ReviewFrom Pavlov to PTSD: The extinction of conditioned fear in rodents, humans, and 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).
References (236)
- et al.
The effect of repetitive transcranial magnetic stimulation on fear extinction in rats
Neuroscience
(2012) - et al.
Infralimbic cortex activation increases c-Fos expression in intercalated neurons of the amygdala
Neuroscience
(2005) - et al.
Fear conditioning in posttraumatic stress disorder: Evidence for delayed extinction of autonomic, experiential, and behavioural responses
Behaviour Research and Therapy
(2007) - et al.
Extinction in multiple contexts does not necessarily make extinction less vulnerable to relapse
Behaviour Research and Therapy
(2006) - et al.
Contextual and temporal modulation of extinction: Behavioral and biological mechanisms
Biological Psychiatry
(2006) - et al.
Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse
Biological Psychiatry
(2003) - et al.
The neural correlates of emotional memory in posttraumatic stress disorder
Biological Psychiatry
(2010) - et al.
Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder
Journal of Psychiatric Research
(2008) - et al.
Preliminary evidence of the short allele of the serotonin transporter gene predicting poor response to cognitive behavior therapy in posttraumatic stress disorder
Biological Psychiatry
(2010) - et al.
Neural networks of information processing in posttraumatic stress disorder: A functional magnetic resonance imaging study
Biological Psychiatry
(2005)
Brain systems mediating aversive conditioning: An event-related fMRI study
Neuron
Chronic antidepressant treatment impairs the acquisition of fear extinction
Biological Psychiatry
Need for speed: Evaluating slopes of OCD recovery in behavior therapy enhanced with d-cycloserine
Behaviour Research and Therapy
Fear conditioning in humans: The influence of awareness and autonomic arousal on functional neuroanatomy
Neuron
Emerging treatments for PTSD
Clinical Psychology Review
Effects of d-cycloserine on extinction: Translation from preclinical to clinical work
Biological Psychiatry
A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder
Biological Psychiatry
Do panic patients process unconditioned fear vs. conditioned anxiety differently than normal subjects?
Psychiatry Research
Pharmacological manipulation of memory reconsolidation: Towards a novel treatment of pathogenic memories
European Journal of Pharmacology
Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)?
Journal of Affective Disorders
Neural functional and structural correlates of childhood maltreatment in women with intimate-partner violence-related posttraumatic stress disorder
Psychiatry Research: Neuroimaging
Association of TPH1, TPH2, and 5HTTLPR with PTSD and depressive symptoms
Journal of Affective Disorders
A review of the modulation of the startle reflex by affective states and its application in psychiatry
Clinical Neurophysiology
Effects of experimental context and explicit threat cues on acoustic startle in Vietnam veterans with posttraumatic stress disorder
Biological Psychiatry
Reduced hippocampal and amygdala activity predicts memory distortions for trauma reminders in combat-related PTSD
Journal of Psychiatric Research
Psychophysiological and subjective indicators of aversive Pavlovian conditioning in generalized social phobia
Biological Psychiatry
Individual differences in recovery from traumatic fear
Trends in Neurosciences
Extinction memory is impaired in schizophrenia
Biological Psychiatry
The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample
Psychopharmacology
Low-dose cortisol for symptoms of posttraumatic stress disorder
The American Journal of Psychiatry
Contextual fear conditioning in humans: Cortical–hippocampal and amygdala contributions
The Journal of Neuroscience
Synaptic correlates of fear extinction in the amygdala
Nature Neuroscience
Genetics of PTSD: Fear conditioning as a model for future research
Psychiatric Annals
Hippocampus function predicts severity of post-traumatic stress disorder
CyberPsychology & Behavior
Influence of trait anxiety on brain activity during the acquisition and extinction of aversive conditioning
Psychological Medicine
Effects of target enhancement and distractor suppression on multiple object tracking capacity
Journal of Vision
Synaptic plasticity in the lateral amygdala: A cellular hypothesis of fear conditioning
Learning & Memory
Context and behavioral processes in extinction
Learning & Memory
Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder
The American Journal of Psychiatry
Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder
Psychological Medicine
The nature and significance of memory disturbance in posttraumatic stress disorder
Annual Review of Clinical Psychology
A multisite analysis of the fluctuating course of posttraumatic stress disorder
JAMA Psychiatry
Amygdala-hippocampal involvement in human aversive trace conditioning revealed through event-related functional magnetic resonance imaging
The Journal of Neuroscience
Two weeks of pretreatment with escitalopram facilitates extinction learning in healthy individuals
Human Psychopharmacology
Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure
The Journal of Neuroscience
Involvement of subcortical and cortical afferents to the lateral nucleus of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli
The Journal of Neuroscience
Human amygdala activity during the expression of fear responses
Behavioral Neuroscience
Functional MRI of human amygdala activity during Pavlovian fear conditioning: Stimulus processing versus response expression
Behavioral Neuroscience
Activity in the human amygdala corresponds to early, rather than late period autonomic responses to a signal for shock
Learning & Memory
Cited by (345)
Some key parameters in contextual fear conditioning and extinction in adult rats
2024, Behavioural Brain ResearchStructural Neuroimaging of Hippocampus and Amygdala Subregions in Posttraumatic Stress Disorder: A Scoping Review
2024, Biological Psychiatry Global Open ScienceTargeting Anxiety Sensitivity With Evidence-Based Psychoeducation: A Randomized Waitlist-Controlled Trial of a Brief Standalone Digital Intervention
2023, Cognitive and Behavioral Practice