Craske Et Al 2012 Role of Inhibition in Exposure Therapy

Journal of
Experimental Psychopathology
JEP Volume 3 (2012), Issue 3, 322–345
ISSN 2043-8087 / DOI:10.5127/jep.026511
Role of Inhibition in Exposure Therapy
Michelle G. Craskea, Betty Liaoa, Lily Browna & Bram Vervlietb

a
Department of Psychology, UCLA
b
Department of Psychology, University of Leuven
Abstract
While many researchers have largely focused on principles of systematic desensitization and habituation
in explaining fear extinction, these processes have mixed evidence at best. In particular, these models
do not account for spontaneous recovery or reinstatement of fear, nor do they explain the context
dependency of extinction or rapid reacquisition. This may in part account for the significant number of
patients who fail to respond to our available treatments which rely on these principles in designing
exposure sessions. However, recent research is converging to suggest that an inhibitory model of fear
reduction, in which the original feared association (CS-US) remains but is inhibited by a newly formed
association (CS-noUS) representing safety, holds promise in explaining the long-term attenuation of fear
and anxiety. This paper reviews research in a number of areas, including neuroimaging,
psychophysiology, and psychopharmacology that all provide support for the inhibition model of anxiety.
Limitations to this body of research are discussed, along with recommendations for future research and
suggestions for improving exposure therapy for fear and anxiety disorders. Clinical implications
discussed in this paper include incorporating random and variable practice in exposure sessions,
multiple contexts, and pharmacological aides, among others.
© Copyright 2012 Textrum Ltd. All rights reserved.
Keywords: role of inhibition, exposure therapy
Correspondence to: Dr. Michelle Craske, UCLA Department of Psychology 405 Hilgard Avenue Los Angeles, CA
90095. Email: [email protected]
Received 09-Dec-2011; received in revised form 14-Mar-2012; accepted 19-Mar-2012
Journal of Experimental Psychopathology, Volume 3 (2012), Issue 3, 322–345 323
Invited Review
Table of Contents
Introduction
Learning Based Models of Exposure therapy: Historical Overview
Exposure therapy: Outcomes
Inhibition Model of Extinction
Neurobiology of Fear Extinction: Evidence for Inhibitory Regulation
Deficits in Extinction Learning in Anxiety Disorders
Enhancing the Formation and Retrieval of Inhibitory Learning and Regulation in Extinction and Exposure
Enhancing Inhibitory Learning
Enhancing Inhibitory Regulation
Weakening the Fear Memory
Enhancing Retrieval of Inhibitory Learning
Summary
References
Introduction
The goal of this review is to outline advances in the behavioral and neurobiological bases of fear learning
that inform ways of optimizing exposure therapy for fear and anxiety disorders. We draw from and
update an earlier review (Craske, Kircanski et al., 2008) to present a paradigmatic shift from fear
reduction throughout exposure as the primary index of successful outcomes to enhancement of inhibitory
learning and inhibitory regulation, independent of fear reduction.
The very influential Emotional Processing Theory (Foa & Kozak, 1986; Foa & McNally, 1996)
emphasized fear habituation as one of the primary underlying processes of successful exposure therapy.
Specifically, the theory purports that both within-session and between-session habituation of fear are
necessary for long-term symptom relief. However, premises of Emotional Processing Theory are only
weakly supported (Craske, Kircanski et al., 2008). More recent theories of exposure therapy that draw
from extinction research highlight the importance of inhibitory regulation, or the formation of safety
learning, as the primary underlying mechanism. In other words, instead of weakening of the original fear
memories, it is now believed that the establishment of new memories that effectively compete with the
original fear memories for control of emotional responding is central to extinction (Bouton, 1993).
Corroborating evidence from neurobiological studies of fear extinction (see Sotres-Bayon, Cain, &
LeDoux, 2006) lends support to this view.
A substantial number of patients fail to achieve clinically significant symptom relief (Loerinc, Meuret,
Twohig & Craske, submitted) from traditional exposure-based therapies. This may derive in part from
deficits in inhibitory learning and regulation (e.g., Craske, Waters et al., 2008; Jovanovic et al., 2010).
Therefore, there is tremendous clinical value to optimizing inhibitory learning during exposure therapy in
order to both enhance treatment efficacy in general and to compensate for the deficits that are present
within the anxious individual prior to beginning exposure therapy. The proposed methods that are
described in this review include enhancing inhibitory learning (by designing exposure practices that
violate explicit expectancies, including multiple conditioned exciters, variable practice, and removal of
safety signals or safety behaviors), enhancing inhibitory regulation (through augmentation with d-
cycloserine and linguistic processing), weakening fear memories (through behavioral or pharmacological
aids to reconsolidation) and enhancing retrieval of inhibitory learning (by retrieval cues, and multiple
contexts).
Learning Based Models of Exposure therapy: Historical Overview

Repeated and systematic exposure to feared cues, both situational and internal (i.e., sensations,
images, memories) is a critical component of cognitive and behavioral therapies for anxiety disorders
(see Longmore & Worrell, 2007; Norton & Price, 2007). Exposure was first instituted as a treatment in
the context of systematic desensitization. Combining Pavlovian extinction learning (i.e., repeated
exposure to the feared conditional stimulus in the absence of the aversive unconditional stimulus) with
Hullian drive theory (i.e., anxiety is an uncomfortable drive that motivates behavior), Wolpe (1958)
attributed anxiety reduction to counter-conditioning or reciprocal inhibition. Specifically, when a response
antagonistic to anxiety can be made to occur in the presence of anxiety provoking stimuli, and results in
a complete or partial suppression of the anxiety response, then the bond between the stimulus and the
anxiety response is weakened. Thus, in systematic desensitization, individuals progress through
increasingly more anxiety provoking imagined encounters with phobic stimuli, while utilizing relaxation as
a reciprocal inhibitor of rising anxiety. As relaxation is intended to compete with and inhibit the anxiety
response, it is essential in this model that anxiety remains weak, or at least weaker than the relaxation
response. Therefore, level of fear responding throughout exposure was considered to be critical to both
the learning process of counter-conditioning throughout treatment and to the overall success of
treatment.
At least two developments challenged premises of reciprocal inhibition. First, graduated imaginal
exposure was shown to be equally effective whether combined with relaxation training or not (e.g.,
McGlynn, Solomon & Barrios, 1979; Dawson & McMurray, 1978; Waters, McDonald, & Koresko, 1972;
Yates, 1975). Also, when relaxation did enhance the efficacy of imaginal systematic desensitization, its
effectiveness was attributed to enhanced vividness of imagery, which was associated with increased
autonomic arousal (Borkovec & Sides, 1979; Levin & Gross, 1985). That is, relaxation was working
against the intended purpose which was to provide a physiological response that was antagonistic to
anxious arousal.
A second challenge to reciprocal inhibition came from evidence for the efficacy of flooding therapy,
involving prolonged and continuous exposure to highly anxiety provoking stimuli until fear responses
decline. Flooding (ungraduated) exposure has been shown to be as effective as graduated exposure, at
least in those willing to undertake intense exposure (e.g., Feigenbaum, 1988) and is commonly used in
exposure to traumatic images for posttraumatic stress disorder (e.g., Foa, Riggs, Massie & Yarczower,
1995; Lyons & Keane, 1989; Pitman et al., 1996), obsessional content in obsessive compulsive disorder
(e.g., Steketee, Foa, & Grayson, 1982) and is sometimes used for in vivo exposure to feared situations
for panic disorder and agoraphobia (e.g., Deacon & Abramowitz, 2006; Morissette, Spiegel, & Heinrichs,
2005). Flooding exposure typically elicits high levels of physiological and reported distress, at least
during the initial phases of exposure. Hence, the effectiveness of flooding challenged the premise of
reciprocal inhibition that anxiety be kept at sufficiently low levels to permit counter-conditioning by an
antagonistic response (e.g., relaxation).
Habituation (i.e., reduction in response strength with repeated stimulus presentations) (Groves &
Thompson, 1970) provided a descriptive framework for responses during systematic desensitization
(Lader & Wing, 1964) and in vivo exposure therapy (i.e., exposure to feared stimuli in real life) because
self-reported fear and physiological arousal most often decline within and across exposure occasions
(e.g., Grayson, Foa, & Steketee, 1982; Kozak, Foa, & Steketee, 1988; Parkinson & Rachman, 1980;
Rachman & deSilva, 1978; Sartory, Rachman, & Grey, 1977). [Although, there often is desynchrony
between decline in self-reports of distress versus physiological indices of arousal (e.g., Craske,
Sanderson, & Barlow, 1987; Gauthier & Marshall, 1977; Lande, 1982).] Habituation models gradually
replaced reciprocal inhibition to become the dominant model of processes of change throughout
exposure therapy (Lader & Mathews, 1968; Watts, 1971; Watts, 1979). However, in common with
reciprocal inhibition models, habituation models ascribe significance to reductions in expressed fear
throughout exposure trials as an index of therapeutic success. Also, traditionally, habituation was viewed
as a transient process, since dishabituation often follows habituation (Groves & Thompson, 1970).
Consequently, habituation could not account for long lasting fear reduction from exposure therapy.
The very influential emotional processing theory (Foa & Kozak, 1986; Foa & McNally, 1996) emphasized
mechanisms of habituation as precursors to cognitive correction. Specifically, emotional processing
theory purports that the effects of exposure therapy derive from activation of a ‘fear structure’ and
integration of information that is incompatible with it, resulting in the development of a non-fear structure
that replaces or competes with the original one. Incompatible information derives first from within-session
habituation, or reduction in fear responding with prolonged exposure to the fear stimulus. Within-session
habituation is seen as a prerequisite for the second piece of incompatible information, which derives
from between-session habituation over repeated occasions of exposure. Between session habituation is
purported to form the basis for long-term learning and to be mediated by changes in ‘‘meaning’’, or
lowered probability of harm (i.e., risk) and lessened negativity (i.e., valence) of the stimulus. Emotional
processing theory guides clinicians to focus on the initial elevation of fear followed by within- and
between-session reductions in fear as signs of treatment success. Although enticing in its face validity,
support for the theory has been inconsistent at best (Craske, Kircanski et al., 2008). Rather, the
evidence suggests that the amount by which fear habituates from the beginning to the end of an
exposure practice is not a good predictor of overall outcomes, in that the amount by which fear declines
does not significantly predict self-report questionnaires or behavioral avoidance testing at follow-up,
covarying baseline levels on those measures (Craske, Kircanski et al., 2008; Baker, Mystkowski, Culver,
Yi, Mortazavi, Craske, 2010; Culver, Stoyanova, & Craske, in press; Kircanksi et al., in press). Also, the
evidence for between-session habituation is mixed (Craske, Kircanski et al., 2008; Baker et al., 2010;
Culver et al., in press; Kircanksi et al., in press, Meuret, Seidel, Rosenfield, Hofmann, & Rosenfield, in
press).
Exposure therapy: Outcomes

We are in need of renewed attention to the mechanisms of exposure therapy to guide approaches that
optimize outcomes. The latter is important since while meta-analyses clearly show that exposure-based
treatments for anxiety disorders are more effective than either wait-list or attention placebo controls
(Norton & Price, 2007; Hofmann & Smits, 2008) or active treatment comparisons (Tolin, 2010), a
substantial number of patients fail to achieve clinically significant improvement. Although rates vary by
the way responder status is operationalized, and the range is wide, the mean nonresponse rate is a full
50% at post-CBT and 49% at follow-up, in studies published since 2000 for anxiety disorders (Loerinc et
al., in preparation). In other words, almost one half of patients remain symptomatic. Thus, there is a need
to find strategies for optimizing exposure therapy.
Inhibition Model of Extinction

A return to the science of fear learning and extinction, in which substantial advances have been made
recently, may offer pathways for enhancing exposure therapy outcomes. It is now thought that inhibitory
learning is central to extinction (Bouton, 1993; Miller & Matzel, 1988; Wagner, 1981), although additional
mechanisms, such as habituation, may be at play as well (Myers & Davis, 2007). Within a Pavlovian
conditioning approach, the inhibitory learning models mean that the original CS-US association learned
during fear conditioning is not erased during extinction, but rather is left intact as a new, secondary
inhibitory learning about the CS-US develops (e.g., Bouton & King, 1983; Bouton, 1993). The new
inhibitory association is dependent on both the CS and the context in which the CS is presented,
whereas the initial excitatory association is independent of context (Bouton, 2004). The effect of changes
to the context used in extinction versus the context used in extinction retest will be described in further
detail below. Thus, the context can be seen as an occasion setter for the inhibitory association, or as a
way of disambiguating the current meaning of the conditioned-and-extinguished CS (i.e., the excitatory
“danger” or inhibitory “safety” meaning). Additionally, the context may serve as a retrieval cue for the
extinction memory that might otherwise be forgotten (Vervliet, Baker & Craske, in press).
More specifically, Bouton and colleagues propose that after extinction, the CS possesses two meanings;
its original excitatory meaning (CS-US) as well as an additional inhibitory meaning (CS-noUS).
Therefore, even though fear subsides with enough trials of the CS in the absence of the US, retention of
at least part of the original association can be uncovered by various procedures, with each one showing
a continuing effect of the original excitatory association after extinction. First, conditional fear shows
spontaneous recovery (Quirk, 2002), meaning that following an interval of time between extinction and
retest (or, re-evaluation of CR strength following completion of extinction training), the strength of the CR
increases in proportion to the amount of time. Clinically, this effect parallels the return of fear that
commonly occurs when a previously feared stimulus is re-encountered after an interval of time since
completion of exposure therapy (e.g., Craske & Rachman, 1986; Craske & Mystkowski, 2006). Thus,
patients whose fear of air travel significantly reduces by the end of treatment is likely to report a return in
their fear of flying if they do not continue to practice air travel once treatment is completed.
Second, renewal of conditional fear occurs if the surrounding context is changed between extinction and
retest, as observed using ABA, ABC or AAB designs to test the same or different contexts during
acquisition, extinction and extinction retest (Bouton, 1993). In other words, fear extinction effects appear
to be specific to the context in which extinction occurred. The extinction context does not become a
general inhibitor or safety signal, because non-extinguished stimuli retain their value when tested in the
extinction context. Findings from animal fear conditioning studies have been replicated in human
conditioning studies (Vansteenwegen et al., 2005; Alvarez Biggs, Chen, Pine, & Grillon, 2008; Milad, Orr,
Pitman, & Rauch, 2005; Milad et al., 2007; Neumann, Waters, & Westbury, 2008). Also, the effects have
been observed in clinical analog samples undergoing exposure therapy and follow-up testing in the
same versus different contexts (Mystkowski, Craske, & Echiverri, 2002; Mystkowski, Mineka, Vernon, &
Zinbarg, 2003; Mysktowski, Craske, Echiverri, & Labus, 2006; Culver, Stoyanova & Craske, 2011). The
clinical relevance of renewal arises when exposure therapy is completed in one or only a limited number
of contexts (such as in the presence of a therapist or always immediately preceding or following a
therapy session), such that fear is likely to return when the phobic stimulus is subsequently encountered
in a different context (such as when alone or when unrelated to a therapy session). For example, the
person who practices exposure to driving on freeways always the day before a treatment session may
experience a return of fear when he drives after treatment is over. Or, the person who practices
exposure to public speaking only in the context of group therapy sessions may experience a return of
fear when he speaks in front of an unfamiliar audience.
Third, reinstatement of conditional fear occurs if unsignaled (or unpaired) US presentations occur in
between extinction and retest (Rescorla & Heth, 1975). Reinstatement is a context-dependent
phenomenon, meaning the effect depends on the fearfulness of the context in which the CS is tested. It
is hypothesized that the context-US association retrieves the extinguished CS-fear from memory
(Bouton, 2002). Reinstatement has been long established in animal fear conditioning studies and more
recently has been shown in human conditioning studies (e.g., Dirikx, Hermans, Vansteenwegen,
Baeyens, & Eelen, 2004; Dirikx, Hermans, Vansteenwegen, Baeyens, & Eelen, 2007; Hermans et al.,
2005; Van Damme, Crombez, Hermans, Koster, & Eccleston, 2006), especially when the CS retains
negative valence following extinction. The clinical implication of reinstatement is that adverse events
following exposure therapy may lead to a return of fear of the previously feared stimulus if it is
encountered in an anxiety inducing context. For example, fear of asking questions in work meetings may
resurge after being rejected in another social situation, or after an unrelated adverse event such as a
motor vehicle accident.
Fourth, rapid reacquisition of the CR is seen if the CS-US pairings are repeated following extinction
(Ricker & Bouton, 1996); being more rapid than the original learning indicates the carry-over effects of
the original acquisition learning. The clinical application is that fears that have subsided may be easily
and rapidly reacquired with re-traumatization, as may occur in combat situations or other dangerous
environments.
An exposure model that takes elements of inhibitory learning into account has the potential to offset
spontaneous recovery, renewal, reinstatement and reacquisition, all of which may lead to resurgence of
fear and anxiety following treatment. Specific ways in which exposure can be designed to offset these
pathways to return of fear are described in sections below.
Neurobiology of Fear Extinction: Evidence for Inhibitory Regulation

The brain-behavior associations underlying fear conditioning and extinction have been well mapped. The
amygdala plays a primary role in fear conditioning. In animals, amygdala lesions interfere with fear
conditioning, and in healthy humans, fMRI studies show elevated amygdala activation during
conditioning (see Shin & Liberzon, 2010, for a review). Conditional fear is presumed to be mediated by
the transmission of sensory information about the CS and US to the amygdala and the subsequent
control of fear reactions via projections from the amygdala to hypothalamic and brainstem regions that
regulate behavioral, endocrine, and autonomic responses (LeDoux, 2000). Other regions associated with
fear conditioning are (1) the hippocampus, which is involved in processing contextual cues of
conditioning, (2) the insular cortex, which is involved in interoception and awareness of and sensitivity to
visceral activity and (3) the dorsal and rostral ACC, which appears to have a role in anticipation of the
CS and US.
The vmPFC is believed to mediate extinction, and the hippocampus to modulate extinction by providing
information regarding safe versus dangerous contexts. In animals, extinction and extinction retest are
impaired by lesions of the vmPFC and enhanced by electrical stimulation of the vmPFC. Human
neuroimaging studies have shown increased vmPFC activation during extinction and at extinction retest
(e.g., Kalisch et al., 2006; Milad et al., 2007; Milad et al., 2009). Also, hippocampal lesions reduce the
context-dependence of extinction in rodents (Bouton, Westbrook, Corcoran, & Maren, 2006), and
hippocampal activation occurs during extinction in humans (Kalisch et al., 2006). Furthermore, vmPFC
and hippocampal activity are positively correlated during extinction and extinction retest (Milad et al.,
2007), suggesting their interaction may be particularly important for effective extinction (Shin & Liberzon,
2010). It is theorized that the PFC exerts inhibitory control over the amygdala through vmPFC activation
of inhibitory lateral nucleus interneurons or inhibitory projections to the central nucleus of the amygdala.
That is, the PFC serves as the neurobiological basis for inhibitory learning. Also, it is presumed that the
hippocampus creates a unique representation of the context in which extinction took place, and
modulates the effect of the PFC on the amygdala (Quirk & Mueller, 2008). In sum, the neurobiology of
extinction supports the inhibitory learning believed to take place during extinction.
Deficits in Extinction Learning in Anxiety Disorders

A meta-analysis of behavioral studies showed that individuals with a variety of anxiety disorders exhibit
stronger responding to the CS+ not only during conditioning but also during extinction relative to controls
(Lissek et al., 2005). Furthermore, in differential conditioning paradigms, they exhibit higher levels of
responding (i.e., skin conductance, startle reflex or expectancy for the US) to the CS- (the stimulus never
paired with the US), during conditioning and extinction, relative to controls. Since the meta-analysis,
additional studies have confirmed either delayed extinction (i.e. elevated responding to the CS+ during
extinction training) or deficits in extinction at retest (i.e., elevated responding to the CS+ at extinction
retest) in anxiety disorders (Blechert, Michael, Vriends, Margraf, & Wilhelm, 2007; Craske, Waters et al.,
2008; Waters, Henry, & Neumann, 2009; Michael, Blechert, Vriends, Margraf, & Wilhelm, 2007; Milad et
al., 2009). Similarly, studies have replicated elevated responding to the CS- in anxious groups (Craske,
Waters et al. 2008; Lissek et al., 2009).
One explanation of these findings is that individuals with anxiety disorders show impaired inhibitory
learning (Lissek et al., 2005). Indeed, impaired inhibitory (or safety) learning to either a stimulus that
does not signal threat (CS-) or to a stimulus that no longer signals threat (CS+ during extinction) has
been theorized to be central to the pathology of anxiety disorders (Davis et al., 2000; Craske, et al.,
2009). In other words, anxiety disorders appear to be associated with difficulties learning to view specific
cues as safe – cues that occur in the same context as danger cues but never actually signal danger
themselves, and cues that used to signal danger and no longer do. Furthermore, these difficulties are
present in children at risk for anxiety disorders, suggesting that they may serve as a pathway for the
acquisition of anxiety disorders (Craske, Waters et al., 2008). Some potential mechanisms of this
impaired inhibitory learning include an attentional bias toward threat (Bar-Haim, Lamy, Pergamin,
Bakersman-Kranenburg, & van IJzendoorn, 2007), difficulty disengaging from threatening stimuli (Mogg,
Holmes, Garner, & Bradley, 2008), interpretation of ambiguous stimuli as threatening (Mathews &
MacLeod, 2005), elevated expectancies for threat (Chan & Lovibond, 1996), and overgeneralization of
fear responding to stimuli that resemble the threat cue (Lissek & Grillon, 2010). The mechanism
underlying inhibitory learning are likely to be multiple, and likely to include both explicit and implicit
processes. With respect to the latter, attentional bias and interpretation bias occur both supraliminally as
well as subliminally (Mathews & MacLeod, 2005), and albeit debated (Lovibond & Shanks, 2002), there
is some evidence for fear learning to occur in the absence of conscious awareness of the CS and its
contingent relationship with the US (Öhman & Mineka, 2001).
In addition to deficits in inhibition, elevated fear CR to the CS- or the CS during extinction could be due
to over-excitation as well, and the usual fear conditioning and extinction paradigms do not tease these
mechanisms apart. Direct evidence of deficits in inhibitory control in anxious individuals is dependent on
laboratory paradigms capable of teasing apart inhibition from excitation during fear learning. Myers and
Davis (2004) adapted paradigms used in earlier learning theory experiments (Wagner & Rescorla, 1972;
Wagner, Logan, Haberlandt, & Price, 1968) to design a novel AX+/BX- “conditional discrimination”
procedure that independently evaluates excitation and inhibition. In this paradigm, A, B, and X are CSs.
An aversive US is administered when A and X are jointly presented, and is not administered when B and
X are jointly presented. Therefore, during conditioning, A becomes excitatory because A and X
presented together predict the US, whereas, B becomes inhibitory because B presented with X predicts
the absence of the US. Critically, the inhibitory impact of B is demonstrated in a “summation test”, when
B reduces fear to A when A and B are jointly presented. This paradigm was later adapted for humans by
Jovanovic and colleagues (2005).
Using this paradigm, evidence for impaired inhibitory mechanisms in anxious individuals was
demonstrated in combat veterans with severe PTSD symptoms (Jovanovic et al., 2009), another sample
of veterans with PTSD (Jovanovic et al., 2007), and a civilian population with high levels of urban trauma
relative to combat veterans with mild PTSD symptoms and healthy controls (Jovanovic et al., 2010).
Also, we found that, in a sample of healthy college students, state anxiety induction prior to fear
conditioning reduced subsequent inhibitory processing compared to individuals who did not undergo
anxiety induction (Liao & Craske, in submission), suggesting a causal role of anxiety in inhibitory
learning. Although replications in other anxious populations and experimental manipulations are
warranted, the results support the inferences from prior behavioral paradigms which suggest that
anxious individuals exhibit deficits in inhibitory learning.
Consequently, at the neural level, one would expect anxious individuals to show deficits in vmPFC
during extinction. Indeed, although limited to only a few studies, there is evidence for decreased
orbitofrontal and medial PFC (including vmPFC/subgenual ACC) during extinction and at extinction
retest in adults with posttraumatic stress disorder and high trait anxiety relative to increased activity in
those areas in healthy controls (e.g., Bremner et al., 2005; Milad et al., 2007; Milad et al., 2009;
Rougemont-Bucking et al., 2011; Indovina et al., 2011).
Thus, the evidence suggests that extinction is mediated by inhibitory learning/regulation and that
individuals with anxiety disorders possess deficits in such inhibitory learning/regulation. Such deficits
may serve as a risk factor for anxiety disorders, explaining the longevity of fears in disordered groups
versus the transient nature of fears in nondisordered samples. At the same time, such deficits may
render individuals with anxiety disorders in need of augmenter of inhibitory learning and regulation during
exposure therapy.
Enhancing the Formation and Retrieval of Inhibitory Learning and

Regulation in Extinction and Exposure
Significant advances are being made in ways to enhance the formation of inhibitory associations
throughout extinction and their retrieval at retest. These advances have direct relevance for exposure
therapy for individuals with anxiety disorders, who appear to be in particular need of such enhancement
strategies given their deficits in inhibitory learning. In this section, we review these advances, updating a
prior review (Craske, Kircanski et al., 2008) where appropriate.
Enhancing Inhibitory Learning

As reviewed in (Craske, Kircanski et al., 2008), one approach is to design exposures in such a way that
the experience maximally violates the negative, excitatory expectancies regarding the rate or frequency
with which aversive outcomes occur (Rescorla & Wagner, 1972; Gallistel & Gibbon, 2000), or the
intensity of the aversive outcome (Davey, 1992), which in turn should enhance the development of
inhibitory expectancies. Methods for maximally violating the expectancy for occurrence of the aversive
include extinction trials with durations that clearly exceed the point at which the US was expected to
occur. However, basic research on the relative durations of the CS during extinction compared to
acquisition has yielded mixed findings (Cain, Blouin, & Barad, 2003 vs Drew, Yang, Ohyama & Baslsam,
2004). In our human laboratory conditioning study, we found no differences in fear responding at re-test
across CS extinction durations ranging from half the CS acquisition duration to twice the CS acquisition
duration (Prenoveau, Craske, Liao, & Ornitz, 2012).
Exposure durations that exceeded expectancies for the timing of an aversive outcome in a human
phobia (acrophobia) sample were as effective as standard exposure therapy, even though conducted
over much fewer exposure trials (Baker, et al., 2010). Prior to beginning an exposure trial, participants
indicated at what length of time in the height situation they fully expected an aversive outcome (i.e.,
falling). Participants were randomized to exposure trials at durations that specifically exceeded the
durations at which they believed a negative outcome was certainly likely to occur (“disconfirmation”) or
exposure trials that discontinued before the duration when they believed the negative event was certain
to occur (“nondisconfirmation”). The two groups were equally effective at post and at follow-up, although
the “disconfirmation” group received only two trials of exposure whereas the “nondisconfirmation” group
received multiple trials of exposure. Given the potency of early session cues in extinction learning
(Bouton & Brooks, 1993), the greater number of times that the phobic height stimulus was approached in
the nondisconfirmation group may have offset the benefits of the disconfirmation trials. Conversely,
greater benefits to disconfirmation trials may have occurred with more trials of exposure.
Conceivably, temporal prediction of US occurrence is not the most relevant dimension for expectancy for
all phobic individuals. For example, the expected size of the US (e.g., the intensity of expected social
rejection for an individual with social anxiety), or its occurrence at any time, regardless of the length of
time spent in the situation (e.g., likelihood of falling from a height at any time while standing at a height)
may be more relevant dimensions. Furthermore, stated expectancies for aversive events are likely to
shift throughout exposure, such that rather than relying on expectancies established prior to starting an
exposure trial, on-line expectancy ratings are needed to continuously guide ongoing exposure.
To this end, we routinely design exposure trials in such a way that they provide experiences that
disconfirm expectancies, and adjust the goals throughout exposure to continuously violate expectancies
as they occur. In this approach, exposure tasks are designed to enhance new learning and are not
guided by premises of fear reduction, nor to “stay in the situation until fear declines”. For example, for
persons who fear not being able to speak when they are anxious in a meeting, we design the exposure
to ask questions in meetings specifically whilst anxious. Similarly, for persons who fear fainting from
panic, sustained panic is necessary to fully violate expectancies. This approach ties exposure
parameters directly to consciously stated expectancies for aversive events, tied to each exposure task.
As such, they overlap with cognitive models of exposure as a vehicle for disconfirming misappraisals
(see Salkovskis et al., 2007). Additional approaches for enhancing inhibitory learning, described below
do not rely upon conscious appraisals of expectancies.
“Super-extinction” involves simultaneous presentation of multiple conditioned excitors throughout
extinction training, which together provide stronger evidence for disconfirmation of “danger” expectancies
than a single conditioned excitor (Rescorla, 2000). That is, a red triangle and a blue square are each
independently paired with shock; then, during extinction, their joint presentation results in superior
extinction than their individual presentations. Animal research has shown positive benefits in terms of
reducing context renewal although this has not been found in human conditioning studies (Vervliet,
Vansteenwegen, Hermans, & Eelen, 2007), perhaps because humans treat the compound presentation
of two stimuli during extinction as a different stimulus than each stimulus presented separately at
extinction retest. In “deepened extinction” (Rescorla, 2006), multiple fear conditional stimuli are first
extinguished separately before being combined during extinction. In animal studies, deepened extinction
procedures decrease spontaneous recovery and reinstatement of fear. Human research in this area is
ongoing and initial results suggest that deepened extinction in healthy controls reduces spontaneous
recovery and reinstatement effects (Culver, Vervliet, & Craske, in submission). Notably, clinical
applications have existed for some time in the form of implementing interoceptive exposure to feared
bodily sensations (e.g., increased heart rate) first alone and then in combination with agoraphobic
situations that also have previously undergone exposure alone (Barlow & Craske, 1994). As with the
procedures for explicitly violating expectancies above, fear reduction is not a goal of this method of
conducting exposures. Rather, the goal is to learn (explicitly or implicitly) that the aversive event occurs
less often or is less intense than expected, achieved in this case through experience with more than one
‘predictor’ of such events.
Varying the to-be-learned task enhances retention of learned non-emotional material (Magill & Hall,
1990; Schmidt & Bjork, 1992, Shea & Morgan, 1979). For example preventing successive trials of the
same task from occurring (called random practice) enhances long-term retention compared to blocked
practice in which all trials of a particular task are completed prior to moving on to the next task (Shea &
Morgan, 1979). Variability is believed to enhance the storage capacity of newly learned information
(Bjork & Bjork, 1992, 2006), pair the information to be learned with more retrieval cues (Estes, 1955),
and generates a rule that captures the invariance among tasks (Schmidt & Bjork, 1992), which renders
the information more retrievable at a later point in time. Variability can be explained by context retrieval
models as well (Bouton, 1993), since variability is more likely to characterize encounters with phobic
stimuli once exposure therapy is complete. Variability in terms of timing between exposure sessions (i.e.,
progressively increasing amount of time, such as 1 day, 4 days, 10 days) has been shown to be more
effective at follow-up than massed exposure in two studies of spider fearful samples (Rowe & Craske,
1998a; Tsao & Craske, 2000). Also, variability in terms of the stimuli used during exposure demonstrated
positive benefits in terms of spontaneous recovery in two other studies of spider fearful and height fearful
samples (Rowe & Craske, 1998b; Lang & Craske, 2000), although a third study of contaminant anxiety
showed trends only (Kircanski, Mortazavi et al., 2012). Traditional exposure proceeds steadily from one
hierarchy item to the next, with each item repeated a number of times until anxiety decreases. Instead, in
variable exposure, exposure was conducted to items from the hierarchy in random order, without regard
to fear levels or fear reduction, although usually beginning with the least anxiety producing item to avoid
treatment refusal. Thus, we routinely conduct exposure with varying stimuli, for varying durations, at
varying levels of intensity, rather than continuing exposure in one situation until fear declines before
moving to the next situation. Notably, such variability typically elicits higher levels of physiological
arousal and subjective anxiety during exposure (e.g., Lang & Craske, 2000), despite beneficial effects in
the long term.
Furthermore, we have recently found that greater variability in terms of fear levels throughout exposure
(i.e., repeated increases following decreases in minute to minute anxiety levels) is a positive predictor of
outcomes in contaminant anxiety and public speaking anxiety (Kircanski, Mortazavi et al., 2012; Culver
et al., in press). Conceivably, emotional state (i.e., fear level) may serve as a retrieval cue; variability in
fear level during exposure would be expected to enhance retrievability of learning, as varying levels of
fear are likely to occur in situations following exposure therapy where retrieval is required (Bjork & Bjork,
1992, 2006). More generally, variability in subjective fear during exposure may aid in generalization, by
learning that one can tolerate exposure to a stimulus across a variety of emotional states. Thus, we
routinely encourage variability in both stimulus and fear response during exposures, such as by
conducting “unpredictable” lengths of exposures to phobic stimuli (with agreement from clients
beforehand).
A fourth strategy is to eliminate ‘‘safety signals’’ or ‘‘safety behaviors.’’ Common safety signals and
behaviors for clients who have anxiety disorders are the presence of another person, therapists,
medications, or food or drink. For persons whose feared outcomes depend upon fear levels (i.e., “fear of
fear”, such as individuals with panic disorder who fear losing control should they panic, or individuals
with social anxiety who fear humiliation when feeling anxious), reduction of fear itself could become a
safety signal. In other words, perceived safety is dependent on fear reduction in the same way that for
someone else perceived safety is dependent on the availability of medications or another person.
Consequently, fear reduction may preclude opportunities to learn that the emotion of fear is non-
threatening. For such individuals, treatment may proceed most effectively by maintaining high levels of
fear throughout exposure. In the experimental literature, safety signals alleviate distress in the short
term, but when they are no longer present, the fear returns (Lovibond, Davis & O’Flaherty, 2000), an
effect that may derive in part from interference with the development of inhibitory associations. In phobic
samples, the availability and use of safety signals and behaviors has been shown to be detrimental to
exposure therapy (Sloan & Telch, 2002), whereas instructions to refrain from using safety behaviors
improved outcomes (Salkovskis, 1991). However, recent data have presented contradictory findings
(Rachman, Shafran, Radomsky, & Zysk, 2011). Specifically, the use of hygienic wipes following
exposures in a healthy undergraduate sample with contamination fears did not preclude reductions in
contamination fear and disgust relative to a control group, and the spontaneous recovery of fear two
weeks later did not differ between the two groups. Similarly, Deacon and colleagues have failed to
replicate the deleterious effect of continuing to engage in safety behaviors (including the availability of
the safety behavior but without actual engagement of it) during exposure in claustrophobic fear (Deacon,
Sy, Lickel, & Nelson, 2010; Sy, Dixon, Lickel, Nelson, & Deacon, 2011).
Enhancing Inhibitory Regulation

Based on evidence for fear extinction to be weakened by antagonists of the glutamate receptors in the
amygdala, Walker, Rattiner, & Davis, (2002) tested and demonstrated that drug agonists of the same
receptors, and in particular, d-cycloserine, enhance extinction in animal studies. Later studies showed
that d-cycloserine is mainly involved in the consolidation of newly formed extinction memories, because
post-extinction administration of the drug produced the same effect (up to four hours). Others have
shown the d-cycloserine prevents reinstatement, although it does not influence renewal and rapid
reacquisition in rodents (Bouton, Vurbic, & Woods, 2008; Ledgerwood, Richardson, & Cranney, 2004;)
and other experimental data show that d-cycloserine may augment fear under some conditions in both
rodent and human samples (Vervliet, 2008). Nevertheless, in excellent clinical translation work, d-
cycloserine has been shown to result in less fear at follow-up, after exposure therapy for specific human
fears (Ressler et al. 2004). Administering d-cycloserine in combination with interoceptive exposure for
panic patients has also resulted in a greater reduction in symptom severity, and a greater likelihood of
achieving a change in clinical status at post-treatment and one-month follow-up compared to exposure
plus placebo (Otto et al., 2010). Similar results have been found in socially phobic samples (at both post-
treatment and one-month follow-up; Hofmann et al., 2006) and some evidence suggests a benefit of
combining d-cycloserine with exposure and response prevention for obsessive-compulsive disorder for
anxiety symptoms at mid-treatment and depressive symptoms at post-treatment (Wilhelm et al., 2008).
In a meta-analysis of the efficacy of d-cycloserine for anxiety disorders, Norberg, Krystal, & Tolin, (2008)
reported effect sizes of d = .90 at post-treatment and d = .40 at follow-up when collapsing across animal,
non-clinical human, and clinical human samples; in human clinical samples only, the effect sizes were d
= .60 at post-treatment and .47 at follow-up. Finally, it is noteworthy that DCS has no measurable effect
on fear levels throughout exposure and yet is most often correlated with improved long term outcomes.
D-cycloserine is already being used as an augmentation strategy by clinicians, and it is listed on the
Department of Veterans Affairs website guide under the Clinician’s Guide for Medications for PTSD
(Jeffreys, 2007).
Another method of enhancing inhibitory regulation involves linguistic processing, or language use, during
extinction learning. According to disruption theory (Lieberman et al., 2007), engaging in linguistic
processing activates the PFC, and as previously mentioned, activation of the ventrolateral PFC reduces
activity in the amygdala, thereby attenuating anxious responding. For instance, in an fMRI study,
Lieberman et al. (2007) found that when participants viewed negatively valenced images paired with
emotion words, the right ventrolateral PFC activity was increased and amygdala activity was reduced in
comparison to participants who viewed the unpaired images. This result has been replicated a number of
times. The exact mechanisms through which linguistic processing affects inhibitory regulation are not
fully understood at this point, but there is a clear relationship between activation in the vmPFC and
attenuation in the amygdala. It appears that engaging the executive functioning cortical areas of the
brain works to dampen the limbic system activity. Therefore, employing linguistic processing during
extinction may activate this feedback mechanism between the PFC and the amygdala.
This hypothesis was further investigated by Tabibnia, Lieberman, & Craske, (2008) who found that
repeated evocative images paired with word labels, notably negatively valenced and irrelevant to the
images, produced a greater reduction in subsequent skin conductance response (SCR) to the images,
one week later, than unpaired images. Furthermore, Kircanski, Lieberman, and Craske, (in press) found
added benefits of labeling feared stimuli and the associated emotional affect in a sample of individuals
with spider phobias as they underwent exposure therapy. In comparison to cognitive reappraisal of
thoughts, distraction, and exposure alone, affective labeling during exposure was found to reduce skin
conductance and increase approach behavior at one week follow up in a context different than the
exposure context (Kirkanski et al., in press). Therefore, these data suggest that linguistic processing in
the form of labeling, as opposed to more traditional cognitive therapy which attempts to change the
content of appraisals, can improve inhibitory regulation during extinction/exposure.
Weakening the Fear Memory

A recent (re-)discovery is that retrieving already stored memories induces a process of reconsolidation
(Amir, Foa, & Coles, 2000), since the memory is written into long term memory again, requiring de novo
neurochemical processes. Thus, it may be possible to change memories during the reconsolidation time
frame upon retrieval. Propranolol, a beta blocker, has been shown to block the reconsolidation of
memories, and Debiec and Ledoux (2004) found that infusions of propranaolol blocked the
reconsolidation of a previously formed CS-US memory, and led to erasure of the fear response and
resistance to reinstatement effects. This suggests that propranolol upon retrieval may be a useful clinical
tool, and indeed, two fear conditioning studies in healthy humans (Kindt, Soeter & Vervliet, 2009; Soeter
& Kindt 2010) and one preliminary study in a PTSD sample (Brunet et al., 2008) replicated the effects.
Monfils, Cowansage, Klann, & LeDoux (2009) used an alternative strategy to make use of
reconsolidation mechanisms to weaken fear memories, hypothesizing that novel information presented
during the reconsolidation window may be incorporated into the memory and change it. Thus, extinction
during a reconsolidation window may weaken the fear memory itself. Monfils et al. found that a brief
presentation of the CS (i.e., phobic stimulus) 30 minutes prior to sustained extinction trials significantly
reduced spontaneous recovery, renewal, reinstatement and rapid reacquisition in a rodent sample. This
effect has since been demonstrated in healthy human samples and tied to underlying cell processes
(Schiller et al., 2010; Clem & Huganir, 2010). On the other hand, an opposite pattern of results was
reported in a rodent sample by another investigator team (Chan, Leung, Westbrook, McNally, 2010).
Furthermore, a recent investigation (Ponnusamy et al., 2011) established the same results whether the
brief exposure to the CS occurred in the window before extinction or in a window after completion of
extinction, which suggests that the results may relate more to enhancing the retrieval of the extinction
learning rather than erasing acquisition learning. It may prove difficult to translate this paradigm to
clinical practice, where timing of exposure to reminders of feared stimuli, especially imaginal (e.g.,
traumatic memories) or interoceptive stimuli (e.g., increased heart rate) or stimuli with high frequency in
the natural environment (e.g., social interactions), is difficult to control outside of the laboratory.
Enhancing Retrieval of Inhibitory Learning

One option for enhancing retrieval of extinction learning and offset context renewal is to include retrieval
cues (of the CS-no US association) during extinction training to be used in other contexts once extinction
is over. This has been shown to be effective in animal studies where various control comparisons allow
the conclusion that retrieval cues become associated with the context in which they occur, and thus
acquire the ability to retrieve the memory of that context and the corresponding extinction memory
(Brooks & Bouton, 1994). The positive effects of retrieval cues on context renewal have been
demonstrated in human conditioning studies as well (Dibbets & Maes, 2011; Vansteenwegen et al.,
2006), although they may acquire an inhibitory value and became a safety signal (Dibbets, Havermans,
& Arntz, 2008). In clinical analog anxious samples, the effects of a retrieval cue upon context renewal
were very weak in one study (Culver et al., 2011), although instructions to mentally reinstate what was
learned during exposure (an instructional retrieval cue) had more robust effects in reducing context
renewal in another study (Mystkowski et al., 2006). In the treatment of anxiety disorders, this approach
simply suggests that patients carry cues (e.g., wrist band) with them to remind them of what they learned
during exposure therapy (as long as the cues do not become safety signals), or are prompted to remind
themselves of what they learned in exposure therapy each time they encounter previously feared
sensations or situations.
Context renewal may be offset by including multiple contexts throughout exposure (Mineka, Mystkowski,
Hladek, & Rodriguez, 1999; Mystkowksi et al., 2002; Rodriguez, Craske, Mineka, & Hladek, 1999).
Although some complexities exist with identifying relevant contexts (Crakse, Kircanksi et al., 2008), the
interdependence of stimulus and context (i.e., unclear boundaries between stimulus versus context)
(Rescorla, 1985), and moderators of context effects such as cue overload (i.e., pervasive associations
with a number of previously formed memories may lessen the influence of contextual variables) (Watkins
& Watkins, 1976; Eich, 1989) and causal relations (Eich, 1985, 1995), multiple contexts have been
shown to offset context renewal in rodent samples (e.g., Gunther, Denniston, & Miller, 1998), and in a
clinical analog study of exposure therapy (Vansteenwegen et al., 2007). On the other hand, one
conditioning study in rodents (Bouton et al., 2006) and another conditioning study in humans (Neumann,
Lipp, & Cory, 2007) failed to demonstrate detectable benefits of multiple contexts throughout extinction
on context renewal, suggesting that the effects are unstable.
Summary
There is compelling evidence to suggest that extinction learning is mediated by inhibitory learning and
regulation. Evidence for the role of inhibitory learning derives from procedures that illustrate the retention
of original excitatory associations (i.e., spontaneous recovery, context renewal, reinstatement and rapid
reacquisition). Notably, these procedures also model return of fear that occurs following exposure
therapy for anxiety disorders. Neurobiological data demonstrating the inhibitory role of the vmPFC on the
amygdala provides further support for inhibitory regulation as a mechanism of action during extinction.
Furthermore, behavioral and neurobiological data indicate that individuals with anxiety disorders show
deficits in inhibitory learning and regulation. Thus, outcomes from exposure therapy are expected to
improve by using strategies designed to enhance inhibitory learning and regulation throughout exposure
therapy. These strategies depart from traditional exposure therapy models, which up until recently, have
emphasized habituation and fear reduction as an index of corrective learning. Instead, inhibitory
augmentation strategies either have no effect or may even increase fear responding throughout
exposure therapy. These strategies, some of which have more empirical support in human phobic
samples than others, include designing exposure trials to disconfirm explicit negative expectancies,
capitalizing on multiple triggers of anxiety during exposure, variability of stimulus and emotional
response, removal of safety signals and safety behaviors, implementing pharmaceutical aides such as d-
cycloserine, linguistic processing (affective labeling more specifically, that differs from cognitive
reappraisal) throughout exposure, behavioral and pharmacological aids to reconsolidation, retrieval cues
and multiple contexts (see Table 1). All of these are promising avenues of inquiry that require additional
research before any firm conclusions are drawn about the optimal conditions for exposure. However,
this area of research provides exciting revelations into the importance of adopting a learning-centered
approach to exposure therapy that allows clients to push their boundaries and reduce avoidance of
feared stimuli.
Table 1: Procedures to use in clinical practice to increase inhibitory learning
Augmentation Administration/timing Reference

Strategy
D-cycloserine Administer DCS immediately before or immediately after fear Norberg et al., 2008
extinction
Propranolol Administer propranolol immediately following retrieval of fear Brunet et al., 2008; Kindt et al.,
memory (i.e., following disclosure of traumatic event) 2009; Soeter & Kindt, 2010
Expectation violation Design exposure experiences to disconfirm expectancies Davey, 1992; Gallistel &
(explicitly or implicitly) for the rate or intensity of an aversive event Gibbon, 2000; Rescorla &
(e.g., continue in feared situation beyond the point at which Wagner, 1972
expected to ‘go crazy’ from fear)
Deepened extinction Exposure to multiple feared cues separately, and then present Culver et al., in preparation;
them simultaneously (e.g., exposure to feared sensation, and to Rescorla, 2006
feared situation, followed by exposure to feared sensation in
feared situation)
Variable practice Vary the specifics of an exposure task from trial to trial (e.g., Culver et al., in press;
exposure to differing contaminants) rather than repeat the same Kircanski et al., in press;
task until fear declines, or vary fear levels within or across trials Schmidt, & Bjork, 1992
by increasing fear following fear reductions
Removal of safety Identify safety signals (objects, people, medication) and safety Salkovskis, 1991; Sloan &
signals or safety behaviors (staying near the exit, over-preparation), and wean Telch, 2002
behaviors them during exposures
Linguistic processing Label emotions and stimuli during exposure Kircanski et al. in press;
Lieberman et al., 2007
Multiple contexts Vary the context of exposure, including specific locations, Culver et al., 2011; Mystkowski
presence of others, times of day, mood states, and temporal et al., 2002; Mystkowski et al.,
relationship to therapy sessions. 2003; Mysktowski et al., 2006
Behavioral aid to Brief exposure to a CS (e.g. the room in which a speech will be Monfils et al., 2009, Schiller et
reconsolidation given), and then wait 30 minutes before engaging in full exposure al., 2010
exercise.
Retrieval cues Carry cues (e.g., wrist band, note-card) which serve as a reminder Brooks & Bouton, 1994;
of what was learned during exposure therapy; or self-instruct to Dibbets & Maes, 2011
remember what was learned in exposure therapy, as the Mystkowski, et al. 2006;
previously feared stimulus is re-encountered. Vansteenwegen et al., 2006
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Role of Inhibition in Exposure Therapy

Michelle G. Craskea, Betty Liaoa, Lily Browna & Bram Vervlietb

Learning Based Models of Exposure therapy: Historical Overview

Exposure therapy: Outcomes

Inhibition Model of Extinction

Neurobiology of Fear Extinction: Evidence for Inhibitory Regulation

Deficits in Extinction Learning in Anxiety Disorders

Enhancing the Formation and Retrieval of Inhibitory Learning and

Enhancing Inhibitory Learning

Enhancing Inhibitory Regulation

Weakening the Fear Memory

Enhancing Retrieval of Inhibitory Learning

Table 1: Procedures to use in clinical practice to increase inhibitory learning

Augmentation Administration/timing Reference

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