The Psychophysiology Of Fear And Anxiety

恐惧和焦虑的心理生理学

• 批准号: 6824277
• 负责人: Christian Grillon
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6824277
• 关键词: NMDA receptors; anxiety; anxiety disorders; association learning; behavioral /social science research tag; benzodiazepines; brain imaging /visualization /scanning; clinical research; computer simulation; conditioning; disease /disorder proneness /risk; family genetics; fear; functional magnetic resonance imaging; human subject; model design /development; personality; psychological models; psychological shock; psychopathology; psychopharmacology; psychophysiology; psychotropic drugs; startle reaction

Our research program is devoted to the study of normal and abnormal emotions with a strong emphasis on fear and anxiety. This research is conducted using psychophysiological, psychopharmacological, and brain imaging techniques. The major areas of investigation include: 1) development of human models of fear and anxiety; 2) research on the relationship between associative learning and emotional reactivity to aversive stimuli; 3) studies of personality and temperamental dimensions of psychopathology; 4) investigations of the effects of psychotropic medications on fear and anxiety in healthy individuals and in clinical groups; 5) identification of the early manifestations of psychiatric illnesses using family studies. Although the experimental approach is restricted to humans, this program of research is strongly influenced by theories and methods from animal analogues of emotion, motivation, and associative learning. Thus, the research relies on efforts to translate findings from animal research into human experimentation and studies of psychopathology. This report focuses on three main areas of interest: 1. Studies of explicit cue fear and contextual fear as models for phasic fear and generalized anxiety, respectively 2. Psychopharmacologic investigations 3. Development of experimental models of human fear and anxiety states 4. High-risk studies 1. Explicit cued fear and contextual anxiety This series of projects focuses on anxiety, as opposed to fear. Fear is associated with a clearly identifiable, imminent threat, whereas anxiety is a generalized fear without object, an apprehensive anticipation of future potential threats. Our working hypothesis is that fear and anxiety can be modeled by cued fear and contextual fear, respectively. The distinction between cued fear and contextual anxiety was first made in fear conditioning studies in animals. Cued fear is elicited by an explicit stimulus (e.g., a light) that predicts a noxious stimulus (e.g., a shock). Contextual fear is caused by the experimental context (i.e., the cage, the experimental room) where an aversive experiment took place. We showed that a similar distinction could be made in human studies. Several features make contextual fear an appealing model of anxiety. Given the potential relevance of contextual fear for our understanding of anxiety disorders and the paucity of human research in this area, we are pursuing several areas of investigations focusing on contextual fear. The first one examines factors that are involved in the modulation of contextual fear. We have developed a protocol to assess the role of predictability on contextual fear using instructed fear procedures. Results showed that contextual fear is increased by unpredictability as long as the aversive event is sufficiently unpleasant. We are currently following-up on these findings in three areas. One investigates brain mechanisms mediating cued fear to signaled shocks and contextual anxiety to unpredictable shock in an fMRI study. A second investigation assesses the effects of psychopharmacological agents. A third area explores the relevance of these findings to psychopathology by investigating contextual fear in individuals diagnosed with an anxiety disorder or selected for low or high trait anxiety. Another factor that affects contextual fear is fear conditioning. Fear conditioning is adaptive because it makes aversive events predictable. We recently reported that cued fear learning deficits were associated with increased contextual fear, suggesting that symptoms of generalized anxiety may be secondary to basic associative learning impairments. A follow-up study identified characteristics associated with cued fear conditioning deficits. Three features emerged in subjects showing poor cued fear conditioning: 1) high trait anxiety, 2) elevated physiological arousal at the time of testing, and 3) reduced orienting responses. These results emphasize the role of attentional factors in the formation of conditioned responses, the subsequent learning of emotional responses, and the development of anxiety. These results link attentional regulation and autonomic flexibility to affective processes. Flexible attention to stimulus changes, as reflected by a robust OR, is a prerequisite for adaptive responses to the environment. 2. Psychopharmacologic investigations Our study relies on the startle reflex to measure fear and anxiety. Startle is potentiated by fear in both humans and animal. In rodents, this so-called 'fear-potentiated startle reflex' effect is reduced by drugs that reduce human anxiety such as the benzodiazepines. However, human studies with benzodiazepines have been contradictory. While two studies reported that benzodiazepines reduced fear-potentiated startle, we have been unable to confirm this effect in a study that included four experiments. We recently pointed out issues in psychopharmacology studies with the startle reflex. One issue is the difficulty in separating the anxiolytic from the sedative effects of benzodiazepines. Another issue is that benzodiazepines have been tested on cued fear models, while contextual fear models may be more relevant. We are currently testing the effect of alprazolam on cued fear and contextual fear. Benadryl is used as a non-anxiolytic sedative control drug. The inability to extinguish intense fear memories is a significant clinical problem. Finding procedures or treatments that facilitate extinction of fear memories is of paramount importance. We are currently examining whether D-cycloserine, a partial agonist at the glycine modulatory site on the NMDA receptor, facilitates extinction. The rationale for this study is that if NMDA receptor antagonists block the acquisition of fear conditioning and of extinction, it is possible that NMDA receptor agonists facilitate this type of learning. Facilitation of extinction would be therapeutically useful. Recently, D-cycloserine was found to produce a dose-dependent facilitation of extinction of conditioned fear in the rat, when assessed with fear-potentiated startle. Our study examines whether the clinically important process of extinction can also be enhanced by D-cycloserine in humans. 3. Development of experimental models of human fear and anxiety states One important aspect of our program of research is to develop procedures to study fear and anxiety in humans. Despite important recent progress, we have become increasingly dissatisfied with traditional fear conditioning protocols. There are two main issues. Conditioned responses are weak (i.e., they extinguished rapidly) and they are not well retained over time. In addition, the stimuli used in these studies are somewhat unsophisticated (e.g., geometric shapes presented on a monitor). These problems limit the development of meaningful fear conditioning procedures, more particularly for psychopharmacology and contextual fear studies. We have embarked on a project that uses computer-generated virtual reality to investigate fear conditioning. We have worked one the programming aspect of the project for the last 6 months and are now in the initial phase of testing. 4. High-risk studies We are involved in two studies examining risk factors for psychiatric disorders. One study is the continuation of a NIDA grant that was given to the present PI when he was at Yale University. The investigation looks at two different familial pathways to drug addiction, antisocial personality and anxiety. The second project is a collaborative study with Dr. Myrna Weissman (Columbia University) examining psychophysiological risk-factors for depression in children and grand-children of individuals with major de

我们的研究项目致力于研究正常和异常情绪，重点关注恐惧和焦虑。这项研究是利用心理生理学、精神药理学和脑成像技术进行的。主要研究领域包括：1）恐惧和焦虑的人类模型的开发； 2）联想学习与厌恶刺激情绪反应关系的研究； 3）精神病理学的人格和气质维度的研究； 4）调查精神药物对健康个体和临床群体的恐惧和焦虑的影响； 5）通过家庭研究识别精神疾病的早期表现。尽管实验方法仅限于人类，但该研究项目深受动物情感、动机和联想学习的理论和方法的影响。因此，该研究依赖于将动物研究结果转化为人体实验和精神病理学研究的努力。本报告重点关注三个主要领域： 1. 分别将外显暗示恐惧和情境恐惧作为阶段性恐惧和广泛性焦虑模型的研究 2. 精神药理学研究 3. 人类恐惧和焦虑状态实验模型的开发 4. 高风险研究 1. 外显暗示恐惧和情境焦虑 这一系列项目的重点是焦虑，而不是恐惧。恐惧与明显可识别的迫在眉睫的威胁相关，而焦虑是一种没有对象的普遍恐惧，是对未来潜在威胁的忧虑预期。我们的工作假设是，恐惧和焦虑可以分别通过暗示恐惧和情境恐惧来建模。暗示恐惧和情境焦虑之间的区别首先是在动物的恐惧条件反射研究中做出的。暗示恐惧是由预测有害刺激（例如电击）的明确刺激（例如光）引起的。情境恐惧是由进行厌恶性实验的实验环境（即笼子、实验室）引起的。我们表明，在人类研究中也可以做出类似的区分。有几个特征使情境恐惧成为一种有吸引力的焦虑模型。鉴于情境恐惧对我们理解焦虑症的潜在相关性以及该领域人类研究的缺乏，我们正在开展以情境恐惧为重点的几个研究领域。第一个研究考察了调节情境恐惧所涉及的因素。我们制定了一项协议，使用指导的恐惧程序来评估可预测性对情境恐惧的作用。结果表明，只要厌恶事件足够令人不愉快，情境恐惧就会因不可预测性而增加。我们目前正在三个领域跟进这些发现。其中一项研究在功能磁共振成像研究中研究了介导暗示恐惧与信号电击以及情境焦虑与不可预测电击的大脑机制。第二项研究评估了精神药理学药物的作用。第三个领域通过调查被诊断为焦虑症或被选择为低或高特质焦虑的个体的情境恐惧，探讨这些发现与精神病理学的相关性。影响情境恐惧的另一个因素是恐惧调节。恐惧调节具有适应性，因为它使厌恶事件变得可预测。我们最近报道，暗示恐惧学习缺陷与情境恐惧增加有关，这表明广泛性焦虑的症状可能继发于基本的联想学习障碍。一项后续研究确定了与暗示的恐惧调节缺陷相关的特征。表现出不良暗示恐惧调节的受试者出现了三个特征：1）高特质焦虑，2）测试时生理唤醒升高，3）定向反应减少。这些结果强调了注意力因素在条件反应的形成、随后的情绪反应的学习以及焦虑的发展中的作用。这些结果将注意力调节和自主灵活性与情感过程联系起来。对刺激变化的灵活关注（如稳健的 OR 所反映的那样）是对环境做出适应性反应的先决条件。 2. 精神药理学研究我们的研究依靠惊吓反射来测量恐惧和焦虑。人类和动物的恐惧都会加剧惊吓。在啮齿动物中，这种所谓的“恐惧增强惊吓反射”效应可以通过减少人类焦虑的药物（例如苯二氮卓类药物）来减弱。然而，对苯二氮卓类药物的人体研究却是矛盾的。虽然两项研究报告称苯二氮卓类药物可以减少恐惧增强的惊吓，但我们无法在一项包含四项实验的研究中证实这种效果。我们最近指出了精神药理学研究中惊吓反射的问题。一个问题是很难将苯二氮卓类药物的抗焦虑作用与镇静作用分开。另一个问题是苯二氮卓类药物已经在提示恐惧模型上进行了测试，而情境恐惧模型可能更相关。我们目前正在测试阿普唑仑对暗示恐惧和情境恐惧的影响。 Benadryl 用作非抗焦虑镇静控制药物。无法消除强烈的恐惧记忆是一个重要的临床问题。寻找有助于消除恐惧记忆的程序或治疗方法至关重要。我们目前正在研究 D-环丝氨酸（NMDA 受体上甘氨酸调节位点的部分激动剂）是否会促进灭绝。这项研究的基本原理是，如果 NMDA 受体拮抗剂阻止恐惧调节和消退的获得，那么 NMDA 受体激动剂可能会促进这种类型的学习。促进灭绝在治疗上是有用的。最近，当用恐惧增强惊吓进行评估时，发现 D-环丝氨酸对大鼠条件性恐惧的消除产生剂量依赖性促进作用。我们的研究检验了 D-环丝氨酸是否也能增强人类临床上重要的消退过程。 3.人类恐惧和焦虑状态实验模型的开发我们研究计划的一个重要方面是开发研究人类恐惧和焦虑的程序。尽管最近取得了重要进展，但我们对传统的恐惧调节方案越来越不满意。有两个主要问题。条件反应很弱（即它们很快消失）并且随着时间的推移它们不能很好地保留。此外，这些研究中使用的刺激有些不复杂（例如，显示器上呈现的几何形状）。这些问题限制了有意义的恐惧调理程序的发展，特别是对于精神药理学和情境恐惧研究。我们已经启动了一个项目，利用计算机生成的虚拟现实来研究恐惧条件反射。在过去的 6 个月里，我们一直致力于该项目的编程方面的工作，现在正处于测试的初始阶段。 4. 高风险研究 我们参与了两项检查精神疾病危险因素的研究。其中一项研究是现任 PI 在耶鲁大学时获得的 NIDA 资助的延续。该调查着眼于吸毒成瘾的两种不同的家庭途径：反社会人格和焦虑。第二个项目是与 Myrna Weissman 博士（哥伦比亚大学）合作进行的一项研究，研究患有严重抑郁症的人的儿童和孙辈的抑郁症心理生理学危险因素。