The Psychophysiology Of Fear And Anxiety

恐惧和焦虑的心理生理学

• 批准号: 7136782
• 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/7136782
• 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; cues; disease /disorder proneness /risk; family genetics; fear; functional magnetic resonance imaging; human subject; model design /development; psychological models; psychological shock; psychopathology; psychopharmacology; psychophysiology; psychotropic drugs; startle reaction; stimulus /response

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) Studies of explicit cue fear and contextual fear as models for phasic fear and generalized anxiety, respectively; 2) investigations of the effects of psychotropic medications on fear and anxiety in healthy individuals and in clinical groups; 3) development of human models of fear and anxiety. 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. 1.) Studies of explicit cue fear and contextual fear as models for phasic fear and generalized anxiety, respectively. 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. 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. Preliminary findings indicate reduced activation in medial prefrontal structures during unpredictable shocks. 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. Preliminary evidence shows that high trait anxious subjects and patients with generalized anxiety disorders or PTSD show increased contextual fear. 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 (Grillon, 2002), suggesting that symptoms of generalized anxiety may be secondary to basic associative learning impairments. Two features emerged in subjects showing poor cued fear conditioning: 1) high trait anxiety and 2) elevated physiological arousal at the time of testing. 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. 2.) Psychopharmacologic investigations. Our study relies on the startle reflex to measure fear and anxiety. Startle is potentiated by fear in both humans and animals. 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 (Baas et al. 2002). We recently pointed out issues in psychopharmacology studies with the startle reflex (Grillon and Baas, 2002). 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 (Grillon, 2002). We are currently testing the effect of alprazolam on cued fear and contextual fear. Benadryl is used as a non-anxiolytic sedative control drug. Results show that the benzodiazepine alprazolam reduced contextual fear but not cued fear. 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 N-methyl-D-aspartate (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 and have recently documented for the first time context conditioning in virtual environment (Baas et al 2004).

我们的研究项目致力于正常和异常情绪的研究，重点是恐惧和焦虑。本研究采用心理生理学、心理药理学和脑成像技术进行。主要研究领域包括：1)显性线索恐惧和情境恐惧分别作为阶段恐惧和广泛性焦虑的模型；2)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；3)人类恐惧和焦虑模型的发展。虽然实验方法仅限于人类，但这一研究项目受到动物情感、动机和联想学习类似物的理论和方法的强烈影响。因此，这项研究依赖于将动物研究结果转化为人类实验和精神病理学研究的努力。