International Review of Psychiatry

ISSN: 0954-0261 (Print) 1369-1627 (Online) Journal homepage: http://www.tandfonline.com/loi/iirp20

Dopamine-related frontostriatal abnormalities

in obesity and binge-eating disorder: Emerging
evidence for developmental psychopathology

Michael Michaelides, Panayotis K. Thanos, Nora D. Volkow & Gene-Jack

Wang

To cite this article: Michael Michaelides, Panayotis K. Thanos, Nora D. Volkow & Gene-Jack
Wang (2012) Dopamine-related frontostriatal abnormalities in obesity and binge-eating disorder:
Emerging evidence for developmental psychopathology, International Review of Psychiatry, 24:3,
211-218, DOI: 10.3109/09540261.2012.679918

To link to this article: https://doi.org/10.3109/09540261.2012.679918

Published online: 24 Jun 2012.

Submit your article to this journal

Article views: 732

View related articles

Citing articles: 18 View citing articles

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=iirp20
International Review of Psychiatry, June 2012; 24(3): 211–218

Dopamine-related frontostriatal abnormalities in obesity and binge-eating

disorder: Emerging evidence for developmental psychopathology

MICHAEL MICHAELIDES1,2, PANAYOTIS K. THANOS1,4,5,6, NORA D. VOLKOW1,4

& GENE-JACK WANG1,3
1Behavioral Neuropharmacology and Neuroimaging Laboratory, Brookhaven National Laboratory, Upton, New York,
2Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, 3Department of
Psychiatry, Mount Sinai School of Medicine, New York, 4Laboratory of Neuroimaging, National Institute for Alcohol Abuse
and Alcoholism, Bethesda, Maryland, 5Department of Psychology, Stony Brook University, New York, and 6Department of
Neuroscience, Stony Brook University, Stony Brook, New York, USA

Abstract
Obesity and binge-eating disorder (BED) frequently arise in adolescence, which is a critical developmental time period
where self-regulatory processes are formed. Indeed, both obesity and BED are thought to arise partly due to deficits in
self-regulatory processes (i.e. lack of inhibitory control to overeat or binge). Recent neuroimaging studies have implicated
the frontal cortex, a brain region involved in regulating inhibitory-control, and the striatum, which is thought to be involved
in food reward, satiety and pleasure, in mediating responses to food cues and feeding in normal-weight individuals as well
as obese and BED subjects. Intriguingly, frontostriatal circuits have been observed to be preferentially modulated in obese
adults and similar associations have been observed in obese/overweight adolescents. Furthermore, brain dopamine (DA)
is selectively altered in striatum in obese relative to normal-weight individuals, and frontostriatal regions constitute a major
component of DA circuitry. The aim of this review will be to present the main findings from neuroimaging studies in
obese and BED adults and adolescents, as these relate to frontostriatal circuitry, and to emphasize the potential for using
functional neuroimaging in both humans and animals with the scope of obtaining information on developmental and
molecular contributions to obesity and BED.

Introduction
frontal brain circuitry in both obese and BED adults
The prevalence of obesity has reached dramatic pro- and adolescents, which are paralleled by impairments
portions and is estimated to currently affect 32% of in inhibitory and cognitive control behaviour. These
US adults (Flegal et al., 2010). Binge-eating disorder recent findings suggest that obesity and BED may be
(BED), which is currently estimated to affect 3.5% attributed, in part, to developmentally associated
and 2% of US adult women and men respectively, is neurobiological impairments. This notion is sup-
also on the rise (Hudson et al., 2007). Besides the ported by the striking increases in childhood cases of
physical health problems associated with obesity and obesity (Faith et al., 2011; Ogden et al., 2010) as well
BED, there have also been reports of psychiatric as the generalized observations of BED onset during
comorbidity with depression and anxiety disorders adolescence.
(Faith et al., 2011), which suggests that part of the Neuroimaging techniques using functional mag-
behavioural phenotype of obese and BED individuals netic resonance imaging (fMRI) offer the ability to
may be related to impairments in brain function. An monitor obese and BED adolescents and adults
important distinction is that this may not occur for across developmental time-spans. These studies have
all obese individuals, the majority of whom exhibit implicated frontostriatal circuitry as being involved
metabolic abnormalities. However, a subset of obese in obesity and BED in both adults and adolescents.
individuals are characterized by excessive, compulsive- However, fMRI is limited in its ability to implicate
like overeating behaviour where obesity is thought to specific molecular determinants of obesity and BED.
be the manifestation of underlying psychopathology Positron emission tomography (PET) provides a way
(Davis & Carter, 2009). Emerging evidence from of assessing the contribution of specific molecular
neuroimaging experiments point to abnormalities in systems in obesity and BED, and studies in adults

Correspondence: Gene-Jack Wang, MD, 30 Bell Ave Building 490, Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
Tel: 631 - 344-3608. Fax: 631 - 344-2358. E-mail: [email protected]

(Received 31 January 2012 ; accepted 15 March 2012 )

ISSN 0954–0261 print/ISSN 1369–1627 online © 2012 Institute of Psychiatry
DOI: 10.3109/09540261.2012.679918
212 M. Michaelides et al.
have implicated the neurotransmitter dopamine (DA) emitting radiotracers that target specific molecular
as heavily involved in obesity and BED within fron- systems in biological tissue. PET utilizes the princi-
tostriatal circuits. Nevertheless, while PET has pro- ples of radioactive decay where positrons emitted
vided insight into potential molecular determinants of from the decaying radioisotope, which is tagged to a
obesity and BED, this method falls short of implicat- radiotracer, will collide with random electrons located
ing similar molecular mechanisms directly in children in close proximity to the decay site. Once the two
and adolescents due to the use of radioactivity. Recent particles collide, an emission of gamma rays is
advances in neuroimaging techniques using small ani- produced which project at opposite directions
mals provide a way for modelling obesity and BED (180 degrees) from the point of collision. PET scan-
across distinct developmental periods and in this way ners are equipped with specialized detectors which
provide tractable models that can be used to enhance pick up this signal. Once the signal is detected, the
insight into the contribution of respective develop- information is processed and the point of annihila-
mentally regulated molecular and genetic determi- tion can be estimated. Further information process-
nants associated with each disorder. This review ing is used to produce a two-dimensional image
focuses on summarizing the recent reports of fronto- rendering of radiotracer occupancy in the targeted
striatal circuit abnormalities observed in obese and tissue. PET imaging facilities are usually equipped
BED adolescents and adults using fMRI and PET, with radioisotope-generating facilities (cyclotrons)
describes the potential involvement of DA as a poten- and radiochemistry workstations for dedicated
tial neurobiological determinant of obesity and BED, radiotracer synthesis. There are many different types
and finally discusses the potential benefit of using ani- of radiotracers that can be applied to the study of
mal models to study the developmental contribution various disease states and neurobiological mecha-
of the brain DA system in obesity and BED. nisms. For the purposes of this review we will focus
on those that have been utilized in the context of
obesity and BED research. These include [15O]H2O,
Functional magnetic resonance imaging which has been used for measuring regional cerebral
Functional magnetic resonance imaging (fMRI) is blood flow (rCBF), 2-deoxy-2-[18F]fluoro-D-glucose
used to assess changes in regional brain blood flow ([18F]FDG), which has been used to measure
that are thought to be driven by the presentation regional brain glucose metabolism (BGluM), and the
of specific stimuli or in response to specific events. dopamine (DA) D2 receptor (D2R) antagonist [11C]
These blood flow-driven responses are based on the raclopride, which has been used to measure D2R
blood oxygen level-dependent (BOLD) contrast sig- availability as well as synaptic DA. A limitation for
nal, which results from a distortion of the magnetic PET is that it involves the administration of radiotrac-
field as a function of changes in the ratio between ers, which restricts its use in children and adolescents
oxygenated and deoxygenated haemoglobin in the since they are more sensitive to the adverse effects of
tissue (Pagoto et al., 2009). These contrast measures radiation. However, with the advent of small animal
are then superimposed onto a structural brain image, imaging scanners, PET provides an avenue for assess-
which allows for determining the approximate ana- ing candidate molecular mechanisms longitudinally
tomical locations of the BOLD signal responses. The in the same subject, thereby allowing for disease pro-
BOLD signal change is then correlated with the gression during various developmental stages.
stimulus or event presentation to determine func-
tional relevance of activated brain areas to the
stimulus presentation or event occurrence. The phys- Frontostriatal abnormalities in obesity
iological relevance of the BOLD signal to neuronal and BED in adults
function centres on the notion that BOLD signal
measures correlate well with local field potentials of Visual and chemosensory food stimulation as well as
neurons in certain brain regions via neurovascular food anticipation and intake preferentially affect
coupling processes (Ojemann et al., 2010). That is, frontostriatal circuitry in adults. In particular, food
the greater the activity in a given brain region, the taste increases striatal rCBF in normal-weight sub-
larger the increase in blood flow to the area with a jects (Gautier et al., 1999), while visual and olfactory
concomitant excess delivery of oxygenated haemo- exposure to food activates orbitofrontal cortex
globin, which generates the BOLD contrast. (OFC), and this activation correlates with hunger
and desire for the presented food (Wang et al., 2004).
Intriguingly, obese individuals show enhanced stri-
atal BOLD signal responses during food anticipation
Positron emission tomography
(Stice et al., 2008). Obese subjects also show
Positron emission tomography (PET) relies on the enhanced striatal and OFC BOLD signal responses
administration and subsequent detection of positron to images of food, and these responses are associated
 Dopamine in obesity and binge-eating during development 213
with susceptibility to weight gain (Rothemund et al., extensively in Mayer et al. (2009). This view is
2007; Stoeckel et al., 2008; Stice et al., 2010a). Con- supported by a recent neuroimaging study that
versely, food intake is associated with decreased stri- implicated frontostriatal circuitry in gastrointestinal
atal BOLD signal responses in obese subjects and interoceptive mechanisms (i.e. afferent signals origi-
weight gain in these subjects is associated with fur- nating in the gut during digestion) (Wang et al.,
ther decreases in striatal BOLD signal responses 2006). In this study, obese subjects with implanted
(Stice et al., 2008), suggesting that overeating is asso- gastric stimulation (IGS) devices (a clinical obesity
ciated with blunted striatal responses to food but intervention that relies on curbing feelings of hunger
elevated frontostriatal responses to food-related cues via the modulation of gastric distention (Cigaina,
(Stice et al., 2011). This differential involvement of 2004)), were scanned using [18F]FDG while the IGS
striatum and OFC in feeding and food-cues is device was either on or off. IGS resulted in increased
intriguing, given similar associations in other disease brain metabolism in striatum and OFC in these sub-
states such as drug addiction where the striatum is jects (Wang et al., 2006) and these increases were
believed to respond to reward or saliency associated paralleled by decreases in ‘emotional eating’ scores.
with the euphoric feelings of drug intake while fron- This latter observation sheds light onto another
tal circuits are associated with drug-related cues and intriguing association, namely, the effect of emotional
craving (Goldstein & Volkow, 2011). Another impor- disturbances in modulating frontostriatal circuitry
tant aspect underlying brain responses to food and subsequently obesity and BED. Emotional cir-
involves how the brain responds to food cues in cuits are thought to be intimately involved in obesity
response to the degree of hunger of the individual. A (Berridge et al., 2010) and BED, given the significant
recent study showed that during a fasted state, obese effect these circuits exert on motivation and behav-
individuals showed enhanced activation of frontal iour (Munsch et al., 2012). Indeed, a recent neu-
cortical regions in response to food cues, while after roimaging study using resting functional connectivity
these subjects were fed a meal, frontostriatal BOLD (method that uses fMRI to assess the functional con-
activation was observed (Martin et al., 2010), impli- nectivity between different brain regions during rest-
cating the striatum in post-ingestive processes and ing conditions) reported impairments in amygdala
satiation. modulation of OFC–ventral striatal connectivity in
Aside from differences in frontostriatal activation obese compared to lean women (Stoeckel et al.,
to food and food cues between obese and normal- 2009). Amygdala function is strongly implicated in
weight subjects, a gender-related component to fron- emotional regulation, particularly via its effects on
tostriatal brain activation by food has also been assigning emotional value to cues associated with a
reported. A recent study reported enhanced frontal given stimulus (Murray, 2007). Such mechanisms
cortical activation in women compared to men in are evolutionarily hard-wired for survival purposes
response to images of high-calorie foods (Killgore & which would also explain their possible involvement
Yurgelun-Todd, 2010b). In another study, male sub- in BED, which is characterized by uncontrollable,
jects exhibited an enhanced ability over females to compulsive eating often associated with emotional
suppress OFC activation in response to food presen- disturbances (Munsch et al., 2012). In sum, these
tation (Wang et al., 2009). Importantly, the enhanced findings highlight a role for frontostriatal circuitry in
OFC suppression in males was paralleled by increases food perception, ingestion, and post-ingestive physi-
in cognitive inhibition of food-related craving (Wang ological mechanisms involved in feeding and possibly
et al., 2009). These observations are intriguing, given satiety, and suggest that imbalances in this circuitry
the gender disparity in BED prevalence, with women may mediate obesity and BED.
showing increased prevalence of BED as compared
to men (Hudson et al., 2007), and the well-described
role of frontostriatal circuitry in disease states associ-
Frontostriatal abnormalities in obesity
ated with impaired inhibitory and cognitive control
in adolescence
behaviours (Blair, 2010) (BED is generally regarded
as a disease characterized by abnormalities in self- Adolescence is generally viewed as a critical transi-
control and inability to exert inhibitory behaviours) tional time period during development, where chil-
(Harrison et al., 2010). dren begin to learn how to develop self-regulatory
Abnormalities in OFC have also been observed in control behaviours that advance their ability to orga-
obsessive compulsive (Aouizerate et al., 2004) and nize thoughts, ideas and emotions which are crucial
hoarding disorders (Tolin et al., 2009), which may for their success later in life (Posner & Rothbart,
have root in primeval ‘hard-wired’ behaviours impor- 2009). Neuroimaging studies in children and adoles-
tant for feeding and survival. Indeed, OFC and stri- cents are challenging primarily due to parental safety
atum show enhanced activation in response to concerns, children’s apprehension towards experi-
post-ingestive physiological processes as reviewed mental equipment, impaired ability of children in
214 M. Michaelides et al.
adhering to study guidelines, as well as difficulty in well as non-food stimuli and that impairments in
discerning child brain anatomy (Ketonen et al., frontostriatal circuitry observed in adults with obesity
2008). For these reasons, neuroimaging studies in and BED may arise in childhood/adolescence, or per-
children and adolescents have not been conducted to haps earlier as part of a genetic predisposition to such
the degree done in adults. Nevertheless, the few neu- imbalances. Indeed, frontostriatal circuit imbalances
roimaging studies that have been conducted to date have been observed in multiple psychopathologies in
have reported striking similarities in brain activation children (Tourette’s, ADHD, obsessive–compulsive
to food and food cues in adults and adolescents. disorder, anorexia and bulimia nervosa) where inhib-
Similar to adults, food images in hungry children itory control-related behaviours are central to the
and adolescents preferentially activate frontal corti- psychopathology. These studies are reviewed exten-
cal regions, including OFC (Holsen et al., 2005). In sively in Marsh et al. (2009) and therefore are beyond
fact, a study that directly compared brain responses the scope of this review.
to food images in adolescents and adults found In sum, when evaluating brain responses to food
significant activation in OFC and striatum in and food cues in obese adults and adolescents, strik-
both groups, and intriguingly, adolescents showed ing similarities and important contrasts emerge.
enhanced activation in frontostriatal regions when Obese adults show increased frontal and striatal
exposed to high-calorie food images and preferential responses to food cues but decreased striatal
OFC activation when exposed to low-calorie food responses in response to feeding. Like adults, obese
images (Killgore & Yurgelun-Todd, 2005). This dif- adolescents show decreased striatal responses to food
ferential pattern of activation highlights developmen- cues after feeding. However, unlike adults, obese
tally mediated regulation of brain activation to food adolescents show increased responses to food cues
that may occur in the transition from adolescence to in frontal but not striatal regions. This contrast high-
adulthood and suggests that impairments in deve- lights frontostriatal circuitry as potential mediators
lopment-specific mechanisms may underlie psycho- of obesity vulnerability that can arise early in child-
pathologies that arise during this transition. hood and adolescence, and specifically the striatum
Neuroimaging studies conducted in obese/over- as a potential predictor of obesity development
weight and normal-weight children assessed BOLD into adulthood. This view agrees with the well-
activation during the viewing of food images and documented role of the striatum in mediating habit-
found enhanced activation in frontal cortical regions ual reinforcement behaviour via changes in synaptic
and decreased activation in striatum in obese subjects plasticity of its medium spiny neurons and suggests
(Davids et al., 2010). Another study examined pre- that this region serves a decisive role in escalation of
and post-meal brain activation during exposure to overweight and obesity during the transition from
food images in obese and normal-weight children and adolescence to adulthood. An important caveat to
found that obese children had enhanced activation in this interpretation is the difficulty of making valid
frontal cortical regions at both pre- and post-meal comparisons between studies assessing brain
scanning sessions compared to normal-weight chil- responses to food in adults and adolescents, since
dren (Bruce et al., 2010). Interestingly, enhanced ideal comparisons would require using the same
striatal activity was observed in normal-weight but imaging paradigms and experimental conditions.
not in obese children during pre-meal sessions com- This highlights the importance of using the same
pared to post-meal sessions. This is an intriguing experimental design, and future studies should take
observation, given the aforementioned reports in such considerations into account so that these com-
adults of striatal activation and its association to post- parisons can be objectively tested.
ingestive mechanisms and satiety. This differential
striatal activation before and after meal consumption
may underlie decreased sensitivity in obese children
Dopamine involvement in obesity and BED
to satiety-specific post-ingestive mechanisms and
requires further investigation. Finally, a more recent The catecholamine DA is a highly conserved neu-
study showed that adolescents at high risk for obesity rotransmitter that has been implicated in feeding
showed enhanced activation in frontostriatal regions and obesity (Volkow et al., 2011). In the brain, DA
in response to both food intake and monetary reward is produced in specific neurons, which originate in
(Stice et al., 2011). This study highlights another the midbrain and project to the striatum as well as
important aspect of frontostriatal circuitry, namely frontal cortex. These anatomical features of DA cir-
that imbalances in this circuitry are not specific to cuits make this neurotransmitter a very attractive
food but can also affect other types of ‘rewarding’ target for studies that focus on elucidating involve-
stimuli. This observation is particularly important ment of frontostriatal circuitry in obesity and BED.
because it highlights that frontostriatal activation in In particular, brain DA function has been impli-
adolescents, like adults, is associated with food as cated in the regulation of cognitive processes (atten-
 Dopamine in obesity and binge-eating during development 215
tion, memory, motivation, reward), behaviour, implicates frontostriatal circuitry in obesity and
physiology as well as metabolism and this diverse perhaps BED. Finally, striatal DA was positively
functional profile is attributed in part to the selec- correlated with restraint behaviour during food pre-
tive regional distribution of its receptors. The D2R sentation (Volkow et al., 2003), a finding which fur-
is of particular interest to obesity and BED research ther implicates DA-specific frontostriatal mechanisms
since it is densely expressed in the striatum, drugs in obesity and BED via its potential regulation of
that block D2R induce weight gain (Baptista, 1999) inhibitory control, saliency attribution and reward
and D2Rs have been implicated in both obesity and mechanisms.
BED (de Weijer et al., 2011; Wang et al., 2001,
2011). In particular, morbidly obese individuals are
characterized by significantly lower striatal D2R
Translational neuroimaging for assessing
(de Weijer et al., 2011; Wang et al., 2001) (Fig. 1),
developmental contributions to frontostriatal
and food presentation elicits greater increases in striatal
impairments in obesity and BED
DA in obese BED subjects compared to non-BED
obese controls (Wang et al., 2011). Intriguingly, the PET in children and adolescents is limited due to
increases in striatal DA in obese BED subjects were radiation exposure, and therefore PET studies to
found to be significantly correlated with binge- assess DA involvement in BED in children and ado-
eating scores (Wang et al., 2011). In fact, similar cor- lescents have not been undertaken. As DA-related
relations have been observed in normal subjects as functions on feeding and obesity observed in humans
well, where increases in striatal DA correlated with have been shown to occur in rodents, an alternative
self-reports of hunger and desire to consume food approach to understand potential involvement of
(Volkow et al., 2002). Finally, subjects with genetic DA in obesity and BED during childhood and ado-
D2R mutations associated with reduced D2R signal- lescence is the use of rodent models that partly
ling showed decreased BOLD signal responses in reflect the human condition. Indeed, the recent
striatum and OFC in response to imagined intake of advent of small animal fMRI and PET scanners and
food stimuli, and these responses were associated the development of sophisticated imaging, image
with future weight gain (Stice et al., 2010). processing and analysis techniques offer a valuable
These findings imply that striatal DA is involved experimental strategy to assess the role of specific
in the motivation to seek and consume food and molecular mechanisms in disease and behaviour
suggest that imbalances in striatal DA signalling with strong experimental control and translational
may mediate susceptibility to obesity and BED. potential (Benveniste & Blackband, 2006). Using
Interestingly, striatal D2R in obese subjects signifi- these imaging methodologies, neural and molecular
cantly correlated with brain metabolism in frontal correlates of disease and related behaviours in
cortical regions (Volkow et al., 2008), which further humans can be subsequently studied using animal

Figure 1. Obesity-related deficits in striatal dopamine D2 receptors (D2R) are conserved across species: (A) representative positron
emission tomography brain scans and (B) Bmax/Kd values of D2R binding in lean and obese humans (Wang et al., 2001) and rats (Thanos
et al., 2008).
216 M. Michaelides et al.
models where experimental factors as well as genetic replicated the decreases in striatal D2R previously
and environmental components relevant to the observed in obese humans (Wang et al., 2001). Spe-
disease or behaviour being studied can be manipu- cifically, genetically obese rats scanned with [11C]
lated and controlled. This type of experimental strat- raclopride showed lower striatal D2R levels com-
egy allows for the estimation of cause–effect pared to lean controls (Thanos et al., 2008b) (Fig. 1)
relationships. In turn, results from animal studies and in a more recent study, striatal D2R levels in
can be translated to humans and eventually lead to normal-weight rats predicted future measures of
therapeutic interventions. One particularly relevant body weight (Michaelides et al., 2012). That is, rats
feature of small animal imaging methods such as with the lowest striatal D2R levels showed the high-
fMRI and PET is that these techniques are generally est body weight 2 months later, while rats with the
non-invasive, reproducible, and allow for longitudi- highest D2R levels showed the lowest body weight.
nal assessment of regional brain activity over time These recent findings suggest that striatal D2R are
and during discrete developmental time periods. involved in body weight regulation and that inherent
This makes small animal imaging a powerful research D2R deficits contribute to increased weight gain and
tool for elucidating neural and molecular correlates eventually obesity. In sum, the ability to study and
associated with development in obesity and BED model human obesity and BED in animals and to
animal models. study these models with PET will allow for longitu-
As of now fMRI experiments in rodents (Schmidt dinal assessment of brain activity and striatal DA in
et al., 2006; Tenney et al., 2004) have not assessed the same animal over time and this, in turn, would
the effects of food stimulation on brain regional acti- allow one to study these models at selective develop-
vation in the context of obesity or BED. This is mental time points and importantly, obtain molecu-
because for fMRI studies the animals need to remain lar insight into the developmental pathophysiology
motionless, which requires the use of anaesthesia, associated with obesity and BED.
which affects the responses to stimulus presentation
and thus limits the ability to study cognitive pro-
cesses. Conversely, PET imaging in rodents has reca- Conclusions
pitulated some of the clinical observations made in
The findings and views presented in this review are
obese and BED populations, and for certain radiotrac-
consistent with the notion that obesity and BED may
ers such as [18F]FDG (used to measure brain glu-
arise in adolescence, in response to deficits in fron-
cose metabolism) and [11C]raclopride (used to
tostriatal circuitry and related DA mechanisms.
measure D2R binding potential) the measurements
These mechanisms are involved in mediating, among
can be made in awake animals. One PET study done
other things, reward and self-regulatory processes.
in genetically obese rats (leptin-receptor deficient)
Interestingly, obese subjects and subjects with BED
examined the brain metabolic responses to food
are also characterized by uniquely altered self-
stimuli in awake rats comparing metabolism in the
regulatory capacity. These associations have recently
absence and in the presence of a bacon scent (Thanos
been observed in obese/overweight adolescents, sug-
et al., 2008a). This study found that while bacon
gesting that obesity and BED onset may be due to
scent decreased glucose metabolism (marker of activ-
developmental factors. In the future, technological
ity) in frontal cortex in both obese and lean rats, the
advancements that will allow the safe and sensitive
decreases were significantly greater in the obese
assessment of molecular profiles in children and ado-
group. This study illustrates the potential of small
lescents will enable direct assessment of the contribu-
animal PET for assessing the effects of exposure to
tion of DA in BED and obesity during childhood and
food stimuli on brain activity in rodent models of
adolescence. In addition, advanced genetic techniques
obesity including those with specific genetic manipu-
will allow us to expand our understanding of how
lations that are relevant to human obesity (i.e. leptin
genes associated with obese and BED phenotypes in
signalling). Indeed, leptin regulation of frontostriatal
humans affect brain function throughout the various
responses to food cues has been demonstrated in
developmental time periods. Finally, small animal
humans with fMRI (Baicy et al., 2007; Farooqi et al.,
imaging and rodent models of obesity and BED may
2007), providing evidence that this peptide regulates
help to obtain an understanding of developmentally
cognitive processes associated with food perception
mediated factors involved in obesity and BED.
and thus individuals with leptin imbalances (obese
individuals are generally leptin-resistant) may be
prone to such deficits. Further evidence of the sig- Declaration of interest: Brain imaging studies were
nificance of small animal imaging to obesity research carried out at Brookhaven National Laboratory with
are recent findings reporting similar deficits in striatal infrastructure support from the US Department of
D2R in obese rats as has been previously reported in Energy OBER (DE-ACO2 - 76CH00016) and under
humans. In particular, rodent PET experiments have support in part by the National Institutes of Health:
 Dopamine in obesity and binge-eating during development 217
5T32DA007135 (M. Michaelides), Z01AA000550 Goldstein, R.Z. & Volkow, N.D. (2011). Dysfunction of the pre-
(N. Volkow) and R01DA7092 (G.-J. Wang), frontal cortex in addiction: Neuroimaging findings and clinical
implications. Nature Reviews. Neuroscience, 12, 652–669.
R01DA00280 (G.-J. Wang), R01MH66961 (G.J. Harrison, A., O’Brien, N., Lopez, C. & Treasure, J. (2010).
Wang). The authors alone are responsible for the Sensitivity to reward and punishment in eating disorders.
content and writing of the paper. Psychiatry Research, 177, 1–11.
Holsen, L.M., Zarcone, J.R., Thompson, T.I., Brooks, W.M.,
Anderson, M.F., Ahluwalia, J.S., ...Savage, C.R. (2005). Neural
mechanisms underlying food motivation in children and ado-
References lescents. Neuroimage, 27, 669–676.
Aouizerate, B., Guehl, D., Cuny, E., Rougier, A., Bioulac, B., Hudson, J.I., Hiripi, E., Pope, H.G., Jr & Kessler, R.C. (2007).
Tignol, J. & Burbaud, P. (2004). Pathophysiology of obsessive– The prevalence and correlates of eating disorders in the National
compulsive disorder: A necessary link between phenomenology, Comorbidity Survey Replication. Biological Psychiatry, 61,
neuropsychology, imagery and physiology. Progress in Neurobiology, 348–358.
72, 195–221. Ketonen, L.M. & Valanne, L. (2008). Neuroimaging of pediatric
Baicy, K., London, E.D., Monterosso, J., Wong, M.L., Delibasi, diseases. Seminars in Neurology, 28, 558–569.
T., Sharma, A. & Licinio, J. (2007). Leptin replacement alters Killgore, W.D. & Yurgelun-Todd, D.A. (2005). Developmental
brain response to food cues in genetically leptin-deficient adults. changes in the functional brain responses of adolescents to
Proceedings of the National Academy of Sciences of the United States images of high and low-calorie foods. Developmental Psychobiology,
of America, 104, 18276–18279. 47, 377–397.
Baptista, T. (1999). Body weight gain induced by antipsychotic Killgore, W.D. & Yurgelun-Todd, D.A. (2010b). Sex differences in
drugs: Mechanisms and management. Acta Psychiatrica Scandi- cerebral responses to images of high versus low-calorie food.
navica, 100, 3–16. Neuroreport, 21, 354–358.
Benveniste, H. & Blackband, S.J. (2006). Translational neuro- Marsh, R., Maia, T.V. & Peterson, B.S. (2009). Functional distur-
science and magnetic-resonance microscopy. Lancet Neurology, bances within frontostriatal circuits across multiple child-
5, 536–544. hood psychopathologies. American Journal of Psychiatry, 166,
Berridge, K.C., Ho, C.Y., Richard, J.M. & DiFeliceantonio, A.G. 664–674.
(2010). The tempted brain eats: Pleasure and desire circuits in Martin, L.E., Holsen, L.M., Chambers, R.J., Bruce, A.S.,
obesity and eating disorders. Brain Research, 1350, 43–64. Brooks, W.M., Zarcone, J.R., ...Savage, C.R. (2010). Neural
Blair, R.J. (2010). Neuroimaging of psychopathy and antisocial mechanisms associated with food motivation in obese and
behavior: A targeted review. Current Psychiatry Reports, 12, healthy weight adults. Obesity, 18, 254–260.
76–82. Mayer, E.A., Aziz, Q., Coen, S., Kern, M., Labus, J.S., Lane, R.,
Bruce, A.S., Holsen, L.M., Chambers, R.J., Martin, L.E., Brooks, ...Tracey, I. (2009). Brain imaging approaches to the study
W.M., Zarcone, J.R., ...Savage, C.R. (2010). Obese children of functional GI disorders: A Rome working team report.
show hyperactivation to food pictures in brain networks linked Neurogastroenterology and Motility, 21, 579–596.
to motivation, reward and cognitive control. International Michaelides, M., Thanos, P.K., Kim, R., Cho, J., Ananth, M.,
Journal of Obesity, 34, 1494–1500. Wang, G.J. & Volkow, N.D. (2012). PET imaging predicts
Cigaina, V. (2004). Long-term follow-up of gastric stimulation future body weight and cocaine preference. Neuroimage, 59,
for obesity: The Mestre 8-year experience. Obesity Surgery, 1508–1513.
14, S14–22. Munsch, S., Meyer, A.H., Quartier, V. & Wilhelm, F.H. (2012).
Davids, S., Lauffer, H., Thoms, K., Jagdhuhn, M., Hirschfeld, H., Binge eating in binge eating disorder: A break-down of emotion
Domin, M., ...Lotze, M. (2010). Increased dorsolateral pre- regulatory process? Psychiatry Research, 195, 118–124.
frontal cortex activation in obese children during observation Murray, E.A. (2007). The amygdala, reward and emotion. Trends
of food stimuli. International Journal of Obesity, 34, 94–104. in Cognitive Sciences, 11, 489–497.
Davis, C. & Carter, J.C. (2009). Compulsive overeating as an Ogden, C.L., Carroll, M.D., Curtin, L.R., Lamb, M.M. & Flegal,
addiction disorder. A review of theory and evidence. Appetite, K.M. (2010). Prevalence of high body mass index in US
53, 1–8. children and adolescents, 2007–2008. Journal of the American
de Weijer, B.A., van de Giessen, E., van Amelsvoort, T.A., Boot, Medical Association, 303, 242–249.
E., Braak, B., Janssen, I.M., ...Booij, J. (2011). Lower striatal Ojemann, G.A., Corina, D.P., Corrigan, N., Schoenfield-
dopamine D2/3 receptor availability in obese compared with McNeill, J., Poliakov, A., Zamora, L. & Zanos, S. (2010).
non-obese subjects. European Journal of Nuclear Medicine and Neuronal correlates of functional magnetic resonance imaging
Molecular Imaging Research, 1, 37. in human temporal cortex. Brain, 133, 46–59.
Faith, M.S., Butryn, M., Wadden, T.A., Fabricatore, A., Nguyen, Pagoto, S.L., Curtin, C., Lemon, S.C., Bandini, L.G., Schneider,
A.M. & Heymsfield, S.B. (2011). Evidence for prospective asso- K.L., Bodenlos, J.S. & Ma,Y. (2009). Association between adult
ciations among depression and obesity in population-based attention deficit/hyperactivity disorder and obesity in the US
studies. Obesity Reviews, 12, e438–453. population. Obesity, 17, 539–544.
Farooqi, I.S., Bullmore, E., Keogh, J., Gillard, J., O’Rahilly, S. Posner, M.I. & Rothbart, M.K. (2009). Toward a physical basis
& Fletcher, P.C. (2007). Leptin regulates striatal regions and of attention and self regulation. Physics of Life Reviews, 6,
human eating behavior. Science, 317, 1355. 103–120.
Flegal, K.M., Carroll, M.D., Ogden, C.L. & Curtin, L.R. Rothemund, Y., Preuschhof, C., Bohner, G., Bauknecht, H.C.,
(2010). Prevalence and trends in obesity among US adults, Klingebiel, R., Flor, H., Klapp, B.F. (2007). Differential activa-
1999–2008. Journal of the American Medical Association, 303, tion of the dorsal striatum by high-calorie visual food stimuli
235–241. in obese individuals. Neuroimage, 37,410–421.
Gautier, J.F., Chen, K., Uecker, A., Bandy, D., Frost, J., Salbe, Schmidt, K.F., Febo, M., Shen, Q., Luo, F., Sicard, K.M.,
A.D., ...Tataranni, P.A. (1999). Regions of the human brain Ferris, C.F., ...Duong, T.Q. (2006). Hemodynamic and meta-
affected during a liquid-meal taste perception in the fasting bolic changes induced by cocaine in anesthetized rat observed
state: A positron emission tomography study. American Journal with multimodal functional MRI. Psychopharmacology, 185,
of Clinical Nutrition, 70, 806–810. 479–486.
218 M. Michaelides et al.
Stice E., Spoor S., Bohon, C., Veldhuizen, M.G., Small, D.M. Volkow, N.D., Wang, G.J. & Baler, R.D. (2011). Reward, dopamine
(2008). Relation of reward from food intake and anticipated and the control of food intake: Implications for obesity. Trends
food intake to obesity: a functional magnetic resonance imaging in Cognitive Sciences, 15, 37–46.
study. J Abnorm Psychol, 117,924–935. Volkow, N.D., Wang, G.J., Fowler, J.S., Logan, J., Jayne, M.,
Stice, E., Yokum, S., Bohon, C., Marti, N. & Smolen, A. (2010). Franceschi, D., ...Pappas, N. (2002). ‘Nonhedonic’ food
Reward circuitry responsivity to food predicts future increases motivation in humans involves dopamine in the dorsal stria-
in body mass: Moderating effects of DRD2 and DRD4. tum and methylphenidate amplifies this effect. Synapse, 44,
Neuroimage, 50, 1618–1625. 175–180.
Stice E., Yokum, S., Blum K., Bohon, C. (2010a). Weight gain is Volkow, N.D., Wang, G.J., Maynard, L., Jayne, M., Fowler, J.S.,
associated with reduced striatal response to palatable food. Zhu, W., ...Pappas, N. (2003). Brain dopamine is associated
J Neurosci, 30,13105–13109. with eating behaviors in humans. International Journal of Eating
Stice, E., Yokum, S., Burger, K.S., Epstein, L.H. & Small, D.M. Disorders, 33, 136–142.
(2011). Youth at risk for obesity show greater activation of stri- Volkow, N.D., Wang, G.J., Telang, F., Fowler, J.S., Thanos, P.K.,
atal and somatosensory regions to food. Journal of Neuroscience, Logan, J., ...Pradhan, K. (2008). Low dopamine striatal D2
31, 4360–4366. receptors are associated with prefrontal metabolism in
Stoeckel, LE., Weller, RE., Cook, EW., 3rd, Twieg, D.B., obese subjects: Possible contributing factors. Neuroimage, 42,
Knowlton, R.,C., Cox, J.E. (2008). Widespread reward-system 1537–1543.
activation in obese women in response to pictures of high- Wang, G.J., Geliebter, A., Volkow, N.D., Telang, F.W., Logan, J.,
calorie foods. Neuroimage 41:636–647. Jayne, M.C., ...Fowler, J.S. (2011). Enhanced striatal dopamine
Stoeckel, L.E., Kim, J., Weller, R.E., Cox, J.E., Cook, E.W., III & release during food stimulation in binge eating disorder.
Horwitz, B. (2009). Effective connectivity of a reward network Obesity, 19, 1601–1608.
in obese women. Brain Research Bulletin, 79, 388–395. Wang, G.J., Volkow, N.D., Logan, J., Pappas, N.R., Wong, C.T.,
Tenney, J.R., Duong, T.Q., King, J.A. & Ferris, C.F. (2004). fMRI Zhu, W., ...Fowler, J.S. (2001). Brain dopamine and obesity.
of brain activation in a genetic rat model of absence seizures. Lancet, 357, 354–357.
Epilepsia, 45, 576–582. Wang, G.J., Volkow, N.D., Telang, F., Jayne, M., Ma, J., Rao, M.,
Thanos, P.K., Michaelides, M., Gispert, J.D., Pascau, J., ...Fowler, J.S. (2004). Exposure to appetitive food stim-
Soto-Montenegro, M.L., Desco, M., ...Volkow, N.D. (2008). uli markedly activates the human brain. Neuroimage, 21,
Differences in response to food stimuli in a rat model of obesity: 1790–1797.
In-vivo assessment of brain glucose metabolism. International Wang, G.J., Volkow, N.D., Telang, F., Jayne, M., Ma, Y.,
Journal of Obesity, 32, 1171–1179. Pradhan, K., ...Fowler, J.S. (2009). Evidence of gender differ-
Thanos, P.K., Michaelides, M., Piyis, Y.K., Wang, G.J. & Volkow, ences in the ability to inhibit brain activation elicited by food
N.D. (2008). Food restriction markedly increases dopamine D2 stimulation. Proceedings of the National Academy of Sciences of the
receptor (D2R) in a rat model of obesity as assessed with in-vivo United States of America, 106, 1249–1254.
muPET imaging ([11C] raclopride) and in-vitro ([3H] spiper- Wang, G.J., Yang, J., Volkow, N.D., Telang, F., Ma, Y.,
one) autoradiography. Synapse, 62, 50–61. Zhu, W., ...Fowler, J.S. (2006). Gastric stimulation in
Tolin, D.F., Kiehl, K.A., Worhunsky, P., Book, G.A. & Maltby, N. obese subjects activates the hippocampus and other regions
(2009). An exploratory study of the neural mechanisms of deci- involved in brain reward circuitry. Proceedings of the National
sion making in compulsive hoarding. Psychological Medicine, 39, Academy of Sciences of the United States of America, 103,
325–336. 15641–15645.