Early hypervigilance and later avoidance: Event-related potentials track the processing of threatening stimuli in anxiety.

Avoidance behavior is a core symptom of anxiety disorders that may hinder adaptation. Anxiety disorders are heterogeneous and previous research suggests to decompose anxiety into two dimensions: anxious apprehension and anxious arousal. How these two dimensions are associated with avoidance of and exposure to threatening stimuli, as well as their accompanying neural processes, is barely understood. We examined threat processing using event-related potentials (N1, LPP) from 134 individuals considering the influence of anxiety dimensions. During a two-phase picture-viewing task the participants watched neutral and threatening pictures, which they were instructed to either avoid or attend to during repeated presentations. Results showed that threatening compared to neutral pictures were associated with increased attention allocation (N1) and in-depth processing (LPP), modulated by task-instructions (lower during avoidance). Further, increased anxious apprehension was associated with heightened automatic attention (increased N1), followed by reduced LPP amplitudes for threatening pictures suggesting reduced in-depth processing. During re-exposure, threatening pictures were associated with increased in-depth processing, with no difference between previously avoided and maintained pictures. Together, these results illustrate that avoidance and high anxious apprehension seem to lead to similar neural changes in the processing of aversive images that may conflict with long-term adaptation.

Neural signature of delayed fear generalization under stress.

Although the generalization of fear to stimuli resembling a threatening stimulus is an adaptive mechanism, fear overgeneralization is maladaptive and thought to play a key role in anxiety-related disorders. Since there is typically a delay between an initial fear experience and a situation in which fear (over)generalization may occur, we assessed delayed fear generalization and its neural signature. Moreover, as stress is known to affect fear learning, we further tested whether acute stress modulates fear generalization. Therefore, we conducted a two-day fear generalization study, with initial fear acquisition on Day 1 and a fear generalization test after a 24-hr delay in the MRI scanner. Prior to fear generalization testing, participants were exposed to a stressor or a control manipulation. Our behavioral data showed the expected generalization of fear. At a neural level, fear generalization was accompanied by increased fear-signaling for stimuli that resembled the conditioned stimulus in the bilateral insula and frontal operculum, whereas activity declined in frontal, hippocampal, and temporal regions, including the ventromedial prefrontal cortex, as stimuli became more similar to the conditioned stimulus. Importantly, stress did not modulate fear generalization, neither on a behavioral nor on a neural level. Interestingly, in an explorative comparison to two other studies that used the same paradigm but tested generalization immediately after acquisition, we observed increased fear generalization in the delayed relative to the immediate generalization test. In sum, our results suggest that stress leaves fear generalization and its neural signature unaffected but that a temporal delay might increase the extent to which fear responses are generalized to stimuli resembling the threatening stimulus.

Acute stress leaves fear generalization in healthy individuals intact.

Because threatening situations often occur in a similar manner, the generalization of fear to similar situations is adaptive and can avoid harm to the organism. However, the overgeneralization of fear to harmless stimuli is maladaptive and assumed to contribute to anxiety disorders. Thus, elucidating factors that may modulate fear (over)generalization is important. Based on the known effects of acute stress on learning, which are at least partly due to noradrenergic arousal, we investigated whether stress may promote fear overgeneralization and whether we could counteract this effect by reducing noradrenergic arousal. In a placebo-controlled, double-blind, between-subjects design, 120 healthy participants underwent a fear-conditioning procedure on Day 1. Approximately 24 hours later, participants received orally either a placebo or the beta-adrenergic receptor antagonist propranolol and were exposed to a stress or control manipulation before they completed a test of fear generalization. Skin conductance responses as well as explicit rating data showed a successful acquisition of conditioned fear on Day 1 and a pronounced fear generalization 24 hours later. Although physiological data confirmed the successful stress manipulation and reduction of noradrenergic arousal, the extent of fear generalization remained unaffected by stress and propranolol. The absence of a stress effect on fear generalization was confirmed by a second study and a Bayesian analysis across both data sets. Our findings suggest that acute stress leaves fear generalization processes intact, at least in a sample of healthy, young individuals.

Noradrenergic stimulation increases fear memory expression.

Fear responses are typically not limited to the actual threatening stimulus but generalize to other stimuli resembling the threatening stimulus. Although this fear generalization is generally adaptive, fear overgeneralization is maladaptive and assumed to contribute to anxiety disorders. Despite the clinical relevance of fear (over)generalization, how the extent of fear generalization is modulated remains not well understood. Based on the known effects of stress on learning and memory, we tested here the impact of major stress mediators, glucocorticoids and noradrenergic arousal, on fear generalization. In a laboratory-based, placebo-controlled, double-blind, between-subject design, 125 healthy participants first underwent a fear conditioning procedure. About 24 h later, participants received orally either a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine, leading to increased noradrenergic stimulation, or both drugs before a test of fear generalization. Skin conductance responses as well as explicit rating data revealed that yohimbine intake led to enhanced fear memory expression, i.e. an enhanced responding to the CS+ but not to stimuli resembling the CS+. Moreover, neither enhanced safety learning nor a mere enhancement of perceptual discrimination ability could explain this result. In contrast to yohimbine, hydrocortisone had no significant effect on fear memory. These findings suggest that noradrenergic arousal strengthens fear memory expression and have important implications for mental disorders in which the overgeneralization of conditioned fear is prominent.

Stress-induced modulation of multiple memory systems during retrieval requires noradrenergic arousal.

Stress has been shown to favor dorsal striatum-dependent 'habit' memory over hippocampus-dependent 'cognitive' memory during learning. Here, we investigated whether stress may modulate the engagement of these 'cognitive' and 'habit' systems also during memory retrieval and if so, whether such a stress-induced shift in the control of memory retrieval depends on noradrenergic activation. To this end, participants acquired a probabilistic classification learning (PCL) task that can be solved by both the 'cognitive' and the 'habit' system, reflected in the distinct behavioral strategies. Twenty-four hours later, participants received either the beta-adrenergic receptor antagonist propranolol or a placebo before they underwent a psychosocial stressor or a non-stressful control manipulation, followed by a retrieval version of the PCL task. Overall, participants showed a practice-dependent shift from 'cognitive' to 'habit' memory. Stressed participants that had received a placebo fell back to a 'cognitive' strategy during retrieval, which was linked to an impairment in retrieval performance. Propranolol blocked this stress-induced shift towards the less efficient strategy. Moreover, our results showed that salivary cortisol was related to the retrieval strategy only when paralleled by increased autonomic arousal. Together, these results indicate that stress effects on the modulation of multiple memory system during retrieval necessitate noradrenergic arousal, with relevant implications for retrieval performance under stress.

Blocking under stress: Sustained attention to stimuli without predictive value?

Learning is blocked when a stimulus is followed by an outcome that is identical to what was expected and thus contains no new information. This classic 'blocking' effect exemplifies that learning is driven by the predictive value of stimuli, which in turn should guide the allocation of attentional resources. Stress is known to be a powerful modulator of learning and memory. However, whether stress may affect attentional processing during predictive learning is largely unknown. Here, we combined electroencephalography and eye-tracking with an experimental stress manipulation and a fear conditioning paradigm designed to probe the blocking effect, to determine if and how stress impacts efficient attentional processing during predictive learning. Participants' explicit ratings indicated, irrespective of stress, a blocking effect. The control group further showed preferential attentional processing of predictive vs. unpredictive stimuli, reflected in differential fixation durations and a differential N2pc. Stress abolished this differentiation and led even to sustained attention, indicated by higher late positive potentials, to stimuli with low predictive value. Moreover, stress resulted in an overall increase in the P3b during the blocking phase, suggesting increased attentional processing, presumably due to impaired access to previously learned associations. Together, our results suggest that while control participants paid particular attention to predictive stimuli and reduced attention to unpredictive stimuli, in line with the classic blocking effect, stress before learning reduced this preferential processing. Thus, the present findings highlight the role of attention allocation for predictive fear learning and suggest that stress may impair efficient information processing against the background of prior experiences.

Glucocorticoids, Noradrenergic Arousal, and the Control of Memory Retrieval.

Glucocorticoids and noradrenaline can enhance memory consolidation but impair memory retrieval. Beyond their effects on quantitative memory performance, these major stress mediators bias the engagement of multiple memory systems toward "habitual" control during learning. However, if and how glucocorticoids and noradrenaline may also affect which memory system is recruited during recall, thereby affecting the control of retrieval, remain largely unknown. To address these questions, we trained healthy participants in a probabilistic classification learning task, which can be supported both by cognitive and habitual strategies. Approximately 24 hr later, participants received a placebo, hydrocortisone, yohimbine (an α2-adrenoceptor antagonist increasing noradrenergic stimulation), or both drugs before they completed a recall test for the probabilistic classification learning task. During training, all groups showed a practice-dependent shift toward more habitual strategies, reflecting an "automatization" of behavior. In the recall test, after a night of sleep, this automatization was even more pronounced in the placebo group, most likely due to offline consolidation processes and with beneficial effects on recall performance. Hydrocortisone or yohimbine intake abolished this further automatization, preventing the shift to a more efficient memory system and leading, in particular in the hydrocortisone group, to impaired recall performance. Our results suggest that glucocorticoids and noradrenergic stimulation may modulate the engagement of different strategies at recall and link the well-known stress hormone-induced retrieval deficit to a change in the system controlling memory retrieval.