Aversive contexts enhance defensive responses to conditioned threat.

The ability to flexibly transition between defensive states is crucial for adaptive responding in life-threatening situations. Potentially threatening situations typically induce a sustained feeling of apprehension in association with hypervigilance, while acute threat is usually characterized by an intense and transient response to cope with the imminent danger. While potential and acute threat states have traditionally been viewed as mutually exclusive, this distinction is being challenged by a growing body of evidence suggesting a more complex interplay during simultaneous activation of these states. However, the interaction between potential and acute threat on a psychophysiological level remains elusive. To fill this gap, 94 healthy individuals participated in one of two contextual fear-conditioning paradigms. In both paradigms, a differential fear-learning phase was conducted, followed by a test phase in which the conditioned stimuli were presented in front of either conditioned or inherently aversive contextual images compared to neutral contexts. To capture defensive responses, we recorded subjective (threat and expectancy ratings) and physiological (electrodermal and cardiovascular) activity to the conditioned stimuli as a function of contextual threat. Besides indices of successful fear conditioning, our results revealed stronger threat and unconditioned stimulus expectancy ratings, cardiac deceleration, and skin conductance responses for threat and safety cues presented in inherently aversive compared to neutral contexts. Conditioned contexts had less impact on physiological responses to threat and safety cues than inherently aversive contexts. These findings provide new insights into the additive nature of defensive responses to fear cues and situations of contextual threat.

The effect of cognitive reappraisal on food craving and consumption: Does working memory capacity influence reappraisal ability? An event-related potential study.

Regulating cravings for unhealthy foods in favour of healthier options is essential for weight management. Cognitive reappraisal, which involves changing the meaning of a stimulus to modify its emotional impact, has shown promise for regulating food craving and consumption. Eighty participants were presented with high-calorie (HC) and low-calorie (LC) food pictures preceded by cues signalling instructions to naturally view the food (i.e., passive viewing; LOOK) or to imagine the future consequences of consuming that food (i.e., cognitive reappraisal; REGULATE). Participants' subjective craving and event-related potentials (ERPs) were measured, and food consumption after the task was assessed. Participants' working memory capacity (WMC) was measured with the automated Operation Span task. During cognitive reappraisal, cravings for HC foods decreased, whereas cravings for LC foods increased, compared to passive viewing. Cravings for LC and HC foods were correlated with consumptions of LC and HC foods, respectively. Occipital N1 (100-200ms) amplitudes were more negative for LC than for HC pictures, but were not modulated by strategy (LOOK or REGULATE), whereas early posterior negativity (EPN; 200-300ms) was not sensitive to food type (HC or LC) or strategy. Late positive potential (LPP; 400-1000ms) ERPs were largest in the HC-REGULATE condition, possibly due to cognitive processes induced by focusing on the consequences of unhealthy foods. Late LPP (1000-3000ms) was not affected by food type or strategy. LPP amplitudes were not correlated with cravings. WMC was weakly correlated with cravings for LC following reappraisal, suggesting that WMC may influence reappraisal ability. In sum, focusing on future consequences of eating may promote healthier food choices through craving regulation. Further research is needed to examine how regulatory effects evolve over time and how they relate to WMC and brain activity.

Testing the Possibility of Model-based Pavlovian Control of Attention to Threat.

Signals for reward or punishment attract attention preferentially, a principle termed value-modulated attention capture (VMAC). The mechanisms that govern the allocation of attention can be described with a terminology that is more often applied to the control of overt behaviors, namely, the distinction between instrumental and Pavlovian control, and between model-free and model-based control. Although instrumental control of VMAC can be either model-free or model-based, it is not known whether Pavlovian control of VMAC can be model-based. To decide whether this is possible, we measured steady-state visual evoked potentials (SSVEPs) while 20 healthy adults took part in a novel task. During the learning stage, participants underwent aversive threat conditioning with two conditioned stimuli (CSs): one that predicted pain (CS+) and one that predicted safety (CS-). Instructions given before the test stage allowed participants to infer whether novel, ambiguous CSs (new_CS+/new_CS-) were threatening or safe. Correct inference required combining stored internal representations and new propositional information, the hallmark of model-based control. SSVEP amplitudes quantified the amount of attention allocated to novel CSs on their very first presentation, before they were ever reinforced. We found that SSVEPs were higher for new_CS+ than new_CS-. This result is potentially indicative of model-based Pavlovian control of VMAC, but additional controls are necessary to verify this conclusively. This result underlines the potential transformative role of information and inference in emotion regulation.

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

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

Attention mechanisms during predictable and unpredictable threat - A steady-state visual evoked potential approach.

Fear is elicited by imminent threat and leads to phasic fear responses with selective attention, whereas anxiety is characterized by a sustained state of heightened vigilance due to uncertain danger. In the present study, we investigated attention mechanisms in fear and anxiety by adapting the NPU-threat test to measure steady-state visual evoked potentials (ssVEPs). We investigated ssVEPs across no aversive events (N), predictable aversive events (P), and unpredictable aversive events (U), signaled by four-object arrays (30s). In addition, central cues were presented during all conditions but predictably signaled imminent threat only during the P condition. Importantly, cues and context events were flickered at different frequencies (15Hz vs. 20Hz) in order to disentangle respective electrocortical responses. The onset of the context elicited larger electrocortical responses for U compared to P context. Conversely, P cues elicited larger electrocortical responses compared to N cues. Interestingly, during the presence of the P cue, visuocortical processing of the concurrent context was also enhanced. The results support the notion of enhanced initial hypervigilance to unpredictable compared to predictable threat contexts, while predictable cues show electrocortical enhancement of the cues themselves but additionally a boost of context processing.

A Scent of Anxiety: Olfactory Context Conditioning and its Influence on Social Cues.

Perception and evaluation of objects are highly dependent on surrounding contexts. Threatening contexts enhance processing of faces. Because odors are assumed to deliver strong contextual information, the present study aimed at demonstrating 1) that odors can constitute threat and safety contexts, and 2) consequently modulate the processing of faces presented in these contexts. Therefore, previously neutral odors were used as contextual stimuli in a context conditioning paradigm, resulting in an olfactory anxiety and a safety context. Then, faces showing angry, neutral, or fearful expressions were presented within both contexts during a test phase to investigate the effects of threat versus safety contexts on face perception. The late positive potential (LPP) from the EEG, skin conductance level, and subjective ratings were recorded. Results reveal successful olfactory context conditioning as reflected in enhanced processing of the anxiety context, indicated by enhanced LPP after conditioning, increased skin conductance level, and marginally respectively increased ratings. Moreover, faces presented within the threat context were rated as more unpleasant and marginally more arousing than faces presented in the safety context. Thus, olfactory stimuli can serve as context in fear conditioning, and a threatening olfactory context seems to enhance processing of stimuli perceived within this context.

Reliance on functional resting-state network for stable task control predicts behavioral tendency for cooperation.

Humans display individual variability in cooperative behavior. While an ever-growing body of research has investigated the neural correlates of task-specific cooperation, the mechanisms by which situation-independent, stable differences in cooperation render behavior consistent across a wide range of situations remain elusive. Addressing this issue, we show that the individual tendency to behave in a prosocial or individualistic manner can be predicted from the functional resting-state connectome. More specifically, connections of the cinguloopercular network which supports goal-directed behavior encode cooperative tendency. Effects of virtual lesions to this network on the efficacy of information exchange throughout the brain corroborate our findings. These results shed light on the neural mechanisms underlying individualists' and prosocials' habitual social decisions by showing that reliance on the cinguloopercular task-control network predicts stable cooperative behavior. Based on this evidence, we provide a unifying framework for the interpretation of functional imaging and behavioral studies of cooperative behavior.

Fearful faces heighten the cortical representation of contextual threat.

Perception of facial expressions is typically investigated by presenting isolated face stimuli. In everyday life, however, faces are rarely seen without a surrounding visual context that affects perception and interpretation of the facial expression. Conversely, fearful faces may act as a cue, heightening the sensitivity of the visual system to effectively detect potential threat in the environment. In the present study, we used steady-state visually evoked potentials (ssVEPs) to examine the mutual effects of facial expressions (fearful, neutral, happy) and affective visual context (pleasant, neutral, threat). By assigning two different flicker frequencies (12 vs. 15Hz) to the face and the visual context scene, cortical activity to the concurrent stimuli was separated, which represents a novel approach to independently tracking the cortical processes associated with the face and the context. Twenty healthy students viewed flickering faces overlaid on flickering visual scenes, while performing a simple change-detection task at fixation, and high-density EEG was recorded. Arousing background scenes generally drove larger ssVEP amplitudes than neutral scenes. Importantly, background and expression interacted: When viewing fearful facial expressions, the ssVEP in response to threat context was amplified compared to other backgrounds. Together, these findings suggest that fearful faces elicit vigilance for potential threat in the visual periphery.

Not so harmless anymore: how context impacts the perception and electrocortical processing of neutral faces.

Our first impression of others is highly influenced by their facial appearance. However, the perception and evaluation of faces is not only guided by internal features such as facial expressions, but also highly dependent on contextual information such as secondhand information (verbal descriptions) about the target person. To investigate the time course of contextual influences on cortical face processing, event-related brain potentials were investigated in response to neutral faces, which were preceded by brief verbal descriptions containing cues of affective valence (negative, neutral, positive) and self-reference (self-related vs. other-related). ERP analysis demonstrated that early and late stages of face processing are enhanced by negative and positive as well as self-relevant descriptions, although faces per se did not differ perceptually. Affective ratings of the faces confirmed these findings. Altogether, these results demonstrate for the first time both on an electrocortical and behavioral level how contextual information modifies early visual perception in a top-down manner.

MicroRNA-663 induction upon oxidative stress in cultured human fibroblasts depends on the chronological age of the donor.

MicroRNAs, regulators of messenger RNA translation, have been observed to influence many physiological processes, amongst them the process of aging. Higher levels of microRNA-663 (miR-663) have previously been observed in human dermal fibroblasts subject to both replicative and stress-induced senescence compared to early passage cells. Also, higher levels of miR-663 have been found in memory T-cells and in human fibroblasts derived from older donors compared to younger donors. In previous studies we observed that dermal fibroblasts from donors of different chronological and biological age respond differentially to oxidative stress measured by markers of cellular senescence and apoptosis. In the present study we set out to study the association between miR-663 levels and chronological and biological age. Therefore we tested in a total of 92 human dermal fibroblast strains whether the levels of miR-663 in non-stressed and stressed conditions (fibroblasts were treated with 0.6 µM rotenone in stressed conditions) were different in young, middle aged and old donors and whether they were different in middle aged donors dependent on their biological age, as indicated by the propensity for familial longevity. In non-stressed conditions the level of miR-663 did not differ between donors of different age categories and was not dependent on biological age. Levels of miR-663 did not differ dependent on biological age in stressed conditions either. However, for different age categories the level of miR-663 in stressed conditions did differ: the level of miR-663 was higher at higher age categories. Also, the ratio of miR-663 induction upon stress was significantly higher in donors from older age categories. In conclusion, we present evidence for an association of miR-663 upon stress and chronological age.

Unconditioned stimulus devaluation decreases the generalization of costly safety behaviors.

Safety behaviors are often maladaptive in clinical anxiety as they typically persist without realistic threat and cause various impairments. In the laboratory, safety behaviors are modelled by responses to a conditioned stimulus (CS) that reduce the occurrence of an expected aversive unconditioned stimulus (US). Preliminary evidence suggests that US devaluation, a procedure that decreases US aversiveness, devalues the threat value of the CS and thus diminishes safety behaviors to the CS. This study (n = 78) aimed to extend this finding and examined whether US-devaluation can reduce the generalization of safety behaviors to various stimuli. After acquiring safety behaviors to CSs of different categories, the US predicted by one CS category was devalued. In test, participants showed a selective reduction in safety behaviors to novel stimuli of the devalued CS category, reflecting a decrease in generalization of safety behaviors. Trait anxiety was associated with persistent generalized safety behaviors to novel stimuli of the devalued category. We discuss how US devaluation may improve treatment outcome but also the challenges of clinical translation.

Profiling microRNA expression during senescence and aging: mining for a diagnostic tool of senescent-cell burden.

In the last decade cellular senescence, a hallmark of aging, has come into focus for pharmacologically targeting aging processes. Senolytics are one of these interventive strategies that have advanced into clinical trials, creating an unmet need for minimally invasive biomarkers of senescent cell load to identify patients at need for senotherapy. We created a landscape of miRNA and mRNA expression in five human cell types induced to senescence in-vitro and provide proof-of-principle evidence that miRNA expression can track senescence burden dynamically in-vivo using transgenic p21 high senescent cell clearance in HFD fed mice. Finally, we profiled miRNA expression in seven different tissues, total plasma, and plasma derived EVs of young and 25 months old mice. In a systematic analysis, we identified 22 candidate senomiRs with potential to serve as circulating biomarkers of senescence not only in rodents, but also in upcoming human clinical senolytic trials.

Vulnerabilities in social anxiety: Integrating intra- and interpersonal perspectives.

What are the major vulnerabilities in people with social anxiety? What are the most promising directions for translational research pertaining to this condition? The present paper provides an integrative summary of basic and applied translational research on social anxiety, emphasizing vulnerability factors. It is divided into two subsections: intrapersonal and interpersonal. The intrapersonal section synthesizes research relating to (a) self-representations and self-referential processes; (b) emotions and their regulation; and (c) cognitive biases: attention, interpretation and judgment, and memory. The interpersonal section summarizes findings regarding the systems of (a) approach and avoidance, (b) affiliation and social rank, and their implications for interpersonal impairments. Our review suggests that the science of social anxiety and, more generally, psychopathology may be advanced by examining processes and their underlying content within broad psychological systems. Increased interaction between basic and applied researchers to diversify and elaborate different perspectives on social anxiety is necessary for progress.

HIV-1 induces telomerase activity in monocyte-derived macrophages, possibly safeguarding one of its reservoirs.

Monocyte-derived macrophages (MDM) are widely distributed in all tissues and organs, including the central nervous system, where they represent the main part of HIV-infected cells. In contrast to activated CD4(+) T lymphocytes, MDM are resistant to cytopathic effects and survive HIV infection for a long period of time. The molecular mechanisms of how HIV is able to persist in macrophages are not fully elucidated yet. In this context, we have studied the effect of in vitro HIV-1 infection on telomerase activity (TA), telomere length, and DNA damage. Infection resulted in a significant induction of TA. This increase was directly proportional to the efficacy of HIV infection and was found in both nuclear and cytoplasmic extracts, while neither UV light-inactivated HIV nor exogenous addition of the viral protein Tat or gp120 affected TA. Furthermore, TA was not modified during monocyte-macrophage differentiation, MDM activation, or infection with vaccinia virus. HIV infection did not affect telomere length. However, HIV-infected MDM showed less DNA damage after oxidative stress than noninfected MDM, and this resistance was also increased by overexpressing telomerase alone. Taken together, our results suggest that HIV induces TA in MDM and that this induction might contribute to cellular protection against oxidative stress, which could be considered a viral strategy to make macrophages better suited as longer-lived, more resistant viral reservoirs. In the light of the clinical development of telomerase inhibitors as anticancer therapeutics, inhibition of TA in HIV-infected macrophages might also represent a novel therapeutic target against viral reservoirs.

Onset and offset of aversive events establish distinct memories requiring fear and reward networks.

Two things are worth remembering about an aversive event: What made it happen? What made it cease? If a stimulus precedes an aversive event, it becomes a signal for threat and will later elicit behavior indicating conditioned fear. However, if the stimulus is presented upon cessation of the aversive event, it elicits behavior indicating conditioned "relief." What are the neuronal bases for such learning? Using functional magnetic resonance imaging (fMRI) in humans we found that a fear-conditioned stimulus activates amygdala but not striatum, whereas a relief-conditioned stimulus activates striatum but not amygdala. Correspondingly, acute inactivation of amygdala or of ventral striatum in rats respectively abolished only conditioned fear or only conditioned relief. Thus, the behaviorally opponent memories supported by onset and offset of aversive events engage and require fear and reward networks, respectively. This may explain attraction to stimuli associated with the cessation of trauma or of panic attacks.

The effect of inherently threatening contexts on visuocortical engagement to conditioned threat.

Fear and anxiety are crucial for adaptive responding in life-threatening situations. Whereas fear is a phasic response to an acute threat accompanied by selective attention, anxiety is characterized by a sustained feeling of apprehension and hypervigilance during situations of potential threat. In the current literature, fear and anxiety are usually considered mutually exclusive, with partially separated neural underpinnings. However, there is accumulating evidence that challenges this distinction between fear and anxiety, and simultaneous activation of fear and anxiety networks has been reported. Therefore, the current study experimentally tested potential interactions between fear and anxiety. Fifty-two healthy participants completed a differential fear conditioning paradigm followed by a test phase in which the conditioned stimuli were presented in front of threatening or neutral contextual images. To capture defense system activation, we recorded subjective (threat, US-expectancy), physiological (skin conductance, heart rate) and visuocortical (steady-state visual evoked potentials) responses to the conditioned stimuli as a function of contextual threat. Results demonstrated successful fear conditioning in all measures. In addition, threat and US-expectancy ratings, cardiac deceleration, and visuocortical activity were enhanced for fear cues presented in threatening compared with neutral contexts. These results are in line with an additive or interactive rather than an exclusive model of fear and anxiety, indicating facilitated defensive behavior to imminent danger in situations of potential threat.

Context-Dependent Responses to the Spread of COVID-19 Among National and International Students During the First Lockdown: An Online Survey.

BACKGROUND: Restrictions to minimize social contact was necessary to prevent the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus but may have impacted individuals' mental well-being. Emotional responses are modulated by contextual information. Living abroad during the coronavirus disease 2019 (COVID-19) pandemic may have boosted the feeling of isolation as the context is unfamiliar. OBJECTIVES: This study compared the psychological impact of social distancing in national students (living in a familiar context) versus international students (living in an unfamiliar context). METHODS: During March/April 2020 (first lockdown in the Netherlands), 850 university students completed an online survey. Structural equation modeling (SEM) was conducted to compare how students' responses to the virus were predicted by health anxiety, emotional distress, and personal traits. RESULTS: Compared with national students, international students showed higher levels in 4 identified factors (COVID-19-related worry, perceived risk of infection, distance from possibly contaminated objects, distance from social situations). The factors were mainly predicted by health anxiety across international students, while emotional distress and individual traits (eg, intolerance of uncertainty) played a role across national students. CONCLUSIONS: In the familiar context, individual characteristics (traits) predicted the responses to the virus, while the unfamiliar context drove individuals' health-focused responses. Living in a foreign country is associated with psychological burdens and this should be considered by universities for more pronounced social support and clear references to health-related institutions.

Better safe than sorry?-On the influence of learned safety on pain perception.

The experience of threat was found to result-mostly-in increased pain, however it is still unclear whether the exact opposite, namely the feeling of safety may lead to a reduction of pain. To test this hypothesis, we conducted two between-subject experiments (N = 94; N = 87), investigating whether learned safety relative to a neutral control condition can reduce pain, while threat should lead to increased pain compared to a neutral condition. Therefore, participants first underwent either threat or safety conditioning, before entering an identical test phase, where the previously conditioned threat or safety cue and a newly introduced visual cue were presented simultaneously with heat pain stimuli. Methodological changes were performed in experiment 2 to prevent safety extinction and to facilitate conditioning in the first place: We included additional verbal instructions, increased the maximum length of the ISI and raised CS-US contingency in the threat group from 50% to 75%. In addition to pain ratings and ratings of the visual cues (threat, safety, arousal, valence, and contingency), in both experiments, we collected heart rate and skin conductance. Analysis of the cue ratings during acquisition indicate successful threat and safety induction, however results of the test phase, when also heat pain was administered, demonstrate rapid safety extinction in both experiments. Results suggest rather small modulation of subjective and physiological pain responses following threat or safety cues relative to the neutral condition. However, exploratory analysis revealed reduced pain ratings in later trials of the experiment in the safety group compared to the threat group in both studies, suggesting different temporal dynamics for threat and safety learning and extinction, respectively. Perspective: The present results demonstrate the challenge to maintain safety in the presence of acute pain and suggest more research on the interaction of affective learning mechanism and pain processing.

Investigating sustained attention in contextual threat using steady-state VEPs evoked by flickering video stimuli.

Anxiety is characterized by anxious anticipation and heightened vigilance to uncertain threat. However, if threat is not reliably indicated by a specific cue, the context in which threat was previously experienced becomes its best predictor, leading to anxiety. A suitable means to induce anxiety experimentally is context conditioning: In one context (CTX+), an unpredictable aversive stimulus (US) is repeatedly presented, in contrast to a second context (CTX-), in which no US is ever presented. In this EEG study, we investigated attentional mechanisms during acquisition and extinction learning in 38 participants, who underwent a context conditioning protocol. Flickering video stimuli (32 s clips depicting virtual offices representing CTX+/-) were used to evoke steady-state visual evoked potentials (ssVEPs) as an index of visuocortical engagement with the contexts. Analyses of the electrocortical responses suggest a successful induction of the ssVEP signal by video presentation in flicker mode. Furthermore, we found clear indices of context conditioning and extinction learning on a subjective level, while cortical processing of the CTX+ was unexpectedly reduced during video presentation. The differences between CTX+ and CTX- diminished during extinction learning. Together, these results indicate that the dynamic sensory input of the video presentation leads to disruptions in the ssVEP signal, which is greater for motivationally significant, threatening contexts.

Examining the impact of cue similarity and fear learning on perceptual tuning.

Past research on the effects of associative aversive learning on discrimination acuity has shown mixed results, including increases, decreases, and no changes in discrimination ability. An animal study found that the type of learning experience determined the direction and extent of learning-induced changes. The current preregistered web-based study aimed to translate these findings to humans. Experiment 1 (N = 245) compared changes in stimulus discrimination between simple learning (only one oriented grating cue), coarse differential conditioning (physically distinct cues), and fine differential conditioning (physically similar cues) as well as to their three respective control groups. The discrimination task consisted of a two-alternative-forced-choice task with oriented grating stimuli. During learning, a specific orientation was paired with unpleasant pictures. Our analysis using generative modeling demonstrated weak to moderate evidence that aversive learning did not alter discrimination acuity in any of the groups. In a follow-up experiment (N = 121), we replicated these findings despite successful learning trajectories in all three groups and a more detailed assessment of discrimination acuity. Contrary to prior assumptions, our findings indicate that aversive learning does not enhance perceptual discrimination, and the presence of additional safety cues does not appear to moderate this effect.