The ventromedial prefrontal cortex in response to threat omission is associated with subsequent explicit safety memory.

In order to memorize and discriminate threatening and safe stimuli, the processing of the actual absence of threat seems crucial. Here, we measured brain activity with fMRI in response to both threat conditioned stimuli and their outcomes by combining threat learning with a subsequent memory paradigm. Participants (N = 38) repeatedly saw a variety of faces, half of which (CS+) were associated with an aversive unconditioned stimulus (US) and half of which were not (CS-). When an association was later remembered, the hippocampus had been more active (than when forgotten). However, the ventromedial prefrontal cortex predicted subsequent memory specifically during safe associations (CS- and US omission responses) and the left dorsolateral prefrontal cortex during outcomes in general (US and US omissions). In exploratory analyses of the theoretically important US omission, we found extended involvement of the medial prefrontal cortex and an enhanced functional connectivity to visual and somatosensory cortices, suggesting a possible function in sustaining sensory information for an integration with semantic memory. Activity in visual and somatosensory cortices together with the inferior frontal gyrus also predicted memory performance one week after learning. The findings imply the importance of a close interplay between prefrontal and sensory areas during the processing of safe outcomes-or 'nothing'-to establish declarative safety memory.

To remember or not to remember: Neural oscillations and ERPs as predictors of intentional associative fear learning.

It is widely accepted that impaired safety learning to a safe stimulus is a pathological feature of anxiety disorders. Safety learning refers to learning that a stimulus is associated with the absence of threat. Cognitive mechanisms that underlie successful threat and safety learning are, however, poorly understood. This study aimed to identify various physiological markers, including neural oscillations and event-related potentials (ERPs) that predict successful threat and safety learning. Therefore, to detect potential differences in these markers, we measured EEG in a fear learning framework combined with a subsequent memory paradigm. Thirty-seven participants were asked to memorize a series of associations between faces and an aversive unconditioned stimulus (US) or its omission. We found a decrease of power in the alpha band in occipital brain regions during learning for both threatening (conditioned stimuli, CS+) and safe faces (control stimuli, CS-) that were subsequently remembered to be associated with a US or not. No effects in theta band were found. In regard to ERPs, a late positive potential (LPP) and a P300 component were larger for remembered than for forgotten CS-US associations. The P300 was also enhanced to remembered US and US omissions, thus replicating previous findings. These results point to the importance of cognitive resource allocation as an underlying mechanism of fear learning and electrophysiological measurements as potential biomarkers for successful threat and safety learning.

Sexual Stimuli Cause Behavioral Disinhibition in Both Men and Women, but Even More So in Men.

In our society men are considered more impulsive than women, especially in the violent and sexual domain. This correlation of sex and impulsivity might trace back to enhanced male impulsivity in general or a domain specific effect of emotions on impulsivity. The evidence for sex differences in the interaction of emotional or sexual stimuli and impulsivity has been relatively inconclusive so far. In this study, we investigated the effects of various emotional stimuli on responsivity in a Go/No-Go task. Participants had to respond quickly to a visual cue and withhold their response to another visual cue, while different emotional pictures were presented in the background, including sexual stimuli, non-sexual positive stimuli and negative stimuli. Both men (N = 37) and women (N = 38) made most commission errors in the sexual condition, indicating a disinhibiting effect in both genders. On top of this, men made even more commission errors than women, specifically in the sexual condition and not in other conditions. Men rated sexual stimuli as more positive, but did not differ from women in arousal ratings and pupil dilation. These findings may partly indicate increased impulsive behavior under sexual arousal in men, most likely driven by enhanced approach motivation due to more positive value but not higher arousal of sexual stimuli. The results are consistent with the theory of evolutionarily based concealment of sexual interest in women.

Subsequent memory effects on event-related potentials in associative fear learning.

Studies of human fear learning suggest that a reliable discrimination between safe and threatening stimuli is important for survival and mental health. In the current study, we applied the subsequent memory paradigm in order to identify neurophysiological correlates of successful threat and safety learning. We recorded event-related potentials, while participants incidentally learned associations between multiple neutral faces and an aversive outcome [unconditioned stimulus (US)/conditioned stimulus (CS)+] or no outcome (noUS/CS-). We found that an enhanced late positive potential (LPP) to both CS+ and CS- during learning predicted subsequent memory. A quadratic relationship between LPP and confidence in memory indicates a possible role in both correct and false fear memory. Importantly, the P300 to the omission of the US (following CS-) was enhanced for remembered CS-, while there was a positive correlation between P300 amplitude to both US occurrence and omission and individual memory performance. A following re-exposure phase indicated that memory was indeed related to subjective fear of the CS+/CS-. These results highlight the importance of cognitive resource allocation to both threat and safety for the acquisition of fear and suggest a potential role of the P300 to US omission as an electrophysiological marker of successful safety learning.

Covariation bias in depression - a predictor of treatment response?

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

Shocking action: Facilitative effects of punishing electric shocks on action control.

Four experiments examined motivational effects of response-contingent electric shocks on action initiation. Although the shock was unambiguously aversive for the individual in line with subjective and functional criteria, results showed that the shock-producing action was initiated faster relative to a response producing no shock. However, no facilitation effect was found when strong shocks were delivered, ruling out increased emotional arousal as an explanation. The action was initiated faster even when the response discontinued to generate a shock. Furthermore, a control experiment with affectively neutral vibrotactile stimulations at homologous sites showed an analogous response facilitation effect. Overall, the results contradict the widespread belief that a contingency with a punishing response effect is sufficient for a response suppression. Instead, the results suggest that punishing action effects can facilitate action initiation via anticipatory feedback processes. Implications for theories and applications of punishment are discussed. (PsycINFO Database Record

Anxious anticipation and pain: the influence of instructed vs conditioned threat on pain.

Negative emotions such as anxiety enhance pain perception. However, certain threat characteristics are discussed to have different or even divergent effects on pain (hypoalgesia vs hyperalgesia). In order to investigate the neurobiological basis of different threats, we compared the impact of conditioned threat (CT) vs instructed threat (IT) on pain using fMRI. In two groups, participants underwent either Pavlovian threat conditioning or an instructed threat procedure. Afterwards, in an identical test phase participants watched the same visual cues from the previous phase indicating potential threat or safety, and received painful thermal stimulation. In the test phase, pain ratings were increased in both groups under threat. Group comparisons show elevated responses in amygdala and hippocampus for pain under threat in the CT group, and higher activation of the mid-cingulate gyrus (MCC) in the IT group. Psychophysiological interaction analyses in CT demonstrated elevated connectivity of the amygdala and the insula for the comparison of pain under threat vs safety. In IT, the same comparison revealed elevated functional connectivity of the MCC and the insula. The results suggest a similar pain augmenting effect of CT and IT, which, however, seems to rely on different networks mediating the impact of threat on pain.

How fear-relevant illusory correlations might develop and persist in anxiety disorders: A model of contributing factors.

Fear-relevant illusory correlations (ICs) are defined as the overestimation of the relationship between a fear-relevant stimulus and aversive consequences. ICs reflect biased cognitions affecting the learning and unlearning of fear in anxiety disorders, and a deeper understanding might help to improve treatment. A model for the maintenance of ICs is proposed that highlights the importance of amplified aversiveness and salience of fear-relevant outcomes, impaired executive contingency monitoring and an availability heuristic. The model explains why ICs are enhanced in high fearful individuals and allows for some implications that might be applied to augment the effectiveness of cognitive behavior therapy, such as emotion regulation and the direction of attention to non-aversive experiences. Finally, we suggest possible future research directions and an alternative measure of ICs.

Fear-relevant illusory correlations in different fears and anxiety disorders: A review of the literature.

Fearful individuals often overestimate the relationship between fear-relevant stimuli and aversive consequences. Such fear-relevant illusory correlations (ICs) might be involved in the maintenance of anxiety disorders. In this literature review, we found clear evidence that ICs are present and enhanced in fear of animals. We also revealed some evidence for ICs related to fear of flying, social anxiety, contamination fear, panic disorder, and post-traumatic stress disorder, but with considerably less clarity. Fear-relevant ICs seem to be best explained by both a priori expectancies and biased encoding of the experienced associations. Studies to date suggest that one important biased encoding process is the enhanced aversiveness/salience of fear-relevant outcomes. Future studies may improve insight by developing more reliable IC measures and testing the effect of encoding processes on treatment outcomes.

Enhanced functional connectivity between sensorimotor and visual cortex predicts covariation bias in spider phobia.

The overestimation of the relationship between fear-relevant stimuli and aversive consequences, a so called covariation bias, might contribute to the maintenance of anxiety disorders. In a recent fMRI study, we confronted spider phobia and healthy participants with pictures of spiders, mushrooms and puppies, randomly followed by painful electric stimuli (US). Spider phobics overestimated the spider-US association and displayed enhanced activity in US-related sensorimotor cortex (paracentral lobule, PCL). Here, we report results from an additional functional connectivity analysis. Within spider phobics but not in healthy controls, USs after spiders led to enhanced connectivity between PCL and left prefrontal cortex (PFC). Most importantly, covariation bias in spider phobia was predicted by connectivity between PCL and visual cortex, insula, primary sensorimotor cortex and secondary somatosensory cortex. Reduced covariation bias was predicted by connectivity between PCL and PFC. In response to spider pictures, the amygdala was functionally connected to somatosensory and visual areas. These results suggest that synchronous activity of sensory cortices may promote fear-sustaining associative memory bias, while right PFC might help to reduce bias.

Brain activity associated with illusory correlations in animal phobia.

Anxiety disorder patients were repeatedly found to overestimate the association between disorder-relevant stimuli and aversive outcomes despite random contingencies. Such an illusory correlation (IC) might play an important role in the return of fear after extinction learning; yet, little is known about how this cognitive bias emerges in the brain. In a functional magnetic resonance imaging study, 18 female patients with spider phobia and 18 healthy controls were exposed to pictures of spiders, mushrooms and puppies followed randomly by either a painful electrical shock or nothing. In advance, both patients and healthy controls expected more shocks after spider pictures. Importantly, only patients with spider phobia continued to overestimate this association after the experiment. The strength of this IC was predicted by increased outcome aversiveness ratings and primary sensory motor cortex activity in response to the shock after spider pictures. Moreover, increased activation of the left dorsolateral prefrontal cortex (dlPFC) to spider pictures predicted the IC. These results support the theory that phobia-relevant stimuli amplify unpleasantness and sensory motor representations of aversive stimuli, which in turn may promote their overestimation. Hyper-activity in dlPFC possibly reflects a pre-occupation of executive resources with phobia-relevant stimuli, thus complicating the accurate monitoring of objective contingencies and the unlearning of fear.

Initial and sustained brain responses to contextual conditioned anxiety in humans.

Contextual fear conditioning takes place if the occurrence of threat cannot be predicted by specific cues. As a consequence the context becomes the best predictor of the threat and later induces anxiety (sustained fear response). Previous studies suggest that both the amygdala and the hippocampus are crucial for contextual fear conditioning. First, we wanted to further elucidate the neuronal correlates of long-lasting contextual threat within a highly ecologically setting created in virtual reality (VR). Second, we wanted to distinguish between initial and sustained components of the anxiety response to a threatening situation. Twenty-four participants were guided through two virtual offices for 30s each. They received unpredictable electric stimuli (unconditioned stimulus, US) in one office (anxiety context, CXT+), but never in the second office (safety context, CXT-). Successful contextual fear conditioning was indexed by higher anxiety and enhanced US-expectancy ratings for CXT+ versus CXT-. Initial neural activity was assessed by modeling the onsets of both contexts, and sustained neural activity by considering the entire context duration (contrasts: CXT+ > CXT-). Amygdala and hippocampus revealed sustained activity. Initial and sustained activities were found in the middle temporal gyrus, and primary motor cortex (M1). Additional initial activity was obvious in orbitofrontal (OFC), dorsomedial (dmPFC), and dorsolateral prefrontal cortex (dlPFC). These results suggest that entering a threatening context initially induces conditioned fear reactions (M1), recall of contingency awareness (dlPFC), and explicit threat appraisal (dmPFC, OFC). While remaining in the threatening context might involve anxiety-like conditioned responses (amygdala, M1) and the generation of a spatial map to predict where and when a threatening event may occur (hippocampus). We conclude that in humans initial versus sustained anxiety responses triggered by a threat associated context are associated with distinguishable brain activation patterns involving a fear network and a "contingency-cognitive" network, respectively.

Supertaster, super reactive: oral sensitivity for bitter taste modulates emotional approach and avoidance behavior in the affective startle paradigm.

People differ in both their sensitivity for bitter taste and their tendency to respond to emotional stimuli with approach or avoidance. The present study investigated the relationship between these sensitivities in an affective picture paradigm with startle responding. Emotion-induced changes in arousal and attention (pupil modulation), priming of approach and avoidance behavior (startle reflex modulation), and subjective evaluations (ratings) were examined. Sensitivity for bitter taste was assessed with the 6-n-propylthiouracil (PROP)-sensitivity test, which discriminated individuals who were highly sensitive to PROP compared to NaCl (PROP-tasters) and those who were less sensitive or insensitive to the bitter taste of PROP. Neither pupil responses nor picture ratings differed between the two taster groups. The startle eye blink response, however, significantly differentiated PROP-tasters from PROP-insensitive subjects. Facilitated response priming to emotional stimuli emerged in PROP-tasters but not in PROP-insensitive subjects at shorter startle lead intervals (200-300ms between picture onset and startle stimulus onset). At longer lead intervals (3-4.5s between picture onset and startle stimulus onset) affective startle modulation did not differ between the two taster groups. This implies that in PROP-sensitive individuals action tendencies of approach or avoidance are primed immediately after emotional stimulus exposure. These results suggest a link between PROP taste perception and biologically relevant patterns of emotional responding. Direct perception-action links have been proposed to underlie motivational priming effects of the startle reflex, and the present results extend these to the sensory dimension of taste.

Illusory correlations between neutral and aversive stimuli can be induced by outcome aversiveness.

Anxiety is often characterised by an overestimation of the contingency between concern-relevant and aversive stimuli, and an amplified aversiveness of such aversive stimuli. Here we tested whether outcome aversiveness causally enhances contingency estimates. Twenty-four participants were exposed to neutral visual cues which were followed by startle sounds. The loudness and hence the aversiveness of the cue was determined by the cue colour while the likelihood of the startle sound always remained constant (50%). Results indicated an illusory correlation specifically for the cue followed by the most aversive startle sound as reflected in enhanced on-line and a posteriori covariation estimates. This bias was positively correlated with state and trait anxiety. Physiological arousal measured by pupil diameter was enhanced in response to the most aversive startle sound confirming its distinct processing. In conclusion, these results suggest that aversive outcomes may induce illusory correlations, most likely in anxious persons, and explain previous findings of illusory correlations in anxiety disorders.

The effects of an unexpected spider stimulus on skin conductance responses and eye movements: an inattentional blindness study.

Are spiders evolutionarily relevant threat cues that capture attention automatically and preattentively-also in non-fearful persons? Previous studies concerning this question did not examine responses to unexpected spider stimuli, although this is an ecologically valid situation. Therefore, we conducted an inattentional blindness (IB) experiment. While unselected participants (N = 120) were focusing their attention on a visual discrimination task, suddenly a spider or a flower image appeared. The rates of reported detection were not enhanced for spider images, and fear of spiders had no moderating influence on IB rates. However, spider pictures in general elicited greater skin conductance responses than flower pictures, and this difference was also observed for pictures that were not reported afterward. Moreover, eye movement data revealed that the spider stimulus was initially fixated more often than the flower stimulus. In sum, our findings imply that enhanced reactions to unexpected spider images are independent of fear level and include early engagement processes. Awareness of a spider picture does not seem to be a prerequisite for elevated arousal.