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Research

The focus of our group is on molecular and systemic mechanisms in the development and treatment of stress-related psychiatric disorders. We are particularly interested in how environmental adversity across the lifespan (prenatal, childhood, adulthood) relates to epigenetic modifications and respective changes of neuroendocrine stress response systems that are directly implicated in the pathogenesis of psychiatric disorders. In our research program, we combine DNA methylation analyses (EPIC array, epigenetic risk scores), gene expression studies, and genetic analyses (polygenic scores) with the assessment of prenatal stressors and critical life events. For a multimodal characterization of individual stress sensitivity, we use experimental stress paradigms (Trier Social Stress Test), stress hormone analyses in hair and saliva (e.g. cortisol) as well as (f)MRI.

  • Epigenetic trajectories in early childhood following perinatal parental stress – insights from the DREAM study (DFG)

    Principal Investigators: Prof. Dr. Nina Alexander, Prof. Dr. Susan Garthus-Niegel, Dr. Susann Schmiedgen

    Accumulating evidence suggests that a mother’s stress level during pregnancy has lasting effects on the development of her child. In this regard, epigenetic signatures such as DNA methylation have emerged as central mechanisms explaining how prenatal maternal stress (PNMS) may get under the skin. Importantly, the few epigenetic studies in this field so far mostly rely on broad retrospective measures of PNMS or assess the epigenetic state at or shortly after birth. To address this gap, the Dresden Study on Parenting, Work, and Mental Health (DREAM; “DResdner Studie zu Elternschaft, Arbeit und Mentaler Gesundheit”) is ideally suited to delineate biological pathways by which prenatal and early postnatal parental stress exposures longitudinally impact on child development. Launched in June 2017, the DREAM study is a prospective cohort study including a total of N = 3,865 individuals expecting a child to assess perinatal stress on a psychological, social, clinical, and biological level during the course from late pregnancy to 4.5 years postpartum, with planned extension into middle childhood. While most prior epigenetic studies focused on severe forms of PNMS an explicit aim of the DREAM study is to investigate a widely neglected source of PNMS, namely the role of work-related stress of the (expectant) mothers. In addition, the DREAM study will further allow to evaluate combined effects of multiple PNMS exposures on the fetal epigenome. While the role of the (becoming) father has been widely neglected in PNMS studies, the assessment of stress exposure in both parents posits a significant strength, e.g., in order to disentangle the effects of PNMS from those of the shared genetic susceptibility. In summary, this project aims to test the hypothesis that cumulative PNMS in general and work-related stress in specific provoke a longitudinal trajectory of epigenetic changes in young children (∼4.5 years) that, in turn, predict early health outcomes. To this end, we will estimate stress-related epigenetic risk scores (ERS) derived from summary statistics of prior epigenome-wide association studies on PNMS, internalizing symptoms, cortisol output, and epigenetic aging. Use of such ERS reflects a powerful strategy to aggregate small effects of single loci, which can then serve to robustly predict health phenotypes. As a secondary goal, we seek to evaluate independent and combined effects of PNMS and early postnatal parental stress during the first years of life on respective ERS. A third goal of the proposed project is to investigate whether ERS mediate changes in stress-related health outcomes (e.g., acute and long-term cortisol output, internalizing symptoms) following exposure to PNMS. Providing an in-depth understanding of the molecular pathways underlying fetal origins of health and disease has now become a public health concern of high priority with the long-term goal of delivering evidence-based prevention strategies.

  • AMIS-II- Analyzing developmental pathways from child maltreatment to internalizing symptoms and disorders- from longitudinal courses to intervention (BMBF)

    Subproject 4: Epigenetic trajectories following maltreatment and intervention in childhood
    Principal Investigator: Prof. Dr. Nina Alexander

    Coordinator: Prof. Dr. Kai von Klitzing, Dr. Lars White

    The detrimental effects of child maltreatment (CM) on disturbances in major biological stress systems and related psychiatric symptoms substantially vary by an individual’s genetic predisposition. Providing an in-depth understanding of the molecular pathways underlying such gene-environment interactions has now become a public health concern of high priority with the long-term goal of delivering evidence-based prevention and treatment strategies.  In this regard, epigenetic signatures such as DNA methylation (DNAM) have emerged as central mechanisms explaining how life events may get under the skin. As one of the largest German high-risk child sample of its kind, the AMIS cohort offers unique opportunities to conduct cutting-edge research on epigenetic trajectories of disease susceptibility and treatment success in maltreated children given that most prior studies are cross-sectional and rely on broad retrospective measures of maltreatment instead of fine-grained multi-source methods as pioneered by AMIS. In a first step, we aim to identify CM-related changes in DNAM that predict cortisol dysregulation and psychiatric outcomes. To this end, we will estimate stress-related epigenetic risk scores (ERS) derived from summary statistics of prior epigenome-wide association studies (EWAS) on cortisol output, internalizing psychopathology, and epigenetic aging. Use of such ERS reflects a powerful strategy to aggregate small effects of single loci, which can then serve to robustly predict health phenotypes. Given potential reversibility of DNAM as a function of environmental change, including psychotherapy, ERS identified in the longitudinal study will then be further investigated (and thus cross-validated) in the intervention component of AMIS-II. Precisely, we will investigate changes in ERS through psychotherapy and their predictive value for treatment success in terms of cortisol normalization and symptom improvement.

  • Research collaborations on behavioral disorders related to violence, neglect, maltreatment, and abuse in childhood and adolescence (BMBF)

    subproject 6: Validation and meta-analyses of objective biomarkers following early adversity and intervention

    Coordinators: Prof. Dr. Nina Alexander,  Prof. Dr. Sabine Herpertz, Prof. Dr. Iris-Tatjana Kolassa, Prof. Dr. Robert Kumsta

    Traumatic stress and in particular childhood maltreatment alters the biological functioning of the body on a systemic scale. So far, changes have been reported on the level of DNA methylation, immune functioning and endocrine signaling, metabolic regulation, and cellular. The rationale for the collaborative effort is to embrace the opportunity to replicate/validate findings on of objective biomarkers following early adversity and intervention across independent cohorts.
    The replication crisis in psychological science in general and in (epi-)genetic research in specific has clearly highlighted the need for collaborative efforts in the relatively new field of behavioral epige netics to replicate results in independent samples as well as across different tissues. Such collaborative and meta-analytical efforts significantly aid the identification of robust biomarkers that can be readily implemented in clinical practice to allow an early allocation of personalized interventions in the future. Thus, to test the robustness, the specificity and the sensitivity of the biomarker findings for a possible clinical application, the results of individual studies need to be replicated in independent clinical cohorts, in particular before and after treatment. With this collaborative project we want to focus on three outcomes, namely 1) stress biomarkers in hair, 2) epigenetics and 3) telomere dynamics in buccal mucosa cells.

  • Psychological and biological risk factors of burnout – Investigating epigenetic risk scores to understand the mechanistic pathways from work-related stress to burnout

    Principal Investigators: Prof. Dr. Nina Alexander, Prof. Dr. Clemens Kirschbaum, Dr. Robert Miller

    According to the World Health Organization, work‐related stress forms a growing health burden and relates to tremendous costs in Western societies. A crucial condition in this context is burnout—a syndrome defined by emotional and physical exhaustion, negative attitudes toward work and negative evaluation of ones work performance that develops in response to chronically adverse working conditions. Today, it remains controversial whether burnout can be reliably distinguished from other stress-related disorders, most notably depression. Consequently, the identification of burnout-specific biomarkers constitutes a promising approach to understand the mechanistic pathways from work-related stress to burnout and to provide a biologically-informed basis for the distinction between burnout and depression. In this regard, epigenetic signatures such as DNA methylation have emerged as central mechanisms explaining how life stress may get under the skin. First cross-sectional findings in this field now call for prospective, longitudinal studies that ideally include high and low risk populations and combine fine-grained assessments of adversity and psychiatric symptoms with stress-related biomarkers. To address this gap, the Dresden Burnout Study (DBS) was initiated as a large-scale, 12-year prospective cohort study with annual assessment of burnout on a psychological, social, clinical, and biological level. In this proposal, we now aim to implement the assessment of epigenetic markers to complement and interpret the extensive multi-level data that has been obtained during the first waves of the DBS. Specifically, we aim to test the hypotheses that (a) work-related stress provokes a longitudinal trajectory of epigenetic changes that (b) predict immunological/endocrine dysregulation and burnout symptoms. To this end, we will estimate epigenetic risk scores (ERS) derived from summary statistics of prior epigenome-wide association studies on biological pathway by which stress may contribute to ensuing burnout symptoms (including cortisol output, inflammatory makers and epigenetic aging). Use of such ERS reflects a powerful strategy to aggregate small effects of single loci, which can then serve to robustly predict health phenotypes. Second, we seek to provide biologically-informed evidence for burnout’s discriminant validity by investigating whether specific ERS differentiate between burnout and depressive symptoms or not. Given that burnout, as compared to other stress-related disorders, has been assumed to first and foremost dependent on occupational adversity, we will illuminate whether (c) work-related stress provokes distinct longitudinal trajectory of ERS changes compared to non-work related stressors (d) that could differentiate burnout from depressive symptoms. Identifying objective risk biomarkers and specific pathological sequelae of burnout may deliver directions for developing personalized prevention and treatment strategies in the future.

  • Long-term effects of prenatal synthetic glucocorticoid exposure on psychosocial stress reactivity and volitional control in children and adolescents (DFG)

    Principal Investigators: Prof. Dr. Nina Alexander, Prof. Dr. Clemens Kirschbaum, Prof. Dr. Shu-Chen Li

    Interactions between the developing individual and his or her developmental contexts are crucial for experience-dependent tuning of behavioural and brain development. Prenatal exposures to unfavorable events in the gestational environment, such as maternal stress or depression, glucocorticoids and substance abuse, are among the earliest adverse contextual influences on development. Of particular relevance to this project are long-term effects of prenatal synthetic glucocorticoid (sGC) exposure on the development of social stress reactivity and volitional control. Thus far, research on hypothalamus-pituitary-adrenal (HPA) axis functioning in humans exposed to antenatal sGC treatment is currently limited to the assessment of a single cortisol baseline measure and stress-induced cortisol secretion shortly after birth with preterm birth being an important confounder. Furthermore, although the HPA-axis is tightly linked to brain networks, such as the prefrontal circuitry, that subserve cognitive and motivational regulatory functions, long-term effects of antenatal sGC exposure on these regulatory functions in humans have been sparsely addessed and are mostly limited to behavioral assessments. To go beyond the current state of the art, this proposed project will assess long-term effects of antenatal sGC on psychosocial stress reactivity, behavioral and brain evoked potential measures of volitional control, using a retrospective longitudinal design. The proposed project has three aims:  First, we plan to carry out a comprehensive assessment of hypothalamus-pituitary-adrenal (HPA) axis functioning in childhood and adolescence to explore (a) whether our previously observed effects of prenatal sGC exposure on stress reactivity in children would persist into adolescence and (b) whether these effects would generalize to measures of long-term changes in basal cortisol secretion. Second, by measuring electroencephalography (EEG) we aim to investigate the effects of antenatal sGC exposure on evoked brain potentials associated with cognitive monitoring, which are known to involve monoaminergic modulations and brain circuits that are tightly linked to the HPA-axis functions. A third goal of the current project is to investigate epigenetic modifications as a potential mechanism in mediating long-term effects of antenatal sGC on stress-related and cognitive measures. Other than the potential gain of understanding basic mechanisms that relate antenatal sGC exposure, monoaminergic modulation and cognition during child and adolescent development, a deeper understanding of long-term effects of antenatal sGC exposure is also of important clinical relevance given the widespread use of sGC (7 to 10% of women in Europe and North America) in obstetric care.