Faculty Bibliography

BACKGROUND:Acute stress leads to a rapid release of noradrenaline and glucocorticoids, which in turn influence cognitive functions such as spatial learning and memory. However, few studies have investigated noradrenergic and glucocorticoid effects on spatial learning and memory in humans. Therefore, we examined the separate and combined effects of noradrenergic and glucocorticoid stimulation on spatial learning and memory. METHODS:One hundred and four healthy men (mean age = 24.1 years ±SD 3.5) underwent the virtual Morris Water Maze (vMWM) task to test spatial learning and spatial memory retrieval after receiving either 10 mg hydrocortisone or 10 mg yohimbine (an alpha 2-adrenergic receptor antagonist that increases noradrenergic activity), 10 mg hydrocortisone and 10 mg yohimbine combined, or placebo. The vMWM task took place 90 min after yohimbine was administered and 75 min after hydrocortisone was administered. Placebo was given at the same times. Salivary cortisol and alpha amylase levels were measured to check pharmacological stimulation. RESULTS:Hydrocortisone and yohimbine increased salivary cortisol and alpha amylase levels. Participants' task performance improved over time, suggesting successful spatial learning. However, separate and combined noradrenergic and glucocorticoid stimulation had no effect on spatial learning and spatial memory retrieval compared with placebo. CONCLUSIONS:In healthy young men, hydrocortisone and/or yohimbine did not alter spatial learning or spatial memory retrieval. Importantly, pharmacological stimulation took place prior to learning. Further studies should examine the effects of glucocorticoid and noradrenergic stimulation during encoding, consolidation, and retrieval.

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.

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).

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.

Objectives: First evidence suggests that lower heart rate variability (HRV) is associated with more cognitive control deficits, a risk factor for the development of intrusive memories. The aim of this study was to determine whether high-frequency (HF) and low-frequency/high-frequency (LF/HF) ratio components of HRV at rest before an intrusion-inducing stressor would predict consecutive intrusive memories.Methods: Healthy female participants (n = 60) watched an established distressing film which induced intrusions. HF and LF/HF ratio were measured for 5 min prior to the stressor. The number of consecutive intrusions resulting from the distressing film was assessed throughout the following 4 days.Results: The main effect LF/HF ratio was associated with more intrusive memories, whereas, the main effect HF was associated with more intrusions on a trend level. The time × HF and time × LF/HF ratio interactions were significant, indicating a different course of number of intrusions over the 4 days depending on HF and LF/HF ratio. The regression-based parameter estimates revealed a significant association of lower HF and number of intrusions on days 1 and 2 and a significant association of higher LF/HF (i.e. lower HRV) and number of intrusions on day 1.Conclusions: The results suggest that higher baseline LF/HF ratio (i.e. lower HRV) predicts more intrusive memories in healthy women after watching a distressing film. Furthermore, the results suggest that women with lower baseline HF and higher LF/HF ratio recover at a slower rate from watching the distressing film by showing a delayed decrease in intrusive memories. Our findings support the notion that lower baseline HRV before a trauma might be a vulnerability factor for subsequent intrusive memories.

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.

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.

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.

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.