4. 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 and 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 disorder to involve an explicit conditioning episode (i.e. the traumatic experience). Of course, the type of US that actually leads to PTSD is much more grievous than the sudden loud noise that Little Albert experienced or the mild finger shock delivered during the fMRI studies just described. And the conditioned fear response is much more debilitating, sometimes lasting decades after a traumatic experience. However, because the underlying processes appear to be similar, the fear conditioning and extinction framework has proven to be valuable in attempting to understand the mediating neurocircuitry and treatment of PTSD (Holmes & Singewald, 2013).
PTSD is a severe anxiety disorder that affects approximately 10–30% of individuals who have experienced or witnessed a psychologically traumatic event (de Vries and Olff, 2009, Dohrenwend et al., 2006 and Weiss et al., 1992) such as sexual assault, combat, natural disaster, motor vehicle accident, or witnessing the death or serious injury of another individual. Individuals with PTSD experience three primary symptoms: (1) unwanted re-experiencing of the event, often in the form of intrusive memories and nightmares; (2) avoidance of reminders of the traumatic event, even in the absence of real danger; and (3) ongoing hypervigilance, including trouble with sleep and concentration. Reminders of the traumatic experience are particularly distracting and distressing to individuals with PTSD (Hayes, VanElzakker, & Shin, 2012). While avoidance and hypervigilance can occur in the absence of trauma-related cues, re-experiencing events may be triggered by a previously neutral cue that was conditioned to the traumatic experience.
PTSD is frequently conceptualized as a memory disorder, within a Pavlovian fear conditioning and extinction framework (Elzinga and Bremner, 2002, Jovanovic and Ressler, 2010, Rubin et al., 2008 and Shin and Handwerger, 2009). According to this framework, multiple cues become associated with a traumatic experience, forming strong sensory memories. This can occur in a manner that Pavlov demonstrated by simultaneously conditioning to a buzzer, a metronome, and tactile stimulation (Pavlov, 1927). Or it can happen by stimulus generalization, like when Little Albert became wary of objects that shared some trait with a white rat (the CS) whose presence predicted a loud, startling noise (Harris, 2011 and Watson and Rayner, 2000). Multiple cues can be conditioned to the same US and as we will review below (Section 5), PTSD is associated with increased acquisition of fear conditioning. Furthermore, anxiety disorders are associated with increased propensity for CS generalization (Lissek et al., 2005). Therefore, it is likely that multiple cues would be capable of triggering a conditioned fear response in a individual with PTSD. Upon encountering conditioned reminders, individuals with PTSD re-live their traumatic experience through sensory memories. These memories are often disjointed and incomplete, with a disorganized and sometimes out-of-sequence narrative (Brewin, 2011). This may reflect the diminished sensory representations of the subcortical pathway discussed earlier (Fig. 1; Section 2; see also Pitman et al., 2012).
If PTSD symptoms emerge from a traumatically stressful conditioning episode, the failure to extinguish or maintain extinction of that conditioned fear allows symptoms to persist. For example, after the invasion of Iraq, US troops frequently faced improvised explosive devices (IEDs) hidden in trash piles along the side of the road. If a soldier survives an IED attack, this event forms a powerful memory and powerful associations. Ideally, such a veteran who has returned to the United States should learn, upon several exposures to trash piles along his street, that they no longer predict violence. If this extinction fails to happen, then even years after the danger has passed, a previously neutral cue (trash, the CS) that was associated with a grave danger (IED explosions, the US) may trigger a fear response (CR) and painful memories. Indeed, even internal cues such as autonomic arousal or thirst can become CSs. For a veteran of war in Iraq, the CSs that cause a fear response could be the sight of a trash pile, the presence of a crowd of people, the feel of hot temperatures under bright sunlight, the sound of Arabic being spoken, the smell of diesel fuel from military vehicles, internal states such as feelings of frustration, or any other cue that was present during the explosion. In his studies of multiple CSs, Pavlov reported that extinguishing one CS also extinguished the others, although subsequent research has found that this is not the case and that extinction is cue-specific (Myers & Davis, 2007).
Although humans are only able to attend to approximately four discreet cues at a time (e.g., Bettencourt & Somers, 2009), our memory of experiences normally feels rich and complete. For example, if you were asked where you were during breakfast this morning, you could easily think of more than four details: the tastes and smells of the food, the table and chair where you sat, what you were wearing, what you ate, what you read or talked about while eating, and even how you felt are all details that you did not plan on remembering, but were encoded into one episodic memory (Rudy, 2009 and Rudy and Tyler, 2010). Pavlov referred to this as “dynamic stereotype”—a neurological mapping of the environment. This is what we mean when we refer to the “context” of a memory, including fear memories. The forming of such cognitive representations of context is rapid and automatic. Context is a crucial variable that serves as something more than just another CS during fear conditioning—it also acts as a safety signal after extinction learning (reviewed in Bouton, Westbrook, et al., 2006; Maren et al., 2013 and Rudy, 2009). This means that extinction is particularly influenced by the context in which it occurs (Bouton, García-Gutiérrez, Zilski, & Moody, 2006).
For example, after a soldier comes back to the United States and repeatedly sees innocuous trash piles, the association between trash and IEDs would ideally become extinguished, at least in the context of the United States. However, if that soldier were re-deployed to Iraq, the association between roadside trash and danger might renew, because that association was appropriate in the context of occupied Iraq, and extinction learning did not occur in that context. Thus, the process of fear extinction has been described as a context-modulated form of inhibitory learning (Bouton, 2004). In other words, because extinction learning forms a new association (CS–noUS) as opposed to “breaking” the conditioned CS–US association, extinction recall involves accessing competing CS associations (CS–US vs. CS–noUS). Therefore, if extinction learning takes place in a different context than conditioning, the CR becomes context-dependent. Just as an ambiguous word (e.g. “lead”) is given meaning by context (i.e. “Metal weights are made of lead” vs. “The winner of the race was in the lead from the start”), the ambiguous CS (a pile of trash) is given meaning by the context (suburban United States vs. occupied Iraq).
However, context often does not serve as an effective safety signal for individuals with PTSD. Even while in the United States, and even after seeing innocuous trash piles many times, a veteran with PTSD may fail to extinguish the association between trash piles and IED explosions (CS–US). The CS continues to elicit a CR, namely distressing sensory memories of an explosion. Empirical fear conditioning and extinction studies of this phenomenon will be discussed in the next section (Section 5). Here, we relate renewal, spontaneous recovery, and reinstatement to the clinical presentation of PTSD.
Exposure-based therapy is used in the treatment of PTSD and is conceptually based upon fear extinction. The phenomenon of renewal (return of a CR in the conditioning context when extinction took place in a different context) is highly relevant to this type of therapy. Exposure to progressively stronger trauma-related stimuli and memories (CSs) serves to create a new association between those cues and safety (CS–noUS; Cukor et al., 2009 and Rothbaum and Davis, 2003). An individual may spend hours in a therapist’s office, talking about his traumatic experience in great detail, effectively extinguishing the CS–US association for any cues that remind him of the trauma. However, because extinction is context-specific, the CS–noUS association arising from exposure therapy only exists in his therapist’s office and not in other contexts. In other words, if fear conditioning took place in Iraq and fear extinction takes place in a therapist’s office, when an individual with PTSD is confronted with a now-ambiguous CS (e.g., trash) in a third context (e.g., a suburban street), the CS–US (trauma) association will beat out the CS–noUS (therapy) association. The CS–noUS fails to oppose the stronger, more salient CS–US association. This is the reason that therapists conduct sessions in multiple settings and use virtual reality to mimic multiple contexts (e.g. Difede et al., 2007, Gerardi et al., 2008 and Rothbaum et al., 1999). Extinction therapy and pharmacological enhancers of extinction will be discussed in more detail below (Section 6.1).
Delayed onset PTSD, in which the emergence of