Associations between oxytocin and vasopressin concentrations, traumatic event exposure and posttraumatic stress disorder symptoms: group comparisons, correlations, and courses during an internet-based cognitive-behavioural treatment

Background: Posttraumatic stress disorder (PTSD) is characterized by impairments in extinction learning and social behaviour, which are targeted by trauma-focused cognitive behavioural treatment (TF-CBT). The biological underpinnings of TF-CBT can be better understood by adding biomarkers to the clinical evaluation of interventions. Due to their involvement in social functioning and fear processing, oxytocin and arginine vasopressin might be informative biomarkers for TF-CBT, but to date, this has never been tested. Objective: To differentiate the impact of traumatic event exposure and PTSD symptoms on blood oxytocin and vasopressin concentrations. Further, to describe courses of PTSD symptoms, oxytocin and vasopressin during an internet-based TF-CBT and explore interactions between these parameters. Method: We compared oxytocin and vasopressin between three groups of active and former male service members of the German Armed Forces (n = 100): PTSD patients (n = 39), deployed healthy controls who experienced a deployment-related traumatic event (n = 33) and non-deployed healthy controls who never experienced a traumatic event (n = 28). PTSD patients underwent a 5-week internet-based TF-CBT. We correlated PTSD symptoms with oxytocin and vasopressin before treatment onset. Further, we analysed courses of PTSD symptoms, oxytocin and vasopressin from pre- to post-treatment and 3 months follow-up, as well as interactions between the three parameters. Results: Oxytocin and vasopressin did not differ between the groups and were unrelated to PTSD symptoms. PTSD symptoms were highly stable over time, whereas the endocrine parameters were not, and they also did not change in mean. Oxytocin and vasopressin were not associated with PTSD symptoms longitudinally. Conclusions: Mainly due to their insufficient intraindividual stability, single measurements of endogenous oxytocin and vasopressin concentrations are not informative biomarkers for TF-CBT. We discuss how the stability of these biomarkers might be increased and how they could be better related to the specific impairments targeted by TF-CBT

Comparison of DSM-5 and proposed ICD-11 criteria for PTSD with DSM-IV and ICD-10: changes in PTSD prevalence in military personnel

Background: Recently, changes have been introduced to the diagnostic criteria for posttraumatic stress disorder (PTSD) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD). Objectives:This study investigated the effect of the diagnostic changes made from DSM-IV to DSM-5 and from ICD-10 to the proposed ICD-11. The concordance of provisional PTSD prevalence between the diagnostic criteria was examined in a convenience sample of 100 members of the German Armed Forces. Method: Based on questionnaire measurements, provisional PTSD prevalence was assessed according to DSM-IV, DSM-5, ICD-10, and proposed ICD-11 criteria. Consistency of the diagnostic status across the diagnostic systems was statistically evaluated. Results: Provisional PTSD prevalence was the same for DSM-IV and DSM-5 (both 56%) and comparable under DSM-5 versus ICD-11 proposal (48%). Agreement between DSM-IV and DSM-5, and between DSM-5 and the proposed ICD-11, was high (both p < .001). Provisional PTSD prevalence was significantly increased under ICD-11 proposal compared to ICD-10 (30%) which was mainly due to the deletion of the time criterion. Agreement between ICD-10 and the proposed ICD-11 was low (p = .014). Conclusion: This study provides preliminary evidence for a satisfactory concordance between provisional PTSD prevalence based on the diagnostic criteria for PTSD that are defined using DSM-IV, DSM-5, and proposed ICD-11. This supports the assumption of a set of PTSD core symptoms as suggested in the ICD-11 proposal, when at the same time a satisfactory concordance between ICD-11 proposal and DSM was given. The finding of increased provisional PTSD prevalence under ICD-11 proposal in contrast to ICD-10 can be of guidance for future epidemiological research on PTSD prevalence, especially concerning further investigations on the impact, appropriateness, and usefulness of the time criterion included in ICD-10 versus the consequences of its deletion as proposed for ICD-11

Associations Between Difficulties in Emotion Regulation and Post-Traumatic Stress Disorder in Deployed Service Members of the German Armed Forces

Background Experiencing a traumatic event can lead to post-traumatic stress disorder (PTSD), but not every traumatized person develops PTSD. Several protective and risk factors have been identified in civilians and veterans to explain why some individuals develop PTSD and others do not. However, no research has confirmed the relationship between emotion regulation and PTSD in deployed German Armed Forces service members after a foreign assignment. Previous studies have identified some protective factors, such as social support, social acknowledgment, specific personal values, and posttraumatic growth, as well as risk factors, like moral injury and emotion regulation. Thus, the aim of the present study is to confirm the relationship between emotion regulation and PTSD and to test for factors that are associated with higher severity of PTSD symptoms in such a sample. Methods Apost-hocsecondary analysis was conducted on data collected in a randomized controlled trial. Participants (N= 72) were male active and former military service members that have returned from deployment and were recruited from the German Armed Forces. These participants were separated into two groups according to PTSD diagnosis based on the results of a structured diagnostic interview. Data from evaluation questionnaires administered upon entry into the study were subjected to a cross-sectional analysis. The measures included the severity of PTSD symptoms, clusters of PTSD symptoms, clinical measures, and several measures assessing PTSD-related constructs. Analyses included the Spearman rank correlation coefficient, X(2)tests for nominal data, Mann-Whitney U-tests for non-parametric data, and a mediation analysis. Results The results of the mediation analysis revealed that difficulties in emotion regulation were significantly associated with the severity of PTSD symptoms, which was mediated by social acknowledgment and experimental avoidance but not by moral injury. The analyses showed that the severity of PTSD symptoms and all clusters of PTSD symptoms were significantly associated with most of the measured constructs in expectable directions. Participants in the PTSD group showed significantly higher mean scores on questionnaires measuring constructs that have been associated with PTSD, like emotion regulation and moral injury. They also showed lower mean scores in questionnaires for social support and social acknowledgment as a victim or survivor than participants in the non-PTSD group. Conclusion The present results show that difficulties in emotion regulation are directly associated with the severity of PTSD symptoms in service members of the German Armed Forces. This association is mediated by social acknowledgment and experimental avoidance, but not by moral injury. Thus, future studies should investigate these potentially crucial factors for better understanding of the development and maintenance of PTSD in service members of the German Armed Forces after deployment to create possible treatment adaptions

Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes

Background & Aims: Selective elimination of virus-infected hepatocytes occurs through virus-specific CD8 T cells recognizing peptide-loaded MHC molecules. Herein, we report that virus-infected hepatocytes are also selectively eliminated through a cell-autonomous mechanism. Methods: We generated recombinant adenoviruses and genetically modified mouse models to identify the molecular mechanisms determining TNF-induced hepatocyte apoptosis in vivo and used in vivo bioluminescence imaging, immunohistochemistry, immunoblot analysis, RNAseq/proteome/phosphoproteome analyses, bioinformatic analyses, mitochondrial function tests. Results: We found that TNF precisely eliminated only virus-infected hepatocytes independently of local inflammation and activation of immune sensory receptors. TNF receptor I was equally relevant for NF-kB activation in healthy and infected hepatocytes, but selectively mediated apoptosis in infected hepatocytes. Caspase 8 activation downstream of TNF receptor signaling was dispensable for apoptosis in virus-infected hepatocytes, indicating an unknown non-canonical cell-intrinsic pathway promoting apoptosis in hepatocytes. We identified a unique state of mitochondrial vulnerability in virus-infected hepatocytes as the cause for this non-canonical induction of apoptosis through TNF. Mitochondria from virus-infected hepatocytes showed normal biophysical and bioenergetic functions but were characterized by reduced resilience to calcium challenge. In the presence of unchanged TNF-induced signaling, reactive oxygen species-mediated calcium release from the endoplasmic reticulum caused mitochondrial permeability transition and apoptosis, which identified a link between extrinsic death receptor signaling and cell-intrinsic mitochondrial-mediated caspase activation. Conclusion: Our findings reveal a novel concept in immune surveillance by identifying a cell-autonomous defense mechanism that selectively eliminates virus-infected hepatocytes through mitochondrial permeability transition. Lay summary: The liver is known for its unique immune functions. Herein, we identify a novel mechanism by which virus-infected hepatocytes can selectively eliminate themselves through reduced mitochondrial resilience to calcium challenge. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

Identification of Phosphorylated p38 as a Novel DAPK-Interacting Partner during TNFα-Induced Apoptosis in Colorectal Tumor Cells

Death-associated protein kinase (DAPK) is a serine/threonine kinase that contributes to pro-apoptotic signaling on cytokine exposure. The role of DAPK in macrophage-associated tumor cell death is currently unknown. Recently, we suggested a new function for DAPK in the induction of apoptosis during the interaction between colorectal tumor cells and tumor-associated macrophages. Using a cell-culture model with conditioned supernatants of differentiated/activated macrophages (U937) and human HCT116 colorectal tumor cells, we replicated DAPK-associated tumor cell death; this model likely reflects the in vivo tumor setting. In this study, we show that tumor necrosis factor-α exposure under conditions of macrophage activation induced DAPK-dependent apoptosis in the colorectal tumor cell line HCT116. Simultaneously, early phosphorylation of p38 mitogen-activated protein kinase (phospho-p38) was observed. We identified the phospho-p38 mitogen-activated protein kinase as a novel interacting protein of DAPK in tumor necrosis factor-α–induced apoptosis. The general relevance of this interaction was verified in two colorectal cell lines without functional p53 (ie, HCT116 p53−/− and HT29 mutant) and in human colon cancer and ulcerative colitis tissues. Supernatants of freshly isolated human macrophages were also able to induce DAPK and phospho-p38. Our findings highlight the mechanisms that underlie DAPK regulation in tumor cell death evoked by immune cells

Digital Interventions for Mental Disorders:Key Features, Efficacy, and Potential for Artificial Intelligence Applications

Mental disorders are highly prevalent and often remain untreated. Many limitations of conventional face-to-face psychological interventions could potentially be overcome through Internet-based and mobile-based interventions (IMIs). This chapter introduces core features of IMIs, describes areas of application, presents evidence on the efficacy of IMIs as well as potential effect mechanisms, and delineates how Artificial Intelligence combined with IMIs may improve current practices in the prevention and treatment of mental disorders in adults. Meta-analyses of randomized controlled trials clearly show that therapist-guided IMIs can be highly effective for a broad range of mental health problems. Whether the effects of unguided IMIs are also clinically relevant, particularly under routine care conditions, is less clear. First studies on IMIs for the prevention of mental disorders have shown promising results. Despite limitations and challenges, IMIs are increasingly implemented into routine care worldwide. IMIs are also well suited for applications of Artificial Intelligence and Machine Learning, which provides ample opportunities to improve the identification and treatment of mental disorders. Together with methodological innovations, these approaches may also deepen our understanding of how psychological interventions work, and why. Ethical and professional restraints as well as potential contraindications of IMIs, however, should also be considered. In sum, IMIs have a high potential for improving the prevention and treatment of mental health disorders across various indications, settings, and populations. Therefore, implementing IMIs into routine care as both adjunct and alternative to face-to-face treatment is highly desirable. Technological advancements may further enhance the variability and flexibility of IMIs, and thus even further increase their impact in people’s lives in the future