Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

Trauma history and course of therapy in a naturalistic cognitive behavior therapy outpatient sample: An archive data study.

OBJECTIVE: Cognitive Behavior Therapy (CBT) is an effective treatment for anxiety and depression disorders. Nonetheless, nearly 50% of all patients do not respond. Besides other factors, nonresponse may be linked to traumatic life events. This study aims to assess the relationship between trauma history, applied therapy interventions, and therapy outcomes. METHODS: We analyzed data from 340 CBT outpatients diagnosed with a depression or anxiety disorder and possibly a trauma history treated under naturalistic conditions. Based on their therapy files, we collected information on trauma history, diagnoses, applied interventions, and severity of depression and anxiety symptoms at the start and end of therapy. The relationship between trauma, diagnoses, and intervention use and the development of depression and anxiety symptoms was analyzed using Linear Mixed Models. RESULTS: Patients with a trauma history reported higher pre- and posttreatment symptom severity than those without trauma. No differences in applied interventions or decrease in symptom severity were found between patients with and without a trauma history. Specialized interventions were seldom applied. CONCLUSION: Although no differences between patients with and without a trauma history were found in therapy response, patients with a trauma history maintained higher levels of symptom severity. These results indicate a need for more personalized interventions and evidence-based guidelines to personalize CBT for patients with a trauma history and high symptom severity.

The application of virtual reality exposure versus relaxation training in music performance anxiety: a randomized controlled study.

BACKGROUND: Performance anxiety is the most frequently reported anxiety disorder among professional musicians. Typical symptoms are - on a physical level - the consequences of an increase in sympathetic tone with cardiac stress, such as acceleration of heartbeat, increase in blood pressure, increased respiratory rate and tremor up to nausea or flush reactions. These symptoms can cause emotional distress, a reduced musical and artistical performance up to an impaired functioning. While anxiety disorders are preferably treated using cognitive-behavioral therapy with exposure, this approach is rather difficult for treating music performance anxiety since the presence of a public or professional jury is required and not easily available. The use of virtual reality (VR) could therefore display an alternative. So far, no therapy studies on music performance anxiety applying virtual reality exposure therapy have investigated the therapy outcome including cardiovascular changes as outcome parameters. METHODS: This mono-center, prospective, randomized and controlled clinical trial has a pre-post design with a follow-up period of 6 months. 46 professional and semi-professional musicians will be recruited and allocated randomly to an VR exposure group or a control group receiving progressive muscle relaxation training. Both groups will be treated over 4 single sessions. Music performance anxiety will be diagnosed based on a clinical interview using ICD-10 and DSM-5 criteria for specific phobia or social anxiety. A behavioral assessment test is conducted three times (pre, post, follow-up) in VR through an audition in a concert hall. Primary outcomes are the changes in music performance anxiety measured by the German Bühnenangstfragebogen and the cardiovascular reactivity reflected by heart rate variability (HRV). Secondary outcomes are changes in blood pressure, stress parameters such as cortisol in the blood and saliva, neuropeptides, and DNA-methylation. DISCUSSION: The trial investigates the effect of VR exposure in musicians with performance anxiety compared to a relaxation technique on anxiety symptoms and corresponding cardiovascular parameters. We expect a reduction of anxiety but also a consecutive improvement of HRV with cardiovascular protective effects. TRIAL REGISTRATION: This study was registered on clinicaltrials.gov. (ClinicalTrials.gov Number: NCT05735860).

Centralized gaze as an adaptive component of defensive states in humans.

Adequate defensive responding is crucial for mental health but scientifically not well understood. Specifically, it seems difficult to dissociate defense and approach states based on autonomic response patterns. We thus explored the robustness and threat-specificity of recently described oculomotor dynamics upon threat in anticipation of either threatening or rewarding stimuli in humans. While visually exploring naturalistic images, participants (50 per experiment) expected an inevitable, no, or avoidable shock (Experiment 1) or a guaranteed, no, or achievable reward (Experiment 2) that could be averted or gained by a quick behavioural response. We observed reduced heart rate (bradycardia), increased skin conductance, pupil dilation and globally centralized gaze when shocks were inevitable but, more pronouncedly, when they were avoidable. Reward trials were not associated with globally narrowed visual exploration, but autonomic responses resembled characteristics of the threat condition. While bradycardia and concomitant sympathetic activation reflect not only threat-related but also action-preparatory states independent of valence, global centralization of gaze seems a robust phenomenon during the anticipation of avoidable threat. Thus, instead of relying on single readouts, translational research in animals and humans should consider the multi-dimensionality of states in aversive and rewarding contexts, especially when investigating ambivalent, conflicting situations.

Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression.

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

Fear conditioning and stimulus generalization in association with age in children and adolescents.

The aim of the study was to investigate age-related differences in fear learning and generalization in healthy children and adolescents (n = 133), aged 8-17 years, using an aversive discriminative fear conditioning and generalization paradigm adapted from Lau et al. (2008). In the current task, participants underwent 24 trials of discriminative conditioning of two female faces with neutral facial expressions, with (CS+) or without (CS-) a 95-dB loud female scream, presented simultaneously with a fearful facial expression (US). The discriminative conditioning was followed by 72 generalization trials (12 CS+, 12 GS1, 12 GS2, 12 GS3, 12 GS4, and 12 CS-): four generalization stimuli depicting gradual morphs from CS+ to CS- in 20%-steps were created for the generalization phases. We hypothesized that generalization in children and adolescents is negatively correlated with age. The subjective ratings of valence, arousal, and US expectancy (the probability of an aversive noise following each stimulus), as well as skin conductance responses (SCRs) were measured. Repeated-measures ANOVAs on ratings and SCR amplitudes were calculated with the within-subject factors stimulus type (CS+, CS-, GS1-4) and phase (Pre-Acquisition, Acquisition 1, Acquisition 2, Generalization 1, Generalization 2). To analyze the modulatory role of age, we additionally calculated ANCOVAs considering age as covariate. Results indicated that (1) subjective and physiological responses were generally lower with increasing age irrespective to the stimulus quality, and (2) stimulus discrimination improved with increasing age paralleled by reduced overgeneralization in older individuals. Longitudinal follow-up studies are required to analyze fear generalization with regard to brain maturational aspects and clarify whether overgeneralization of conditioned fear promotes the development of anxiety disorders or vice versa.

Can Religiosity and Social Support Explain Effects of Trait Emotional Intelligence on Health-Related Quality of Life: A Cross-Cultural Study.

Religion and social support along with trait emotional intelligence (EI) help individuals to reduce stress caused by difficult situations. Their implications may vary across cultures in reference to predicting health-related quality of life (HRQoL). A convenience sample of N = 200 chronic heart failure (CHF) patients was recruited at cardiology centers in Germany (n = 100) and Pakistan (n = 100). Results indicated that trait-EI predicted better mental component of HRQoL in Pakistani and German CHF patients. Friends as social support appeared relevant for German patients only. Qualitative data indicate an internal locus of control in German as compared to Pakistani patients. Strengthening the beneficial role of social support in Pakistani patients is one example of how the current findings may inspire culture-specific treatment to empower patients dealing with the detrimental effects of CHF.

Relevance of Religiosity for Coping Strategies and Disability in Patients with Fibromyalgia Syndrome.

Coping strategies are essential for the outcome of chronic pain. This study evaluated religiosity in a cohort of patients with fibromyalgia syndrome (FMS), its effect on pain and other symptoms, on coping and FMS-related disability. A total of 102 FMS patients were recruited who filled in questionnaires, a subgroup of 42 patients participated in a face-to-face interview, and data were evaluated by correlation and regression analyses. Few patients were traditionally religious, but the majority believed in a higher existence and described their spirituality as "transcendence conviction". The coping strategy "praying-hoping" and the ASP dimension "religious orientation" (r = 0.5, P < 0.05) showed a significant relationship independent of the grade of religiosity (P < 0.05). A high grade of belief in a higher existence was negatively associated with the choice of ignoring as coping strategy (r = - 0.4, P < 0.05). Mood and affect-related variables had the highest impact on disability (b = 0.5, P < 0.05). In this cohort, the grade of religiosity played a role in the choice of coping strategies, but had no effects on health and mood outcome.

Efficacy of temporally intensified exposure for anxiety disorders: A multicenter randomized clinical trial.

BACKGROUND: The need to optimize exposure treatments for anxiety disorders may be addressed by temporally intensified exposure sessions. Effects on symptom reduction and public health benefits should be examined across different anxiety disorders with comorbid conditions. METHODS: This multicenter randomized controlled trial compared two variants of prediction error-based exposure therapy (PeEx) in various anxiety disorders (both 12 sessions + 2 booster sessions, 100 min/session): temporally intensified exposure (PeEx-I) with exposure sessions condensed to 2 weeks (n = 358) and standard nonintensified exposure (PeEx-S) with weekly exposure sessions (n = 368). Primary outcomes were anxiety symptoms (pre, post, and 6-months follow-up). Secondary outcomes were global severity (across sessions), quality of life, disability days, and comorbid depression. RESULTS: Both treatments resulted in substantial improvements at post (PeEx-I: dwithin = 1.50, PeEx-S: dwithin = 1.78) and follow-up (PeEx-I: dwithin = 2.34; PeEx-S: dwithin = 2.03). Both groups showed formally equivalent symptom reduction at post and follow-up. However, time until response during treatment was 32% shorter in PeEx-I (median = 68 days) than PeEx-S (108 days; TRPeEx-I = 0.68). Interestingly, drop-out rates were lower during intensified exposure. PeEx-I was also superior in reducing disability days and improving quality of life at follow-up without increasing relapse. CONCLUSIONS: Both treatment variants focusing on the transdiagnostic exposure-based violation of threat beliefs were effective in reducing symptom severity and disability in severe anxiety disorders. Temporally intensified exposure resulted in faster treatment response with substantial public health benefits and lower drop-out during the exposure phase, without higher relapse. Clinicians can expect better or at least comparable outcomes when delivering exposure in a temporally intensified manner.

Immersive virtual reality during gait rehabilitation increases walking speed and motivation: a usability evaluation with healthy participants and patients with multiple sclerosis and stroke.

BACKGROUND: The rehabilitation of gait disorders in patients with multiple sclerosis (MS) and stroke is often based on conventional treadmill training. Virtual reality (VR)-based treadmill training can increase motivation and improve therapy outcomes. The present study evaluated an immersive virtual reality application (using a head-mounted display, HMD) for gait rehabilitation with patients to (1) demonstrate its feasibility and acceptance and to (2) compare its short-term effects to a semi-immersive presentation (using a monitor) and a conventional treadmill training without VR to assess the usability of both systems and estimate the effects on walking speed and motivation. METHODS: In a within-subjects study design, 36 healthy participants and 14 persons with MS or stroke participated in each of the three experimental conditions (VR via HMD, VR via monitor, treadmill training without VR). RESULTS: For both groups, the walking speed in the HMD condition was higher than in treadmill training without VR and in the monitor condition. Healthy participants reported a higher motivation after the HMD condition as compared with the other conditions. Importantly, no side effects in the sense of simulator sickness occurred and usability ratings were high. No increases in heart rate were observed following the VR conditions. Presence ratings were higher for the HMD condition compared with the monitor condition for both user groups. Most of the healthy study participants (89%) and patients (71%) preferred the HMD-based training among the three conditions and most patients could imagine using it more frequently. CONCLUSIONS: For the first time, the present study evaluated the usability of an immersive VR system for gait rehabilitation in a direct comparison with a semi-immersive system and a conventional training without VR with healthy participants and patients. The study demonstrated the feasibility of combining a treadmill training with immersive VR. Due to its high usability and low side effects, it might be particularly suited for patients to improve training motivation and training outcome e. g. the walking speed compared with treadmill training using no or only semi-immersive VR. Immersive VR systems still require specific technical setup procedures. This should be taken into account for specific clinical use-cases during a cost-benefit assessment.

Efficacy of a web-based intervention for improving psychosocial well-being in patients with implantable cardioverter-defibrillators: the randomized controlled ICD-FORUM trial.

AIMS: Anxiety, depression, and reduced quality of life (QoL) are common in patients with implantable cardioverter-defibrillators (ICDs). Treatment options are limited and insufficiently defined. We evaluated the efficacy of a web-based intervention (WBI) vs. usual care (UC) for improving psychosocial well-being in ICD patients with elevated psychosocial distress. METHODS AND RESULTS: This multicentre, randomized controlled trial (RCT) enrolled 118 ICD patients with increased anxiety or depression [≥6 points on either subscale of the Hospital Anxiety and Depression Scale (HADS)] or reduced QoL [≤16 points on the Satisfaction with Life Scale (SWLS)] from seven German sites (mean age 58.8 ± 11.3 years, 22% women). The primary outcome was a composite assessing change in heart-focused fear, depression, and mental QoL 6 weeks after randomization to WBI or UC, stratified for age, gender, and indication for ICD placement. Web-based intervention consisted of 6 weeks' access to a structured interactive web-based programme (group format) including self-help interventions based on cognitive behaviour therapy, a virtual self-help group, and on-demand support from a trained psychologist. Linear mixed-effects models analyses showed that the primary outcome was similar between groups (ηp2 = 0.001). Web-based intervention was superior to UC in change from pre-intervention to 6 weeks (overprotective support; P = 0.004, ηp2 = 0.036), pre-intervention to 1 year (depression, P = 0.004, ηp2 = 0.032; self-management, P = 0.03, ηp2 = 0.015; overprotective support; P = 0.02, ηp2 = 0.031), and 6 weeks to 1 year (depression, P = 0.02, ηp2 = 0.026; anxiety, P = 0.03, ηp2 = 0.022; mobilization of social support, P = 0.047, ηp2 = 0.018). CONCLUSION: Although the primary outcome was neutral, this is the first RCT showing that WBI can improve psychosocial well-being in ICD patients.

Conjunctive and Elemental Representations of a Context in Humans.

The dual-process theory assumes that contexts are encoded in an elemental and in a conjunctive representation. However, this theory was developed from animal studies, and we still have to explore if and how elemental and conjunctive representations contribute to, for example, contextual anxiety in humans. Therefore, 28 participants underwent differential context conditioning in a newly developed flip-book paradigm. Virtual rooms were presented similar to a flip-book, that is, as a stream of 49 consecutive screenshots creating the impression of walking through the rooms. This allowed registration of event-related brain potentials triggered by specific screenshots. During two acquisition phases, two rooms were shown in this way for six times each. In one room, the anxiety context (CTX+), mildly painful electric stimuli (unconditioned stimuli [USs]) were administered unpredictably after 12 distinct screenshots, which became threat elements, whereas 12 selected comparable screenshots became nonthreat elements (elemental representation); all screenshots represented the anxiety context (conjunctive representation). In the second room, the safety context (CTX-), no USs were applied; thus, all screenshots created the safety context whereby 12 preselected screenshots represented safety elements. Increased US expectancy ratings for threat versus nonthreat or safety elements reflected elemental representation. Conjunctive representation was evident in differential ratings (arousal and contingency) and increased P100 and early posterior negativity amplitudes for threat and nonthreat CTX+ versus safety CTX- screenshots. These differences disappeared during two test phases without US delivery indicating successful extinction. In summary, we revealed the first piece of evidence for the simultaneous contributions of elemental and conjunctive representation during context conditioning in humans.

Extending the vulnerability-stress model of mental disorders: three-dimensional NPSR1 × environment × coping interaction study in anxiety.

BACKGROUND: The general understanding of the 'vulnerability-stress model' of mental disorders neglects the modifying impact of resilience-increasing factors such as coping ability. AIMS: Probing a conceptual framework integrating both adverse events and coping factors in an extended 'vulnerability-stress-coping model' of mental disorders, the effects of functional neuropeptide S receptor gene (NPSR1) variation (G), early adversity (E) and coping factors (C) on anxiety were addressed in a three-dimensional G × E × C model. METHOD: In two independent samples of healthy probands (discovery: n = 1403; replication: n = 630), the interaction of NPSR1 rs324981, childhood trauma (Childhood Trauma Questionnaire, CTQ) and general self-efficacy as a measure of coping ability (General Self-Efficacy Scale, GSE) on trait anxiety (State-Trait Anxiety Inventory) was investigated via hierarchical multiple regression analyses. RESULTS: In both samples, trait anxiety differed as a function of NPSR1 genotype, CTQ and GSE score (discovery: ß = 0.129, P = 3.938 × 10-8; replication: ß = 0.102, P = 0.020). In A allele carriers, the relationship between childhood trauma and anxiety was moderated by general self-efficacy: higher self-efficacy and childhood trauma resulted in low anxiety scores, and lower self-efficacy and childhood trauma in higher anxiety levels. In turn, TT homozygotes displayed increased anxiety as a function of childhood adversity unaffected by general self-efficacy. CONCLUSIONS: Functional NPSR1 variation and childhood trauma are suggested as prime moderators in the vulnerability-stress model of anxiety, further modified by the protective effect of self-efficacy. This G × E × C approach - introducing coping as an additional dimension further shaping a G × E risk constellation, thus suggesting a three-dimensional 'vulnerability-stress-coping model' of mental disorders - might inform targeted preventive or therapeutic interventions strengthening coping ability to promote resilient functioning.

An investigation of genetic variability of DNA methyltransferases DNMT3A and 3B does not provide evidence for a major role in the pathogenesis of panic disorder and dimensional anxiety phenotypes.

While DNA methylation patterns have been studied for a role in the pathogenesis of anxiety disorders, the role of the enzymes establishing DNA methylation-DNA methyltransferases (DNMTs)-has yet to be investigated. In an effort to investigate DNMT genotype-specific effects on dimensional anxiety traits in addition to the categorical phenotype of panic disorder, 506 panic disorder patients and 3112 healthy participants were assessed for anxiety related cognition [Agoraphobic Cognitions Questionnaire (ACQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] as well as pathological worry [Penn State Worry Questionnaire (PSWQ)] and genotyped for five single nucleotide polymorphisms (SNPs) in the DNMT3A (rs11683424, rs1465764, rs1465825) and DNMT3B (rs2424932, rs4911259) genes, which have previously been found associated with clinical and trait-related phenotypes. There was no association with the categorical phenotype panic disorder. However, a significant association was discerned between DNMT3A rs1465764 and PSWQ scores in healthy participants, with the minor allele conveying a protective effect. In addition, a marginally significant association between questionnaire scores (PSWQ, ASI) in healthy participants and DNMT3B rs2424932 was detected, again with the minor allele conveying a protective effect. The present results suggest a possible minor role of DNMT3A and DNMT3B gene variation in conveying resilience towards anxiety disorders. As the observed associations indicated a protective effect of two SNPs particularly with pathological worry, future studies are proposed to explore these variants in generalized anxiety disorder rather than panic disorder.

Serotonergic influence on depressive symptoms and trait anxiety is mediated by negative life events and frontal activation in children and adolescents.

Depression and anxiety are common in childhood and adolescence. Even though cardinal symptoms differ, there is a considerable overlap regarding the pathogenic influence of serotonergic innervation, negative life experience, disturbed emotion perception/affect regulation, and impaired neural functioning in the fronto-limbic circuit. In this study, we examined the effect of the 5-HTTLPR/rs25531 genotype on depressive symptoms and trait anxiety under the consideration of the amount of negative life events in healthy children and adolescents (N = 389). In a subsample of 49 subjects, we performed fMRI to add fronto-limbic brain activation as a second interacting factor. Across all subjects, negative life events moderated the influence of the 5-HTTLPR/rs25531 genotype on both depressive symptoms and trait anxiety. In the fMRI subsample, 5-HTTLPR/rs25531 S + S/LG + S/LA + LGLA + LGLG genotype-associated left middle frontal gyrus (MFG) activation mediated the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms, however, only in combination with negative life events. Genetic influence on trait anxiety was predominantly mediated by negative life events; only LALA genotype-specific activation in the right MFG worked as a mediator in combination with negative life events. The present findings hint towards distinct mechanisms mediating the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms and anxiety, with negative life events playing a crucial role in both phenotypes. With regard to depressive symptoms, however, this influence was only visible in combination with MFG activation, whereas, in anxiety, it was independent of brain activation.

Anxiety risk SNPs on chromosome 2 modulate arousal in children in a fear generalization paradigm.

Alterations in fear learning/generalization are considered to be relevant mechanisms engendering the development of anxiety disorders being the most prevalent mental disorders. Although anxiety disorders almost exclusively have their first onset in childhood and adolescence, etiological research focuses on adult individuals. In this study, we evaluated findings of a recent meta-analysis of genome-wide association studies in adult anxiety disorders with significant associations of four single nucleotide polymorphisms (SNPs) in a large cohort of 347 healthy children (8-12 years) characterized for dimensional anxiety. We investigated the modulation of anxiety parameters by these SNPs in a discriminative fear conditioning and generalization paradigm in the to-date largest sample of children. Results extended findings of the meta-analysis showing a genomic locus on 2p21 to modulate anxious personality traits and arousal ratings. These SNPs might, thus, serve as susceptibility markers for a shared risk across pathological anxiety, presumably mediated by alterations in arousal.

Human BDNF rs6265 polymorphism as a mediator for the generalization of contextual anxiety.

The Met allele of the human brain-derived neurotrophic factor (BDNF) gene might be a risk factor for anxiety disorders and is associated with reduced hippocampal volume. Notably, hippocampus plays a crucial role in contextual learning and generalization. The role of the BDNF gene variation in human context-conditioning and generalization is still unknown. We investigated 33 carriers of the Met allele (18 females) and 32 homozygous carriers of the Val allele (15 females) with a virtual-reality context-conditioning paradigm. Electric stimulations (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but never in another virtual office (CTX-). During generalization, participants revisited CTX+ and CTX- and a generalization office (G-CTX), which was a mix of the other two. Rating data indicated successful conditioning (more negative valence, higher arousal, anxiety and contingency ratings for CTX+ than CTX-), and generalization of conditioned anxiety by comparable ratings for G-CTX and CTX+. The startle data indicated discriminative learning for Met allele carriers, but not for Val homozygotes. Moreover, a trend effect suggests that startle responses of only the Met carriers were slightly potentiated in G-CTX versus CTX-. In sum, the BDNF polymorphism did not affect contextual learning and its generalization on a verbal level. However, the physiological data suggest that Met carriers are characterized by fast discriminative contextual learning and a tendency to generalize anxiety responses to ambiguous contexts. We propose that such learning may be related to reduced hippocampal functionality and the basis for the risk of Met carriers to develop anxiety disorders.

Covariation bias in depression - a predictor of treatment response?

Covariation bias, defined as an overestimation of the relationship between fear-relevant stimuli and aversive consequences, is a well-investigated cognitive bias in anxiety disorders. As patients with affective disorders also show biased information processing, the aim of the present study was to investigate whether depressed patients also display a covariation bias between negative stimuli and aversive consequences. Covariation estimates of 62 inpatients with a current severe depressive episode were assessed at admission (n = 31) or after 6 weeks of treatment (n = 31) and were compared in a between-group design with 31 age- and sex-matched healthy controls. All participants showed a covariation bias for the relationship between negative stimuli and aversive consequences. Moreover, covariation bias at admission was significantly associated with various clinician- and self-reported dimensional measures of treatment response assessed 6 weeks later (Global Assessment of Functioning, Clinical Global Impression Scale, and Beck Depression Inventory), i.e., patients with a stronger bias showed greater impairment after 6 weeks of treatment. Categorical analyses revealed that overall, treatment non-responders-but not responders-were characterized by a covariation bias. The naturalistic study design without standardized pharmacological and psychotherapeutic treatments is a central limitation. We conclude that the covariation bias may constitute a possible marker in the field of emotional information processing in the search for effective predictors of therapy outcome.

Plasticity of Functional MAOA Gene Methylation in Acrophobia.

Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.

Effects of context preexposure and delay until anxiety retrieval on generalization of contextual anxiety.

Animal studies suggest that time delay between acquisition and retrieval of contextual anxiety increases generalization. Moreover, such generalization is prevented by preexposure to the context (CTX), presumably due to an improved representation of such context. We investigated whether preexposure and time-passing modulate generalization of contextual anxiety, in humans. On Day 1, 42 participants (preexposure group) explored two virtual offices, while 41 participants (no-preexposure group) explored a virtual stadium. On Day 2 (24 h later), all participants learned to associate one office (CTX+) with unpredictable unconditioned stimuli (USs), and another office (CTX-) with safety. On Day 3, either 24 h (recent test) or 2 wk (remote test) later, participants revisited CTX- and CTX+ without USs, as well as a generalization context (G-CTX). Results revealed successfully conditioned anxiety and anxiety generalization for ratings (G-CTX was as aversive as CTX+ was), while safety generalization was found for startle responses (G-CTX elicited startle attenuation as CTX- did). Time between learning and testing enhanced generalization as reflected by comparable startle responses to all three offices in the remote test. Contextual preexposure facilitated extinction of explicit conditioned anxiety assessed with ratings. These results suggest that memory trace of a context degrades with passage of time in humans like in animals and, consequently, anxiety generalization enhances. After context preexposure, high cognitive processes seem to be crucially involved in facilitating extinction (or safety) learning.