Faculty Bibliography

Posttraumatic stress responses are characterized by a heterogeneity in clinical appearance and etiology. This heterogeneity impacts the field's ability to characterize, predict, and remediate maladaptive responses to trauma. Machine learning (ML) approaches are increasingly utilized to overcome this foundational problem in characterization, prediction, and treatment selection across branches of medicine that have struggled with similar clinical realities of heterogeneity in etiology and outcome, such as oncology. In this article, we review and evaluate ML approaches and applications utilized in the areas of posttraumatic stress, stress pathology, and resilience research, and present didactic information and examples to aid researchers interested in the relevance of ML to their own research. The examined studies exemplify the high potential of ML approaches to build accurate predictive and diagnostic models of posttraumatic stress and stress pathology risk based on diverse sources of available information. The use of ML approaches to integrate high-dimensional data demonstrates substantial gains in risk prediction even when the sources of data are the same as those used in traditional predictive models. This area of research will greatly benefit from collaboration and data sharing among researchers of posttraumatic stress disorder, stress pathology, and resilience.

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.

BACKGROUND:Alterations of the hypothalamic-pituitary-adrenal (HPA) axis are a prominent finding in patients with major depressive disorder (MDD). Inconsistencies regarding a hyper- or hypoactive HPA axis may be explained by the moderating effect of childhood adverse experiences (ACE) which are associated with both HPA axis dysfunction and MDD in adulthood. We aimed to systematically disentangle the effects of ACE and MDD on HPA axis by comparing healthy women with and without childhood adversity and women with MDD with and without ACE. METHODS:The dexamethasone/corticotropin-releasing hormone (DEX/CRH) test was administered in 35 women with MDD and ACE as determined by a clinical interview (SCID, Early Trauma Inventory), 51 women with MDD without ACE, 21 women with ACE but no current or lifetime MDD and 37 healthy women without either MDD or ACE. RESULTS:There were no group differences in age, smoking, body mass index, and intake of oral contraceptives. Free salivary cortisol responses were not significantly different between the four groups. CONCLUSIONS:This study shows no evidence for a dysregulation of the HPA axis as measured by the DEX/CRH test in depressed women with and without childhood adversity as compared to mentally healthy women with or without early life stress. Our results do not support the assumption of distinct neuroendocrine endophenotypes in MDD with regard to ACE.

Atrial natriuretic peptide (ANP) exerts anxiolytic effects in animals and humans. Patients with anxiety, trauma-associated and depressive disorders exhibit lower ANP plasma levels compared to healthy individuals. However, the role of ANP in patients with major depressive disorder (MDD) with and without concomitant adverse childhood experiences (ACE) and in healthy individuals with and without ACE is not clear. We recruited a total of 93 women: 23 women with MDD and ACE, 24 women with MDD without ACE, 22 women with ACE but no current or lifetime MDD, and 24 healthy women without ACE. ANP plasma levels were measured with a radioimmunoassay. The four groups did not differ in demographic and clinical variables. We found a positive correlation between age and plasma levels of ANP (r = .39; p <  .001). After controlling for age, there was no significant main effect of MDD or ACE on ANP plasma levels, but a significant interaction between MDD and ACE such that ACE was associated with reduced basal ANP levels in the absence of MDD. We assume that low plasma ANP might be a consequence of ACE in the absence of current psychopathology. Therefore, future studies are needed to replicate our findings and to characterize the influencing factors of ACE on ANP more comprehensively, for example by including a comprehensive trauma and comorbidity anamnesis as well as cardiovascular state and risk factors.

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis such as altered glucocorticoid receptor sensitivity and increased immune reactivity might contribute to the pathogenesis of major depressive disorder (MDD). Exposure to adverse childhood experiences (ACE) precipitates vulnerability to MDD and might be associated with endocrine and immune alterations in the disorder. In order to disentangle the effects of ACE and MDD, we recruited 87 women: n = 23 with MDD and ACE as determined by clinical interview and questionnaires (Structured Clinical Interview for DSM-IV, Early Trauma Inventory, Childhood Trauma Questionnaire), n = 24 with MDD without ACE, n = 21 with ACE but no current or lifetime MDD, and n = 26 healthy women without either MDD or ACE. Glucocorticoid signaling and mitogen-stimulated proliferation were analyzed ex vivo in peripheral blood-derived mononuclear cells. Additionally, mRNA expression of the glucocorticoid and the mineralocorticoid receptor (GR / MR) was assessed. Peripheral GR sensitivity as well as GR and MR expression levels were not significantly different between groups. Women with ACE showed an increased immune response after mitogen stimulation independent of the presence of MDD. Our results provide evidence for a functionally altered ex-vivo immune response in cell cultures from women with a history of ACE. Thus, ACE might contribute to the pathogenesis of MDD through inflammatory pathways.

Risk taking is influenced by stress, with riskier decisions after exposure to an acute stressor and consecutively elevated cortisol levels. In the brain, cortisol acts on two receptors with different functional profiles: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). In the current study we investigated the effect of MR stimulation on risk taking behavior in 80 young healthy participants (40 women, mean age=23.9). We administered 0.4mg fludrocortisone, a MR agonist, in a between-subjects, placebo controlled design. Subsequently, participants conducted an established risk taking paradigm, the Balloon-Analogue-Risk-Task (BART). We also used two questionnaires to assess risk taking and decision behavior as trait measures. We found a treatment effect with riskier decisions in the fludrocortisone group. Furthermore, we found a sex effect with more risk taking in men. There was no statistically significant interaction between both factors. Our results indicate that acute MR stimulation leads to riskier decisions in women and men. Our findings argue for an important role of the MR in decision making processes.

BACKGROUND:Adverse childhood experiences (ACE) increase the risk to develop major depressive disorder (MDD) and obesity or metabolic syndrome in adulthood. In addition, ACE may be associated with an exaggerated endocrine response to stress, which, in turn, may lead to enhanced food intake resulting in obesity and metabolic problems. METHODS:We systematically examined the stress response and consecutive food intake in 32 women with MDD and ACE as determined by a clinical interview (Early Trauma Inventory), 52 women with MDD without ACE, 22 women with ACE but no current or lifetime MDD and 37 healthy women without either MDD or ACE. All participants underwent a psychosocial stress test (Trier Social Stress Test, TSST) and a control condition (Placebo-TSST) before they were offered a buffet of snacks. Participants were not aware that the primary outcome variable was the amount of consumed kilocalories (kcal). RESULTS:The four groups did not differ in demographic variables. Stress resulted in higher cortisol release and higher blood pressure compared to the control condition. Patients with MDD without ACE had a significantly lower cortisol response to stress compared to controls. Across groups, we found higher kcal intake after stress compared to the control condition. Comparing high and low cortisol responders to stress, higher kcal intake after stress was only seen in those with low cortisol release. CONCLUSIONS:This study provides evidence that blunted rather than enhanced cortisol release to stress might lead to increased food intake, independent from MDD and ACE.

Adverse childhood experiences (ACE) enhance the risk for mental disorders, e.g. major depressive disorder (MDD). Increasing evidence suggests an association between ACE and impaired physical health, e.g. metabolic syndrome. The aim of this study was to assess several metabolic risk markers in healthy individuals with and without ACE and depressed patients with and without ACE. We examined glucose and insulin release in the oGTT in 33 women with MDD and ACE, 47 women with MDD without ACE, 21 women with ACE but no current or lifetime MDD and 36 healthy women without either MDD or ACE. Several metabolic markers such as triglycerides, cholesterol, LDL, HDL, HbA1c, BMI and waist to hip ratio were assessed. The four groups did neither differ in insulin release and glucose concentrations in the oGTT nor with respect to other metabolic variables. Depressed patients with and without psychotropic medication did not differ in any outcome variable, but there was a trend towards higher glucose concentrations in the oGTT in patients with current psychotropic medication. In this physically healthy sample neither ACE nor MDD were associated with metabolic risk factors. Thus, metabolic alterations might not directly be linked to ACE and depression.