment and are considered treatment-resistant. The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in treatment-resistant MDD, but it is unknown whether its acute psychological effects are related to the later antidepressant effect. Therefore, we investigated the association between antidepressant responses to ketamine and the quality of ketamine-induced psychological experiences in MDD. A total of 31 patients (M = 49.5 ± 11.2 years, 16 women) were treated with three ketamine infusions per week (0.5 mg/ kg over 40 min) administered for two consecutive weeks. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, after four and 24 h and at end of treatment. The 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) was applied four hours after the first infusion to assess the subjective quality of acute psychological effects. Patients with a ≥ 50% MADRS reduction from baseline to end of treatment were considered as responders. After six infusions, 17 of 31 patients (55%) showed a response to ketamine treatment, while 14 patients (45%) had no response. Anxiety-related experiences induced by ketamine were significantly higher in non-responders. Percentage MADRS reduction after four hours and individual levels of ketamine-induced anxiety were predictive of a response at end of treatment. The study demonstrated the considerable impact of ketamine-induced anxiety on the antidepressant efficacy of ketamine. It underpins the importance of considering patients' subjective experiences and underlines the possibility of a phenotypic response predictor.

It is well known that elevated cortisol after stress or after exogenous administration impairs episodic memory retrieval including autobiographical memory (AM) retrieval. This impairment might be mediated by deactivation of a neural network associated with memory retrieval including the prefrontal cortex (PFC) and limbic structures. However, the neural underpinnings of these cortisol effects on AM retrieval have not been investigated yet. In this study, thirty-three healthy women received either placebo or 10 mg hydrocortisone in a double blind cross-over design before completing an AM test during fMRI. In this test, participants are asked to recall specific events from their own past in response to a cue word. In a first step, we analyzed the neural underpinnings of AM retrieval in the placebo condition. We found an activation pattern consistent with core regions involved in autobiographical memory recall, including the ventromedial PFC, anterior medial (am)PFC, inferior frontal gyrus, the posterior cingulate cortex, the tempoparietal junction, the middle temporal gyrus and the hippocampus. Further, we analyzed brain activation during AM retrieval after hydrocortisone compared to placebo. Region of interest (ROI) analyses revealed a hydrocortisone-induced deactivation during AM retrieval in the right amPFC. Results of the ROI analyses were non-significant in the left and right hippocampus, the left and right vmPFC and the left amPFC In sum, during AM retrieval hydrocortisone had the most pronounced effects on the amPFC. This might be explained by the strong involvement of this brain region in self-referential behavior, which is essential for recalling autobiographic information.

The influence of stress on executive functions has been demonstrated in numerous studies and is potentially mediated by the stress-induced cortisol release. Yet, the impact of cortisol on cognitive flexibility and task switching in particular remains equivocal. In this study, we investigated the influence of pharmacological glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) stimulation, two corticosteroid receptor types known to be responsible for cortisol effects on the brain. We conducted two experiments, each with 80 healthy participants (40 women and 40 men), and tested the effect of the unspecific MR/GR agonist hydrocortisone (Experiment I) and the more specific MR agonist fludrocortisone (Experiment II) on switch costs and task rule congruency in a bivalent, cued task switching paradigm. The results did not confirm our hypotheses; we found no significant effects of our manipulations on task switching capacity, although general switching and congruency effects were observed. We discuss the absence of MR/GR-mediated effects and propose alternative mechanisms that could explain stress induced effects on task switching.

Individuals tend to make riskier decisions in response to stress. The magnitude of the stress effect on decision-making under risk seems to depend on the stressor type and the decision situation. We examined the effects of physiological and combined physiological and psychosocial stress on decision-making under risk and whether risk taking differs between women and men. Ninety female (n = 45) and male (n = 45) students completed a decision-making under risk task with explicit probabilities and without feedback after exposure to physiological (Cold Pressor Test, CPT), combined physiological and psychosocial (Socially Evaluated Cold Pressor Test, SECPT), or no stress (Warm Water Test, WWT). Subjective stress ratings, salivary cortisol, blood pressure, and heart rate indicated increased stress reactions to the CPT and SECPT compared with the WWT. We found no effect of condition, indicating no difference in risk taking between the CPT, SECPT, and WWT. We did find a sex effect, showing that men made riskier decisions compared with women. Unexpectedly, a Condition × Sex interaction indicated increased risk taking in men compared with women in reaction to the CPT and in women in reaction to the SECPT compared with the WWT. In summary, our results suggest that the sex of the individuum making the decision in combination with the stressor type influence decisions made under risk. (PsycINFO Database Record (c) 2019 APA, all rights reserved).