Patho- and therapyepigenetics of anxiety and stress-related disorders
Klinik für Psychiatrie und Psychotherapie, Universitätsklinikum Freiburg, Deutschland
Epigenetic mechanisms such as DNA methylation are biochemical modifications of the DNA or its spatial structure. They regulate gene function, can be modified by environmental influences and are temporally dynamic. Altered DNA methylation patterns are not only implied in the mediation of environmental factors towards increasing – or decreasing – the risk for mental disorders, but have moreover been suggested as predictors and signatures of treatment response.
Here, recent findings on DNA methylation in candidate genes (MAOA, SLC6A4, OXTR) will be reviewed with regard to categorical diagnoses of mental disorders such as panic disorder, specific phobia and obsessive-compulsive disorder (OCD). Also, the role of DNA methylation as a predictor or dynamic correlate of psychotherapeutic treatment response applying a ‘therapy-epigenetic’ approach in anxiety disorders and OCD will be discussed.
Epigenetic research carries great potential for clinical application and is hoped to in the future move the field towards more targeted, personalized and innovative treatment options in line with a ‘precision medicine’ approach.
Predictive value of clinical data, process variables and brain imaging data for treatment outcome in spider phobia
1Department of Psychiatry and Psychotherapy, University of Münster; 2Department of Clinical Psychology, University of Siegen; 3Institute for Biomagnetism and Biosignalanalysis, University of Münster; 4Department of Psychology, Humboldt-Universität zu Berlin; 5Department of Psychiatry, Psychosomatics, and Psychotherapy, Center of Mental Health, University Hospital of Würzburg; 6Institute of Medical Psychology and Systems Neuroscience, University of Münster
Evidenced-based psychotherapeutic interventions, e.g. exposure therapy, for anxiety disorders are available. Still, knowledge about theranostic markers for personalized therapy is missing. Identifying bio-behavioral markers of treatment (non-)response for exposure therapy might advance individual treatment selection in terms of precision medicine and improve response rates.
Clinical features, treatment process variables and brain imaging data were used to identify markers for treatment outcome. Data at baseline and post-treatment is available from n=187 patients with spider phobia receiving a one-session virtual-reality exposure treatment (VRET). An external cross-validation protocol based on a bi-centric study design was used to evaluate the robustness and generalizability of predictors identified.
One session of VRET was highly effective on a group-level and showed long-term stability (~6 month). Within-session fear reduction, but not expectancy violation and initial fear activation showed significant association with treatment outcome. Clinical data predicted individual short-term symptom reductions above chance, but accuracies dropped to non-significance in the between-site prediction and for predictions of long-term outcomes. Treatment process variables were predictive regarding combined long-term reduction of symptoms and behavioral avoidance. Preliminary analysis regarding the brain data revealed smaller left amygdala volumes and larger gray matter volumes in the left medial superior frontal gyrus in responders as morphometric moderators of treatment outcome (Münster site).
The study offers the exceptional possibility to investigate theranostic markers for a model disorder of fear circuitry dysfunctions. Results of this study might further bridge the gap between basic and clinical research and – as a long-term goal – bring stratified therapy approaches into reach.
Overgeneralization of fear is associated with later non-response to virtual reality exposure therapy in spider phobia – evidence from magnetoencephalography
1Institute for Clinical Psychology, University of Siegen; 2Institute for Biomagnetism and Biosignalanalysis, University of Münster; 3Department of Psychiatry and Psychotherapy, University of Münster; 4Center for Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg; 5Institute of Medical Psychology and Systems Neuroscience, University of Münster; 6Department of Psychology, Humboldt-Universität zu Berlin
As overgeneralization of fear is considered a crucial pathogenic marker of anxiety disorders, we investigated associations of pre-treatment fear generalization and treatment success. 90 patients with spider phobia (SP) completed a One-Session Virtual Reality Exposure Therapy, a clinical and a magnetoencephalography (MEG) assessment before, and a clinical assessment after therapy. Based on self-reported symptom reductions in the Spider Phobia Questionnaire, patients were categorized as responders (> 30% reduction) or non-responders. The MEG-assessment consisted of baseline, conditioning, and subsequent generalization phases. In the conditioning phases, aversive unconditioned stimuli (US) were either paired or never paired with differently tilted Gabor gratings (CS+, CS-). In the subsequent generalization phase, fear ratings, US expectancy ratings and event-related fields to CS+, CS- and seven different generalization (GS) stimuli that ranged on a perceptual continuum from CS+ to CS- were obtained. Non-responders compared to responders showed behavioral overgeneralization indicated by more linear generalization gradients in fear ratings. Analyses of MEG source estimations revealed that linear generalization gradients in frontal clusters also differentiated between (later) non-responders and responders. While stronger (inhibitory) frontal activations to safety-signaling CS- and GS compared to CS+ declined over time in non-responders, responders maintained these activations at early and late processing stages. Results provide initial evidence that pre-treatment differences of behavioral and neural markers of fear generalization may hold predictive information regarding later responses to behavioral exposure. Our findings demonstrate the relevance of inhibitory learning functions and their spatio-temporal neural reflections in this interplay.
Brain activity predicting behavioural outcomes in a combined neuromodulation and inhibitory control task in patients with binge eating disorder
1University Hospital Tübingen, Psychosomatic Medicine & Psychotherapy, Tübingen, Germany; 2University Hospital Tübingen, Psychiatry & Psychotherapy, Tübingen, Germany; 3Department of Psychology, Haliç University, Istanbul, Turkey; 4University of Münster, Department of Psychiatry and Psychotherapy, Münster, Germany
Background: Impaired inhibitory control, particularly towards food stimuli, might represent a risk factor for Binge Eating Disorder (BED). Inhibitory control means the ability to suppress a dominant behaviour and is localized in the dorsolateral prefrontal cortex (dlPFC). We are developing a computer-based training programme to increase inhibitory control that is supported by transcranial direct current stimulation.
Methods: We assess food-related inhibitory control in patients with BED in a double blind study with a so-called antisaccade task via eye tracking at baseline with electroencephalography (EEG, T0) and anodal stimulation of the right dlPFC (1mA vs. 2mA) vs. sham stimulation in a crossover design (T1, T2). The aim of this study is to explore, if neurological markers for inhibitory control from the EEG (ERN, P3, N2) are involved in the execution of the antisaccade task and if they are predicting outcomes at T1 and T2.
Results: There was a stable learning effect in the antisaccade task over time and over stimulation conditions. Additionally, patients in the 2 mA vs. sham condition improved in the task and in binge eating frequency in the 2 mA condition, but not in the 1 mA condition. All EEG markers differed at erroneous antisaccade trials from right antisaccade trials and especially P3 predicted task outcomes at T1 and T2.
Conclusion: Inhibitory control and attentional processes are involved in this task and related to improvements, which suggests that a direct training of food-related inhibitory control constitutes a promising treatment approach in patients with BED.