Aversive Outcomes Research Articles

Unrelenting Fear Under Stress: Neural Circuits and Mechanisms for the Immediate Extinction Deficit.

Therapeutic interventions for disorders of fear and anxiety rely on behavioral approaches that reduce pathological fear memories. For example, learning that threat-predictive stimuli are no longer associated with aversive outcomes is central to the extinction of conditioned fear responses. Unfortunately, fear memories are durable, long-lasting, and resistant to extinction, particularly under high levels of stress. This is illustrated by the “immediate extinction deficit,” which is characterized by a poor long-term reduction of conditioned fear when extinction procedures are attempted within hours of fear conditioning. Here, I will review recent work that has provided new insight into the neural mechanisms underlying resistance to fear extinction. Emerging studies reveal that locus coeruleus norepinephrine modulates amygdala-prefrontal cortical circuits that are critical for extinction learning. These data suggest that stress-induced activation of brain neuromodulatory systems biases fear memory at the expense of extinction learning. Behavioral and pharmacological strategies to reduce stress in patients undergoing exposure therapy might improve therapeutic outcomes.

Alpha-band EEG suppression as a neural marker of sustained attentional engagement to conditioned threat stimuli.

Attention helps us to be aware of the external world, and this may be especially important when a threat stimulus predicts an aversive outcome. Electroencephalogram (EEG) alpha-band suppression has long been considered as a neural signature of attentional engagement. The present study was designed to test whether attentional engagement, as indexed by alpha-band suppression, is increased in a sustained manner following a conditioned stimulus (CS) that is paired with an aversive (CS+) vs neutral (CS-) outcome. We tested 70 healthy young adults in aversive conditioning and extinction paradigms. One of three colored circles served as the CS+, which was paired in 50% of the trials with a noise burst (unconditioned stimulus, US). The other colored circles (CS-) were never paired with the US. For conditioning, we found greater alpha-band suppression for the CS+ compared to the CS-; this suppression was sustained through the time of the predicted US. This effect was significantly reduced for extinction. These results indicate that conditioned threat stimuli trigger an increase in attentional engagement as subjects monitor the environment for the predicted aversive stimulus. Moreover, this alpha-band suppression effect may be valuable for future studies examining normal or pathological increases in attentional monitoring following threat stimuli.

Outcome-Locked Cholinergic Signaling Suppresses Prefrontal Encoding of Stimulus Associations.

Acetylcholine (ACh) is thought to control arousal, attention, and learning by slowly modulating cortical excitability and plasticity. Recent studies, however, discovered that cholinergic neurons emit precisely timed signals about the aversive outcome at millisecond precision. To investigate the functional relevance of such phasic cholinergic signaling, we manipulated and monitored cholinergic terminals in the mPFC while male mice associated a neutral conditioned stimulus (CS) with mildly aversive eyelid shock (US) over a short temporal gap. Optogenetic inhibition of cholinergic terminals during the US promoted the formation of the CS-US association. On the contrary, optogenetic excitation of cholinergic terminals during the US blocked the association formation. The bidirectional behavioral effects paralleled the corresponding change in the expression of an activity-regulated gene, c-Fos in the mPFC. In contrast, optogenetic inhibition of cholinergic terminals during the CS impaired associative learning, whereas their excitation had marginal effects. In parallel, photometric recording from cholinergic terminals in the mPFC revealed strong innate phasic responses to the US. With subsequent CS-US pairings, cholinergic terminals weakened the responses to the US while developing strong responses to the CS. The across-session changes in the CS- and US-evoked terminal responses were correlated with associative memory strength. These findings suggest that phasic cholinergic signaling in the mPFC exerts opposite effects on aversive associative learning depending on whether it is emitted by the outcome or the cue.SIGNIFICANCE STATEMENT Drugs compensating for the decline of acetylcholine (ACh) are used for cognitive impairment, such as Alzheimer's disease. However, their beneficial effects are limited, demanding new strategies based on better understandings of how ACh modulates cognition. Here, we report that by manipulating ACh signals in the mPFC, we can control the strength of aversive associative learning in mice. Specifically, the suppression of ACh signals during an aversive outcome facilitated its association with a preceding cue. In contrast, the suppression of ACh signals during the cue impaired learning. Considering that this paradigm depends on the brain regions affected in Alzheimer's disease, our findings indicate that precisely timed control of ACh signals is essential to refine ACh-based strategies for cognitive enhancement.

A Computational Model of Hopelessness and Active-Escape Bias in Suicidality.

Currently, psychiatric practice lacks reliable predictive tools and a sufficiently detailed mechanistic understanding of suicidal thoughts and behaviors (STB) to provide timely and personalized interventions. Developing computational models of STB that integrate across behavioral, cognitive and neural levels of analysis could help better understand STB vulnerabilities and guide personalized interventions. To that end, we present a computational model based on the active inference framework. With this model, we show that several STB risk markers - hopelessness, Pavlovian bias and active-escape bias - are interrelated via the drive to maximize one's model evidence. We propose four ways in which these effects can arise: (1) increased learning from aversive outcomes, (2) reduced belief decay in response to unexpected outcomes, (3) increased stress sensitivity and (4) reduced sense of stressor controllability. These proposals stem from considering the neurocircuits implicated in STB: how the locus coeruleus - norepinephrine (LC-NE) system together with the amygdala (Amy), the dorsal prefrontal cortex (dPFC) and the anterior cingulate cortex (ACC) mediate learning in response to acute stress and volatility as well as how the dorsal raphe nucleus - serotonin (DRN-5-HT) system together with the ventromedial prefrontal cortex (vmPFC) mediate stress reactivity based on perceived stressor controllability. We validate the model by simulating performance in an Avoid/Escape Go/No-Go task replicating recent behavioral findings. This serves as a proof of concept and provides a computational hypothesis space that can be tested empirically and be used to distinguish planful versus impulsive STB subtypes. We discuss the relevance of the proposed model for treatment response prediction, including pharmacotherapy and psychotherapy, as well as sex differences as it relates to stress reactivity and suicide risk.

Aversive view memories and risk perception in navigating ants

Many ants establish foraging routes through learning views of the visual panorama. Route models have focused primarily on attractive view use, which experienced foragers orient towards to return to known sites. However, aversive views have recently been uncovered as a key component of route learning. Here, Cataglyphis velox rapidly learned aversive views, when associated with a negative outcome, a period of captivity in vegetation, triggering increases in hesitation behavior. These memories were based on the accumulation of experiences over multiple trips with each new experience regulating forager hesitancy. Foragers were also sensitive to captivity time differences, suggesting they possess some mechanism to quantify duration. Finally, we analyzed foragers' perception of risky (i.e. variable) versus stable aversive outcomes by associating two sites along the route with distinct captivity schedules, a fixed or variable duration, with the same mean across training. Foragers exhibited fewer hesitations in response to risky outcomes compared to fixed ones, indicating they perceived risky outcomes as less severe. Results align with a logarithmic relationship between captivity duration and hesitations, suggesting that aversive stimulus perception is a logarithm of its actual value. We discuss how aversive view learning could be executed within the mushroom bodies circuitry following a prediction error rule.

Conditioned up and down modulations of short latency gamma band oscillations in visual cortex during fear learning in humans

Over the course of evolution, the human brain has been shaped to prioritize cues that signal potential danger. Thereby, the brain does not only favor species-specific prepared stimulus sets such as snakes or spiders but can learn associations between new cues and aversive outcomes. One important mechanism to achieve this is associated with learning induced plasticity changes in sensory cortex that optimizes the representation of motivationally relevant sensory stimuli. Animal studies have shown that the modulation of gamma band oscillations predicts plasticity changes in sensory cortices by shifting neurons’ responses to fear relevant features as acquired by Pavlovian fear conditioning. Here, we report conditioned gamma band modulations in humans during fear conditioning of orthogonally oriented sine gratings representing fear relevant and irrelevant conditioned cues. Thereby, pairing of a sine grating with an aversive loud noise not only increased short latency (during the first 180 ms) evoked visual gamma band responses, but was also accompanied by strong gamma power reductions for the fear irrelevant control grating. The current findings will be discussed in the light of recent neurobiological models of plasticity changes in sensory cortices and classic learning models such as the Rescorla–Wagner framework.

Group differences in agency modulate error monitoring.

Mistakes can lead to aversive outcomes. Error monitoring may help prevent mistakes, but it might be maladaptive for individuals who lack control over aversive outcomes, as it consumes cognitive processing resources that could be allocated elsewhere. Here, we examined the effect of agency (i.e., control over punishment) on error monitoring using the error-related negativity (ERN), an event-related potential measure of error monitoring and error rate. Ninety unselected participants performed a flanker task in which they were shocked according to their own errors (controllable punishment, n=47) or were shocked in accordance with another participant's errors (uncontrollable punishment, n=43). Participants without agency over punishment showed smaller ERNs and higher error rates compared with participants with agency. Furthermore, punishment only reduced error rates for participants with agency. Together, these results provide the first experimental evidence that agency modulates error monitoring and suggest an adaptive process in which error monitoring is increased/decreased depending on its utility.

Working Memory Performance for Differentially Conditioned Stimuli.

Previous work suggests that threat-related stimuli are stored to a greater degree in working memory compared to neutral stimuli. However, most of this research has focused on stimuli with physically salient threat attributes (e.g., angry faces), failing to account for how a “neutral” stimulus that has acquired threat-related associations through differential aversive conditioning influences working memory. The current study examined how differentially conditioned safe (i.e., CS–) and threat (i.e., CS+) stimuli are stored in working memory relative to a novel, non-associated (i.e., N) stimuli. Participants (n = 69) completed a differential fear conditioning task followed by a change detection task consisting of three conditions (CS+, CS–, N) across two loads (small, large). Results revealed individuals successfully learned to distinguishing CS+ from CS– conditions during the differential aversive conditioning task. Our working memory outcomes indicated successful load manipulation effects, but no statistically significant differences in accuracy, response time (RT), or Pashler’s K measures of working memory capacity between CS+, CS–, or N conditions. However, we observed significantly reduced RT difference scores for the CS+ compared to CS– condition, indicating greater RT differences between the CS+ and N condition vs. the CS– and N condition. These findings suggest that differentially conditioned stimuli have little impact on behavioral outcomes of working memory compared to novel stimuli that had not been associated with previous safe of aversive outcomes, at least in healthy populations.

Behavioral and neural mechanisms of latent inhibition.

Fear is an adaptive emotion that serves to protect an organism against potential dangers. It is often studied using classical conditioning paradigms where a conditioned stimulus is paired with an aversive unconditioned stimulus to induce a threat response. Less commonly studied is a phenomenon that is related to this form of conditioning, known as latent inhibition. Latent inhibition (LI) is a paradigm in which a neutral cue is repeatedly presented in the absence of any aversive associations. Subsequent pairing of this pre-exposed cue with an aversive stimulus typically leads to reduced expression of a conditioned fear/threat response. In this article, we review some of the theoretical basis for LI and its behavioral and neural mechanisms. We compare and contrast LI and fear/threat extinction-a process in which a previously conditioned cue is repeatedly presented in the absence of aversive outcomes. We end with highlighting the potential clinical utility of LI. Particularly, we focus on how LI application could be useful for enhancing resilience, especially for individuals who are more prone to continuous exposure to trauma and stressful environments, such as healthcare workers and first responders. The knowledge to be gained from advancing our understanding of neural mechanisms in latent inhibition could be applicable across psychiatric disorders characterized by exaggerated fear responses and impaired emotion regulation.

Lower Levels of Directed Exploration and Reflective Thinking Are Associated With Greater Anxiety and Depression.

Anxiety and depression are often associated with strong beliefs that entering specific situations will lead to aversive outcomes – even when these situations are objectively safe and avoiding them reduces well-being. A possible mechanism underlying this maladaptive avoidance behavior is a failure to reflect on: (1) appropriate levels of uncertainty about the situation, and (2) how this uncertainty could be reduced by seeking further information (i.e., exploration). To test this hypothesis, we asked a community sample of 416 individuals to complete measures of reflective cognition, exploration, and symptoms of anxiety and depression. Consistent with our hypotheses, we found significant associations between each of these measures in expected directions (i.e., positive relationships between reflective cognition and strategic information-seeking behavior or “directed exploration”, and negative relationships between these measures and anxiety/depression symptoms). Further analyses suggested that the relationship between directed exploration and depression/anxiety was due in part to an ambiguity aversion promoting exploration in conditions where information-seeking was not beneficial (as opposed to only being due to under-exploration when more information would aid future choices). In contrast, reflectiveness was associated with greater exploration in appropriate settings and separately accounted for differences in reaction times, decision noise, and choice accuracy in expected directions. These results shed light on the mechanisms underlying information-seeking behavior and how they may contribute to symptoms of emotional disorders. They also highlight the potential clinical relevance of individual differences in reflectiveness and exploration and should motivate future research on their possible contributions to vulnerability and/or maintenance of affective disorders.

History-dependent dopamine release increases cAMP levels in most basal amygdala glutamatergic neurons to control learning.

Dopaminergic inputs to basal amygdala (BA) instruct learning of motivational salience. This learning depends on intracellular plasticity signals such as cyclic adenosine monophosphate (cAMP), which is regulated by activation of dopamine receptors. We examine the dynamics of dopamine release and downstream signaling during multiple salient events occurring within tens of seconds. We perform real-time tracking and manipulation of cAMP in BA neurons invitro and invivo. Optogenetically evoked release of dopamine drives proportional increases in cAMP in almost all BA glutamatergic neurons, suggesting widespread actions of dopamine across neurons preferring positive or negative valence. This cAMP response decreases across trials with short intertrial intervals owing to depression of dopamine release. No such depression is evident when photostimulating cAMP production directly. cAMP and protein kinase A responses to repeated appetitive or aversive stimuli also exhibit pronounced depression. Thus, history-dependent dynamics of dopamine and cAMP may regulate learning of temporally clustered, salient stimuli.

Anhedonia in Anxiety Disorders.

Humans, like other animals, are fundamentally motivated to pursue rewarding outcomes and avoid aversive ones. Anxiety disorders are conceptualized, defined, and treated based on heightened sensitivity to perceived aversive outcomes, including imminent threats as well as those that are uncertain yet could occur in the future. Avoidance is the central strategy used to mitigate anticipated aversive outcomes - often at the cost of sacrificing potential rewards and hindering people from obtaining desired outcomes. It is for these reasons that people are often motivated to seek treatment. In this chapter, we consider whether and how anhedonia - the loss of interest in pursuing and/or reduced responsiveness to rewarding outcomes - may serve as a barrier to recovering from clinically impairing anxiety. Increasingly recognized as a prominent symptom in many individuals with elevated anxiety, anhedonia is not explicitly considered within prevailing theoretical models or treatment approaches of anxiety. Our goal, therefore, is to review what is known about anhedonia within the anxiety disorders and then integrate this knowledge into a functional perspective to consider how anhedonia could maintain anxiety and limit treatment response. Our overarching thesis is that anhedonia disrupts the key processes that are central to supporting anxiety recovery. We end this chapter by considering how explicitly targeting anhedonia in treatment can optimize outcomes for anxiety disorders.

Avoiding a feared stimulus: Modelling costly avoidance of learnt fear in a sensory preconditioning paradigm

Avoidance of learnt fear prevents the onset of a feared stimulus and the threat that follows. In anxiety-related disorders, it turns pathological given its cost and persistence in the absence of realistic threat. The current study examined the acquisition of costly avoidance of learnt fear in healthy individuals (n = 45), via a sensory preconditioning paradigm. Two neutral preconditioning stimuli (PSs) were paired with two neutral conditioned stimuli (CSs). One CS then came to predict an aversive outcome whereas the other CS came to predict safety. In test, participants engaged in stronger avoidance to the PS associated with the fear-related CS than the PS associated with the safety-related CS. Of note, executing behavioral avoidance led to missing out a competing reward, thus rendering avoidance costly. The results also provide preliminary evidence that threat anticipation and a negative change in valence play a role in driving costly avoidance of learnt fear. Future studies should examine how avoidance of learnt fear maintains pathological anxiety.

Imagery Rescripting Versus Extinction: Distinct and Combined Effects on Expectancy and Revaluation Learning

Anxiety disorders are effectively treated with exposure therapy, but relapse remains high. Fear may reinstate after reoccurrence of the negative event because the expectancy of the aversive outcome (unconditioned stimulus [US]) is adjusted but not its evaluation. Imagery rescripting (ImRs) is an intervention that is proposed to work through revaluation of the US. The aim of our preregistered study was to test the effects of ImRs and extinction on US expectancy and US revaluation. Day 1 ( n = 106) consisted of acquisition with an aversive film clip as US. The manipulation (ImRs + extinction, extinction-only, or ImRs-only) took place on Day 2. Reinstatement of fear was tested on Day 3. Results showed expectancy learning in both extinction conditions but not in the ImRs-only condition and no enhanced revaluation learning in ImRs. The combination of ImRs and extinction slowed down extinction but did not protect against reinstatement, which pleads in favor of stand-alone interventions in clinical practice.

Parenting in a Pandemic: Parental stress, anxiety and depression among parents during the government-initiated physical distancing measures following the first wave of COVID-19.

Drawing on the tenets of family stress theory, the aim of this study is to examine parents' perceived stress, symptoms of anxiety, depression, and associated risk- and protective factors across demographic subgroups during in the first wave of the COVID-19 pandemic. Norwegian parents (N=2868; 79.5% mothers) with >1 child under 18years of age completed an online survey two weeks after the implementation of government-initiated distancing measures. The survey includes measures of COVID-related risk factors (parental stress, burnout, depression, anxiety, anger of parents towards children, difficulty working from home, and positive beliefs about worry) and protective factors (self-efficacy and social support). Mothers, parents living with more than one child, and parents with a psychiatric diagnosis reported greater levels of parental stress, more burnout, and more anger towards their children, as well as less social support. Almost 25% of the parents reported anxiety and depression that are clinically significant. Parents who followed distancing measures reported significantly higher distress. Anger of parents towards children explains 41% of the variation in parental stress. These findings indicate that parents have experienced symptoms of deteriorated mental health due to the COVID- 19 pandemic, including parental stress, anxiety, and depression. The study presents practical implications for meso- and macro-level policymaking and offers support to further the potential aims of public health and clinical interventions. Future studies to monitor long-term aversive mental health outcomes among parents are warranted.

The association between mnemonic discrimination ability and differential fear learning

Background and objectivesIt is important to be able to learn which stimuli in our surroundings predict aversive outcomes. To maintain emotional well-being, it is similarly important to be able to learn which stimuli predict safety. The ability to discriminate between stimuli that predict danger and safety has been suggested to not only have an emotional component, but also a cognitive one. One such candidate mechanism is mnemonic discrimination (MD), the ability to differentiate between two memories that are similar but not identical. In the present study, we wanted to examine if MD performance helps to explain inter-individual differences in the ability to acquire a differentiated fear response during fear conditioning. MethodsParticipants performed a task assessing MD ability, and then underwent a fear conditioning procedure. Fear responses were measured using skin conductance responses (SCRs). ResultsResults revealed no support for MD ability being associated with to which degree a differentiated fear response was acquired, or with the time needed to acquire such a response. LimitationsOur only outcome measurement was SCRs. Future studies need to include fear ratings, expectancy ratings and neural responses. Future studies also need to examine this using a stimulus material where the conditioned stimulus and the safety stimulus are more difficult to distinguish from each other. ConclusionsIf MD ability has a role in inhibiting overgeneralization of fear learning, this does not seem to be driven by MD already during the initial learning.

You do it to yourself: Attentional capture by threat-signaling stimuli persists even when entirely counterproductive.

Recent research has demonstrated a counterproductive attentional bias toward threat-related stimuli: under conditions in which fixating on a color distractor stimulus sometimes resulted in an immediate shock, participants were nevertheless more likely to look at this threat-related distractor than a neutral distractor matched for physical salience. However, participants in that prior research may not have realized that their own actions caused delivery of aversive outcomes, such that monitoring for the threat-related distractor may not have been counterproductive from participants' perspective. In Experiment 1 of the current study, we demonstrate that the attentional bias to the threat-related distractor persists (and indeed, becomes stronger) when participants are made explicitly aware that looking at this stimulus is the sole cause of aversive events, which are otherwise avoidable. In Experiment 2 we replicate the bias in informed participants under conditions in which there is additional (reward-driven) motivation to avoid attending to distractors. Taken together with prior findings, the observation of an attentional bias toward the threat-related distractor under these explicitly counterproductive conditions provides strong support for the idea that threat-related stimuli are automatically prioritized by our attentional system. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Motivational Salience Guides Attention to Valuable and Threatening Stimuli: Evidence from Behavior and Functional Magnetic Resonance Imaging.

Rewarding and aversive outcomes have opposing effects on behavior, facilitating approach and avoidance, although we need to accurately anticipate each type of outcome to behave effectively. Attention is biased toward stimuli that have been learned to predict either type of outcome, and it remains an open question whether such orienting is driven by separate systems for value- and threat-based orienting or whether there exists a common underlying mechanism of attentional control driven by motivational salience. Here, we provide a direct comparison of the neural correlates of value- and threat-based attentional capture after associative learning. Across multiple measures of behavior and brain activation, our findings overwhelmingly support a motivational salience account of the control of attention. We conclude that there exists a core mechanism of experience-dependent attentional control driven by motivational salience and that prior characterizations of attention as being value driven or supporting threat monitoring need to be revisited.

Aversive outcomes impact human olfactory discrimination learning and generalization.

Learning associations between sensory stimuli and outcomes, and generalizing these associations to novel stimuli, are a fundamental feature of adaptive behavior. Given a noisy olfactory world, stimulus generalization holds unique relevance for the olfactory system. Recent studies suggest that aversive outcomes induce wider generalization curves by modulating discrimination thresholds, but evidence for similar processes in olfaction does not exist. Here, we use a novel olfactory discrimination learning paradigm to address the question of how outcome valence impacts associative learning and generalization in humans. Subjects underwent discrimination learning, where they learned to associate odor mixtures with either aversive (shock) or neutral (air puff) outcomes. We find better olfactory learning for odors associated with aversive compared to neutral outcomes. We further show that generalization gradients are also modulated by outcome valence, with the shock group exhibiting a steeper gradient. Computational modeling revealed that differences in generalization are driven by a narrower excitatory gradient in the shock group, indicating more discriminatory responses. These findings provide novel evidence that olfactory learning and generalization are strongly affected by the valence of outcomes. This adaptive mechanism allows for behavioral flexibility in novel situations with related stimuli and with outcomes of different valences. Because odor stimuli differ considerably from one encounter to the next, adaptive generalization may be especially important in the olfactory system. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Costly habitual avoidance is reduced by concurrent goal-directed approach in a modified devaluation paradigm

Avoidance habits potentially contribute to maintaining maladaptive, costly avoidance behaviors that persist in the absence of threat. However, experimental evidence about costly habitual avoidance is scarce. In two experiments, we tested whether extensively trained avoidance impairs the subsequent goal-directed approach of rewards. Healthy participants were extensively trained to avoid an aversive outcome by performing simple responses to distinct full-screen color stimuli. After the subsequent devaluation of the aversive outcome, participants received monetary rewards for correct responses to neutral object pictures, which were presented on top of the same full-screen colors. These approach responses were either compatible or incompatible with habitual avoidance responses. Notably, the full-screen colors were not relevant to inform approach responses. In Experiment 1, participants were not instructed about post-devaluation stimulus-response-reward contingencies. Accuracy was lower in habit-incompatible than in habit-compatible trials, indicating costly avoidance, whereas reaction times did not differ. In Experiment 2, contingencies were explicitly instructed. Accuracy differences disappeared, but reaction times were slower in habit-incompatible than in habit-compatible trials, indicating low-cost habitual avoidance tendencies. These findings suggest a small but consistent impact of habitual avoidance tendencies on subsequent goal-directed approach. Costly habitual responding could, however, be inhibited when competing goal-directed approach was easily realizable.