Fear Generalization and Anxiety: Behavioral and Neural Mechanisms

doi:10.1016/j.biopsych.2015.04.010

Biological Psychiatry

Volume 78, Issue 5, 1 September 2015, Pages 336-343

https://doi.org/10.1016/j.biopsych.2015.04.010 Get rights and content

Abstract

Fear can be an adaptive emotion that helps defend against potential danger. Classical conditioning models elegantly describe how animals learn which stimuli in the environment signal danger, but understanding how this learning is generalized to other stimuli that resemble aspects of a learned threat remains a challenge. Critically, the overgeneralization of fear to harmless stimuli or situations is a burden to daily life and characteristic of posttraumatic stress disorder and other anxiety disorders. Here, we review emerging evidence on behavioral and neural mechanisms of generalization of emotional learning with the goal of encouraging further research on generalization in anxiety disorders. We begin by placing research on fear generalization in a rich historical context of stimulus generalization dating back to Pavlov, which lays the foundation for theoretical and experimental approaches used today. We then transition to contemporary behavioral and neurobiological research on generalization of emotional learning in humans and nonhuman animals and discuss the factors that promote generalization on the one hand from discrimination on the other hand.

Section snippets

Stimulus Generalization

Classical conditioning techniques have proved to be a highly effective tool to investigate generalization of learning across species. The earliest demonstrations from Pavlov’s laboratory revealed generalization of conditioned learning using sensory stimuli that approximated a conditioned stimulus (CS) (e.g., a tone of a 1000 Hz) paired with an unconditioned stimulus (US) (e.g., food). In these experiments, it was observed that the conditioned response (CR) (e.g., salivation) was not specific to

Fear Learning and Generalization in Anxiety Disorders

Classical fear conditioning has proved an exceptional model to conceptualize the etiology and maintenance of pathological anxiety and is a useful experimental tool for investigating abnormal emotional learning and regulation in anxiety disorders. The earliest laboratory studies of fear conditioning showed that learned fear responses [e.g., Little Albert’s fear of rats (17)] provide an analog to behavioral reactions stemming from real-world emotional experiences. The monumental shift away from

Perceptual Mechanisms and similarity

Perceptual similarity is the most accessible factor to investigate in stimulus generalization research, as the degree of similarity can be quantified as distance between points along a continuum. This largely explains why most studies test generalization along simple sensory dimensions and why this approach has been adapted to most fear generalization studies in humans. Thus far, fear generalization has been tested between stimuli that vary in color (39), size (28), shape (40, 41), facial

Neurobehavioral Mechanisms oF fear learning and generalization

Neural models derived from nonhuman animals (55, 56) and extended to humans using functional magnetic resonance imaging (fMRI) (57) provide a developing picture of how classical fear conditioning is acquired, expressed, generalized, extinguished, and recovered following extinction. Neuroanatomical models of fear conditioning continue to evolve and have been covered in a number of detailed reviews (55, 58, 59). To briefly summarize, these models center on the role of the amygdala as a site of

Human neuroimaging of fear generalization

Human neuroimaging research on fear generalization is only now starting to gather attention, but an early picture is beginning to develop that implicates the neurocircuitry involved at initial learning as supporting fear generalization (Figure 2). For instance, Dunsmoor et al. (86) first identified a number of regions involved in fear acquisition, including the insula, thalamus, cingulate cortex, and striatum, and then probed activity in these regions in a subsequent generalization test. Each

Conclusions and future directions

After nearly a century of research on classical conditioning, this basic paradigm continues to afford critical insight into the nature of learning and memory across species. As attention returns to models of stimulus generalization to examine fear conditioning, there is exciting potential for new insights that will shed new light on disorders of fear and anxiety characterized by broad generalization and failure to discriminate threat from safety. More research is needed to understand the neural

Acknowledgments and Disclosures

This work was supported by ISF #26613, I-CORE #51/11, and ERC-FP7-StG #281171 Grants to R. Paz.

We thank Elizabeth Phelps for valuable comments on an earlier version.

Dr. Dunsmoor and Dr. Paz report no biomedical financial interests or potential conflicts of interest.

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Excessive fear generalization has been associated with pathological anxiety, including posttraumatic stress disorder (PTSD). However, studies investigating the longitudinal relationship between generalization and the development of anxiety symptomatology are scarce. This study aims to test the predictive value of fear generalization for PTSD symptoms in a high-risk profession sample and to explore the relationship between generalization and neuroticism, which are both linked to PTSD.
Longitudinal data from a multi-wave study in 529 Dutch fire-fighters were used. Fear generalization, PTSD symptoms and neuroticism were assessed at baseline. PTSD symptoms were reevaluated at six, 12, 18, and 24 months. Generalization was assessed in a differential conditioning paradigm by measuring expectancies of an aversive outcome when presented with stimuli similar to previously conditioned stimuli.
Higher expectancy ratings towards stimuli most similar to safety signals predicted PTSD symptoms at follow-up after controlling for baseline PTSD symptoms, whereas higher expectancy ratings towards stimuli most similar to danger signals was associated with neuroticism. Neuroticism weakened the predictive power of fear generalization when considered simultaneously.
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Using unconditioned responses to predict fear acquisition, fear extinction learning, and extinction retention patterns: Sex hormone status matters
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Following a traumatic event, fear dysregulation can increase the likelihood of developing post-traumatic stress disorder (PTSD). This psychopathology is twice as prevalent in women than in men. High physiological reactivity following trauma may be an early risk indicator for the development of PTSD. Elevated physiological reactivity and low estradiol levels have individually been associated with higher fear acquisition and/or lower extinction retention. Thus, sex hormone status may also modulate fear regulation abilities. However, it is unknown whether these two vulnerability factors interact to modulate fear learning and regulation. Using a fear conditioning and extinction protocol, we examined whether physiological reactivity to the aversive stimulus during fear acquisition training predicted fear responses during fear learning, extinction learning, and extinction retention. We verified whether these associations differed according to sex hormone status. Seventy-seven non-clinical participants were recruited including oral contraceptive users (n = 18), early follicular women (n = 20, [low estradiol]), mid-cycle women (n = 20, [high estradiol]), and men (n = 19). Participants underwent a three-day fear conditioning and extinction protocol (day 1: fear acquisition training; day 2: extinction training; day 3: retention test). Skin conductance responses were recorded. In early follicular women, physiological reactivity predicted conditioned and extinguished stimulus fear responses during all phases. For the remaining women, this effect was only present during fear learning and extinction learning. These findings highlight the importance of considering physiological reactivity and sex hormone status following a traumatic event. This knowledge could aid in the early identification of those at higher risk of developing PTSD.
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Various psychiatric diseases are characterized by aberrant cognition and emotional regulation. This includes inappropriately attributing affective salience to innocuous cues, which can be investigated using translationally relevant preclinical models of fear discrimination. Activity in the underpinning corticolimbic circuitry is governed by parvalbumin-expressing GABAergic interneurons, which also regulate fear discrimination. Kv3 voltage-gated potassium channels are highly expressed in these neurons and are important for controlling their activity, suggesting that pharmacological Kv3 modulation may regulate fear discrimination. We determined the effect of the positive Kv3 modulator AUT00206 given systemically to female rats undergoing limited or extended auditory fear discrimination training, which we have previously shown results in more discrimination or generalization, respectively, based on freezing at retrieval. We also characterized darting and other active fear-related responses. We found that limited training resulted in more discrimination based on freezing, which was unaffected by AUT00206. In contrast, extended training resulted in more generalization based on freezing and the emergence of discrimination based on darting during training and, to a lesser extent, at retrieval. Importantly, AUT00206 given before extended training had dissociable effects on fear discrimination and expression at retrieval depending on the response examined. While AUT00206 mitigated generalization without affecting expression based on freezing, it reduced expression without affecting discrimination based on darting, although darting levels were low overall. These results indicate that pharmacological Kv3 modulation regulates fear discrimination and expression in a response-dependent manner. They also raise the possibility that targeting Kv3 channels may ameliorate perturbed cognition and emotional regulation in psychiatric disease.
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ReviewFear Generalization and Anxiety: Behavioral and Neural Mechanisms

Abstract

Section snippets

Stimulus Generalization

Fear Learning and Generalization in Anxiety Disorders

Perceptual Mechanisms and similarity

Neurobehavioral Mechanisms oF fear learning and generalization

Human neuroimaging of fear generalization

Conclusions and future directions

Acknowledgments and Disclosures

Psychology of Learning and Motivation-Advances in Research and Theory

Behav Res Ther

Trends Cogn Sci

Behav Res Ther

Neuropharmacology

Behav Res Ther

Biol Psychiatry

Biol Psychol

Neurobiol Learn Mem

Neurobiol Learn Mem

Neuron

Neuron

Neurobiol Learn Mem

Biol Psychiatry

Trends Neurosci

Neuroimage

Biol Psychol

Conditioned Reflexes

Principles of Behavior

Statistical Learning Theory

Signal Detection Theory and Psychophysics

Negative valence widens generalization of learning

J Neurosci

Biological studies of post-traumatic stress disorder

Nat Rev Neurosci

How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD

Am J Psychiatry

Toward an account of clinical anxiety predicated on basic, neurally mapped mechanisms of pavlovian fear-learning: The case for conditioned overgeneralization

Depress Anxiety

The Pavlovian theory of generalization

Psychol Rev

Stimulus generalization of conditioned responses

Psychol Bull

Stimulus-generalization

Psychol Bull

Discriminability and stimulus-generalization

J Exp Psychol

Toward a universal law of generalization for psychological science

Science

Learning models of PTSD: Theoretical accounts and psychobiological evidence [published online ahead of print November 20]

Int J Psychophysiol.

Conditioned emotional reactions

J Exp Psychol

A contemporary learning theory perspective on the etiology of anxiety disorders: It׳s not what you thought it was

Am Psychol

Acquired equivalence and distinctiveness of cues

J Exp Psychol Anim Behav Process

Conceptual similarity promotes generalization of higher order fear learning

Learn Mem

Using Pavlovian higher-order conditioning paradigms to investigate the neural substrates of emotional learning and memory

Learn Mem

Stimulus typicality determines how broadly fear is generalized

Psychol Sci

A modern learning theory perspective on the etiology of panic disorder

Psychol Rev

Overgeneralization of conditioned fear as a pathogenic marker of panic disorder

Am J Psychiatry

Ventromedial prefrontal cortex reactivity is altered in generalized anxiety disorder during fear generalization

Depress Anxiety

Diagnostic and Statistical Manual of Mental Disorders

Emotional processing of fear: Exposure to corrective information

Psychol Bull

Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors

Front Psychiatry

Review
Fear Generalization and Anxiety: Behavioral and Neural Mechanisms