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Abstract The classical conditioning paradigm of fear learning has spawned a number of experimental variations for the explanation of posttraumatic stress disorder (PTSD) etiology. These paradigms include extinction learning and recall, fear inhibition, fear generalization, and conditioned avoidance. As such, each of these paradigms have significant applications for understanding the development, maintenance, treatment, and relapse of the fear-related features of PTSD. In the present review, we describe each of these conditioning-based paradigms with reference to the clinical applications, and supported by case examples from patients with severe PTSD symptoms. We also review the neurobiological models of conditioning and extinction in animals, psychiatrically healthy humans, and PTSD patients, and discuss the current balance of evidence suggesting a number of biological, behavioral, and cognitive mechanisms/moderators of the conditioning and extinction process in experimental and clinical contexts. Highlights • Classical conditioning paradigm of fear learning are discussed in terms of their relevance to the etiology and treatment of Posttraumatic Stress Disorder (PTSD) • Clinically relevant paradigms include extinction learning and recall, fear inhibition, fear generalization, and conditioned avoidance • Each of these conditioning-based paradigms is discussed with reference to clinical applications and case examples from patients with severe PTSD symptoms [ABSTRACT FROM AUTHOR]

Abstract Fear reinstatement is one of several paradigms designed to measure fear return following extinction, as a laboratory model for the relapse of Posttraumatic Stress Disorder (PTSD) symptoms. Sleep is a key factor in emotional memory consolidation, and here we examined the relationship between sleep quality and fear reinstatement in PTSD, relative to trauma-exposed and non-exposed controls. The Pittsburgh Sleep Quality Index (PSQI) was used as a subjective measure of sleep quality, and skin conductance responses (SCR) and unconditioned stimulus (US)-expectancy ratings were used to index threat responses during a differential fear conditioning, extinction, and reinstatement paradigm. There were no significant between-group differences in the reinstatement of conditioned responding. Sleep disturbance and sleep onset latency were significant moderators between reinstatement of fear and PTSD symptom severity, such that there was a positive relationship between PTSD symptoms and fear reinstatement for higher levels – but not lower levels – of sleep disturbance and sleep onset latency. To our knowledge, this is the first study to investigate PTSD-specific reinstatement patterns and sleep as a boundary condition of reinstatement. Future research using polysomnographic measures of sleep-wave architecture may further clarify the relationship between fear reinstatement and sleep quality in clinical samples with PTSD relative to controls. Highlights • Sleep quality is a key factor in PTSD and fear extinction recall. • Fear reinstatement has not been investigated in PTSD. • PTSD was not associated with impaired fear reinstatement in isolation. • Sleep disturbance and sleep onset latency moderated reinstatement in PTSD. [ABSTRACT FROM AUTHOR]

The low expression Met allele of the BDNF Val66Met polymorphism is associated with impaired fear extinction in healthy controls, and poorer response to exposure therapy in patients with Posttraumatic Stress Disorder (PTSD). Given that fear extinction underlies exposure therapy, this raises the question of the impact of BDNFVal66Met polymorphism on fear extinction in PTSD, yet this question has not yet been examined. One hundred and six participants (22 PTSD, 46 trauma-exposed controls (TC) and 38 non-trauma exposed controls (NTC)) completed a fear conditioning and extinction task and saliva samples were taken for DNA extraction and genotyped for the BDNF Val66Met polymorphism. Moderation analyses using PROCESS examined whether BDNF genotype (Val–Val vs Met carriers) moderated the relationship between PTSD symptom severity (and diagnostic status) and skin conductance response (SCR) amplitude during fear extinction. The PTSD group displayed significantly slower fear extinction learning compared to TC and NTC in the early extinction phase. The BDNF Val66Met polymorphism moderated the relationship between PTSD and fear extinction learning, such that poorer fear extinction learning was associated with greater PTSD symptom severity (and PTSD diagnostic status) in individuals with the low-expression Met allele, but no relationship was demonstrated in individuals with the Val–Val allele. This study reveals that impaired fear extinction learning is particularly evident in individuals with PTSD who carry the low-expression BDNF Met allele and importantly not in those with the Val–Val allele. This provides novel evidence of a link between BDNF and impaired fear extinction learning in PTSD, which may contribute to poorer response to exposure therapy. [ABSTRACT FROM AUTHOR]

Objective Posttraumatic stress symptoms (PTSS) are commonly associated with impairments in extinguishing fear to signals previously associated with danger, and also with inhibiting fear to safety signals. Previous studies indicate that PTSS are associated with low cortisol activity, and cortisol is shown to facilitate fear extinction. Few studies have examined the influence of cortisol reactivity on fear extinction in PTSS. Method We used a standardized fear conditioning and extinction paradigm to investigate the relationship between fear extinction and endogenous salivary cortisol activity in participants with high PTSS ( n = 18), trauma-exposed controls ( n = 33), and non-trauma-exposed controls ( n = 27). Skin conductance response (SCR) was used as an index of conditioned responding. Saliva samples were collected at baseline, and 20 min post-fear acquisition for basal and reactive cortisol levels, respectively. Results PTSS participants demonstrated a slower rate of extinction learning during the early extinction phase. A moderation analysis revealed that cortisol reactivity was a significant moderator between fear inhibition to the safety signal (CS−) during early extinction and PTSS, but not to the threat signal (CS+). Specifically, this interaction was significant in two ways: (1) participants with elevated cortisol reactivity showed lower PTSS as fear inhibition improved; and (2) participants with low cortisol reactivity showed higher PTSS as fear inhibition improved. Conclusion The findings of the present study show that the relationship between fear inhibition and cortisol reactivity is complex, and suggest that cortisol reactivity shapes safety signal learning in PTSS. [ABSTRACT FROM AUTHOR]

Recent prospective studies in emergency services have identified impaired fear extinction learning and memory to be a significant predictor of Posttraumatic Stress Disorder (PTSD), complementing a wealth of cross-sectional evidence of extinction deficits associated with the disorder. Additional fields of research show specific risk factors and biomarkers of the disorder, including candidate genotypes, stress and sex hormones, cognitive factors, and sleep disturbances. Studies in mostly nonclinical populations also reveal that the aforementioned factors are involved in fear extinction learning and memory. Here, we provide a comprehensive narrative review of the literature linking PTSD to these risk factors, and linking these risk factors to impaired fear extinction. On balance, the evidence suggests that fear extinction may play a role in the relationship between risk factors and PTSD. Should this notion hold true, this review carries important implications for the improvement of exposure-based treatments, as well as strategies for the implementation of treatment. [ABSTRACT FROM AUTHOR]

Persistent avoidance may be influenced by prior negative reinforcement rate (i.e., how effective the response is at controlling threat). In clinical settings, the effectiveness of extinction-based methods for treating anxiety-related avoidance may be impacted by prior reinforcement rate. Here, we conducted a laboratory-based treatment study to investigate the persistence of avoidance following response-prevention extinction (RPE) when prior avoidance had been differentially effective at cancelling shock. Participants in three negative reinforcement rate groups (100%, 50%, and 0%) completed a validated avoidance conditioning paradigm involving Pavlovian fear extinction, RPE, and re-extinction phases. It was hypothesised that partially reinforced avoidance would lead to diminished resistance to fear extinction following response prevention, compared to continuously- or never-reinforced avoidance. Persistent avoidance was related to prior negative reinforcement rate, with higher rates more resistant to extinction. These findings illustrate the role of reinforcement rate in the persistence of avoidance and may aid understanding of treatment relapse. • Prior effectiveness of avoidance may influence treatment outcomes. • Extinction and recovery of partially reinforced avoidance after response-prevention. • Avoidance recovery related to prior reinforcement rate. • Avoidance associated with trait intolerance of uncertainty and baseline fear. [ABSTRACT FROM AUTHOR]

Background and Objectives: In 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.Methods: Following 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.Results: Counterconditioning led to diminished threat expectancy and reduced avoidance relative to no-counterconditioning. Fear ratings did not differ between groups.Limitations: No physiological measures were obtained.Conclusions: Implemented online during the pandemic with COVID-19-relevant appetitive stimuli, counterconditioning was effective at reducing persistent avoidance and threat expectancy. [ABSTRACT FROM AUTHOR]

Sleep has been found to play a key role in fear conditioning, extinction learning and extinction recall, and sleep disturbances are linked to many mental disorders including post-traumatic stress disorder (PTSD). Previous studies examining associations between sleep and fear or extinction processes primarily focused on objectively measured sleep architecture. Little research has so far focused on subjective sleep measures and particularly in clinical populations, which often experience subjectively poor sleep, including PTSD. Here we investigated whether subjective sleep disturbance, sleep onset latency, wake after sleep onset or sleep efficiency were related to fear conditioning, extinction learning or extinction recall in a large sample of individuals with a range of PTSD symptom severity (n = 248). Overall, we did not find that subjective sleep was associated with fear conditioning or extinction processes. However, exploratory analyses examining the moderating effect of sex found that shorter sleep onset latency and greater sleep efficiency were associated with improved extinction recall in women with higher PTSD symptom severity. This suggests that less time falling asleep and longer time asleep while in bed may be protective in highly symptomatic women against the commonly observed impaired extinction recall in PTSD. More studies are needed to explore sex-specific effects further. • Subjective sleep is not associated with fear conditioning or extinction learning. • Sex moderates the sleep-extinction recall relationship. • Greater sleep quality enhances extinction recall in women with higher PTSD severity. • In men, the sleep-extinction recall association needs to be explored further. [ABSTRACT FROM AUTHOR]

Low levels of estradiol in women have been associated with impaired fear extinction recall, with suggestions this may promote the return of fear and heighten the female vulnerability for anxiety disorders. A particularly important measure for the return of fear is reinstatement, but no human studies to date have examined the impact of estradiol on fear reinstatement. Forty-two healthy females completed a differential fear conditioning, extinction and reinstatement task with skin conductance response (SCR) amplitude indexing level of conditioned fear. Saliva samples were taken to measure estradiol and progesterone. To examine fear reinstatement, SCR amplitude was compared between the last trial of the late extinction phase to the first re-extinction trial following the unsignaled presentation of two aversive electric shocks. No significant effects of estradiol were found for acquisition of fear conditioning or fear extinction learning. Lower estradiol predicted a significantly larger generalized SCR amplitude at re-extinction (post-reinstatement) in women. This provides novel evidence suggesting a protective role of estradiol in potentially reducing the relapse of fear following re-exposure to aversive stimuli, although further research is necessary in clinical populations to clarify this effect. • Estradiol is implicated in fear extinction recall. • No human studies have examined the influence of estradiol on fear reinstatement. • Lower estradiol predicted increased fear reinstatement in women. • Progesterone did not predict significant differences in fear reinstatement. • Estradiol may be important in protecting against the return of fear. [ABSTRACT FROM AUTHOR]