Timing of extinction relative to acquisition: A parametric analysis of fear extinction in humans.

Fear extinction is a reduction in conditioned fear following repeated exposure to the feared cue in the absence of any aversive event. Extinguished fear often reappears after extinction through spontaneous recovery. Animal studies suggest that spontaneous recovery can be abolished if extinction occurs within minutes of acquisition. However, a limited number of human extinction studies have shown that short interval extinction does not prevent the return of fear. For this reason, we performed an in-depth parametric analysis of human fear extinction using fear-potentiated startle. Using separate single-cue and differential conditioning paradigms, participants were fear conditioned and then underwent extinction either 10 min (Immediate) or 72 hr (Delayed) later. Testing for spontaneous recovery occurred 96 hr after acquisition. In the single cue paradigm, the Immediate and Delayed groups exhibited differences in context, but not fear, conditioning. With differential conditioning, there were no differences in context conditioning and the Immediate group displayed less spontaneous recovery. Thus, the results remain inconclusive regarding spontaneous recovery and the timing of extinction and are discussed in terms of performing translational studies of fear in humans. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Delayed extinction attenuates conditioned fear renewal and spontaneous recovery in humans.

This study investigated whether the retention interval after an aversive learning experience influences the return of fear after extinction training. After fear conditioning, participants underwent extinction training either 5 min or 1 day later and in either the same room (same context) or a different room (context shift). The next day, conditioned fear was tested in the original room. When extinction took place immediately, fear renewal was robust and prolonged for context-shift participants, and spontaneous recovery was observed in the same-context participants. Delayed extinction, by contrast, yielded a brief form of fear renewal that reextinguished within the testing session for context-shift participants, and there was no spontaneous recovery in the same-context participants. The authors conclude that the passage of time allows for memory consolidation processes to promote the formation of distinct yet flexible emotional memory traces that confer an ability to recall extinction, even in an alternate context, and minimize the return of fear. Furthermore, immediate extinction can yield spontaneous recovery and prolong fear renewal. These findings have potential implications for ameliorating fear relapse in anxiety disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Strain difference in the effect of infralimbic cortex lesions on fear extinction in rats.

The infralimbic division of the medial prefrontal cortex (IL) has been implicated in the consolidation and retention of extinction memories. However, the effects of IL lesions on the retention of extinction memory are inconsistent. In the present experiments, we examined whether rat strain influences the effects of IL lesions on extinction. In Experiment 1, Sprague-Dawley (SD) or Long-Evans (LE) rats received a standard auditory fear conditioning procedure, which was followed by an extinction session; freezing served as the index of conditional fear. Our results reveal that focal IL lesions impair the retention of extinction in SD, but not LE rats. In addition to the strain difference in sensitivity to IL lesions, LE rats exhibited significantly higher levels of contextual fear before the outset of extinction training than SD rats. In a second experiment we thus examined whether contextual fear influenced the sensitivity of extinction to IL lesions in LE rats. LE rats received the same conditioning as in Experiment 1, and then were either merely exposed to a novel context or administered unsignaled shocks in that context, followed by extinction and test sessions. Our results reveal that LE rats with IL lesions showed normal extinction regardless of the levels of contextual fear manifest before extinction. Thus, we conclude that rat strain is an important variable that influences the role of infralimbic cortex in fear extinction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Deepened extinction from compound stimulus presentation.

Three experiments with rats and 2 with pigeons explored the effect of presenting 2 extinguished excitatory stimuli in compound. Four learning situations were used: Pavlovian magazine approach, Pavlovian fear conditioning, and instrumental discriminative instrumental learning in rats, as well as Pavlovian sign tracking in pigeons. All 5 experiments confirmed D. Reberg's (1972) observation that even after extinction of the individual stimuli, presenting them in compound evoked substantial responding. Moreover, nonreinforcement of that compound deepened extinction of an element more substantially than did additional presentation of that element alone. Such compound exposure reduced spontaneous recovery, reduced reinstatement, and slowed subsequent reconditioning. The primary determinant seemed to be the enhanced associative strength rather than the enhanced conditioned responding that occurred during the nonreinforced compound. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction.

Several recent studies have shown that chromatin, the DNA-protein complex that packages genomic DNA, has an important function in learning and memory. Dynamic chromatin modification via histone deacetylase (HDAC) inhibitors and histone acetyltransferases may enhance hippocampal synaptic plasticity and hippocampus-dependent memory. Little is known about the effects of HDAC inhibitors on extinction, a learning process through which the ability of a previously conditioned stimulus, such as a conditioning context, to evoke a conditioned response is diminished. The authors demonstrate that administration of the HDAC inhibitors sodium butyrate (NaB) systemically or trichostatin A (TSA) intrahippocampally prior to a brief (3-min) contextual extinction session causes context-evoked fear to decrease to levels observed with a long (24-min) extinction session. These results suggest that HDAC inhibitors may enhance learning during extinction and are consistent with other studies demonstrating a role for the hippocampus in contextual extinction. Molecular and behavioral mechanisms through which this enhanced extinction effect may occur are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Observational fear conditioning in the acquisition and extinction of attentional bias for threat: An experimental evaluation.

Anxious persons show automatic and strategic attentional biases for threatening information. Yet, the mechanisms and processes that underlie such biases remain unclear. The central aim of the present study was to elucidate the relation between observational threat learning and the acquisition and extinction of biased threat processing by integrating emotional Stroop color naming tasks within an observational differential fear conditioning procedure. Forty-three healthy female participants underwent several consecutive observational fear conditioning phases. During acquisition, participants watched a confederate displaying mock panic attacks (UCS) paired with a verbal stimulus (CS+), but not with a second nonreinforced verbal stimulus (CS-). As expected, participants showed greater magnitude electrodermal and verbal-evaluative (e.g., distress, fear) conditioned responses to the CS+ over the CS- word. Participants also demonstrated slower color-naming latencies to CS+ compared to the CS- word following acquisition and showed attenuation of this preferential processing bias for threat following extinction. Findings are discussed broadly in the context of the interplay between fear learning and processing biases for threat as observed in persons suffering from anxiety disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned stimulus familiarity determines effects of MK-801 on fear extinction.

Six experiments studied the role of conditioned stimulus (CS) familiarity in determining the effects of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 on fear extinction. Systemic administration of MK-801 (0.1 mg/kg) impaired initial extinction but not reextinction learning. MK-801 impaired reextinction learning when the CS was relatively novel during reextinction training but not initial extinction learning when the CS was relatively familiar during initial extinction training. A context change failed to reinstate the sensitivity of initial fear extinction learning about a relatively familiar CS to MK-801. These experiments show that CS familiarity is an important determinant of effects of MK-801 on fear extinction learning: MK-801 impaired extinction learning about novel stimuli but spared extinction learning about familiar stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired trace and contextual fear conditioning in aged rats.

Trace and contextual fear conditioning were evaluated in adult (3-6 months), early middle-aged (8-12 months), late middle-aged (16-20 months), and aged (24-33 months) Sprague-Dawley rats. After trace conditioning, aged animals exhibited significantly less freezing to the tone conditioned stimulus and training context. Levels of trace-cue and context conditioning were negatively correlated with age (r = -0.56 and -0.59, respectively) and positively correlated with each other (r = +0.52). Aged rats showed robust conditioning in short- and long-delay fear paradigms, suggesting that the trace interval, rather than the use of a long interstimulus interval, is responsible for the aging-related deficits in trace fear conditioning. The authors suggest that these aging-related conditioning deficits furnish useful indices of functional changes within hippocampus or perirhinal cortex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spontaneous recovery of extinguished fear responses deepens their extinction: A role for error-correction mechanisms.

A series of experiments used a within-subject design to study spontaneous recovery of fear responses (freezing) to an extinguished conditioned stimulus (CS) in rats. Experiments 1, 2, 3, and 4 demonstrated that: a remotely extinguished CS elicited more freezing than a recently extinguished one on a common test; that the CS showing recovery underwent greater response loss across additional extinction than the one lacking recovery; and that spontaneous recovery and deepening of response loss survived reconditioning. Experiment 5 demonstrated that an excitor extinguished in compound with a CS showing recovery suffered greater loss than an excitor extinguished in compound with a CS not showing recovery, implying that the differential change is regulated by a common error term. Experiments 6 and 7 demonstrated that extinction of a compound composed of two CSs, one showing recovery and a second lacking recovery, produced greater loss to the CS that showed recovery, implying that the change is also regulated by individual error term. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amygdalar unit activity during three learning tasks: Eyeblink classical conditioning, Pavlovian fear conditioning, and signaled avoidance conditioning.

Neural activity in central and basolateral amygdala nuclei (CeA and BLA, respectively) was recorded during delay eyeblink conditioning, Pavlovian fear conditioning, and signaled barpress avoidance. During paired training, the CeA exhibited robust learning-related excitatory activity during all 3 tasks. By contrast, the BLA exhibited minimal activity during eyeblink conditioning, while demonstrating pronounced increases in learning-related excitatory responsiveness during fear conditioning and barpress avoidance. In addition, the relative amount of amygdalar activation observed appeared to be related to the relative intensity of the unconditioned stimulus and somatic requirements of the task. Results suggest the CeA mediates the Pavlovian association between sensory stimuli and the BLA mediates the modulation of instrumental responding through the assignment of motivational value to the unconditioned stimulus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Temporally massed CS presentations generate more fear extinction than spaced presentations.

Rodent fear conditioning models both excitatory learning and the pathogenesis of human anxiety, whereas extinction of conditional fear is a paradigm of inhibitory learning and the explicit model for behavior therapy. Many studies support a general learning rule for acquisition: Temporally spaced training is more effective than massed training. The authors asked whether this rule applies to extinction of conditional fear in mice. The authors find that both short- and long-term fear extinction are greater with temporally massed presentations of the conditional stimulus (CS). The data also indicate that once CS presentations are sufficiently massed to initiate, or "induce," extinction learning, further CS presentations are more effective when spaced. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reversal learning and resistance to extinction: A supplementary report.

Several very recent and highly relevant articles provide substantiation for some hypotheses advanced in a previous review in an analysis of the overtraining reversal data. These same data permit the rejection of an hypothesis advanced by another reviewer to account for the results. It can now be shown fairly conclusively that amount of reward determines the direction of the ORE following position response training and that the variables affecting overtraining reversal data with exteroceptive discriminative stimuli remain unidentified. (16 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of yohimbine on the extinction of conditioned fear: A role for context.

Six experiments with rat subjects examined the effect of yohimbine, an alpha-2 adrenergic autoreceptor antagonist, on the extinction of conditioned fear to a tone. Experiments 1 and 2 demonstrated that systemic administration of yohimbine (1.0 mg/kg) facilitated a long-term decrease in freezing after extinction, and this depended on pairing drug administration with extinction training. However, Experiments 3 and 4 demonstrated that yohimbine did not eradicate the original fear learning: Freezing was renewed when the tone was tested outside of the extinction context. Experiments 5 and 6 found that the contextually specific attenuation of fear produced by yohimbine transferred to another extinguished conditional stimulus (CS) and not to a nonextinguished CS. The results suggest that yohimbine, when administered in the presence of a neutral context, creates a form of inhibition in that context that allows that specific context to reduce fear of an extinguished CS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spatial exploration is required for the formation of contextual fear memory.

The acquisition of contextual fear in mice is thought to require the formation of a conjunctive representation of the conditioning chamber. This can be achieved during a minimum of 20 to 40 s of exploration immediately prior to the shock or during preexposure to the context at an earlier time. An animal receiving less time in the chamber will show reduced freezing 24 hr later, a condition termed the immediate shock deficit (ISD). In this study, the authors have attempted to uncouple the formation of a contextual representation, based on the conjunction of a defined set of cues, from the establishment of a spatial representation, which requires active exploration, by inserting a transparent plastic partition in the center of the chamber. Taking advantage of the ISD and the context preexposure effect, the authors found that animals preexposed to one side of the chamber on Day 1, but shocked on the other side on Day 2, show significantly less fear than animals exposed to and shocked on the same side. Our results indicate that spatial exploration is necessary for mice to benefit from contextual preexposure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rapid reacquisition of fear to a completely extinguished context is replaced by transient impairment with additional extinction training.

A series of experiments studied reacquisition of fear reactions to a completely extinguished context. Reacquisition was rapid when reconditioning occurred as soon as the fear reactions were completely extinguished, showing that the original conditioning was intact. However, when reconditioning occurred after massive extinction training, fear reactions were depressed but then recovered across a long retention interval. This recovery was due to reconditioning and was similar to that produced by conditioning a massively preexposed context. These results show that massive extinction converts a potentially dangerous context into one that is merely familiar. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Facilitation of fear extinction by midbrain periaqueductal gray infusions of rb101(s), an inhibitor of enkephalin-degrading enzymes.

μ-Opioid receptors in the ventrolateral quadrant midbrain periaqueductal gray (vIPAG) contribute to extinction of conditioned fear. The present experiment studied whether fear extinction could be facilitated by infusions of a peptidase inhibitor that reduces catabolism of vIPAG enkephalins. Rats were trained to fear an auditory conditioned stimulus. Fear was then extinguished. Extinction training was preceded by infusions of vehicle or RB101(S), an inhibitor of enkephalin catabolising enzymes. RB101(S) dose dependently facilitated extinction as indexed by performance during extinction and on a drug-free test. This facilitation was not observed when RB101(S) was infused outside the vIPAG. These results confirm that vIPAG endogenous opioids contribute to fear extinction and show that extinction can be facilitated by manipulations that increase vIPAG opioid neuromodulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fear conditioning in panic disorder: Enhanced resistance to extinction.

Enhanced conditionability has been proposed as a crucial factor in the etiology and maintenance of panic disorder (PD). To test this assumption, the authors of the current study examined the acquisition and extinction of conditioned responses to aversive stimuli in PD. Thirty-nine PD patients and 33 healthy control participants took part in a differential aversive conditioning experiment. A highly annoying but not painful electrical stimulus served as the unconditioned stimulus (US), and two neutral pictures were used as either the paired conditioned stimulus (CS+) or the unpaired conditioned stimulus (CS-). Results indicate that PD patients do not show larger conditioned responses during acquisition than control participants. However, in contrast to control participants, PD patients exhibited larger skin conductance responses to CS+ stimuli during extinction and maintained a more negative evaluation of them, as indicated by valence ratings obtained several times throughout the experiment. This suggests that PD patients show enhanced conditionability with respect to extinction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A role for α?-adrenergic receptors in extinction of conditioned fear and cocaine conditioned place preference.

Previous work has demonstrated an important role for adrenergic receptors in memory processes in fear and drug conditioning paradigms. Recent studies have also demonstrated alterations in extinction in these paradigms using drug treatments targeting β- and α2-adrenergic receptors, but little is known about the role of α?-adrenergic receptors in extinction. The current study examined whether antagonism of α?-adrenergic receptors would impair the consolidation of extinction in fear and cocaine conditioned place preference paradigms. After contextual fear conditioning, injections of the α?-adrenergic receptor antagonist prazosin (1.0 or 3.0 mg/kg) following nonreinforced context exposures slowed the loss of conditioned freezing over the course of 5 extinction sessions (Experiment 1). After cocaine place conditioning, prazosin had no effect on the rate of extinction over 8 nonreinforced test sessions. Following postextinction reconditioning, however, prazosin-treated mice showed a robust place preference, but vehicle-treated mice did not, suggesting that prazosin reduced the persistent effects of extinction (Experiment 2). These results confirm the involvement of the α?-adrenergic receptor in extinction processes in both appetitive and aversive preparations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Potentiation and overshadowing in Pavlovian fear conditioning.

The present experiments addressed a fundamental discrepancy in the Pavlovian conditioning literature concerning responding to a target cue following compound reinforced training with another cue of higher salience. Experiment 1 identified one determinant of whether the target cue will be overshadowed or potentiated by the more salient cue, namely contiguity between compound CS termination and US presentation. Overshadowing and potentiation were observed with delay and trace procedures, respectively. Experiments 2 and 3 contrasted elemental and configural explanations of potentiation. Both experiments supported a configural account. Experiments 3 and 4, by manipulating prior learning experiences to bias subjects to encode the same compound elementally or configurally, demonstrated decreased potentiation and overshadowing, respectively. Overall, these experiments demonstrate potentiation with nontaste stimuli and identify one variable that determines whether overshadowing or potentiation will occur. Moreover, they show that prior experiences can determine how a compound is encoded and are compatible with the idea of flexible encoding as a principle of information processing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Resistance to extinction in evaluative conditioning.

A well-demonstrated phenomenon in traditional Pavlovian conditioning research with humans is that of experimental extinction. In contrast, human evaluative conditioning research suggests that evaluative learning shows marked resistance to extinction. Here, the authors replicate both findings concurrently. Two differential fear conditioning experiments with an electrocutaneous stimulus as the unconditioned stimulus evidenced (a) sensitivity to extinction using an autonomic skin-conductance measure and (b) complete resistance to extinction using an affective-priming measure. The results corroborate the idea that evaluative conditioning is more resistant to extinction than is expectancy learning (F. Baeyens, P. Eelen, & G. Crombez, 1995). (PsycINFO Database Record (c) 2011 APA, all rights reserved)