Differential acquisition,extinction, and reinstatement of conditioned suppression in mice

In animals, the reappearance of conditioned fear responses after extinction has been primarily investigated using single-cue conditioning paradigms. However, a differential paradigm can overcome several of the disadvantages associated with a single-cue procedure. In the present study, the reinstatement phenomenon was assessed in mice using a differential conditioned suppression paradigm. In a first phase, one conditioned stimulus (CS + ) was consistently paired with an unconditioned stimulus (US; footshock) while another CS (CS–) was not, resulting in selective suppression of previously trained instrumental behaviour during the CS + . After the extinction phase, half of the animals (reinstatement group) were presented with unsignalled USs, while the other half were not (control group). A differential return of conditioned responding was observed in the reinstatement group, but not in the control group. The implications of these findings for future conditioning research are discussed.     

Differential acquisition, extinction, and reinstatement of conditioned suppression in mice

In animals, the reappearance of conditioned fear responses after extinction has been primarily investigated using single-cue conditioning paradigms. However, a differential paradigm can overcome several of the disadvantages associated with a single-cue procedure. In the present study, the reinstatement phenomenon was assessed in mice using a differential conditioned suppression paradigm. In a first phase, one conditioned stimulus (CS + ) was consistently paired with an unconditioned stimulus (US; footshock) while another CS (CS-) was not, resulting in selective suppression of previously trained instrumental behaviour during the CS + . After the extinction phase, half of the animals (reinstatement group) were presented with unsignalled USs, while the other half were not (control group). A differential return of conditioned responding was observed in the reinstatement group, but not in the control group. The implications of these findings for future conditioning research are discussed.     

Reinstatement of fear in humans: autonomic and experiential responses in a differential conditioning paradigm

The present study investigated reinstatement of fear in humans using an aversive differential conditioning paradigm. Two neutral human face pictures were presented during habituation, acquisition, extinction, and postreinstatement phases. One picture served as a conditioned stimulus (CS) reinforced by an unconditioned stimulus (US) in the form of electrical stimulation (CS+) and the second picture as a control stimulus that was never reinforced (CS-). The prediction that in a reinstatement manipulation a previously extinguished fear response in humans can be reinstated in a reinstatement group by the mere presentation of three unpredicted electrical stimulations (USs) was tested. Participants in the control group were not exposed to unpredicted USs and no reinstatement effect was expected. Outcome measures included subjective US expectancy ratings and skin conductance responses. Results showed non-selective return of the fear response due to fear recovery associated with both CSs (CS+/CS-) in the reinstatement group. Unexpected fear recovery was observed for both CSs (CS+/CS-) in control participants. Results are discussed with respect to context conditioning, fear generalisation, and anxiety-related cognitive mechanisms underlying fear recovery after extinction.     

Conditioned fear extinction and reinstatement in a human fear-potentiated startle paradigm

The purpose of this study was to analyze fear extinction and reinstatement in humans using fear-potentiated startle. Participants were fear conditioned using a simple discrimination procedure with colored lights as the conditioned stimuli (CSs) and an airblast to the throat as the unconditioned stimulus (US). Participants were extinguished 24 h after fear conditioning. Upon presentation of unsignaled USs after extinction, participants displayed significant fear reinstatement. In summary, these procedures produced robust fear-potentiated startle, significant CS+/CS- discrimination, within-session extinction, and significant reinstatement. This is the first demonstration of fear extinction and reinstatement in humans using startle measures.     

Reinstatement of extinguished conditioned responses and negative stimulus valence as a pathway to return of fear in humans

The present study investigated reinstatement of conditioned responses in humans by using a differential Pavlovian conditioning procedure. Evidence for reinstatement was established in a direct (fear rating) and in an indirect measure (secondary reaction time task) of conditioning. Moreover, the amount of reinstatement in the secondary reaction time task was significantly correlated with the difference in valence between the conditioned stimulus (CS)+ and the CS-after extinction. These data provide clear evidence for reinstatement and for the role of negative stimulus valence in the return of conditioned responding after extinction.     

Pavlovian Disgust Conditioning and Generalization: Specificity and Associations With Individual Differences

Although studies have identified differences between fear and disgust conditioning, much less is known about the generalization of conditioned disgust. This is an important gap in the literature given that overgeneralization of conditioned disgust to neutral stimuli may have clinical implications. To address this knowledge gap, female participants (n = 80) completed a Pavlovian conditioning procedure in which one neutral food item (conditioned stimulus; CS+) was followed by disgusting videos of individuals vomiting (unconditioned stimulus; US) and another neutral food item (CS–) was not reinforced with the disgusting video. Following this acquisition phase, there was an extinction phase in which both CSs were presented unreinforced. Importantly, participants also evaluated generalization stimuli (GS+, GS?) that resembled, but were distinct from, the CS after each conditioning phase. As predicted, the CS+ was rated as significantly more disgusting and fear inducing than the CS? after acquisition and this pattern persisted after extinction. However, disgust ratings of the CS+ after acquisition were significantly larger than fear ratings. Participants also rated the GS+ as significantly more disgusting, but not fear inducing, than the GS? after acquisition. However, this effect was not observed after extinction. Disgust proneness did predict a greater increase in disgust and fear ratings of the CS+ relative to the CS? after acquisition and extinction. In contrast, trait anxiety predicted only higher fear ratings to the CS+ relative to the CS? after acquisition and extinction. Disgust proneness nor trait anxiety predicted the greater increase in disgust to the GS+ relative to the GS? after acquisition. These findings suggest that while conditioned disgust can generalize, individual difference variables that predict generalization remain unclear. The implications of these findings for disorders of disgust are discussed.     

Shaking That Icky Feeling: Effects of Extinction and Counterconditioning on Disgust-Related Evaluative Learning

Learned disgust appears to play an important role in certain anxiety disorders, and can be explained by the process of evaluative conditioning, in which an affective evaluative reaction evoked by an unconditional stimulus (US) is transferred to a conditional stimulus (CS). Much remains unknown about how disgust-related evaluative learning can be effectively eliminated. Study 1 of the present investigation examined the effects of extinction on reducing the negative evaluation of a CS that was acquired during disgust conditioning. Participants completed acquisition trials, with a disgusting picture as US and two neutral pictures as CS (CS + was paired with the US; CS- was unpaired), followed by extinction trials ("CS only"; experimental condition) or a filler task (control condition). Extinction trials reduced acquired US expectancy to the CS +, but did not extinguish negative evaluations of the CS +. Study 2 examined the effects of counterconditioning on evaluative learned disgust. After disgust acquisition trials, counterconditioning trials followed in which the CS + was paired with a pleasant US (experimental condition) or a filler task (control condition). Counterconditioning trials reduced acquired US expectancy to the CS + and reduced evaluative conditioned disgust. Implications of the potential differential effects of extinction and counterconditioning on evaluative learning for exposure-based treatment of specific anxiety disorders are discussed.     

Post-extinction conditional stimulus valence predicts reinstatement fear: Relevance for long-term outcomes of exposure therapy

Exposure therapy for anxiety disorders is translated from fear conditioning and extinction. While exposure therapy is effective in treating anxiety, fear sometimes returns after exposure. One pathway for return of fear is reinstatement: unsignaled unconditional stimuli following completion of extinction. The present study investigated the extent to which valence of the conditional stimulus (CS+) after extinction predicts return of CS+ fear after reinstatement. Participants (N = 84) engaged in a differential fear conditioning paradigm and were randomised to reinstatement or non-reinstatement. We hypothesised that more negative post-extinction CS+ valence would predict higher CS+ fear after reinstatement relative to non-reinstatement and relative to extinction retest. Results supported the hypotheses and suggest that strategies designed to decrease negative valence of the CS+ may reduce the return of fear via reinstatement following exposure therapy.     

US habituation,like CS extinction,produces a decrement in conditioned fear responding that is NMDA dependent and subject to renewal and reinstatement

Just as fear can be learned, it can also be inhibited. The most common way of reducing learned fear is through extinction, where the conditioned stimulus (CS) previously paired with an aversive unconditioned stimulus (US) is repeatedly presented on its own. Another, much less commonly studied, way to inhibit learned fear is by habituating, or devaluing, the US. In this procedure, fear responding to a CS is reduced by repeatedly presenting the US in the absence of the CS following the conditioning phase. The purpose of the present study was to directly compare the effects of US habituation and CS extinction on a learned fear response (freezing). Experiment 1 demonstrated that US habituation given either after (Experiment 1A) or before (Experiment 1B) fear conditioning reduced freezing to the CS at test. We then showed that the reduction in freezing resulting from either US habituation or CS extinction was context-specific (i.e., a change in context led to a renewal of the learned fear response; Experiment 2) and, furthermore, was attenuated when a pre-test shock was given (i.e., reinstatement of fear was observed in both cases; Experiment 3). Finally, Experiment 4 demonstrated that an injection of the NMDA antagonist MK-801 prior to US habituation impaired long-term retention of the learning that takes place during this procedure. Together, these results suggest that the decrement in conditioned fear responses produced by US habituation and CS extinction could rely on overlapping processes.     

Verbal instructions targeting valence alter negative conditional stimulus evaluations (but do not affect reinstatement rates)

Negative conditional stimulus (CS) valence acquired during fear conditioning may enhance fear relapse and is difficult to remove as it extinguishes slowly and does not respond to the instruction that unconditional stimulus (US) presentations will cease. We examined whether instructions targeting CS valence would be more effective. In Experiment 1, an image of one person (CS+) was paired with an aversive US, while another (CS?) was presented alone. After acquisition, participants were given positive information about the CS+ poser and negative information about the CS? poser. Instructions reversed the pattern of differential CS valence present during acquisition and eliminated differential electrodermal responding. In Experiment 2, we compared positive and negative CS revaluation by providing positive/negative information about the CS+ and neutral information about CS?. After positive revaluation, differential valence was removed and differential electrodermal responding remained intact. After negative revaluation, differential valence was strengthened and differential electrodermal responding was eliminated. Unexpectedly, the instructions did not affect the reinstatement of differential electrodermal responding.     

Associative learning versus fear habituation as predictors of long-term extinction retention

Violation of unconditioned stimulus (US) expectancy during extinction training may enhance associative learning and result in improved long-term extinction retention compared to within-session habituation. This experiment examines variation in US expectancy (i.e., expectancy violation) as a predictor of long-term extinction retention. It also examines within-session habituation of fear-potentiated startle (electromyography, EMG) and fear of conditioned stimuli (CS) throughout extinction training as predictors of extinction retention. Participants (n?=?63) underwent fear conditioning, extinction and retention and provided continuous ratings of US expectancy and EMG, as well as CS fear ratings before and after each phase. Variation in US expectancy throughout extinction and habituation of EMG and fear was entered into a regression as predictors of retention and reinstatement of levels of expectancy and fear. Greater variation in US expectancy throughout extinction training was significantly predictive of enhanced extinction performance measured at retention test, although not after reinstatement test. Slope of EMG and CS fear during extinction did not predict retention of extinction. Within-session habituation of EMG and self-reported fear is not sufficient for long-term retention of extinction learning, and models emphasizing expectation violation may result in enhanced outcomes.     

Rapid reaquisition in conditioning of the rabbit's nictitating membrane response.

Reacquisition after extinction often appears faster than original acquisition. However, data from conditioned suppression studies indicate that this effect may arise from spontaneous recovery and reinstatement of unextinguished contextual stimuli related to the unconditioned stimulus (US). In the present experiments using the rabbit nictitating membrane preparation, spontaneous recovery was eradicated before reaquisition training. US contextual stimuli were controlled by retaining the US during extinction through explicit unpairings of the conditioned stimulus (CS) and US. Attempts were also made to drive the associative strength of the CS into the inhibitory region by differential conditioning and conditioned inhibition procedures. In all cases, reacquisition was very rapid in comparison with a rest control. The results are discussed with respect to their implications for CS and US processing models of conditioning.     

Return of fear after retrospective inferences about the absence of an unconditioned stimulus during extinction

We examined whether the effect of an extinction phase can be influenced retrospectively by information about the cause of the absence of the unconditioned stimulus (US) during that phase. Participants were subjected to a differential fear conditioning procedure, followed by an extinction procedure. Afterwards, half of the participants were presented with information about a technical failure, which explained why the US had been absent during the extinction phase. The other participants received information that was unrelated to the US. During a subsequent presentation of the target conditioned stimulus (CS), only the former group of participants showed renewed anticipatory skin conductance responding and a return of US expectancy. The results are in accordance with a propositional account of associative learning and highlight the importance of retrospective reasoning as a cause of relapse after exposure therapy.     

Cross-US reinstatement of human conditioned fear: Return of old fears or emergence of new ones?

Re-exposure to the unconditioned stimulus (US) following fear extinction in the laboratory produces reinstatement of fear. Similarly in clinical situations, anxiety patients may experience adverse events that reinstate fear following successful exposure therapy. The current study employed two USs, shock and loud noise, to examine whether a US that is qualitatively different but of the same valence as the original acquisition US can produce reinstatement in human fear conditioning. Both standard and cross-US reinstatement manipulations led to elevated fear as indexed by skin conductance. However, cross-US reinstatement was accompanied by elevated expectancy of the US that had been presented during the reinstatement manipulation, not the US that had been used to establish fear in acquisition. This result implies that reinstatement may involve the development of new fears. Context conditioning and cognitive processes were implicated as possible mechanisms. The current findings suggest that clinical relapse attributed to reinstatement may not always reflect the reactivation of old fears but may instead represent new fears worthy of clinical examination.     

Return of fear in a human differential conditioning paradigm caused by a stimulus change after extinction

In a human fear conditioning experiment, 32 participants were trained in a differential conditioning procedure with geometrical shapes as CS+ and CS- (four presentations each), and an electric shock as US. Measures of conditioned responding were skin conductance response (SCR) and retrospective US-expectancy ratings. For half of the participants (Generalization Group, GG), the subsequent extinction phase consisted of four nonreinforced presentations of generalization stimuli (GS+ and GS-). Participants from the Extinction control Group received an equal amount of nonreinforced presentations of the CSs. Finally, all participants were tested with the original CSs. The results from both measures clearly show an increase in the size of the discrimination upon the stimulus change after extinction in the GG. Because this pattern is not observed in the Extinction control Group, extinction performance appears to be somehow restricted to the perceptual characteristics of the extinction stimulus. Interestingly, the size of the conditioned SCR discrimination in the GG is not influenced by the stimulus change after acquisition. This observation points to a differential impact of stimulus change after acquisition vs. extinction treatment. The findings are discussed from the theoretical perspective of renewal and the clinical perspective of Return of Fear.     

The effects of physical context changes and multiple extinction contexts on two forms of renewal in a conditioned suppression task with humans

Three experiments examined the effects of physical context changes and multiple extinction contexts on the renewal of conditioned suppression in humans. A conditioned suppression task used an undesirable event as the unconditional stimulus (US). One conditional stimulus (CS+) predicted the occurrence of the US and another (CS−) predicted US absence. In Experiment 1 (N = 32), conditioned suppression was acquired to the CS+ in one context and extinguished in a different context. An increase in suppression was found for the CS+ and not for the CS− when subsequent test trials were conducted in the acquisition context (ABA renewal). Experiment 2 (N = 32) tested for ABC Renewal and showed increased suppression to both the CS+ and CS− when test was conducted in a novel context. Experiment 3 (N = 80) showed that these two effects were abolished when extinction was conducted in multiple contexts. The experiments extend the ABA renewal of conditioned suppression found with non-human animal subjects and the reduction of renewal by extinction in multiple contexts. Context changes may also facilitate cue competition effects after training with elementary stimuli, as shown by the effects of US omission in the ABA and ABC renewal groups.     

Revisiting the learning-without-awareness question in human pavlovian autonomic conditioning: Focus on extinction in a dichotic listening paradigm

Numerous studies have indicated that, consistent with current “cognitive” accounts of information processing, human Pavlovian autonomic discrimination acquisition cannot occur without awareness of the CS-US relationship. However, extinction studies have suggested that awareness is not necessary, findings that, in information-processing terms, have been explained by assuming that the processing by the extinction stage is parallel (automatic) rather than serial (controlled). This explanation was tested in an 80-subject study. The first, acquisition phase was a standard semantic differential conditioning arrangement with a 96-db white noise as US, and a “long” CS-US interval of 8 s, with ten trials each of CS+ (paired with US) and CS− (unpaired) trials. In extinction (USs omitted), in order to obtain non-autonomic indices of processing and thereby test the information-processing account of “unaware” autonomic conditioning during extinction, a dichotic listening task was implemented, with the CSs presented in the unattended channel (ear), while the subject had to perform a semantic differential reaction task in an attended-to channel (other ear). In early extinction, the electrodermal response occurring at an interval of 9–15 s after CS onset (i.e., following placement of the US during acquisition) and the finger-pulse-volume response occurring at an interval of 4–11 s after CS onset both showed reliable conditioning, but reaction-time and subjective-report data for the recognized critical words indicated serial rather than parallel processing of the CSs during extinction.     

非条件刺激降低再评估对条件性恐惧消退的影响

诸多情绪障碍治疗的关键在于促进条件性恐惧反应的消退, 研究证明非条件刺激再评估能够引起恐惧反应的变化。本研究将非条件刺激降低再评估范式应用于消退训练, 以主观预期值、皮电反应作为恐惧反应指标, 考察恐惧习得后非条件刺激强度降低对条件性恐惧消退的影响, 并运用评价性条件作用探讨非条件刺激再评估的作用机制。结果表明：在消退阶段, 降低组对条件刺激的皮电反应显著低于控制组。同时评价性条件作用结果显示：经过非条件刺激再评估, 降低组较控制组对条件刺激的评价更为正性。说明非条件刺激降低再评估有效改变条件刺激的负性效价, 降低个体的恐惧反应、促进恐惧消退。     

The development of an attentional bias for angry faces following Pavlovian fear conditioning

Although it is well documented that fear responses develop following aversive Pavlovian conditioning, it is unclear whether fear learning also manifests in the form of attentional biases for fear-related stimuli. Boschen, Parker, and Neumann (Boschen, M. J., Parker, I., & Neumann, D. L. (2007). Changes in implicit associations do not occur simultaneously to Pavlovian conditioning of physiological anxiety responses. Journal of Anxiety Disorders, 21, 788-803.) showed that despite the acquisition of differential skin conductance conditioned responses to angry faces paired (CS+) and unpaired (CS−) with an aversive shock, development of implicit associations was not subsequently observed on the Implicit Association Test. In the present study, participants (N = 76) were assigned either to a Shock or NoShock group and completed a similar aversive Pavlovian conditioning procedure with angry face CS+ and CS− stimuli. Participants next completed a visual probe task in which the angry face CS+ and CS− stimuli were paired with angry face control stimuli and neutral faces. Results confirmed that differential fear conditioning was observed in the Shock group but not in the NoShock group, and that the Shock group subsequently showed a selective attentional bias for the angry face CS+ compared with the CS− and control stimuli during the visual probe task. The findings confirm the interplay between learning-based mechanisms and cognitive processes, such as attentional biases, in models of fear acquisition and have implications for treatment of the anxiety disorders.     

Lesions of rat infralimbic cortex enhance recovery and reinstatement of an appetitive Pavlovian response

The prefrontal cortex (PFC) has a well-established role in the inhibition of inappropriate responding, and evidence suggests that the infralimbic (IL) region of the rat medial PFC (MPFC) may be involved in some aspects of extinction of conditioned fear. MPFC lesions including, but not those sparing the IL cortex increase spontaneous recovery of extinguished conditioned fear when tested 24 h after an initial extinction session. The current experiment extended these findings by use of appetitive rather than aversive conditioning. Ten IL-lesioned and 11 sham-operated rats were trained on a Pavlovian task in which a conditioned stimulus (CS) was followed by food pellets (the unconditioned stimulus or US). IL lesions had no effect on extinction of the conditioned response (CR, magazine entries) during the first extinction session. However, the level of spontaneous recovery between the first extinction session and a second, 24 h later, was increased in IL-lesioned rats relative to sham animals. In contrast, evidence of savings measured between the extinction sessions did not differ between groups. Furthermore, reinstatement of the CR following unsignaled delivery of the US was also increased in IL-lesioned rats.