The impact of extinction timing on pre-extinction arousal and subsequent return of fear.

Exposure-based therapy is effective in treating anxiety, but a return of fear in the form of relapse is common. Exposure is based on the extinction of Pavlovian fear conditioning. Both animal and human studies point to increased arousal during immediate compared to delayed extinction (>+24 h), which presumably impairs extinction learning and increases the subsequent return of fear. Impaired extinction learning under arousal might interfere with psychotherapeutic interventions. The aim of the present study was to investigate whether arousal before extinction differs between extinction groups and whether arousal before extinction predicts the return of fear in a later (retention) test. As a highlight, both the time between fear acquisition and extinction (immediate vs. delayed) and the time between extinction and test (early vs. late test) were systematically varied. We performed follow-up analyses on data from 103 young, healthy participants to test the above hypotheses. Subjective arousal ratings and physiological arousal measures of sympathetic and hypothalamic pituitary adrenal axis activation (tonic skin conductance and salivary cortisol) were collected. Increased pre-extinction arousal in the immediate extinction group was only confirmed for subjective arousal. In linear regression analyses, none of the arousal measures predicted a significant return of fear in the different experimental groups. Only when we aggregated across the two test groups, tonic skin conductance at the onset of extinction predicted the return of fear in skin conductance responses. The overall results provide little evidence that pre-extinction arousal affects subsequent extinction learning and memory. In terms of clinical relevance, there is no clear evidence that exposure could be improved by reducing subjective or physiological arousal.

The impact of past childhood adversity and recent life events on neural responses during fear conditioning.

BACKGROUND AND PURPOSE: Many studies have shown that exposure to life events can have a negative impact on mental health. Life events like the death of a spouse or the birth of a child pose a challenge and require temporal or permanent adjustments. Meta-analyses on brain stress responses found bilateral anterior insula activation in response to acute stress. Fear conditioning is assumed a crucial mechanism for the development of anxiety disorders associated with increased activation in the bilateral amygdala. Empirical evidence is lacking regarding the relationship of exposure to recent life events and past childhood adversity with neural processing during fear conditioning. METHODS: In the present study, we analyzed data from 103 young, healthy participants. Multiple linear regressions were performed on functional magnetic resonance imaging activation during fear conditioning with the Life Events Scale for Students and the Childhood Trauma questionnaire included as covariates in two separate models. RESULTS: We found a positive relationship between the number of life events in the last year and left amygdala activation to the conditioned stimulus. A second finding was a positive relationship between childhood adversity and right anterior insula response to the unconditioned stimulus. CONCLUSIONS: Many studies have shown increased amygdala activity after stressful life events. In addition, the anterior insula is activated during acute stress. The present study points to stressor-induced increased salience processing during fear conditioning. We suggest that this could be a potential mechanism for resilience versus mental illness.

Repressive and vigilant coping styles in stress and relaxation: evidence for physiological and subjective differences at baseline, but not for differential stress or relaxation responses.

Introduction: Previous research suggested differential stress reactivity depending on individuals' coping style, e.g., as classified by the model of coping modes. Specifically, stronger physiological reactivity and weaker subjective stress ratings were found for repressors than for sensitizers. However, it remains to be investigated (i) whether these findings, which are largely based on social stress induction protocols, also generalize to other stressors, (ii) whether repressors vs. sensitizers also exhibit differential stress recovery following the application of a relaxation method, and (iii) which stress reactivity and recovery patterns are seen for the two remaining coping styles, i.e., fluctuating, and non-defensive copers. The current study thus examines stress reactivity in physiology and subjective ratings to a non-social stressor and the subsequent ability to relax for the four coping groups of repressors, sensitizers, fluctuating, and non-defensive copers. Methods: A total of 96 healthy participants took part in a stress induction (Mannheim Multicomponent Stress Test) and a subsequent relaxation intervention. Subjective ratings of stress and relaxation, heart rate (HR), heart rate variability (HRV), and blood pressure were assessed during the experiment. HR and blood pressure are markers of the sympathetic stress response that can be regulated by relaxation, while HRV should increase with relaxation. To investigate long-term relaxation effects, subjective ratings were also assessed on the evening of testing. Results: Despite successful stress induction, no differential responses (baseline to stress, stress to relaxation) were observed between the different coping groups on any of the measures. In contrast, a strong baseline effect was observed that persisted throughout the experiment: In general, fluctuating copers showed lower HR and higher HRV than non-defensive copers, whereas repressors reported lower subjective stress levels and higher levels of relaxation during all study phases. No differences in subjective ratings were observed in the evening of testing. Conclusion: Contrary to previous research, no differential stress reactivity pattern was observed between coping groups, which could be due to the non-social type of stressor employed in this study. The novel finding of physiological baseline differences between fluctuating and non-defensive individuals is of interest and should be further investigated in other stressor types in future research.

Neural correlates of immediate versus delayed extinction when simultaneously varying the time of the test in humans.

Anxiety disorders are effectively treated with exposure therapy based on the extinction of Pavlovian fear conditioning. Animal research indicates that both the timing of extinction and test are important factors to reduce the return of fear. However, empirical evidence in humans is incomplete and inconsistent. In this neuroimaging study, we, therefore, tested 103 young, healthy participants in a 2-factorial between-subjects design with the factors extinction group (immediate, delayed) and test group (+1 day and +7 days). Immediate extinction led to greater retention of fear memory at the beginning of extinction training indicated by increased skin conductance responses. A return of fear was observed in both extinction groups, with a trend toward a greater return of fear in immediate extinction. The return of fear was generally higher in groups with an early test. Neuroimaging results show successful cross-group fear acquisition and retention, as well as activation of the left nucleus accumbens during extinction training. Importantly, the delayed extinction group showed a larger bilateral nucleus accumbens activation during test. This nucleus accumbens finding is discussed in terms of salience, contingency, relief, and prediction error processing. It may imply that the delayed extinction group benefits more from the test as a new learning opportunity.

Facilitating relaxation and stress reduction in healthy participants through a virtual reality intervention: study protocol for a non-inferiority randomized controlled trial.

BACKGROUND: Repeated or chronic stress is considered a major source of disease, in terms of both somatic and mental illnesses. The prevention of stress-related disease by interventions for relaxation has thus increased societal relevance. In this randomized controlled non-inferiority trial, we will compare a newly developed virtual reality (VR) environment for relaxation to an active control group applying a freely chosen relaxation method. To test if our VR environment supports relaxation in a situation of acute stress, a standardized stress induction protocol will precede the relaxation phase. METHODS: One hundred healthy participants will be recruited from the University of Siegen and randomly assigned to the VR or the active control group that will be free to choose their own relaxation strategy. The multi-sensory VR includes visual, acoustic, and haptic features to induce a strong feeling of presence. The laboratory testing will comprise a baseline measurement, a stress induction, a relaxation intervention, and a recovery measurement. The primary outcomes are self-reported stress and relaxation measured with a visual analog scale (VAS) at pre- and post-baseline, at the start, middle, and end of the stress induction, at pre- and post-relaxation, at pre- and post-recovery, and in the evening of testing. Secondary outcomes are the physiological parameters, namely heart rate and heart rate variability, tonic skin conductance level as well as the number of non-specific skin conductance responses, systolic and diastolic blood pressure and respiratory rate recorded during the four experimental phases as well as state mood, and state rumination assessed at four time points (pre- and post-stress, post-relaxation, and in the evening of testing). Finally, post-event processing will be assessed after relaxation and in the evening of testing. Repeated measures ANOVAs will be performed to test for statistical effects of group, time, and group × time interaction. DISCUSSION: The newly developed, multi-sensory VR offers an intervention for relaxation without prior training. Its immersive character might increase efficacy compared to other relaxation methods, especially in situations of acute stress. Future directions could be the development of a mobile version of the VR to enhance accessibility for users. To achieve a transfer of training effects to real life, VR components should successively be eliminated until relaxation is practiced without guidance by the VR. TRIAL REGISTRATION: ISRCTN Registry ISRCTN11162338 . Retrospectively registered on January 22, 2021.

Individualizing deep dynamic models for psychological resilience data.

Deep learning approaches can uncover complex patterns in data. In particular, variational autoencoders achieve this by a non-linear mapping of data into a low-dimensional latent space. Motivated by an application to psychological resilience in the Mainz Resilience Project, which features intermittent longitudinal measurements of stressors and mental health, we propose an approach for individualized, dynamic modeling in this latent space. Specifically, we utilize ordinary differential equations (ODEs) and develop a novel technique for obtaining person-specific ODE parameters even in settings with a rather small number of individuals and observations, incomplete data, and a differing number of observations per individual. This technique allows us to subsequently investigate individual reactions to stimuli, such as the mental health impact of stressors. A potentially large number of baseline characteristics can then be linked to this individual response by regularized regression, e.g., for identifying resilience factors. Thus, our new method provides a way of connecting different kinds of complex longitudinal and baseline measures via individualized, dynamic models. The promising results obtained in the exemplary resilience application indicate that our proposal for dynamic deep learning might also be more generally useful for other application domains.

The Frequent Stressor and Mental Health Monitoring-Paradigm: A Proposal for the Operationalization and Measurement of Resilience and the Identification of Resilience Processes in Longitudinal Observational Studies.

Resilience has been defined as the maintenance or quick recovery of mental health during and after times of adversity. How to operationalize resilience and to determine the factors and processes that lead to good long-term mental health outcomes in stressor-exposed individuals is a matter of ongoing debate and of critical importance for the advancement of the field. One of the biggest challenges for implementing an outcome-based definition of resilience in longitudinal observational study designs lies in the fact that real-life adversity is usually unpredictable and that its substantial qualitative as well as temporal variability between subjects often precludes defining circumscribed time windows of inter-individually comparable stressor exposure relative to which the maintenance or recovery of mental health can be determined. To address this pertinent issue, we propose to frequently and regularly monitor stressor exposure (E) and mental health problems (P) throughout a study's observation period [Frequent Stressor and Mental Health Monitoring (FRESHMO)-paradigm]. On this basis, a subject's deviation at any single monitoring time point from the study sample's normative E-P relationship (the regression residual) can be used to calculate that subject's current mental health reactivity to stressor exposure ("stressor reactivity," SR). The SR score takes into account the individual extent of experienced adversity and is comparable between and within subjects. Individual SR time courses across monitoring time points reflect intra-individual temporal variability in SR, where periods of under-reactivity (negative SR score) are associated with accumulation of fewer mental health problems than is normal for the sample. If FRESHMO is accompanied by regular measurement of potential resilience factors, temporal changes in resilience factors can be used to predict SR time courses. An increase in a resilience factor measurement explaining a lagged decrease in SR can then be considered to index a process of adaptation to stressor exposure that promotes a resilient outcome (an allostatic resilience process). This design principle allows resilience research to move beyond merely determining baseline predictors of resilience outcomes, which cannot inform about how individuals successfully adjust and adapt when confronted with adversity. Hence, FRESHMO plus regular resilience factor monitoring incorporates a dynamic-systems perspective into resilience research.

Replication of fMRI group activations in the neuroimaging battery for the Mainz Resilience Project (MARP).

Motivated by the recent replicability crisis we tested replicability of functional magnetic resonance imaging (fMRI) group activations in two independent samples. An identical behavioral and fMRI test battery for the longitudinal investigation of stress resilience mechanisms was developed for the Mainz Resilience Project (MARP) and conducted in a discovery (N = 54) and a replication sample (N = 103). The test battery consisted of a stress reactivity task, a reward sensitivity task, a fear conditioning and extinction paradigm, two volitional reappraisal tasks and an emotional interference inhibition task. Replicability of group activations was tested with the Jaccard index and the Intra Class Correlation (ICC). Overall, we observed good to excellent replicability of activations at the whole brain level. Only a minority of contrasts showed unsatisfactory replicability. Replicability at the level of individual regions of interest (ROIs) was generally lower. Tasks with stronger activation in the discovery sample showed better replicability.

The relationship between neuroticism and appetitive conditioning.

Appetitive conditioning is considered a central mechanism for the vulnerability to psychiatric disorders. However, the investigation of individual differences that are related to altered appetitive learning has been almost neglected so far. The aim of this study was to investigate the link between neuroticism and appetitive conditioning processes. 79 subjects participated in a differential conditioning procedure in which a conditioned stimulus (CS+) was paired with a reward (money) after a fast behavioral response, while a second conditioned stimulus (CS-) was never followed by a reward, irrespective of the behavioral response. As a main result, neuroticism correlated negatively with the underlying neural processes of appetitive conditioning in females, but not in males. In detail, higher levels of neuroticism were associated with decreased neural responses in the left (p = .001) and right amygdala (p = .011), left (p = .063) and right (p = .019) nucleus accumbens, and left (p = .002) and right (p = .021) orbitofrontal cortex (all results are family-wise-error-corrected). The present results support previous findings, which also showed an inverse sex-specific effect in the context of neuroticism and emotional processing in females. In addition, the findings suggest that neuroticism is not solely linked to increased amygdala sensitivity during the processing of negative stimuli but also to decreased neural responses when processing rewarding stimuli. Possible explanations for the sex differences and implications are discussed.

Population-based validation of a German version of the Brief Resilience Scale.

Smith and colleagues developed the Brief Resilience Scale (BRS) to assess the individual ability to recover from stress despite significant adversity. This study aimed to validate the German version of the BRS. We used data from a population-based (sample 1: n = 1.481) and a representative (sample 2: n = 1.128) sample of participants from the German general population (age ≥ 18) to assess reliability and validity. Confirmatory factor analyses (CFA) were conducted to compare one- and two-factorial models from previous studies with a method-factor model which especially accounts for the wording of the items. Reliability was analyzed. Convergent validity was measured by correlating BRS scores with mental health measures, coping, social support, and optimism. Reliability was good (α = .85, ω = .85 for both samples). The method-factor model showed excellent model fit (sample 1: χ2/df = 7.544; RMSEA = .07; CFI = .99; SRMR = .02; sample 2: χ2/df = 1.166; RMSEA = .01; CFI = 1.00; SRMR = .01) which was significantly better than the one-factor model (Δχ2(4) = 172.71, p < .001) or the two-factor model (Δχ2(3) = 31.16, p < .001). The BRS was positively correlated with well-being, social support, optimism, and the coping strategies active coping, positive reframing, acceptance, and humor. It was negatively correlated with somatic symptoms, anxiety and insomnia, social dysfunction, depression, and the coping strategies religion, denial, venting, substance use, and self-blame. To conclude, our results provide evidence for the reliability and validity of the German adaptation of the BRS as well as the unidimensional structure of the scale once method effects are accounted for.