An exploratory domain analysis of deployment risks and protective features and their association to mental health, cognitive functioning and job performance in military personnel.

BACKGROUND: Meta-analyses of military deployment involve the exploration of focused associations between predictors and peri and post-deployment outcomes. OBJECTIVE: We aimed to provide a large-scale and high-level perspective of deployment-related predictors across eight peri and post-deployment outcomes. DESIGN: Articles reporting effect sizes for associations between deployment-related features and indices of peri and post-deployment outcomes were selected. Three-hundred and fourteen studies (N = 2,045,067) and 1,893 relevant effects were retained. Deployment features were categorized into themes, mapped across outcomes, and integrated into a big-data visualization. METHODS: Studies of military personnel with deployment experience were included. Extracted studies investigated eight possible outcomes reflecting functioning (e.g., post-traumatic stress, burnout). To allow comparability, effects were transformed into a Fisher's Z. Moderation analyses investigating methodological features were performed. RESULTS: The strongest correlates across outcomes were emotional (e.g., guilt/shame: Z = 0.59 to 1.21) and cognitive processes (e.g., negative appraisals: Z = -0.54 to 0.26), adequate sleep on deployment (Z = -0.28 to - 0.61), motivation (Z = -0.33 to - 0.71), and use of various coping strategies/recovery strategies (Z = -0.25 to - 0.59). CONCLUSIONS: Findings pointed to interventions that target coping and recovery strategies, and the monitoring of emotional states and cognitive processes post-deployment that may indicate early risk.

Investigating two mobile just-in-time adaptive interventions to foster psychological resilience: research protocol of the DynaM-INT study.

BACKGROUND: Stress-related disorders such as anxiety and depression are highly prevalent and cause a tremendous burden for affected individuals and society. In order to improve prevention strategies, knowledge regarding resilience mechanisms and ways to boost them is highly needed. In the Dynamic Modelling of Resilience - interventional multicenter study (DynaM-INT), we will conduct a large-scale feasibility and preliminary efficacy test for two mobile- and wearable-based just-in-time adaptive interventions (JITAIs), designed to target putative resilience mechanisms. Deep participant phenotyping at baseline serves to identify individual predictors for intervention success in terms of target engagement and stress resilience. METHODS: DynaM-INT aims to recruit N = 250 healthy but vulnerable young adults in the transition phase between adolescence and adulthood (18-27 years) across five research sites (Berlin, Mainz, Nijmegen, Tel Aviv, and Warsaw). Participants are included if they report at least three negative burdensome past life events and show increased levels of internalizing symptoms while not being affected by any major mental disorder. Participants are characterized in a multimodal baseline phase, which includes neuropsychological tests, neuroimaging, bio-samples, sociodemographic and psychological questionnaires, a video-recorded interview, as well as ecological momentary assessments (EMA) and ecological physiological assessments (EPA). Subsequently, participants are randomly assigned to one of two ecological momentary interventions (EMIs), targeting either positive cognitive reappraisal or reward sensitivity. During the following intervention phase, participants' stress responses are tracked using EMA and EPA, and JITAIs are triggered if an individually calibrated stress threshold is crossed. In a three-month-long follow-up phase, parts of the baseline characterization phase are repeated. Throughout the entire study, stressor exposure and mental health are regularly monitored to calculate stressor reactivity as a proxy for outcome resilience. The online monitoring questionnaires and the repetition of the baseline questionnaires also serve to assess target engagement. DISCUSSION: The DynaM-INT study intends to advance the field of resilience research by feasibility-testing two new mechanistically targeted JITAIs that aim at increasing individual stress resilience and identifying predictors for successful intervention response. Determining these predictors is an important step toward future randomized controlled trials to establish the efficacy of these interventions.

The impact of physical fitness on resilience to modern life stress and the mediating role of general self-efficacy.

Substantial evidence shows that physical activity and fitness play a protective role in the development of stress related disorders. However, the beneficial effects of fitness for resilience to modern life stress are not fully understood. Potentially protective effects may be attributed to enhanced resilience via underlying psychosocial mechanisms such as self-efficacy expectations. This study investigated whether physical activity and fitness contribute to prospectively measured resilience and examined the mediating effect of general self-efficacy. 431 initially healthy adults participated in fitness assessments as part of a longitudinal-prospective study, designed to identify mechanisms of resilience. Self-efficacy and habitual activity were assessed in parallel to cardiorespiratory and muscular fitness, which were determined by a submaximal step-test, hand strength and standing long jump test. Resilience was indexed by stressor reactivity: mental health problems in relation to reported life events and daily hassles, monitored quarterly for nine months. Hierarchical linear regression models and bootstrapped mediation analyses were applied. We could show that muscular and self-perceived fitness were positively associated with stress resilience. Extending this finding, the muscular fitness-resilience relationship was partly mediated by self-efficacy expectations. In this context, self-efficacy expectations may act as one underlying psychological mechanism, with complementary benefits for the promotion of mental health. While physical activity and cardiorespiratory fitness did not predict resilience prospectively, we found muscular and self-perceived fitness to be significant prognostic parameters for stress resilience. Although there is still more need to identify specific fitness parameters in light of stress resilience, our study underscores the general relevance of fitness for stress-related disorders prevention.

Impact of COVID-19 lockdown on mental health in Germany: longitudinal observation of different mental health trajectories and protective factors.

The COVID-19 pandemic and resulting measures can be regarded as a global stressor. Cross-sectional studies showed rather negative impacts on people's mental health, while longitudinal studies considering pre-lockdown data are still scarce. The present study investigated the impact of COVID-19 related lockdown measures in a longitudinal German sample, assessed since 2017. During lockdown, 523 participants completed additional weekly online questionnaires on e.g., mental health, COVID-19-related and general stressor exposure. Predictors for and distinct trajectories of mental health outcomes were determined, using multilevel models and latent growth mixture models, respectively. Positive pandemic appraisal, social support, and adaptive cognitive emotion regulation were positively, whereas perceived stress, daily hassles, and feeling lonely negatively related to mental health outcomes in the entire sample. Three subgroups ("recovered," 9.0%; "resilient," 82.6%; "delayed dysfunction," 8.4%) with different mental health responses to initial lockdown measures were identified. Subgroups differed in perceived stress and COVID-19-specific positive appraisal. Although most participants remained mentally healthy, as observed in the resilient group, we also observed inter-individual differences. Participants' psychological state deteriorated over time in the delayed dysfunction group, putting them at risk for mental disorder development. Consequently, health services should especially identify and allocate resources to vulnerable individuals.

A ventral striatal prediction error signal in human fear extinction learning.

Animal studies have shown that the prediction error (PE) signal that drives fear extinction learning is encoded by phasic activity of midbrain dopamine (DA) neurons. Thus, the extinction PE resembles the appetitive PE that drives reward learning. In humans, fear extinction learning is less well understood. Using computational neuroimaging, a previous study from our group reported hemodynamic activity in the left ventral putamen, a subregion of the ventral striatum (VS), to correlate with a PE function derived from a formal associative learning model. The activity was modulated by genetic variation in a DA-related gene. To conceptually replicate and extend this finding, we here asked whether an extinction PE (EPE) signal in the left ventral putamen can also be observed when genotype information is not taken into account. Using an optimized experimental design for model estimation, we again observed EPE-related activity in the same striatal region, indicating that activation of this region is a feature of human extinction learning. We further observed significant EPE signals across wider parts of the VS as well as in frontal cortical areas. These results may suggest that the prediction errors during extinction learning are available to larger parts of the brain, as has also been observed in human neuroimaging studies of reward PE signaling. Conclusive evidence that the human EPE signal is of DAergic nature is still outstanding.

Longitudinal determination of resilience in humans to identify mechanisms of resilience to modern-life stressors: the longitudinal resilience assessment (LORA) study.

Resilience is the maintenance and/or quick recovery of mental health during and after periods of adversity. It is conceptualized to result from a dynamic process of successful adaptation to stressors. Up to now, a large number of resilience factors have been proposed, but the mechanisms underlying resilience are not yet understood. To shed light on the complex and time-varying processes of resilience that lead to a positive long-term outcome in the face of adversity, the Longitudinal Resilience Assessment (LORA) study has been established. In this study, 1191 healthy participants are followed up at 3- and 18-month intervals over a course of 4.5 years at two study centers in Germany. Baseline and 18-month visits entail multimodal phenotyping, including the assessment of mental health status, sociodemographic and lifestyle variables, resilience factors, life history, neuropsychological assessments (of proposed resilience mechanisms), and biomaterials (blood for genetic and epigenetic, stool for microbiome, and hair for cortisol analysis). At 3-monthly online assessments, subjects are monitored for subsequent exposure to stressors as well as mental health measures, which allows for a quantitative assessment of stressor-dependent changes in mental health as the main outcome. Descriptive analyses of mental health, number of stressors including major life events, daily hassles, perceived stress, and the ability to recover from stress are here presented for the baseline sample. The LORA study is unique in its design and will pave the way for a better understanding of resilience mechanisms in humans and for further development of interventions to successfully prevent stress-related disorder.

L-DOPA improves extinction memory retrieval after successful fear extinction.

RATIONALE: A promising strategy to prevent a return of fear after exposure-based therapy in anxiety disorders is to pharmacologically enhance the extinction memory consolidation presumed to occur after exposure. Accumulating evidence suggests that the effect of a number of pharmacological consolidation enhancers depends on a successful fear reduction during exposure. Here, we employed the dopamine precursor L-DOPA to clarify whether its documented potential to enhance extinction memory consolidation is dependent on successful fear extinction. METHODS: In two double-blind, randomized and placebo-controlled experiments (experiment 1: N = 79, experiment 2: N = 32) comprising fear conditioning (day 1), extinction followed by administration of 150 mg L-DOPA or placebo (day 2) and a memory test (day 3) in healthy male adults, conditioned responses were assessed as differential skin conductance responses. We tested whether the effect of L-DOPA on conditioned responses at test depended on conditioned responses at the end of extinction in an experiment with a short (10 trials, experiment 1) and long (25 trials, experiment 2) extinction session. RESULTS: In both experiments, the effect of L-DOPA was dependent on conditioned responses at the end of extinction. That is, post-extinction L-DOPA compared to placebo administration reduced conditioned responses at test only in participants showing a complete reduction of conditioned fear at the end of extinction. CONCLUSION: The results support the potential use of L-DOPA as a pharmacological adjunct to exposure treatment, but point towards a common boundary condition for pharmacological consolidation enhancers: a successful reduction of fear in the exposure session.

Author Correction: Dopamine-dependent prefrontal reactivations explain long-term benefit of fear extinction.

In the original version of this Article, the fourth sentence of the legend to Figure 1b incorrectly read "Note, that the group difference stemmed from significantly smaller CS+ evoked SCRs averaged across the whole test phase, but the speed of re-extinction did not differ significantly between drug groups (control analysis with stimulus (CS+, CS-) and trial (1-10) as within-, and group (placebo, L-DOPA) as between-subject factor: stimulus × group, F1,297 = 6.57, P = 0.02, partial η2 = 0.17; stimulus × trial × group, F1,297 = 1.32, P = 0.23; n = 35)". The correct version states "F1,33 = 6.58" instead of "F1,297 = 6.57", and "F9,297 = 1.32" instead of "F1,297 = 1.32". These errors have now been corrected in both the PDF and HTML versions of the Article. The correct values were used in the statistical analysis and the errors do not affect the conclusions.

Dopamine-dependent prefrontal reactivations explain long-term benefit of fear extinction.

Fear extinction does not prevent post-traumatic stress or have long-term therapeutic benefits in fear-related disorders unless extinction memories are easily retrieved at later encounters with the once-threatening stimulus. Previous research in rodents has pointed towards a role for spontaneous prefrontal activity occurring after extinction learning in stabilizing and consolidating extinction memories. In other memory domains spontaneous post-learning activity has been linked to dopamine. Here, we show that a neural activation pattern - evoked in the ventromedial prefrontal cortex (vmPFC) by the unexpected omission of the feared outcome during extinction learning - spontaneously reappears during postextinction rest. The number of spontaneous vmPFC pattern reactivations predicts extinction memory retrieval and vmPFC activation at test 24 h later. Critically, pharmacologically enhancing dopaminergic activity during extinction consolidation amplifies spontaneous vmPFC reactivations and correspondingly improves extinction memory retrieval at test. Hence, a spontaneous dopamine-dependent memory consolidation-based mechanism may underlie the long-term behavioral effects of fear extinction.

[Who stays healthy? The problem of predicting resilience]. / Wer bleibt gesund? Zum Problem der Vorhersage von Resilienz.

BACKGROUND: Resilience is a complex construct commonly defined as a dynamic process of maintenance or rapid restoration of mental health during and following exposure to stress and trauma. Resilient individuals show no or only minimal disruption in their overall functioning following trauma. Predictors of individual resilience are currently unclear. OBJECTIVE: Are there significant and reliable predictors of resilience? MATERIAL AND METHODS: Analysis and summary of recent studies on psychosocial and neurobiological resilience predictors derived from longitudinal studies. RESULTS: Less than half of the studies on psychosocial and neurobiological predictors reviewed indexed predictors for resilience prior to exposure to the traumatic event. The results are heterogeneous and often not replicated across studies. Even significant predictors often explain only a relatively small or clinically insignificant amount of variance in resilience. CONCLUSION: The results are not yet ready for direct implementation into practice and the development of appropriate prevention programs on the basis of significant predictors.

[Resilience trajectories-examples from longitudinal studies]. / Verläufe von Resilienz ­ Beispiele aus Längsschnittstudien.

BACKGROUND: According to current research concepts resilience can be defined as adaptation to past and ongoing exposure. Accordingly, adaptation to exposure is a dynamic process, which can be different in different population groups. Prospective longitudinal studies provide unique opportunities to investigate resilience processes. OBJECTIVES: The aim of this article is to define the concept of resilience, describe examples of longitudinal studies investigating resilience in children, adults and older individuals, exemplary describe four ongoing longitudinal resilience studies in which the authors of the article are participating and identify and analyze methodological challenges in empirical resilience research. MATERIAL AND METHODS: This study was based on a qualitative literature review of published prospective studies investigating resilience listed in PubMed and study protocols of the four longitudinal studies. RESULTS: The exemplarily described studies have shown that resilience processes are changeable in all age groups and subject to a variety of influencing factors. The specific and potentially age-associated types of alterations have so far been difficult to determine and need further clarification. DISCUSSION: In view of the dynamic course of resilience, prospective longitudinal studies are urgently needed. Prospective longitudinal studies have the potential to identify resilience mechanisms and predictors of the course of resilience in different population groups, such as children, adolescents, adults and older individuals. Furthermore, resilience research needs to develop an improved and precise assessment of exposure to stressors.

[Current concepts of resilience research]. / Aktuelle Konzepte der Resilienzforschung.

BACKGROUND: Stress-related mental disorders are the most prevalent and cost-intensive disorders of our time. On the other hand, the maintenance of mental health despite stressors, i. e. resilience, is a frequent phenomenon. Research on psychological resilience and its underlying mechanisms offers innovative possibilities for health promotion. It requires a consistent understanding of resilience and adequate methods of operationalization. OBJECTIVES: Modern concepts of the definition, operationalization and assessment of resilience as well as its implications for study designs in resilience research. MATERIAL AND METHODS: Analysis and discussion of current works and expert recommendations for the design of resilience research. RESULTS: Resilience research is undergoing a period of transition. Based on a new understanding of resilience as a dynamic and modifiable process, new approaches for operationalization and assessment were proposed. These include, for example, a transdiagnostic approach and the identification of resilience mechanisms, the consideration of stressor exposure in measuring the construct, and longitudinal cohort studies. CONCLUSIONS: In the upcoming decades, further profitable findings from current prospective longitudinal studies can be expected. One challenge for future resilience research consists in the continuous dissemination and implementation of the approaches described.

Intervention studies to foster resilience - A systematic review and proposal for a resilience framework in future intervention studies.

Psychological resilience refers to the phenomenon that many people are able to adapt to the challenges of life and maintain mental health despite exposure to adversity. This has stimulated research on training programs to foster psychological resilience. We evaluated concepts, methods and designs of 43 randomized controlled trials published between 1979 and 2014 which assessed the efficacy of such training programs and propose standards for future intervention research based on recent developments in the field. We found that concepts, methods and designs in current resilience intervention studies are of limited use to properly assess efficacy of interventions to foster resilience. Major problems are the use of definitions of resilience as trait or a composite of resilience factors, the use of unsuited assessment instruments, and inappropriate study designs. To overcome these challenges, we propose 1) an outcome-oriented definition of resilience, 2) an outcome-oriented assessment of resilience as change in mental health in relation to stressor load, and 3) methodological standards for suitable study designs of future intervention studies. Our proposals may contribute to an improved quality of resilience intervention studies and may stimulate further progress in this growing research field.

GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

Deficient inhibitory processing in trait anxiety: Evidence from context-dependent fear learning, extinction recall and renewal.

BACKGROUND: Impaired fear inhibition has been described as a hallmark of pathological anxiety. We aimed at further characterizing the relation between fear inhibition and anxiety by extending previous work to contextual safety stimuli as well as to dimensional scores of trait anxiety in a large sample. METHODS: We employed a validated paradigm for context-dependent fear acquisition/extinction (day 1) and retrieval/expression (day 2) in 377 healthy individuals. This large sample size allowed the employment of a dimensional rather than binary approach with respect to individual differences in trait anxiety. RESULTS: We observed a positive correlation on day 1 between trait anxiety with all CSs that possess an inherent inhibitory component, conveyed either by reliable non-reinforcement of a specific CS in a dangerous context (safe cue) or by the context itself (i.e., safe context). No correlation however was observed for a CS that possesses excitatory (threatening) properties only. These results were observed during fear learning (day 1) for US expectancy and fear ratings but not for SCRs. No such pattern was evident during fear and extinction retrieval/expression (day 2). CONCLUSION: We provide further evidence that high trait anxiety is associated with the inability to take immediate advantage of environmental safety cues (cued and contextual), which might represent a promising trans-diagnostic marker for different anxiety disorders. Consequently, the incorporation of methods to optimize inhibitory learning in current cognitive behavioral therapy (CBT) treatments might open up a promising avenue for precision medicine in anxiety disorders. LIMITATIONS: We did not include patients diagnosed with anxiety disorders.

Dopamine receptor 4 promoter polymorphism modulates memory and neuronal responses to salience.

Animal models and human functional imaging data implicate the dopamine system in mediating enhanced encoding of novel stimuli into human memory. A separate line of investigation suggests an association between a functional polymorphism in the promoter region for the human dopamine 4 receptor gene (DRD4) and sensitivity to novelty. We demonstrate, in two independent samples, that the -521C>T DRD4 promoter polymorphism determines the magnitude of human memory enhancement for contextually novel, perceptual oddball stimuli in an allele dose-dependent manner. The genotype-dependent memory enhancement conferred by the C allele is associated with increased neuronal responses during successful encoding of perceptual oddballs in the ventral striatum, an effect which is again allele dose-dependent. Furthermore, with repeated presentations of oddball stimuli, this memory advantage decreases, an effect mirrored by adaptation of activation in the hippocampus and substantia nigra/ventral tegmental area in C carriers only. Thus, a dynamic modulation of human memory enhancement for perceptually salient stimuli is associated with activation of a dopaminergic-hippocampal system, which is critically dependent on a functional polymorphism in the DRD4 promoter region.

Altered cingulate and amygdala response towards threat and safe cues in attention deficit hyperactivity disorder.

BACKGROUND: Emotional dysregulation is becoming increasingly recognized as an important feature of attention deficit hyperactivity disorder (ADHD). In this study, two experiments were conducted investigating the neural response to either verbally instructed fear (IF) or uninstructed (classically conditioned) fear (UF) using the skin conductance response (SCR) and functional magnetic resonance imaging (fMRI). METHOD: In the conditioning phase of the UF experiment (17 ADHD and 17 healthy controls), subjects experienced an unconditioned stimulus (UCS, unpleasant electrodermal stimulation) paired with a former neutral conditioned stimulus (CS+), whereas a control stimulus (CS-) was never paired with the UCS. In the subsequent test phase, only the CS+ and the CS- were presented. In the IF experiment (13 ADHD and 17 healthy controls), subjects were only told that an independently experienced UCS might occur together with the CS+ but not the CS- during testing. No UCS was presented. RESULTS: Groups did not detectably differ in SCR or neural responses to UF. In IF, ADHD patients showed a trend-line decreased SCR and significantly decreased activation of the dorsal anterior cingulate cortex (dACC), a region prominently involved in fear responding, to the CS+. This was accompanied by higher amygdala activation to the CS-. CONCLUSIONS: During IF, ADHD patients showed deficits in regions centrally involved in fear learning and expression in terms of diminished CS+-related dACC and increased CS--related amygdala signals. This suggests an impaired processing of verbally transmitted aversive information, which is central for conveying fear information in social contexts. This result extends the growing literature on emotional alterations in ADHD.

The role of sleep and sleep deprivation in consolidating fear memories.

Sleep, in particular REM sleep, has been shown to improve the consolidation of emotional memories. Here, we investigated the role of sleep and sleep deprivation on the consolidation of fear memories and underlying neuronal mechanisms. We employed a Pavlovian fear conditioning paradigm either followed by a night of polysomnographically monitored sleep, or wakefulness in forty healthy participants. Recall of learned fear was better after sleep, as indicated by stronger explicitly perceived anxiety and autonomous nervous responses. These effects were positively correlated with the preceding time spent in REM sleep and paralleled by activation of the basolateral amygdala. These findings suggest REM sleep-associated consolidation of fear memory in the human amygdala. In view of the critical participation of fear learning mechanisms in the etiology of anxiety and post-traumatic stress disorder, deprivation of REM sleep after exposure to distressing events is an interesting target for further investigation.