Temporally and anatomically specific contributions of the human amygdala to threat and safety learning.

Neural plasticity in subareas of the rodent amygdala is widely known to be essential for Pavlovian threat conditioning and safety learning. However, less consistent results have been observed in human neuroimaging studies. Here, we identify and test three important factors that may contribute to these discrepancies: the temporal profile of amygdala response in threat conditioning, the anatomical specificity of amygdala responses during threat conditioning and safety learning, and insufficient power to identify these responses. We combined data across multiple studies using a well-validated human threat conditioning paradigm to examine amygdala involvement during threat conditioning and safety learning. In 601 humans, we show that two amygdala subregions tracked the conditioned stimulus with aversive shock during early conditioning while only one demonstrated delayed responding to a stimulus not paired with shock. Our findings identify cross-species similarities in temporal- and anatomical-specific amygdala contributions to threat and safety learning, affirm human amygdala involvement in associative learning and highlight important factors for future associative learning research in humans.

Cumulative lifetime stressor exposure assessed by the STRAIN predicts economic ambiguity aversion.

Uncertainty is inherent in most decisions humans make. Economists distinguish between two types of decision-making under non-certain conditions: those involving risk (i.e., known outcome probabilities) and those that involve ambiguity (i.e., unknown outcome probabilities). Prior research has identified individual differences that explain risk preferences, but little is known about factors associated with ambiguity aversion. Here, we hypothesized that cumulative exposure to major psychosocial stressors over the lifespan might be one factor that predicts individuals' ambiguity aversion. Across two studies (Study 1: n = 58, Mage = 25.7; Study 2: n = 188, Mage = 39.81), we used a comprehensive lifetime stressor exposure inventory (i.e., the Stress and Adversity Inventory for Adults, or STRAIN) and a standard economic approach to quantify risk and ambiguity preferences. Greater lifetime stressor exposure as measured by the STRAIN, particularly in early life, was associated with higher aversion to ambiguity but not risk preferences.

Reappraisal-but not Suppression-Tendencies Determine Negativity Bias After Laboratory and Real-World Stress Exposure.

Higher reactivity to stress exposure is associated with an increased tendency to appraise ambiguous stimuli as negative. However, it remains unknown whether tendencies to use emotion regulation strategies-such as cognitive reappraisal, which involves altering the meaning or relevance of affective stimuli-can shape individual differences regarding how stress affects perceptions of ambiguity. Here, we examined whether increased reappraisal use is one factor that can determine whether stress exposure induces increased negativity bias. In Study 1, healthy participants (n = 43) rated the valence of emotionally ambiguous (surprised) faces before and after an acute stress or control manipulation and reported reappraisal habits. Increased negativity ratings were milder for stressed individuals that reported more habitual reappraisal use. In Study 2 (n = 97), we extended this investigation to real-world perceived stress before and during the COVID-19 pandemic. We found that reappraisal tendency moderates the relationship between perceived stress and increased negativity bias. Collectively, these findings suggest that the propensity to reappraise determines negativity bias when evaluating ambiguity under stress. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42761-021-00059-5.

Quantifying the subjective cost of self-control in humans.

Since Odysseus committed to resisting the Sirens, mechanisms to limit self-control failure have been a central feature of human behavior. Psychologists have long argued that the use of self-control is an effortful process and, more recently, that its failure arises when the cognitive costs of self-control outweigh its perceived benefits. In a similar way, economists have argued that sophisticated choosers can adopt "precommitment strategies" that tie the hands of their future selves in order to reduce these costs. Yet, we still lack an empirical tool to quantify and demonstrate the cost of self-control. Here, we develop and validate an economic decision-making task to quantify the subjective cost of self-control by determining the monetary cost a person is willing to incur in order to eliminate the need for self-control. We find that humans will pay to avoid having to exert self-control in a way that scales with increasing levels of temptation and that these costs appear to be modulated both by motivational incentives and stress exposure. Our psychophysical approach allows us to index moment-to-moment self-control costs at the within-subject level, validating important theoretical work across multiple disciplines and opening avenues of self-control research in healthy and clinical populations.

Evidence for a minimal role of stimulus awareness in reversal of threat learning.

In an ever-changing environment, survival depends on learning which stimuli represent threat, and also on updating such associations when circumstances shift. It has been claimed that humans can acquire physiological responses to threat-associated stimuli even when they are unaware of them, but the role of awareness in updating threat contingencies remains unknown. This complex process-generating novel responses while suppressing learned ones-relies on distinct neural mechanisms from initial learning, and has only been shown with awareness. Can it occur unconsciously? Here, we present evidence that threat reversal may not require awareness. Participants underwent classical threat conditioning to visual stimuli that were suppressed from awareness. One of two images was paired with an electric shock; halfway through the experiment, contingencies were reversed and the shock was paired with the other image. Despite variations in suppression across participants, we found that physiological responses reflected changes in stimulus-threat pairings independently of stimulus awareness. These findings suggest that unconscious affective processing may be sufficiently flexible to adapt to changing circumstances.

Trait impulsivity and acute stress interact to influence choice and decision speed during multi-stage decision-making.

Impulsivity and stress exposure are two factors that are associated with changes in reward-related behavior in ways that are relevant to both healthy and maladaptive decision-making. Nonetheless, little empirical work has examined the possible independent and joint effects of these factors upon reward learning. Here, we sought to examine how trait impulsivity and acute stress exposure affect participants' choice behavior and decision speed in a two-stage sequential reinforcement-learning task. We found that more impulsive participants were more likely to repeat second-stage choices after previous reward, irrespective of stress condition. Exposure to stress, on the other hand, was associated with an increased tendency to repeat second-stage choices independent of whether these choices previously led to a reward, and this tendency was exacerbated in more impulsive individuals. Such interaction effects between stress and impulsivity were also found on decision speed. Stress and impulsivity levels interacted to drive faster choices overall (again irrespective of reward) at both task stages, while reward received on the previous trial slowed subsequent first-stage choices, particularly among impulsive individuals under stress. Collectively, our results reveal novel, largely interactive effects of trait impulsivity and stress exposure and suggest that stress may reveal individual differences in decision-making tied to impulsivity that are not readily apparent in the absence of stress.

Cortisol responses enhance negative valence perception for ambiguous facial expressions.

Stress exposure elicits a prolonged neuroendocrine response, marked by cortisol release, which can influence important forms of affective decision-making. Identifying how stress reactivity shapes subjective biases in decisions about emotional ambiguity (i.e., valence bias) provides insight into the role stress plays in basic affective processing for healthy and clinical populations alike. Here, we sought to examine how stress reactivity affects valence decisions about emotional ambiguity. Given that stress prioritizes automatic emotional processing which, in the context of valence bias, is associated with increased negativity, we tested how individual differences in acute stress responses influence valence bias and how this decision process evolves over time. Participants provided baseline ratings of clear (happy, angry) and ambiguous (surprised) facial expressions, then re-rated similar stimuli after undergoing an acute stress or control manipulation a week later; salivary cortisol was measured throughout to assay stress reactivity. Elevations in cortisol were associated with more negative ratings of surprised faces, and with more direct response trajectories toward negative ratings (i.e., less response competition). These effects were selectively driven by the stress group, evidencing that increased stress reactivity is associated with a stronger negativity bias during ambiguous affective decision-making.

Stress attenuates the flexible updating of aversive value.

In a dynamic environment, sources of threat or safety can unexpectedly change, requiring the flexible updating of stimulus-outcome associations that promote adaptive behavior. However, aversive contexts in which we are required to update predictions of threat are often marked by stress. Acute stress is thought to reduce behavioral flexibility, yet its influence on the modulation of aversive value has not been well characterized. Given that stress exposure is a prominent risk factor for anxiety and trauma-related disorders marked by persistent, inflexible responses to threat, here we examined how acute stress affects the flexible updating of threat responses. Participants completed an aversive learning task, in which one stimulus was probabilistically associated with an electric shock, while the other stimulus signaled safety. A day later, participants underwent an acute stress or control manipulation before completing a reversal learning task during which the original stimulus-outcome contingencies switched. Skin conductance and neuroendocrine responses provided indices of sympathetic arousal and stress responses, respectively. Despite equivalent initial learning, stressed participants showed marked impairments in reversal learning relative to controls. Additionally, reversal learning deficits across participants were related to heightened levels of alpha-amylase, a marker of noradrenergic activity. Finally, fitting arousal data to a computational reinforcement learning model revealed that stress-induced reversal learning deficits emerged from stress-specific changes in the weight assigned to prediction error signals, disrupting the adaptive adjustment of learning rates. Our findings provide insight into how stress renders individuals less sensitive to changes in aversive reinforcement and have implications for understanding clinical conditions marked by stress-related psychopathology.

Acute stress does not affect risky monetary decision-making.

The ubiquitous and intense nature of stress responses necessitate that we understand how they affect decision-making. Despite a number of studies examining risky decision-making under stress, it is as yet unclear whether and in what way stress alters the underlying processes that shape our choices. This is in part because previous studies have not separated and quantified dissociable valuation and decision-making processes that can affect choices of risky options, including risk attitudes, loss aversion, and choice consistency, among others. Here, in a large, fully-crossed two-day within-subjects design, we examined how acute stress alters risky decision-making. On each day, 120 participants completed either the cold pressor test or a control manipulation with equal probability, followed by a risky decision-making task. Stress responses were assessed with salivary cortisol. We fit an econometric model to choices that dissociated risk attitudes, loss aversion, and choice consistency using hierarchical Bayesian techniques to both pool data and allow heterogeneity in decision-making. Acute stress was found to have no effect on risk attitudes, loss aversion, or choice consistency, though participants did become more loss averse and more consistent on the second day relative to the first. In the context of an inconsistent previous literature on risk and acute stress, our findings provide strong and specific evidence that acute stress does not affect risk attitudes, loss aversion, or consistency in risky monetary decision-making.

The Effects of Social Context and Acute Stress on Decision Making Under Uncertainty.

Uncertainty preferences are typically studied in neutral, nonsocial contexts. This approach, however, fails to capture the dynamic factors that influence choices under uncertainty in the real world. Our goal was twofold: to test whether uncertainty valuation is similar across social and nonsocial contexts, and to investigate the effects of acute stress on uncertainty preferences. Subjects completed matched gambling and trust games following either a control or a stress manipulation. Those who were not under stress exhibited no differences between the amount of money gambled and the amount of money entrusted to partners. In comparison, stressed subjects gambled more money but entrusted less money to partners. We further found that irrespective of stress, subjects were highly attuned to irrelevant feedback in the nonsocial, gambling context, believing that every loss led to a greater chance of winning (the gamblers' fallacy). However, when deciding to trust a stranger, control subjects behaved rationally, treating each new interaction as independent. Stress compromised this adaptive behavior, increasing sensitivity to irrelevant social feedback.

The influence of acute stress on the regulation of conditioned fear.

Fear learning and regulation is a prominent model for describing the pathogenesis of anxiety disorders and stress-related psychopathology. Fear expression can be modulated using a number of regulatory strategies, including extinction, cognitive emotion regulation, avoidance strategies and reconsolidation. In this review, we examine research investigating the effects of acute stress and stress hormones on these regulatory techniques. We focus on what is known about the impact of stress on the ability to flexibly regulate fear responses that are acquired through Pavlovian fear conditioning. Our primary aim is to explore the impact of stress on fear regulation in humans. Given this, we focus on techniques where stress has been linked to alterations of fear regulation in humans (extinction and emotion regulation), and briefly discuss other techniques (avoidance and reconsolidation) where the impact of stress or stress hormones have been mainly explored in animal models. These investigations reveal that acute stress may impair the persistent inhibition of fear, presumably by altering prefrontal cortex function. Characterizing the effects of stress on fear regulation is critical for understanding the boundaries within which existing regulation strategies are viable in everyday life and can better inform treatment options for those who suffer from anxiety and stress-related psychopathology.

Young and old Pavlovian fear memories can be modified with extinction training during reconsolidation in humans.

Extinction training during reconsolidation has been shown to persistently diminish conditioned fear responses across species. We investigated in humans if older fear memories can benefit similarly. Using a Pavlovian fear conditioning paradigm we compared standard extinction and extinction after memory reactivation 1 d or 7 d following acquisition. Participants who underwent extinction during reconsolidation showed no evidence of fear recovery, whereas fear responses returned in participants who underwent standard extinction. We observed this effect in young and old fear memories. Extending the beneficial use of reconsolidation to older fear memories in humans is promising for therapeutic applications.

Acute stress impairs the retrieval of extinction memory in humans.

Extinction training is a form of inhibitory learning that allows an organism to associate a previously aversive cue with a new, safe outcome. Extinction does not erase a fear association, but instead creates a competing association that may or may not be retrieved when a cue is subsequently encountered. Characterizing the conditions under which extinction learning is expressed is important to enhancing the treatment of anxiety disorders that rely on extinction-based exposure therapy as a primary treatment technique. The ventromedial prefrontal cortex, which plays a critical role in the expression of extinction memory, has been shown to be functionally impaired after stress exposure. Further, recent work in rodents has demonstrated that exposure to stress leads to deficits in extinction retrieval, although this has yet to be tested in humans. To explore how stress might influence extinction retrieval in humans, participants underwent a differential aversive learning paradigm, in which one image was probabilistically paired with an aversive shock while the other image denoted safety. Extinction training directly followed, at which point reinforcement was omitted. A day later, participants returned to the lab and either completed an acute stress manipulation (i.e., cold pressor), or a control task, before undergoing an extinction retrieval test. Skin conductance responses and salivary cortisol concentrations were measured throughout each session as indices of fear arousal and neuroendocrine stress response, respectively. The efficacy of our stress induction was established by observing significant increases in cortisol for the stress condition only. We examined extinction retrieval by comparing conditioned responses during the last trial of extinction (day 1) with that of the first trial of re-extinction (day 2). Groups did not differ on initial fear acquisition or extinction, however, a day later participants in the stress group (n=27) demonstrated significantly lower extinction retrieval (i.e., greater fear recovery) than those in the control group (n=25). Our results suggest that acute stress impairs the retrieval of extinction learning and offers insight into why treatment strategies used in the clinic may be challenging to recruit in daily life where stress is pervasive.

Working-memory capacity protects model-based learning from stress.

Accounts of decision-making have long posited the operation of separate, competing valuation systems in the control of choice behavior. Recent theoretical and experimental advances suggest that this classic distinction between habitual and goal-directed (or more generally, automatic and controlled) choice may arise from two computational strategies for reinforcement learning, called model-free and model-based learning. Popular neurocomputational accounts of reward processing emphasize the involvement of the dopaminergic system in model-free learning and prefrontal, central executive-dependent control systems in model-based choice. Here we hypothesized that the hypothalamic-pituitary-adrenal (HPA) axis stress response--believed to have detrimental effects on prefrontal cortex function--should selectively attenuate model-based contributions to behavior. To test this, we paired an acute stressor with a sequential decision-making task that affords distinguishing the relative contributions of the two learning strategies. We assessed baseline working-memory (WM) capacity and used salivary cortisol levels to measure HPA axis stress response. We found that stress response attenuates the contribution of model-based, but not model-free, contributions to behavior. Moreover, stress-induced behavioral changes were modulated by individual WM capacity, such that low-WM-capacity individuals were more susceptible to detrimental stress effects than high-WM-capacity individuals. These results enrich existing accounts of the interplay between acute stress, working memory, and prefrontal function and suggest that executive function may be protective against the deleterious effects of acute stress.

Cognitive emotion regulation fails the stress test.

Cognitive emotion regulation has been widely shown in the laboratory to be an effective way to alter the nature of emotional responses. Despite its success in experimental contexts, however, we often fail to use these strategies in everyday life where stress is pervasive. The successful execution of cognitive regulation relies on intact executive functioning and engagement of the prefrontal cortex, both of which are rapidly impaired by the deleterious effects of stress. Because it is specifically under stressful conditions that we may benefit most from such deliberate forms of emotion regulation, we tested the efficacy of cognitive regulation after stress exposure. Participants first underwent fear-conditioning, where they learned that one stimulus (CS+) predicted an aversive outcome but another predicted a neutral outcome (CS-). Cognitive regulation training directly followed where participants were taught to regulate fear responses to the aversive stimulus. The next day, participants underwent an acute stress induction or a control task before repeating the fear-conditioning task using these newly acquired regulation skills. Skin conductance served as an index of fear arousal, and salivary α-amylase and cortisol concentrations were assayed as neuroendocrine markers of stress response. Although groups showed no differences in fear arousal during initial fear learning, nonstressed participants demonstrated robust fear reduction following regulation training, whereas stressed participants showed no such reduction. Our results suggest that stress markedly impairs the cognitive regulation of emotion and highlights critical limitations of this technique to control affective responses under stress.

Extinction training during the reconsolidation window prevents recovery of fear.

Fear is maladaptive when it persists long after circumstances have become safe. It is therefore crucial to develop an approach that persistently prevents the return of fear. Pavlovian fear-conditioning paradigms are commonly employed to create a controlled, novel fear association in the laboratory. After pairing an innocuous stimulus (conditioned stimulus, CS) with an aversive outcome (unconditioned stimulus, US) we can elicit a fear response (conditioned response, or CR) by presenting just the stimulus alone. Once fear is acquired, it can be diminished using extinction training, whereby the conditioned stimulus is repeatedly presented without the aversive outcome until fear is no longer expressed. This inhibitory learning creates a new, safe representation for the CS, which competes for expression with the original fear memory. Although extinction is effective at inhibiting fear, it is not permanent. Fear can spontaneously recover with the passage of time. Exposure to stress or returning to the context of initial learning can also cause fear to resurface. Our protocol addresses the transient nature of extinction by targeting the reconsolidation window to modify emotional memory in a more permanent manner. Ample evidence suggests that reactivating a consolidated memory returns it to a labile state, during which the memory is again susceptible to interference. This window of opportunity appears to open shortly after reactivation and close approximately 6 hrs later, although this may vary depending on the strength and age of the memory. By allowing new information to incorporate into the original memory trace, this memory may be updated as it reconsolidates. Studies involving non-human animals have successfully blocked the expression of fear memory by introducing pharmacological manipulations within the reconsolidation window, however, most agents used are either toxic to humans or show equivocal effects when used in human studies. Our protocol addresses these challenges by offering an effective, yet non-invasive, behavioral manipulation that is safe for humans. By prompting fear memory retrieval prior to extinction, we essentially trigger the reconsolidation process, allowing new safety information (i.e., extinction) to be incorporated while the fear memory is still susceptible to interference. A recent study employing this behavioral manipulation in rats has successfully blocked fear memory using these temporal parameters. Additional studies in humans have demonstrated that introducing new information after the retrieval of previously consolidated motor, episodic, or declarative memories leads to interference with the original memory trace. We outline below a novel protocol used to block fear recovery in humans.