Review
From Pavlov to PTSD: The extinction of conditioned fear in rodents, humans, and anxiety disorders

https://doi.org/10.1016/j.nlm.2013.11.014Get rights and content

Highlights

  • Pavlovian fear conditioning and extinction relate to PTSD and other anxiety disorders.

  • Such studies in rodents inform human psychophysiological and neuroimaging studies.

  • Gene and twin studies have revealed vulnerabilities to PTSD and anxiety disorders.

  • Treatment of PTSD and anxiety disorders use Pavlovian fear extinction as a template.

Abstract

Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov’s dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders.

Introduction

In his classical conditioning and extinction experiments, Ivan Pavlov rang a bell (the conditioned stimulus; CS), immediately before giving his dogs food (specifically meat powder, the unconditioned stimulus; US; Pavlov, 1927). On its own, the meat powder made the dogs salivate (the unconditioned response; UR). After repeating this predictive pairing several times, Pavlov’s dogs began salivating to the mere sound of the bell—even when no meat powder was presented—making salivation the conditioned response (CR). The sound of the bell predicted something agreeable and biologically valuable: food. However, not all of Pavlov’s USs were pleasant, and not all CRs conveyed his dogs’ anticipation of something enjoyable. In addition to learning about nourishment sources, it is important for an organism to be able to predict threats to health and safety. For example, when Pavlov repeatedly paired the sound of a metronome (CS) with subsequent application of a small amount of sour-tasting diluted acid (US) onto a dog’s tongue, the dog eventually learned the association. Henceforth, upon presentation of the CS alone, the dog exhibited what Pavlov called a “defensive reflex”: it shook its head, salivated profusely, and moved its tongue as if to expel a toxic substance, even though no acid was there. A similar process was demonstrated with an 11-month-old child in Watson and Rayner’s famous “Little Albert” experiments of 1920. Watson and Rayner paired Albert’s touching of a white rat (CS) with a sudden fear-arousing noise (US) made by striking a steel bar behind him (Watson & Rayner, 2000). Upon subsequent presentations of the rat, Albert no longer exhibited his natural curiosity, but rather withdrew his hand. This learned response seemed to generalize to cotton balls, a Santa Claus mask, a brown bunny, and a black fur coat. The Little Albert experiment is an early precursor of what is now known as fear conditioning.

It is not known whether Little Albert subsequently experienced fear around rats and furry objects (if he survived into adulthood at all) or if he was healthy and well-adjusted (Harris, 2011). Of course, modern ethical standards would not allow such a methodology. Still, it is likely that, after the experiment was over, Little Albert encountered other rats or other furry objects in the absence of a loud noise. Eventually, he should have learned that such objects no longer predicted a frightening clang, and his fear response should have declined. This process is known as fear extinction learning. When the CS no longer predicts the US, the conditioned fear response is extinguished.

How do these processes of fear conditioning and fear extinction work? Why is it that with very severe USs, some individuals are burdened by fear and anxiety for decades? The goal of this review is to examine the underlying mechanisms and neurocircuitry of fear conditioning and extinction, as well as to explore how these processes can inform our understanding of anxiety disorders such as posttraumatic stress disorder (PTSD). We will first discuss fear conditioning and extinction in rodents, and then in healthy humans. Finally, we’ll discuss fear conditioning and extinction in individuals with PTSD and other anxiety disorders, with an emphasis on how extinction learning relates to treatment.

Section snippets

Fear conditioning in rodents

When rodents sense danger, one species-specific behavioral response is to freeze all movement in order to avoid detection by predators. Rodent fear conditioning and extinction studies typically use a foot shock as the US. The fear response is operationalized as the percentage of time a rodent spends engaging in freezing behavior. When a light or tone (CS) repeatedly predicts a foot shock (US) delivered through an electrified metal cage floor, rodents are conditioned to make a CS–US association.

Fear conditioning and extinction in healthy humans

In human fear conditioning studies, the dependent measure quantifying fear (the UR or CR) is usually a psychophysiological response such as skin conductance response (SCR) or fear-potentiated startle. Functional neuroimaging studies frequently associate SCR with change in brain activity, but less frequently use fear-potentiated startle, as movement disrupts brain imaging. These studies usually use a finger or wrist shock as the US and often compare a conditioned cue (CS+) to an unconditioned or

The fear conditioning model of PTSD

For decades, psychologists have theorized that pathological anxiety may reflect a failure to extinguish conditioned fear. In the 1970s, a “conditioning model of neurosis” emerged, which held that impaired extinction for certain CRs form the basis of anxieties, phobias, and compulsions (Eysenck, 1979, Pitman and Orr, 1986). In 1980, PTSD became a formal diagnosis in the DSM-III and was considered by many to be uniquely relevant to the conditioning framework because it is the only anxiety

Psychophysiological studies

As detailed in Section 3.1.1, psychophysiological measures are a valuable tool for assessing fear conditioning and extinction in healthy humans. Researchers have also used these tools to explore fear conditioning and extinction abnormalities in PTSD (reviewed in Lissek et al., 2005, Pitman et al., 2012). Based upon that literature, Guthrie and Bryant (2006) suggested that alterations in psychophysiological responses that characterize PTSD during fear conditioning and extinction include (1)

Extinction in other anxiety disorders

The National Institute of Mental Health (NIMH) recently issued a strategic plan that calls for research using dimensions of observable behavior and neurobiological measures to characterize mental disorders (Research Domain Criteria [RDoC]; Insel et al., 2010, Morris and Cuthbert, 2012). This strategic plan emphasizes examining a single domain (such as fear conditioning/extinction) at multiple levels (from genes to brain function to observable behavior) that cuts across traditional disorder

Conclusion

In summary, fear conditioning and extinction has been a fruitful paradigm for understanding PTSD and other anxiety disorders. Rodent and healthy human studies have demonstrated that fear conditioning involves the amygdala and dACC creating a CS–US association. Fear extinction involves the vmPFC and hippocampus interacting to form a context-dependent CS–noUS association. Genetic studies have explained some of the variance in conditioning and extinction in healthy individuals, and may yield

Acknowledgments

The authors are supported in part by NIMH 5R01MH054636. MBV is supported by a National Defense Science and Engineering Graduate Fellowship (NDSEG).

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