预期错误在复合恐惧记忆提取消退中的作用

基于记忆再巩固理论的提取消退范式被证明是一种有效和颇有前景的消除不良记忆的方法。本研究将预期错误(Prediction Error, PE)应用于提取消退范式中, 采用多感官复合刺激模型(声音 + 图片)作为条件刺激, 以皮电反应作为恐惧反应指标, 考察在提取阶段不同的预期错误设置(无PE、单个负性PE、单个正性PE和多重PE)对条件性恐惧记忆提取消退效果有何差异。结果表明：无PE组和多重PE组出现了恐惧的自发恢复和重建效应, 而负性PE组和正性PE组均没有出现恐惧的自发恢复和重建效应。说明了在对复合恐惧记忆进行提取消退时, 提取阶段适当的PE才能使记忆进入再巩固过程, 随后传统消退达到抑制恐惧返回效果, 提取阶段没有PE或PE量过多都不能达到恐惧消退效果。     

条件性恐惧提取消退的性别差异

基于记忆再巩固理论的提取消退范式能够有效地削弱非适应性恐惧记忆。性别差异是个体差异性研究的关键变量, 但在提取消退范式的研究中仍然比较少见关于性别差异的探索。因此本研究以立体几何图形作为条件刺激, 腕部电击作为非条件刺激, 皮肤电反应为恐惧反应指标, 探究提取消退范式在恐惧消退效果上是否存在性别差异。结果表明, 在恐惧自发恢复测试中, 提取消退范式的所有被试都成功抑制了恐惧复发, 但恐惧重建测试中只有女性被试抑制了恐惧复发。这说明, 提取消退范式在抑制恐惧自发恢复方面效果显著, 在恐惧重建上女性的消退效果显著优于男性。     

预期错误与急性应激对不同强度恐惧记忆提取消退的影响

在条件性恐惧记忆再巩固模型下, 预期错误被证明是引发记忆不稳定的必要条件, 但其在不同强度恐惧记忆下的作用尚不明确。对于高强度可能导致的提取无效, 缺乏相应的探索以寻找解决办法, 而应激(stress)在其中发挥的作用值得探索。本研究考察人类被试中, 预期错误在不同强度恐惧记忆下的作用, 以及提取之后施加外源性应激对于消退进程的影响。结果发现, 对于较弱的恐惧记忆, 单个预期错误提取后消退可显著抑制恐惧自发恢复; 而对于较强恐惧记忆, 单个预期错误不能提取恐惧记忆进入再巩固, 已消退的记忆还会复发; 且在该种情况下, 如果在提取后施加外源性急性应激, 会进一步增大恐惧恢复。     

认知重评对负性效价的抑制促进条件性恐惧消退

认知重评能有效降低个体对情感刺激的负性情绪体验, 但指导性认知重评在恐惧记忆治疗中效果存在争议。本文将认知重评范式与辨别式条件恐惧反应范式结合, 以效价和US预期值为指标, 探讨指导性认知重评训练对恐惧情绪习得和消退的影响效果。以低认知重评能力个体为被试, 在实验前24 h进行指导性认知重评训练。条件性恐惧任务为期2天, 第一天完成条件性恐惧的习得和消退任务, 第二天完成条件性恐惧的再消退任务。结果显示, 经过重评训练后个体在条件性恐惧任务中的恐惧情绪效价显著较低, 说明认知重评有效降低低认知重评能力个体在急性应激状态下的负性情绪体验。所有被试均成功完成辨别式条件性恐惧的习得和消退任务, 因此重评训练并不削弱个体对危险或者安全信息的辨别能力。但在条件性恐惧的消退过程中, 认知重评指导训练加快了恐惧消退, 且24 h后测得的条件性恐惧程度显著较低, 说明指导性重评提高了条件性恐惧记忆的消退效率, 并减弱了条件性恐惧的消退返回。     

远期恐惧记忆再巩固更新机制的线索选择性特点

已有动物和人类研究均表明, 通过记忆的再巩固更新机制能有效削弱新形成的条件性恐惧记忆(1天), 并且存在线索选择性特点。然而创伤后应激障碍(PTSD)往往在形成相当一段时间后才能得到治疗, 且现实生活中人们通常一次习得对多个线索的恐惧。因此找到针对多线索创伤记忆的有效治疗方法显得尤为重要。目前未有人研究远期恐惧记忆的再巩固更新机制是否存在线索选择性特点。为探究远期恐惧记忆(>7天)的再巩固更新机制是否同样存在线索选择性特点, 本研究采用被试内实验设计, 以皮肤电作为恐惧反应指标, 多个线索作为条件刺激进行恐惧习得, 习得14天后给被试单独呈现一个线索进行恐惧记忆提取, 10分钟后进行消退训练, 24小时后对不同线索进行自发恢复测试。结果显示：未提取线索的自发恢复程度显著高于提取线索。说明远期记忆(14天)的再巩固更新机制同样存在线索选择性特点, 并确认了提取消退作为一种行为手段对远期恐惧记忆再巩固进行干预的有效性, 对临床干预具有一定指导意义。     

条件性恐惧记忆提取消退干预范式

提取消退(retrieval-extinction, Ret+Ext)范式是基于记忆再巩固理论, 利用消退训练(extinction, Ext)能改变条件刺激(conditioned stimulus, CS)的恐惧效价特点, 把消退训练应用到再巩固时间窗内来改写(rewrite)恐惧记忆, 消除恐惧反应。提取消退范式是对传统暴露疗法和药物治疗的创新和拓展, 不仅为创伤性记忆的治疗提供一种非侵入性的技术, 而且也为改写人类记忆、积极心理学探索人类幸福感方面开辟了一种全新的理论视角。     

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。     

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。     

阻碍条件性恐惧记忆消退的原因分析

创伤后应激障碍是个体经历严重应激后形成的一种焦虑障碍,对其治疗的关键是消退由创伤应激导致的条件性恐惧记忆,但目前最有效的暴露疗法并不能真正有效地抑制患者恐惧记忆的表达.对条件性恐惧的动物模型研究发现情绪性增强效应、恐惧记忆二级条件化与再巩固、内侧前额叶皮层功能不足等均能够阻碍条件性恐惧记忆的消退.针对这几个方面可以探索治疗创伤后应激障碍的相应方法.     

自悯写作对恐惧消退的促进作用

先前研究表明,自悯干预能够改善焦虑相关精神疾病的心理症状,然而自悯改善焦虑的作用机制尚不清楚。以恐惧消退为基础的暴露疗法是治疗焦虑症的关键疗法,研究自悯干预如何促进恐惧消退从而增强暴露疗法的效果有助于阐释暴露疗法的作用机制。本研究共56名有效健康被试,在恐惧习得之后,将匹配自悯水平和焦虑水平的被试随机分配进行自悯写作或非自悯日常写作,最后进行恐惧消退测试,并通过检测写作前后的正负性情绪变化以及恐惧消退早期、晚期的电击预期反应和皮肤电反应来探究自悯写作对恐惧消退的影响及其作用机制。结果显示,两种写作任务均降低了被试的负性情绪;相比于非自悯日常写作,自悯写作显著降低了被试在恐惧消退早期和晚期的对威胁和安全线索的电击预期反应。相比于消退晚期,自悯组消退早期的皮肤电反应更弱。这一结果表明,自悯写作能够调节对威胁和安全线索的反应来促进恐惧消退。本研究首次运用实验室恐惧消退模型探讨自我怜悯调节威胁刺激的加工机制,有助于解释自悯改善焦虑症状的心理和生理机制,并强调了在基于恐惧消退范式的暴露疗法中增加认知干预的必要性。     

Mismatch between what is expected and what actually occurs triggers memory reconsolidation or extinction

In previous experiments on contextual memory, we proposed that the unreinforced re-exposure to the learning context (conditioned stimulus, CS) acts as a switch guiding the memory course toward reconsolidation or extinction, depending on reminder duration. This proposal implies that the system computes the total exposure time to the context, from CS onset to CS offset, and therefore, that the reminder presentation must be terminated for the switching mechanism to become operative. Here we investigated to what extent this requirement is necessary, and we explored the relation between diverse phases in the reconsolidation and extinction processes. We used the contextual memory model of the crab Chasmagnathus which involves an association between the learning context (CS) and a visual danger stimulus (unconditioned stimulus, US). Administration of cycloheximide was used to test the lability state of memory at different time points. The results show that two factors, no-reinforcement during the reminder (i.e., CS re-exposure) and CS offset are the necessary conditions for both processes to occur. Regardless of the reminder duration, memory retrieved by unreinforced CS re-exposure emerges intact and consolidated when tested before CS offset, suggesting that neither reconsolidation nor extinction is concomitant with CS re-exposure. Either process could only be triggered once the definitive mismatch between CS and US is confirmed by CS termination without the expected reinforcement.     

Different mechanisms of fear extinction dependent on length of time since fear acquisition

Fear extinction is defined as a decline in conditioned fear responses (CRs) following nonreinforced exposure to a feared conditioned stimulus (CS). Behavioral evidence indicates that extinction is a form of inhibitory learning: Extinguished fear responses reappear with the passage of time (spontaneous recovery), a shift of context (renewal), and unsignaled presentations of the unconditioned stimulus (reinstatement). However, there also is evidence to suggest that extinction is an "unlearning" process corresponding to depotentiation of potentiated synapses within the amygdala. Because depotentiation is induced more readily at short intervals following LTP induction and is not inducible at all at a sufficient delay, it may be that extinction initiated shortly following fear acquisition preferentially engages depotentiation/"unlearning," whereas extinction initiated at longer delays recruits a different mechanism. We investigated this possibility through a series of behavioral experiments examining the recoverability of conditioned fear following extinction. Consistent with an inhibitory learning mechanism of extinction, rats extinguished 24-72 h following acquisition exhibited moderate to strong reinstatement, renewal, and spontaneous recovery. In contrast, and consistent with an erasure mechanism, rats extinguished 10 min to 1 h after acquisition exhibited little or no reinstatement, renewal, or spontaneous recovery. These data support a model in which different neural mechanisms are recruited depending on the temporal delay of fear extinction.     

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.     

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.     

Effects of intra-amygdala infusion of CB1 receptor agonists on the reconsolidation of fear-potentiated startle

The cannabinoid CB1 receptor has been shown to be critically involved in the extinction of fear memory. Systemic injection of a CB1 receptor antagonist prior to extinction training blocked extinction. Conversely, administration of the cannabinoid uptake inhibitor AM404 facilitated extinction in a dose-dependent manner. Here we show that bilateral infusion of CB1 receptor agonists into the amygdala after memory reactivation blocked reconsolidation of fear memory measured with fear-potentiated startle. The effect was dose-dependent and could be blocked by AM251, a specific CB1 receptor antagonist. In contrast, the effect of CB1 agonists on reconsolidation was no longer seen if memory reactivation was omitted. Concomitant with block of reconsolidation, CB1 agonist-treated animals did not exhibit shock-induced reinstatement or spontaneous recovery of fear. The absence of recovery was not attributable to permanent damage to the amygdala in WIN-treated rats, nor did the effect result from alteration of baseline startle or shock reactivity. These results suggest that CB1 agonists could impair fear memory via blocking reconsolidation.     

A developmental dissociation in reinstatement of an extinguished fear response in rats

Recently, studies from our laboratory have shown that 16-day-old rats, in contrast to 23-day-old rats, fail to show either ABA renewal or recovery of an extinguished fear response following a pre-test injection of FG7142 [Kim, J. H. & Richardson, R. (2007). A developmental dissociation of context and GABA effects on extinguished fear in rats. Behavioral Neuroscience; Yap & Richardson, unpublished data]. The present study, using freezing as a measure of learned fear, extends these findings by examining whether there is a developmental difference in susceptibility to reinstatement following extinction. 16- and 23-day-old rats were trained to fear a white-noise conditioned stimulus (CS) by pairing it with a shock unconditioned stimulus (US). This fear was subsequently extinguished by non-reinforced presentations of the CS. Some rats received a post-extinction Reminder which consisted of a single presentation of a reduced-intensity US. Experiments 1 and 2 demonstrated that this Reminder was effective in reinstating extinguished fear in 23-day-olds, and that this reinstatement effect was context-specific in rats this age. In contrast, 16-day-old rats failed to show the reinstatement effect in either experiment. The failure to observe a post-extinction reinstatement effect in the 16-day-olds was not due to a general ineffectiveness of the Reminder treatment at this age because it did alleviate spontaneous forgetting in rats this age (Experiment 3). Taken together, the results suggest that fundamentally different processes may mediate extinction early in development compared to later in development.