创伤后应激障碍的动物模型及其神经生物学机制

创伤后应激障碍是指个体由于经历对生命具有威胁的事件或严重的创伤,导致症状长期持续的精神障碍。研究创伤后应激障碍的主要动物模型为条件性恐惧和应激敏感化模型。研究表明,创伤后应激障碍中长时程留存的恐惧性记忆、高唤醒等症状与大脑杏仁核、内侧前额叶皮层和海马三个脑区及下丘脑-垂体-肾上腺轴负反馈功能增强密切相关。其中杏仁核活动增强是条件性恐惧记忆获得、保持和表达的关键神经基础。内侧前额叶皮层对杏仁核的去抑制及海马向杏仁核传递的威胁性环境信息,促进创伤后应激障碍症状的出现。在经历创伤应激后糖皮质激素受体的上调及多巴胺活动的增强是创伤后应激障碍产生的主要神经基础。对创伤后应激障碍的药物治疗研究证明多巴胺D2受体在改善患者症状中的作用比较重要,但仍需作更深入的探索     

干预条件性恐惧记忆表达的相关影响因素分析

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, 对其治疗的关键是熄灭由创伤应激导致的条件性恐惧记忆。条件性恐惧的动物模型研究发现恐惧记忆一旦获得后就难以熄灭, 容易复发, 而这一点也是PTSD的关键临床症状表现之一。因此, 如何更好更持久地熄灭恐惧记忆, 是一个具有重要理论和临床意义的研究热点。本文围绕促进恐惧记忆的长久消退和破坏恐惧记忆的再巩固两方面的行为或药理干预及机制进行综述。针对本文所述的几种基础实验处理, 临床上可以研究治疗创伤后应激障碍的相应疗法。     

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.     

分类和概念对恐惧泛化的影响机制

恐惧泛化与多种焦虑障碍的病理基础密切相关。例如创伤后应激障碍个体往往持续地逃避与创伤事件有关的刺激,遭受着创伤痛苦折磨。本文在厘清知觉辨别与恐惧泛化关系的基础上,着力于高级认知过程(分类与概念相似性、典型性和人工概念)对恐惧泛化的影响,回顾了恐惧泛化的相关神经机制,并揭示恐惧泛化对焦虑障碍患者的临床治疗启示。未来研究应将知觉和高级认知维度的恐惧泛化进行整合研究,同时扩充恐惧习得和泛化的神经回路,以促进人类恐惧泛化更深入的研究。     

情景变换诱发已消退恐惧记忆重现的神经环路

暴露疗法是治疗创伤后应激障碍的主要行为疗法。当被试反复暴露于可引起恐惧反应的条件刺激(如白噪音), 但却不伴有非条件刺激(如足底电击)时, 恐惧记忆将被消退, 形成消退记忆。但恐惧记忆并未从根本上被擦除, 当被试在消退训练以外的情景暴露于条件刺激时, 已消退的恐惧记忆将会重现。海马、内侧前额叶皮层、杏仁核等脑区及其相互连接的神经环路是情景诱发恐惧记忆重现的生理基础。情景变化诱发恐惧记忆重现过程中, 海马可能是通过直接投射至杏仁核基底核、杏仁核外侧核或通过边缘前皮质间接调控杏仁核基底核、杏仁核外侧核的功能, 产生恐惧反应。     

急性应激对威胁刺激注意定向和注意解除的影响:认知神经机制研究

急性应激和注意偏向是焦虑障碍和创伤后应激障碍发生和症状保持的两个重要因素。急性应激导致交感神经系统激活以及儿茶酚胺和糖皮质激素分泌增加,因而影响对威胁刺激的注意偏向。但是急性应激如何影响注意偏向中的注意定向和注意解除尚不清楚。本项目采用点探测任务、威胁线索空间提示任务,结合恐惧条件反射、眼动和事件相关电位技术,研究急性应激对注意定向和注意解除影响的认知神经机制。研究结果可为治疗焦虑和创伤后应激障碍提供支持,为公共卫生管理政策的制定提供建议。     

恐惧记忆习得与消退的性别差异及其神经机制

大多数人在其一生中都会经历创伤事件，但只有少数人会发展成为创伤后应激障碍（PTSD）。焦虑障碍的易感性和保护因素成为一个重要议题。基于恐惧记忆习得与消退模型的研究发现女性个体表现出“易习得、难消退”的特点。在恐惧相关脑区的脑生理结构、功能/结构连接性、以及大脑可塑性的性别差异可能是该特征的根本原因。性激素作为一种焦虑障碍的保护因素，可以调节这种性别差异，这种调节效应可能是通过影响大脑结构形态（如神经细胞的形态和数量）、调控与记忆相关基因的表达（如HDAC4）而实现的。雌性激素水平的不稳定性可能是女性易感焦虑障碍的重要原因。未来对性别差异的深入研究将有助于推进个性化医疗。     

影响应激障碍治疗方案确立的临床特征

急性应激障碍和创伤后应激障碍是近些年创伤后研究的重要内容.为了更加全面地评估遭遇创伤事件患者的情况,本文将从年龄、性别、种族和文化因素、生理与心理共病、过去受伤史、攻击行为、自伤和自杀行为7个方面阐述影响应激障碍的因素,以期在影响应激治疗因素层面为临床治疗提供依据.     

主动反刍、创伤后应激障碍与创伤后成长的关系:一项来自汶川地震后青少年的长程追踪研究

本文以追踪研究的方式, 在汶川地震后3.5年、4.5年和5.5年三个时间点, 采用反刍问卷、创伤后应激障碍问卷和创伤后成长问卷对汶川地震后245名中学生进行调查。通过建立交叉滞后模型, 考察主动反刍、创伤后应激障碍与创伤后成长的相互作用关系。结果发现, 震后3.5~5.5年间, 创伤后应激障碍对主动反刍具有跨时间点的正向预测作用, 主动反刍对创伤后应激障碍跨时间点的预测作用不显著;主动反刍与创伤后成长之间存在跨时间点的相互正向预测关系;创伤后应激障碍与创伤后成长之间跨时间点的直接预测作用不显著, 但震后3.5年的创伤后应激障碍可以通过震后4.5年的主动反刍间接地正向预测震后5.5年的创伤后成长;创伤后应激障碍与创伤后成长的横断关系随着时间历程的变化而逐渐减弱。     

创伤后应激障碍研究进展

文章概括了国内外近年来对创伤后应激障碍的研究,分别介绍了其基本概念、临床分型、理论模型、评估诊断,以及治疗方法。对这一心理障碍的进一步研究能充实心理咨询治疗的课题,并具有重要的社会意义。     

Learning and memory in conditioned fear extinction: effects of D-cycloserine

This review addresses the effects of the cognitive enhancer D-cycloserine (DCS) on the memory processes that occur in conditioned fear extinction, which is the experimental model for exposure techniques to reduce clinical anxiety. All reported rat studies show an enhanced fear extinction effect when DCS is administered acutely before or shortly after extinction training. DCS also promotes the generalization of this fear extinction effect. In addition, DCS reduces some forms of relapse (reduced reinstatement, reduced spontaneous recovery), but not others (contextual renewal, rapid reacquisition). It is argued that this pattern of results is best explained by assuming that DCS promotes extinction learning to the background context, resulting in enhanced contextual inhibition. Four human studies have produced mixed results, but some methodological issues complicate the reported failures. It is concluded that DCS is a promising tool as an adjunct to extinction techniques in exposure treatment, but that more pre-clinical and clinical research is needed to fully characterize its behavioral consequences.     

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.     

Thwarting the renewal (relapse) of conditioned fear with the explicitly unpaired procedure: Possible interpretations and implications for treating human fears and phobias

In three experiments using the barpress conditioned suppression task with albino rats, we studied the renewal (relapse) of conditioned fear in an ABA fear-renewal paradigm. We found that explicitly unpaired (EU) deliveries of conditioned stimuli (CSs) and unconditioned stimuli (USs) in Context B thwarted fear renewal in Context A. Evidence contraindicated a suggestion by Rauhut, Thomas, and Ayres (2001) that US habituation plays a key role in this effect. For example, renewal was thwarted only when EU CSs and USs were intermingled rather than given in succession. The possibility that EU treatments thwart renewal by creating a CS that inhibits fear in the test context also received no support. Thus, summation and retardation tests in Context A found no evidence that the EU CS became inhibitory, finding instead evidence for a residual excitation. Other possible interpretations of the results and some implications for clinical practice are noted.     

Treatments that weaken Pavlovian conditioned fear and thwart its renewal in rats: implications for treating human phobias

In experiments using a total of 144 albino rat subjects, the authors assessed the ability of fear-weakening treatments to prevent fear renewal (relapse). Conditioned suppression of operant behavior served as the measure of fear in an A-B-A (acquisition-treatment-test) renewal paradigm. In Experiment 1, 100 nonreinforced exposures to a feared cue during treatment (extinction) did not reduce fear renewal relative to 20 exposures. In Experiment 2, explicitly unpaired (EU) treatments thwarted both renewal and reacquisition. In Experiment 3, conditioned inhibition (CI) and differential conditioning (DC) treatments weakened renewal and resisted both reacquisition and a form of reinstatement. In Experiment 4, EU, DC, and CI treatments all thwarted renewal. Evidence suggested that the ability of the treatments to do so reflected the combined effects of transfer of extinction across treatment and test contexts and habituation to the unconditioned stimulus.     

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。     

Extensive extinction in multiple contexts eliminates the renewal of conditioned fear in rats

Two studies examined whether nonreinforcement of a stimulus in multiple contexts, instead of a single context, would decrease renewal of conditioned fear in rats (as assessed by conditioned suppression of lever pressing). In Experiment 1, renewal was measured after 36 nonreinforced CS trials delivered during six extinction sessions in a single context or two extinction sessions in each of three different contexts. The number of extinction contexts did not have an effect on renewal. In Experiment 2, groups received either 36 or 144 nonreinforced CS trials during six or twenty-four extinction sessions in a single context or three different contexts. Again, renewal was not influenced by the number of extinction contexts when only 36 trials were given. However, when 144 trials were used, renewal was completely eliminated when extinction was divided between 3 contexts, but was not weakened when the sessions took place in a single context. The results suggest that the use of multiple treatment settings in exposure-based therapies is only likely to reduce relapse if a sufficient number of sessions are provided in each of the treatment settings.     

Role of context similarity in ABA, ABC, and AAB renewal paradigms: Implications for theories of renewal and for treating human phobias

Using barpress conditioned suppression, we studied the renewal of conditioned fear in rats, an animal model for the relapse of human fears and phobias. We demonstrated ABA renewal when the only differences between Contexts A and B included (1) their odor, (2) their location (i.e., side of room), and (3) unintended differences between copies of the same box at the two sites. Removing either the odor or location cues abolished the renewal effect. We then directly compared the effects of ABA and AAB procedures under two levels of context similarity. Although AAB renewal occurred, ABA renewal was stronger. Adding multiple context distinctions to the three listed above did not significantly enhance either form of renewal. Finally, we directly compared the strengths of AAB, ABC, and ABA renewal. AAB renewal, though again significant, was weaker than ABA and ABC renewal, which did not differ significantly. Fear renewal (relapse) can thus be reduced by extinguishing the fear in the acquisition context, regardless of the nature of the test context.