Extinction in fear conditioning: Effects on startle modulation and evaluative self-reports

A basic feature of human evaluative conditioning is that the reported acquired valence of a previously neutral conditioned stimulus (CS) that has been paired with a valenced unconditioned stimulus (US), is resistant to extinction. The present study investigated whether startle modulation, sometimes presented as an index of acquired valence, reflected this basic feature. In a differential fear conditioning paradigm ( n = 38) with an electrocutaneous stimulus as the US, a strong extinction manipulation was conducted by removing the US-electrodes and by extended extinction trials. At the end of extinction, the results corroborated previous findings of evaluative conditioning in that the reported valence for CS+ was still more negative than for CS−, despite disappearance of the differential skin conductance responses. However, startle modulation did not show resistance-to-extinction. Results were discussed in terms of recent conceptualizations of extinction.     

Delayed extinction fails to reduce skin conductance reactivity to fear‐conditioned stimuli

A brief 10‐min time delay between an initial and subsequent exposure to extinction trials has been found to impair memory reconsolidation in fear‐conditioned rodents and humans, providing a potential means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder (PTSD). The present study used videos of biologically prepared, conditioned stimuli (tarantulas) to test the efficacy of delayed extinction in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, the delayed‐extinction intervention failed to reduce reactivity to the conditioned stimulus paired with the extinction delay. These results are partially consistent with other recent, mixed findings and point to a need for testing other candidate interventions designed to interfere with the reconsolidation process.     

REM sleep deprivation affects extinction of cued but not contextual fear conditioning

Previous research has demonstrated that rapid eye movement (REM), or paradoxical, sleep deprivation can interfere with the retention of certain types of learning tasks, particularly spatial learning. The present study investigated the effects of 6 h of REM sleep deprivation on the retention and extinction of both cued and contextual conditioning tasks in rats. Sleep-deprived animals showed normal retention of both types of conditioning tasks but retarded extinction of the cued task and a trend toward attenuated spontaneous recovery of the contextual task. The results provide further evidence for the involvement of REM sleep in learning and memory processes.     

Contextual fear extinction ameliorates sleep disturbances found following fear conditioning in rats

STUDY OBJECTIVE: To examine the effects of fear extinction on subsequent sleep in rats and to compare it with the effects seen following contextual reminders of fear. DESIGN: Habituation of the rats to handling and baseline recordings were obtained over 2 consecutive days. Afterward, the rats were subjected to shock training (ST; day 1), context reexposure (CR; either 30 or 60 min; day 2), and fear recall (R; day 3). Percentage time spent in freezing (FT%) was observed during ST, CR, and R exposures. Sleep was recorded for 20 h (8-h light and 12-h dark period) following ST, CR, and R. SETTING: NA SUBJECTS: The subjects were outbred Wistar rats randomly assigned to one of two groups: contextual fear (FR; n = 7) or contextual extinction (EXT; n = 7). INTERVENTIONS: The rats were surgically implanted with electrodes for recording the electroencephalogram and electromyogram for determining arousal state. MEASUREMENTS AND RESULTS: There were no differences between groups on FT% during ST or the first 30 min of CR; however, during R, the FR group had greater FT% than EXT. Sleep did not differ between groups following ST. Following CR, EXT exhibited significantly more total sleep, NREM, and REM than FR. After R, there were no differences between groups. CONCLUSIONS: Rats that exhibit extinction of contextual fear show significantly increased sleep compared to rats who continue to exhibit contextual fear. This suggests that sleep disturbances normally experienced in humans following traumatic events or reminders may be ameliorated by therapies that address and eliminate the associated fear.     

Fear extinction in humans: Effects of acquisition-extinction delay and masked stimulus presentations

Fear extinction can be viewed as an inhibitory learning process. This is supported by post-extinction phenomena demonstrating the return of fear, such as reinstatement. Recent work has questioned this account, claiming that extinction initiated immediately after fear acquisition can abolish the return of fear. In the current study, participants were fear conditioned to four different conditioned stimuli (CS) and underwent extinction either immediately or after a 24h delay. During extinction, we manipulated CS contingency awareness by presenting two of the CSs (one CS+, one CS-) under non-masked conditions and the other two CSs under masked conditions. Compared to delayed extinction, immediate extinction of non-masked CSs promoted less extinction of fear-potentiated startle and shock expectancy ratings and less reinstatement of fear-potentiated startle without affecting shock expectancy ratings. Critically, future research should clarify how the differences between immediate and delayed extinction in within-session extinction modulate the recovery of fear.     

Reconsolidation in a human fear conditioning study: A test of extinction as updating mechanism

Disrupting reconsolidation seems to be a promising approach to dampen the expression of fear memory. Recently, we demonstrated that disrupting reconsolidation by a pharmacological manipulation specifically targeted the emotional expression of memory (i.e., startle response). Here we test in a human differential fear-conditioning paradigm with fear-relevant stimuli whether the spacing of a single unreinforced retrieval trial relative to extinction learning allows for “rewriting” the original fear association, thereby preventing the return of fear. In contrast to previous findings reported by Schiller et al. (2010), who used a single-method for indexing fear (skin conductance response) and fear-irrelevant stimuli, we found that extinction learning within the reconsolidation window did not prevent the recovery of fear on multiple indices of conditioned responding (startle response, skin conductance response and US-expectancy). These conflicting results ask for further critical testing given the potential impact on the field of emotional memory and its application to clinical practice.     

Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders

Anxiety disorders are highly prevalent. Fear conditioning and extinction learning in animals often serve as simple models of fear acquisition and exposure therapy of anxiety disorders in humans. This article reviews the empirical and theoretical literature on cognitive processes in fear acquisition, extinction, and exposure therapy. It is concluded that exposure therapy is a form of cognitive intervention that specifically changes the expectancy of harm. Implications for therapy research are discussed.     

Facilitating actions of an AMPA receptor potentiator upon extinction of contextually conditioned fear response in stressed mice

Extinction of conditioned fear response is thought to be a biological process underlying exposure therapy for anxiety disorders. We have previously reported that an AMPA receptor potentiator, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetamide (PEPA), facilitates extinction of fear memory formed through contextual fear conditioning in mice that had never been exposed to experimental stress. On the other hand, recent findings suggest that the fear extinction is impaired in stressed rats or mice. The purpose of the present study was to examine whether PEPA facilitates impaired extinction of fear in stressed mice. For this purpose, mice were applied stress (a 2 h restraint, a 20 min forced swim, and ether inhalation), and contextual fear conditioning was carried out 7 days later. After 1–3 days of conditioning, mice were re-exposed to the context for 6 min, and behavioral freezing response was measured. The time mice spent frozen decreased following every extinction session, and the decrease was remarkably slower in the stressed mice than in control non-stressed mice. PEPA (3, 10, 30 mg/kg body weight) or vehicle was intraperitoneally administered into stressed mice once before the first extinction session. The significant decrease of the freezing response in the extinction sessions was only seen in the 30 mg/kg PEPA-administered stressed mice, compared with vehicle-administered stressed mice. A similar extent of decrease in the freezing response in the extinction sessions was observed in the PEPA-administered (30 mg/kg) and d-cycloserine-administered (30 mg/kg) mice. These results suggest that PEPA facilitates extinction of contextual fear in stressed mice.     

Startle modulation and explicit valence evaluations dissociate during backward fear conditioning

Blink startle magnitude is linearly modulated by affect such that, relative to neutral stimuli, startle magnitude is inhibited during pleasant stimuli and potentiated during unpleasant stimuli. Andreatta, Mühlberger, Yarali, Gerber, and Pauli (2010), however, report a dissociation between startle modulation and explicit valence evaluations during backward conditioning, a procedure in which the unconditional stimulus precedes the conditional stimulus (CS). Relative to controls, startles elicited during the CS were inhibited, suggesting that the CS had acquired positive valence, but participants still evaluated the CS as unpleasant after the experiment. In Experiment 1, we aimed to replicate this dissociation using a trial‐by‐trial measure of CS valence to measure startle modulation and CS valence simultaneously during forward and backward differential fear conditioning. In Experiment 2, we examined whether early and late portions of the CS could acquire differential valence by presenting startle probes at early and late probe positions during the CS. In both experiments, the dissociation between startle modulation and explicit valence evaluations in backward conditioning replicated, with CS+ evaluated as less pleasant than CS‐, but startles elicited during CS+ inhibited relative to CS‐. In Experiment 2, we provide preliminary evidence that this inhibition was present early, but not late, during the CS+. The results replicate the dissociation between implicit and explicit CS valence reported by Andreatta et al. (2010) using a trial‐by‐trial measure of valence. We also provide preliminary evidence that this dissociation may occur because the implicit and explicit measures are recorded at different times during the CS presentation.     

No effect of trait anxiety on differential fear conditioning or fear generalization

Previous studies have shown that individuals with anxiety disorders exhibit deficits in fear inhibition and excessive generalization of fear, but little data exist on individuals at risk from these disorders. The present study examined the role of trait anxiety in the acquisition and generalization of fear in 126 healthy participants selected on the basis of their trait-anxiety scores. Measures of conditioning included fear-potentiated startle, skin conductance response and online risk ratings for the unconditioned stimulus. Contrary to our hypotheses, trait anxiety did not have any effect either on the acquisition or the generalization of fear. Our results suggest that these fear conditioning processes are not impaired in individuals at risk from anxiety.     

Inconsistent analytic strategies reduce robustness in fear extinction via skin conductance response

Robustness of fear conditioning and extinction paradigms has become increasingly important for many researchers interested in improving the study of anxiety and trauma disorders. We recently illustrated the wide variability in data analysis techniques in this paradigm, which we argued may result in a lack of robustness. In the current study, we resampled data from six of our own fear acquisition and extinction data sets, with skin conductance as the outcome. In the resampled and original data sets, we found that effect sizes that were calculated using discrepant statistical strategies, sourced from a non-exhaustive search of high-impact articles, were often poorly correlated. The main contributors to poor correlations were the selection of trials from different stages of each experimental phase and the use of average compared to trial-by-trial analysis. These findings reinforce the importance of focusing on robustness in the psychophysiological measurement of fear acquisition and extinction in the laboratory and may guide prospective researchers in which decisions may most impact the robustness of their results.     

Modeling fear‐conditioned bradycardia in humans

Across species, cued fear conditioning is a common experimental paradigm to investigate aversive Pavlovian learning. While fear‐conditioned stimuli (CS+) elicit overt behavior in many mammals, this is not the case in humans. Typically, autonomic nervous system activity is used to quantify fear memory in humans, measured by skin conductance responses (SCR). Here, we investigate whether heart period responses (HPR) evoked by the CS, often observed in humans and small mammals, are suitable to complement SCR as an index of fear memory in humans. We analyze four datasets involving delay and trace conditioning, in which heart beats are identified via electrocardiogram or pulse oximetry, to show that fear‐conditioned heart rate deceleration (bradycardia) is elicited and robustly distinguishes CS+ from CS?. We then develop a psychophysiological model (PsPM) of fear‐conditioned HPR. This PsPM is inverted to yield estimates of autonomic input into the heart. We show that the sensitivity to distinguish CS+ and CS? (predictive validity) is higher for model‐based estimates than peak‐scoring analysis, and compare this with SCR. Our work provides a novel tool to investigate fear memory in humans that allows direct comparison between species.     

A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans

People at high risk for alcoholism show deficits in aversive learning, as indicated by impaired electrodermal responses during fear conditioning, a basic form of associative learning that depends on the amygdala. A positive family history of alcohol dependence has also been related to decreased amygdala responses during emotional processing. In the present study we report reduced amygdala activity during the acquisition of conditioned fear in healthy carriers of a risk variant for alcoholism (rs2072450) in the NR2A subunit-containing N-methyl-d-aspartate (NMDA)-receptor. These results indicate that rs2072450 might confer risk for alcohol dependence through deficient fear acquisition indexed by a diminished amygdala response during aversive learning, and provide a neural basis for a weak behavioral inhibition previously documented in individuals at high risk for alcohol dependence. Carriers of the risk variant additionally exhibit dampened insula activation, a finding that further strengthens our data, given the importance of this brain region in fear conditioning.     

Sensitivity to masked conditioned stimuli predicts conditioned response magnitude under masked conditions

Expression of conditioned fear has been reported to be independent of perceptual awareness of conditioned stimuli (CSs). Previous studies have been criticized, however, for not adequately assessing perceptual awareness. We fear-conditioned participants to one of two symbols and measured skin conductance responses to dichoptically masked and unmasked CSs. Participants also performed a target detection task and sensitivity (d') to the masked conditioned stimuli (CS+, CS-) was measured. Results showed that sensitivity under masking conditions was related to conditioned responses to masked CSs but not unmasked CSs. Thus, a strong relationship between expression of conditioned fear and awareness of the CS+ emerges when the latter is assessed by signal detection methods. Without consensus on how awareness should be defined, these findings bring balance to previous studies that have typically used less sensitive assessments of awareness.     

Affective learning: Awareness and aversion

In two studies, we investigated the influence of aversive and nonaversive reinforcers on startle reactivity, visceral responses, and self-report during Pavlovian conditioning. Furthermore, we assessed how awareness of the stimulus contingencies affect conditioned discrimination in the different response systems. Conditioned potentiation of the startle response was only observed in the context of aversive learning. Moreover, blink potentiation occurred without awareness of the relationship between the conditioned and unconditioned stimulus. In contrast, skin conductance conditioning was independent of the aversiveness of the reinforcer and was only obtained for those individuals who could correctly verbalize the stimulus contingency in a postconditioning recognition test. Cardiac responses varied with the task demands of the situation and covaried with individual response stereotypes.     

On the resistance to extinction of fear conditioned to angry faces

The present study investigated whether, like fear conditioned to pictures of snakes and spiders, fear conditioned to angry faces resists extinction even after verbal instruction and removal of the shock electrode. Participants were trained in a differential Pavlovian fear conditioning procedure with angry face or happy face conditional stimuli (CSs). Prior to extinction, half the participants in each group were informed that no more unconditional stimuli would be presented and the shock electrode was removed. In the absence of this manipulation, participants showed resistance to extinction after training with angry face CSs, but not after training with happy face CSs. Instructed extinction and electrode removal abolished fear conditioning regardless of the emotion expressed by the CS faces. This finding suggests that fear conditioned to angry faces, like fear conditioned to racial out-group faces, is more malleable than fear conditioned to snakes and spiders.     

Amphetamine and extinction of cued fear

Much research is focused on developing novel drugs to improve memory. In particular, psychostimulants have been shown to enhance memory and have a long history of safe use in humans. In prior work, we have shown that very low doses of amphetamine administered before training on a Pavlovian fear-conditioning task can dramatically facilitate the acquisition of cued fear. The current experiment sought to expand these findings to the extinction of cued fear, a well-known paradigm with therapeutic implications for learned phobias and post-traumatic stress disorder. If extinction reflects new learning, one might expect drugs that enhance the acquisition of cued fear to also enhance the extinction of cued fear. This experiment examined whether 0.005 or 0.05 mg/kg of d-amphetamine (therapeutic doses shown to enhance acquisition) also enhance the extinction of cued fear. Contrary to our hypothesis, amphetamine did not accelerate extinction. Thus, at doses that enhance acquisition of conditioned fear, amphetamine does not appear to enhance extinction.     

Resting heart rate variability is associated with inhibition of conditioned fear

Startle blink as well as skin conductance responses (SCR) are widely used indices of learning processes associated with fear conditioning and extinction. During safety learning, the amygdala is under top‐down inhibitory control by the prefrontal cortex (PFC). The capacity of the PFC to exert inhibitory control over subcortical brain structures may be indexed by resting state vagally mediated heart rate variability (HRV). The present study investigated the association of resting HRV with startle blink and SCR during conditioned fear inhibition and extinction. Participants first learned to discriminate a threat cue (A) signaling an aversive unconditioned stimulus from a safety signal (B), which were each presented together with a third stimulus X (AX+/BX?). Then, both the threat and safety signal were presented together (AB) to test whether the presence of the learned safety signal inhibits the fear response to the danger signal. Finally, AX was presented without reinforcement (AX?) to investigate fear extinction. Higher HRV was associated with pronounced fear inhibition and fear extinction. Resting HRV levels were associated with fear extinction as indexed by startle blink potentiation but not SCR, which presumably reflect more cognitive aspects of learning. Resting HRV may reflect the capacity of the prefrontal cortex to inhibit subcortical fear responses in the presence of safety or when former threat cues are presented in the absence of threat.     

Effects of beta blockade, PTSD diagnosis, and explicit threat on the extinction and retention of an aversively conditioned response

An aversively conditioned SC response was assessed in 18 males meeting DSM-IV criteria for chronic posttraumatic stress disorder (PTSD) and 10 trauma-exposed males who never developed PTSD. Effects of beta blockade on acquisition and retention of a conditioned response (CR) were examined by administering propranolol HCl before acquisition or following extinction trials. Retention of the CR was assessed 1 week following acquisition under conditions of non-threat and threat. Conditioned stimuli were colored circles and the unconditioned stimulus (UCS) was a "highly annoying" electrical stimulus. The propranolol failed to produce any measurable effects on acquisition or retention of the CR and there was no evidence of increased conditionability in individuals diagnosed with PTSD. One week following acquisition, the differential CR to the reinforced stimulus was evident only in the threat condition. This suggests that belief in the presence of a threat is necessary and sufficient for activating a previously established CR.     

Selectivity of conditioned fear of touch is modulated by somatosensory precision

Learning to initiate defenses in response to specific signals of danger is adaptive. Some chronic pain conditions, however, are characterized by widespread anxiety, avoidance, and pain consistent with a loss of defensive response specificity. Response specificity depends on ability to discriminate between safe and threatening stimuli; therefore, specificity might depend on sensory precision. This would help explain the high prevalence of chronic pain in body areas of low tactile acuity, such as the lower back, and clarify why improving sensory precision may reduce chronic pain. We compared the acquisition and generalization of fear of pain‐associated vibrotactile stimuli delivered to either the hand (high tactile acuity) or the back (low tactile acuity). During acquisition, tactile stimulation at one location (CS+) predicted the noxious electrocutaneous stimulation (US), while tactile stimulation at another location (CS−) did not. Responses to three stimuli with decreasing spatial proximity to the CS+ (generalizing stimuli; GS1–3) were tested. Differential learning and generalization were compared between groups. The main outcome of fear‐potentiated startle responses showed differential learning only in the hand group. Self‐reported fear and expectancy confirmed differential learning and limited generalization in the hand group, and suggested undifferentiated fear and expectancy in the back group. Differences in generalization could not be inferred from the startle data. Specificity of fear responses appears to be affected by somatosensory precision. This has implications for our understanding of the role of sensory imprecision in the development of chronic pain.