Exposure therapy in eating disorders revisited

Neuroscience and Biobehavioral Reviews 37 (2013) 193–208

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Review

Exposure therapy in eating disorders revisited Antonia Koskina ∗ , Iain C. Campbell, Ulrike Schmidt Section of Eating Disorders (PO59), Institute of Psychiatry, King’s College London, De Crespigny Park, London SE5 8AF, United Kingdom

a r t i c l e

i n f o

Article history: Received 24 August 2012 Received in revised form 10 November 2012 Accepted 21 November 2012 Keywords: Eating disorders Exposure Learning Anorexia nervosa Bulimia nervosa Virtual reality

a b s t r a c t Exposure therapy is a widely used and effective form of treatment in anxiety disorders and addictions but evidence for its usefulness in eating disorders (ED) is inconsistent. This paper systematically reviews the literature on the use of exposure therapy in ED, the theory underpinning its use, and the deficits in current knowledge. Databases were searched to 2012. In addition, potential improvements in the use of exposure techniques in ED are considered by drawing upon theory and research involving neuropharmacology, basic and clinical neuroscience, contemporary behavioural and neurobiological research, and technologies such as virtual reality (VR). © 2012 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Exposure techniques in ED: a review of the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. In vivo food exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Exposure with response prevention of purging (ERP-P) for BN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Exposure with response prevention of bingeing (ERP-B) for BN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Food exposure in AN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. In vivo body image exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Food and body image exposure using virtual reality (VR) protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Main findings from the systematic review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Extinction, learning theory and their relevance to exposure treatment in ED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Use of a fear extinction model: neural correlates, clinical applications and limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Integration of animal and clinical findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Integration of findings from basic and clinical neuroscience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Use of pharmacological agents as an adjunct to exposure treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Use of neuromodulation as an adjunct to exposure treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recommendations for clinical practice and future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The eating disorders (ED), anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED) and related partial or mixed

∗ Corresponding author. Tel.: +44 7801 954 151; fax: +44 2078 480 182. E-mail address: [email protected] (A. Koskina). 0149-7634/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neubiorev.2012.11.010

193 194 195 195 195 195 198 200 200 200 201 202 202 202 202 203 203 204 205 205

syndromes (eating disorder not otherwise specified; EDNOS) are disorders with significant physical and psychosocial disability and frequent relapse (Treasure et al., 2010a). Whilst AN has been documented historically and cross-culturally, BN and related disorders are seen as modern Western phenomena observed in cultures where food is plentiful and – against a societal trend of growing obesity – slimness is highly valued (Habermas, 2005; Schmidt and Treasure, 1993; Silverman, 1988).

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There is an ongoing debate on classification (Hebebrand and Bulik, 2010; Knoll et al., 2011) but ED can be conceptualised as being on a spectrum of over- and under-eating and this is associated with altered weight and with altered food associated reward. This may manifest itself in a number of ways, for example as a dread of food, or a phobic avoidance of eating, fullness or fatness. Alternatively, it may be manifest as an excessive desire to eat, overeating of highly palatable foods or a mixture of both dread and desire and over- and under-consumption. In addition, an overvaluation of body shape and weight is usually present (APA, 2000) and in AN, there is often significant hyperactivity (Hebebrand and Bulik, 2010). The aetiology of ED is complex, with overlapping and distinct risk factors for different types of ED, including sociocultural and other environmental factors, temperamental, endocrine, developmental, genetic and epigenetic factors (Becker, 2007; Becker et al., 2005; Campbell et al., 2011; Connan et al., 2007; Day et al., 2011; Fairburn et al., 1999, 1998, 1997; Jacobi et al., 2004; Monteleone and Maj, 2008; Pike et al., 2008; Pjetri et al., 2012; Stice, 2002; Stice et al., 2005; Striegel-Moore et al., 2007, 2005) and gene–environment interactions (GxE) (Karwautz et al., 2011). Effective treatments exist for some of the ED. Cognitive behavioural therapy (CBT) is the treatment of choice for adolescents and adults with BN and BED, with good acceptability and efficacy (Fairburn et al., 2009; Hay and Claudino, 2010; Schmidt et al., 2007). However, if CBT fails, the best course of action is somewhat unclear. Whilst family-based interventions are generally recommended in the case of adolescents with AN (Lock, 2011; NICE, 2004), for adults with AN, there is no gold-standard treatment, and outcomes are poor (Schmidt et al., 2012). Thus, novel approaches to treatment are needed. These require an improved understanding of the neurobiological and psychological underpinnings of ED and this has greatly improved in the last decade due to advances in neuroimaging, in learning theory, in new pharmacological and physiological interventions and from information from animal studies. Among the many factors that influence food intake in humans and animals, learning and conditioning (Pavlovian and instrumental) processes have an important role in determining food preferences and when, how often, and how much food is consumed (Bouton, 2011; Epstein et al., 2009). Thus, distinct environmental cues (or specific contexts) can override homeostatic signals and stimulate or inhibit eating in the sated or hungry state. Rodent models of such cue-induced feeding or feeding inhibition have been developed (Petrovich, 2011). Inter-individual differences in both fear and appetitive conditioning and ability to extinguish learned associations are to some extent, heritable (Malkki et al., 2010, 2011; Mineka and Oehlberg, 2008). Interestingly, in the context of ED, sex differences have also been noted with fear-induced feeding cessation being more difficult to extinguish in female rather than male rats (Petrovich and Lougee, 2011). Conditioning processes have been proposed to play an important role in the development and maintenance of ED, via conditioned food avoidance (Strober, 2004; Treasure et al., 2011) or conditioned (excessive) food reward (Bouton, 2011). Traits which are common in ED, such as anxiety and behavioural inhibition seem to facilitate acquisition of conditioned fears and may also account for inter-individual differences in extinction learning (Mineka and Oehlberg, 2008). Indeed, an early report of AN described selfconditioned food avoidance in a patient who imagined putrid cat’s pudding when pressed to eat, thus inducing vomiting (Hewett, 1873). Studies in rodents have found that experience of activity based anorexia (ABA) in adolescence leads to anxiety-like behaviour in adulthood (Kinzig and Hargrave, 2010), and enhanced conditioned taste aversion learning (Liang et al., 2011). Acquisition of conditioned reward and conditioned fear are based on distinct neural circuitry and neurochemistry, but

common final pathways seem to be involved in the extinction1 of both processes, with pre-frontal cortex glutamatergic pathways having a central role (for review, see Kaplan et al., 2011). Exposure treatment is a clinical intervention based on the principles of Pavlovian conditioning and which targets conditioned fear responses and conditioned reward and aims to reduce or extinguish these responses. A large evidence base supports the efficacy of exposure treatment in anxiety disorders, including specific phobias (Wolitzky-Taylor et al., 2008), panic disorder (Westen and Morrison, 2001), obsessive compulsive disorder (Foa et al., 2005; Franklin et al., 2000) and post-traumatic stress disorder (Cukor et al., 2010; Powers et al., 2010; Rothbaum and Schwartz, 2002). Exposure treatment in anxiety disorders is based on the premise that phobic anxiety and avoidance are typically cue controlled (Jansen et al., 1992). Using graded exposure to fear-inducing stimuli, techniques attempt to break the pattern of avoidance that strengthens the fear response. The patient learns by experience that the feared consequences do not occur and develops new non-fear associations with the stimuli (Abramowitz et al., 2010). Exposure has also been used with partial success to minimise craving and relapse in substance abuse disorders (Kaplan et al., 2011). A number of studies have applied exposure treatments in ED and there is a resurgence of interest in this method. This paper critically reviews the evidence on the use of exposure techniques as applied to ED, and identifies deficits in knowledge. In addition, it discusses how the efficacy of exposure therapy for ED might be improved by drawing upon theory and research from neuropharmacology, contemporary learning theory, and technologies that use virtual reality. Recommendations for research are also made.

2. Exposure techniques in ED: a review of the evidence PubMed and Web of Science databases were searched to 2012. Search terms included: Eating disorders, anorexia nervosa, bulimia nervosa, binge eating disorder, cue exposure, response prevention, exposure therapy, imagined exposure and mirror exposure. To ensure no significant reference was overlooked, the specific terms and Boolean operators included: (exposure or exposure therapy or cue exposure or response prevention or mirror exposure or imagined exposure or imagery exposure) and (eating disorders or anorexia nervosa or bulimia nervosa or binge eating disorder). This search produced 708 results. Abstracts were scanned for their suitability and studies were included if they involved the application of exposure techniques in an ED sample either alone, or in comparison to another treatment or control condition. Studies from an early review (Carter and Bulik, 1994) were gathered and included, as some of these publications did not appear in any of the investigated search engines. Overall, 31 studies were considered suitable for inclusion. Although imaginal exposure techniques were searched for, exposure in vivo or exposure using virtual reality technologies appeared to be the only methods cited in the literature. Search

1 Kamboj et al. (2011) point out that the terms extinction and habituation are used interchangeably in the literature: “However ‘extinction’ is perhaps more clearly defined as a neurobiological process involving reduction in the conditioned response following repeated exposure to the conditioned stimulus, with concurrent reduction in neural activity in central nervous structures in which the CS–CR and/or CS–CS relationships are represented. Habituation on the other hand, also involves responsiveness with repeated stimulation, but in addition to the neurobiological and behavioural changes seen in extinction, may also encompass confounding factors such as fatigue and ‘stimulus’ ‘satiation,’ especially in human studies (Groves and Thompson, 1970).“Whilst we agree with Kamboj et al.’s definition for pragmatic reasons, we decided to use the two terms interchangeably here, as we review some animal literature where extinction is the term commonly used and human literature where the term habituation is preferred.

A. Koskina et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 193–208

results yielded two main categories of exposure techniques: Food Exposure and Body Image Exposure. 2.1. In vivo food exposure Food exposure for people with BN and/or AN binge/purge subtype (ANBP) usually focuses on the prevention of bingeing or purging whereas, for those with the restrictive subtype of AN (ANR), graded food exposure is used to introduce the consumption of feared foods. These are described below. 2.1.1. Exposure with response prevention of purging (ERP-P) for BN The earliest proponents of exposure techniques in ED used Exposure with Response Prevention (of purging) (ERP) as a treatment for BN based on an ‘anxiety reduction model’ (Rosen and Leitenberg, 1982): in this, eating elicits fear of weight gain and purging reduces the associated anxiety, analogous to the role of excessive hand washing or checking in OCD. Thus, purging behaviours negatively reinforce binge eating by removing the fear of weight gain. ERP for purging (ERP-P) is used to gradually expose patients with BN or ANBP to feared food cues and prevent vomiting after consumption, thereby extinguishing anxiety via habituation. The therapist remains with the patient until the urge to vomit has passed, during which time the therapist elicits and challenges distorted beliefs (Leitenberg et al., 1988; Rosen and Leitenberg, 1982). ERP-P has also been conceptualised within a social learning theory framework: Wilson et al. (1986) proposed that ERP-P enhances the patient’s sense of self-efficacy and bolsters their ability to cope with high-risk situations. Nine studies applying ERP-P techniques were identified (one single case study, two case series, one cross-over study, one nonrandomised controlled trial and four RCTs). Early case series, cross-over and controlled studies provided proof of concept for ERP-P by demonstrating a reduction in vomiting at post-treatment (Giles et al., 1985; Gray and Hoage, 1990; Leitenberg et al., 1984; Rosen and Leitenberg, 1982; Rossiter and Wilson, 1985). However, the majority of these studies did not include any data on change in bingeing frequency and the proportion of participants who met criteria for BN at treatment completion and follow-up is not known. Randomised controlled trials (RCT) are detailed in Table 1 . Data showed ERP-P to be superior (in terms of reduction of vomiting) compared to waiting list, but not to CBT (Leitenberg et al., 1988), nor was the addition of ERP-P to CBT (Agras et al., 1989; Leitenberg et al., 1988), or to cognitive restructuring (Wilson et al., 1991) superior to these interventions alone. All four RCTs were small and probably under-powered. Where reported, acceptability of ERP-P appeared to be reasonable, with control or comparison treatment conditions experiencing similar or higher attrition rates than ERP-P (Wilson et al. (1986): 25% of control group; 22% of ERP group; Agras et al. (1989), 5.9% of ERP-P group; 22.7% of CBT group; 15.8% of selfmonitoring condition and 5.3% of the wait list). In all the reviewed studies, ERP-P involved eliciting and challenging distorted cognitions during exposure, an approach that is largely considered part of cognitive treatment. This makes it difficult to attribute findings solely to the effect of exposure. Whilst methodological limitations permeate these early studies, there are also some conceptual concerns about the theoretical basis of ERP-P. Firstly, although it is hypothesised that eating in ERP-P induces an urge to purge, food consumption could also produce an urge to binge, via priming, or indeed, an urge to restrict intake (Carter and Bulik, 1994). It is unclear therefore, which specific urges arise during ERP-P, as urges to binge and/or to restrict are not usually measured as outcome variables. Secondly, there is concern about the emphasis on vomiting as a central maintaining factor in BN (Carter and Bulik, 1994; Schmidt and Marks,

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1989) because a subgroup of individuals with BN, and those with BED, engage in binges without purging. The ERP-P model does not take into account the cues that precede bingeing, and places little emphasis on binge eating as a maintaining factor in eating disordered behaviour (Carter and Bulik, 1994). Lastly, ERP-P is logistically complex and time-consuming, and the need to organise binge conditions for each patient in a naturalistic setting may limit its application. 2.1.2. Exposure with response prevention of bingeing (ERP-B) for BN An alternative exposure technique that uses a classical conditioning model has been proposed (Jansen et al., 1992, 1989). Exposure with Response Prevention of Bingeing (ERP-B), also named Cue Exposure, conceptualises excessive food intake (i.e. bingeing) as the unconditioned stimulus (US), and stimuli specifically associated with binge-eating (e.g. the sight or taste of palatable food, emotional states, or time of day) as the conditioned stimuli (CS). This model for binge eating hypothesises that if a CS predicts bingeing (US), and elicits physiological responses such as craving, then repeated or prolonged exposure to the CS in the absence of the US, will result in extinction of craving (Jansen et al., 1992, 1989). ERP-B involves exposing patients to binge foods and preventing bingeing whilst the food is touched and smelled. Small amounts may also be tasted to elicit or increase the urge to binge (Schmidt and Marks, 1988). Six studies were found to use ERP-B techniques: one single case study (Jansen et al., 1989); four case series (Schmidt and Marks, 1988; Kennedy et al., 1995; Toro et al., 2003; Martinez-Mallen et al., 2007) and one non-randomised controlled trial (Jansen et al., 1992). Three studies evaluated both ERP-P and ERP-B: one cross-over study (Schmidt and Marks, 1989), and two RCTs (Cooper and Steere, 1995; Bulik et al., 1998a). See Table 1 for details of RCTs. Early case studies and other non-RCT data on ERP-B appeared to yield positive results in terms of symptom reduction, and the procedure was well tolerated. It is also of note that some of these studies showed promising results in individuals who had had not improved with CBT or pharmacological treatments (Martinez-Mallen et al., 2007; Toro et al., 2003), suggesting that exposure treatment may be of use as a second line treatment in these situations. One small RCT compared CBT with a combination of ERP-P followed by ERP-B (Cooper and Steere, 1995). Whilst there was similar improvement in both groups, only those treated with CBT maintained their gains whereas those treated with exposure relapsed. One larger RCT (Bulik et al., 1998a) combined CBT sequentially with either ERP-P, ERP-B, or a relaxation control condition. Post treatment and at a 3-year follow up there was no significant difference in outcome between groups (Carter et al., 2003). However, at a 5year follow-up, both the ERP-P and ERP-B groups showed greater BN symptom reduction than the condition which combined CBT with relaxation, thus providing some evidence of a ‘conditioned inoculation’ in those who received exposure treatment (McIntosh et al., 2011) (Table 1). 2.1.3. Food exposure in AN Studies using food exposure techniques for treating people with AN are relatively uncommon (Boutelle, 1998). Models have emphasised the symptom overlaps between AN and anxiety disorders and suggested that exposure and response prevention may be useful due to its established efficacy in anxiety disorders (Foa et al., 2005; Whittal et al., 2005). These models draw parallels between AN, OCD and phobic anxiety disorder, and propose that fear and anxiety are integral to the perpetuation of detrimental eating habits (Hildebrandt et al., 2010; Steinglass et al., 2011a). Specifically, premeal anxiety in AN is negatively correlated with subsequent food intake (Steinglass et al., 2010). Exposure with response prevention

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Table 1 RCTs using in vivo exposure in ED. Author and Year

Method

Comments

CR + ERP-P significantly lowered bingeing and vomiting, increased self-efficacy and dietary control compared to CR; gains maintained at FU. All treatment groups sig improved on most outcomes. Slightly better outcomes on vomiting and food consumed in a test meal for the ERP-P groups. 3 treatment groups reduced purging but CBT superior (80%); addition of ERP-P did not enhance CBT and may have been deleterious.

Small uncontrolled sample; no comparison group data at FU as some psb went on to receive ERP-P; groups not given same amount of CR each; no sig differences on many outcomes. Weak positive results for ERP; possible cross-contamination between CBT and ERP-P; no measures of bingeing PTc or FU; group format meant less time for each ps. Short time frame—ERP-P possibly displaced some essential elements of CBT; short 1 h sessions; unequal amounts of CBT—cannot assess the ‘additive hypothesis.’ Small sample; no wait list control; unequal time allocated to CBT so cannot address whether ERP-P has advantages; few exposure sessions; possible cross-contamination with CBT. Small sample, possible type II error; mix of ERP-P and ERP-B shortens the duration of each technique, may have reduced efficacy; possible cross-contamination of procedures. Significant drop-out rate (N = 102 at 12 month FU); possible biased sample from the exclusion of those on medication; no non-CBT control group; possibly substantial improvement occurring from 8 sessions of CBT obscured effects of exposure techniques. Drop-out and randomisation meant only 92 completed CBT+ behaviour therapy (ERP-P, ERP-B or Relaxation); no mention of whether ps received other therapies in between FUs.

Na

Study population

Exposure situation

No of sessions

Follow-up (FU)

Wilson et al. (1986)

ERP-P

17 (12)

BN sample; within 10% normal BMI

Random allocation to CRe or CR + ERP-P; treatment in groups of 2/3. ERP-P introduced in session 4.

16

6 and 12 months

Leitenberg et al. (1988)

ERP-P

47

BN sample

24

6 months

Agras et al. (1989)

ERP-P

77 (67)

BN sample

14

6 months

Wilson et al. (1991)

ERP-P

22

BN sample, within 15% normal weight range

4 groups: (1) ERP-P in clinic; (2) ERP-P multiple settings; (3) CBTd ; (4) Wait list control. Treatment in groups of 3; exposure uniform for 6 weeks, then personalised. 4 groups: (1) CBT; (2) CBT + ERP-P; (3) Self-monitoring; (4) Wait list control. Exposure began in session 7 and food intake increased over time. RCT of (1) CBT, and (2) CBT + ERP-P. Exposure introduced between sessions 10 and 13.

20

3 and 12 months

88% of CBT group stopped bingeing PT and 63% ceased purging. For CBT + ERP-P, bingeing and purging cessation were both at 67%. Gains maintained at FU.

Cooper and Steere (1995)

ERP-B and ERP-P

27

BN sample

2 groups: (1) CBT without exposure, and (2) ERP-P (4 sessions) and ERP-B (4 sessions). Exposure group received no cognitive restructuring techniques.

19

12 months

Both groups reduced bingeing and vomiting; at FU high relapse in ERP group. Those receiving CBT maintained gains.

Bulik et al. (1998a)

ERP-B and ERP-P

135 (106)

BN sample

Ps received 8 sessions of CBT and were then randomised to either (1) ERP-P, (2) ERP-B, or (3) Relaxation training. Exposure stimuli were tailored to the individual. In ERP-B participants did not consume any binge food.

8

6 and 12 month

ERP-B group had better outcomes on abstinence of purging PT (non-sig). ERP-B sig reduced anxiety towards binge cues, food restriction, depression and body dissatisfaction. At 12 months ERP-B decreased restriction.

Carter et al. (2003)

ERP-B and ERP-P

113 (92)

Former BN Sample (85% no current dx)

3 year follow up from Bulik et al. (1998a,b)

–

2 and 3 years

85% of Ps had no current BN. No clear advantages for those receiving ERP-P or ERP-B over Relaxation, but treatment effects stable.

A. Koskina et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 193–208

Key outcomes

Intervention Type

Table 1 (Continued) Author and Year

Method

Comments

4 and 5 years

Abstinence from bingeing sig higher for ERP-P and ERP-B (43% and 54%) than Relaxation group. Purging lower in exposure groups.

4

PT

No differences between medication groups in test or training meal consumption. Collapsing medication groups showed exposure group increased food intake from baseline to final meal.

FU period uncontrolled for further treatment; exposure may be most effective to those not responding to CBT; analysis included some ps who did not complete treatment. Difficult to determine specific contribution of Exposure + DCS, other interventions ongoing on ward; wide range of BMI; small sample; comparison data taken from a previous study; no long term FU; brief number of sessions.

3

1 month

Exposure group fared better PT and at FU on avoidance, body checking, weight and shape concerns, body dissatisfaction, dieting, depression and self-esteem.

Na

Study population

Exposure situation

No of sessions

Follow-up (FU)

McIntosh et al. (2011)

ERP-B and ERP-P

109

Former BN sample

5 year follow up from Bulik et al. (1998a,b)

–

Steinglass et al. (2007)

AN food exposure

11

AN inpatients (5 AN binge/purge; 4 AN restrictive; 2 atypical AN)

Delinsky and Wilson (2006)

Body image exposure

45 (41)

Females w/weight and shape concerns (scoring >4 on EDE-Q subscale)

Food Exposure (without response prevention) ± D-Cycloserine (DCS) vs placebo. Two test meals at baseline and post-training. 4 training meals twice-weekly: training meals consumed after receiving DCS or Placebo pill. Comparison group without exposure. Mirror exposure (ME) vs Non-directive body image treatment. ME: Ps asked to systematically and mindfully describe themselves head to toe, without skipping or dwelling on features. Critical and subjective terms were discouraged. Second session in more revealing clothing.

a b c d e

Non-ED sample; no information on screening for other mental health problems or history of ED. Possible self-selected sample bias; unknown additive effect of mindfulness techniques; drop-outs had sig. higher levels of depression

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Key outcomes

Intervention Type

N: no. of participants; where possible those after drop-out is reported as (N). Ps: participants. PT: post treatment. CBT: cognitive behavioural therapy. CR: cognitive restructuring.

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for AN (AN-EXRP) uses graded food exposure to reduce avoidance and facilitate habituation to anxiety surrounding the anticipation and ingestion of feared food (Steinglass et al., 2011a). AN-EXRP aims to increase flexibility in food choice and caloric consumption, and hence to improve the ability to maintain weight and prevent relapse. One question in this context is whether the structured, regular and supervised eating of meals that is part of most specialist in-patient and day-care programmes for AN could be acting as a form of exposure therapy, i.e. by facilitating habituation to different high calorie foods. However, this may not be a particular effective form of exposure: in a study of in-patients with AN, eating behaviour remained highly abnormal after treatment (Walsh, 2011), suggesting that for some patients the experience of eating during in-patient treatment could simply reinforce fears and negative beliefs about eating. Another possibility is that the experience of exposure to calorie dense food in inpatient settings does not generalise well to naturalistic settings. This is considered further in our discussion but suggests a need for further investigation of the effects of regular eating in this clinical setting. Three studies have used food exposure techniques in people with AN: one single case study (Boutelle, 1998), one case series (Steinglass et al., 2011b) and one RCT (Steinglass et al., 2007). All used AN-EXRP with some degree of success: however, two involved atypical participants, i.e. one was a case study of a male with AN (Boutelle, 1998), and the other treated a weight restored AN group (Steinglass et al., 2011b), Thus, the extent to which AN-EXRP is useful for treating people acutely ill with AN is unclear. The third study, a small RCT, investigated the effect of D-cycloserine (DCS) on food exposure (Steinglass et al., 2007) (see Table 1): it did not involve response prevention and was based on evidence that DCS enhances fear extinction during exposure therapy in anxiety disorders (Hofmann et al., 2006a; Kushner et al., 2007; Ressler et al., 2004). DCS compared to placebo had no effect in any of the training or test meals (Steinglass et al., 2007). When the medication groups were collapsed, some improvement was seen on final test meal consumption in those receiving exposure therapy (Steinglass et al., 2007). However, interpretation of the findings is difficult because the exposure therapy was concurrent with inpatient treatment, and the comparison group was from a previous study. Use of DCS to augment exposure techniques is discussed below. In conclusion, the use of exposure therapy in AN is limited; studies are preliminary, have small sample sizes, some potential confounds and weakly positive results. However, on theoretical grounds this treatment appears to have potential, and is relatively acceptable to patients. 2.2. In vivo body image exposure Exposure techniques have been used to reduce body dissatisfaction, body checking and avoidance in individuals with ED, and have been incorporated into therapeutic modalities such as CBT for body image disturbance (Cash and Lavallee, 1997), mindfulness based mirror exposure (Wilson, 2004), and cognitive dissonance based mirror exposure for ED prevention programmes (Stice and Presnell, 2007). Body image exposure techniques use mirrors or videos to encourage individuals to look systematically at each part of their bodies for an extended period of time, often whilst wearing tight fitting clothing (Cash and Lavallee, 1997; Vocks et al., 2007, 2008). Exposure sessions, are often supplemented with additional exposure homework assignments (Key et al., 2002; Rushford and Ostermeyer, 1997; Vocks et al., 2008). Several mechanisms have been proposed to explain the changes that occur during these procedures. Information processing theories suggest that negative self-schemas regarding one’s own body are activated when people with ED look in the mirror, and these lead to negative emotions and cognitions (Hilbert et al., 2002;

Vocks et al., 2007). As many individuals with ED overestimate their own body dimensions and focus on perceived negative aspects (Jansen et al., 2005), exposure may allow corrective feedback to be received regarding body size and this may lead to increased body acceptance, decreased fear of weight gain (Rushford and Ostermeyer, 1997; Vocks et al., 2007) and sensitisation to positive aspects of the body (Jansen et al., 2005). In terms of learning theory, looking systematically and repeatedly at each part of the body during the exposure exercise is thought to reduce negative emotions via habituation (Vocks et al., 2008). It has been hypothesised that prolonged and repeated exposure weakens the association between the conditioned stimulus of ‘seeing one’s own body’ and conditioned negative responses (Hilbert et al., 2002), and prevents avoidance (Wilson, 2004). Finally, from the perspective of social learning theory, it has been proposed that the experience of mirror exposure enhances self-efficacy as individuals learn they are able to expose themselves to avoided and feared situations (Vocks et al., 2008). The extent to which these explanations contribute to the mechanisms of change during exposure is unclear, and it is likely that each is in operation to some degree. A recent study used a non-clinical sample of female undergraduates to examine the relative effectiveness of three different approaches to mirror exposure: cognitive dissonance-based mirror exposure (in which participants described positive aspects of themselves when viewing their image), a mindfulness-based mirror exposure (in which participants practiced breathing meditation mindfulness techniques before completing mirror exposure), and a neutral nonjudgmental approach to mirror exposure (Luethcke et al., 2011). All three variants of mirror exposure improved ED risk factors, but only the cognitive dissonance mirror exposure significantly improved levels of body image satisfaction. These findings suggest that introducing a cognitive component to body image exposure exercises strengthens the effect of the technique; however, data should be interpreted with caution as effect sizes were small in this non-clinical sample. Comparisons of the different varieties of mirror exposure have not been conducted in clinical samples. Eight studies have investigated body image exposure techniques in patients with AN, BN or BED or in women with high weight and shape concerns. Of these, six are case-control studies (Norris, 1984; Rushford and Ostermeyer, 1997; Hilbert et al., 2002; Tuschen-Caffier et al., 2003; Vocks et al., 2007, 2008), one is a non-randomised controlled trial (Key et al., 2002) and one an RCT (Delinsky and Wilson, 2006) (see Table 1). Preliminary evidence from case control studies comparing ED with healthy controls (HC) suggests that body image exposure leads to short-term improvements on outcomes, such as low mood, selfesteem, body image, body checking, weight/shape concerns, etc. and in some of these studies to greater improvements in the ED group than in HC. It is of note that these studies usually just give one or two exposure sessions and several report no follow-up data. At this stage, therefore, it is difficult to draw conclusions about the relative efficacy of body image approaches in different EDs, particularly as no studies incorporated an ED control group condition into their design (all use healthy controls as a basis for comparison). One RCT in women with high shape and weight concerns compared mindfulness-based body image exposure to a control treatment involving non-directive body image treatment, and found the exposure condition to be superior to control treatment (Delinsky and Wilson, 2006): applying the methodology used in this study to a clinical sample might increase insight into the efficacy of body image exposure in ED. A final point to consider when implementing mirror exposure techniques is the variation that may occur within ED individuals depending on the type of body image disturbance present and the associated idiosyncratic safety-seeking behaviours. For example, some may engage in excessive checking behaviour to monitor their

Table 2 RCTs using virtual reality (VR) in ED. Author and Year

Method a

Key outcomes

Comments

Study population

Procedure

No of sessions

Follow-up (FU)

˜ et al. (1999) Perpiná

18 (13)

7 AN; 6 BN

8 sessions in Standard body image condition + 6 sessions of either VR or relaxation

PTc

VR group significantly improved levels of body dissatisfaction, body avoidance and fear of weight gain. No sig difference on other ED symptoms.

Small sample size, limited psb information given, i.e. age, sex; significant drop out; no FU.

Riva et al. (2002b)

20

Female BED

(1) 7 VR sessions over 6.5 weeks. (2) Nutritional groups 3x per week, 6.5 weeks.

PT

VR group significantly reduced levels of body dissatisfaction, increased self-efficacy and motivation to change vs controls.

Small preliminary trial; unequal amount of therapeutic time allocated to each condition; no FU data.

Riva et al. (2003)

36

Female BED

2 groups: (1) Standard body image treatment + relaxation; and (2) Standard body image treatment + VR. VR therapy included 6 settings exposing ps to food and body image. Residential weight control treatment with low calorie diet and physical training with either: (1) VR sessions with food and body image exposure; or (2) psycho-nutritional groups based on CBTd principles. 3 groups: (1) Nutritional groups weekly + low kcal diet and physical training; (2) ECTe —treatment as with group 1 + weekly motivational groups and bi-weekly VR sessions (Riva et al., 2002a, b); (3) CBT–treatment as group 1 + weekly motivational groups and biweekly individual CBT

(1) 5; (2) 5 nutritional groups, 5 motivational groups and 10 VR sessions; (3) 5 nutritional groups, 5 motivational groups and 10 CBT sessions

PT and 6 month PT

PT: ECT showed superior improvement in body image and acceptance, physical satisfaction and social skills. Weight loss and reduced bingeing in all conditions. 6 months: ECT group sig improved on ED symptoms and body image; 77% free from bingeing (vs 56% of group 3 and 22% of group 1).

Small sample with low power; some weight gain shown in all groups at 6 months PT; some cognitive techniques used in ECT as well as CBT; no information on randomisation procedures or blinding.

Riva et al. (2004)

120

68 obese; 51 ED (36 BED, 12 BN and 3 EDNOS)

4 groups: (1) ECT + psychological and nutritional groups; (2) Individual CBT + psychological and nutritional groups; (3) Nutritional group treatment only; or (4) Waiting list NB. ECT = 45 min sessions with 15 minute VR exposure in which ps are immersed in food, body or interpersonal related environments.

(1) 10 ECT + 5 Psychological groups and 4–6 nutritional groups (2) 10 CBT + 5 Psychological and 4–6 nutritional groups (3) 4–6 nutritional groups

PT

Treatment groups improved significantly on measures of weight, eating control, body dissatisfaction and other psychopathology. Little difference between ECT and CBT groups. No change in waiting list group

Preliminary data with low power per group; no information on randomisation; no primary outcome defined; no indication of blinding procedures; drop-out unreported and no FU data; ECT and CBT used in combination with other treatments; difficult to isolate effects of VR as brief exposure to VRET (15 min) and 30 min of cognitive techniques.

a b c d e

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N

N: no. of participants; where possible those after drop-out is reported as (N). Ps: participants. PT: post treatment. CBT: cognitive behavioural therapy. ECT: experiential cognitive therapy. 199

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body image, whilst others avoid their reflection. Most commonly, individuals with ED alternate between both checking and avoidance, depending on factors such as mood and changes in eating, and weight (Shafran et al., 2004; Reas et al., 2005). Identifying the relevance of such safety behaviours before engaging in exposure is important in order to minimise their use and maximise the effectiveness of the intervention. 2.3. Food and body image exposure using virtual reality (VR) protocols A number of protocols using virtual environments have been developed to provide alternative ways of delivering exposure therapy (de Carvalho et al., 2010; Meyerbröker and Emmelkamp, 2010; ˜ et al., 2003). During virtual reality exposure therapy (VRET), Perpiná patients are able to see fear or other salient (e.g. appetitive, or drug-cue) stimuli overlaid into a variety of visually realistic contexts, thus allowing interaction with them in real time. To improve patients’ sensory experience, auditory, tactile and olfactory stimuli can also be delivered (Bordnick et al., 2011). In ED, virtual kitchens, supermarkets and restaurants have been developed in which eating behaviour can be assessed (Riva et al., 2002a, 2004). In addition, body image exposure techniques have also been adapted for virtual environments, with technologies including virtual clothes shops, gymnasia, and swimming pools (Gutiérrez-Maldonado et al., 2010; Riva et al., 2004). Several studies have assessed the potency of virtual versus real life stimuli and of different virtual environments (salient or neutral) in eliciting emotional responses in ED patients. Details of RCTs are outlined in Table 2. A small study compared AN, BN and healthy participants’ response to different food cues (real food, virtual food and photographs) with regards to self-reported anxiety and physiological response (heart rate, respiration and skin conductance). Food craving was not assessed. ED groups were indistinguishable: they all showed higher anxiety levels in response to food stimuli than control participants and higher anxiety levels to real and virtual foods compared to photographs, with no difference between real and virtual food (Gorini et al., 2010). In a series of studies (Ferrer-García et al., 2009; Gutiérrez-Maldonado et al., 2006, 2010) patients were randomly exposed to different virtual environments: an emotionally neutral living room, kitchens with high and low calorie food, a restaurant with high and low calorie food, and a swimming pool. Anxiety and depression were measured before and after each environment. Patients showed higher anxiety in high calorie environments and the swimming pool, than in neutral environments with no differences between AN and BN participants (Gutiérrez-Maldonado et al., 2006). Healthy controls only showed increased levels of anxiety in the swimming pool (FerrerGarcía et al., 2009). ED participants also experienced higher levels of body image distortion and dissatisfaction after virtually eating high calorie foods compared to low-calorie foods, whereas control participants’ body image was unchanged across different situations (Gutiérrez-Maldonado et al., 2010). These studies suggest that virtual environments can effectively elicit ED-related fears. Treatment studies using virtual food and body image exposure are emerging (see Table 2 for review of RCTs, and Ferrer-García and Gutiérrez-Maldonado, 2012). A small early RCT (n = 18) in ED patients combined standard body image treatment with either relaxation or virtual reality therapy (exposure to food and body ˜ et al., image), and the latter produced better outcomes (Perpiná 1999). Riva and colleagues have developed Experiential Cognitive Therapy (ECT) (Riva et al., 2004). This consists of ten 45 min sessions with a therapist. In each of these sessions, the patient enters different virtual environments (food-, body- or interpersonal related) for 15 min and is encouraged to interact with them. Prior to this, the therapist introduces the particular environment and then, with

the patient explores their thoughts and feelings about this; at the end of the session, there is further reflection about the patient’s thoughts feelings and behaviours. These authors have conducted several RCTs (Riva et al., 2004, 2002b, 2003) mainly in patients with BED or obesity in which they compared ECT with CBT (Riva et al., 2004, 2003) or psychonutritional groups (Riva et al., 2002b): ECT was as efficacious as the comparison treatment, and showed advantages on some outcome measures. These studies have a number of methodological limitations which make it difficult to interpret the findings. Some of these concerns are the conduct and reporting of these RCTs (see Table 2 for details). Other problems concern the fact that ECT and CBT were combined with other treatment components. Finally, the VRET-component in ECT involved very brief exposure to different environments (15 min) coupled with 30 mins of cognitive techniques, thus making it difficult to identify the primary therapeutic mechanism. A case study (Cardi et al., 2012) used a non immersive virtual reality module as an add-on to the Maudsley Model of treatment for adults with AN (MANTRA) (Schmidt and Treasure, 2006), in a female outpatient who had not responded to CBT, pharmacological treatment, or a recovery group. The technology is termed ‘non-immersive’ as it does not use a head-mounted display. The module was delivered prior to MANTRA treatment, and used graded exposure to feared foods in a virtual kitchen. Reductions in anxiety levels, safety behaviours, and fears in relation to food were seen on completion of the module. In addition, ED symptoms were reduced and body mass index (BMI, kg/m2 ) increased significantly (Cardi et al., 2012), suggesting it may be a beneficial adjunct to the treatment of AN. Overall, VRET appears to be a promising approach, but further evidence is needed to assess its therapeutic utility in ED. Potential side-effects of VRET are limited, although some participants mention nausea or drowsiness as a problem (de Carvalho et al., 2010). Other potential disadvantages are equipment costs (Riva et al., 2002a) and the fact that it is not possible to personalise VRET environments or alter exposure paradigms during a session, e.g. by introducing anxiety modulators (as one could do in real life exposure) (de Carvalho et al., 2010). 3. Discussion This discussion considers the results of the systematic review and outlines some of the challenges to increasing the efficacy and acceptability of exposure treatment in ED. It proposes that if the theoretical rationale associated with exposure treatment in ED was improved, the field would advance. In this context it considers how evidence from behavioural and neurobiological correlates of fear extinction, including concepts from learning theory, and a consideration of the neural circuitry underlying the ability to extinguish fear and clinical anxiety, might be of value. It also considers how pharmacological agents and neuromodulation may act as useful adjuncts to exposure therapy. Lastly, it makes recommendations for clinical practice and research. 3.1. Main findings from the systematic review Two different food exposure paradigms have been used in the treatment of BN and to a much lesser extent for other ED that involve binge eating (binge-purge AN): (a) cue exposure to the sight, smell and taste of binge foods and (b) exposure to eating (binge) foods and response prevention of vomiting. Most studies using these paradigms were conducted in the 1980s and 90s. Whilst there is a sizeable number of studies, with the exception of the trial by Bulik et al. (1998a) there is limited high quality evidence. For example, RCTs are small and hence underpowered and

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this, together with different exposure protocols, makes it difficult to draw definitive conclusions. So what explains the decline in research in exposure therapy after the initial surge of studies into its use for ED? An important reason is the emergence of CBT as the pre-eminent treatment for bulimic eating disorders (Fairburn et al., 2009; NICE, 2004), together with the fact that early trials did not establish exposure treatments as superior to CBT or as improving outcomes if combined with CBT. Moreover, food exposure treatment is logistically difficult and time-consuming and attrition in some trials was high, suggesting that it is neither sufficiently acceptable nor practical. However, the case series by Toro et al. (2003) and Martinez-Mallen et al. (2007) which used cue exposure to food with good outcomes in patients who had not responded to CBT or medication suggest that it is worth exploring cue-exposure as a second line treatment. Use of exposure to food as a phobic stimulus in AN is in its infancy, but given the lack of effective treatments for adults with AN, it is worth pursuing. Body image exposure treatments appear promising, but high quality RCT-based evidence from clinical populations is lacking. Given that contemporary CBT treatments for bulimic disorders include some focus on improving body image (which may or may not have elements of body image exposure) it would be of interest to establish how much the inclusion of a body image exposure component adds to CBT for BN or related disorders. Protocols utilising virtual reality technologies are a promising method for delivering exposure interventions: they appear to be well tolerated and, in addition, may act as an intermediary step for socialising patients to exposure prior to in vivo work. Many studies provide insufficient methodological details making it difficult to determine the effective components of protocols. Because of such issues, questions remain. For example, (a) how effective are exposure techniques in ED? (b) for whom are they most effective? (c) how are they best applied, and (d) how do they work? In addition, as many of the reviewed studies combine exposure techniques with cognitive treatment techniques, it is important to determine the contribution of exposure in the context of more established treatments such as CBT. On the basis of the findings above, it appears that the use of exposure therapy in ED can be improved. It is proposed that this will be helped if the theoretical, methodological and therapeutic underpinnings of different exposure treatments in ED are better understood and integrated into practice. Some of the main areas for consideration are described below. 3.2. Extinction, learning theory and their relevance to exposure treatment in ED Learning theory suggests extinction is not simply a weakening of the original CS-US association, or of forgetting, but is an active learning process that devalues conditioned cues and contexts, and masks or inhibits the original learning (Bouton, 2004; Myers and Davis, 2007). Furthermore, during exposure to conditioned stimuli, both extinction and reconsolidation can occur. Reconsolidation is the preservation of the original memory after initial retrieval: it is most prominent when coincident with the conditioned stimuli, and needs to be inhibited for effective extinction (Kaplan et al., 2011). One problem with food exposure techniques (ERP-B and ERP-P) in ED is that there is usually no attempt to disrupt the original fearful or conditioned appetitive memory from being reconsolidated during exposure, i.e. no competing non-threat memory associations are being formed to inhibit the negative thoughts and safety behaviours on the one hand, or craving/desire on the other, that often arise in response to food. Therefore, during exposure, instead of extinguishing fears or desires, the procedure may continually reconsolidate and strengthen existing conditioned responses to

201

food. This may partly explain why re-feeding treatment of inpatients with AN, (who are often treated for long periods with regular meals in structured and supervised conditions), does not reduce anxiety around food. In addition, reinforcement of fears and negative meanings attached to food and weight gain may be coupled with subtle cognitive avoidance manoeuvres or safety behaviours, which serve to prevent disconfirmation of a feared outcome and interfere with treatment (Salkovskis, 1991). These factors may help explain why therapeutic effects of food exposure in ED are moderate, and often temporary. Knowledge from learning theory may also explain why body image exposure techniques, which inhibit negative interpretations of one’s body and prevent avoidance, are relatively more easily implemented and more successful (Vocks et al., 2007, 2008). Extinction learning is fragile and context-dependent, where ‘context’ incorporates a variety of background stimuli, including physical environment, internal state, emotions, and time (Bouton, 2004, 2011; Conklin and Tiffany, 2002). In addition, if conditioned fear or appetitive cues are encountered some time after extinction, conditioned responding often spontaneously recovers as the conditioned stimulus is presented in a differing temporal context (Bouton, 2011; Havermans and Jansen, 2003; Myers and Davis, 2007). Research on optimum timing for modifying fears has targeted the reconsolidation phase, which occurs over a brief period (∼6 h) after memories are reactivated/retrieved (Quirk et al., 2010; Schiller et al., 2010; Taylor et al., 2009). During this time period, stored information is labile and vulnerable to disruption, and fear memories may be permanently ‘updated’ with new information (Quirk et al., 2010). Studies with healthy participants showed extinction training during the reconsolidation phase reduced fear specific to the reactivated memory, which did not show spontaneous recovery and did not return following a reinstating fearful stimulus (Schiller et al., 2010). These data are encouraging, as the fear reduction lasted at least a year. It is unclear whether the reconsolidation-extinction technique can alter fear memories in patients suffering from psychiatric disorders (Quirk et al., 2010), but it might be developed to ameliorate some of the high anxiety and emotional dysregulation found in ED patients. Clinic or hospital environments may only weakly approximate to the reality of home, or other environments where individuals routinely engage in ED behaviours. In addition, cognitive inflexibility and difficulties with set shifting seen in ED (e.g. Tchanturia et al., 2012) may contribute to individuals having difficulties in generalising learning across situations. Exposure in a naturalistic setting can be logistically difficult, expensive and time consuming (Bulik et al., 1998b) and thus, protocols may be insufficiently efficacious to inhibit the original behaviours. Therefore, what is ‘learned’ in treatment settings may not generalise to a home environment and individuals may remain vulnerable to relapse when faced with fearful or appetitive stimuli or stressors. Incorporating retrieval cues into self-guided exposure may reduce the probability of context renewal and spontaneous recovery effects (Brooks, 2000; Brooks and Bouton, 1993; Craske et al., 2008; Havermans and Jansen, 2003): retrieval cues are salient features of the extinction environment that facilitate retrieval of the extinction learning when presented outside of the original context. In terms of exposure cues in ED, (certainly in relation to food cues), patients often experience complex mixed emotions including both dread and desire, the nature of which often changes rapidly. Furthermore, certain cues may only be relevant in certain contexts e.g. binge associated food cues may not always induce the urge to binge in an individual with BN. Rather, it may be the presence of food in a combination of circumstances (e.g. low mood, being alone, time of day, following several days of restriction, etc.). Thus, it is difficult to construct a universally applicable exposure protocol, based on a clear hierarchy. In people with AN,

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food restriction, an emaciated body image and increased physical activity become highly rewarding (Keating, 2010): therefore, in the future, variations of exposure paradigms are likely to be developed that couple the conditioned reward response to more salutary stimuli (Zink and Weinberger, 2010). 3.3. Use of a fear extinction model: neural correlates, clinical applications and limitations There is evidence that neural circuits involving the amygdala, the ventromedial prefrontal cortex and hippocampus underlie the ability to extinguish fear and that clinical anxiety is associated with changes in this circuitry. Evidence also suggests that a fear extinction model is useful in predicting vulnerability to anxiety disorders and treatment response although important caveats have been noted in relation to its use as an explanatory model (Graham and Milad, 2011). A fear extinction model does not capture all aspects of clinical anxiety, in particular cognitive components such as anticipatory anxiety and avoidance (Shin and Liberzon, 2010) and it does not capture all aspects of any given anxiety disorder. For example, the pathogenesis of obsessive compulsive disorder (OCD) is not well modelled by extinction and may be associated with different neural circuits (Shin and Liberzon, 2010). Lastly, whilst extinction is a key component of CBT for anxiety disorders, it is not the only mechanism of therapeutic change. CBT also involves exposure to the feared outcome itself, an aspect that may be better modelled by habituation paradigms (Storsve et al., 2010, 2012). Whilst the caveats associated with using a fear extinction model are noted, it is also noted that in ED (which has a higher incidence in females), there are studies showing that oestradiol modulates prefrontal cortex and amygdala activity during fear extinction in women and female rats (Zeidan et al., 2011). Moreover, a study assessing the involvement of oestradiol in fear extinction in a clinically anxious group, found that in women with PTSD, low oestrogen levels were associated with impaired extinction learning and greater symptom severity (Glover et al., 2012): if this is applicable to AN, it may mean, for example that when ill and have low circulating oestrogen levels, patients might be more resistant to fear extinction. 3.4. Integration of animal and clinical findings In anxiety disorders, integration of animal and human research has increased understanding of behavioural aspects of extinction, the associated neural circuitry of fear acquisition and extinction, and the clinical applications/limitations of the extinction model across different anxiety disorders (Graham and Milad, 2011; Milad and Quirk, 2012). Animal models of ED exist. For example, the activity-based anorexia (ABA) model has been extensively used genetic studies related to responsivity to dietary restraint (Kas et al., 2009; Gelegen et al., 2006, 2007, 2008): although anxiety is a component of ABA, it has not been extensively studied. Models of binge eating have focused on behavioural and neurochemical signs of addiction and hence are applicable to issues of learning reward and stress responsivity (Corwin et al., 2011; Oswald et al., 2011). It can be argued that exposure techniques in ED will be improved if more integration can be achieved, between animal and clinical studies, but as yet, this has not occurred to a substantial extent. 3.5. Integration of findings from basic and clinical neuroscience Recent years have seen a burgeoning of neuroscience data related to ED (Frank and Kaye, 2012; Kidd and Steinglass, 2012) and the emergence of neurobiological models, in particular of AN (e.g. Strober, 2004; Steinglass and Walsh, 2006; Kaye et al., 2009). These models may seek to explain the core deficits in ED and the

strength of disorder-specific conditioned responses: in turn this may impact on the efficacy of exposure interventions. For example, neuroimaging (fMRI; PET) studies suggest people with ED show fear-related brain responses to food and body cues, and altered reward processing (Brooks et al., 2011). Alterations in some neural circuits are reported to be present in the ill state and to persist after recovery (Frank and Kaye, 2012): this is in accord with the idea that altered systems confer vulnerability to illness and are not causal and may have implications for the duration of treatment and for its transferability to different contexts. As an example, people at risk of developing AN are proposed to have a trait alteration that increases activity in central serotonergic (5HT) systems and that this is exacerbated by puberty-related hormonal changes (Kaye, 2008; Kaye et al., 2009). Increased synaptic 5-HT is hypothesised to be associated with anxiety and stress sensitivity and to lead to hyper-responsiveness in the amygdala to relevant environmental stimuli, whether these are positive or threatening (Hariri et al., 2002). As synaptic 5-HT is proposed to be reduced by food restriction (which lowers dietary tryptophan, the 5-HT precursor) (Frank and Kaye, 2012), this provides a biological basis for the vicious cycle that can arise in AN sufferers where eating exaggerates and food restriction reduces anxious mood, making eating and food exposure treatment highly aversive: this may have dietary implications that should be addressed as part of treatment. Neuropsychological studies in ED indicate that people with AN have poor attention and concentration (Kidd and Steinglass, 2012), and difficulties in set shifting and global processing (Roberts et al., 2007; Lopez et al., 2009).They are also reported to have difficulty learning new behaviours (Steinglass and Walsh, 2006) and in extinguishing old ones (Strober, 2004). A cognitive profile associated with BN is less well established but data suggest individuals have higher levels of impulsivity (Kemps and Wilsdon, 2010), poorer decision making abilities under conditions of risk, increased reward sensitivity and in particular high sensitivity to ED related cues (Van den Eynde et al., 2010, 2011). Cognitive difficulties are most pronounced in in-patients with AN (e.g. Tchanturia and Lock, 2011), i.e. those with the most severe and chronic form of the illness. It is possible that weak central coherence in both AN and BN (Lopez et al., 2009) contributes to body image disturbance, as difficulties with global processing may lead to a tendency to focus on specific disliked body parts when evaluating their shape or weight. This may have some explanatory power for the efficacy of mirror exposure work in modifying distorted body image. Such interventions encourage a more global and comprehensive evaluation of the body, and discourage detail-focused (local) processing of negatively evaluated body parts (Vocks et al., 2007, 2008). 3.6. Use of pharmacological agents as an adjunct to exposure treatment Extensive data indicates that pharmacological treatments improve extinction learning (Bouton et al., 2008; Cukor et al., 2010; Davis et al., 2006; Hofmann, 2007; Kaplan et al., 2011; Marin et al., 2011; Norberg et al., 2008; Ressler et al., 2004; Vervliet, 2007). Preclinical studies report that extinction learning can be blocked by N-methyl-d-aspartate (NMDA) glutamate receptor antagonists, and facilitated with d-cycloserine (DCS), a partial agonist/antagonist at the NMDA receptor (Hofmann et al., 2006a; Norberg et al., 2008). DCS has been investigated as an adjunct to exposure techniques in anxiety disorders and addictions in both animal and human studies. Clinical trials have shown that it enhances fear reduction during exposure therapy in anxiety disorders such as acrophobia (Ressler et al., 2004), social anxiety disorder (Hofmann et al., 2006b), OCD (Kushner et al., 2007) and panic disorder (Otto et al., 2010; Hofmann, 2007) possibly

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by promoting extinction learning to background context which enhances contextual inhibition (Vervliet, 2007). The situation in addictions is less clear with some animal studies finding that DCS facilitates extinction of cocaine-self-administration (Thanos et al., 2011) whilst others suggest that it potentiates reconsolidation of cocaine-associated memories (Lee et al., 2009). In humans, DCS combined with cue exposure therapy is reported to attenuate conditioned reactivity to smoking cues within sessions, but with no clear between session habituation (Santa Ana et al., 2009). In cocaine-dependent individuals, craving to cocaine cues increased after DCS administration (Price et al., 2009) and in a study of heavy non-dependent drinkers, it did not appear to enhance habituation to alcohol cue reactivity (Kamboj et al., 2011). Thus, the utility of DCS as an adjunct to exposure treatment of addictions is uncertain although the data from studies of anxiety are promising. A preliminary placebo-controlled RCT has been conducted using DCS as an adjunct to food exposure in patients with AN (Steinglass et al., 2007). Food consumption increased in the participant group but without a significant parallel improvement in pre- and postmeal anxiety, and no benefits resulted from the addition of DCS compared to placebo. The authors suggest that any drug effect may have been obscured by the exposure intervention. The study was limited by its small sample size, baseline differences between the DCS and placebo groups, a highly variable BMI range of patients and a low number of exposure sessions. The latter may be important given that AN is more treatment resistant than height or social phobia (on which the protocol was based). Duration of sessions may also be important, because without prolonged exposure treatment, DCS might enhance the reconsolidation of the fear memory and increase anxiety (Lee et al., 2006; Vervliet, 2007). Lastly, Steinglass et al. (2007) note that their patients used ‘numerous cognitive strategies to avoid anxiety whilst eating’ and without the provision of an extinction memory to inhibit these safety behaviours, this may have further reconsolidated negative beliefs surrounding food. Further studies of DCS as an adjunct to exposure in people with ED are needed to address these issues. Finally, it is possible that other glutamatergic medications may also be beneficial (Olive et al., 2011). Other pharmacological agents of interest include GABA-B (␥amino-butyric acid B) receptor agonists (e.g. baclofen; sodium oxybate), which facilitate extinction learning of conditioned drug reward in animals [e.g. (Heinrichs et al., 2010)] and in animal and clinical trials of substance use, reduce intake, craving and anxiety (for reviews see Broft et al., 2007). In rats, baclofen suppresses binge eating of pure fat, but not sugar-bingeing (Berner et al., 2009). Small open-label studies of baclofen (Broft et al., 2007) and sodium oxybate (McElroy et al., 2011) in patients with BN or BED found that they reduced bingeing and food craving. Another pharmacological approach, which has yet to be examined in ED, is the use of glucocorticoids (corticosterone in animals and cortisol, or its analogues, in humans). Glucocorticoids are proposed to have a dual action in that they may facilitate consolidation of extinction learning during exposure therapy, and impair retrieval of aversive memories (Bentz et al., 2010). Studies involving cortisol treatment in PTSD (Aerni et al., 2004) and phobias (de Quervain et al., 2011; Soravia et al., 2006) have shown promising results and thus cortisol or its analogues may be of value in ED. In the context of stress reduction and glucocorticoid use, it is noted that there have also been studies involving propranolol (a beta adrenergic antagonist) as a compound that may dull the emotional pain associated with the recall of upsetting experiences (Pitman et al., 2002; Vaiva et al., 2003; Kindt et al., 2009). Finally, another avenue for adjunctive pharmacological treatment of extinction learning is via epigenetic regulation of gene expression (Kaplan et al., 2011). Valproic acid (valproate), an anticonvulsant and a mood stabiliser, enhances extinction (but also acquisition and reconsolidation of conditioned fear) possibly via its function as a histone deacetylase

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inhibitor (Bredy and Barad, 2008). To date, only case studies have evaluated valproate in the treatment of bulimic disorders and the results have been mixed (McElroy et al., 2009). However, it provides the possibility of other epigenetic based interventions e.g. the use of S-adenosyl methionine (SAM) as a potential DNA methyl donor and of Vit B12 because of its involvement in SAM synthesis (Duthie et al., 2002; Mariman, 2008; Waterland and Michels, 2007): this is of note as epigenetic changes have been implicated in memory consolidation (Roth and Sweatt, 2009; Campbell et al., 2011, for review) 3.7. Use of neuromodulation as an adjunct to exposure treatment Brain stimulation studies in animals and fMRI studies in humans concur that the infralimbic region, which is a part of the ventromedial prefrontal cortex (vmPFC) is involved in fear extinction (Milad and Quirk, 2012; Phelps et al., 2004; Milad et al., 2007) and it has been proposed that brain stimulation techniques be investigated as a means of facilitating extinction learning and make exposure more tolerable by reducing fear and anxiety (e.g. Rodriguez-Romaguera et al., 2012). Transcranial magnetic stimulation (TMS) is a non-invasive technique that modulates brain activity of a targeted area. In rats, high frequency repetitive (r) TMS paired with exposure to a conditioned stimulus (CS) has been reported to facilitate fear extinction and the effect persisted after 24 h without further stimulation (Baek et al., 2012). This suggests rTMS may augment exposure treatment. In clinical studies, our group has shown in sham-controlled randomised experiments that one-off high frequency i.e. stimulatory, rTMS applied to the left dorsolateral pre-frontal cortex (DLPFC) reduces food craving elicited by cue exposure to highly palatable food stimuli healthy people with high levels of food craving and people with bulimic disorders (Uher et al., 2005; Van den Eynde et al., 2010). In the bulimic patients, binge-eating was reduced over the next 24 h in those who received real rather than sham rTMS. Moreover, in an uncontrolled case series in patients with AN, rTMS (again applied to the left DLPFC) reduced feeling full, feeling fat and feeling anxious, (i.e. core symptoms of AN) following exposure to visual and real food stimuli (Van den Eynde et al., 2011). These findings suggest that rTMS combined with exposure therapy is potentially useful for facilitating extinction memory in the treatment of ED. 4. Recommendations for clinical practice and future research People with AN are highly anxious and avoidant and also are cognitively and behaviourally inflexible and rule bound. Cognitive aspects of anxiety are prominent in ED (Sternheim et al., 2011, 2012), particularly in AN (Startup et al., 2012). Dread of food, eating and weight gain may border on delusional. AN typically is ego-syntonic (Vitousek et al., 1998) with sufferers valuing their emaciated state. These characteristics result in reluctance to change and this makes a purely behavioural intervention, such as exposure treatment challenging—especially, as in food exposure, where the feared outcome (weight gain) is a treatment goal. Exposure interventions in ED must be sufficiently robust to deal with issues arising from the complexities that characterise these disorders. For the majority of patients, especially those with AN, this will mean that exposure interventions should be integrated into a broader treatment programme. As a minimum, it should be established that patients are motivated to comply with exposure treatment. This may involve extensive preparatory work or a ‘pre-exposure intervention’, e.g. use of motivational interviewing or anxiety management techniques (including relaxation

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or cognitive techniques). In addition, prior to exposure treatment, there should be an investigation of idiosyncratic safety behaviours that may prevent new learning. Another, albeit more time intensive and specialised option, may involve the use of cognitive remediation therapy (CRT), which targets the neurocognitive deficits found in ED: this aims to reduce cognitive rigidity and encourage ‘bigger picture’ thinking (Tchanturia et al., 2008). Exposure interventions should be based on a theoretical rationale that incorporates knowledge of learning, extinction and reconsolidation, and which is optimised for neurocognitive endophenotypes found in ED. To tackle cognitive rigidity and difficulty in integrating and generalising new information, exposure should be conducted in vivo where possible (as opposed to imaginal or purely in clinic settings), in situations relevant to the individual. Incorporation of naturalistic exposure is routine in the treatment of anxiety disorders and it is suggested that exposure protocols for EDs should investigate context manipulation, e.g. some sessions towards the end of treatment could be conducted in multiple settings (home, restaurant, supermarket). In the addictions field, personal environments (e.g. a favourite pub) rather than standard environments (any pub) are more powerful in eliciting craving, enhancing stimulus vividness, relevance, positive affect and excitement as well as eliciting greater heart rate changes (Conklin et al., 2010), i.e. personalising exposure makes treatment more effective. Such exposures could be therapist assisted, or self-guided homework exercises in the form of behavioural experiments. During self-guided exposures, stimuli such as specific items of clothing worn during treatment foods eaten, or cue cards with reminders of the exposure setting, may function as appropriate retrieval cues. Several methods have been developed to reduce eating related anxiety during and after food exposure and these may help disrupt reconsolidation of food-related fear memories. For example, in 64 inpatients with AN, progressive muscle relaxation, guided imagery or self-directed relaxation were used to reduce post-meal anxiety (Shapiro et al., 2008), and therapeutic ‘vodcasts’, (i.e. audio and visual presentations, aimed at modifying negative reactions to food), played to the individual during mealtimes have been piloted (Treasure et al., 2010b). By providing competing non-threat memory associations during and after food consumption, these strategies may be useful additions to exposure therapy protocols for AN and BN patients (Treasure et al., 2011). Data from this review also indicate that technologies using virtual environments provide alternative ways of delivering exposure therapy that has promising outcomes. The approach is flexible in that users are able to manipulate a large number of stimuli, and the virtual environment can be structured according to the needs of individual patients, whilst monitoring their responses to the virtual ˜ et al., 2003; Vincelli et al., 2003). Importantly, it scenario (Perpiná has been suggested that as virtual exposure ED patients are exposed to anxiety provoking cues in a ‘safer’ environment, VRET may be ˜ et al., 2003). This approach could also help better tolerated (Perpiná overcome context renewal of fear memories, as exposure occurs in customised situations that enable individuals to better extrapolate learning to their daily lives. Overall, it is possible VRET may be a useful intervention for ED and its implementation is recommended either as a stand alone treatment or as an intermediary step prior to in vivo exposure. Exposure therapy in ED may also be augmented with the use of pharmacological agents and/or the addition of a neuromodulation component such as rTMS. Further research in these areas is recommended. Any future research on exposure treatment of ED needs to include multiple outcomes. Thus, alongside self-report and other explicit methods of outcome assessment (e.g. reduction in subjective fear and anxiety related to food or urges to eat) the success of exposure treatment should be assessed using implicit methods

Box 1 Recommendations for improving the efficacy of exposure therapy in ED 1. Preparatory work

2. Optimised exposure protocols

1. Adjuncts to exposure therapy

• Assessment of safety behaviours and idiosyncratic cognitive strategies

• Naturalistic and personalised exposure settings

• Motivational Interviewing

• Multiple contexts

• Further research investigating D-Cycloserine (DCS), glucocorticoids, GABA-B receptor agonists and valproic acid in ED • Exploration of rTMS as an adjunct to exposure

• Anxiety Management

• Graded exposure: Therapist led → self-guided homeworks • Include retrieval cues and individualised exposure cues • Provide a non-threatening memory to disrupt reconsolidation, e.g. relaxation, vodcasts. • Use of virtual technologies

• Cognitive Remediation Therapy

such as psychophysiology, eye tracking, startle response or fMRI. Further advances are likely to come from use of animal models of ED to explore cue-induced feeding or feeding inhibition and their extinction.

5. Summary and conclusions To our knowledge, this is the first paper in almost two decades to systematically review the literature on the use of exposure techniques in people with an ED. Considering the methodological limitations, and given what is now known about the mechanisms of extinction and reconsolidation, it is not surprising that early studies using exposure techniques (mainly in BN) did not establish if this treatment is a credible alternative to CBT. However, with new knowledge, exposure treatments are beginning to regain popularity and appear to be a promising area of intervention, particularly in relation to AN where advances in treatment are scarce. We have considered developments in contemporary behavioural and neurobiological research into extinction, neuropharmacology, and virtual technologies and in Box 1 propose several ways in which this knowledge might be used to increase the clinical efficacy of exposure techniques in ED. We suggest that patients should be adequately prepared prior to engagement in exposure work, and that protocols should be optimised to incorporate advances in learning theory and the mechanisms of extinction and reconsolidation. Pharmacological agents are a promising avenue of future research, and should be investigated to establish whether they enhance extinction learning in people with ED. In addition, neuromodulation may be a useful adjunct to exposure treatment. Finally, any future research trials of exposure therapy for ED should aim for a robust sample size, maximised homogeneity of participants in terms of BMI and other symptom characteristics, a sufficient duration of exposure, and the provision of salient extinction memories to prevent reconsolidation of negative beliefs and inhibit safety behaviours.

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