Funding by the DFG

Applicants: Prof. Dr. Katja Wingenfeld und Prof. Dr. Hauke Heekeren (Freie Universität, FU)
Participating individuals: Sophie Metz, Catarina Rosada, Prof. Dr. Christian Otte & Dr. Adrian Fischer (FU)

Incidental affective states, i.e., affective states that are unrelated to the decision at hand, can influence decision making. Acute stress is such an affective state and is a powerful contextual modulator of decision-making processes. It appeared that after stress exposure, individuals make riskier decisions.
In terms of physiological and neurohormonal changes, the stress response has been well characterized: Exposure to stress elicits an array of autonomic, endocrine, and behavioral responses. The physiological stress response is mediated by the hypothalamic-pituitary adrenal (HPA) axis and the locus coeruleus noradrenergic (LC-NA) system with cortisol and norepinephrine (NE) as their end products.
There is compelling evidence that the stress hormones cortisol and NE influence cognitive processes. However, so far only very few studies have used pharmacological approaches to specify the role of stress neuromodulators on decision making. These studies are poorly comparable due to differences in the experimental design, e.g., the decision making task used. Furthermore, the neural underpinnings of stress effects on decision making are so far uninvestigated.
The aim of the project is to clarify the role of the major stress neuromodulators, NE and cortisol, in their contribution to different processes related to decision making under risk. To this end, we will combine precise pharmacological stimulation, behavioral modeling, and fMRI methods to systematically disentangle the effects of stress hormones on risk attitudes and loss aversion as well as their relation to neural correlates of processing subjective value and risk.

• Metz, S., Waiblinger-Grigull, T., Schulreich, S., Chae, W. R., Otte, C., Heekeren, H. R., & Wingenfeld, K. (2020). Effects of hydrocortisone and yohimbine on decision-making under risk. Psychoneuroendocrinology, 114, 104589.
• Nowacki, J., Heekeren, H. R., Deuter, C. E., Joerißen, J. D., Schröder, A., Otte, C., & Wingenfeld, K. (2019). Decision making in response to physiological and combined physiological and psychosocial stress. Behavioral neuroscience, 133(1), 59.
• Nowacki, J., Duesenberg, M., Deuter, C. E., Otte, C., & Wingenfeld, K. (2019). Delayed effects of psychosocial stress on risk taking. Stress, 22(4), 446-454.
• Deuter, C. E., Wingenfeld, K., Schultebraucks, K., Hellmann-Regen, J., Piber, D., & Otte, C. (2017). Effects of mineralocorticoid-receptor stimulation on risk taking behavior in young healthy men and women. Psychoneuroendocrinology, 75, 132-140

“Fight-or-flight” versus “tend-and-befriend” response to behavioral and pharmacological interventions in patients with borderline personality disorder.

Funding by the DFG
Applicants: Prof. Dr. Katja Wingenfeld, Prof. Dr. Christian Otte, Prof. Dr. Stefan Röpke und Prof. Dr. Oliver T. Wolf (Ruhr Universität Bochum)

Borderline personality disorder (BPD) is characterized by several symptoms, which occur within social contexts, such as fear of abandonment or unstable social relationships. Furthermore, there is evidence that BPD patients are more sensitive to social rejection and negative evaluation, which is an important facet of many stressful situations within the psychosocial context.In recent studies, we found that psychosocial stress led to reduced emotional empathy in BPD, while healthy controls scored higher on emotional empathy after stress (Wingenfeld, Duesenberg et al. 2018). The results in healthy individuals suggest enhanced prosocial behavior, which can be interpreted as “tend-and-befriend” behavior after stress (Wolf, Schulte et al. 2015). In contrast, reduced emotional empathy in BPD might reflect an inhibition of prosocial behavior after stress in favor of a “fight-or-flight” response. We hypothesize that perceived social exclusion might be one reason for these differences, as BPD patients are characterized by high sensitivity to social exclusion (Staebler, Renneberg et al. 2011).

Additionally, we could show that after pharmacological stimulation with fludrocortisone – a mineralocorticoid receptor agonist – BPD patients and healthy women had higher emotional empathy scores compared to placebo (Wingenfeld, Kuehl et al. 2014).In our current project, we will further investigate this topic.

• Wingenfeld, K., Duesenberg, M., Fleischer, J., Roepke, S., Dziobek, I., Otte, C. & Wolf, O.T. (2018). Psychosocial stress differentially affects emotional empathy in women with borderline personality disorder and healthy controls. Acta Psychiatrica Scandinavica, 137, 206-215.
• Wingenfeld, K., Kuehl, L.K., Dziobek, I., Roepke, S., Otte, C. & Hinkelmann, K. (2016). Effects of mineralocorticoid receptor blockade on empathy in patients with major depressive disorder. Cognitive, Affective, and Behavioral Neuroscience, 16(5), 902-10.
• Wingenfeld, K., et al. (2014). Enhanced emotional empathy after mineralocorticoid receptor stimulation in women with borderline personality disorder and healthy women. Neuropsychopharmacology 39(8): 1799-1804.

Funded by the German Research Foundation (DFG) and NeuroCure

Scientists in charge: Prof. Dr. Christian Otte, Prof. Dr. Katja Wingenfeld

Early traumatisation appears to be associated with a change in the function of hormonal stress systems. Reduced basal concentrations of cortisol with simultaneously increased cortisol release in response to stress have been described. Neuronal imaging studies also indicate an altered fronto-limbic network characterized by increased reactivity of the amygdala, decreased activity of various prefrontal areas, and altered reactivity of the hippocampus. Clinically, people with early traumatization and post-traumatic stress disorder often suffer from problems in the regulation of emotions and their cognitive control.

Various studies have investigated the interaction between hormonal and neuronal stress systems and cognitive function in 1) healthy individuals with early traumatization and 2) patients with post-traumatic stress disorder (PTSD) and borderline personality disorder (BPD) using functional magnetic resonance imaging (fMRI). Both methods of psychosocial stress induction ("Montreal Stress Imaging Task", "Trier Social Stress Test") and experimental-pharmacological methods (administration of hydrocortisone versus placebo) were used.

First results suggest that hydrocortisone induced neuronal activity during autobiographical memory recall and functional connectivity between hippocampus and prefrontal areas are influenced by traumatic experiences in childhood. These studies should help to better understand the effects of early traumatization in life history. We also hope to develop hypotheses as to why some people develop mental illness as a result of traumatic stress, while others do not.

• Metz, S., Duesenberg, M., Hellmann-Regen, J., Wolf, O. T., Roepke, S., Otte, C., & Wingenfeld, K. (2020). Blunted salivary cortisol response to psychosocial stress in women with posttraumatic stress disorder. Journal of Psychiatric Research.
• Golde, S., Wingenfeld, K., Riepenhausen, A., Schröter, N., Fleischer, J., Prüssner, J., ... & Gold, S. M. (2020). Healthy women with severe early life trauma show altered neural facilitation of emotion inhibition under acute stress. Psychological medicine, 50(12), 2075-2084.
• Metz, S., Fleischer, J., Gärnter, M., Golde, S., Duesenberg, M., Roepke, S., ... & Wingenfeld, K. (2019). Effects of hydrocortisone on autobiographical memory retrieval in patients with posttraumatic stress disorder and borderline personality disorder: the role of childhood trauma. Neuropsychopharmacology, 44(12), 2038-2044.
• Metz, S., Fleischer, J., Grimm, S., Gärnter, M., Golde, S., Duesenberg, M., ... & Wingenfeld, K. (2019). Resting-state functional connectivity after hydrocortisone administration in patients with post-traumatic stress disorder and borderline personality disorder. European Neuropsychopharmacology, 29(8), 936-946.
• Kuehl, L. K., Schultebraucks, K., Deuter, C. E., May, A., Spitzer, C., Otte, C., & Wingenfeld, K. (2019). Stress effects on cognitive function in patients with major depressive disorder: Does childhood trauma play a role?. Development and Psychopathology, 1-10.
• Duesenberg, M., Wolf, O.T., Metz, S., Roepke, S., Fleischer, J., Elias, V., Renneberg, B., Otte, C. & Wingenfeld, K. (2019). Psychophysiological stress response and stress effects on memory in Borderline Personality Disorder. European Journal of Psychotraumatology, 10: 1568134.

Funding by the DFG
Applicant: Dr. Linn Kühl
Co-applicant: Prof. Dr. Christian Otte, Prof. Dr. Katja Wingenfeld

Stress plays a central role in the development and maintenance of major depression. Many studies have shown alterations in physiological stress regulation systems for depressive patients. Both the hypothalamus-hypophysis-adrenergic axis (HHNA) and the locus-coeruleus-noradrenergic system (LC-NA-system) were investigated. At a central level, changes in the LC-NA system were observed, which particularly affect a change in the response of adrenergic receptors (regulation of alpha2-adrenergic receptors) in depressive patients. These changes seem to be particularly relevant in patients with early traumatizations. The LC-NA system not only influences the physiological stress response, but also has key effects on cognitive functions. For example, norepinephrine has effects on functions such as attention, learning and memory in healthy volunteers. Although major depression is characterized by various cognitive deficits, such as memory and attention, the relationship between the LC-NA system and cognition in these patients has hardly been investigated. In an initial study, our research group has therefore investigated the effect of stimulation of noradrenergic activity on various memory functions.

In this project, the relationship between the LC-NA system and different attention processes in patients with major depression is to be investigated for the first time, taking into account possible early traumatic experiences. In a placebo-controlled design, the effects of noradrenergic stimulation by administration of the alpha2 receptor blocker yohimbine on different attention processes in patients with major depression compared to healthy control subjects are investigated.

The results of this study could lead to a better understanding of cognitive deficits and the role of the alpha2-adrenergic system in depressive patients and thus contribute to new therapeutic options.

• Deuter, C. E., Wingenfeld, K., Otte, C., Bustami, J., Kaczmarczyk, M., & Kuehl, L. K. (2020). Noradrenergic system and cognitive flexibility: Disentangling the effects of depression and childhood trauma. Journal of Psychiatric Research.
• Kuehl, L. K., Deuter, C. E., Hellmann-Regen, J., Kaczmarczyk, M., Otte, C., & Wingenfeld, K. (2020). Enhanced noradrenergic activity by yohimbine and differential fear conditioning in patients with major depression with and without adverse childhood experiences. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 96, 109751.
• Kuehl, L. K., Schultebraucks, K., Deuter, C. E., May, A., Spitzer, C., Otte, C., & Wingenfeld, K. (2019). Stress effects on cognitive function in patients with major depressive disorder: Does childhood trauma play a role?. Development and psychopathology, 1-10.
• De Punder, K., Entringer, S., Heim, C., Deuter, C. E., Otte, C., Wingenfeld, K., & Kuehl, L. K. (2018). Inflammatory measures in depressed patients with and without a history of adverse childhood experiences. Frontiers in psychiatry, 9, 610.

Funding by the DFG
Applicant: Dr. Christian Deuter
Co-applicants: Prof. Dr. Christian Otte, Prof. Dr. Katja Wingenfeld

Stress affects several physiological and psychological domains and triggers a shift in information processing which is mediated by two separate neuroendocrine systems: the fast-responding catecholaminergic system and the slower glucocorticoid system. The glucocorticoid system is based on the hypothalamic-pituitary-adrenal axis, with cortisol as the main downstream glucocorticoid in humans. According to the network model of Hermans et al. (2014), two separate brain networks are implicated in the acute stress response. The salience network is responsible for exogenous attention, especially to potential threats, and the fast mobilization of energy. Resources are primarily allocated to this network from immediately after the onset of the stressor until about one hour after stress exposure. In this early part of the stress response, the executive control network that mediates deliberate thinking and planned action is down-regulated. This process is initially driven by catecholaminergic activation, which sets in immediately, within seconds after stress exposure. Within minutes, rapid non-genomic effects of cortisol also come into play and start to modulate the catecholaminergic effects. Cortisol can easily cross the blood-brain barrier and feeds back on the brain via two different receptor types: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). While GRs are widely distributed in the brain, MRs are primarily located in limbic structures and the prefrontal cortex, which are areas critical for cognition and emotion. Several human and animal studies indicated a role for membrane-bound MRs in the early phase of the stress response, and in rapid cortisol effects on emotional and cognitive processes. However, while rapid stress effects are often attributed to the MR, recent research in animals indicates a role of the - supposedly membrane bound and non-genomic - GR in rapid stress effects as well.These rapid effects are regionally and functionally specific and may differ between MRs and GRs. Overall, effects of GRs tend to suppress, and those of MRs to enhance neural excitability.In the proposed project, we plan to systematically disentangle MR vs. GR effects in the early stress response on emotional and cognitive processes that represent the salience network (attentional vigilance to emotional stimuli as determined by emotional dot-probe), the executive control network (working memory as assessed by n-back task) or both networks (risk taking as assessed by balloon analogue risk task). To our best knowledge, this would be the first project to investigate the differential contribution of both receptor systems on these cognitive domains in such a systematic manner.

Funding by the German Research Foundation (DFG)
Applicants: Prof. Dr. Katja Wingenfeld and Prof. Dr. Stefan Röpke

Recent data suggest that the cannabinoid-system is involved in stress regulation and posttraumatic stress disorder (PTSD) after traumatic events. In own of our own studies, we found reduced concentrations of the endocannabinoid arachidonylethanolamide (AEA) in BPD patients compared to healthy women (see Fig 1a). Furthermore, we found a correlation between hair concentrations of AEA and cortisol (p = .06; Fig 1b).

Low endocannabinoid signaling has been found in PTSD patients and might even present a precondition to develop PTSD after trauma. In consequence, increased endocannabinoid signaling during acquisition and consolidation of traumatic events might be a promising approach to prevent the development of PTSD. The aim of the current project is to investigate the impact of an activation of the cannabinoid system with an exogenous cannabinoid dronabinol (delta-9-tetrahydrocannabinol) on the formation of intrusive memories after analog trauma.

A well-established stress-film paradigm will be used to induce intrusive symptoms in healthy participants. In a double-blind placebo-controlled study, the impact of exogenous dronabinol on intrusive symptoms during exposure to a trauma film will be examined. The primary hypothesis is that exogenous oral dronabinol will decrease the number of intrusive memories recorded in the four days following experimental trauma compared with placebo controls.

This project will contribute to the current understanding of intrusive memory formation in PTSD and may guide the development of future pharmacological preventions.

• Wingenfeld, K., Dettenborn, L., Kirschbaum, C., Gao, W., Otte, C., & Roepke, S. (2018). Reduced levels of the endocannabinoid arachidonylethanolamide (AEA) in hair in patients with borderline personality disorder–a pilot study. Stress, 21(4), 366-369.

Funding by the German Research Foundation (DFG)
Applicant: Prof. Dr. K. Wingenfeld
Co-applicant: Prof. Dr. C. Spitzer, Prof. Dr. C. Otte
Cooperation partner: Asklepios Fachklinikum Tiefenbrunn


Previous traumatic stress is associated with abnormalities of the hypothalamic hypohyses adrenal cortex axis (HHNA). This is reflected in an increased reactivity to stress, reduced feedback sensitivity and changes in glucocorticoid receptors (GR). People with early traumatization have an increased risk of developing metabolic disorders such as diabetes mellitus type II or metabolic syndrome.

In a DFG-funded study, we investigated participants with and without early traumatization, taking into account the factor of depression, measurements of HHNA activity and assessment of GR. In addition, we also recorded various markers of metabolic syndrome and carried out an oral glucose tolerance test. We also looked into the question of whether eating habits changed after a stressful situation in people with early traumatization and thus represent a risk factor for the development of later metabolic abnormalities.

This study is intended to investigate a previously neglected aspect of the consequences of early traumatisation. These results can lead to a better understanding of stress-related eating habits and their consequences.

• Spitzer, C., Otte, C., Kuehl, L. K., May, A., Schultebraucks, K., Hellmann-Regen, J., & Wingenfeld, K. (2018). The dexamethasone corticotropin releasing hormone test in healthy and depressed women with and without childhood adversity. Psychoneuroendocrinology, 87, 147-151.
• Wingenfeld, K., Kuehl, L. K., Boeker, A., Schultebraucks, K., Schulz, A., Stenzel, J., ... & Otte, C. (2017). Are adverse childhood experiences and depression associated with impaired glucose tolerance in females? An experimental study. Journal of Psychiatric Research.
• Wingenfeld, K., Kuehl, L. K., Boeker, A., Schultebraucks, K., Ritter, K., Hellmann-Regen, J., ... & Spitzer, C. (2017). Stress reactivity and its effects on subsequent food intake in depressed and healthy women with and without adverse childhood experiences. Psychoneuroendocrinology, 80, 122-130.
• Culverhouse, R. C., Saccone, N. L., Horton, A. C., Ma, Y., Anstey, K. J., Banaschewski, T., ... & Goldman, N. (2017). Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression. Molecular psychiatry.

Funding: BIH Charité Clinician Scientist Program
Applicant: Dominique Piber, M.D.
In cooperation with: Christian Otte, M.D., Stefan Gold, PhD

Depression is a highly prevalent disorder and associated with alterations in numerous biological systems, including a dysregulation of the immune system. One promising marker in this regard are monocyte cell populations. Indeed, we have recently demonstrated that depressed patients show an increased cell count particularly in non-classical monocytes (Figure 1).

Depression is strongly associated with metabolic diseases, such as obesity. Converging data implicate that the link between depression und obesity might be mediated by shared inflammatory pathways. In a current research project funded by the BIH Charité Clinician Scientist Program (IKDAS-study: Immundysregulation bei komorbider Depression und Adipositas), we will examine shared mechanisms of immune dysfunction in depression and comorbid obesity. In total, we will recruit 200 subjects, including: patients with depression (n=50); patients with obesity (n=50); patients with comorbid depression and obesity (n=50); and healthy controls (n=50). The study aims to improve the understanding of the biological link between depression and obesity.

• Hasselmann, H., Gamradt, S., Taenzer, A., Nowacki, J., Zain, R., Patas, K., ... & Gold, S. M. (2018). Pro-inflammatory monocyte phenotype and cell-specific steroid signaling alterations in unmedicated patients with major depressive disorder. Frontiers in immunology, 9, 2693.

EU-PEARL has the ambition of transforming the current approach of conducting single-compound clinical trials into cross-company collaborative Integrated Research Platforms (IRPs) that will rebalance clinical studies on both patients and novel molecules for medical needs. Patient-centric data and knowledge sharing have the potential to accelerate the development of new treatments and reduce the operational costs of clinical trials, and thereby improve clinical effectiveness, patients’ satisfaction and societal access to timely and affordable medicines. EU-PEARL will set the stage for shaping clinical trials of the future. The outputs will be made more patient friendly by increasing the likelihood of patients receiving active treatment and will give prescribers access to direct comparisons of different treatments on registration outcomes that will better inform treatment decisions (easier enrolment with less invasiveness, decreased use of placebo arms, faster results). This will change the industry paradigm from competition to cooperation in four disease areas and provide the framework for designing IRPs in other disease areas. It will establish the IRP as a sustainable and scalable European and global solution for the next stage of developing novel therapies for patients.