The etiology of anxiety disorders is complex, involving genetic and environmental factors. The research conducted in the Outpatient Clinic for Anxiety Disorders aims to integrate different levels of anxiety pathophysiology. We investigate dynamic molecular and endocrinological changes during the therapeutic process in order to detect a biomarker panel which can be used for characterization of symptom clusters, disease status and outcome prediction. We use translational approaches applying a variety of methods from clinical and preclinical research to get the whole picture of anxiety pathophysiology. This project is supported by the EraNet Neuron and is an international collaboration.
Furthermore, we perform candidate gene and genome-wide analysis to detect gene clusters contributing to the pathophysiology of panic attacks and other anxiety disorders. One important target, which has been detected in a recent genome-wide analysis, is the transmembrane protein 132 D (TMEM132D). Genetic variants in this gene are associated with panic disorder and severity of anxiety symptomatology in other psychiatric conditions. Previous studies suggest a role of TMEM132D in the brain connectivity function and the processing of anxiety-relevant stimuli. Further imaging and molecular studies are ongoing to further characterize the role and possible utility of TMEM132D in the treatment of anxiety (Fig. 1).
Molecular Pathways of Depression
Deciphering the molecular underpinnings of affective disorders remains a major challenge. We aim at translating questions arising from clinical observations into strategies in basic research employing tools from biochemistry, molecular biology and cell biology; we engage in collaborations wherever needed. Currently, we focus on regulatory and regulated molecules (including epigenetics) of the stress hormone axis, and in particular chaperones like FKBP51. Our strategy includes the search for novel pathways of antidepressants as another entry point into disease-relevant molecular networks. The physiological relevance of these molecular pathways is tested in animal models and clinical samples (Fig 3).
Epigenomics of Early-Life Stress
Childhood trauma, maltreatment, but also interpersonal loss, are known causes of early-life stress (ELS) and strong risk factors for depression. Maternal neglect is the most common form of maltreatment, accounting for some 80 % of all cases.
We hypothesize that ELS leaves an enduring trace in the neural cells and circuits that govern behavior and physiology, including the neuroendocrine response to challenging stimuli. Epigenetic processes involving DNA methylation and chromatin structure provide the long sought-after link between environmental stimuli and sustained changes in gene expression, physiology and behavior. Experience-dependent methyl marking of DNA is now recognized as an important contribution to the dynamic regulation of gene transcription that supports synaptic plasticity and long-term behavioral adaptation.
Our aim is to decipher the convergence of pathways and mechanisms responsible for translating early experiences into alterations in brain function through epigenetically altered gene transcription, neurocircuit reorganisation and functional outcome. The project is approached from a top-down (neural circuitry to stress-related epigenomics and phenotypes) and bottom-up scale (genetic variants encoding changes in neuronal connectivity important for the processing of future stressors) to understand the mechanisms through which early trauma and neglect encode future vulnerability or resilience to depression (Fig. 4).
The aim of the Psychophysiology Lab is to examine physiological readouts for affective processes relevant to psychiatric disorders. The emphasis lies on stressing the system in order to see whether it dysfunctions, which typically requires a task such as playing loud sounds or administering mild electric shocks during on-screen picture viewing. Among the readouts are startle electromyography which is measured with electrodes on the muscle surrounding the eye (orbicularis oculi), heart rate as measured with pulse oximetry, the galvanic skin response measured on the fingers and eye tracking with a high-speed camera for gaze direction and pupil size measurements (Fig.).
A further aim is to examine such psychophysiological readouts in the magnetic resonance scanner, and to investigate the correlations between physiological responses and brain activity and connectivity as measured with functional magnetic resonance imaging (fMRI). With this line of research, we evaluate the neural circuitry associated with physiological responses during a task and during rest – and whether the so-called ‘resting state’ is really a resting state.
Measurements of subjects and patients take place in the Psychophysiology Lab and in the MR-scanner, also as part of the project Biological Classification Of Mental Disorders (BeCOME).