Acta Psychiatr Scand 2015: 131: 244–255 © 2014 John Wiley & Sons A/S.

John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
All rights reserved ACTA PSYCHIATRICA SCANDINAVICA
DOI: 10.1111/acps.12335

Review
The neurobiology of eating disorders—a
clinical perspective
von Hausswolff-Juhlin Y, Brooks SJ, Larsson M. The neurobiology of Y. von Hausswolff-Juhlin1,2,
eating disorders—a clinical perspective. S. J. Brooks1,3, M. Larsson2
1
Center for Psychiatry Research, Karolinska Institute,
Objective: To provide a neurobiological basis of eating disorders for 2
Stockholm Centre for Eating Disorders, Stockholm,
clinicians and to enlighten how comparing neurobiology and eating Sweden and 3Department of Psychiatry, Groote Schur
disorders with neurobiology of other psychiatric illnesses can improve Hospital, Cap Town, South Africa
treatment protocols.
Method: A selective review on the neurobiology of eating disorders.
The article focuses on clinical research on humans with consideration of
the anatomical, neural, and molecular basis of eating disorders.
Results: The neurobiology of people with eating disorders is altered.
Many of the neurobiological regions, receptors, and chemical substrates Key words: comorbidity; eating disorder; neurobiology;
that are affected in other mental illnesses also play an important role in neuroimaging; psychopharmacology
eating disorders. More knowledge about the neurobiological overlap Yvonne von Hausswolff-Juhlin, Stockholm Center for
between eating disorders and other psychiatric populations will help Eating Disorders, Wollmar Yxkullsgatan 25, 118 50
when developing treatment protocols not the least regarding that Stockholm, Sweden.
E-mail: yvonne.vonhausswolff-juhlin@ki.se
comorbidity is common in patients with EDs.
Conclusion: Knowledge about the underlying neurobiology of eating
disorders will improve treatment intervention and will benefit from
comparisons with other mental illnesses and their treatments. Accepted for publication August 18, 2014

Summations
• Eating disorders are illnesses which are strongly linked to neurobiological alterations.
• Knowledge about the neurobiology of eating disorders and other illnesses and cognitive deficits will
improve treatment intervention.

Considerations
• This is a selective review not a full systematic review.
• The studies of neurobiology of eating disorders are often small and seldom randomized.
• The neuroimaging studies were done without taking the patients psychiatric comorbidity into account.

treatment of EDs is poor as relapse is high, espe-

Introduction
Eating disorders are severe psychiatric diseases,
which affect up to 7–10% of the female popula-
tion with a massive cost to the health care system
(1–5). More females than males are affected, with
an onset in the early teens for Anorexia Nervosa
(AN) and late teens for Bulimia Nervosa (BN)
(6). AN has among the highest mortality rate
in the mental illnesses not least owing to the
elevated risk of suicide but also because of physi-
cal complications (7, 8). The effectiveness of
cially when it comes to treating adults with AN,
which suggests that further research is needed to
understand the underlying causes of the develop-
ment and maintenance of these disorders to be
able to improve treatment protocols. Thus, the
neurobiological substrates of disordered eating
are one important aspect to consider and there-
fore this article focuses on some of the neurobio-
logical evidence associated with EDs, which may
inform clinicians and help to progress the evolu-
tion of treatment.

244

Etiology
Many different theories have addressed the etiol-
ogy of EDs focusing mainly on the physical, social,
family structure, and neurobiological links (9–11).
Contempory studies are now beginning to view the
etiologies for EDs as multifactorial (12). Several
predisposing factors are, however, evident such as:
female sex giving a specific interest to the endocri-
nological system given that most EDs start to
develop in puberty; family history of EDs suggest-
ing a genetic predisposition, especially to account
for cognitive deficits that often occur before the
onset of disordered eating behaviour; perfectionis-
tic personality and low self-esteem also linked to
inheritable risk factors and a risk factor for depres-
sion (13–17).
Diagnoses
Current nosologic classifications of dysfunctional
eating behaviour in the DSM 5 list the following
diagnoses: Pica, Rumination disorder, Avoidant/
restrictive food intake disorder, AN, BN, binge
eating disorder (BED, a’binge’ is classified as eat-
ing large amounts of food over short periods of
time), Other Specified Feeding or Eating disorder
and Unspecified Feeding or Eating disorder. How-
ever, those with a history of ED may pass through
several ED diagnoses over time, ranging between
food restriction and binge eating behaviour (18). It
is also of note that the criteria for EDs will likely
change dramatically in the future as well as other
psychiatric diagnoses, to reflect a shift from cate-
gorical diagnoses to transdiagnostic spectrum
considerations (19, 20). For example, the newly
revised DSM diagnostic system was very recently
subject to two rather critical responses from the
British Psychological Society (BPS)’s Division of
Clinical Psychology (DCP) and via the National
Institute of Mental Health (NIMH)’s Research
Document (RDoc). Both the BPS and NIMH
suggest that the neurobiological model of psychiat-
ric illness should concur with a transdiagnostic,
sociobiological model, rather than adhering strictly
to rigid criteria, to improve clinical treatment pro-
vision.
Nevertheless, despite the current and continuing
debate regarding diagnosis issues with regard to
EDs, this article will focus on the neurobiology of
the three main ED diagnoses: AN, BN, and BED.
The focus on these three diagnoses as they are the
most studied in research, particularly studies of a
neurobiological nature and, besides Other Speci-
fied Feeding or Eating disorder and Unspecified
Feeding or Eating disorder that incorporates
Neurobiology of eating disorders
components of the three, the most observed in
clinic practice. Thus, a summary from how they
are currently presented in the DSM 5 published in
May 2013; AN—characterized by a restriction of
energy intake, a significantly low body weight and
an intense fear of becoming fat although the
patient is underweight; BN—characterized by
recurrent episodes of binge eating and inappropri-
ate compensatory behaviours to prevent weight
gain; BED—characterized by recurrent episodes of
binge eating but no compensatory behaviours.
Although a focus on these three diagnoses there
are not in the article neither a clear distinction
between them neither specific chapters about them
in the result section due to reasons mentioned
above about that one ED often changes into
another.
Somatic complications
All EDs are psychiatric diseases inflicting both
mental and, more than most other psychiatric ill-
nesses, somatic processes with severe, often fatal
complications. The somatic complications of AN
affect all organ systems (21). Severe malnutrition
over long periods may also result in osteoporosis
(22). The somatic complications in BN are simi-
lar to those in AN, but to a lesser extent as a
consequence of less starvation and malnutrition.
However, it is more common that patients with
BN suffer from dental health problems and hypo-
kalemic problems owing to their binge purge
cycles (23, 24). Given that BED is often associ-
ated with overweight or obesity, the complica-
tions in BED differ somewhat from the other
EDs. Along with obesity, there follows other
metabolic and cardiovascular complications and
a higher incidence of metabolic syndrome, with
core symptoms such as hypertension and insulin
resistance, when compared with those suffering
from other EDs (25, 26).
Treatment of EDs
Early intervention appears to be the most effective
treatment for those with EDs, and there is some
evidence that family therapy has the most robust
success rate when treating children and adolescents
(27). One difficulty, however, with treating patients
with EDs is that a long period of time has often
elapsed before the patient comes to treatment and
so the neural complications are likely to be embed-
ded. For example, those who are diagnosed with
BN spend approximately 8.3 years with an episode
before seeking treatment (28). For AN in adults,
there is no consistent evidence to date for an
245
Hausswolff-Juhlin et al.
effective treatment of choice. For BN sufferers of
all ages, there is evidence to show that CBT and
Interpersonal therapy (ITP) has beneficial effects
(29). When it comes to using pharmacological
treatment for patients with EDs, the effectiveness
for treatment of AN is poor. A task force on ED of
the World Federation of Societies of Biology
concluded a grade B evidence (limited positive evi-
dence from controlled studies) for using olanza-
pine, a low-dose anti-psychotic for weight gain.
Whereas for the antipsychotic drugs quetiapine
and risperdone a grade C evidence (positive evi-
dence from uncontrolled studies) was given, but
there was no conclusive evidence for treating
patients with antidepressant medication (30).
When treating BN with pharmacology, there is
strong evidence (grade A) that the use of the
selective serotonin reuptake inhibitor (SSRI) Fluo-
xetine, an antidepressant, in a high dose gives good
effect and decreases binge eating. Furthermore,
also Topiramate and Tricyclic antidepressants have
grade A evidence when treating BN. The effect
seems to be reduced episodes of binge eating (31).
While there are some excellent contemporary
reviews of the neurobiology of EDs (13), these pre-
vious reviews are mainly research-oriented and
therefore not necessarily accessible to clinicians.
Aims of the study
Our first aim for this review is to appraise selected
aspects of the neurobiology of EDs from a clinical
perspective to make neurobiological knowledge
more accessible and of interest to ED clinicians.
Furthermore, against the background of treatment
difficulties in EDs and a high psychiatric comor-
bidity, we aim to enlighten clinicians on how
knowledge of the neurobiology of EDs can help
formulate better treatment protocols by discussing
the value of comparing the neurobiology of the
patient with EDs with the neurobiology of other
psychiatric illnesses especially taking into regard
psychiatric comorbidity.
Material and methods
This article highlights the neurobiology of
EDs from a clinical perspective through articles
selected from MEDLINE and PubMed. It is a
selective review from a clinical viewpoint, provid-
ing clinicians with neurobiological knowledge.
Important, more in-depth reviews in the area
have been examined and cited. This article focuses
on clinical research carried out in humans. We
have used the search words comorbidity, EDs,
neurobiology, neuropsychology, neuroimaging,
246
psychopharmacology, AN, BN and BED. We have
focused on articles from the last 25 years. The first
two sections of the results focuses on psychiatric
and somatic comorbidity. Following this, we sum-
marize the neuropsychological changes of the main
EDs to better understand the neurobiological
changes. The results overall focus on AN and BN
as most studies are conducted on these diagnoses.
However, we have deliberately not made any
specific chapters about the different EDs in the sec-
tions because a person with an ED often experi-
ences a myriad of symptoms over the course of the
illness in a transdiagnostic fashion and because
one ED often changes into another (18). First, the
article focuses on the neurobiological structures,
second, on different neuronal systems encompass-
ing the neuropeptides, and, finally, proposing
hypotheses regarding how to best put neurobiolog-
ical knowledge into use when treating a patient
with an ED.
Results
EDs and psychiatric comorbidity
Psychiatric comorbidity is common in patients
with EDs, and may indicate broader neurobiologi-
cal susceptibilities that underlie common psychiat-
ric complaints. Many studies have reported a
prevalence of other psychiatric conditions, up to
80% (32–34). The most common diagnoses are
anxiety disorder and depression (35). Specifically,
obsessive compulsive disorder (OCD) and social
phobia are the most common anxiety disorders
which may give an inclination about a predisposi-
tion to ‘excessively ruminate’ overall for patients
with EDs (32, 36–38). Temperamental traits that
may underlie the potential predispositions outlined
above, link EDs to other psychiatric populations,
including: cognitive persistence, which is highest
for AN, and novelty seeking, which is highest for
BN (39). Furthermore, symptoms akin to ADHD
and Asperger’s disorder can often also be observed
in patients with EDs (40, 41). Others suggest that
EDs have commonalities with schizophrenia, in
terms of persecutory delusions, and distortion
regarding sense of self, bipolar disorder, and sub-
stance abuse (42) particularly in males (43). More-
over, in recent years, the addiction model of
obesity and binge eating has linked EDs to sub-
stance abuse and drug addiction (44).
EDs and somatic comorbidity
Somatic comorbidity is also a factor to be consid-
ered when treating patients with EDs and it is

helpful to know more about this issue when treat-
ing patients with specific somatic diseases with
known risks for developing EDs. One area of
importance is endocrinological disease, which can
be associated with EDs. For example, patients with
type 1 diabetes mellitus have a higher risk for
developing EDs than healthy controls (45). Addi-
tionally, the comorbidity between specific gastroin-
testinal diseases and EDs has also been shown; one
example is AN and celiac disease (46). Further-
more, a high comorbidity exists between Polycystic
Ovary Syndrome (PCO) and BN, most probably
partly owing to insulin resistance and increased
hunger (47). Furthermore, it is also important to
exclude lesions of the hypothalamus and other
related areas connected with appetite and eating
from cancer that can lead to weight loss before
treatment of an ED. The hypothalamus, particu-
larly a region known as the paraventricular
nucleus, is highly implicated in the regulation of
feeding. Thus, endocrine disturbances associated
with the hypothalamic-pituitary-adrenal (HPA)
axis could easily be mistaken for an ED (48).
The neuropsychology of EDs and important circuits
The first study of the staving brain was conducted
seventy years ago when Keys et al. described
severe changes including impaired concentration,
alertness, comprehension, and judgment, difficulty
in making decisions, increased irritability, and
depression. The study was conducted on healthy
men recruited for military service, and the purpose
was to study the effects of starvation on brain
function in a military situation. Thus, the recruits
were put into a situation where they starved, and
the neuropsychological changes, also seen in
patients with EDs, was evident (49). Later studies
have repeatedly shown that patients with AN have
specific thinking styles with characteristics of see-
ing things in detail, perfectionism and being inflexi-
ble. Studies show difficulties in ‘set shifting’—a
term used to describe concrete adherence to rigid
rules rather than being able to adjust to changing
rules; weak ‘central coherence’—a term used to
describe how patients focus on the small details
and have difficulties with seeing the ‘larger picture’.
For instance, patients with EDs easily get stuck on
small details, the size of separate body parts rather
than the bigger picture as body size as a whole or
in relation to others (50, 51). Additionally, emo-
tional-processing difficulties are often present, par-
ticularly recognizing one’s own and other’s
emotions and altered reward sensitivity, for exam-
ple, being sensitive to punishment and insensitive
to the rewarding aspects of life (52). While for
Neurobiology of eating disorders
many these symptoms are reduced following re-
feeding, in some these symptoms persist. The traits
may also be seen in first-degree relatives who do
not exhibit disordered eating behaviours (53, 54).
An elegant review demonstrates differences
between dorsal and ventral fronto-striatal circuitry
involving the prefrontal cortex, basal ganglia, pari-
etal cortex, and insular cortex (55). Specifically, the
dorsal circuitry is purported to be associated with
aberrant cognitions associated with excessive inhi-
bition of appetite, whereas the ventral circuitry is
pertinent to a dysfunctional sense of self and body-
image distortion, also involving the parietal cortex.
The basal ganglia, in particular the striatum (dor-
sal and ventral), is associated with abnormal
responses to food and hijacked motivation in those
with EDs. The amygdala, also part of the basal
ganglia, is highly implicated in anxiety and fear
and may be linked to a learned fear of food (56).
Superior working memory performance in EDs,
particularly AN, may underlie the predisposition
to OCD symptoms and ruminations, as well as an
inability to exercise flexible thought, particularly in
relation to cognitive strategies to avoid food
intake, as working memory involves a tendency to
‘practice a cognitive strategy’ while avoiding irrele-
vant or unwanted stimuli (57). Patients with AN
furthermore show inadequate self-perception of
body weight and shape (58) as well as excessive
concerns/cognitive ruminations about eating, body
shape, and weight (59). Taking the evidence
together, there is now greater acknowledgment
that the psychological profile in AN is associated
with neurobiological patterns. Thus, the neurobiol-
ogy is an important factor to consider in the
pathogenesis of cognitive deficits that pertain to
symptoms in those with ED (60).
Methods for neuroimaging
Most commonly, structural and functional brain
imaging using Magnetic Resonance Imaging
(MRI) techniques has been done in those with
EDs. Structural and functional Magnetic Reso-
nance Imaging (sMRI and fMRI), as well as Posi-
tron Emission Tomography (PET) and Single
Photon Emission Computed Tomography
(SPECT) have been used for radio ligand binding
to examine receptors in brain tissue. Additionally,
Diffusion Tensor Imaging (DTI) provides informa-
tion regarding the structure of white matter tracts
connecting different regions of the brain. Further-
more, Magnetic Resonance Spectroscopy (MRS)
uses the magnetic resonance properties in the brain
to study metabolites, which can reflect how the
neurons in a given area are functioning. sMRI
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Hausswolff-Juhlin et al.
provides information about the structure, volume
and cortical thickness of grey and white matter, as
well as cerebro-spinal fluid (CSF), and can be use-
ful to examine brain tissue atrophy in disease and
increased tissue following recovery. fMRI, in con-
trast, examines real time brain function, by mea-
suring the ratio of oxygen in the blood supplied to
activated clusters of neurons during an ED-related
task. fMRI can also be used to measure resting
state activation, independent from any task-based
activity. PET and SPECT are useful to determine
up regulation and down regulation of receptors in
specific brain regions, to indirectly signify levels of
neurotransmitters released in the brain (61–63).
Neurobiological structures associated with ED pathology
Repeated structural neuroimaging studies illustrate
in general, cerebral atrophy and enlarged ventricles
in patients with AN, and deficits in both grey and
white matter, as illustrated by a recent meta-analy-
sis. Severe malnutrition and unstable periods of
bingeing and purging are linked to atrophy in gray
matter and white matter and concomitant
increases in cerebrospinal fluid in the brain (64).
Some studies show that changes are fully reversible
after weight restoration, while in others there is no
restoration observed. An interesting point is that
some of the changes resemble those in alcoholics,
that is, greater CSF volumes and smaller gray mat-
ter volumes than in controls (65, 66). General cere-
bral atrophy is also shown but to a lesser extent, in
patients with BN (67). Furthermore, research has
shown that patients with BN have enlarged lateral
ventricles although normal weight which suggests
that the enlarged ventricles are not only because of
low weight but may be a predisposing disturbance
in the development of an ED (68). In studies of
brain lesions, it has been shown that simple
changes in appetite and eating behaviour occur
with hypothalamic and brain stem lesions but diag-
nostic EDs are associated with right frontal and
temporal lobe damage (69).
Activity in the parietal cortex has been shown in
repeated studies to be decreased in the starving
brain but some studies have also shown an increase
in activation (70, 71). Thus what is certain is that
the parietal cortex is being affected, which is likely
to have an impact on body-image distortion, given
that this region of the brain is associated with body
representation. For instance, one finding is that
patients with AN lack insight into the severity of
the illness, a lack also reflected in neurological
patients with damage to the parietal cortex or its
connections (72). There have also been findings to
indicate that the parietal cortex is affected in BN
248
and a hypothesis is that EDs overall have parietal
dysfunction (73).
The frontal cortex and its neurocircuitry also
have been studied as an area of interest for the
development of AN. The neuroimaging studies are
not consistent on the most affected areas (74–77).
An area to further study is the orbitofrontal cor-
tex. It is a cortical area which process auditory,
gustatory, olfactory, somatosensory, and visual
information (78). A meta-analysis of fMRI in
which the orbitofrontal cortex was activated
revealed that the medial orbitofrontal cortex is
involved in response to the pleasantness of, for
instance, taste or smell and the lateral orbitofron-
tal cortex is involved in monitoring punishing stim-
uli (79). Furthermore, the dorsolateral prefrontal
cortex (DLPFC) is strongly implicated in AN, per-
haps as an indicator of cognitive control and
restraint. The DLPFC is also strongly linked to
working memory function, as well as OCD symp-
toms (80–84).
When presented with food images during an
fMRI scan, women with BN identify the food as
disgusting and they show more activation in the
anterior cingulate cortices and medial orbitofron-
tal and less in the prefrontal cortex suggesting that
patients with BN may have vulnerabilities in cogni-
tive control systems that weaken their ability to
control the urge to binge on large quantities of
food which could explain some compulsive behav-
iour seen in these conditions (84).
Autism-spectrum disorders have commonalities
with AN, particularly in terms of deficits in theory
of mind (ToM) and self/other emotional process-
ing, as well as extreme male brain thinking styles
pertaining to excessive attention to detail and
rigidity of thought (85–87). Specifically, the neuro-
biology-linking autism spectrum disorder to AN
seems to involve fronto-striatal circuitry, implicat-
ing an excessive restraint of appetitive and emo-
tional systems in both conditions. Another recent
fMRI study compared females with AN to those
with BN, while thinking about eating food shown
in images (82). It was found that those with BN
had greater insular cortex and striatal activation to
the food, suggesting a hyperactive reward response
to food, which may impinge on vulnerable cogni-
tive control systems in the prefrontal cortex and
weaken self-restraint. Similar changes that have
been observed in the frontal cortex have been
observed to some extent in patients with anxiety
disorders (78), for example, increased perfusion
was observed in the temporal cortex (88). One
study shows higher central blood flow in bilateral
medial temporal lobes similar to results in patients
with psychotic disorders which may be related to

the body-image distortion in patients with AN
(89). However, one study of adolescent ED
patients showed reduced activation in middle and
anterior temporal cortex and in the medial pre-
frontal cortex where the later was correlated with
clinical outcome (90).
Increased perfusion has also been shown in the
amygdala-hippocampal complex and a decrease of
perfusion was found in the right insula (88, 91).
Most recently, differential activation in the
visual cortex between females with AN and healthy
controls has been shown during the Embedded
Figures Test, which measures excessive attention
to small detail, a common neuropsychological defi-
cit in those with AN (86).
The 5-HT neuronal system and dopaminergic transmission
Studies have shown that the 5-HT neuronal system
is affected in EDs. In different areas of the brain,
an increase of binding to 5-HT1A receptors and a
decrease in binding to 5-HT2A receptors is shown
(92–95). The 5-HT disturbances most probably
contribute to vulnerability for restricted eating and
an altered 5-HT neuronal system activity has also
been shown in a small study after recovery (96).
There appear to be many links between cognitive
and personality traits and neurobiology. For
instance, in a study on personality traits, patients
with AN score higher on harm avoidance and
lower on novelty and reward dependence studies
(97). The former has been shown to correlate with
5-HT2A binding in the lateral and medial orbito-
frontal cortex, part of the cingulate cortex and the
parietal cortex (95, 98). In theory, the 5-HT system
could explain parts of the high anxiety and obses-
sional behaviours in patients with AN also seen in
other illnesses with similar symptoms (99–101).
Dysregulation in the serotonergic neural circuitry
is linked to symptoms in people with ED, such as
impulse control (102), obsessive-compulsiveness
and anxiety (103), depression (104), and altered
satiety (105, 106). Others have demonstrated
altered serotonin function in people with AN
(107), which may be linked to higher states of anxi-
ety. Food restriction in women with AN can
reduce levels of plasma tryptophan (a precursor to
5-HT) and may be a way for these women to regu-
late their experience of anxiety (108). Conversely,
in people with ED, eating leads to the onset of
dysmorphia (109), and it has been suggested that a
normal amount of food intake leads to an exces-
sive 5-HT response in mesolimbic regions (110).
Dysregulated eating behaviour is likely to con-
tribute to both state effects of starvation, and trait,
premorbid, effects leading to illness, in people with
Neurobiology of eating disorders
ED. For example, brain imaging studies show that,
in comparison with healthy controls, people cur-
rently ill with, or recovered from an ED have dys-
regulated binding potentials in 5-HT1A, 5-HT1B,
and 5-HT2A receptors (96, 111, 112). Other imag-
ing studies using PET show that dysregulation of
serotonergic function is linked to the experience of
anxiety in healthy people (113–115). Despite
abnormalities in 5HT function, people with AN do
not respond well when treated with Selective
Serotonin Reuptake Inhibitors (SSRIs) (116).
However, dysfunction in 5-HT neurocircuitry is
likely to lead to a reduction in the amount of 5-HT
released at the synapse; SSRIs rely on synaptic
release of 5-HT, so this could explain the ineffi-
ciency of this treatment (117). An increased
5-HT1A receptor activity may also explain poor
response to 5-HT medication in patients ill with
AN (95). The serotonergic neural circuitry is com-
plex, incorporating different receptor types and it
is currently still unclear how dysregulation of the
serotonergic pathways link aversion and appetite.
It has been proposed that 5-HT neurocircuitry
functions antagonistically with appetite-related
DA neurocircuitry (118). Others have suggested
that 5-HT influences ‘action choice’, for example,
deciding whether to take an immediate reward or
to delay it, via top-down lateral prefrontal cortex
(PFC) modulatory effects on the dorsal and ventral
striatum (119, 120). This proposal is supported by
the observations that an increased serotonergic
response in the PFC is linked to behavioural inhi-
bition, whereas a decreased response is linked to
impulsiveness (121). Therefore, in people with ED,
it is possible that there is an imbalance between
5HT and DA dorsal and ventral neurocircuitry,
associated with dysregulated appetite, behavioural
inhibition and impulsivity (117).
It is unclear how neural mechanisms might be
associated with comorbidity for anxiety in people
with ED. (118). Interceptive awareness of appetite
in people with ED may activate an anxiety
response, congruent with current concerns about
shape, weight, and eating. This may also link to
excessive top-down restriction—that delays an
immediate reward vs. impulsivity—that impinges
upon top-down control. Disturbances in 5HT reg-
ulation associated with a propensity to be anxious
could predate the onset of an ED. For example,
changes in puberty might lead to disturbances in
the 5HT and DA neurocircuitry, which coincide
with increases in life stressors associated with
sociocultural pressures (117).
Lack of impulse control in BN has been linked
to 5-HT1A receptor binding among non-medi-
cated patients with BN, in that there appears to be
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Hausswolff-Juhlin et al.
an up regulation of these receptors in the prefron-
tal cortex (122). Another study implicates 5-HT
alteration after recovery from BN, suggesting that
altered 5-HT neuronal system may be a predisposi-
tion or a scar of previous illness (94). There are
also results suggesting that the serotonin trans-
porter availability in BN is reduced in hypotha-
lamic and thalamic regions, and that this is more
pronounced in those with a longer period of illness
(123).
Dysfunctional dopaminergic transmission in
fronto-striatal circuits could account for some of
the core traits in ED (124). For example, one PET
study showed increased D2/D3 receptor binding in
the ventral striatum, a region activated during the
experience of rewarding stimuli, in people recov-
ered from AN (125). A reduced ventral striatal
response to reward has been demonstrated using
fMRI, in people who have recovered from AN and
BN, which may indicate a failure to form hedonic
associations with rewarding stimuli (126). The
same study showed a positive correlation between
trait anxiety and caudate activation. This could
indicate a more ‘strategic’ rather than a ‘hedonic’
response to an emotionally charged situation, for
example, responding to immediate monetary loss
and reward. Overall, it has been suggested that
people with ED are less able to modulate sponta-
neous affective responses linked to striatal activa-
tion, but rely more on top-down strategies that
utilize PFC regions such as the DLPFC (117).
Individuals with BED are characterized by com-
pulsive overeating and impulsivity, which shares
similarities with compulsive and impulsive binge
eating in those with BN. However, those with
BED appear to lack the sporadic attempts at cog-
nitive control of appetite. In a study by Wang
et al., 10 obese BED patients and eight obese sub-
jects without BED were studied with PET.
Changes in extracellular dopamine in the striatum
in response to food stimulation in food-deprived
subjects were evaluated after placebo and after oral
methylphenidate (MPH), a drug that blocks the
dopamine reuptake transporter and thus amplifies
dopamine signals. Dopamine increase in the cau-
date was significantly correlated with the binge eat-
ing scores but not with BMI. These results identify
dopamine neurotransmission in the caudate as
being of relevance to the neurobiology of BED,
and links to fMRI findings in BN. The lack of cor-
relation between BMI and dopamine changes sug-
gests that dopamine release per se does not predict
BMI within a group of obese individuals but that
it predicts binge eating (127).
Some evidence, although as yet inconclusive,
suggests that those with EDs are more sensitive to
250
reward and punishment, further pointing to the
involvement of neurobiological systems (128). In
the brain, basal ganglia structures such as the dor-
sal and ventral striatum, hippocampus and amyg-
dala complex are implicated in the experience of
reward and punishment, via dense networks of DA
and 5HT-releasing neuronal populations and
receptors, mainly modulated by 5HT (129).
Neuropeptides involved in regulation of appetite
The regulation of appetite is assisted by the secre-
tion of neuropeptides, such as leptin, insulin, ghre-
lin, and orexin, but these are dysregulated in
people with AN and BN (130). Dopaminergic
transmission is inhibited by gamma-amino butyric
acid (GABA) and excited by glutamate, and the
actions of these neurotransmitter systems are med-
iated by these peripheral hormones. It is therefore
likely that peripheral hormone release in people
with ED leads to dysfunctional DA activation and
disturbances in normal appetite (131).
Dysfunctional leptin signalling between the PNS
and CNS likely contributes to the physiological,
behavioural and psychological disturbances in peo-
ple with ED, for example, in feeding, mood, and
impulse control (130). Leptin is released from adi-
pose tissue to signal increased energy stores and to
initiate feelings of satiety. In people with AN, lep-
tin levels drop to extremely low levels, because of
regular fasting and weight loss and reduced adi-
pose storage. In people with BN, leptin levels are
also extremely low despite an increase in weight,
food consumption and adipose storage compared
with people with AN. Alterations in overall food
consumption in people with ED seem to disrupt
leptin regulation, with some evidence that the level
of leptin increases after re-feeding (132).
Insulin is a polypeptide released by the beta cells
of the pancreas in response to food intake. A
recent review and meta-analysis found reduced lev-
els of insulin in all people with ED (133), which
may suggest that severely altered food intake, both
restriction and bingeing, disrupts insulin function.
Amylin is a polypeptide that is co-secreted with
insulin by the beta cells of the pancreas to decrease
food intake. The anorexigenic effects of amylin
may be induced by increasing the transport of the
5-HT precursor tryptophan, which may inhibit
appetitive neural circuits (134).
Ghrelin, a gastric hormone that functions antag-
onistically with leptin, has orexigenic, adipogenic
and somatotropic effects (135). Ghrelin is a starva-
tion-signalling molecule that acts to stimulate feed-
ing in healthy people. Levels of ghrelin are reduced
in obesity (136), and increased in people who

restrict their calorie intake (137). In comparison to
healthy controls, people with AN have increased
plasma ghrelin (138); in people with BN, the levels
are increased or normal (139), and in people with
Binge Eating Disorder (BED), the levels are
reduced (140). Ghrelin also stimulates DA release
at the VTA and influences top-down cortical
responses, and are therefore likely involved in the
hedonic aspects of eating, rather than purely for
homeostatic balance (141). Preprandial levels of
ghrelin are suppressed by oxyntomodulin (142),
and therefore, it is likely that levels of oxyntomod-
ulin are reduced in people with BN, but elevated or
normal in people with AN.
Cholecystokinin (CCK) is a gastrointestinal hor-
mone that induces satiety and reduces food intake.
Baseline concentrations of plasma CCK are nor-
mal in people with BN but are increased, both at
baseline and postprandially in people with AN.
Therefore, increases in levels of CCK may contrib-
ute to food restriction in people with AN (143).
There is currently some debate over the role of
Pancreatic peptide YY (PYY), a gut-regulatory
peptide released in the gastrointestinal tract. Some
suggest that PYY is a potent anorexigenic peptide
that signals satiety and inhibits feeding. For exam-
ple, circulatory PYY increases postprandially and
decreases during fasting, the proportion of circula-
tory PYY being related to the calorie content
consumed (144). During high plasma PYY concen-
trations, feeding behaviour is predicted by neural
activation in the orbitofrontal cortex (OFC), a
region associated with the cognitive evaluation of
the hedonic value of food, whereas low concentra-
tions of PYY are associated with hypothalamic
activation (145). This suggests that low levels of
PYY may initiate homeostatic regulation of feed-
ing, whereas high levels of PYY may be linked to
hedonic aspects of feeding. A recent meta-analysis
shows that people with ED have higher baseline
concentrations of PYY in comparison to controls
(133), which in part supports the view that PYY is
linked to satiation. Oxyntomodulin is released
from the gut post-prandially in proportion to
energy intake, and interacts with appetite-reducing
hypothalamic nuclei. It is negatively correlated
with hunger levels, suppresses appetite and reduces
food intake. Levels of oxytomodulin are elevated
in people with AN (142).
Low concentration of triidothyronine is an indi-
cator of starvation and in patients with BN ven-
tricular size was inversely correlated with plasma
levels of triidothyronine. As the patients with BN
were of normal weight, the morphological brain
changes may reflex that to a certain extent
the atrophy is owing to extreme dieting itself.
Neurobiology of eating disorders
Additionally, in those with BN, it is also confirmed
that the pituitary gland is significantly smaller
(146), which could be linked to differences in endo-
crinology, particularly in relation to anxiety and
stress which is governed by the hypothalamic-pitu-
itary-adrenal (HPA) axis. This neurobiological
stress system is particularly pertinent, given that
the hypothalamus is strongly associated with feed-
ing behaviour.
The insula and noradrenergic dysregulation hypothesis
The insula cortex is currently being studied as a
specific area of importance for the risk of develop-
ment of AN, particularly in terms of anxiety and
altered body perception. The insula hypothesis is
based on anatomical and clinical research of insula
damage in neuroscientific studies including taste,
reward, and self-image processing. The hypothesis
is strengthened by the difficulty that patients with
AN have in integrating higher conceptual with
lower perceptual functions, as well as interceptive
awareness and perception of emotion. The insula -
with its crucial role as an ‘island’ between the left
and right hemisphere and between prefrontal cog-
nitive and mesolimbic affective states, may give
one explanation to this.
Prominent researchers in the field propose a
three-factor neurobiological model of body distor-
tion, whereby the homunculus and body represen-
tation is mapped primarily in the sensory-motor
cortex, secondarily in the parietal cortex, and
thirdly, as an integration of bodily perception, in
the insular cortex. This model, known as the nor-
adrenergic dysregulation hypothesis proposes that
monoamine dysregulation contributes to impaired
neuroplasticity in these brain regions, resulting in
body image distortion and impaired feeding behav-
iour (147).
Discussion
This article has been written to give clinicians in
the field of EDs a base knowledge of the neurobiol-
ogy of EDs. On the background on etiology, diag-
nostical issues, treatment interventions of EDs
with a possibility to refer the neurobiological find-
ings to knowledge about psychiatric and somatic
comorbidity and the neuropsychology of EDs the
aim has been to stimulate more in-depth explora-
tion of these issues and to highlight the importance
of examining neurobiology to improve treatment
intervention. New methods being used in psychiat-
ric research will help clinicians gain a better under-
standing of the complexity of the neurobiology of
EDs and eventually of the neurobiology of
251
Hausswolff-Juhlin et al.
co-morbid conditions hopefully in further applying
this improved knowledge in the area to good use.
Understanding more about the neurobiology of
EDs will most certainly help to understand which
areas of the brain are connected with a specific
symptom, regardless of current diagnostic criteria.
Given that psychiatric comorbidity is so common,
a consideration of the neurobiology of the psychi-
atric comorbidity (if existant) to the ED will help
to better understand individual need when clini-
cians are designing treatment for tailored interven-
tion. We argue that treatment methods, that have
been useful in other psychiatric illnesses or cogni-
tive disabilities but with the same affected parts of
neurobiology, will most probably help when treat-
ing patients with EDs. We hypothize this could be
a ‘short-cut’ to find better ways of treating EDs
and suggest studies on the latter.
Dysregulation in the neurobiological systems
seems to commonly spur symptoms of anxiety and
depression in all EDs. For those with AN, it seems
that excessive attention to detail, perseveration,
inflexible, autistic-like thinking style is linked to an
imbalance between fronto-striatal systems, and
that that this imbalance impinges on primary
somatosensory cortex, secondary parietal cortex
and tertiary insular cortex levels of body represen-
tation. For those with BN and BED, alterations in
the mesolimbic reward pathway may underlie
over-eating. Given however that one ED diagnosis
often ‘changes’ into another, according to the cur-
rent diagnostic classification system, it could also
be especially interesting to see whether there is any
connection in the comorbidity and neurobiology
during transitions. Could it be, for example, that
the strictly restrictive forms of AN has a higher
comorbidity with restrictive comorbidity such as
perfectionistic personality disorder, social phobia,
OCD and Asperger’s syndrome and more seldom
‘becomes’ BN and that the non-restrictive forms of
AN with self-purging more often changes into BN?
If this is the case, could it be that these patients
have a higher comorbidity with other illnesses with
lack of impulse control such as for instance
ADHD, substance abuse, and borderline personal-
ity disorder? If so, could we see this in the area of
neurobiology and take this into consideration even
before choosing the treatment method to give the
best possible prognosis for the patient with ED?
It is likely that our current knowledge of EDs
will look very different in the future, owing to
rapid progression in neurobiological findings both
in EDs and their comorbid disorders. Taking
this into account, contemporary neurbiological
research will likely provide a more solid ground for
strengthening treatment methods—psychologically
252
and pharmacologically—saving and improving the
quality of lives for those with EDs.
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