Elsevier

Biological Psychiatry

Volume 52, Issue 10, 15 November 2002, Pages 958-975
Biological Psychiatry

Review article
Startle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology

https://doi.org/10.1016/S0006-3223(02)01665-7Get rights and content

Abstract

The aim of this article is to review studies on human anxiety using the startle reflex methodology and to apply the literature on context conditioning in rats to interpret the results. A distinction is made between cued fear (as in specific phobia), a phasic response to an explicit threat cue, and anxiety, a more sustained and future-oriented response not linked to a specific discrete cue. Experimentally, contextual fear, as opposed to cued fear, may best reflect the feeling of aversive expectation about potential future dangers that characterizes anxiety. Following a brief description of the neurobiology of cued fear and context conditioning, evidence is presented showing that anxious patients are overly sensitive to threatening contexts. It is then argued that the degree to which contextual fear is prompted by threat depends on whether the danger is predictable or unpredictable. Consistent with animal data, unpredictable shocks in humans result in greater context conditioning compared to predictable shocks. Because conditioning promotes predictability, it is proposed to use conditioning procedures to study the development of appropriate and inappropriate aversive expectations. Cued fear learning is seen as an adaptive process by which undifferentiated fear becomes cue-specific. Deficits in cued fear learning lead to the development of nonadaptive aversive expectancies and an attentional bias toward generalized threat. Lacking a cue for threat, the organism cannot identify periods of danger and safety and remains in a chronic state of anxiety. Factors that may affect conditioning are discussed.

Introduction

Anxiety disorders present both overlapping and distinctive characteristics. One accepted distinction is that which exists between fear and anxiety. Fear is associated with a clearly identified imminent threat, whereas anxiety is a generalized fear without object (Marks 1987), an apprehensive anticipation of future potential threats (Barlow 2000). Recent animal studies have identified separate neural systems that may be associated with these two aversive states, the amygdala and the bed nucleus of the stria terminalis (BNST) (Davis 1998). The amygdala mediates fear responses to explicit threatening stimuli. The bed nucleus of the stria terminalis is an area adjacent to the amygdala that may play a role in chronic stress associated with more long-lasting aversive states not clearly linked to an explicit cue (Davis 1998). The objective of this review is to examine the relevance of these findings to human anxiety and anxiety disorders.

There are several animal models to explore aversive responses. The challenge has been to understand how the repertoires of these responses resemble the characteristics of human fear and anxiety. For example, ethoexperimental animal models based on the natural defensive repertoires of wild and laboratory rodents to predators present similarities with behavioral symptoms of anxiety disorders (Blanchard et al 1993). An important differentiation has been made between the patterns of defensive behaviors elicited by actual dangers and by potential or ambiguous threats as proxies for fear and anxiety, respectively (Blanchard et al 1993); however, to better understand psychological and neural mechanisms of fear and anxiety in humans, there is a need for investigative tools that can translate animal research into human experimentations. Combining Pavlovian aversive conditioning with the startle reflex methodology may be one of the most powerful ways to develop such cross-species studies.

Pavlovian aversive conditioning is the process by which initially neutral stimuli come to elicit defensive responses following their repeated association with an aversive event. Aversive conditioning procedures present several advantages for the study of human anxiety and anxiety disorders. Because brain structures activated during aversive conditioning procedures are highly preserved across species, inferences about neural structures involved in human fear and anxiety can be made based on animal studies (LeDoux 1995). In addition, conditioning studies in humans lag far behind animal research. Hence, the animal literature provides a rich source of theoretical information and empirical data on which to build and develop human research. Furthermore, the startle reflex methodology provides a unique tool to more directly link animal and human research, since inference about aversive states is made using the same measure in the two species. Finally, aversive conditioning provides a framework to study cognitive and emotional interactions during the processing of threat information. Indeed, aversive events usually do not happen unexpectedly. Their occurrence may be predicted based on prior experience. Associative learning mechanisms, such as classical fear conditioning, are central to the development of appropriate expectancies about upcoming events.

The present article will first review findings from startle studies in animals and in humans that suggest the existence of at least two distinct defense mechanisms, one activated by explicit cues and the other by threatening contexts. Studies will then be presented that provide emerging evidence that these defense systems are differentially activated in anxious individuals or in patients with anxiety disorders compared to healthy subjects. It will be shown that in threatening contexts, anxious patients generate aversive responses in a less discriminating manner compared to nonanxious subjects. It will be argued that these aversive responses resemble symptoms in animals during context conditioning. Finally, the possible role of factors that affect associative learning and conditioned responses in the etiology and maintenance of anxiety and anxiety disorders will be discussed.

Section snippets

Apprehension/general distress versus explicit cued fear

Clinicians have long recognized that anxiety is not a unitary phenomenon and that it can take several forms Barlow 2000, Kandel 1983. The DSM-IV identifies several specific anxiety disorders, suggesting heterogeneity of symptoms and etiology among them (American Psychiatric Association 1994). Anxiety disorders are thought to result from abnormal processing of threat-related stimuli Beck and Clark 1997, Eysenck 1991, as well as functional deficits in brain pathways underlying fear learning and

Pavlovian conditioning

The distinction between qualitatively different fear/anxiety systems is consistent with findings from animal models Blanchard et al 1993, Davis 1998, File et al 1998, File et al 1999. The assumption underlying most animal models of anxiety disorders is that anxiety evolves from defense mechanisms essential for survival, which are highly conserved across species LeDoux 1995, Rodgers 1997. According to this view, symptoms of pathologic anxiety (hypervigilance, anxious anticipation, avoidance,

The startle reflex and aversive states

The central nucleus of the amygdala has extensive connections to hypothalamic and brainstem sites responsible for the physiologic signs and behavioral symptoms of fear (Davis 2000). In humans, these physiologic responses can be measured using psychophysiological techniques. Most of our knowledge on fear conditioning in humans is derived from investigations of electrodermal activity and, to a lesser degree, of cardiovascular activity. A relatively new measure, the startle reflex, may be the most

Fear-Potentiated startle

Fear-potentiated startle refers to the increase or potentiation of the startle reflex during fear states elicited by the anticipation of an aversive stimulus (e.g., a shock). This effect was first described in animals using aversive conditioning procedures by Brown et al (1951) and has been investigated extensively by Davis and his collaborators (Davis 1998). In a typical experiment, the amplitude of the startle reflex elicited by a startling stimulus (e.g., loud noise) is measured either in

The neurobiology of contextual fear

Recent evidence from animal studies in Davis’ laboratory indicates that the startle reflex is potentiated in conditions that are reminiscent of generalized anxiety rather than fear. For example, under certain conditions, baseline startle reflex shows a gradual elevation over the course of aversive conditioning that may reflect a response to chronic stress (Gewirtz et al 1998). This elevation is blocked by lesions of the bed nucleus of the stria terminalis but not by lesions of the amygdala

Contextual fear in humans

The startle reflex is also highly sensitive to contextual stressors in humans. During fear conditioning procedures, various contextual cues can potentiate startle. For example, startle is affected by the aversive nature of the experiment itself. Thus, baseline startle is greater before a fear conditioning experiment during which shocks are administered, compared to an experiment where there is no aversive stimulus (Bocker et al 2001). The shock electrodes are also potent contextual cues,

Contextual fear and anxiety disorders

Recently, we have reported that darkness is also a powerful aversive stimulus in Vietnam veterans with posttraumatic stress disorder (PTSD). PTSD veterans show an exaggerated facilitation of startle in the dark (Grillon et al 1998b). Poor sleep and fear of the dark are frequent symptoms in hypervigilant Vietnam veterans with PTSD. The onset of darkness signals a period of anxious anticipation, a scanning of the environment for potential dangers, and an inability to feel safe. As one veteran

Classical conditioning, contextual fear, and sensitization

The literature on the effects of unpredictable and uncontrollable aversive events provides important insights into features of anxiety disorders associated with contextual fear. Predictability and controllability are central to several models of anxiety Barlow 2000, Foa et al 1992, Mineka and Kihlstrom 1978. Barlow (2000) talks about anxious apprehension as a state of nervous helplessness due to a perceived inability to predict or control upcoming events. Barlow’s model of anxiety is based on

Context conditioning in veterans with PTSD

Most evidence showing enhanced contextual fear in patients with anxiety disorders is derived from threat of shock paradigms, where information concerning danger is verbally mediated. Recently, we have investigated contextual fear using conditioning in Gulf war veterans with PTSD (Grillon and Morgan 1999). In this study, a differential conditioning procedure was used. During differential fear conditioning, only one of two stimuli, the CS+, is paired with a shock. Conditioned fear usually

Associative learning deficits and contextual fear

Unpredictable aversive events increase anxious apprehension, but most of the events in our surroundings are not necessarily unpredictable or unexpected. Associative learning and conditioning are mechanisms by which organisms derive predictability, reduce uncertainty, and learn to predict events in the environment. An important development in the learning theory literature in recent years is the acknowledgment that conditioning is not a low-level reflexive stimulus-response process but a highly

Cued fear conditioning and anxiety

What are the factors that may interfere with contingency awareness or cued fear conditioning? The study by Grillon (2002) showed that the unaware subjects had higher levels of trait anxiety as measured with the Spielberger State and Trait Anxiety Inventory (Spielberger 1983). The differential conditioning study by Chan and Lovibond (1996) also suggests that anxiety interferes with cued fear conditioning. These authors specifically examined the effect of trait anxiety on contingency awareness by

Orienting, conditioning, autonomic flexibility, and risks for anxiety

Given the role of cognitive process in conditioning, controlled perceptual/attentional behaviors are necessarily engaged during the formation of CS-US associations. The organism needs to orient, pay attention, process information, and rehearse in short-term memory Dickinson 1980, Rescorla 1980. Deficits at any level of these cognitive operations could interfere with successful cued fear conditioning.

In order for a subject to discover the significance of a CS as a signal for the US, the CS needs

The hippocampus and associative learning deficits

The hippocampus has been shown to be involved in context conditioning Kim and Fanselow 1992, Phillips and LeDoux 1992; however, this has been an area of controversy Fanselow 2000, Gewirtz et al 2000. Several studies indicate that lesions of the hippocampus either do not affect Gisquet-Verrier et al 1999, McNish et al 1997 or even increase context conditioning (Winocur et al 1987). The latter study was based on a previous report by Odling-Smee (1975) that demonstrated that the amount of

Conclusion

The aim of this review was to interpret findings from studies on human anxiety using the startle reflex in light of animal data. Animal studies have identified two neural circuits involving the amygdala and the bed nucleus of the stria terminalis that may be associated with explicitly cued fear and generalized anxiety to threatening contexts, respectively. Threat prompts either a brief period of fear or a more generalized state of anxious apprehension, according to whether the danger is

Acknowledgements

This review was supported in part by NIMH Grant No. 5R01 MH53618. The author thanks Dr. Rezvan Ameli for editorial assistance.

Aspects of this work were presented at the conference, “Learning and Unlearning Fears: Preparedness, Neural Pathways, and Patients,” held March 21, 2002 in Austin, TX. The conference was supported by an unrestricted educational grant to the Anxiety Disorders Association of America (ADAA) from Wyeth Pharmaceuticals, and jointly sponsored by the ADAA, the ADAA Scientific

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