Progress in Neuro-Psychopharmacology & Biological Psychiatry 80 (2018) 132–142

Contents lists available at ScienceDirect

Progress in Neuro-Psychopharmacology & Biological

Psychiatry
journal homepage: www.elsevier.com/locate/pnp

Neuroendocrinology and brain imaging of reward in eating disorders: A

possible key to the treatment of anorexia nervosa and bulimia nervosa
Alessio Maria Monteleone a, Giovanni Castellini b, Umberto Volpe a, Valdo Ricca b, Lorenzo Lelli b,
Palmiero Monteleone a,c,⁎, Mario Maj a
a
Department of Psychiatry, University of Naples SUN, Naples, Italy
b
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
c
Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, Section of Neurosciences, University of Salerno, Salerno, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Anorexia nervosa and bulimia nervosa are severe eating disorders whose etiopathogenesis is still unknown. Clin-
Received 30 December 2016 ical features suggest that eating disorders may develop as reward-dependent syndromes, since eating less food is
Accepted 28 February 2017 perceived as rewarding in anorexia nervosa while consumption of large amounts of food during binge episodes in
Available online 1 March 2017
bulimia nervosa aims at reducing the patient's negative emotional states. Therefore, brain reward mechanisms
have been a major focus of research in the attempt to contribute to the comprehension of the pathophysiology
Keywords:
Anorexia nervosa
of these disorders. Structural brain imaging data provided the evidence that brain reward circuits may be altered
Brain imaging in patients with anorexia or bulimia nervosa. Similarly, functional brain imaging studies exploring the activation
Bulimia nervosa of brain reward circuits by food stimuli as well as by stimuli recognized to be potentially rewarding for eating dis-
Eating disorders ordered patients, such as body image cues or stimuli related to food deprivation and physical hyperactivity,
Neuroendocrinology showed several dysfunctions in ED patients. Moreover, very recently, it has been demonstrated that some of
Reward the biochemical homeostatic modulators of eating behavior are also implicated in the regulation of food-related
and non-food-related reward, representing a possible link between the aberrant behaviors of ED subjects and
their hypothesized deranged reward processes. In particular, changes in leptin and ghrelin occur in patients
with anorexia or bulimia nervosa and have been suggested to represent not only homeostatic adaptations to
an altered energy balance but to contribute also to the acquisition and/or maintenance of persistent starvation,
binge eating and physical hyperactivity, which are potentially rewarding for ED patients. On the basis of such
findings new pathogenetic models of EDs have been proposed, and these models may provide new theoretical
basis for the development of innovative treatment strategies, either psychological and pharmacological, with
the aim to improve the outcomes of so severe disabling disorders.
© 2017 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
2. Neuroimaging studies on reward mechanisms in eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
2.1. General considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
2.2. Looking at food. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
2.3. Eating food: the consummatory phase of reward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
2.4. Restrained eating and over-control as sources of reward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
2.5. Body image tasks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
2.6. Hyperactivity and physical exercise. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.7. The classic reward stimuli: monetary tasks in EDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.8. Morphological studies on brain volume . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

Abbreviations: ABA, activation-based anorexia; AN, anorexia nervosa; ANR, anorexia nervosa restrictive subtype; ANB, anorexia nervosa binge-purging subtype; ACC, anterior
cingulated cortex; BN, bulimia nervosa; DLPFC, dorsolateral prefrontal cortex; ED, eating disorder; fMRI, functional magnetic resonance imaging; GM, grey matter; NAc, nucleus
accumbens; OFC, orbitofrontal cortex; PFC, prefrontal cortex; TSST, Trier Social Stress Test; VTA, ventral tegmental area; WM, white matter.
⁎ Corresponding author at: Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Allende, 80049 Baronissi, Salerno, Italy.
E-mail address: monteri@tin.it (P. Monteleone).

http://dx.doi.org/10.1016/j.pnpbp.2017.02.020
0278-5846/© 2017 Elsevier Inc. All rights reserved.
 A.M. Monteleone et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 80 (2018) 132–142 133

3. Neuroendocrine studies on reward mechanisms in eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

3.1. General considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
3.2. Leptin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
3.3. Ghrelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Disclosure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Funding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

1. Introduction
Anorexia nervosa (AN) and bulimia nervosa (BN) are complex psy-
chiatric disorders of great importance for public health policies, since
they are associated with a high burden of morbidity and mortality be-
cause of their severe medical and psychological consequences. They
are characterized by aberrant eating behaviors aiming at maintaining
a low body weight because of the patient's pathological fear of weight
gain, associated with alterations in the perception of his/her own body
shape. In AN, restriction of food intake and physical hyperactivity are
the main aberrant behaviors through which a low body weight is
attained, although in some cases binge eating followed by compensato-
ry purging or non-purging behaviors also occurs. Therefore, two types of
AN are identified: the AN restrictive subtype (ANR) and the AN binge-
purging subtype (ANBP) (American Psyhiatric Association, 2013). BN,
instead, is characterized by binge eating episodes followed by self-in-
duced vomiting or by other behaviors, such as misuse of laxatives, di-
uretics or prolonged starvation, which aim to compensate for the
excess of food ingested in order to prevent weight gain.
Although at present the etiopathogenesis of these eating disorders
(EDs) is still unknown, it is widely acknowledged that biological, socio-
cultural and psychological factors likely influence their development,
progression and outcome. Recently, the hypothesis that alterations in
brain reward mechanisms might be involved in the pathophysiology
of EDs has been put forward. Indeed, AN has long been conceptualized
as a starvation-dependent syndrome developing because eating less
food is perceived as rewarding initially, and is then maintained through
conditioning to the situations providing reward (Bergh and Sodersten,
1996; Støving et al., 2009). Similarly, binge eating patients with BN usu-
ally report strong urges to eat with a sense of loss of control over their
consummatory behavior before bingeing and a transient reduction of
negative emotional states after bingeing. Therefore, it has been sug-
gested that increased food-derived feelings of pleasure, which follow
the consumption of large amounts of food during binge episodes, may
help the patient to reduce his/her negative emotional states. Further-
more, a clinical key symptom of EDs is represented by anhedonia, that
is the reduced patients' ability to experience reward. Therefore, in the
last years, brain reward circuitry and mechanisms have been a major
focus of research in the pathophysiology of EDs.
The main reward circuit in the brain includes the ventral tegmen-
tal area (VTA) whose dopaminergic neurons project to the nucleus
accumbens (NAc), which is part of the ventral striatum (Fig. 1).
Once the VTA is activated by environmental rewarding stimuli, do-
pamine is released in the NAc (Bromberg-Martin et al., 2010) and in-
duces motivational processes, which lead to the consumption of
reward (Volkow et al., 2008). Several other limbic regions receive
projections from VTA, such as hypothalamus, amygdala, hippocam-
pus, and cingulate gyrus (Fock and Khoo, 2013). The phasic release

Fig. 1. Schematic representation of brain reward circuits. ACC anterior cingulated cortex; Amy amygdala; DS dorsal striatum; Hipp hippocampus; IC insular cortex; LH lateral
hypothalamus; mPFC medial prefrontal cortex; NAc nucleus accumbens; OFC orbitofrontal cortex; VTA ventral tegmental area.
134 A.M. Monteleone et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 80 (2018) 132–142
of dopamine from VTA to amygdala and hippocampus reflects sa-
lience attribution and promotes associative learning, which repre-
sents a form of reinforcement activating memory process. The
amygdala and the hippocampus presumably play a key role in asso-
ciating reward-predicting cues with positive emotions elicited by
the actual reward. Indeed, dopaminergic activation seems to en-
hance hippocampus-dependent long-term memory formation so
that reward-related stimuli and contexts are reliably recognized in
future situations (Everitt and Robbins, 2005).
The brain reward system also integrates basic and emotional stimuli,
such as hunger, satiety, desire, pleasure and fear, with higher order cog-
nitive processes aimed at modulating further actions or representation
of the general experience. These high order processes involve anterior
cingulate cortex (ACC), orbitofrontal cortex (OFC) and ventromedial
prefrontal cortex (PFC), which are necessary for identification of re-
warding stimuli, inhibition of emotional responses, and promote behav-
ioral outcomes (Haber and Knutson, 2010; Wittman et al., 2010; Sripada
et al., 2011). Overall, the PFC provides inhibitory influences on motiva-
tion and reward-directed behavior, integrating sensory inputs, memo-
ries, goals, and physiological states with the aim to provide an
adequate performance (Miller and Cohen, 2001). ACC and dorsolateral
prefrontal cortex (DLPFC) may also serve to monitor potential conflict
situations induced by reward stimuli (Walton et al., 2003; Vogt et al.,
2005). Therefore, they have a gating role in action selection following re-
ward cues (Goldstein and Volkow, 2011). Indeed, by a top-down effect,
both OFC and ACC provide a negative feedback to mesolimbic areas reg-
ulating reward-seeking motivation (Goldstein and Volkow, 2011).
Schematically (Fig. 1), the brain reward system includes a ventral
bottom-up circuit and a dorsal top-down circuit. The ventral bottom-
up limbic neural circuit, which includes amygdala, anterior insula, ante-
rior ventral striatum, ventral regions of the ACC, and OFC, is involved in
identifying rewarding and emotionally significant stimuli and generat-
ing affective responses to these stimuli (Phillips et al., 2003). The dorsal
top-down neural circuit, which includes dorsal regions of the caudate,
DLPFC, parietal cortex and other regions, is thought to modulate selec-
tive attention, planning, and effortful regulation of affective states
(Phillips et al., 2003). Both circuits are involved in identifying the re-
warding and affective valence of environmental stimuli, in selecting ad-
equate behavioral responses by assessing the future consequences of
one's own actions (response selection), and in inhibiting inadequate be-
haviors (response inhibition).
Other than dopamine, several biochemical factors have been recog-
nized to act as endogenous modulators of reward mechanisms.
Among these, some of the substances primarily involved in the homeo-
static regulation of eating behavior have been found to modulate also
food-related reward. Indeed, in humans, eating has both a homeostatic
and a hedonic component, since food consumption is driven not only by
conditions of negative energy balance, but also by a purely cognitive/ex-
ecutive decision to consume food just for pleasure even if the subject is
not in a state of energy depletion (hedonic eating). A complex and finely
tuned network of endogenous biochemical modulators of appetite has
been characterized (Rui, 2013), and it is becoming more and more evi-
dent that these regulators act not only on hypothalamic and brainstem
homeostatic centers controlling hunger and satiety but also affect the
non-homeostatic cognitive, emotional and rewarding component of
food intake by modulating the activity of the above described brain re-
ward circuitry (Volkow et al., 2011). Furthermore, it has been clearly
established that some of the endogenous modulators of food-related re-
ward also intervene in the modulation of non-food-related reward, such
as reward generated by drugs of abuse, alcohol or nicotine (Shalev et al.,
2001). Alterations in central and peripheral regulators of energy balance
have been largely reported in AN and BN (see for review: Tortorella et
al., 2014), and although these changes have been interpreted as homeo-
static adaptations to malnutrition, it has been argued that they may con-
tribute also to the appearance and/or persistence of dysregulated
reward mechanisms of EDs.
In this article we provide a summary of the most relevant brain im-
aging studies suggesting the existence of alterations in brain reward cir-
cuitry in patients with AN and BN and report the evidences proposing a
putative involvement of some peptidergic modulators of eating behav-
ior, namely leptin and ghrelin, in the development and/or the mainte-
nance of aberrant rewarding behaviors of EDs patients, such as self-
starvation, binge eating and physical hyperactivity.
2. Neuroimaging studies on reward mechanisms in eating disorders
2.1. General considerations
Brain imaging represents a valid tool to elucidate brain mechanisms
related to EDs psychopathology. In general, neuroimaging studies in EDs
present some methodological issues related to specific features of the
disorders. For example, considering the frequent crossover and diagnos-
tic instability of EDs (Tozzi et al., 2005; Castellini et al., 2011), neurobi-
ological traits cannot be evaluated on the basis of categorical diagnoses.
Moreover, some of the brain volume changes might be related to the
states of dehydration or malnutrition, which are typical of the acute
phases of the EDs, rather than to underlying specific ED pathophysiolog-
ical mechanisms. Furthermore, the interpretation of reward stimuli by
ED patients cannot be as simple as in other psychiatric conditions,
since, for example, a typical rewarding gustatory stimulus such as su-
crose ingestion can be perceived as aversive or threatening by persons
with AN or BN because of their fear of weight gain due to drinking a
high-caloric sweet food. Finally, although food-related reward may
have an obvious relevance in the pathophysiology of EDs, food con-
sumption is not the only reward-linked behavior, since different psy-
chological and behavioral dimensions are recognized as potential
sources of reward mechanisms activation in EDs patients, such as
body image perception, physical exercise, binge eating and dieting.
Therefore, in this review, we present brain imaging studies that ex-
plored brain activation by food-related reward stimuli as well as studies
that explored brain activation induced by body image cues or by stimuli
related with food deprivation and physical activity or by typical mone-
tary rewarding tasks.
2.2. Looking at food
In general, the decision of assuming or to give up eating is largely
conditioned by visual stimuli and their subsequent integration with
memories and motivational cues. Visual detection of food usually acti-
vates anticipatory responses associated with reward system, and this
process determines the subsequent feeding behavior of each person
(Stice et al., 2009). Indeed, the sight of food elicits a wide range of
physiological, emotional and cognitive processes. It has been proposed
that vulnerability to EDs might be related to inappropriate processing
of visual perception of food. The typical fMRI task of viewing food pic-
tures shows that, in healthy persons, food stimuli compared to non-
food cues activate occipital structures such as the fusiform and the
middle occipital gyrus, parietal areas such as the postcentral gyrus, pre-
frontal regions such as the ACC, the medial PFC, the lateral PFC and the
OFC, and the limbic and paralimbic structures such as the insula, amyg-
dala and striatum (Simmons et al., 2005; Uher et al., 2006; Schur et al.,
2009; Grimm et al., 2012; Wagner et al., 2012; Kroemer et al., 2013). Re-
ward of food is associated to its hedonic properties and caloric content,
as BOLD activation in areas of the brain reward circuitry, such as the in-
sular cortex/frontal operculum, striatum, amygdala, occipital lobe, hy-
pothalamus, thalamus, anterior cingulate and lateral PFC, seems to be
higher when presenting highly palatable or caloric food cues (Beaver
et al., 2006; Cornier et al., 2007; Goldstone et al., 2009; Passamonti et
al., 2009; Schur et al., 2009; Batterink et al., 2010; Yokum et al., 2011;
Frank et al., 2013).
Uher et al. (2004) compared the neural response to visual food stim-
uli in a group of healthy participants and a group of women with AN and
 A.M. Monteleone et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 80 (2018) 132–142
BN. Overall, AN and BN patients reported higher activation of the medial
PFC and inhibition of the lateral PFC. Moreover, patients with AN were
found to inhibit the OFC and insula when viewing food (Holsen et al.,
2012; Uher et al., 2003), which suggests that they may be less prone
to respond to the hedonic aspects of food. On the contrary, BN patients
seemed to overactivate the insula (Schienle et al., 2009), which may be
suggestive of enhanced reward processing in this disorder.
According to the “reward contamination” model (Keating, 2010;
Keating et al., 2012), it has been hypothesized that in AN patients nor-
mal rewarding stimuli (e.g., high-calorie foods) are experienced as aver-
sive. For example, amygdala hyper-reactivity has been found in ANR
women during symptom provocation using visual food stimuli
(Pietrini et al., 2011), suggesting a heightened fear response. According
to this explanation, some prefrontal areas normally implicated in con-
flict monitoring, reward processing and punishment information, such
as ACC and medial PFC were found to be hyper-activated in AN patients
in response to images of sweet foods (Uher et al., 2003, 2004; Brooks et
al., 2011a).
Differences according to specific eating behaviors have been identi-
fied. ANR patients reported increased activity in parahippocampal gyrus
and ACC and decreased activity in the visual cortex, as compared with
ANBP patients (Brooks et al., 2012). Furthermore, food images elicited
a stronger response in the ventral striatum and ACC in BN than in
healthy controls and patients with binge eating disorder (Weygandt et
al., 2012). Some of the mentioned functional abnormalities appear to
be state-dependent. Accordingly, recovered AN patients reported in-
creased activation in response to food stimuli in OFC, medial and lateral
PFC, and dorsal and anterior cingulate gyrus when compared with
symptomatic AN patients (Uher et al., 2003; Cowdrey et al., 2011;
Holsen et al., 2012).
2.3. Eating food: the consummatory phase of reward
There are several fMRI evidences of distinct patterns of brain activa-
tion in ED patients in response to gustatory stimuli. Compared to
healthy controls, individuals recovered from AN were found to exhibit
lower activity in the insula, ventral and dorsal striatal regions in re-
sponse to a sucrose stimulus (Wagner et al., 2008; Oberndorfer et al.,
2013). Conversely, Vocks et al. (2011) detected increased right amygda-
la and left medial temporal gyrus responses to chocolate milk in symp-
tomatic AN patients while Cowdrey et al. (2011) found increased neural
response to the pleasant chocolate taste in the ventral striatum of recov-
ered AN patients. However, the pleasant taste stimuli adopted by Vocks
et al. (2011) and by Cowdrey et al. (2011) were not basic pure tastes,
since they imply also cognitive and emotional aspects, which could in-
duce in AN patients a fear of weight gain due to drinking a high-caloric
food such as chocolate milk. The unpredictable or predictable nature of
the taste stimulus presentation also seems to play a significant role in
brain activation, since AN women exhibited increased responses in
brain reward areas to randomly given sweet taste stimuli (Cowdrey et
al., 2011; Oberndorfer et al., 2013).
Differences between AN and BN have been found in encoding re-
ward to food taste. As compared to AN patients, BN patients showed
greater activation to a high fat/high viscosity solution in the anterior
ventral striatum (Devue et al., 2007). Similarly, sucrose stimulation in
BN women was associated with lower ACC activation (Frank et al.,
2006) and heightened anterior insula activation (Oberndorfer et al.,
2013). Finally, a positive correlation between negative affect and activ-
ity in the putamen, caudate, and pallidum during anticipated receipt of
chocolate milkshake was detected in BN patients (Bohon and Stice,
2011).
A recent review by Frank (2015) summarizes that repeated sweet
taste stimuli are associated with reduced activation of taste-reward re-
gions, such as the insula and ventral striatum, in AN, but increased acti-
vation in BN. The author suggests that during repeated taste application,
AN subjects activate an hyper-control response in order to avoid a too
135
high stimulation; during the random application of tastants, instead,
this control is not possible and an enhanced responsiveness comes to
light. In BN, a reduced biological responsiveness to taste stimulation be-
comes obvious during random application, while the repeated taste
stimulation could kindle and enhance the low baseline response,
maybe through the repeated hedonic experience.
2.4. Restrained eating and over-control as sources of reward
PFC has been found to be responsible for restraint habits in several
experimental conditions, since in healthy subjects restrained food in-
gestion was found to increase BOLD activity in the lateral and medial
PFC and in the OFC (Hare et al., 2009; Hollmann et al., 2012). The re-
sponse associated with food restriction seems to vary in relation to the
degree of perceived hunger. Whereas unrestrained eaters activate the
striatum, amygdala/parahippocampal gyrus (Coletta et al., 2009;
Demos et al., 2011) and the medial PFC (Paulus and Frank, 2003) in
the fast state, restrained eaters show the highest activity in the medial
PFC, insula and NAc after food consumption (Coletta et al., 2009;
Demos et al., 2011).
Presentation of food stimuli during a state of food deprivation in AN
has been associated with activation of the prefrontal and central cortices
as well as the dorsal posterior cingulate cortex, and additional activation
in the OFC and cingulate cortex was also seen when subjective ratings of
food valence were included as a covariate (Gizewski et al., 2010). Sever-
al studies suggest a role for altered dopaminergic function in the facili-
tation of aberrant reward associations in AN (Fladung et al., 2010;
Frank et al., 2012; Giel et al., 2013; Kullmann et al., 2013; O'Hara et al.,
2015). Accordingly, persons vulnerable to EDs may activate dopaminer-
gic motivational circuits differently from healthy controls resulting in
the attribution of appetitive value to aversive stimuli (such as persistent
restrained eating) because of differences in long-term cognitive goals
(e.g., the pursuit of thinness, dietary restriction, and further weight
loss).
2.5. Body image tasks
Patients with EDs typically overvalue their body shape and weight,
and body image disturbances – defined as “a disturbance in the way in
which one's body weight or shape is experienced” (American
Psychiatric Association, 2013)- is one of the core psychopathological
features of EDs. In the last years, studies in this field achieved progres-
sive improvement, for example adopting tasks with individuals' own
body image, rather than drawings or images taken from magazine,
thus eliciting a more robust interoceptive and emotional-motivational
processing pattern (Friederich et al., 2010). The circuitry associated
with this kind of task include DLPFC, supplementary motor, insular, in-
ferior parietal (representation of one's own body schema), fusiform
(human face recognition process), occipito-temporal (the so called
“extrastriate body area”) and cingulate regions (Pietrini et al., 2011).
It has been reported that in response to body image stimuli, AN pa-
tients showed increased activation of emotion processing-related areas
(frontal, striatal, and insular cortices, amygdala) and decreased activa-
tion in visuospatial body processing-related areas (parietal cortices).
In particular, Fladung et al. (2010) found a ventral striatal activity in
AN patients in response to pictures of underweight females. Such stim-
uli are closely linked to starvation and seem to have rewarding proper-
ties for these patients. New models of ideal beauty have been proposed
by industry in western countries, which influenced the unrealistic ex-
pectations of EDs patients. Therefore, some studies considered the neu-
ral activation of AN patients when comparing themselves with idealized
female bodies. An increased brain activation relative to controls was
found in AN women, especially in regions associated with emotional
and rewarding responses, such as insula and putamen, as well as in
DLPFC, which is devoted to modulate such responses (Friederich et al.,
2010; Mohr et al., 2010).
136 A.M. Monteleone et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 80 (2018) 132–142
On the contrary, a task resembling body image distortion has been
proposed especially for AN persons, with a presentation of oversized-
self-body images. Data from this kind of tasks provided evidences of
an enhanced emotional involvement and a related prefrontal activation
as modulatory mechanism in AN, in response to one's own body image.
Indeed, when viewing oversized self-body images, individuals with AN
show activations in the amygdala (Miyake et al., 2010) and DLPFC
(Castellini et al., 2013). Finally, Fladung et al. (2010) examined re-
sponses to disease-specific and self-referential stimuli (i.e., under-
weight, normal weight, and overweight female bodies). In AN,
underweight female stimuli elicited the highest activity in the
mesolimbic reward network, while normal weight cues produced the
highest activity in healthy controls. These results were consistent with
their behavioral data in that individuals with AN provided increased
pleasure ratings in response to underweight relative to normal weight
stimuli, a response opposite to healthy controls.
According to the overall pattern of activation in response to body
image tasks, it seems possible to conclude that increased activity in
the insula and striatum may reflect an implicit attribution of motiva-
tional salience towards illness related cues (e.g., thinness), while in-
creased activation of regions such as the amygdala and PFC to images
of overweight bodies may reflect activation of ‘top-down’ cognitive con-
trol to reduce the effects of threatening stimuli.
2.6. Hyperactivity and physical exercise
Excessive physical exercise is one of the most frequent compensato-
ry behaviors of both AN and BN patients. It has been hypothesized that
rewarding experiences underpin and maintain hyperactivity in AN
(Scheurink et al., 2010), and that hyper-exercising reduces anxiety asso-
ciated with food consumption (Keating et al., 2012). Few studies
adopted neurobiological paradigms to evaluate reward system func-
tioning in response to hyperactivity tasks. For example, Giel et al.
(2013) explored attentional processing in response to pictures
depicting exercise versus inactivity in patients with AN, healthy endur-
ance athletes and healthy non-athletes using eye-tracking technology.
They found a pronounced bias in overall attentional engagement to-
wards stimuli associated with physical activity in patients and athletes
as compared to non-athletes. Using startle eye-blink modulation, it
has been shown that, relative to controls, individuals recovered from
AN show an appetitive appraisal of images depicting active female bod-
ies (O'Hara et al., 2016).
To our knowledge, only one neuroimaging study found that exer-
cise-specific tasks (e.g. images of physical activity) increased PFC activa-
tion in AN patients as compared to athlete and non-athlete healthy
controls (Kullmann et al., 2013), which suggests an increased inhibitory
input in AN, possibly secondary to a reward stimulus, after exercise task
stimulation.
2.7. The classic reward stimuli: monetary tasks in EDs
Monetary tasks are the classical paradigms adopted trans-
nosographically to elicit reward activation. In these kind of stimuli, re-
warding activation is associated with subjects' performances: money
is maximally salient when its receipt is dependent on a correct behav-
ioral response (active task) and minimally salient when its receipt is
completely independent (passive task). (McClure et al., 2003;
O'Doherty et al., 2003). Typically, rewarding money stimuli elicit dorsal
(caudate) and central (nucleus accumbens) striatum activation. How-
ever, as previously reported, it is important to distinguish between he-
donic component and saliency of the stimuli. Compared with previous
discussed tasks, the abstract nature of monetary rewards allows for a
non-salient presentation, which would be difficult to achieve with pri-
mary rewards, such as gustatory paradigms.
fMRI studies have shown abnormal striatal and PFC activity in re-
sponse to monetary stimuli in AN before and after weight restoration
(Wagner et al., 2007; Decker et al., 2014). Moreover, compared to con-
trol women, subjects who had recovered from AN or BN who performed
a monetary task showed altered patterns of response in the ventral and
dorsal striatum to wins and losses with a reduced difference in brain re-
sponses to gain versus loss, which suggests that ED patients may have
difficulty in discriminating between positive and negative feedback
(Wagner et al., 2007, 2010), perhaps related to their increased sensitiv-
ity to both reward and punishment. Ill AN adolescents also exhibited an
exaggerated response to losses compared to wins in posterior executive
and sensorimotor striatal regions (Bischoff-Grethe et al., 2013). More-
over, in monetary tasks, recovered AN individuals but not recovered
BN ones showed an exaggerated response to both reward and punish-
ment in dorsal executive regions (e.g., dorsal caudate, DLPFC, parietal
cortex) as compared to controls (Wagner et al., 2007). This may indicate
enhanced inhibitory activity, which may be linked to anxiety in AN,
given positive correlations between anxiety scores and brain response
in the caudate in recovered AN patients (Wagner et al., 2007). As the
dorsal caudate has been associated with inhibitory control (Konishi et
al., 1998), one possible interpretation is that recovered bulimic patients
have disturbed executive function in linking stimulus cues with
valenced outcomes, which is reflected in their occasional impulsive,
disinhibited behavior. Together, these data support the hypothesis
that AN and BN patients experience altered reward sensitivity related
to limbic (reward) circuitry but differ in their inhibitory response,
with increased behavioral inhibition related to overactive cognitive
neural circuitry in AN and decreased inhibitory control as manifested
in dysfunctional executive processes in BN (Phillips et al., 2003).
2.8. Morphological studies on brain volume
Research on morphological brain structure in EDs has been often in-
consistent (Van den Eynde et al., 2012) with the majority of studies
underlining reduced total grey matter (GM) and white matter (WM)
volumes in the acute stages of illness, and reduced or normal total vol-
umes after recovery (Van den Eynde et al., 2012; Frank, 2015).
Focusing on regional specific volume alterations that could be impli-
cated in the reward system processing, some findings suggested re-
duced GM volume of insula, hypothalamus, amygdala and cingulate
cortex in AN patients (Muhlau et al., 2007; McCormick et al., 2008;
Boghi et al., 2011; Frank, 2015). Moreover, one study found an increase
GM volume of DLPFC in AN patients, in contrast to others that reported
reduced DLPFC volume (Joos et al., 2010; Suchan et al., 2010; Brooks et
al., 2011b; Friederich et al., 2012). The studies performed in BN patients
suggested a reduced caudate volume in dorsal striatum but normal NAc
volume (Coutinho et al., 2015) and normal or increased localized GM
volume in OFC and striatum (Van den Eynde et al., 2012; Schafer et al.,
2010). According to Frank (2015), reduced dorsal striatum volumes
predicted sensitivity to reward in AN and BN patients.
The OFC plays a relevant role in food intake control and satiety
(Rolls, 2008). It is possible that increased volume of OFC in EDs could
drive food avoidance by means of early satiety experience and disturbed
reward valuation of food stimuli (Frank et al., 2012). As for BN, Amianto
et al. (2013) documented the presence of atrophy of the caudate nucle-
us, possibly involved in binge-eating behaviors. In fact, the caudate nu-
cleus is a core unit within the basal ganglia involved in reward,
motivation and self-regulation processes (Robbins and Everitt, 1996;
Berridge et al., 2010), and some studies have shown that BN patients
are characterized by alteration of self-regulation processes, linked to a
deficit in the recruitment of fronto-striatal circuits (Marsh et al.,
2009), which, according to Amianto et al. (2013), supports the recently
outlined concept of the “impulse control model” of EDs (Brooks et al.,
2012).
A few studies evaluated WM integrity in EDs by means of magnetic
resonance diffusion tensor imaging (DTI), and focused on the fornix
area, which is part of the limbic system. Data obtained seem to suggest
a reduced fornix fractional anisotropy in both AN and BN patients, thus
 A.M. Monteleone et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 80 (2018) 132–142
indicating a worse axonal coherence, density and myelination (Frank,
2015).
3. Neuroendocrine studies on reward mechanisms in eating
disorders
3.1. General considerations
Eating is essential for survival in all living species; so complex and
finely tuned mechanisms have evolved to regulate this behavior. Both
central and peripheral endogenous substances participate in this modu-
lation, and it is intuitive that alterations in the physiology of one of more
of endogenous modulators may lead to an altered eating behavior.
Moreover, since eating not only aims at maintaining the organism's en-
ergy homeostasis (homeostatic eating) but it is driven also by the plea-
sure connected with the ingestion of food, especially when high
palatable foods are consumed, (hedonic eating), both homeostatic and
reward brain systems intervene in its modulation. These neural systems
have reciprocal synaptic connections and they cross-talk in order to in-
tegrate homeostatic and rewarding aspects of food intake (Volkow et
al., 2011). Therefore, it is not surprising that endogenous biochemical
modulators of homeostatic food intake are involved also in hedonic eat-
ing as well as in the regulation of non-food related rewarding behaviors.
Alterations of eating behavior are pathognomonic and paradigmatic
for the nosographic definition of EDs; so a great deal of research has
been done on endogenous modulators of feeding in AN and BN. Findings
in this field suggest that alterations in the physiology of eating regulato-
ry substances occur in the acute phase of an ED and generally disappear
with the recovery from the ED, representing mainly homeostatic adap-
tations to the altered energy balance. Notwithstanding, the role of these
feeding regulators in the modulation of reward has suggested that their
alterations in the acute phase of an ED may contribute to the appearance
and/or the persistence of some aberrant rewarding behaviors of ED pa-
tients, such as prolonged starvation, binge eating and physical over-
exercising. Therefore, in the following paragraphs, literature data
supporting the role of some endogenous eating modulators, such as lep-
tin and ghrelin, in the regulation of brain reward mechanisms and, con-
sequently, in the pathogenesis of aberrant rewarding behaviors of ED
patients will be presented.
3.2. Leptin
Leptin, a peptide released primarily from adipose tissue, conveys to
the brain information on body fat mass and amount of energy stored
in adipocytes. Leptin plays a major role in regulating energy balance,
by decreasing food intake, suppressing hunger and increasing energy
expenditure (Blundell et al., 2001). While controversial data have
been reported on leptin production in BN, previous studies have long
established that plasma and cerebrospinal fluid leptin levels are reduced
in underweight patients with AN, gradually increase during refeeding
and normalize after weight recovery (Tortorella et al., 2014), suggesting
adaptive homeostatic changes of this peptide in relation to BW fluctua-
tions in AN.
Besides the well-known direct effects on the regulation of energy
homeostasis, leptin has also been investigated to unveil its role within
the brain reward system, modulating both food-related and non-food-
related reward. The main hypothesis concerning the role of leptin in re-
ward processing stems from the evidence that leptin receptors are pres-
ent on dopaminergic neurons of the VTA (Krugel et al., 2003). Animal
studies provided the evidence that dietary regimens increasing body
weight (which, in turn, determines an increase of leptin levels) induce
a decrease in reward-related behaviors, while caloric restriction or dep-
rivation promote a decrease of leptin levels and an augmentation of re-
ward-related behaviors (Davis et al., 2010). In animals trained to self-
administer sucrose (Cowely et al., 2001) or heroin (Shalev et al., 2001)
central administration of leptin induced a decrease in those rewarding
137
behavioral responses. Such effects may be explained by the leptin ability
to decrease mesolimbic dopaminergic firing and dopamine release in
the NAc (Krugel et al., 2003; van der Plasse et al., 2015). Although the
mesolimbic dopaminergic system remains the main site of the re-
ward-related leptin action, other putative central mechanisms have
been proposed for the modulating role of leptin on food-related reward
(Thompson and Borgland, 2013; Kanoski et al., 2014).
A recent wave of fMRI studies in humans shed further light on the
role of leptin in reward processing. Simon et al. (2014) investigated in
healthy volunteers with different body weights [from “low” body
mass index (BMI) to obesity class II BMI] the performance to a mone-
tary/food incentive delay task. The authors reported not only the specif-
ic activation of ventral striatum (a human brain area which has been
repeatedly reported as having a pivotal role in anticipation of reward),
but also that anticipatory food reward processing specifically predicted
individual BMI (both current and lifetime), with the mediation of circu-
lating leptin levels. Farooqi et al. (2007), instead, investigated satiated
patients with congenital leptin deficiency during exposure to food visu-
al stimuli and reported an activation of NAc and caudate associated to
food “wanting”; however, when patients were administered for a
week with leptin such effect disappeared. Another study (Farr et al.,
2014) on three subjects with acquired leptin deficiency (a condition
quite different from congenital leptin deficiency) showed that the
short-term (1 week) use of metreleptin (i.e., recombinant leptin) was
associated to an enhancement of the activity in bilateral insula, dorsolat-
eral prefrontal and medial frontal cortices to the view of food images
during the fasting state; to the contrary, the long-term (24 weeks) ad-
ministration of metreleptin resulted again in an enhanced brain re-
sponse in the fasting state, but in a decreased brain activation in the
fed state. A very recent study (Farr et al., 2016) investigated with a
cross-over placebo-controlled design the effects of liraglutide (a long-
acting glucagon-like peptide-1 receptor agonist) in twenty patients
with diabetes and reported that, during the presentation of highly desir-
able vs. less desirable food cues, the glucagon-like peptide-1 agonist in-
duced a significant decrease of leptin levels, which was specifically
associated to significant differences in the activation of midbrain,
precuneus, and DLPFC, and pre- and sensorimotor-related motor cortex,
parietal cortex and the thalamus. This evidence suggests that the mod-
ulating effects of leptin on brain areas is not limited to midbrain reward-
sensitive areas and that leptin exerts an influence over a more widely
distributed neural network, which should be investigated in more
detail.
In the light of the above reported data, the independently replicated
and consolidated finding of lower circulating leptin in underweight sub-
jects with AN might contribute to strengthen the aberrant starvation be-
havior of these patients. It is very likely that the experience of
controlling food is perceived with a positive valence by AN subjects;
so, it could be hypothesized that the reduction of adipose tissue, with
consequent decrease in leptin production, might reinforce dopaminer-
gic tone in brain reward circuits and thus strengthen dieting behavior
(Monteleone and Maj, 2013a).
Another putative specific role of leptin in EDs concerns physical hy-
peractivity, which represents one of the major compensatory behaviors
in these patients. Underweight subjects with AN often display overexer-
cise, which has been reported to be inversely correlated with food in-
take (Hebebrand et al., 2003; Holtkamp et al., 2003a, 2003b) and
directly correlated to lower leptin levels, although this correlation is
lost in severely emaciated AN patients (Hebebrand et al., 2003).
Hebebrand et al. (2003) explained this apparent contradiction postulat-
ing an “inverted U” dynamic by which the effect of hypolectinemia on
activity levels declines when subjects are close to starvation and
death. Besides the postulated anxiolitic properties of physical exercise,
a specific reward mechanism involving leptin has been put forward to
explain overexercise in AN. Animal data based on the “activation-
based anorexia” (ABA) experimental paradigm provide evidence that
low plasma leptin levels are correlated with increase in rats' running
138 A.M. Monteleone et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 80 (2018) 132–142
activity (de Rijke et al., 2005), while continuous infusion of leptin re-
duces rats' hyperactivity (Exner et al., 2000), with an elective leptin
site of action located at the VTA (Verhagen et al., 2011). This evidence
suggests that a reduced leptin signaling in this area may be related to
an increase in mesolimbic dopaminergic activity and to a consequent
enhancement of reward properties of physical activity. A study on
obese humans indeed reported that fasting leptin was specifically asso-
ciated with reward (both “wanting” and “liking”) for high-fat food and
that a decline in leptin levels were associated with greater physical ex-
ercise and increased “liking”, proposing that leptin may play an active
role in mediating food reward during exercise-induced weight-loss
(Hopkins et al., 2014). A recent study in AN patients and female athletes
explored the reward value of hyperactivity information by using eye-
tracking and psychometrics (Giel et al., 2013) and found that subjects
with AN tend to be more engaged towards stimuli associated with phys-
ical activity, to a degree which resulted to be significantly related to trait
reward sensitivity and amount of physical exercise, thus providing ex-
perimental support to the idea that exercise-related stimuli are per-
ceived by AN patients as rewarding and motivating. Authors did not
report a significant correlation with circulating leptin levels, but the rel-
atively low number of subjects (15 for each group) may partially explain
such a negative finding.
3.3. Ghrelin
Ghrelin is a 28-amino-acid peptide, mainly secreted by endocrine
cells of the gastric mucosa, which has orexigenic effects and promotes
gastric empting. Recent scientific evidence supports the hypothesis
that this hormone has more and more complex physiological roles,
well beyond the mere regulation of systemic energy homeostasis
(Müller et al., 2015).
Animal studies have demonstrated that ghrelin receptors are
expressed on dopaminergic neurons in the VTA, where ghrelin stimu-
lates dopamine neuronal activity, synapse formation, and dopamine
turnover in the NAc (Abizaid et al., 2006). Several studies have investi-
gated the effects of local injection of ghrelin into rodents' brain and con-
firmed the stimulatory and dopamine-enhancing effects of ghrelin as
well as the increase in the extracellular concentration of accumbal do-
pamine (Jerlhag et al., 2007; Cone et al., 2014; Wei et al., 2016). Similar-
ly, systemic (intraperitoneal) administration of ghrelin to rats was
reported to activate mesolimbic DA system and produce accumbal do-
paminergic overflow (Jerlhag, 2008). These ghrelin-induced neurobio-
logical effects on dopaminergic transmission have been associated to
several behavioral changes in animals such as an increase of licking pat-
terns (Overduin et al., 2012), greater locomotor activity (Jerlhag et al.,
2007) and enhanced food consumption (Perello et al., 2010; Skibicka
et al., 2012), which altogether seem to be in line with the idea that
ghrelin enhance the incentive value for motivated behaviors, such as
food seeking and consuming. Indeed, several studies have clarified
that ghrelin effects on dopaminergic VTA-NAc projections enhance
food reward/choice rather than exerting a direct effect on food intake
(Skibicka et al., 2013; Schéle et al., 2016). Furthermore, ghrelin has
been shown to be able not only to enhance reward for food-cues but
also to induce a reinstatement of behavioral responses for high palatable
food following a period of abstinence (St-Onge et al., 2016). Recently,
studies employing ghrelin receptors' antagonists have provided further
evidence in favor of the central role of ghrelin in modulating dopami-
nergic transmission in brain reward circuits by showing that ghrelin an-
tagonists induce an attenuation of the reward value of palatable food
(Wei et al., 2016; St-Onge et al., 2016), alcohol (Stevenson et al.,
2016), cocaine (Cepko et al., 2014) and morphine (Sustkova-Fiserova
et al., 2014; Engel et al., 2015). The exploration of in vivo brain activity
by means of fMRI contributed to further refine the effects of ghrelin
onto brain networks. In an experiment on male and ovariectomized fe-
male rats, Sárvári et al. (2014) demonstrated that the systemic adminis-
tration of ghrelin induced significantly different BOLD responses within
region typically reported as part of the limbic/reward system (such as
PFC and NAc) and within hypothalamic centers (like the lateral hypo-
thalamus, ventromedial nucleus, paraventricular nucleus and suprachi-
asmatic nucleus), somehow confirming the crucial role of ghrelin in
both reward and energy homeostasis modulation.
Several studies have investigated circulating ghrelin in subjects with
EDs and reported that baseline ghrelin levels are increased in under-
weight subjects with AN, did not respond adequately after the con-
sumption of food (Tortorella et al., 2014) and show an exaggerated
response after sham feeding (Monteleone et al., 2008). Recently, the ev-
idence of increased ghrelin secretion in healthy subjects during hedonic
eating (Monteleone et al., 2012a, 2013b) seems to suggest a role for pe-
ripheral ghrelin in the modulation of food-related pleasure in humans.
When peripheral ghrelin levels were measured in underweight and re-
cently weight-restored AN subjects during “hedonic eating”, a deranged
ghrelin response was found in underweight patients with AN but not in
short-term weight restored ones, suggesting that the dysregulation of
peripheral ghrelin and food-related reward mechanisms could act as a
maintaining mechanisms of reduced motivation towards food intake,
rather than as causal factor of AN (Monteleone et al., 2016).
In humans, neuroeconomic paradigms demonstrated that the ad-
ministration of ghrelin increased the amount of money an individual
is prepared to pay for individual food items and decreased their willing-
ness to spend money for non-food items (Tang et al., 2011). Malik et al.
(2008) showed that, in healthy volunteers, the intravenous administra-
tion of ghrelin increased the neural response to food pictures in anterior
insula, striatum, amygdala, OFC (the activations within the latter two
brain regions also correlated with self-rated hunger scores). However,
a subsequent study (Goldstone et al., 2014) evaluating the effect of
acyl-ghrelin (that is the active form of ghrelin) after overnight fast and
after breakfast in 22 healthy controls during an fMRI food-picture eval-
uation task partially confirmed the previous results, since ghrelin ad-
ministration was significantly associated to activations in OFC and in
hippocampus without significant effect on NAc, caudate, insula or
amygdala.
Holsen et al. (2012), by adopting a food-cue fMRI paradigm, report-
ed significant relationship between circulating levels of ghrelin and ac-
tivity of hypothalamus, amygdala and anterior insula (i.e., reward-
related brain areas) in response to high-calorie foods in healthy
women, but not in underweight or weight-restored AN patients. The
same group (Holsen et al., 2014) investigated the relationship between
brain activation prompted by visual food cues and fasting levels of acyl-
ated ghrelin in a group of subjects with AN. They found a significant pos-
itive association between fasting acylated ghrelin and activity in the
right amygdala, hippocampus, insula, and OFC in response to high-calo-
rie foods in healthy subjects; those with AN had different association
patterns with weight-restored AN women exhibiting a negative rela-
tionship between ghrelin and activity in the left hippocampus, and
symptomatic AN women showing a positive association between ghrel-
in and activity in the right OFC.
Other studies focused their interest in revealing the role of ghrelin in
modulating reward through its influence on memory and learning pro-
cesses (Wise, 2002). Animal studies revealed that ghrelin receptors are
present on hippocampal neurons and that ghrelin knockout mice not
only had a lower number of spine synapses in hippocampus but also
performed worse than their wild counterparts in a spatial memory
learning test (Diano et al., 2006). More recently, Kanoski et al. (2013)
used a multimodal rat behavioral model to explore ghrelin signaling in
the ventral hippocampus and reported that intrahippocampal ghrelin
delivery increased food intake, spontaneous meal initiation and willing-
ness to work for sucrose reward; these changes were associated with a
downstream activation of dopaminergic neurons in the NAc and seem
to confirm that ghrelin might be implicated in cognitive and motiva-
tional aspects of feeding control. Since in primates mesolimbic dopami-
nergic neurons have been shown to be easily conditioned to stimuli
predicting reward (Schultz et al., 1997), it has been proposed
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(Monteleone and Maj, 2013a) that in the presence of starvation-associ-
ated cues, the enhanced ghrelin tone of symptomatic AN women may
facilitate, through the stimulation of the dopamine reward system, the
patient's control over food ingestion, since this is perceived as reward-
ing. This is in line with the “starvation-dependent syndrome” model
for the development and maintenance of eating disorders (Støving et
al., 2009).
Ghrelin has also been repeatedly reported to be involved in the path-
ophysiology of binge eating behaviors for its role in promoting food in-
gestion and increasing food-related reward. Binge eating has been
interpreted as a possible response to stress or negative mood, in
which the binge-compensate pattern of intake represents the chance
to reduce negative feelings and increase feelings of pleasure (according
to the so called “affect regulation theory” of binge eating; Johnson and
Larson, 1982; Heatherton and Baumeister, 1991). Animal findings
have confirmed that inducing stress in rodents increases the levels of
ghrelin (Kristenssson et al., 2006). A recent experiment on ghrelin-re-
ceptor knockout mice with free access to a high-fat diet reported that,
with respect to wild type mice, the rodents with ghrelin signaling deficit
had a reduced activation in the NAc shell and consumed fewer calories
(King et al., 2016), providing further evidence to the idea that ghrelin
enhances the rewarding value of palatable foods and that the increase
in motivation for such foods might be related to bingeing behaviors.
Furthermore, ghrelin injection in lateral ventricles of mice has been
shown to increase impulsive behaviors and impulsive choices and that
ghrelin receptor stimulation within the VTA was sufficient to increase
impulsive behavior (Anderberg et al., 2016) while ghrelin-receptor
knockout mice were shown to fail to escalate in high fat intake during
repeated accesses and did not engage the dopaminergic mesolimbic
pathway in response to high fat food (Valdivia et al., 2015). All together
animal studies seem to lean towards the involvement of ghrelin signal-
ing in binge-eating behaviors mediated by dopaminergic reward mech-
anisms. In humans, the use of experimental procedures that allow the
controlled induction of psychological stress (such as the Trier Social
Stress Test, TSST) has been associated to an increase of ghrelin plasma
levels in obese subjects with and without binge eating (Rouach et al.,
2007). A similar result was reported in a sample of subjects with BN
where the amplification of the ghrelin secretion in response to TSST
would be in line with the hypothesis that BN patients attempt to reduce
stress, anxiety and negative emotions by binge eating and increasing
food-related feelings of pleasure (Monteleone et al., 2012b).
Finally, ghrelin has been recently postulated as being also crucially
involved in physical hyperactivity. A recent animal study confirmed
that ghrelin was able to prevent ABA in obese ob/ob mice and authors
support the pharmacological use of ghrelin for treatment of anorexia ac-
companied by elevated physical activity (Legrand et al., 2016). In this
line, a positive correlation between the number of steps/day and pe-
ripheral levels of ghrelin has been detected in over-exercising AN
women, further supporting an implication of the orexigenic peptide
hormone in the regulation of rewarding physical hyperactivity in AN
(Hofmann et al., 2016).
4. Conclusions
Different neurocognitive models have been proposed to support the
involvement of reward mechanisms in the pathogenesis of EDs. Accord-
ing to O'Hara et al. (2016), a first pathogenetic model sustains that EDs
can be associated with an anhedonic state, due to a reduced dopaminer-
gic activation of reward system (Davis and Woodside, 2002; Kaye et al.,
2005). A second model suggests a reduction of reward activation sec-
ondary to hypertrophic “top-down” cognitive control mediated by dor-
sal brain structures (Brooks et al., 2011b; Kaye et al., 2009). With
reference to this “top-down” approach, which involves neural circuits
linked to habit formation (Steinglass and Walsh, 2016), Walsh (2013)
proposed that, especially in ANR, dietary restraint is experienced as re-
warding initially, and then persists and becomes highly resistant to
139
treatment interventions, since it becomes an habit, although it is threat-
ening for the individual's health. The third model refers to the so called
“reward contamination”, which is related to specific behaviors, such as
eating restraint or purging, which become paradoxically rewarding, be-
cause of a supposed development of inappropriate overlapping neural
pathways, which simultaneously process reward and punishment
(Keating, 2010; Keating et al., 2012).
The above reviewed brain imaging and neuroendocrine findings
provide the evidence that alterations in both food-related and non-
food-related reward mechanisms may occur in patients with AN or
BN, and support the idea that these dysfunctions may be involved in
the pathophysiology of EDs. At present, it is still debated whether
most of those neurobiological changes represent state-dependent mod-
ifications due to the acute phase of the ED or if they represent a biolog-
ical background, which favor the appearance of the ED, since some of
them persist or are found in patients recovered from an ED. Anyway, in-
dependently from the primary or secondary nature of the above de-
scribed alterations of reward mechanisms in ED patients, these
findings suggest new pathogenetic frameworks for the development
of both psychological and pharmacological new therapeutic strategies
for the treatment and/or the prevention of EDs.
It is widely acknowledged that the therapeutic outcomes of AN and
BN patients are not satisfactory, and only a few psychological interven-
tions have received an evidence-based validation for their efficacy in ED
patients (National Collaborating Centre for Mental Health, 2004). The
scenario is even more frustrating in the field of pharmacological treat-
ments, where only binge-eating syndromes have evidence-based drug
treatments (National Collaborating Centre for Mental Health, 2004).
Therefore, the development of effective interventions is a priority in
the field of EDs and new pathogenetic models for these syndromes are
welcomed in the effort to develop more efficacious treatment strategies
for AN and BN. According to these considerations, it is of note that de-
spite the increasing amount of neurobiological data about reward cir-
cuits and mechanisms, no therapeutic intervention devoted to the
management of EDs has been specifically focused on reward so far. In
our opinion, the above discussed alterations in reward mechanisms sug-
gest the need to take into account these theoretical aspects in psycho-
logical interventions and to explore whether such implementation
ameliorate the outcomes of ED patients. Similarly, the awareness that
some endogenous eating regulatory substances also impact on reward-
ing mechanisms, should prompt researchers to assess whether agonists
or antagonists of these modulators could be useful in the amelioration of
aberrant rewarding behaviors of ED patients. Further studies are needed
to understand how the knowledge deriving from reward models of EDs
can be translated in successful psychological and/or pharmacological in-
terventions for both AN and BN patients.
Disclosure
The authors declare that they have no conflicts of interest to disclose.
Funding
This research did not receive any specific grant from funding agen-
cies in the public, commercial or not-for-profit sectors.
Contributors
All authors participated in bibliography search, manuscript prepara-
tion and revision and approved the final version of the paper.
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