Hungry for reward: How can neuroscience inform the development of treatment for Anorexia Nervosa?

Behaviour Research and Therapy xxx (2014) 1e13

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Hungry for reward: How can neuroscience inform the development of treatment for Anorexia Nervosa? Rebecca J. Park*, Lauren R. Godier, Felicity A. Cowdrey Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford, OX3 7JX, United Kingdom

a r t i c l e i n f o

a b s t r a c t

Article history: Received 26 March 2014 Received in revised form 4 July 2014 Accepted 16 July 2014 Available online xxx

Dysfunctional reward from the pursuit of thinness presents a major challenge to recovery from Anorexia Nervosa (AN). We explore the neuroscientific basis of aberrant reward in AN, with the aim of generating novel hypotheses for translational investigation, and elucidate disease mechanisms to inform the development of targeted interventions. Relevant neuroimaging and behavioural studies are reviewed. These suggest that altered eating in AN may be a consequence of aberrant reward processing combined with exaggerated cognitive control. We consider evidence that such aberrant reward processing is reflected in the compulsive behaviours characterising AN, with substantial overlap in the neural circuits implicated in reward processing and compulsivity. Drawing on contemporary neuroscientific theories of substance dependence, processes underpinning the shift from the initially rewarding pursuit of thinness to extreme and compulsive weight control behaviours are discussed. It is suggested that in AN, weight loss behaviour begins as overtly rewarding, goal-directed and positively reinforced, but over time becomes habitual and increasingly negatively reinforced. Excessive habit formation is suggested as one underlying mechanism perpetuating compulsive behaviour. Ongoing research into the behavioural and neural basis of aberrant reward in AN is required to further elucidate mechanisms. We discuss clinical and transdiagnostic implications, and propose that future treatment innovation may benefit from the development of novel interventions targeting aberrant reward processing in AN. © 2014 Elsevier Ltd. All rights reserved.

Keywords: Compulsivity Anorexia Nervosa Neuroimaging Reward Habit Neuromodulation

Anorexia Nervosa (AN) is a severely debilitating psychiatric disorder of unknown aetiology characterised by the relentless and compulsive pursuit of self-starvation, leading to severe emaciation. There is clear evidence of biological influences and significant heritability (Boraska et al., 2014; Bulik et al., 2006), with a stereotypical presentation predominantly in females and a narrow range of onset (American Psychiatric Association, 2013). AN has low rates of full recovery and around 25% of individuals develop a chronic course (Berkman, Lohr, & Bulik, 2007) It ranks among the top 10 debilitating diseases of young women (Mathers, Vos, Stevenson, & Begg, 2000) and has the highest mortality rate of any psychiatric disorder (Arcelus, Mitchell, Wales, & Nielsen, 2011). Sadly AN remains one of the most challenging of psychiatric disorders to treat, particularly in adults (Bulik, 2014). There is a paucity of evidence-based treatments, including no pharmacological treatment of benefit (McKnight & Park, 2010; Watson & Bulik, 2012) and no clearly recommended psychological treatment * Corresponding author. Tel.: þ44 (0)1865 226385. E-mail address: [email protected] (R.J. Park).

(National Institute for Health and Care Excellence, 2004). In the quest to develop novel interventions, there is increasing interest in the neurobiological factors underlying AN (Kaye, Fudge, & Paulus, 2009; Kaye et al., 2013). This paper describes recent research into the neuroscience of reward and compulsivity in AN, in order to generate novel hypotheses for translational investigations to elucidate disease mechanisms and inform the development of targeted interventions.

The problem of aberrant reward in AN Individuals with AN experience perverse reward from the pursuit of thinness, and compulsively engage in extreme dietary restraint, often combined with over exercising. They describe selfstarvation as providing a sense of power and achievement, and are perpetually preoccupied with control of eating, weight and shape (Cowdrey & Park, 2012; Cowdrey, Stewart, Roberts, & Park, 2013; Park, Dunn, & Barnard, 2011, 2012; Rawal, Park, & Williams, 2010; Rawal, Williams, & Park, 2011). This perversion of reward

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Please cite this article in press as: Park, R. J., et al., Hungry for reward: How can neuroscience inform the development of treatment for Anorexia Nervosa?, Behaviour Research and Therapy (2014), http://dx.doi.org/10.1016/j.brat.2014.07.007

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Fig. 1. Neural Response to sight and taste of rewarding and aversive food stimuli: Taste of chocolate: A) Shows significantly increased activation in the ventral striatum in women recovered from AN compared to controls. B) Shows the larger effect size of the increased activation in women recovered from AN compared to controls for the chocolate taste and tasteless control condition. Sight and taste of mouldy strawberries: A) Shows significantly increased activation in the caudate and anterior cingulate in recovered AN compared to controls. B) effect size of the increased activation in recovered AN compared to controls for the mouldy strawberry taste and picture, and the tasteless and grey picture control condition. Reproduced with permissions and adapted from : F.A. Cowdrey, R.J. Park, C.J. Harmer & C. McCabe, 2011, Biological Psychiatry, 70(8), pp.736e743.

becomes accentuated in line with starvation (Keys, Brozek, Henschel, Mickelsen, & Taylor, 1950; Park et al., 2011). Qualitative reports from patients confirm that AN behaviour is associated with a rewarding sense of personal meaning: “My anorexia makes me feel special, different and safe: nothing else in my life gives me this sense” (Park et al., 2011, p. 423), but takes on a compulsive quality which is experienced as central to the illness and a major barrier to recovery: “The compulsive nature of behaviour in eating disorders is what characterises them … if restriction/exercise weren't compulsive, anorexia would be easy to overcome because it would be a conscious choice to ‘switch off’ the thoughts and stop the behaviours. The problem is that behaviours become compulsive and so it becomes more difficult to not engage in them” e Participant aged 21, 2 year history of restrictive AN (Godier & Park, unpublished data). The perversely rewarding nature of AN not only presents a major barrier to engaging patients in treatments which are experienced as highly aversive (Park et al., 2012) but also contributes to high treatment drop-out and relapse rates (Watson & Bulik, 2012).

reward and also it's motivational salience-defined as the process through which a stimulus is converted from a neutral representation into an attractive and wanted incentive that a person will work to acquire (Berridge & Robinson, 1998). Neural circuits subserving these regions are also strongly implicated in compulsivity (Everitt & Robbins, 2005) and, as will be discussed below, are therefore potentially of transdiagnostic significance (Robbins, Gillan, Smith, de Wit, & Ersche, 2012). The majority of neuroimaging studies in AN have investigated recovered subjects to avoid the confounds of starvation, but findings in recovered and ill subjects have been surprisingly similar (Frank et al., 2012; Kaye et al., 2013). It remains unclear whether parallels identified in reward circuitry are due to a scarring effect of starvation, or represent an underlying vulnerability (Cowdrey, Park, Harmer, & McCabe, 2011). Prospective longitudinal studies of individuals prior to illness onset are needed to clarify this issue. To illustrate exactly how regions of the brain involved in reward processing are different in those with a history of AN, the next section will briefly consider recent neuroimaging studies using symptom-provoking paradigms.

What is known about the neural basis of aberrant reward in AN? Neuroimaging studies in AN have demonstrated functional and structural abnormalities in areas of the brain known to be involved in reward processing (Kaye et al., 2009; Kaye et al., 2013). In particular, abnormalities have been found in the anterior cingulate (AC), involved in emotional evaluation and response selection, the orbitofrontal cortex (OFC), a key area linking food and other types of reward to hedonic experience (Berridge & Kringelbach, 2008) and the ventral striatum (VS), incorporating the nucleus accumbens (NAc). The VS is an area integral for coding the pleasure of a

Aberrant food reward in AN: increased neural responsivity to rewarding and aversive stimuli Our research in individuals recovered from AN was the first functional magnetic resonance imaging (fMRI) study to include the sight and taste of both rewarding and aversive food stimuli (Cowdrey et al., 2011) (See Fig. 1). Despite no self-reported differences, we found that compared to controls, individuals recovered from AN demonstrated heightened neural activation to both pleasurable food reward stimuli (liquid chocolate) in the putamen, an

Please cite this article in press as: Park, R. J., et al., Hungry for reward: How can neuroscience inform the development of treatment for Anorexia Nervosa?, Behaviour Research and Therapy (2014), http://dx.doi.org/10.1016/j.brat.2014.07.007

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area linked to habit learning (Tricomi, Balleine, & O'Doherty, 2009), and in the VS, indexing motivational salience. (See Fig. 1) (Berridge, Ho, Richard, & DiFeliceantonio, 2010). In addition to increased VS response to chocolate, we also found increased activation in the medial prefrontal cortex (MPC) to the sight of chocolate in recovered AN. The MPC subserves various behaviours guided by emotional and motivational factors including feeding, so this increased activation may represent an increased attempt to regulate the response to appetitive food cues in AN which may otherwise be experienced as threatening. Individuals recovered from AN, compared to control women, also demonstrated heighted neural activity to aversive food stimuli in the caudate, putamen, and insula, areas implicated in disgust processing, compulsivity, habit learning and interoception (Cowdrey et al., 2011; Everitt & Robbins, 2005; Kaye et al., 2009) (See Fig. 1). Exaggerated activity in the dorsolateral prefrontal cortex (DLPFC) to aversive food taste and pictures was also shown in recovered AN. The DLPFC plays a crucial role in working memory, planning, and sequencing, and is also extensively connected to a variety of brain areas including the striatum, which incorporates the VS and dorsal striatum (DS) (also referred to as the caudate and putamen). It has been suggested that the DLPFC may modulate striatal activity that underlies the approach or avoidance of food (Kaye et al., 2009). Increased activation in this area to the aversive stimuli in recovered AN may therefore represent an enhanced attempt to minimize exposure to the food stimuli. This would be in line with the proposal that even after recovery, individuals with AN have higher levels of harm avoidance and respond to such stimuli in a strategic way, opposed to relying on hedonic properties (Davis, Patte, Curtis, & Reid, 2010; Kaye et al., 2009). Interestingly, an increased VS response to chocolate was also found using the same fMRI paradigm in chocolate cravers with no history of eating disorders (Rolls & McCabe, 2007). Furthermore, a similar pattern of increased VS response to food reward has subsequently been demonstrated in those currently ill with AN, the opposite of that found in individuals with obesity (Frank et al., 2012). As food deprivation amplifies reward processes (Cameron, Goldfield, Finlayson, Blundell, & Doucet, 2014), it is possible that self-enforced abstinence in AN serves a purpose; when starving, food becomes more rewarding. This hypothesis would in part explain some typical behaviours seen in AN, in common with observational studies of starvation (Keys et al., 1950), such as saving one's food allowance to the end of the day. Subsequent studies have confirmed aberrancies in taste circuits (Frank et al., 2012; Oberndorfer, Frank, et al., 2013), which are intimately involved in both reward and interoceptive processing (Kaye et al., 2013). For example, Oberndorfer and colleagues found that compared to healthy controls, individuals recovered from AN showed increased activation of the anterior insula, an area of the brain involved in appetite and interoceptive regulation, during anticipation of food versus non-food stimuli (Oberndorfer, Simmons, et al., 2013). In line with our findings as well as studies from other groups (Wagner et al., 2008) subjective ratings of the food cues were not significantly correlated with activity in the insula in the recovered AN group, unlike in healthy controls, which suggests that in AN there may be a disconnect between subjective and objective interoceptive states which is exacerbated by food probes even after recovery from AN. Top-down control over reward processes In contrast to the task based neuroimaging paradigms described above, resting state functional connectivity is a neuroimaging approach that uses spontaneous fluctuations in the resting brain, enabling temporal correlations between brain areas to be mapped

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(Biswal et al., 2010; Greicius, Supekar, Menon, & Dougherty, 2009). Regions showing a strong temporal coherence are termed “resting state networks” and are thought to reflect intrinsic properties of functional brain organization. The default mode network (DMN) encompasses brain regions including the posterior cingulate, the precuneus and parts of the prefrontal cortex. This network is more active at rest than during attention-demanding tasks and is therefore thought to be associated with stimulus-independent thought and self-reflection (Raichle et al., 2001). In the first resting state study in recovered AN, we found increased functional connectivity between the DMN and both the precuneus and the DLPFC (Cowdrey, Filippini, Park, Smith, & McCabe, 2012), supporting the hypothesis that resting state networks involving self-referential processing and cognitive control may be dysfunctional in AN. This finding has recently been replicated in those with current AN (Lee et al., 2014; McFadden, Tregellas, Shott, & Frank, 2014). Evidence from resting state studies in those ill and recovered from AN is consistent with the hypothesis that increased control over reward processes, mediated by ‘top-down’ modulatory neurocircuits such as DLPFC (Kaye et al., 2009), may be a key factor in the maintenance of AN (Cowdrey et al., 2012). While casual relationships have not yet been established, the increased activity in regions involved in self-referential processing identified in the resting state studies, is consistent with rumination on control of eating, weight and shape, which has been discussed as a cognitiveemotional maintaining factor in AN (Kaye et al., 2009; Park et al., 2011, 2012) with some supporting evidence (Cowdrey et al., 2011; Cowdrey et al., 2012; Cowdrey, Stewart, et al., 2013; Rawal et al., 2011; Wildes, Ringham, & Marcus, 2010). In summary, neuroimaging studies suggest that altered eating may be a consequence of aberrant reward processing (Cowdrey et al., 2011; Frank et al., 2012; Frank, Shott, Hagman, & Mittal, 2013) in the context of heightened cognitive control processes (Cowdrey et al., 2012; Kaye et al., 2009; Park et al., 2011) and interoceptive deficits, leading to poor awareness of homeostatic needs (Kaye et al., 2013). Taken together these studies suggest that an imbalance between ‘bottom-up’ ventral neurocircuits subserving, reward, emotion and interoception, and ‘top-down’ dorsal neurocircuits subserving planning and behavioural consequences, may underpin the stubborn persistence of AN psychopathology (Kaye et al., 2009; Park et al., 2011, 2012). Dissociable elements of food reward The concept of reward is of course not unitary: humans describe, liking, wanting, longing, and craving reward stimuli such as sex, food and drugs. Based on systematic study of the neural substrates of reward in rodents and humans, Berridge and colleagues have argued that reward can be usefully split into the two dissociable components e the motivational salience component, otherwise termed as ‘wanting’, and the hedonic, pleasure component known as ‘liking’, each with distinct neural substrates (Berridge, 2009). Whilst dopaminergic activity in the VS is thought to mediate the motivational ‘wanting’ aspect of food reward, hedonic hotspots in the NAc and the OFC mediate affective ‘liking’ (Berridge, 2009). Further, there is evidence that the motivational, ‘wanting’ and hedonic ‘liking’ aspects of reward have explicit conscious and implicit unconscious components (Berridge & Robinson, 2003). Thus, in relation to food reward, explicit ‘wanting’ refers to the conscious, cognitive desire to consume a food, whilst explicit ‘liking’ refers to the conscious feeling of pleasurable niceness from the ingestion of a specific food. In contrast, the implicit components of reward are unconscious in the sense that they occur at a level that is not accessible to conscious experience (Berridge & Robinson, 2003).

Please cite this article in press as: Park, R. J., et al., Hungry for reward: How can neuroscience inform the development of treatment for Anorexia Nervosa?, Behaviour Research and Therapy (2014), http://dx.doi.org/10.1016/j.brat.2014.07.007

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In health, these dissociable components of reward operate in concert, but pathology may arise when the core processes of liking and wanting cease to operate in tandem (Berridge et al., 2010). For example, disproportionately increased ‘wanting’ compared to ‘liking’, experienced subjectively as a compulsive need (Everitt & Robbins, 2005), may explain drug-seeking behaviours in addictions and the ingestion of high calorie foods in binge-eaters (Berridge, 2009). Implicit ‘wanting’ e as distinct from conscious desires e can therefore occur in the absence of cognitively driven, explicit wanting, or even in conflict to it. This could be the case in AN where there is a cognitive preoccupation with dietary restraint which may be function to counter the implicit processes at work. In this situation, desires can become dreads (Berridge, 2009). ‘Liking’ and ‘Wanting’ components of reward in AN The hypothesis that increased ‘wanting’ may underpin certain behavioural features of AN is supported by evidence from neuroimaging studies. For example, studies have shown that the VS, indexing motivational salience, shows increased activation to images of thin women in those with AN compared to healthy controls (Fladung et al., 2010). Interestingly, this effect is amplified by € ll, Bauer, & Gro €n, 2013). duration of illness (Fladung, Schulze, Scho Other studies have also reported increased activation in VS to other disorder-relevant cues such as a food tastes and images (Cowdrey et al., 2011; Frank et al., 2012). The finding of increased neural activation to food in reward regions of the brain is intriguing as it may be assumed that ‘wanting’ food is theoretically incompatible with the pursuit of thinness which characterises AN. It may therefore be that as self-starvation increases in AN, controlled processing amplifies to keep increased implicit ‘wanting’ of unsafe energy dense foods at bay (Cowdrey et al., 2011) as these threaten the pursuit of thinness which is central to AN. The hypothesis that enhanced ‘wanting’ of food may contribute to AN psychopathology is further supported by behavioural evidence from a study comparing controls with individuals ill, weightrestored and recovered from AN (Cowdrey, Finlayson, & Park, 2013). In this study, a novel paradigm, the Leeds-Oxford Food preference task, was employed to examine separately ‘liking’ and ‘wanting’ for foods of different energy densities, at both an implicit and explicit level. Explicit ‘liking’ and ‘wanting’ responses to high and low calorie foods were derived from analogue ratings, whilst implicit ‘wanting’ was identified using reaction time in a forcedchoice procedure. We found that underweight AN participants explicitly wanted high calorie foods less than weight-restored, recovered or control groups, while both underweight and weightrestored AN groups demonstrated less implicit ‘wanting’ for high calorie food, but more implicit ‘wanting’ for low calorie food, a strikingly inverted pattern to controls (See Fig. 2). Further analysis by AN subtype revealed that those with restrictive AN also showed less explicit and implicit ‘liking’ of high calorie foods. These results are particularly intriguing given that fasting normally increases food reward, but preferentially to high rather than low energy dense foods (Cameron et al., 2014). Whilst these results need to be cross-validated by more direct measures of brain processes, the research provides evidence for the hypothesis that aberrant food reward processing, a perversion of ‘wanting’ vs. ‘liking’, in the presence of excessive higher cognitive controlled processing (Cowdrey et al., 2012), may in part explain the compulsive drive for self-starvation in AN. Summary  Recent studies of AN suggest that altered eating is a consequence of aberrant reward processing (Cowdrey, Finlayson,

Fig. 2. Implicit ‘wanting’ for high and low calorie foods in underweight, weight restored and recovered AN, and healthy controls. As assessed by the Leeds-Oxford Food Preference Task: Underweight and weight restored AN groups have significantly increased implicit ‘wanting’ for low calorie foods and decreased implicit wanting for high calorie foods, an inverted pattern to healthy controls. Reaction times (RTs) to a behavioral forced-choice methodology was used as an indirect index of implicit wanting. Within this paradigm, each of the food stimuli was paired with another from a different food category. Participants were then asked to select the food that they “most want to eat now” using a keyboard response. The speed with which one stimulus is chosen in preference to its alternative provides a quantifiable measure which may relate to the implicit wanting for that food item. RTs were transformed into standardized scores (‘D-RT’) using a validated algorithm. D-RT is calculated as follows: (1) compute overall standard deviation (SD) from pooled response trials; (2) compute average RT for each category; (3) compute average RT for relevant comparison categories; (4) calculate difference between category mean and comparison mean; (5) divide by pooled SD. The lower the D-RT, the greater the implicit wanting for that food category relative to other categories in the task. Final scores were inverted for ease of interpretation; therefore, the higher the D-RT, the greater the implicit wanting for that food category relative to other categories in the task. Hcal ¼ High Calorie Picture Condition; LCal ¼ Low Calories Picture Condition. Reproduced with permission and adapted from “Liking compared to wanting for high- and low-calorie foods in Anorexia Nervosa: aberrant food reward even after weight restoration,” by F.A. Cowdrey, G. Finlayson, & R.J. Park, 2013, American Journal of Clinical Nutrition, 97(3), 463e470.

et al., 2013; Cowdrey et al., 2011; Frank et al., 2012; Frank et al., 2013), in the context of heightened cognitive control processes (Cowdrey et al., 2012; Cowdrey, Stewart, et al., 2013; Kaye et al., 2009; Park et al., 2011).  In particular there is evidence of an imbalance between ‘bottom-up’ ventral-limbic circuits, subserving reward and emotional processes, and ‘top-down’ dorsal-executive circuits subserving planning and consequences (Kaye et al., 2009).  This altered balance between aspects of reward and inhibitory control in part explains the striking ability of those with AN to sustain self-starvation.

When aberrant rewards become compulsive in AN It has been suggested that pathologies of reward emerge when the distinct components, motivational ‘wanting’ and hedonic ‘liking’, become functionally dissociated (Berridge et al., 2010). For example, in substance addiction there is evidence that sensitized ‘wanting’ to reward cues can occur even if liking declines for the same reward. This can lead to the compulsive urge to seek and take drugs, in the absence of any ‘liking’ of the effects of the drugs (Everitt & Robbins, 2005). In AN, a similar dissociation between ‘liking’ and ‘wanting’ for food reward may contribute to the persistence of compulsions to extreme control of eating, weight and/or shape. Such compulsivity may be seen as a clinical manifestation of aberrant reward processing (Robbins et al., 2012), and is a central and challenging feature of AN:

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“Compulsion is like a tidal wave- it has so much force it just knocks you over and it is near impossible to push it out of the way and then it consumes you completely. I get scared by how much it controls me.” Participant aged 22, history of binge/purge AN for 11 years (Godier & Park, unpublished data). Compulsivity has been defined as a trait leading to behaviour that is inappropriate to the situation, which persists despite having no relationship with any overall goal, and results in undesirable consequences (Dalley, Everitt, & Robbins, 2011). Analogous to drug seeking in addiction (Robbins et al., 2012), dietary restriction in AN has a compulsive quality. However, for a substantial proportion of individuals with AN, ‘pure’ restriction cannot be sustained and periods of restriction are punctuated with binge eating and compensatory purging (Fairburn, Cooper, & Shafran, 2003), which also appear to have compulsive quality. Compulsive over-exercise is also a common feature, reported to be more prevalent in restrictive AN (80%), compared to the binge-purging subtype (43%) (Dalle Grave, Calugi, & Marchesini, 2008). The compulsive quality of restriction, binge e purging and over-exercise in AN mean that the behaviour is repeatedly reinforced over time and this in turn contributes to the maintenance of disorder. Parallels between AN and other compulsive disorders Compulsivity manifests with differing foci in others psychiatric disorders, for example, pursuit of thinness in AN, cleanliness or checking in obsessive compulsive disorder (OCD) or drug seeking in addictions. Arguably, it can therefore be conceptualised as a transdiagnostic dimension which may be underpinned by common neural mechanisms (Robbins et al., 2012). Obsessions and compulsions in AN have strong parallels with OCD, but with a psychopathology-specific focus on control of eating, weight and shape. Comorbidity is high between AN and OCD (Halmi et al., 1991), and most prevalent in the restrictive subtype of AN (Fornari et al., 1992; Lilenfeld et al., 1998). The presence of premorbid obsessive compulsive symptoms is a risk factor for developing AN (Anderluh, Tchanturia, Rabe-Hesketh, Collier, & Treasure, 2008), and symptoms remains elevated to some extent even after recovery (Holtkamp, Muller, Heussen, Remschmidt, & Herpertz-Dahlmann, 2005). Familiality is reported, with the first degree relatives of individuals with AN showing an elevated risk for OCD (Bellodi et al., 2001), and candidate gene studies suggest common genetic liability between the two disorders (Mas et al., 2013). Comorbidity with Obsessive-Compulsive Personality Disorder (OCPD) is also high (Lilenfeld, Wonderlich, Riso, Crosby, & Mitchell, 2006), and indeed the excessive self-control (Pinto, Steinglass, Greene, Weber, & Simpson, 2013), perfectionism and rigidity seen in OCPD (Ansell et al., 2010) may parallel AN more closely. As no studies to date have compared neural processes in AN individuals with and without OCD/OCPD, it remains unclear if this pattern of comorbidity is a distinct subtype, or an extreme phenotype of restrictive AN. Aspects of the compulsive behaviours seen in AN have also increasingly been compared to the compulsive drug-seeking behaviour inherent in substance-dependence (BarbarichMarsteller, Foltin, & Walsh, 2011; Scheurink, Boersma, Nergardh, & Sodersten, 2010; Zink & Weinberger, 2010). The developmental period of onset is similar, with an initial phase of reward seeking, in the form of weight loss behaviours which are initially experienced as rewarding and pleasurable (Park et al., 2011, 2012; Scheurink et al., 2010) akin to a drug. This is followed by a narrowing of the behavioural repertoire and the lack of ability to cease behaviours despite their adverse consequences (Kalivas & Volkow, 2005). The compulsive drug seeking behaviour of addicts appears to parallel

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the relentlessness with which individuals with AN pursue weight loss. They also find it increasingly difficult to refrain from weight loss behaviour over time, despite adverse consequences, and even describe symptoms of withdrawal similar to those experienced in drug addiction (Allegre, Souville, Therme, & Griffiths, 2006). Despite these phenotypic similarities there are distinct differences between AN and substance-dependence which makes the notion of ‘addicted to starvation’ over simplistic. In fact in terms of comorbidity, a lower incidence of substance-dependence has been reported in restrictive AN than in other types of eating disorders (Holderness, Brooks-Gunn, & Warren, 1994; Kaye et al., 2013). In contrast, there is a higher incidence of substance dependence over all in those with an eating disorder diagnosis than in the general population (Baker et al., 2013; CASA, 2003). This suggests that there may be a specific relationships between certain eating disorder subtypes, in particular those who engage in binge-purge behaviour which may itself take on an addictive quality, and rates of substance abuse (O'Brien & Vincent, 2003). There are also notable distinctions at a neurobiological level. In particular dopaminergic rewards systems are hyper-responsive in restrictive AN and hypo-responsive in individuals with substanceabuse and binge eating (Kaye et al., 2013). As will be discussed below, this hyper-responsivity may be in part explained by the effects of starvation on reward systems. Behavioural paradigms have also identified notable distinctions in information processing between AN and substance dependence (Kaye et al., 2013), reflected in marked differences in the ability to delay reward in AN as compared to substance dependence. Substance dependent individuals and those with binge eating disorder show a preference for smaller immediate reward (Davis et al., 2010), whereas individuals with AN favour delayed larger rewards (Steinglass et al., 2012). That said, starvation in those vulnerable to AN may produce an immediately rewarding sense of control (Park et al., 2012), acting as a positive reinforcer of behaviour. Equally, avoiding negative consequences such as dysphoric mood during refeeding, which some individuals with AN experience as ‘withdrawal symptoms’ from starvation, may be an important short term goal. Perhaps as a consequence of these immediate reinforcers, the long term goal of weight loss becomes irrationally overvalued (Barbarich-Marsteller et al., 2011). Interestingly, individuals with OCPD are more able to delay reward than those with OCD, and this ability to delay reward is associated with perfectionism and rigidity (Pinto et al., 2013). This supports the suggestion that AN may parallel OPCD more closely than OCD. However, studies looking at decision making processes in AN, OCD and substance dependence suggest in all three disorders a tendency to make disadvantageous decisions when choosing between immediate or long term gains (Lawrence et al., 2006; Tchanturia, Liao, et al., 2007; Verdejo-Garcia et al., 2007). A number of neuropsychological studies in AN have shown that currently ill individuals with AN fail to learn avoidance of ‘risky’ choices in monetary reward paradigms. This finding is suggested to reflect an inability to incorporate reward-based feedback in AN (Abbate-Daga et al., 2011; Brogan, Hevey, & Pignatti, 2010; Cavedini et al., 2004). Whilst individuals with AN may show the ability to delay reward in general, a possible impairment in reward-based decision making may lead them to engage in compulsive weight loss behaviours despite adverse outcomes. The role of impulsivity Compulsivity is sometimes confused with impulsivity e the tendency to perform actions prematurely without foresight (Dalley et al., 2011). In those with EDs, the presence of binge-purge behaviours appears to be associated with higher levels of impulsivity

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Fig. 3. Representation of the cortico-striatal circuitry in the development compulsive and impulsive behaviour. Adapted from Brewer and Potenza (2008); Fineberg et al. (2010); Robbins (2007). In both circuits activity in the striatal component drives behaviour, whilst activity in the prefrontal component inhibits behaviour. Both failures in ‘top down’ control of the prefrontal components, and over activity of ‘bottom up’ striatal activity can result in increases in compulsive or impulsive behaviour. These circuits are suggested to be intercommunicating, with abnormalities in one circuit potentially leading to abnormalities in the other circuit. Models of addiction suggest that what begins as impulsive behaviour may transition with repetition over time to become compulsive, which is reflected in a shift of control from corresponding impulsive to compulsive neural circuitry (Everitt & Robbins, 2005; Robbins, 2012). Abbreviations: OFC ¼ Orbitofrontal Cortex; ACC ¼ Anterior Cingulate Cortex; vmPFC ¼ ventromedial prefrontal cortex; VS ¼ Ventral Striatum; NAc ¼ Nucleus Accumbens.

compared to those with ‘pure’ restricting type AN (Claes, Vandereycken, & Vertommen, 2005; Favaro et al., 2005; Rosval et al., 2006; Waxman, 2009). This may explain higher levels of comorbidity between eating disorders characterised by bingepurge behaviours and addictions (O'Brien & Vincent, 2003). Based on the evidence of dysfunctional reward processes in eating disorders described above, one hypothesis is that individuals higher in impulsivity may be less able to sustain starvation instead acting on the body's demand for food. This contributes to binge-purge behaviours which take on a compulsive quality with repeated engagement. In contrast, pure restriction may be more shaped by compulsivity. The balance between compulsivity and impulsivity may therefore contribute to the specific presentation of eating disorder. In models of addictive behaviour, it is suggested that behaviour that begins as impulsive, and goal directed in the pursuit of reward, transitions to become compulsive with repeated engagement (Everitt & Robbins, 2005; Robbins et al., 2012), with a corresponding shift in control of behaviour in the overlapping and inter-communicating neural circuits involved in impulsiveecompulsive behaviour (See Fig. 3). What is known of the neurocircuitry of compulsivity? There is substantial overlap in the neural circuits implicated in reward processing and compulsivityeimpulsivity. Models of the neurocircuitry involved in compulsive behaviour suggest the involvement of a cortico-striatal thalamic circuit (CSTC), consisting of a striatal (the caudate) and prefrontal (the OFC) component (Brewer & Potenza, 2008; Fineberg et al., 2010; Robbins, 2007). The bottom-up striatal component is responsible for driving compulsive behaviour, and the top-down prefrontal component controls or inhibits this behaviour. Abnormalities in either of these components (hypoactivity/hyperactivity) may result in an increase in compulsive behaviours (Brewer & Potenza, 2008; Fineberg et al., 2010; Robbins, 2007) (See Fig. 3). This framework has some parallels in AN, echoing the existing evidence (Kaye et al., 2009; Kaye et al., 2013) of imbalanced ventral-

limbic and dorsal-executive circuits. As discussed above, several neuroimaging studies using symptom-provoking paradigms have revealed abnormalities in regions within the CSTC circuit in AN (Cowdrey et al., 2011; Frank et al., 2012). Furthermore, AN has been associated with increased caudate function, measured both directly during a monetary reward task (Wagner et al., 2007) and indirectly during exposure to aversive food stimuli (Cowdrey et al., 2011). Reduced activity in the OFC whilst viewing disorder-related stimuli has also been found in AN (Uher et al., 2004), and alterations in OFC volume has been reported (Frank et al., 2013). Abnormalities in the ‘compulsive’ circuit are implied by deficits in neuropsychological tasks thought to tap this construct. Setshifting tasks, in which attention is required to switch between multiple tasks, or elements of a task (Miyake et al., 2000), is thought to measure cognitive inflexibility, a rigid cognitive style suggested to contribute to compulsivity (Fineberg et al., 2010). Individuals with AN are often described as having low cognitive flexibility (Tchanturia et al., 2004), and consistently show poor setshifting abilities (Bühren et al., 2012; Holliday, Tchanturia, Landau, Collier, & Treasure, 2005; Steinglass, Walsh, & Stern, 2006). Impaired behavioural set shifting, which relies on cortical inhibition of striatal processes (Robbins et al., 2012), is associated with hypoactivation in the ventral-striato-thalamic loop and with hyperactivation of frontoparietal networks in those with AN (Zastrow et al., 2009). Poor set-shifting has been suggested as an endophenotype of both AN and BN, and is associated with both longer illness duration and increased disorder-related rituals (Roberts, Tchanturia, & Treasure, 2010). Indirect evidence that CSTC circuits are involved in compulsivity derives from the results of deep brain stimulation (DBS) studies (Oudijn, Storosum, Nelis, & Denys, 2013), and lesions to targets within the CSTC (Figee, Wielaard, Mazaheri, & Denys, 2013). DBS is a reversible, adjustable neurosurgical treatment that involves implanting electrodes that send electrical impulses to chosen locations in the brain (Rauch, 2003). Symptomatic alleviation in treatment resistant OCD and addictions following DBS targeted within the CSTC circuit (Denys et al., 2010; Figee, Luigjes, et al.,

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2013; Kuhn et al., 2007; Liu et al., 2008; Muller et al., 2009) supports the involvement of these circuits in compulsivity. There are preliminary suggestions that this circuit may indicate potential targets for DBS for severe enduring AN (Nestler, 2013): Case reports and series of DBS targeted at the NAc, part of the CSTC, in AN patients have also reported symptom alleviation both in the presence and absence of comorbid OCD (McLaughlin et al., 2013; Wu et al., 2013). Does compulsivity reflect dysregulated habit formation? “It is the way it starts as a need, a compulsion to lose weight or gain control, then the habits you develop to fulfil that become ingrained and the compulsion is no longer owned by you.” Participant aged 22, history of binge/purge AN for 11 years (Godier & Park, unpublished data). As echoed in the above patient experience, compulsivity can also be described as a tendency to carry out repetitive acts in a habitual manner (Fineberg et al., 2010). Habits are described as behaviours that are not innate, are engaged in repeatedly and become fixed, occur without conscious effort and can be elicited by external stimuli (Graybiel, 2008). Two distinct types of learning are involved in the development of behaviour that is not innate or is outside of conscious awareness: action-outcome learning and stimulus-response learning (Robbins et al., 2012). Action-outcome (also referred to as goal-directed learning) occurs when a particular action leads to a rewarding outcome. If at any point the action no longer leads to reward, the frequency of that action will decrease (Balleine & O'Doherty, 2010). However, if these new actions are engaged in repeatedly (over-trained), they may become insensitive to the outcome, and will be repeated even when they do not result in reward (stimulus-response learning) (Graybiel, 2008). Thus, behaviour can become a habitual response to environmental stimuli associated with the rewarding outcome (Steinglass & Walsh, 2006). The development of substance dependence has been described in terms of a transition from initially goal-directed drug taking, driven by the rewarding properties of the drug, to progressively more compulsive drug seeking controlled by the habit system (Everitt & Robbins, 2005), and ultimately driven by environmental stimuli associated with the drug (Belin et al., 2011). Research indicates neural distinctions between goal-directed and habit learning. In humans, the ventromedial PFC has been linked to goal directed learning (Daw, Niv, & Dayan, 2005), while the putamen has been linked to habit learning (Tricomi et al., 2009). Cortico-striatal connectivity-as indexed by Diffusion Tensor Imaging (DTI), which measures the strength of white matter tracts-has been associated with differences in habit and goaldirected control of actions (de Wit et al., 2012). In a behavioural learning task, the tendency to rely on habits was associated with white matter tract strength between both premotor cortex and posterior putamen, and grey matter density in the posterior putamen; while the tendency to use goal directed control was associated with tract strength in the ventromedial PFC from the caudate (de Wit et al., 2012). The cortico-striatal circuitry implicated in habit vs goal directed behavioural control is similar to that suggested in models of the neurocircuitry of compulsivity (see Fig. 3), supporting the suggestion that compulsive behaviour may be underpinned by habitual control of behaviour, as these constructs appear to be indexed by overlapping neurocircuitry. Walsh (Walsh, 2013) elegantly outlines the mechanisms by which aberrant habit formation may contribute to the maintenance of AN. It is suggested that restrictive eating may begin as the result of goaldirected (action outcome) learning, whereby self-starvation behaviour becomes associated with a rewarding outcome (weight loss). If this restrictive eating behaviour is repeated enough it may become

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subject to habit learning, and relatively insensitive to reward (weight loss). In this way, weight loss behaviour becomes highly practiced and over trained, and weight loss as a rewarding outcome may only be intermittently needed, or even no longer necessary for this behaviour to continue. Despite the suggested distinction between goal-directed and habit learning, early description of habits describe them as a form of automatic goal-directed behaviour. Bargh (Bargh, 1989) suggests that habits form as the instrumental link between goals and actions, and are automatically activated when a relevant goal is present. This may be particularly relevant for disorders such as AN, in which automatic habits, which take the form of compulsive weight loss behaviours, may occur unconsciously in the persistent presence of long term weight loss goals. The fact that habitual behaviour is outcome independent makes it highly resistant to change, reflecting the treatment resistance often seen in individuals with AN (Walsh, 2013). It is further suggested that during the process of habit formation in AN, restrictive behaviour itself becomes rewarding through conditioned reinforcement; a set of cues begin to develop which take on rewarding properties themselves (Everitt & Robbins, 2005). This process is also seen in substance-dependence, in which cues associated with drug taking become associated with craving for drugs and drug taking (Wikler, 1973). Individuals with AN may thus start to find that the reward of weight loss is no longer required as the now habitual weight loss behaviours themselves and associated cues have become rewarding or reinforcing. This may help explain increased activation in the VS, suggested to reflect the attribution of motivational salience, in response to disorder related cues in AN (Cowdrey et al., 2011; Fladung et al., 2010; Fladung et al., 2013). There is initial supporting evidence that areas associated with habit learning and goal-directed behaviour are dysfunctional during symptom-provocation in AN (Rothemund et al., 2011). However, further studies are needed to investigate the hypothesis of an overreliance on habit formation at the expense of goal directed actions and neural circuits involved. The role of starvation in aberrant reward and compulsive behaviour The evidence reviewed so far suggests that extreme weight loss behaviours seen in AN are associated with aberrant neurocircuitry and dysfunctional mechanisms of reward that promote compulsive behaviour. Importantly, there is evidence to suggest that the physiological consequences of starvation promote reward, compulsivity and habit learning, and thus starvation may be intrinsically linked to the development of compulsive weight loss behaviours in AN. Behavioural evidence in humans suggesting that starvation is associated with the development of compulsive behaviours derives from the Minnesota Experiment (Keys et al., 1950), in which previously healthy males were restricted to half their average food intake for six months. These individuals developed food rituals and obsessions, some of which persisted after food restriction ceased, and some engaged in binge eating or excessive exercise. They also experienced cognitive impairment and periods of low mood during the study. These individuals were psychologically and physically healthy prior to the experiment, suggesting that these symptoms were due to the food restriction imposed during the experiment. It is thus possible that starvation effects impact on aberrant neurocircuitry, and dysfunctional mechanisms of learning and reward, to promote compulsive behaviour in a vicious circle. Evidence of increased reward during periods of starvation comes largely from animal studies. Chronic food restriction is shown to increase reward effectiveness when electrically stimulating brain reward circuitry in rats (Fulton, Richard, Woodside, & Shizgal, 2004). Moreover, a lower body weight leads to a weaker

Please cite this article in press as: Park, R. J., et al., Hungry for reward: How can neuroscience inform the development of treatment for Anorexia Nervosa?, Behaviour Research and Therapy (2014), http://dx.doi.org/10.1016/j.brat.2014.07.007

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stimulation threshold for reward (Abrahamsen, Berman, & Carr, 1995). This effect can also be seen in relation to drug reward, as chronic food restriction in rats has been found to enhance the rewarding properties of drugs by up-regulating synaptic plasticity in the NAc (Carr, 2007). This increased sensitivity to reward during food restriction may further help to explain reports of increased salience and attention for disorder-related cues in AN (Fladung et al., 2010; Fladung et al., 2013; Giel et al., 2013). Chronic food restriction may enhance the experience of reward in AN, and positively reinforce disorder-related compulsions. Animal studies have also provided evidence of the link between food restriction and over-exercise. In the animal model of AN, Activity Based Anorexia (ABA), compulsive hyperactivity becomes intrinsically linked to food restriction. Rats on a restricted diet given free access to a running wheel will increase activity to the point of death (Adan et al., 2011; Routtenberg & Kuznesof, 1967). Interestingly, young female rats, which parallels more closely human AN, show particular susceptibility to this effect (Hancock & Grant, 2009). These rats also show Food Anticipation Activity (FAA), in which an increase in physical activity precedes a meal (Mistlberger, 1994). This increase in activity preceding a meal has also been documented in AN patients (Scheurink et al., 2010). These phenomena have been suggested to reflect an evolutionary advantage of increased activity (foraging) during times of famine (Illius, Tolkamp, & Yearsley, 2002), and appear to show a link between food restriction and increased physical activity. Evidence from the ABA model also suggests a role for dopamine and serotonin dysfunction in the development of hyperactivity during food restriction (Verhagen, Luijendijk, Hillebrand, & Adan, 2009; Verhagen, Luijendijk, Korte-Bouws, Korte, & Adan, 2009). Antagonism of dopamine receptors is shown to increase food intake and decrease overall physical activity in ABA rats (Verhagen, Luijendijk, Hillebrand, et al., 2009; Verhagen, Luijendijk, Korte-Bouws, et al., 2009). Similarly, dopamine depletion and receptor blockade in the NAc decreases FAA (Barbano & Cador, 2006; McCullough & Salamone, 1992). Serotonin has a suppressive effect on food intake (Simansky, 1996) and a decrease in food intake is seen in rats treated with serotonergic agonists (Clifton et al., 2000; Lee et al., 2002). Furthermore, a decrease in serotonin release in the NAc is seen in ABA rats (Verhagen, Luijendijk, Korte-Bouws, et al., 2009). Given that AN is associated with altered dopamine and serotonin levels (Kaye et al., 2013), this evidence may suggest that alterations in these neurotransmitters during the chronic food restriction of AN may increase vulnerability to compulsive exercising. The over-reliance on habit learning suggested to lead to compulsive behaviour may also be potentiated in times of stress. Stress is shown to modulate cognitive memory systems in favour of neo-striatum dependent habit systems (Schwabe et al., 2007). Furthermore, participants exposed to an experimental stressor subsequently rely on habits during an instrumental learning task, and show reduced knowledge of the action-outcome associations needed for goal-directed behaviour (Schwabe & Wolf, 2009). Food shortage has also been associated with impairments in memory in animals (Plaçais & Preat, 2013), and even brief food restriction is shown to lead to alterations in gene expression of stress hormones (Guarnieri et al., 2012). Thus in AN, psychological and physical stressors associated with the disorder, as well as chronic food restriction, may promote reliance on habits, and thus promote compulsive behaviour. Summary  Compulsive behaviour in AN may represent underlying disturbances in brain circuits mediating reward processing and compulsivity.

 Whilst there are parallels at the neural and behavioural level to other disorders with compulsive qualities, such as substancedependence and OCD, there are also features which are unique to AN. In particular, starvation and weight loss is associated with physiological changes that promote compulsive behaviour, and food restriction is associated with an increase in reward sensitivity and positive reinforcement.  That said, transdiagnostic processes relevant to other disorders of reward and compulsivity e for example habit learning e may be relevant to treatment development for AN. Further, investigating abnormalities in neural circuitry and related brain areas may aid understanding of mechanisms involved in the development of compulsive behaviour across disorders. Implications for assessment and treatment Many neuroscientific studies to date have served to generate rather than evaluate hypotheses. Such hypotheses can be evaluated for example in experimental designs and with state of the art neuroimaging strategies. However scientific rigour is of paramount importance, as weak designs, and/or naïve interpretation of findings e for example failing to take into account general effects of psychiatric comorbidity or chronicity on social, emotional and neural function e can result in erroneous hypotheses, due to confusion between epiphenomena and specific processes underpinning core pathology. There is now an urgent need to evaluate specific hypotheses derived from neuroscientific findings, and translate these into an applied understanding of mechanisms to inform the development of targeted interventions. The pathogenesis of AN is multifactorial but underlying mechanisms remain poorly understood, despite clear evidence of biological influences and significant heritability (Bulik et al., 2006). Neuroscientific understanding has the potential to augment current knowledge and guide treatment development for AN (Park et al., 2011, 2012). We suggest that dysregulated reward processing and compulsivity are central to the maintenance of AN and may serve as potential targets for novel strategies to augment existing treatments. Ongoing research investigating the neural and behavioural correlates of reward and compulsivity in AN, alongside other compulsive disorders, is needed to fully validate this suggestion. If validated, treatments which target key mechanisms and neural circuits underpinning aberrant reward processing may have efficacy in AN. While these hypotheses await further investigation; a number of clinical implications are suggested. Implications for assessment “Compulsions should be caught early before they solidify into ‘behaviours’. Need to be challenged in order to recover/manage” Participant aged 21, history of restrictive AN for 7.5 years (Godier & Park, unpublished data). Given the escalation of aberrant reward and habits over time (Fladung et al., 2013), early intervention should be a priority. This is particularly relevant for individuals who develop AN in adolescence (Chui et al., 2008); brain maturation in adolescence is characterized by the emergence of executive function (for example, goal planning and inhibition of impulsive behaviour) mediated by the prefrontal cortex. However, it is predicted that once starvation is severe and/or longstanding, neural changes impacting on reward processing will be more pronounced (Fladung et al., 2013) and the degree of compulsivity will be resistant to change. Here, approaches directly targeting reward processes and compulsivity may be needed for full recovery. Novel transdiagnostic tools need to be developed for systematic measurement and evaluation of compulsivity and habitual

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behaviour. These will require cross validation against existing gold standard measures of AN psychopathology, such as the Eating Disorder Examination (Cooper & Fairburn, 1987) and the YaleBrown Eating Disorder Scale (Mazure, Halmi, Sunday, Romano, & Einhorn, 1994). Not only will systematic measurement validate the importance of these concepts in AN, but will facilitate the evaluation of novel interventions designed to target them. Assessment of AN would also benefit from incorporating measures of impulsivity versus compulsivity and habitual behaviours, together with a thorough evaluation of binge-purge and substanceabuse symptoms. These factors may guide different treatment approaches which in turn may impact on treatment response. Implications for cognitive and behavioural strategies The importance of re-patterning habitual cognitive and behavioural patterns, alongside reversing starvation, has been emphasised in the treatment of AN (Park et al., 2011, 2012), and some strategies previously aimed at behavioural change and habit breaking in other disorders have been translated for use in AN, although with limited evidence of efficacy to date. Given the effects of starvation on neurobiological maintaining mechanisms reviewed above, it is likely to be of crucial importance to reverse starvation effects in tandem. Mindfulness can be seen as a means of curbing habitual thinking and may have some application to AN, with provisos (Rodríguez, Cowdrey, & Park, 2013). Mindfulness Based Cognitive Therapy (MBCT) requires effortful processing which may be a problem in established AN, or in starvation (Park et al., 2012; Rodríguez et al., 2013). Nonetheless, in motivated patients and those with a short history, in whom neural changes are like to be less marked (Fladung et al., 2013), ruminative preoccupation with control of eating weight and shape may be targeted using mindfulness strategies to address these habitual patterns of ruminative thinking (Cowdrey, Stewart, et al., 2013; Park et al., 2012). Neuroimaging studies demonstrate that MBCT training develops interoceptive awareness. Such training reduces controlled processing during interoceptive attention, altering functional connectivity between dorsomedial PFC and the insula, an area key to interoceptive awareness (Farb, Segal, & Anderson, 2013). MBCT thus may be a helpful strategy to improve interoceptive deficits, and ameliorate the tendency for ruminative preoccupation and excessive controlled processing in those with AN. As mindful attention is difficult to achieve during starvation (Cowdrey, Stewart, et al., 2013; Park et al., 2012), MBCT is predicted to be best employed as potential relapse prevention strategy . Cognitive Remediation Therapy (CRT) and Exposure Response Therapy (ERT) also aim to target habitual behaviour although their strategies differ. CRT was originally developed for use in the treatment of psychosis, and has also been adapted for use in eating disorders to improve cognitive flexibility and break cognitive habits. Preliminary research into CRT has found improvements in self-reported cognitive flexibility in individuals with AN (Tchanturia, Davies, & Campbell, 2007) but appears to have limited impact on weight. ERT, which aims to work by extinguishing a previously conditioned response, has been used successfully in the treatment of OCD (Foa et al., 2005) and addictions (Kaplan, Heinrichs, & Carey, 2011). In AN, there is some evidence that graded exposure to food cues may reduce meal-related anxiety post-treatment (Steinglass et al., 2012) with a recent report that this exposure therapy may be more effective than CRT following weight restoration (Steinglass et al., 2014). However, evidence of long term efficacy for any of these strategies, especially for adults with longstanding AN, is lacking.

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Whilst there is preliminary support for the use of strategies such as mindfulness and exposure-based strategies, given the degree of entrenched overlearning underpinning aberrant reward in severe AN, such strategies alone may be more effective for early intervention and/or relapse prevention than in chronic illness (Rodríguez et al., 2013). Additional treatment modalities, specifically addressing aberrant reward processing and compulsivity, may be needed for those with longstanding enduring AN. For example, neuromodulatory strategies may enhance the efficacy of psychological approaches. There is preliminary evidence that this may be the case in individuals with treatment resistant OCD; one study showed that previously treatment resistant patients were able to benefit from CBT to combat compulsions only after they had received DBS to the NAc (Denys et al., 2010).

Neuromodulation as a future treatment for AN Neuromodulatory techniques such as transcranial magnetic stimulation (TMS) and DBS applied to targets in reward and compulsivity circuits, have potential as tools for treatment development in longstanding AN (for recent review see McClelland, Bozhilova, Campbell, & Schmidt, 2013). Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method used successfully to treat psychiatric disorders, such as depression. A key mechanism of action of rTMS is thought to be in increasing neuroplasticity, so it is thought to be of value in chronic or treatment-resistant mental disorders. In rTMS a stimulating coil is held close to the head and this generates strong magnetic fields which excites neurons in a localized area. Preliminary studies suggest that rTMS to the DLPFC has some efficacy across compulsive disorders, such as OCD and substancedependence (Barr et al., 2011; Blom, Figee, Vulink, & Denys, 2011). In AN, there is some evidence that rTMS reduces anxiety and potentially the urge to exercise (Van den Eynde, Guillaume, Broadbent, Campbell, & Schmidt, 2013). Further research into the neural circuitry involved in AN will aid the empirical development of targeted TMS loci (McClelland et al., 2013). As discussed previously, DBS to CSTC targets such as the NAc, has shown promise in terms of alleviating symptoms and improving quality of life in treatment resistant depression, addictions and OCD (Kringelbach, Jenkinson, Owen, & Aziz, 2007; Sankar, Tierney, & Hamani, 2012). However in AN, despite an emerging scientific rationale for use of DBS (Nestler, 2013; Oudijn et al., 2013), there are only a few published case reports and case series (Lipsman, Woodside, Giacobbe, Hamani, et al., 2013; Wu et al., 2013) detailing such intervention, and these have used different neural targets. For example, in a small group of treatment-refractory AN patients, Lipsman and colleagues demonstrated DBS to the subcallosal cingulate, a target used for DBS in depression, to be reasonably safe in AN (ref). DBS to this area in AN was associated with improvements in co-morbid mood and anxiety symptoms, which was maintained at 6 months follow-up, and translated into increases in BMI overtime (Lipsman, Woodside, Giacobbe, Hamani, et al., 2013; Lipsman, Woodside, Giacobbe, & Lozano, 2013). Although ED preoccupations and rituals decreased, the authors speculate that the primary effect of DBS was improved utilization of conventional AN treatment as a result of improved mood and affective regulation. Case reports in AN of DBS to the NAc, part of the VS directly implicated in reward processing, suggest positive outcomes in terms of weight recovery and resolution of both AN and comorbid pathology (McLaughlin et al., 2013; Wu et al., 2013). However, existing studies have not to date reported on underlying neural processes or the complex ethical issues involved in using this type of intervention with AN patients.

Please cite this article in press as: Park, R. J., et al., Hungry for reward: How can neuroscience inform the development of treatment for Anorexia Nervosa?, Behaviour Research and Therapy (2014), http://dx.doi.org/10.1016/j.brat.2014.07.007

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Of relevance to the neural basis of aberrant reward in AN, it has been suggested that DBS works by rebalancing resting-state networks (Kringelbach et al., 2007), which we and others have found aberrant in AN (Cowdrey et al., 2012; Lee et al., 2014; McFadden et al., 2014). In those with OCD, DBS targeted at the NAc normalises excessive connectivity between the NAc and prefrontal cortex (Figee, Luigjes, et al., 2013), and in line with symptomatic improvement in compulsivity, induces dopamine release in the VS (Figee et al., 2014). This area is key to motivational salience ‘wanting’, found to be so aberrant in AN (Cowdrey, Finlayson, et al., 2013; Fladung et al., 2010; Fladung et al., 2013). Future studies which combine DBS with multimodal imaging strategies such as fMRI which indexes blood flow, DTI which indexes integrity of neural tracts and magnetoencephalography (MEG) which measures neural activity in real time, will offer important new information about the neural dynamics of AN. Investigations of response to experimental interventions such as DBS should optimally include assessment of putative mechanisms underlying AN pathology, in particular compulsivity and food related reward-liking vs wanting (Cowdrey, Finlayson, et al., 2013). Using such methodologies DBS can be seen as a translational strategy, not only for alleviating suffering, but also for gaining new insights into the neural processes underlying psychopathology. Such research is needed to better elucidate a scientific rationale for optimal DBS targets in AN (Nestler, 2013). Ethical considerations regarding invasive techniques in AN are of paramount importance, and should be incorporated into all DBS research designs. Given the inherent medical risks of DBS, this approach may only really be justified in patients with severe intractable AN who have capacity (Oudijn et al., 2013). At present DBS in AN remains an experimental approach which warrants further investigation in the most severely and enduringly affected patients. Pharmacological strategies Drug studies in AN are made difficult by high rates of attrition, the medical and neurobiological complexities of starvation, and the need for stratification by comorbidity and subtypes. These issues lead to problems in systematic development and hypothesis testing. The striking lack of efficacy of medications on core AN pathology may in part be a function of starvation effects on neurochemistry. Dopaminergic and serotonergic dysfunction seen in AN (Kaye et al., 2009; Kaye et al., 2013) have most recently been potential targets for pharmacological interventions, yet no consistent substantial benefit has been demonstrated (Lebow, Sim, Erwin, & Murad, 2013). Serotinergic medications used in OCD are ineffective in addressing core restrictive AN psychopathology, although they do reduce bingeepurge behaviour. This lack of impact on restrictive symptoms is often attributed to starvation effects on neural systems. Atypical antipsychotics, such as Quetiapine and Olanzepine which target dopaminergic dysfunction, may reduce anxiety and anorexic rumination in low dose, but do not significantly or consistently promote weight gain (Lebow et al., 2013). Moreover, in individuals with binge purge subtypes of ED, such medications can exacerbate bingeing, reduce sense of control and subsequently have a negative overall impact on core ED psychopathology (McKnight & Park, 2010). This has led researchers to explore weight neutral medications, such as Aripiprazole which shows preliminary promise in case series of AN (Trunko, Schwartz, Duvvuri, & Kaye, 2011), reducing distress and anorexic ruminations around food alongside improved mood and anxiety. The analysis presented in this paper leads us to speculate an alternative avenue of enquiry, in the form of novel pharmacological interventions targeting limbic neuromodulators and neurotransmitters such as glutamate e which modulates dopaminergic

reward systems (Everitt & Robbins, 2005). Animal and human evidence suggests that dopmaine modulation of glutaminergic transmission plays a role in reward and reinforcement, (Kenny & Markou, 2004). The use of drugs that target glutamate pathways (Cousins, Roberts, & de Wit, 2002) has shown some benefit in the treatment of substance use disorders (Clarke, Dalley, Crofts, Robbins, & Roberts, 2004; Olive, Cleva, Kalivas, & Malcolm, 2012), behavioural addictions (Olive et al., 2012), binge eating (Guardia, Rolland, Karila, & Cottencin, 2011), and OCD (Pittenger, Bloch, & Williams, 2011). For example there is some evidence that Topirimate and Memantine, both of which act on glutaminergic transmission, reduce binge eating, in addition to reducing alcohol craving (Olive et al., 2012). Moreover, a recent case series suggests Lamotrigine may be helpful for binge purge behaviours in low weight AN (Trunko et al., 2011), although it is unclear if there is any direct effect on the compulsion to dietary restriction in AN. Additionally, there is some evidence that N-acetylcysteine (NAC) which is a derivative of the amino acid cysteine and acts on glutaminergic transmission, may be of benefit in syndromes characterised by compulsive behaviours, including for example, cannabis dependence (Gray et al., 2012) and trichotillomania (Dean, Giorlando, & Berk, 2011). Given its relative safety and tolerability, as a naturally occurring amino acid, NAC may prove acceptable to individuals with AN who would otherwise be averse to taking medication, and future studies into AN may be warranted. Importantly, we suggest that future investigations of drug response should optimally include assessment of putative mechanisms underlying AN as a reward pathology, in particular compulsivity and measures of food related reward e such liking vs wanting. Summary  For individuals with a first-episode of AN or for whom the duration of illness is short, psychological treatments which focus on re-patterning habitual cognitive and behavioural patterns may be sufficient to alter reward contingencies and shift habitual eating disorder thoughts and behaviours.  For those with severe and/or long-standing AN, neuromodulatory techniques and pharmacological treatments may additionally be required to rebalance aberrant neural processes.  More research is needed to clarify specific neural targets and establish ethically sound research protocols. Concluding remarks In this review of the neuroscience underpinning AN, we have considered the neural underpinnings of aberrant reward, compulsivity and habit formation in AN. We have noted parallels between the findings in AN and other psychiatric disorders. Conceptualising compulsivity as a transdiagnostic feature united by common pathological processes may help in the development of novel cognitive, behavioural and neural interventions, which are effective across diagnostic boundaries. These are urgently needed given the poor outcome and limited evidence base for treatment of AN, especially in adulthood. Future research should aim to directly test these concepts, for by examining the behavioural and neural basis of aberrant habit formation in relation to compulsivity in AN, and developing treatments targeting neural circuitry underlying aberrant reward and compulsivity. References Abbate-Daga, G., Buzzichelli, S., Amianto, F., Rocca, G., Marzola, E., McClintock, S. M., et al. (2011). Cognitive flexibility in verbal and nonverbal domains and decision making in anorexia nervosa patients: a pilot study. BMC Psychiatry, 11, 162.

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