Stressing Out About the Heart: A Narrative Review of the Role of Psychological Stress in Acute Cardiovascular Events

Objectives: Survivors of acute cardiovascular disease (CVD) events, such as acute coronary syndrome (ACS) and stroke, may experience significant psychological distress during and following the acute event. Long-term adverse effects may follow, including the development of posttraumatic stress disorder (PTSD), increased overall all-cause mortality, and recurrent cardiac events. The goal of this concepts paper is to describe and summarize the rates of adverse psychological outcomes, such as PTSD, following cardiovascular emergencies, to review how these psychological factors are associated with increased risk of future events and long-term health and to provide a theoretical framework for future work. Methods: A panel of two board-certified emergency physicians, one with a doctorate in experimental psychology, along with one PhD clinical psychologist with expertise in psychoneuroendocrinology were co-authors involved in the paper. Each author used various search strategies (e.g., PubMed, Psycinfo, Cochrane, and Google Scholar) for primary research and reviewed articles related to their section. The references were reviewed and evaluated for relevancy and included based on review by the lead authors RESULTS: A meta-analysis of 24 studies (N > 2,300) found the prevalence of ACS-induced PTSD at nearly 12%, while a meta-analysis of nine studies (N = 1,138) found that 25% of survivors of transient ischemic attack and stroke report PTSD symptoms. The presence of PTSD doubles 3-year risk of CVD/mortality risk in ACS survivors. Cardiac patients treated during periods of ED overcrowding, hallway care, and perceived poor clinician-patient communication appear at greater risk for subsequent PTSD. Conclusions: Psychological stress is often present in patients undergoing evaluation for acute CVD events. Understanding such associations provides a foundation to appreciate the potential contribution of psychological variables on acute and long-term cardiovascular recovery, while also stimulating future areas of research and discovery

Effects of oral contraceptives on intrusive memories: a secondary analysis of two studies using the trauma film paradigm in healthy women

Background: Women are more likely to develop post-traumatic stress disorder (PTSD) than men. Recent research suggests an impact of oral contraceptive (OC) intake on PTSD and intrusive memories, a hallmark symptom of PTSD. Although a majority of women use OCs at some point in their lives, the effects on PTSD pathogenesis are only poorly understood.Objective: In the current paper, we aimed to investigate the impact of OC intake on the acquisition and consolidation of intrusive memories in healthy women after watching a trauma film paradigm.Methods: We performed a secondary analysis of a pooled dataset (N = 437) of two previously conducted and published studies investigating the effect of oxytocin on the development of intrusive memories. Results: Women taking OCs showed an attenuated decline of intrusive memories over time after having watched the trauma film compared to naturally cycling women (F(2.75, 1167) = 3.79, p = .03, eta(2)(p) = .01).Conclusion: These findings indicate that the intake of OCs is associated with the development of intrusive memories after a trauma film paradigm. This indication emphasizes the need to further investigate the complex impact of OCs and gonadal hormones on fear learning processes and PTSD

Predicting non-response to multimodal day clinic treatment in severely impaired depressed patients: a machine learning approach

A considerable number of depressed patients do not respond to treatment. Accurate prediction of non-response to routine clinical care may help in treatment planning and improve results. A longitudinal sample of N = 239 depressed patients was assessed at admission to multi-modal day clinic treatment, after six weeks, and at discharge. First, patient’s treatment response was modelled by identifying longitudinal trajectories using the Hamilton Depression Rating Scale (HDRS-17). Then, individual items of the HDRS-17 at admission as well as individual patient characteristics were entered as predictors of response/non-response trajectories into the binary classification model (eXtremeGradient Boosting; XGBoost). The model was evaluated on a hold-out set and explained in human-interpretable form by SHapley Additive explanation (SHAP) values. The prediction model yielded a multi-class AUC = 0.80 in the hold-out set. The predictive power for the binary classification yielded an AUC = 0.83 (sensitivity = .80, specificity = .77). Most relevant predictors for non-response were insomnia symptoms, younger age, anxiety symptoms, depressed mood, being unemployed, suicidal ideation and somatic symptoms of depressive disorder. Non-responders to routine treatment for depression can be identified and screened for potential next-generation treatments. Such predictors may help personalize treatment and improve treatment response

Identifying predictive features of autism spectrum disorders in a clinical sample of adolescents and adults using machine learning

Diagnosing autism spectrum disorders (ASD) is a complicated, time-consuming process which is particularly challenging in older individuals. One of the most widely used behavioral diagnostic tools is the Autism Diagnostic Observation Schedule (ADOS). Previous work using machine learning techniques suggested that ASD detection in children can be achieved with substantially fewer items than the original ADOS. Here, we expand on this work with a specific focus on adolescents and adults as assessed with the ADOS Module 4. We used a machine learning algorithm (support vector machine) to examine whether ASD detection can be improved by identifying a subset of behavioral features from the ADOS Module 4 in a routine clinical sample of N = 673 high-functioning adolescents and adults with ASD (n = 385) and individuals with suspected ASD but other best-estimate or no psychiatric diagnoses (n = 288). We identified reduced subsets of 5 behavioral features for the whole sample as well as age subgroups (adolescents vs. adults) that showed good specificity and sensitivity and reached performance close to that of the existing ADOS algorithm and the full ADOS, with no significant differences in overall performance. These results may help to improve the complicated diagnostic process of ASD by encouraging future efforts to develop novel diagnostic instruments for ASD detection based on the identified constructs as well as aiding clinicians in the difficult question of differential diagnosis

No association between major depression with and without childhood adversity and the stress hormone copeptin

Background: Adverse childhood experiences (ACE) are associated with an increased risk of major depressive disorder (MDD) and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Within the HPA axis, corticotropin-releasing hormone and vasopressin (AVP) synergistically stimulate the release of adrenocorticotropic hormone, which promotes cortisol release. The cleavage product copeptin is produced during AVP synthesis and is a surrogate marker of AVP release. Children with ACE and young adults with depressive symptoms have higher levels of copeptin than healthy controls. Objective: To uncover the effects of MDD and ACE on copeptin levels in adult females. Methods: We recruited 94 women (mean age: 34.0 +/- 3.6 years): 23 with MDD and ACE, 24 with MDD without ACE, 22 with ACE without MDD, and 25 healthy controls. ACE was defined as repeated sexual or physical abuse at least once a month over at least one year before the age of 18 years. MDD was defined by the DSM-IV criteria. Copeptin plasma levels were measured with an immunoluminometric assay. Results: The four groups did not differ in demographic variables. We found a significant negative correlation between body mass index (BMI) and copeptin plasma levels (r = -.21; p = .045). Copeptin plasma levels did not differ between the four groups after controlling for BMI. Conclusion: Neither MDD nor ACE was associated with altered plasma copeptin levels. Thus, copeptin does not seem to play a major role in MDD and ACE in adult females

Intranasal oxytocin administration impacts the acquisition and consolidation of trauma-associated memories: a double-blind randomized placebo-controlled experimental study in healthy women

Intrusive memories are a hallmark symptom of post-traumatic stress disorder (PTSD) and oxytocin has been implicated in the formation of intrusive memories. This study investigates how oxytocin influences the acquisition and consolidation of trauma-associated memories and whether these effects are influenced by individual neurobiological and genetic differences. In this randomized, double-blind, placebo-controlled study, 220 healthy women received either a single dose of intranasal 24IU oxytocin or a placebo before exposure to a trauma film paradigm that solicits intrusive memories. We used a "general random forest" machine learning approach to examine whether differences in the noradrenergic and hypothalamic-pituitary-adrenal axis activity, polygenic risk for psychiatric disorders, and genetic polymorphism of the oxytocin receptor influence the effect of oxytocin on the acquisition and consolidation of intrusive memories. Oxytocin induced significantly more intrusive memories than placebo did (t(188.33) = 2.12, p = 0.035, Cohen's d = 0.30, 95% CI 0.16-0.44). As hypothesized, we found that the effect of oxytocin on intrusive memories was influenced by biological covariates, such as salivary cortisol, heart rate variability, and PTSD polygenic risk scores. The five factors that were most relevant to the oxytocin effect on intrusive memories were included in a Poisson regression, which showed that, besides oxytocin administration, higher polygenic loadings for PTSD and major depressive disorder were directly associated with a higher number of reported intrusions after exposure to the trauma film stressor. These results suggest that intranasal oxytocin amplifies the acquisition and consolidation of intrusive memories and that this effect is modulated by neurobiological and genetic factors. Trial registration: NCT03031405

Der Einfluss des Mineralocorticoidrezeptors auf Kognitive Funktionen, die Stimmung und soziale Kognition

Stress-exposure leads to a boost of cortisol that acts via the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Evidence shows that stress influences cognitive performance and emotion processing. During stress, the MR is important for appraisal and emotion regulation, whereas the GR is crucial for reallocation of energy, which is important for the modulation of behavior and memory processes. The MR and GR work together in a complementary way. Imbalances due to chronic stress and depression can result in altered cognitive and emotional processes, especially in reaction to stress-exposure. The objective of this dissertation project is to help disentangle the complex interaction of the MR and the GR. Since previous studies have first and foremost examined the role of the GR, the role of the MR is understudied, despite the fact that novel preclinical and clinical studies have shown that the MR plays a crucial role on cognitive functioning and emotional processes. The aim of the present dissertation is to extend the existing body of knowledge with regard to whether and how human MR occupation influences cognitive functioning, mood and social cognition in patients with Addison’s disease and in healthy participants. The following research questions are examined: 1) Is the state-of-the-art hormone replacement therapy with synthetic MR and GR agonists in patients with Addison’s disease on a par with normal endogenous cortisol of healthy subjects with regard to neuropsychological function? 2) What are the acute effects of high MR occupation compared to low MR occupation with regard to neuropsychological functions, in particular, with regard to prefrontal cortex- and limbic structure-related functions like cognition and mood in patients with Addison’s disease? 3) What is the role of the MR on more specialized domains like social cognition in young healthy subjects? To investigate cognitive functioning and mood in patients with Addison’s disease we used a well-established neuropsychological test battery that comprised verbal memory, visual-spatial memory, executive function, attention, working memory and autobiographical memory. To examine the role of the MR on social cognition, i.e. selective attention and emotion recognition, we used the emotional dot-probe task as well as the facial emotion recognition task. The main results of the dissertation are, first, that long-term hormone substitution with fludrocortisone and hydrocortisone in patients with Addison’s disease has no influence on cognitive performance, except on verbal learning. Second, high MR occupation has beneficial effects on cognitive performance in verbal memory and on a trend level on attention and executive function as well as beneficial effects on self-reported mood in patients with Addison’s disease, even when the daily dose of fludrocortisone was skipped only once. Third, selective MR stimulation with the potent MR-agonist fludrocortisone results in a shift of selective attention towards sad faces in healthy subjects. However, MR stimulation has no beneficial effect on emotion recognition. In sum, the present studies corroborate previous findings on MR functioning in preclinical studies and in humans, e.g. in depressed and healthy participants. However, this dissertation presents these effects for the first time in patients with lack of endogenous cortisol. The results indicate that high MR occupation is beneficial for cognitive functioning and mood. Moreover, the MR seems to play a crucial role in quick automatic emotional processing, meaning a shift in selective attention towards negative emotional cues after MR stimulation.Stress führt zu einer Ausschüttung von Kortisol, das über den Mineralocorticoidreceptor (MR) und den Glucocorticoidreceptor (GR) wirkt. Forschungsergebnisse zeigen, dass Stress die kognitive Leistungsfähigkeit sowie emotionale Reaktionen beeinflusst. Bei Stress spielt der MR eine wichtige Rolle für die Bewertung der Situation und für die Regulation von Emotionen. Der GR hingegen ist wichtig für die Umverteilung metabolischer Energie und die Verhaltensanpassung sowie für Gedächtnisprozesse. Der MR und der GR arbeiten zusammen und ergänzen sich gegenseitig. Chronischer Stress und Depression können zu einem Ungleichgewicht zwischen MR und GR und somit zu einer veränderten Stressreaktion führen sowie zu veränderten kognitiven und emotionalen Prozessen. Gegenstand der vorliegenden Dissertation ist es, das komplexe Zusammenwirken von MR und GR weiter zu untersuchen. Bisherige Studien habe insbesondere die Rolle des GR erforscht. Tierstudien und erste klinische Studien konnten aber zeigen, dass der MR eine wichtige Rolle bei kognitiven Funktionen und bei Emotionen spielt. Ziel der vorliegenden Dissertation ist es, den bereits existierenden Wissensstand zu erweitern und zu untersuchen, welchen Einfluss der MR auf kognitive Funktionen, die Stimmung und soziale Kognition bei Patienten mit Morbus Addison und bei gesunden Probanden ausübt. Dabei ergeben sich folgende Fragestellungen: 1) Welchen Einfluss hat die langjährige „state-of-the-art“ Substitutionstherapie mit synthetischen MR- und GR-Agonisten bei Patienten mit Morbus Addison auf die kognitive Leistungsfähigkeit im Vergleich zu normaler endogener Kortisolausschüttung bei gesunden Probanden? 2) Welchen Einfluss übt eine hohe MR Besetzung im Vergleich zu einer geringen MR Besetzung auf die kognitive Leistungsfähigkeit und die Stimmung bei Patienten mit Morbus Addison aus? 3) Welchen Einfluss hat eine MR Stimulierung auf komplexere psychologische Funktionen wie die soziale Kognition? Um diese Fragestellungen zu untersuchen, wurde eine gut etablierte neuropsychologische Testbatterie eingesetzt, die das verbale Gedächtnis, das visuell-räumliche Gedächtnis, die Exekutivfunktion, Aufmerksamkeit, das Arbeitsgedächtnis sowie das autobiographische Gedächtnis umfasste. Um den Einfluss des MR auf soziale Kognition zu untersuchen, wurden ein emotionales Dot-Probe-Paradigma und eine Emotionserkennungsaufgabe verwendet. Wichtige Hauptbefunde waren erstens, dass eine jahrelange Hormon-substitution keinen nachteiligen Einfluss auf die kognitive Leistungsfähigkeit von Patienten mit Morbus Addison im Vergleich zu gesunden Kontrollprobanden hatte, außer im Bereich des verbalen Gedächtnisses. Dies konnte gezeigt werden, trotz einer durchschnittlich seit ca. 18 Jahren (SD = 11) andauernden Erkrankung und Behandlung mit Hydro- und Fludrocortison. Trotzdem war die selbstberichtete Lebensqualität von Patienten mit Morbus Addison im Vergleich zu gesunden Probanden signifikant beeinträchtigt. Zweitens zeigten Patienten mit Morbus Addison bei hoher MR Besetzung eine bessere kognitive Leistungsfähigkeit (verbales Gedächtnis, Aufmerksamkeit und Exekutivfunktion) und eine bessere Stimmung im Vergleich zu einer geringen MR Besetzung; Und dies, obwohl die reguläre Fludrocortisoneinnahme nur einmal ausgelassen wurde. Drittens führte die akute MR Stimulierung bei Gesunden zu einer gesteigerten selektiven Aufmerksamkeit für traurige Gesichter. Hingegen scheint der MR keine Rolle bei der Emotionserkennung zu spielen. Die vorliegenden Befunde bekräftigen die Ergebnisse früherer Untersuchungen zur Rolle des MR. Zudem konnten die Studien dieser Dissertation zeigen, dass dies auch auf Patienten zutrifft, die kein endogenes Kortisol bilden (d.h. bei Patienten mit Morbus Addison). Die Ergebnisse unterstreichen, dass eine hohe MR Besetzung zu einer besseren kognitiven Leistungsfähigkeit und Stimmung führt. Zudem konnte gezeigt werden, dass der MR eine wichtige Rolle bei der Regulierung von schnellen, automatischen Verarbeitungsprozessen spielt, wie bei der selektiven Aufmerksamkeit