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Abstract Stereotypes can exert a powerful influence on our interactions with others, potentially leading to prejudice when factual evidence is ignored. Here, we identify neuroanatomical and developmental factors that influence the real-time integration of stereotypes and factual evidence during live social interactions. The study uses precisely quantified communicative exchanges in a longitudinal cohort of seventeen-year-olds followed since infancy, testing their ability to moderate stereotype tendencies toward children as contrary evidence accumulates. Our results indicate that the impact of stereotypes on communicative behavior is linked to individual variations in gray matter density and cortical thickness in the right anterior cingulate gyrus. In contrast, the ability to moderate stereotype tendencies is influenced by developmental exposure to social interactions during the initial years of life, beyond the effects of familial environment and later experiences. These findings pinpoint a key brain structure underlying stereotype tendencies and suggest that early-life social experiences have lasting consequences on how individuals integrate factual evidence in interpersonal communication.

Abstract Avoidance, a hallmark of anxiety-related psychopathology, often comes at a cost; avoiding threat may forgo the possibility of a reward. Theories predict that optimal approach-avoidance arbitration depends on threat-induced psychophysiological states, like freezing-related bradycardia. Here we used model-based fMRI analyses to investigate whether and how bradycardia states are linked to the neurocomputational underpinnings of approach-avoidance arbitration under varying reward and threat magnitudes. We show that bradycardia states are associated with increased threat-induced avoidance and more pronounced reward-threat value comparison (i.e., a stronger tendency to approach vs. avoid when expected reward outweighs threat). An amygdala-striatal-prefrontal circuit supports approach-avoidance arbitration under threat, with specific involvement of the amygdala and dorsal anterior cingulate (dACC) in integrating reward-threat value and bradycardia states. These findings highlight the role of human freezing states in value-based decision making, relevant for optimal threat coping. They point to a specific role for amygdala/dACC in state-value integration under threat.

Abstract Anxious individuals consistently fail in controlling emotional behavior, leading to excessive avoidance, a trait that prevents learning through exposure. Although the origin of this failure is unclear, one candidate system involves control of emotional actions, coordinated through lateral frontopolar cortex (FPl) via amygdala and sensorimotor connections. Using structural, functional, and neurochemical evidence, we show how FPl-based emotional action control fails in highly-anxious individuals. Their FPl is overexcitable, as indexed by GABA/glutamate ratio at rest, and receives stronger amygdalofugal projections than non-anxious male participants. Yet, high-anxious individuals fail to recruit FPl during emotional action control, relying instead on dorsolateral and medial prefrontal areas. This functional anatomical shift is proportional to FPl excitability and amygdalofugal projections strength. The findings characterize circuit-level vulnerabilities in anxious individuals, showing that even mild emotional challenges can saturate FPl neural range, leading to a neural bottleneck in the control of emotional action tendencies.

We often forego a larger future reward in order to obtain a smaller reward immediately, known as impatient intertemporal choice. The current study investigated the role of Pavlovian-to-instrumental transfer (PIT) as a mechanism contributing to impatient intertemporal choice, following a theoretical framework proposing that cues associated with immediate gratification trigger a Pavlovian approach response, interfering with goal-directed (instrumental) inhibitory behavior. We developed a paradigm in which participants first learned to make instrumental go/no-go responses in order to win rewards and avoid punishments. Next, they learned the associations between Pavlovian cues and rewards varying in amount and delay. Finally, we tested whether these (task-irrelevant) cues exerted transfer effects by influencing instrumental actions while participants again completed the go/no-go task. Across two experiments, Pavlovian cues associated with larger (versus smaller) and immediate (versus delayed) rewards were evaluated more positively, reflecting the successful acquisition of Pavlovian cue–outcome associations. These findings replicated the previously reported classical transfer effect of reward amount on instrumental behavior, as large (versus smaller) cues increased instrumental approach. In contrast, we found no evidence for the hypothesized transfer effects for reward delay, contrary to the proposed role of PIT in impatient intertemporal choice. These results suggest that although both reward amount and delay were important in the evaluation of cues, only the amount associated with cues influenced instrumental choice. We provide concrete suggestions for future studies, addressing instrumental outcome identity, competition between cue–amount and cue–delay associations, and individual differences in response to Pavlovian cues.

Disulfide-containing poly(amidoamine) (PAA) is a cationic and bioreducible polymer, with potential use as a nanocarrier for mRNA delivery in the treatment of several diseases including osteoarthritis (OA). Successful transfection of joint cells with PAA-based nanoparticles (NPs) was shown previously, but cell uptake, endosomal escape and nanoparticle biodegradation were not studied in detail. In this study, C28/I2 human chondrocytes were transfected with NPs co-formulated with a PEG-polymer coating and loaded with EGFP mRNA for confocal imaging of intracellular trafficking and evaluation of transfection efficiency. Compared with uncoated NPs, PEG-coated NPs showed smaller particle size, neutral surface charge, higher colloidal stability and superior transfection efficiency. Furthermore, endosomal entrapment of these PEG-coated NPs decreased over time and mRNA release could be visualized both in vitro and in live cells. Importantly, cell treatment with modulators of the intracellular reducing environment showed that glutathione (GSH) concentrations affect translation of the mRNA payload. Finally, we applied a D-optimal experimental design to test different polymer-to-RNA loading ratios and dosages, thus obtaining an optimal formulation with up to ≈80% of GFP-positive cells and without toxic effects. Together, the biocompatibility and high transfection efficiency of this system may be a promising tool for intra-articular delivery of therapeutical mRNA in OA treatment.

Defensive stress reactions, such as freezing and active fight-or-flight, are relevant for coping with threat. Action-preparatory activity supporting these reactions, including the amygdala, has been posited as a potential marker for stress-resilience. We considered the successive COVID-19 lockdowns as two pervasive stressors, to prospectively investigate the predictive value of neural threat-responses towards symptom development. Five years prior to the COVID-19 pandemic, 17-year-old adolescents (n = 64, Baseline-17) performed the fMRI-adapted Go/Nogo Under Threat (GUNT) task, where threat-anticipatory freezing reactions and transition to action are evoked to avoid a shock. A majority (n = 44) made themselves available for follow-up assessments before COVID (Baseline-20, age 20), during the first COVID-19 lockdown in the Netherlands (LD1, age 22.5), and during a second lockdown (LD2, age 23). The GUNT task quantified neural (thalamic, subcortical, amygdala) and physiological (bradycardia) markers of threat-anticipatory freezing and transition to action (mediated by anterior cingulate cortex). Threat-anticipatory amygdala responses (Baseline-17) were linked to stressor resilience, as quantified by self-reported anxiety symptoms between LD1 and LD2. However, stronger amygdala responses to low threat cues (Baseline-17) were associated with stronger anxiety symptoms. These effects occurred over and above early-life stress, COVID-19 stress burden, and overall symptom changes between age 17 and 20. These findings suggest that amygdala responses to acute threat provide a marker for resilience against real-life stressors, with adequate threat discrimination signaling resilience and stronger amygdala responses to low threat predicting vulnerability. The findings support the notion that neural responses to threat are instrumental for adaptive coping with pervasive stress.

BackgroundStress-related mental disorders are highly prevalent and pose a substantial burden on individuals and society. Improving strategies for the prevention and treatment of mental disorders requires a better understanding of their risk and resilience factors. This multicenter study aims to contribute to this endeavor by investigating psychological resilience in healthy but susceptible young adults over 9 months. Resilience is conceptualized in this study as the maintenance of mental health or quick recovery from mental health perturbations upon exposure to stressors, assessed longitudinally via frequent monitoring of stressors and mental health. ObjectiveThis study aims to investigate the factors predicting mental resilience and adaptive processes and mechanisms contributing to mental resilience and to provide a methodological and evidence-based framework for later intervention studies. MethodsIn a multicenter setting, across 5 research sites, a sample with a total target size of 250 young male and female adults was assessed longitudinally over 9 months. Participants were included if they reported at least 3 past stressful life events and an elevated level of (internalizing) mental health problems but were not presently affected by any mental disorder other than mild depression. At baseline, sociodemographic, psychological, neuropsychological, structural, and functional brain imaging; salivary cortisol and α-amylase levels; and cardiovascular data were acquired. In a 6-month longitudinal phase 1, stressor exposure, mental health problems, and perceived positive appraisal were monitored biweekly in a web-based environment, while ecological momentary assessments and ecological physiological assessments took place once per month for 1 week, using mobile phones and wristbands. In a subsequent 3-month longitudinal phase 2, web-based monitoring was reduced to once a month, and psychological resilience and risk factors were assessed again at the end of the 9-month period. In addition, samples for genetic, epigenetic, and microbiome analyses were collected at baseline and at months 3 and 6. As an approximation of resilience, an individual stressor reactivity score will be calculated. Using regularized regression methods, network modeling, ordinary differential equations, landmarking methods, and neural net–based methods for imputation and dimension reduction, we will identify the predictors and mechanisms of stressor reactivity and thus be able to identify resilience factors and mechanisms that facilitate adaptation to stressors. ResultsParticipant inclusion began in October 2020, and data acquisition was completed in June 2022. A total of 249 participants were assessed at baseline, 209 finished longitudinal phase 1, and 153 finished longitudinal phase 2. ConclusionsThe Dynamic Modelling of Resilience–Observational Study provides a methodological framework and data set to identify predictors and mechanisms of mental resilience, which are intended to serve as an empirical foundation for future intervention studies. International Registered Report Identifier (IRRID)DERR1-10.2196/39817

BackgroundRepetitive transcranial magnetic stimulation (rTMS) on the dorsolateral prefrontal cortex (DLPFC) is an effective treatment for depression that has been proposed to work via the enhancement of cognitive control. Cognitive control training (CCT) can also alleviate depression by relying on DLPFC activation. As the additive effects of rTMS and CCT are unclear, we set out to conduct a within-subject pilot study in healthy controls.MethodsSeventeen participants received two sessions of individualized resting-state connectivity-guided high-frequency rTMS, while randomly performing CCT or a control task. After each session, a negative mood was induced.ResultsWe found effects on mood and cognitive control after rTMS + CCT as well as rTMS + control, which were indiscriminative between conditions. Based on the statistical evidence for the absence of an additive effect of CCT, we did not perform a full study.ConclusionOur results demonstrate no differential effects of single sessions combining rTMS and CCT in a healthy population, even with the methodological improvement of individualized neuronavigation. The improvement in cognitive control seen in both conditions could indicate that a simple cognitive task is sufficient when studying additive rTMS effects. Future studies should focus on augmenting the effects of various cognitive tasks and compare the present interventions with rTMS or cognitive tasks alone.

Abstract Threatening situations ask for rapid and accurate perceptual decisions to optimize coping. Theoretical models have stated that psychophysiological states, such as bradycardia during threat-anticipatory freezing, may facilitate perception. However, it’s unclear if this occurs via enhanced bottom-up sensory processing or by relying more on prior expectations. To test this, 52 (26 female) participants completed a visual target-detection paradigm under threat-of-shock (15% reinforcement rate) with a manipulation of prior expectations. Participants judged the presence of a backward-masked grating (target presence rate 50%) after systematically manipulating their decision criterion with a rare (20%) or frequent (80%) target presence rate procedure. Threat-of-shock induced stronger heart rate deceleration compared to safe, indicative of threat-anticipatory freezing. Importantly, threat-of-shock enhanced perceptual sensitivity but we did not find evidence of an altered influence of the effect of prior expectations on current decisions. Correct target detection (hits) was furthermore accompanied by an increase in the magnitude of this heart rate deceleration compared to a missed target. While this was independent of threat-of-shock manipulation, only under threat-of-shock this increase was accompanied by more hits and increased sensitivity. Together, these findings suggest that under acute threat participants may rely more on bottom-up sensory processing versus prior expectations in perceptual decision-making. Critically, bradycardia may underlie such enhanced perceptual sensitivity.

Abstract Simultaneous execution of memory retrieval and cognitively demanding interventions alter the subjective experience of aversive memories. This principle can be used in treatment to target traumatic memories. An often-used interpretation is that cognitive demand interferes with memory reconsolidation. Laboratory models applying this technique often do not meet some important procedural steps thought necessary to trigger reconsolidation. It remains therefore unclear whether cognitively demanding interventions can alter the reconsolidation process of aversive memories. Here, 78 (41 included) healthy participants completed an established 3-day threat conditioning paradigm. Two conditioned stimuli were paired with a shock (CS+ s) and one was not (CS-). The next day, one CS+ (CS+ R), but not the other (CS+), was presented as a reminder. After 10 min, participants performed a 2-back working memory task. On day three, we assessed retention. We found successful acquisition of conditioned threat and retention (CS+ s > CS-). However, SCRs to the CS+ R and the CS+ during retention did not significantly differ. Although threat conditioning was successful, the well-established cognitively demanding intervention did not alter the reconsolidation process of conditioned threat memories. These findings challenge current views on how cognitively demand may enhance psychotherapy-outcome.

Abstract Substantial individual differences exist in how acute stress affects large-scale neurocognitive networks, including salience (SN), default mode (DMN), and central executive networks (CEN). Changes in the connectivity strength of these networks upon acute stress may predict vulnerability to long-term stress effects, which can only be tested in prospective longitudinal studies. Using such longitudinal design, we investigated whether the magnitude of acute-stress-induced functional connectivity changes (delta-FC) predicts the development of post-traumatic stress-disorder (PTSD) symptoms in a relatively resilient group of young police students that are known to be at high risk for trauma exposure. Using resting-state fMRI, we measured acute-stress-induced delta-FC in 190 police recruits before (baseline) and after trauma exposure during repeated emergency-aid services (16-month follow-up). Delta-FC was then linked to the changes in perceived stress levels (PSS) and post-traumatic stress symptoms (PCL and CAPS). Weakened connectivity between the SN and DMN core regions upon acute-stress induction at baseline predicted longitudinal increases in perceived-stress level but not of post-traumatic stress symptoms, whereas increased coupling between the overall SN and anterior cerebellum was observed in participants with higher clinician-rated PTSD symptoms, particularly intrusion levels. All the effects remained significant when controlling for trauma-exposure levels and cortisol-stress reactivity. Neither hormonal nor subjective measures exerted similar predictive or acquired effects. The reconfiguration of large-scale neural networks upon acute-stress induction is relevant for assessing and detecting risk and resilience factors for PTSD. This study highlights the SN connectivity-changes as a potential marker for trauma-related symptom development, which is sensitive even in a relatively resilient sample.

Emotional cues draw attention, thereby enabling enhanced processing. Electrophysiological brain research in humans suggests that increased gamma band activity and decreased alpha band activity over posterior brain areas is associated with the allocation of attention. However, emotional events can alternate quickly, like rapidly changing news items and it remains unknown whether the modulation of brain oscillations happens in a stimulus induced manner, changing with each individual stimulus, or whether the events lead to prolonged, state-like changes. To investigate this, we measured the electroencephalogram (EEG) during a passive viewing task (N = 32) while emotional pictures International Affective Picture System (IAPS) were presented in blocks containing either pleasant and neutral or unpleasant and neutral pictures. As predicted, we found decreased alpha and increased gamma power over posterior areas in response to unpleasant compared to pleasant pictures (and also compared to neutral pictures for gamma power). When testing the neutral pictures of the unpleasant and pleasant block against each other, we found no significant difference, which speaks to a stimulus induced effect of alpha and gamma power rather than a state effect. In addition, the inter-trial interval (ITI) between the pictures did not differ between the unpleasant and pleasant block either, corroborating this conclusion. Since emotional pictures can at the same time elicit a freezing-like response and we were interested in whether this freezing-like response co-occurs with enhanced attention, we also collected postural sway data. However, within this EEG-setup, postural analyses indicated no stimulus-related effects nor a correlation with EEG-data. We interpret the alpha and gamma band results as reflecting event-related attention toward unpleasant compared to pleasant (and neutral) pictures and discuss this finding in light of previous EEG research and in combination with behavioral research on threat-induced reductions in body sway (freezing-like response).

Abstract Individuals with a social anxiety disorder (SAD) show hypofunctioning of the hypothalamus–pituitary-gonadal (HPG) axis, which is linked to social fear and avoidance behavior. As testosterone administration has been shown to facilitate social-approach behavior in this population, it may enhance the effectiveness of exposure treatment. In this proof-of-concept study, we performed a randomized clinical assay in which 55 women diagnosed with SAD received two exposure therapy sessions. Session 1 was supplemented with either testosterone (0.50 mg) or placebo. Next, transfer effects of testosterone augmentation on within-session subjective fear responses and SAD symptom severity were assessed during a second, unenhanced exposure session (session 2) and at a 1-month follow-up, respectively. The participants having received testosterone showed a more reactive fear pattern, with higher peaks and steeper reductions in fear levels in session 2. Post-hoc exploration of moderating effects of endogenous testosterone levels, revealed that this pattern was specific for women with high basal testosterone, both in the augmented and in the transfer session. In contrast, the participants with low endogenous testosterone showed reduced peak fear levels throughout session 1, again with transfer to the unenhanced session. Testosterone did not significantly affect self-reported anxiety. The effects of testosterone supplementation on fear levels show transfer to non-enhanced exposure, with effects being modulated by endogenous testosterone. These first preliminary results indicate that testosterone may act on important fear mechanisms during exposure, providing the empirical groundwork for further exploration of multi-session testosterone-enhanced exposure treatment for SAD.

Abstract Successful responding to acutely threatening situations requires adequate approach–avoidance decisions. However, it is unclear how threat-induced states—like freezing-related bradycardia—impact the weighing of the potential outcomes of such value-based decisions. Insight into the underlying computations is essential, not only to improve our models of decision-making but also to improve interventions for maladaptive decisions, for instance in anxiety patients and first-responders who frequently have to make decisions under acute threat. Forty-two participants made passive and active approach–avoidance decisions under threat-of-shock when confronted with mixed outcome-prospects (i.e., varying money and shock amounts). Choice behavior was best predicted by a model including individual action-tendencies and bradycardia, beyond the subjective value of the outcome. Moreover, threat-related bradycardia (high-vs-low threat) interacted with subjective value, depending on the action-context (passive-vs-active). Specifically, in action-contexts incongruent with participants’ intrinsic action-tendencies, stronger bradycardia related to diminished effects of subjective value on choice across participants. These findings illustrate the relevance of testing approach–avoidance decisions in relatively ecologically valid conditions of acute and primarily reinforced threat. These mechanistic insights into approach–avoidance conflict-resolution may inspire biofeedback-related techniques to optimize decision-making under threat. Critically, the findings demonstrate the relevance of incorporating internal psychophysiological states and external action-contexts into models of approach–avoidance decision-making.

A compelling amount of animal and human research has shown that perceived maternal stress during pregnancy can affect the neurodevelopment of the offspring. Prenatal maternal cortisol is frequently proposed as the biological key mechanism underlying this link; however, literature that investigates the effects of prenatal cortisol on subsequent neurodevelopment in humans is scarce. By using longitudinal data from a relatively large community sample of mother–child dyads (N = 73), this pre-registered study prospectively examined the role of maternal prenatal cortisol concentrations on subsequent individual differences in gray matter volume (GMV) and hippocampal subfield volumes at the onset of puberty of the offspring (12 years of age). Two markers of cortisol, that is, evening cortisol and circadian decline over the day, were used as indicators of maternal physiological stress during the last trimester of pregnancy. The results indicate that prenatal maternal cortisol levels were not associated with GMV or hippocampal subfield volumes of the children. These findings suggest that late pregnancy maternal cortisol may not be related to the structural development of the offspring’s brain, at least not in healthy community samples and at the onset of puberty. When examining the influence of prenatal stress on offspring neurodevelopment, future investigations should delineate gestational timing effects of the cortisol exposure, cortisol assessment method, and impact of additional biomarkers, as these were not investigated in this study.

Summary: Background: The freezing response is a universal response to threat, linked to attentive immobility and action preparation. It is relevant for acute stress coping in animals and humans, and subtle deviations in toddler freezing duration (absence of, or excessively long reactions) have been linked to higher risk for internalizing symptoms in adolescence. Yet, while individual freezing tendencies are relatively stable throughout life, little is known about their gene-environment aetiology. Methods: We investigated the heritability of toddler freezing in the Quebec Newborn Twin Study (QNTS; n=508 twins) by fitting behavioural genetic models to video-coded freezing responses during a robot confrontation. Furthermore, we examined the predictive associations between toddler freezing and internalizing symptoms (anxiety and depressive symptoms), as they unfold during adolescence (ages 12–19 years) using linear mixed-effects models. Findings: Freezing was found to be moderately heritable (45% of the variance accounted for by genetic factors). The remaining variance was explained by unique environmental factors, including measurement error. No significant contribution of shared environmental factors was noted. Additionally, shorter freezing was associated with more internalizing symptoms in adolescence at trend level, a pattern that was significant for depressive but not anxiety symptoms. Interpretation: Freezing is an adaptive coping mechanism in early childhood, which is partly driven by genetic factors. Crucially, the absence or shorter duration of these behaviours may signal vulnerability to depressive problems later in life. Funding: Canadian Institutes of Health Research and Research Fund of Quebec–Health and Society and Culture. Consolidator grant from the European Research Council (ERC_CoG-2017_772337).

It is widely recognized that police performance may be hindered by psychophysiological state changes during acute stress. To address the need for awareness and control of these physiological changes, police academies in many countries have implemented Heart-Rate Variability (HRV) biofeedback training. Despite these trainings now being widely delivered in classroom setups, they typically lack the arousing action context needed for successful transfer to the operational field, where officers must apply learned skills, particularly when stress levels rise. The study presented here aimed to address this gap by training physiological control skills in an arousing decision-making context. We developed a Virtual-Reality (VR) breathing-based biofeedback training in which police officers perform deep and slow diaphragmatic breathing in an engaging game-like action context. This VR game consisted of a selective shoot/don’t shoot game designed to assess response inhibition, an impaired capacity in high arousal situations. Biofeedback was provided based on adherence to a slow breathing pace: the slower and deeper the breathing, the less constrained peripheral vision became, facilitating accurate responses to the in-game demands. A total of nine male police trainers completed 10 sessions over a 4-week period as part of a single-case experimental ABAB study-design (i.e., alternating sessions with and without biofeedback). Results showed that eight out of nine participants showed improved breathing control in action, with a positive effect on breathing-induced low frequency HRV, while also improving their in-game behavioral performance. Critically, the breathing-based skill learning transferred to subsequent sessions in which biofeedback was not presented. Importantly, all participants remained highly engaged throughout the training. Altogether, our study showed that our VR environment can be used to train breathing regulation in an arousing and active decision-making context.

Effective stress recovery is crucial to prevent the long-term consequences of stress exposure. Studies have suggested that listening to music may be beneficial for stress reduction. Thus, music listening stands to be a promising method to promote effective recovery from exposure to daily stressors. Despite this, empirical support for this opinion has been largely equivocal. As such, to clarify the current literature, we conducted a systematic review with meta-analysis of randomized, controlled experimental studies investigating the effects of music listening on stress recovery in healthy individuals. In fourteen experimental studies, participants (N = 706) were first exposed to an acute laboratory stressor, following which they were either exposed to music or a control condition. A random-effects meta-regression with robust variance estimation demonstrated a non-significant cumulative effect of music listening on stress recovery g = 0.15, 95% CI [-0.21, 0.52], t(13) = 0.92, p = 0.374. In healthy individuals, the effects of music listening on stress recovery seemed to vary depending on musical genre, who selects the music, musical tempo, and type of stress recovery outcome. However, considering the significant heterogeneity between the modest number of included studies, no definite conclusions may currently be drawn about the effects of music listening on the short-term stress recovery process of healthy individuals. Suggestions for future research are discussed.

Effective stress recovery is crucial to prevent the long-term consequences of stress exposure. Studies have suggested that listening to music may be beneficial for stress reduction. Thus, music listening stands to be a promising method to promote effective recovery from exposure to daily stressors. Despite this, empirical support for this opinion has been largely equivocal. As such, to clarify the current literature, we conducted a systematic review with meta-analysis of randomized, controlled experimental studies investigating the effects of music listening on stress recovery in healthy individuals. In fourteen experimental studies, participants (N = 706) were first exposed to an acute laboratory stressor, following which they were either exposed to music or a control condition. A random-effects meta-regression with robust variance estimation demonstrated a non-significant cumulative effect of music listening on stress recovery g = 0.15, 95% CI [-0.21, 0.52], t(13) = 0.92, p = 0.374. In healthy individuals, the effects of music listening on stress recovery seemed to vary depending on musical genre, who selects the music, musical tempo, and type of stress recovery outcome. However, considering the significant heterogeneity between the modest number of included studies, no definite conclusions may currently be drawn about the effects of music listening on the short-term stress recovery process of healthy individuals. Suggestions for future research are discussed.

[This corrects the article DOI: 10.1371/journal.pone.0260952.].

As part of the Dutch national science program “Professional Games for Professional Skills” we developed a stress-exposure biofeedback training in virtual reality (VR) for the Dutch police. We aim to reduce the acute negative impact of stress on performance, as well as long-term consequences for mental health by facilitating physiological stress regulation during a demanding decision task. Conventional biofeedback applications mainly train physiological regulation at rest. This might limit the transfer of the regulation skills to stressful situations. In contrast, we provide the user with the opportunity to practice breathing regulation while they carry out a complex task in VR. This setting poses challenges from a technical – (real-time processing of noisy biosignals) as well as from a user-experience perspective (multi-tasking). We illustrate how we approach these challenges in our training and hope to contribute a useful reference for researchers and developers in academia or industry who are interested in using biosignals to control elements in a dynamic virtual environment.

Acutely challenging or threatening situations frequently require approach-avoidance decisions. Acute threat triggers fast autonomic changes that prepare the body to freeze, fight or flee. However, such autonomic changes may also influence subsequent instrumental approach-avoidance decisions. Since defensive bodily states are often not considered in value-based decision-making models, it remains unclear how they influence the decision-making process. Here, we aim to bridge this gap by discussing the existing literature on the potential role of threat-induced bodily states on decision making and provide a new neurocomputational framework explaining how these effects can facilitate or bias approach-avoid decisions under threat. Theoretical accounts have stated that threat-induced parasympathetic activity is involved in information gathering and decision making. Parasympathetic dominance over sympathetic activity is particularly seen during threat-anticipatory freezing, an evolutionarily conserved response to threat demonstrated across species and characterized by immobility and bradycardia. Although this state of freezing has been linked to altered information processing and action preparation, a full theoretical treatment of the interactions with value-based decision making has not yet been achieved. Our neural framework, which we term the Threat State/Value Integration (TSI) Model, will illustrate how threat-induced bodily states may impact valuation of competing incentives at three stages of the decision-making process, namely at threat evaluation, integration of rewards and threats, and action initiation. Additionally, because altered parasympathetic activity and decision biases have been shown in anxious populations, we will end with discussing how biases in this system can lead to characteristic patterns of avoidance seen in anxiety-related disorders, motivating future pre-clinical and clinical research.

The endeavor to understand the human brain has seen more progress in the last few decades than in the previous two millennia. Still, our understanding of how the human brain relates to behavior in the real world and how this link is modulated by biological, social, and environmental factors is limited. To address this, we designed the Healthy Brain Study (HBS), an interdisciplinary, longitudinal, cohort study based on multidimensional, dynamic assessments in both the laboratory and the real world. Here, we describe the rationale and design of the currently ongoing HBS. The HBS is examining a population-based sample of 1,000 healthy participants (age 30-39) who are thoroughly studied across an entire year. Data are collected through cognitive, affective, behavioral, and physiological testing, neuroimaging, bio-sampling, questionnaires, ecological momentary assessment, and real-world assessments using wearable devices. These data will become an accessible resource for the scientific community enabling the next step in understanding the human brain and how it dynamically and individually operates in its bio-social context. An access procedure to the collected data and bio-samples is in place and published on https://www.healthybrainstudy.nl/en/data-and-methods/access. Trail registration: https://www.trialregister.nl/trial/7955.

Previous work has shown relations between domain-general processes, domain-specific processes, and mathematical ability. However, the underlying neurophysiological effects of mathematical ability are less clear. Recent evidence highlighted the potential role of beta oscillations in mathematical ability. Here we investigate whether domain-general (working memory) and domain-specific (number sense) processes mediate the relation between resting-state beta oscillations and mathematical ability, and how this may differ as a function of development (children vs. adults). We compared a traditional analysis method normally used in EEG studies with a more recently developed parameterization method that separates periodic from aperiodic activity. Regardless of methods chosen, we found no support for mediation of working memory and number sense, neither for children nor for adults. However, we found subtle differences between the methods. Additionally, we showed that the traditional EEG analysis method conflates periodic activity with aperiodic activity; in addition, the latter is strongly related to mathematical ability and this relation differs between children and adults. At the cognitive level, our findings do not support previous suggestions of a mediation of working memory and number sense. At the neurophysiological level our findings suggest that aperiodic, rather than periodic, activity is linked to mathematical ability as a function of development.

Control over emotional action tendencies is essential for everyday interactions. This cognitive function fails occasionally during socially challenging situations, and systematically in social psychopathologies. We delivered dual-site phase-coupled brain stimulation to facilitate theta-gamma phase-amplitude coupling between frontal regions known to implement that form of control, while neuropsychologically healthy human male participants were challenged to control their automatic action tendencies in a social–emotional approach/avoidance-task. Participants had increased control over their emotional action tendencies, depending on the relative phase and dose of the intervention. Concurrently measured fMRI effects of task and stimulation indicated that the intervention improved control by increasing the efficacy of anterior prefrontal inhibition over the sensorimotor cortex. This enhancement of emotional action control provides causal evidence for phase-amplitude coupling mechanisms guiding action selection during emotional-action control. Generally, the finding illustrates the potential of physiologically-grounded interventions aimed at reducing neural noise in cerebral circuits where communication relies on phase-amplitude coupling.

The short (S) allele of the serotonin transporter-linked promoter region (5-HTTLPR) polymorphism has been linked to reactive aggression in men, but this association is less consistent in females. Reactive aggression has been particularly described as a result of fear-driven defense to threat, but how this interaction between defensive behavior and aggression is expressed in S-allele carriers remains unknown. In order to explore this interplay between 5-HTTLPR genotype, defensive behavior and reactive aggression, we combined genotyping with objective measures of action tendencies toward angry faces in an approach-avoidance task (AAT) and reactive aggression in the Taylor aggression paradigm (TAP) in healthy females, N = 95. This study shows that female S-allele carriers in general display increased implicit reactive aggression (administering aversive white noise) toward opponents. Furthermore, we found that threat-avoidance tendencies moderate the association between 5-HTTLPR genotype and aggression displayed on the TAP. Together, these findings indicate a positive correlation between avoidance of angry faces in the AAT and reactive aggression in the TAP exclusively present in S-allele carriers.

Background: Interpersonal deficits are a core symptom of borderline personality disorder (BPD), which could be related to increased social threat sensitivity and a tendency to approach rather than avoid interpersonal threats. The neuropeptide oxytocin has been shown to reduce threat sensitivity in patients with BPD and to modify approach–avoidance behavior in healthy volunteers.Methods: In a randomized, double-blind placebo-controlled between-subject design, 53 unmedicated women with BPD and 61 healthy women participated in an approach–avoidance task 75 min after intranasal substance administration (24 IU of oxytocin or placebo). The task assesses automatic approach–avoidance tendencies in reaction to facial expressions of happiness and anger.Results: While healthy participants responded faster to happy than angry faces, the opposite response pattern, that is, faster reactions to angry than happy faces, was found in patients with BPD. In the oxytocin condition, the “congruency effect” (i.e., faster avoidance of facial anger and approach of facial happiness vice versa) was increased in both groups. Notably, patients with BPD exhibited a congruency effect toward angry faces in the oxytocin but not in the placebo condition.Conclusions: This is the second report of deficient fast, automatic avoidance responses in terms of approach behavior toward interpersonal threat cues in patients with BPD. Intranasally administered oxytocin was found to strengthen avoidance behavior to social threat cues and, thus, to normalize fast action tendencies in BPD. Together with the previously reported oxytocinergic reduction of social threat hypersensitivity, these results suggest beneficial effects of oxytocin on interpersonal dysfunctioning in BPD.

Growing up in an urban area has been associated with an increased chance of mental health problems in adults, but less is known about this association in adolescents. We examined whether current urbanicity was associated with mental health problems directly and indirectly via biological stress system functioning. Participants (n = 323) were adolescents from the Dutch general population. Measures included home and laboratory assessments of autonomic nervous system and hypothalamic-pituitary-adrenal axis functioning, neighborhood-level urbanicity and socioeconomic status, and mother- and adolescent self-reported mental health problems. Structural equation models showed that urbanicity was not associated with mental health problems directly. Urbanicity was associated with acute autonomic nervous system and hypothalamic-pituitary-adrenal axis reactivity such that adolescents who lived in more urban areas showed blunted biological stress reactivity. Furthermore, there was some evidence for an indirect effect of urbanicity on mother-reported behavioral problems via acute autonomic nervous system reactivity. Urbanicity was not associated with overall autonomic nervous system and hypothalamic-pituitary-adrenal axis reactivity or basal hypothalamic-pituitary-adrenal axis functioning. Although we observed some evidence for associations between urbanicity, biological stress reactivity and mental health problems, most of the tested associations were not statistically significant. Measures of long-term biological stress system functioning may be more relevant to the study of broader environmental factors such as urbanicity.

Social anxiety disorder (SAD) is a prevalent and disabling mental disorder, associated with significant psychiatric co-morbidity. Previous research on structural brain alterations associated with SAD has yielded inconsistent results concerning the direction of the changes in gray matter (GM) in various brain regions, as well as on the relationship between brain structure and SAD-symptomatology. These heterogeneous findings are possibly due to limited sample sizes. Multi-site imaging offers new opportunities to investigate SAD-related alterations in brain structure in larger samples.An international multi-center mega-analysis on the largest database of SAD structural T1-weighted 3T MRI scans to date was performed to compare GM volume of SAD-patients (n=174) and healthy control (HC)-participants (n=213) using voxel-based morphometry. A hypothesis-driven region of interest (ROI) approach was used, focusing on the basal ganglia, the amygdala-hippocampal complex, the prefrontal cortex, and the parietal cortex. SAD-patients had larger GM volume in the dorsal striatum when compared to HC-participants. This increase correlated positively with the severity of self-reported social anxiety symptoms. No SAD-related differences in GM volume were present in the other ROIs. Thereby, the results of this mega-analysis suggest a role for the dorsal striatum in SAD, but previously reported SAD-related changes in GM in the amygdala, hippocampus, precuneus, prefrontal cortex and parietal regions were not replicated. Our findings emphasize the importance of large sample imaging studies and the need for meta-analyses like those performed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium. Keywords: Social anxiety disorder, Structural MRI, Voxel-based morphometry, Gray matter, Mega-analysis, Striatum

Freezing behavior, a commonly observed defensive stress response, shows relatively high stability over time in animals. Given the relevance of freezing for stress-coping and human psychopathology, it is relevant to know whether freezing behavior is also stable in humans, particularly during adolescence, when most affective symptoms develop. In a prospective longitudinal study, we investigated freezing-like behavior in response to social threat in 75 adolescents at age 14, repeated 3 years later at age 17. We used a well-established method combining electrocardiography (ECG; heart rate) and posturography (body sway) in response to emotional picture-viewing of angry, happy, and neutral faces. We hypothesized that individual differences in freezing-like behavior in response to social threat—operationalized by contrasting angry vs. neutral faces—would be relatively stable over time. Our results indeed showed relative stability between ages 14 and 17 in individual differences in freezing-like behavior in heart rate (r = 0.82), as well as in combined heart rate and body sway measures (r = 0.65). These effects were not specific for the angry vs. neutral contrast; they were also visible in other emotion contrasts. Exploratory analysis in males and females separately showed stability in body sway specifically for angry vs. neutral faces only in females. Together, these results suggest moderate to strong stability in human freezing-like behavior in response to social threat from mid to late adolescence (with exception for the body sway measure in males). This relative stability was not specific for threat-induction and may reflect a general stability that is particularly strong for heart rate. The fact that this relative stability was found over a relatively long time range of 3 years is promising for studies aiming to use freezing-like behavior as a marker for internalizing symptoms in adolescent development.

Background: Control over automatic tendencies is often compromised in challenging situations when people fall back on automatic defensive reactions, such as freeze–fight–flight responses. Stress-induced lack of control over automatic defensive responses constitutes a problem endemic to high-risk professions, such as the police. Difficulties controlling automatic defensive responses may not only impair split-second decisions under threat, but also increase the risk for and persistence of posttraumatic stress disorder (PTSD) symptoms. However, the significance of these automatic defensive responses in the development and maintenance of trauma-related symptoms remains unclear due to a shortage of large-scale prospective studies. Objective: The ‘Police-in-Action’ study is conducted to investigate the role of automatic defensive responses in the development and maintenance of PTSD symptomatology after trauma exposure. Methods: In this prospective study, 340 police recruits from the Dutch Police Academy are tested before (wave 1; pre-exposure) and after (wave 2; post-exposure) their first emergency aid experiences as police officers. The two waves of data assessment are separated by approximately 15 months. To control for unspecific time effects, a well-matched control group of civilians (n = 85) is also tested twice, approximately 15 months apart, but without being frequently exposed to potentially traumatic events. Main outcomes are associations between (changes in) behavioural, psychophysiological, endocrine and neural markers of automatic defensive responses and development of trauma-related symptoms after trauma exposure in police recruits. Discussion: This prospective study in a large group of primary responders enables us to distinguish predisposing from acquired neurobiological abnormalities in automatic defensive responses, associated with the development of trauma-related symptoms. Identifying neurobiological correlates of (vulnerability for) trauma-related psychopathology may greatly improve screening for individuals at risk for developing PTSD symptomatology and offer valuable targets for (early preventive) interventions for PTSD.

Neuroticism and extraversion are personality factors associated with the vulnerability for developing depression and anxiety disorders, and are possibly differentially related to brain structures implicated in the processing of emotional information and the generation of mood states. To date, studies on brain morphology mainly focused on neuroticism, a dimension primarily related to negative affect, yielding conflicting findings concerning the association with personality, partially due to methodological issues and variable population samples under study. Recently, extraversion, a dimension primarily related to positive affect, has been repeatedly inversely related to with symptoms of depression and anxiety disorders. In the present study, high resolution structural T1-weighted MR images of 65 healthy adults were processed using an optimized Voxel Based Morphometry (VBM) approach. Multiple regression analyses were performed to test for associations of neuroticism and extraversion with prefrontal and subcortical volumes. Orbitofrontal and right amygdala volume were both positively related to extraversion. Extraversion was differentially related to volume of the anterior cingulate cortex in males (positive) and females (negative). Neuroticism scores did not significantly correlate with these brain regions. As extraversion is regarded a protective factor for developing anxiety disorders and depression and has been related to the generation of positive affect, the present results indicate that the reduced likelihood of developing affective disorders in individuals high on extraversion is related to modulation of emotion processing through the orbitofrontal cortex and the amygdala.