Standard Extinction Research Articles

Leveraging occasional reinforced extinction via mental imagery of the unconditioned stimulus to optimize extinction learning

Occasionally presenting the unconditioned stimulus (US) during extinction training (occasional reinforced extinction, ORE) either unpaired or paired with the conditioned stimulus (CS) provides initial evidence for a less pronounced return of fear. However, translating this approach into clinical practice is challenging due to ethical and practical concerns of exposing patients to the original USs. The present study investigated extinction of fear responses in a novel approach employing ORE using vivid fear imagery of the US instead of actually exposing to it. Three experimental groups underwent differential fear conditioning. Subsequently, participants either received a non-reinforced (standard extinction, N = 25), occasional paired (N = 26), or occasional unpaired (N = 25) reinforced extinction training, followed by assessments for spontaneous recovery, reinstatement, and reacquisition of fear responses. Response patterns during spontaneous recovery, reinstatement and reacquisition showed no benefit from either paired or unpaired imaginative ORE. The current findings suggest that incorporating fear imagery of the US in ORE so far does not result in reducing the return of fear. Further investigation is needed to determine whether imaginal ORE with adjustments could still be a readily applicable strategy for translating the ORE approach into clinical practice.

Between Scylla and Charybdis: Fixed-Ratio Avoidance Response Effort and Unavoidable Shock Extinction in Humans

Avoidance of potential threat may become maladaptive when it is indiscriminate and resistant to change. Here, we investigated the resistance to change of high and low avoidance response effort when avoidance extinction involved unavoidable presentations of the aversive event (shock) in humans. Following fear conditioning, participants prevented upcoming shock delivery by responding on high (i.e., fixed ratio, FR-20) and low (FR-5) negative reinforcement schedules. Next, noneliminable shock was used for an avoidance extinction procedure whereby responding was followed by, rather than prevented, shock. During a subsequent standard extinction and response prevention test phase, we found that High effort (FR-20) avoidance would be more readily extinguished than Low effort (FR-5) avoidance. It was also predicted that fear, threat expectancy, and psychophysiological (skin conductance) responses would decrease on avoidable trials and increase on unavoidable trials before extinguishing to low levels. It was found that in the final extinction re-test phase when avoidance was possible, responding increased, particularly for low effort cues. Both fear and expectancy remained high. Individual differences on clinically relevant measures of trait anxiety, intolerance of uncertainty and experiential avoidance were associated with greater levels of fear and threat expectancy. Overall, unavoidable shock extinction may hold promise for further translational investigations of avoidance learning, extinction, and clinical treatment development.

The effect of gradual extinction training on the renewal of electrodermal conditional responses.

Extinction, the repeated presentation of a conditional stimulus (CS) without the unconditional stimulus (US), is the standard paradigm to reduce conditional responding acquired by the repeated pairing of CS and US in acquisition. However, this reduction of conditional responding is prone to relapse. In rodent fear-conditioning, gradual extinction, the fading out of CS-US pairings during extinction, has been shown to reduce the return of fear. The current study replicated the gradual extinction procedure in human fear conditioning and assessed whether it reduced the return of fear due to ABA renewal and reacquisition. During extinction, one group received standard extinction, a second received gradual extinction (increasing the spacing of USs presented after the 1st, 3rd, 6th, 10th, and 15th CS+ trials), and a third received reversed extinction training (decreasing the spacing of USs presented after the 1st, 6th, 10th, 13th, and 15th CS+ trials). Larger renewal and faster reacquisition of differential electrodermal responses to CS+ and CS- were expected after standard and reversed extinction than after gradual extinction training. The results were inconclusive due to the failure to find extinction of differential electrodermal responses and US expectancy ratings in both gradual and reversed extinction groups. Despite successful extinction in group standard, renewal was only observed in US expectancy. Visualization of US expectancy ratings during extinction suggested that potential identification of the US presentation patterns during extinction in the gradual and reversed groups delayed extinction learning.

Prediction error determines how memories are organized in the brain.

How is new information organized in memory? According to latent state theories, this is determined by the level of surprise, or prediction error, generated by the new information: a small prediction error leads to the updating of existing memory, large prediction error leads to encoding of a new memory. We tested this idea using a protocol in which rats were first conditioned to fear a stimulus paired with shock. The stimulus was then gradually extinguished by progressively reducing the shock intensity until the stimulus was presented alone. Consistent with latent state theories, this gradual extinction protocol (small prediction errors) was better than standard extinction (large prediction errors) in producing long-term suppression of fear responses, and the benefit of gradual extinction was due to updating of the conditioning memory with information about extinction. Thus, prediction error determines how new information is organized in memory, and latent state theories adequately describe the ways in which this occurs.

Occasional Reinforced Extinction as a Method for Relapse Prevention: A Critical Systematic Review and Future Directions

IntroductionExtinction is more vulnerable than the original acquisition memory, as relapse phenomena have systematically shown in the literature with different species and procedures. One strategy potentially useful to mitigate relapse is occasional reinforced extinction (ORE). In contrast to a standard extinction procedure, this strategy consists of the inclusion of a gradual and sparse number of conditioned stimulus–unconditioned stimulus pairings within the extinction phase. Here, we provide a comprehensive review of the available literature on ORE.MethodWe conducted a literature search using three databases (Web of Science, Scopus, and PsycInfo) in July 2022, with an additional citation search. We collected data on different variables of interest, like the relapse phenomena being studied, the outcome measures, or the specific effects obtained.ResultsA total of 350 studies were identified from the main database search, including 10 in the review. Five additional studies from the citation search were also included. The final sample consisted of 15 empirical reports. The observed procedural variability makes it difficult to evaluate the effectiveness of ORE to reduce different forms of relapse as the strategy has not consistently shown a general advantage over standard extinction.ConclusionThe current evidence assessing the effectiveness of ORE does not appear to be consistent, although there are plenty theoretical studies recommending and discussing the potential effectiveness of such technique. Moreover, the lack of conclusive laboratory evidence calls into question how general the potential benefits of its use in clinical settings would be.

Carbon Dioxide Reactivity Differentially Predicts Fear Expression After Extinction and Retrieval-Extinction in Rats

BackgroundCues present during a traumatic event may result in persistent fear responses. These responses can be attenuated through extinction learning, a core component of exposure therapy. Exposure/extinction is effective for some people, but not all. We recently demonstrated that carbon dioxide (CO2) reactivity predicts fear extinction memory and orexin activation and that orexin activation predicts fear extinction memory, which suggests that a CO2 challenge may enable identification of whether an individual is a good candidate for an extinction-based approach. Another method to attenuate conditioned responses, retrieval-extinction, renders the original associative memory labile via distinct neural mechanisms. The purpose of the current study was to examine whether we could replicate previous findings that retrieval-extinction is more effective than extinction at preventing the return of fear and that CO2 reactivity predicts fear memory after extinction. We also examined whether CO2 reactivity predicts fear memory after retrieval-extinction. MethodsMale rats first underwent a CO2 challenge and fear conditioning and were assigned to receive either standard extinction (n = 28) or retrieval-extinction (n = 28). Then, they underwent a long-term memory (LTM) test and a reinstatement test. ResultsWe found that retrieval-extinction resulted in lower freezing during extinction, LTM, and reinstatement than standard extinction. Using the best subset approach to linear regression, we found that CO2 reactivity predicted LTM after extinction and also predicted LTM after retrieval-extinction, although to a lesser degree. ConclusionsCO2 reactivity could be used as a screening tool to determine whether an individual may be a good candidate for an extinction-based therapeutic approach.

Extinction of negative conditioned stimulus valence in human fear conditioning

Fear conditioning is a common experimental paradigm for modelling the development, and exposure-based treatment, of anxiety disorders. Measures of fear such as threat-expectancy, physiological arousal, and fear ratings typically extinguish, however feared stimuli may still be evaluated negatively (i.e. retain negative valence). This systematic review provides the first investigation of the relationship between fear conditioning methodology and extinction of negative stimulus valence. Principal findings were that type of CS (conditioned stimulus) and the CS-US pairing (i.e. specific combination of CS and unconditioned stimulus) predicted extinction outcome. Extinction of absolute negative CS valence was always achieved with shape CSs; often achieved with low fear-relevant animals as CSs, and less frequently achieved with faces as CSs – particularly neutral faces paired with a shock US. Modified extinction procedures typically achieved the same outcome as standard extinction procedures, except for partially-reinforced extinction, which was less effective than standard extinction, and positive imagery training, which was more effective than standard extinction. Further studies are warranted to evaluate the influence of fear conditioning methodology on extinction of absolute negative CS valence.

An HST Study of the Substellar Population of NGC 2024

We performed an HST/WFC3-IR imaging survey of the young stellar cluster NGC 2024 in three filters probing the 1.4 μm H2O absorption feature, characteristic of the population of low-mass and substellar-mass objects down to a few Jupiter masses. We detect 812 point sources, 550 of them in all three filters with signal-to-noise ratio greater than 5. Using a distance-independent two-color diagram, we determine extinction values as high as A V ≃ 40. We also find that the change of effective wavelengths in our filters results in higher A V values as the reddening increases. Reconstructing a dereddened color–magnitude diagram, we derive a luminosity histogram both for the full sample of candidate cluster members and for an extinction-limited subsample containing the 50% of sources with A V ≲ 15. Assuming a standard extinction law like Cardelli et al. with a nominal R V = 3.1, we produce a luminosity function in good agreement with the one resulting from a Salpeter-like initial mass function for a 1 Myr isochrone. There is some evidence of an excess of luminous stars in the most embedded region. We posit that the correlation may be due to those sources being younger, and therefore overluminous, than the more evolved and less extincted cluster's stars. We compare our classification scheme based on the depth of the 1.4 μm photometric feature with the results from the spectroscopic survey of Levine et al., and we report a few peculiar sources and morphological features typical of the rich phenomenology commonly encountered in young star-forming regions.

Intermixed safety cues facilitate extinction retention in adult and adolescent mice

Extinction learning is tremendously adaptive as it allows an animal to adjust their behavior in a changing environment. Yet, extinction is not without limitations and fear often reemerges over time (i.e. spontaneous recovery). Relative to adults, adolescent rodents and humans are particularly prone to spontaneous recovery following extinction. In this study, we aimed to address whether combining methods of fear regulation (extinction and conditioned inhibition) can facilitate extinction retention. Early adolescent (29 days old, n = 81) and adult (70 days old, n = 80) mice underwent extinction with or without a safety cue present. Safety cue presentations were systematically varied to overlap with or alternate with fear cue presentations. We found that initial safety learning was faster in adolescent mice. In addition, intermixing safety cues into extinction reduced spontaneous recovery during a test two weeks later. The decrease in spontaneous recovery relative to a standard extinction protocol was greater in adolescents than adults. Together, our findings provide initial evidence that safety learning may be inherently stronger during adolescence. These results inform the parameters by which conditioned safety and extinction learning may be merged to augment the inhibition of fear. While methods to enhance fear regulation are valuable for any age, the potential to do so during adolescence is particularly striking.

Enhancing Associative Learning in Rats With a Computationally Designed Training Protocol

BackgroundLearning requires the activation of protein kinases with distinct temporal dynamics. In Aplysia, nonassociative learning can be enhanced by a computationally designed learning protocol with intertrial intervals (ITIs) that maximize the interaction between fast-activated PKA (protein kinase A) and slow-activated ERK (extracellular signal-regulated kinase). Whether a similar strategy can enhance associative learning in mammals is unknown. MethodsWe simulated 1000 training protocols with varying ITIs to predict an optimal protocol based on empirical data for PKA and ERK dynamics in rat hippocampus. Adult male rats received the optimal protocol or control protocols in auditory fear conditioning and fear extinction experiments. Immunohistochemistry was performed to evaluate pCREB (phosphorylated cAMP response element binding)\\protein levels in brain regions that have been implicated in fear acquisition. ResultsRats exposed to the optimal conditioning protocol with irregular ITIs exhibited impaired extinction memory acquisition within the session using a standard footshock intensity, and stronger fear memory retrieval and spontaneous recovery with a weaker footshock intensity, compared with rats that received massed or spaced conditioning protocols with fixed ITIs. Rats exposed to the optimal extinction protocol displayed improved extinction of contextual fear memory and reduced spontaneous recovery compared with rats that received standard extinction protocols. Moreover, the optimal conditioning protocol increased pCREB levels in the dentate gyrus of the dorsal hippocampus, suggesting enhanced induction of long-term potentiation. ConclusionsThese findings demonstrate that a computational model–driven behavioral intervention can enhance associative learning in mammals and may provide insight into strategies to improve cognition in humans.

Approximating exposure therapy in the lab: Replacing the CS+ with a similar versus a different stimulus and including additional stimuli resembling the CS+ during extinction

Recent studies have shown that extinction training including the conditional stimulus (CS+) and stimuli that are similar to the CS + enhances extinction retention and generalisation to novel stimuli. However, in a clinical setting, the CS+ is rarely available for use during exposure therapy. The aim of the present study was to determine if replacing the CS+ with a similar versus different stimulus, and including other similar stimuli during extinction, could reduce fear at test on par with extinction using the original CS+ with and without other similar stimuli. In an experiment conducted in a single session, participants completed a habituation phase followed by an acquisition phase using two dog images presented with (CS+) and without (CS-) an acoustic unconditional stimulus (US). Participants were randomly allocated to four extinction conditions: similar CS + dog with novel dog images (Similar replacement extinction condition); different CS + dog with novel dog images (Different replacement extinction condition); original CS + dog with novel dog images (Multiple extinction control condition); and original CS + without novel dog images (Standard extinction control condition). All participants completed a test phase with the original CSs followed by a generalisation test with another two novel dog images. All groups acquired, and then extinguished differential skin conductance responses (SCRs) with no differences observed between groups. Whereas the Similar replacement extinction group and the Multiple and Standard extinction control groups did not exhibit significant differential SCRs when re-exposed to the original CS + relative to the CS- at test, differential responding to the CSs was significant at test in the Different replacement extinction group. There were no significant differences between groups in SCRs to the two novel dog images during the generalisation phase and in between-phase subjective ratings. Findings suggest that replacement stimuli used during extinction should be as similar as possible to the CS + to reduce physiological arousal to the original CS+.

Evaluating the effects of counterconditioning, novelty-facilitated, and standard extinction on the spontaneous recovery of threat expectancy and conditioned stimulus valence.

Extinction training has proved effective to diminish the expectancy of the aversive unconditioned stimulus (US). However, the negative valence of the conditioned stimulus (CS) may still stay intact. In fact, several studies have suggested that the CS negative valence may be a factor that promotes the return of fear. Our study focuses on the role of changes in the CS valence as a potential mechanism to reduce the spontaneous recovery of threat expectancies. To do that, we evaluated counterconditioning (CC), a technique aimed to reduce the CS negative valence by paring it with a positive stimulus and compared its efficacy to that of a novelty-facilitated extinction (NFE) and a standard extinction interventions. Using a 2-day protocol, participants first learned the relationship between a figure and an aversive sound, using a differential conditioning paradigm, and were then randomly assigned to one of three different groups. For the CC group, CS+ or cue A was paired with a positive US. The standard extinction group was exposed to cue A alone. For a third NFE group, cue A was followed by a neutral US. Finally, on the second day, spontaneous recovery was tested. Our findings did not provide evidence to suggest that CC could be more effective to prevent or reduce the return of threat expectancies or influence valence ratings when compared with NFE and standard extinction.

Counterconditioning reduces contextual renewal in a novel context but not in the acquisition context

As extinction is a context-dependent form of learning, conditioned responses tend to return when the conditioned stimulus (CS) is encountered outside the extinction context, known as contextual renewal. Counterconditioning is a technique that may lead to a more persistent reduction of the conditioned response. However, the effects of aversive-to-appetitive counterconditioning on contextual renewal in rodent studies are mixed. Further, research in humans is sparse, particularly direct statistical comparisons between counterconditioning and standard extinction techniques within the same study. Using a causal associative learning framework (the allergist task) implemented online, we compared the effectiveness of counterconditioning to standard extinction in preventing the renewal of judgements on the allergic properties of different food items (CSs). In a between-subjects design, 328 participants first learned that particular food items (CSs) lead to an allergic reaction in a specific restaurant (context A). Next, one CS was extinguished (no allergic reaction) while another CS was counterconditioned (positive outcome) in restaurant B. Causal judgements of the allergic properties of food items occurred in either the response acquisition context (ABA group, N = 112), the response reduction context where extinction and counterconditioning had occurred (ABB group, N = 107), or a novel context (ABC group, N = 109). Results showed that counterconditioning, compared to extinction, diminished the renewal of causal judgements to the CS in a novel context (ABC group). Still, casual judgements returned for both counter-conditioned and extinguished CSs in the response acquisition context (ABA group). Counterconditioning and extinction were similarly effective at preventing recovery of causal judgements in the response reduction context (ABB group); however, only in context B did participants choose the counter-conditioned CS as less likely to cause an allergic reaction in comparison to the extinguished CS. These findings indicate scenarios in which counterconditioning is more effective than standard extinction at diminishing the return of threat associations, with implications for improving the generalization of safety learning.

Online counterconditioning with COVID-19-relevant stimuli in lockdown: Impact on threat expectancy, fear, and persistent avoidance

Background and objectivesIn counterconditioning, a conditioned aversive stimulus (CS) is paired with an appetitive stimulus to reduce fear and avoidance. Findings are, however, mixed on the relative impact of counterconditioning versus standard extinction, where the CS is presented in the absence of the aversive event. This analogue treatment study investigated the impact of counterconditioning relative to standard extinction on threat expectancy, fear, and persistent avoidance with an online fear-conditioning task conducted with COVID-19-relevant appetitive stimuli during the pandemic. MethodsFollowing habituation, in which two CSs (male faces wearing face-coverings) were presented in the absence of the unconditioned stimulus (US; a loud female scream), participants (n = 123) underwent threat-conditioning where one stimulus (CS+) was followed by the US and another (CS-) was not. In avoidance learning, the US could be prevented by making a simple response in the presence of the CS+. Next, participants received either counterconditioning in which trial-unique positively rated images of scenes from before the COVID-19 pandemic and its associated restrictions (e.g., hugging others and holding hands) were presented with the CS + or no-counterconditioning (i.e., extinction). In the final test phase, avoidance was available, and all US deliveries were withheld. ResultsCounterconditioning led to diminished threat expectancy and reduced avoidance relative to no-counterconditioning. Fear ratings did not differ between groups. LimitationsNo physiological measures were obtained. ConclusionsImplemented online during the pandemic with COVID-19-relevant appetitive stimuli, counterconditioning was effective at reducing persistent avoidance and threat expectancy.

Rewarded Extinction Increases Amygdalar Connectivity and Stabilizes Long-Term Memory Traces in the vmPFC.

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study with both female and male participants, we compared counterconditioning (CC; a form of rewarded-extinction) to standard extinction at recent (24 h) and remote (approximately one month) retrieval tests. Relative to standard extinction, rewarded extinction diminished 24-h relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ventral striatum, whereas the retrieval of standard-extinction memories was associated with connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). One month later, the retrieval of both standard-extinction and rewarded-extinction was associated with amygdala-vmPFC connectivity. However, only rewarded extinction created a stable memory trace in the vmPFC, identified through overlapping multivariate patterns of fMRI activity from extinction to 24-h and one-month retrieval. These findings provide new evidence that reward may generate a more stable and enduring memory trace of attenuated threat in humans.SIGNIFICANCE STATEMENT Prevalent treatments for pathologic fear and anxiety are based on the principles of Pavlovian extinction. Unfortunately, extinction forms weak memories that only temporarily inhibit the retrieval of threat associations. Thus, to increase the translational relevance of extinction research, it is critical to investigate whether extinction can be augmented to form a more enduring memory, especially after long intervals. Here, we used a multiday fMRI paradigm in humans to compare the short-term and long-term neurobehavioral effects of aversive-to-appetitive counterconditioning (CC), a form of augmented extinction. Our results provide novel evidence that including an appetitive stimulus during extinction can reduce short-term threat relapse and stabilize the memory trace of extinction in the ventromedial prefrontal cortex (vmPFC), for at least one month after learning.

Explaining the effectiveness of fear extinction through latent-cause inference

Acquiring fear responses to predictors of aversive outcomes is crucial for survival. At the same time, it is important to be able to modify such associations when they are maladaptive, for instance in treating anxiety and trauma-related disorders. Standard extinction procedures can reduce fear temporarily, but with sufficient delay or with reminders of the aversive experience, fear often returns. The latent-cause inference framework explains the return of fear by presuming that animals learn a rich model of the environment, in which the standard extinction procedure triggers the inference of a new latent cause, preventing the unlearning of the original aversive associations. This computational framework had previously inspired an alternative extinction paradigm – gradual extinction – which indeed was shown to be more effective in reducing the return of fear. However, the original framework was not sufficient to explain the pattern of results seen in the experiments. Here, we propose a formal model to explain the effectiveness of gradual extinction in reducing spontaneous recovery and reinstatement effects, in contrast to the ineffectiveness of standard extinction and a gradual reverse control procedure. We demonstrate through quantitative simulation that our model can explain qualitative behavioral differences across different extinction procedures as seen in the empirical study. We verify the necessity of several key assumptions added to the latent-cause framework, which suggest potential general principles of animal learning and provide novel predictions for future experiments.

A Preliminary Test of Novelty-Facilitated Extinction in Individuals With Pathological Anxiety.

Studies with rodents and healthy humans suggest that replacing the expected threat with a novel outcome improves extinction and reduces the return of conditioned fear more effectively than threat omission alone. Because of the potential clinical implications of this finding for exposure-based anxiety treatments, this study tested whether the same was true in individuals with pathological anxiety (i.e., met DSM-5 diagnostic criteria for an anxiety disorder and/or obsessive-compulsive disorder (OCD). In this preliminary test of novelty-facilitated extinction, 51 unmedicated individuals with pathological anxiety were randomized to standard extinction (n = 27) or novelty-facilitated extinction (n = 24). Participants returned 24 h later to test extinction recall and fear reinstatement. Skin conductance responses (SCR) were the dependent measure of conditioned fear. Participants in both groups learned the fear association but variably extinguished it. Novelty did not facilitate extinction in this preliminary trial. Findings underscore the importance of translating paradigms from healthy humans to clinical samples, to ensure that new treatment ideas based on advances in basic neuroscience are relevant to patients.

The influence of dispositional cognitive reappraisal and expressive suppression on post‐retrieval and standard extinction

Individual differences in the ability to habitually regulate emotion may impact the efficacy of fear memory extinction. The aim of this study was to assess the relationship between dispositional cognitive reappraisal and expressive suppression with post-retrieval and standard extinction. Fear memory and extinction were measured with the recovery of skin conductance responses. We also examined the relationship between a temporal feature of electrodermal responding (half-recovery time) and each of the emotion regulation strategies. University students (N=80) underwent a three-day fear conditioning procedure using a within-subject design consisting of acquisition on day one, post-retrieval extinction and standard extinction on day two, and recovery test on day three. Individual difference data on self-reported levels of cognitive reappraisal, expressive suppression, trait anxiety, and depression were collected. We did not detect a relationship between the two emotion regulation strategies measured in this study and acquisition or extinction. We found, however, that increased dispositional use of cognitive reappraisal was associated with lower spontaneous recovery to both the post-retrieval extinction and standard extinction stimulus after controlling for age, trait anxiety, and depression. There were no associations between expressive suppression and conditioned responses. We also observed patterns of faster dissipation of arousal for reappraisal and slower for suppression to the conditioned stimulus during extinction training, which may represent the unique influence of each emotion strategy on the regulation of fear. We conclude greater daily use of cognitive reappraisal, but not expressive suppression, associates with extinction retention after receiving both standard and post-retrieval extinction.

Comparing three extinction methods to reduce fear expression and generalization

Fear extinction is easy to achieve but difficult to maintain, as evidenced by the relapse of fear after extinction. Counterconditioning and novelty-facilitated extinction have been shown to interfere with fear expression without erasing it. Because of the similarity between the two extinction paradigms, we extended the standard extinction, which merely omitted the expected threat outcomes after exposure to original threat cues. The modified paradigm provided a stimulus (neutral picture or positive picture) to replace the omitted threat outcomes during extinction. Sixty-four healthy volunteers were randomized into three groups for a three-day procedure: fear acquisition (day 1), fear extinction (day 2), and fear recall and generalization test (day 3). Our results showed the modified extinction paradigm failed to prevent fear expression in spontaneous recovery and reinstatement tests. However, novelty-facilitated extinction showed powerful effects in preventing fear generalization. Besides, there was a negative correlation between spontaneous recovery index and emotion regulation scores. We speculated that emotion and prediction error may be important factors influencing fear extinction and affect fear recall and generalization. Overall, this study suggests that novelty-facilitated extinction had a superior effect in preventing fear generalization, providing new perspectives for enhancing the effect of exposure therapy.

Cortisol before extinction generalization alters its neural correlates during retrieval

While generalization of fear seems to be naturally acquired as frequently observed in fear-related disorders, extinction learning appears to be stimulus-specific. Thus, treatments aiming to generalize extinction learning comprise the chance to overcome stimulus-specificity and consequently reduce relapse. One suggested candidate is the timing-dependent administration of the stress hormone cortisol.In the present pre-registered, three-day fear conditioning study, we aimed to create a generalized extinction memory trace in 60 healthy men and women using multiple sizes of one conditioned stimulus (CS+G; generalized) during extinction training, whereas the other CS (CS+N; non-generalized) and the CS- were solely presented in their original sizes. Extinction training took place either after pharmacological administration of 20 mg cortisol or placebo. Following successful fear acquisition on day one, generalization effects during extinction training and retrieval were investigated in the comparison of CS+G and CS+N. Insula and dorsal anterior cingulate cortex (dACC) activation for CS+G as compared to CS+N extending to the second half of extinction training indicated prolonged fear processing during extinction training for the CS+G on day two. During retrieval on day three, an activation of the anterior hippocampus occurred for CS+N minus CS+G in the cortisol but not in the placebo group. Additionally, a more posterior hippocampal activation (compared to the other hippocampal activation) was observed for the contrast CS+G minus CS+N. In accordance with our hypotheses, amygdala and dACC responding during reinstatement test was reduced for the CS+G as compared to CS+N. However, cortisol did not modulate amygdala responding, but abolished the CS+G/CS+N differentiation in the dACC relative to placebo. Generalization and cortisol effects were not mirrored in skin conductance responses. In conclusion, extinction generalization processes appear to rely on prolonged fear processing still present in the second half of extinction training that in turn leads to reduced fear-related processing after reinstatement. Cortisol administration prior to extinction training, however, selectively reduced fear-related activation for standard extinction but did not further reduce fear-related activation for extinction generalization.