Neural systems involved in fear and anxiety measured with fear-potentiated startle

A good deal is now known about the neural circuitry involved in how conditioned fear can augment a simple reflex (fear-potentiated startle). This involves visual or auditory as well as shock pathways that project via the thalamus and perirhinal or insular cortex to the basolateral amygdala (BLA). The BLA projects to the central (CeA) and medial (MeA) nuclei of the amygdala, which project indirectly to a particular part of the acoustic startle pathway in the brainstem. N-methyl-D-aspartate (NMDA) receptors, as well as various intracellular cascades in the amygdala, are critical for fear learning, which is then mediated by glutamate acting in the CeA. Less predictable stimuli, such as a long-duration bright light or a fearful context, activate the BLA, which projects to the bed nucleus of the stria terminalis (BNST), which projects to the startle pathway much as the CeA does. The anxiogenic peptide corticotropin-releasing hormone increases startle by acting directly in the BNST. CeA-mediated behaviors may represent stimulus-specific fear, whereas BNST-mediated behaviors are more akin to anxiety. NMDA receptors are also involved in extinction of conditioned fear, and both extinction in rats and exposure-based psychotherapy in humans are facilitated by an NMDA-partial agonist called D-cycloserine. ((c) 2006 APA, all rights reserved).     

Enhancing exposure-based therapy from a translational research perspective

Combining an effective psychological treatment with conventional anxiolytic medication is typically not more effective than unimodal therapy for treating anxiety disorders. However, recent advances in the neuroscience of fear reduction have led to novel approaches for combining psychological therapy and pharmacological agents. Exposure-based treatments in humans partly rely on extinction to reduce the fear response in anxiety disorders. Animal studies have shown that D-cycloserine (DCS), a partial agonist at the glycine recognition site of the glutamatergic N-methyl-D-aspartate receptor facilitates extinction learning. Similarly, recent human trials have shown that DCS enhances fear reduction during exposure therapy of some anxiety disorders. This article discusses the biological and psychological mechanisms of extinction learning and the therapeutic value of DCS as an augmentation strategy for exposure therapy. Areas of future research will be identified.     

Recalling safety: cooperative functions of the ventromedial prefrontal cortex and the hippocampus in extinction

Anxiety disorders are commonly treated with exposure-based therapies that rely on extinction of conditioned fear. Persistent fear and anxiety following exposure therapy could reflect a deficit in the recall of extinction learning. Animal models of fear learning have elucidated a neural circuit for extinction learning and recall that includes the amygdala, ventromedial prefrontal cortex (vmPFC), and hippocampus. Whereas the amygdala is important for extinction learning, the vmPFC is a site of neural plasticity that allows for the inhibition of fear during extinction recall. We suggest that the vmPFC receives convergent information from other brain regions, such as contextual information from the hippocampus, to determine the circumstances under which extinction or fear will be recalled. Imaging studies of human fear conditioning and extinction lend credence to this extinction network. Understanding the neural circuitry underlying extinction recall will lead to more effective therapies for disorders of fear and anxiety.     

Safety Behavior After Extinction Triggers a Return of Threat Expectancy

Safety behavior is involved in the maintenance of anxiety disorders, presumably because it prevents the violation of negative expectancies. Recent research showed that safety behavior is resistant to fear extinction. This fear conditioning study investigated whether safety behavior after fear extinction triggers a return of fear in healthy participants. Participants learned that two stimuli (A and C) were followed by an aversive loud noise (“threat”), and one stimulus (B) was not. Participants then learned to use safety behavior that prevented the loud noise. Next, A and C were no longer followed by the loud noise, which typically led to extinction of threat expectancy. Safety behavior then became available again for C, but not for A and B. All participants used safety behavior on these C trials. In a final test phase, A, B, and C were presented once without the availability to use safety behavior. At each stimulus presentation, participants rated threat expectancy by indicating to what extent they expected that the loud noise would follow. Compared with the last extinction trial, threat expectancy increased for C in the test phase, whereas it did not increase for A and B. Hence, safety behavior after the extinction of classically conditioned fear caused a partial return of fear. The findings suggest that safety behavior may be involved in relapse after exposure-based therapy for anxiety disorders.     

Clinical perspectives on the combination of D-cycloserine and cognitive-behavioral therapy for the treatment of anxiety disorders

In a particular success for translational research agendas, characterization of the neuronal circuits underlying fear extinction, and basic research in animal extinction paradigms, has led to intervention studies examining the use of D-cycloserine (DCS) to enhance therapeutic learning from exposure-based cognitive-behavioral therapy (CBT). In this article, we review these intervention studies, and discuss DCS augmentation of CBT relative to more traditional combination-treatment strategies in the treatment of anxiety disorders. We offer an accounting, based on evidence for internal context effects, of current limitations in the combination of antidepressant or benzodiazepine medications with CBT and discuss the advantages of isolated-dosing strategies with DCS relative to these limitations. This strategy is contrasted with the chronic-dosing applications of DCS for schizophrenia and Alzheimer's disease, and future directions for isolated-dosing strategies are discussed.     

A randomized controlled trial of the effect of D-cycloserine on extinction and fear conditioning in humans

Previous research has shown that D-cycloserine (DCS) facilitates extinction of Pavlovian fear conditioning in rats and enhances exposure therapy in humans. The aim of this study was to test the effect of DCS on extinction of fear conditioning in humans. In three experiments, 238 participants were given either DCS (50 or 500 mg) or placebo 2-3 h before extinction training following a differential shock conditioning paradigm. Clear extinction and recovery (return of fear) effects were observed on both skin conductance and self-reported shock expectancy measures in three studies. DCS had no influence on these effects. The same pattern was observed when the analysis was restricted to aware participants or to good conditioners, when fear-relevant cues (pictures of snakes) were used as the conditioned stimuli, or when analysis was restricted to heightened snake-fearful participants. These results suggest that DCS may not enhance the extinction, or prevent the recovery, of learned fear in a differential Pavlovian conditioning paradigm in humans. Further experimental research is needed to better understand the mechanisms underlying the therapeutic effects of DCS.     

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.     

Neurocognitive mechanisms of anxiety: an integrative account

Anxiety can be hugely disruptive to everyday life. Anxious individuals show increased attentional capture by potential signs of danger, and interpret expressions, comments and events in a negative manner. These cognitive biases have been widely explored in human anxiety research. By contrast, animal models have focused upon the mechanisms underlying acquisition and extinction of conditioned fear, guiding exposure-based therapies for anxiety disorders. Recent neuroimaging studies of conditioned fear, attention to threat and interpretation of emotionally ambiguous stimuli indicate common amygdala-prefrontal circuitry underlying these processes, and suggest that the balance of activity within this circuitry is altered in anxiety, creating a bias towards threat-related responses. This provides a focus for future translational research, and targeted pharmacological and cognitive interventions.     

人类记忆再巩固研究现状及临床应用

巩固的记忆被提取后,进入不稳定状态,再重新稳定下来,这个过程称为记忆再巩固。本文首先阐述人类记忆再巩固主要研究方法和经典范式,梳理记忆再巩固在人类恐惧记忆和情景记忆两个方面的相关研究,并从认知神经科学角度整理记忆再巩固的加工机制。然后总结记忆再巩固应用于创伤性应激障碍和药物成瘾等心理障碍临床治疗的相关文献。最后本文提出未来研究的方向和建议,希冀对人类记忆再巩固的理论研究和临床应用提供新思路。     

Non-differential return of fear in humans after a reinstatement procedure

The present experiment investigated reinstatement of fear in humans using a differential fear conditioning preparation. In this experiment, one neutral stimulus (conditioned stimulus; CS+) was paired with an aversive stimulus (unconditioned stimulus; US) during the acquisition phase, while another neutral stimulus was not (CS−). This procedure led to a difference in responding between the CS+ and the CS− (i.e., differential conditioning). After this acquisition phase, an extinction phase followed, during which both CSs were presented without the US, resulting in a decrease in differential conditioned responding. Reinstatement refers to the return of extinguished conditioned responses due to the experience of US-only trials after the extinction phase. This phenomenon was investigated by presenting half of the participants (reinstatement group) with unpredictable USs after the extinction phase. The control group did not receive these USs after the extinction procedure. The results show that return of fear was clearly apparent after the reinstating USs. This return of fear was, however, not limited to the CS+. An increase in ‘conditioned’ responding was also observed for the control stimulus. This interesting observation will be discussed against the background of a number of recent theoretical conceptualizations of reinstatement.     

Conducting extinction in multiple contexts does not necessarily attenuate the renewal of shock expectancy in a fear-conditioning procedure with humans

The renewal of Pavlovian-conditioned responses may provide a model for the relapse of fear following extinction-based treatments for anxiety disorders. Renewal can be observed if conditional stimulus (CS) and unconditional stimulus (US) pairings are given in one context, extinction trials of CS presentations in a second context, prior to test trials of CS presentations in the original acquisition context (ABA renewal). We examined ABA renewal in humans by using a fear-conditioning procedure with an unpleasant shock US. A renewal of rated shock expectancy was demonstrated with this procedure. Conducting extinction treatment in multiple contexts was expected to attenuate the renewal effect. However, the renewal of shock expectancy persisted when extinction treatment was given across three or five different contexts. With the current renewal design, learning task, and measure of conditioned behaviour, extinction treatment does not appear to readily generalise to the test context. The use of multiple extinction treatments in a clinical setting may not necessarily reduce the likelihood of relapse via a renewal effect.     

Classical fear conditioning in the anxiety disorders: a meta-analysis

Fear conditioning represents the process by which a neutral stimulus comes to evoke fear following its repeated pairing with an aversive stimulus. Although fear conditioning has long been considered a central pathogenic mechanism in anxiety disorders, studies employing lab-based conditioning paradigms provide inconsistent support for this idea. A quantitative review of 20 such studies, representing fear-learning scores for 453 anxiety patients and 455 healthy controls, was conducted to verify the aggregated result of this literature and to assess the moderating influences of study characteristics. Results point to modest increases in both acquisition of fear learning and conditioned responding during extinction among anxiety patients. Importantly, these patient-control differences are not apparent when looking at discrimination studies alone and primarily emerge from studies employing simple, single-cue paradigms where only danger cues are presented and no inhibition of fear to safety cues is required.     

条件性恐惧记忆消退返回的性别差异

采用预期判断任务考察男女性对已消退的条件性恐惧记忆是否会出现消退返回的现象。结果表明: (1)在对已习得的条件性恐惧记忆消退后4个小时进行测试, 被试整体会出现明显的消退返回现象; (2)对消退返回现象的性别差异进行比较, 女性比男性的消退返回现象更突出, 并且差异显著; (3)与男性相比, 女性对条件性恐惧记忆具有易习得难消退的趋势, 但是性别差异不显著。研究结果验证了消退返回现象存在的普遍性, 并且有着显著的性别差异, 为以后对创伤后应激障碍患者的治疗应考虑性别因素提供了心理学依据。     

The Effect of Counterconditioning on Evaluative Responses and Harm Expectancy in a Fear Conditioning Paradigm

In fear conditioning, extinction targets harm expectancy as well as the fear response, but it often fails to eradicate the negative affective value that is associated with the conditioned stimulus. In the present study, we examined whether counterconditioning can serve to reduce evaluative responses within fear conditioning. The sample consisted of 70 nonselected students, 12 of whom were men. All participants received acquisition with human face stimuli as the conditioned stimuli and an unpleasant white noise as the unconditioned stimulus. After acquisition, one third of the sample was allocated to an extinction procedure. The other participants received counterconditioning with either a neutral stimulus (neutral tone) or a positive stimulus (baby laugh). Results showed that counterconditioning (with both neutral and positive stimuli), in contrast to extinction, successfully reduced evaluative responses. This effect was found on an indirect measure (affective priming task), but not on self-report. Counterconditioning with a positive stimulus also tended to enhance the reduction of conditioned skin conductance reactivity. The present data suggest that counterconditioning procedures might be a promising approach in diminishing evaluative learning and even expectancy learning in the context of fear conditioning.     

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.     

条件性恐惧泛化的性别差异

恐惧的过度泛化是焦虑障碍的核心症状之一, 表现为患者对与原危险刺激极不相似的中性刺激也有着较高强度的恐惧反应。临床上, 女性比男性更有可能患焦虑障碍, 因而对恐惧泛化进行性别差异研究可以为解释女性有着更高焦虑障碍发病率提供新的角度, 同时为临床治疗提供参考。本研究采用辨别性条件恐惧范式, 以主观预期值和皮电反应值作为测量指标, 从行为和生理两个层面对条件性恐惧泛化程度和恐惧泛化消退的性别差异进行研究。结果发现, 在恐惧泛化程度上, 未出现显著性别差异。在恐惧泛化消退上, 在主观预期值和皮电反应值两个层面均有着显著性别差异, 具体表现为相较于男性, 女性恐惧泛化的消退更慢, 持续时间更长。研究结果表明, 女性焦虑障碍高发病率的潜在影响因素之一可能在于女性对于恐惧泛化刺激的难以消除。     

Instructed fear learning,extinction, and recall: additive effects of cognitive information on emotional learning of fear

The effects of instruction on learning of fear and safety are rarely studied. We aimed to examine the effects of cognitive information and experience on fear learning. Fourty healthy participants, randomly assigned to three groups, went through fear conditioning, extinction learning, and extinction recall with two conditioned stimuli (CS+). Information was presented about the presence or absence of conditioned stimulus–unconditioned stimulus (CS–US) contingency at different stages of the experiment. Information about the CS–US contingency prior to fear conditioning enhanced fear response and reduced extinction recall. Information about the absence of CS–US contingency promoted extinction learning and recall, while omission of this information prior to recall resulted in fear renewal. These findings indicate that contingency information can facilitate fear expression during fear learning, and can facilitate extinction learning and recall. Information seems to function as an element of the larger context in which conditioning occurs.     

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.     

Facilitation of fear extinction by D-cycloserine: theoretical and clinical implications

Anxiety disorders are among the most common psychological disturbances in the industrialized world. Current behavioral therapy procedures for these disorders are somewhat effective, but their efficacy could be substantially improved. Because these procedures are largely based on the process of extinction, manipulations that enhance extinction may lead to improvements in treatment effectiveness. We review the evidence that D-cycloserine (DCS), a partial NMDA agonist, facilitates extinction of learned fear in rats. Although only a few studies have examined the effects of DCS on extinction of learned fear, this work suggests that this drug may have a number of potential clinical benefits. In addition, attempts at interpreting this research illustrate our limited understanding of the processes involved in extinction.     

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.