Content uploaded by Walter H Kaye
Author content
All content in this area was uploaded by Walter H Kaye on Sep 23, 2019
Content may be subject to copyright.
Neurobiology of Anorexia and Bulimia Nervosa Purdue Ingestive
Behavior Research Center Symposium Influences on Eating and
Body Weight over the Lifespan: Children and Adolescents
Walter Kaye, M.D. [Professor of Psychiatry]
Director, Eating Disorders Research Module, University of Pittsburgh Medical Center, Western
Psychiatric Institute & Clinic, 3811 O’Hara Street, 600 Iroquois Building, Pittsburgh PA 15213, Email:
kayewh@upmc.edu, Program Director, Eating Disorders Program, University of California, San
Diego, 8950 Villa La Jolla Drive, Suite C207, La Jolla CA 92037
Introduction
Anorexia nervosa (AN) and bulimia nervosa (BN) are related disorders of unknown etiology
that most commonly begin during adolescence in women (DSM-IV; Table 1[MSOffice1]).
They are frequently chronic and often disabling conditions that are characterized by aberrant
patterns of feeding behavior and weight regulation, and deviant attitudes and perceptions
toward body weight and shape. In AN, an inexplicable fear of weight gain and unrelenting
obsession with fatness, even in the face of increasing cachexia, accounts for a protracted course,
extreme medical and psychological morbidity, and standardized mortality rates exceeding
those of all other psychiatric disorders. BN usually emerges after a period of food restriction,
which may or may not have been associated with weight loss. Binge eating is followed by
either self-induced vomiting, or by some other means of compensation for the excess of food
ingested. Although abnormally low body weight is an exclusion for the diagnosis of BN, some
25% to 30% of bulimics have a prior history of AN.
Because AN and BN present most often during adolescence in women, they are often theorized
to be caused by cultural pressures for thinness (1) since dieting and the pursuit of thinness are
common in industrialized countries. Still, AN and BN affect only an estimated 0.3% to 0.7%
and 1.5% to 2.5%, respectively, of females in the general population (2). This disparity between
the high prevalence of pressures for thinness and the low prevalence of eating disorders (EDs),
combined with clear evidence of AN occurring at least several centuries ago (3), the stereotypic
presentation, substantial heritability, and developmentally specific age-of-onset distribution,
underscores the possibility of contributing biological vulnerabilities.
Considering that transitions between syndromes occur in many, it has been argued that AN
and BN share at least some risk and liability factors (4,5). In fact, AN and BN are cross
transmitted in families. (6,7) Moreover there is an increased prevalence of AN and BN as well
as subthreshold forms of ED in relatives, consistent with the possibility of a continuum of
transmitted liability in at risk families manifesting a broad spectrum of eating disorder
phenotypes (7). Twin studies can differentiate genetic from environmental effects by
comparing concordance for a trait, or disorder, between identical (monozygotic; MZ) and
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting
proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could
affect the content, and all legal disclaimers that apply to the journal pertain.
NIH Public Access
Author Manuscript
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
Published in final edited form as:
Physiol Behav. 2008 April 22; 94(1): 121–135. doi:10.1016/j.physbeh.2007.11.037.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
fraternal (dizygotic; DZ) twins. Twin studies of AN and BN suggest there is approximately a
50 to 80% genetic contribution to liability (4,8-11) accounted for by additive genetic factors.
These heritability estimates are similar to those found in schizophrenia and bipolar disorder,
suggesting that AN and BN may be as genetically-influenced as disorders traditionally viewed
as biological in nature.
Clinical Symptoms and Puzzling behaviors
The DSM-IV diagnostic criteria for AN and BN focus on eating behavior and body image
distortions. Because of their unusual and prominent nature, these symptoms tend to capture
much attention. The pathogenesis of the disturbed eating behaviors is poorly understood (5,
12). Individuals with AN rarely have complete suppression of appetite, but rather exhibit an
ego-syntonic resistance to feeding drives while simultaneously being preoccupied with food
and eating rituals to the point of obsession. Individuals with AN severely restrict food intake,
particularly fats and carbohydrates, but rarely stop eating completely; rather they restrict their
caloric intake to a few hundred calories a day. They tend to be vegetarians, have monotonous
choices in food intake, select unusual combinations of foods and flavors, and have ritualized
eating behaviors. Similarly, BN is not associated with a primary, pathological increase in
appetite; rather, like individuals with AN, individuals with BN have a seemingly relentless
drive to restrain their food intake, an extreme fear of weight gain, and often have a distorted
view of their actual body shape. Loss of control with overeating in individuals with BN usually
occurs intermittently and typically only some time after the onset of dieting behavior.
Restrained eating behavior and dysfunctional cognition relating weight and shape to self-
concept are shared by all types of patients with EDs.
AN and BN individuals commonly have clusters of other puzzling symptoms. Excessive
exercise and motor restlessness are common in AN (13). While not well studied, excessive
exercise is thought to be associated particularly with the purging subtype of AN, as well as
with a constellation of anxious/obsessional temperament. Individuals with AN often have
resistance to treatment (14). In part this is due to the ego syntonic nature of the disorder, which
is demonstrated by the patient’s denial of being underweight and refusal to accept the
seriousness of the medical consequences of the disorder. Consequently, few control trials of
any therapy have been performed, in part, because it has been difficult to enlist cooperation of
individuals with AN, and in part because psychological and pharmacological strategies that
have been successful in other disorders appear to be less effective in this illness.
Mood and impulse control
Individuals with AN and BN have elevated rates of lifetime diagnoses of anxiety and depressive
disorders, and obsessive-compulsive disorder (6,15-17). In addition, individuals with AN and
BN are both consistently characterized by perfectionism, obsessive-compulsiveness,
neuroticism, negative emotionality, harm avoidance, low self-directedness, low
cooperativeness, and traits associated with avoidant personality disorder (PD). Consistent
differences that emerge between ED groups are high constraint and persistence, low novelty
seeking, constriction of affect and emotional expressiveness, ahendonia and asceticism, and
reduced social spontaneity in restrictor-type AN. Individuals with BN are more likely to have
high impulsivity, sensation seeking, novelty seeking, and traits associated with borderline PD
in BN, and substance abuse (18).
In summary, individuals with restricting type AN are more likely to have restricted eating,
constricted affect and emotional mood expression, and impulse over control, as well as
personality traits of marked rigidity, conformity, and reduced social spontaneity. Individuals
with BN may show similar traits, but in addition, may exhibit histories of episodic overeating,
extremes of intense affect, and impulse dysregulation. Thus several domains (eating, affect,
Kaye Page 2
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
impulse control) are involved in systematic ways, specifically, over control in AN, and switches
between over control and under control in BN, which raises the question of whether there is a
disturbance of modulation of multiple systems.
Neurocognition
Individuals with AN have an obsessive, perseverative, and rigid personality style and have
difficulty shifting sets. While those with AN do well on goal directed behavior, they have
difficulties incorporating feedback and modifying their behavior. For example, they often feel
that they should be able to do things perfectly without making mistakes, and they have little
appreciation for the fact that mistakes are a normal learning experience. Moreover, they often
fail to accurately recognize and incorporate affective and social stimuli in the environment, as
confirmed by laboratory tests (19,20). Those ill with and REC from (REC) AN tend (21) to
have delayed setshifting, which allows for the adaptation of behavior in line with changing
demands of the environment. Furthermore, individuals with AN have enhanced ability to pay
attention to detail or use a logical/analytic approach but exhibit worse performance with global
strategies (19,22).
State and Trait
It has long been debated whether symptoms in individuals with AN and BN are cause or
consequence of malnutrition. Confounding this understanding is the issue that most studies of
symptoms have been done when individuals are ill with an ED. Recent studies have shown
that the majority of people with AN and BN exhibit childhood perfectionism, obsessive-
compulsive personality patterns, and anxiety that predate the onset of AN and BN (16,23,24).
Moreover, studies done on 3 continents (Table 2) have shown that in AN and BN individuals
with a lifetime history of an anxiety disorder diagnosis, the anxiety disorder most often began
in childhood before the onset of the ED (25-28). The most common (15) premorbid childhood
disorders were OCD and social phobia. In summary, such symptoms may be susceptibility
factors that make people vulnerable to developing an ED. Malnutrition tends to exaggerate
premorbid behavioral traits,(29) , not cause them.
It is important to note that such temperament and personality traits persist after recovery from
an ED. While a definition of recovery has not been formalized, investigators tend to include
people after they were at a stable and healthy body weight for months or years, were not
malnourished, and had not engaged in pathological eating behavior during that period of
recovery. Some investigators include a criterion of normal menstrual cycles and a minimal
duration of recovery, such as one year. Investigators (30-33) have found that women who were
long-term REC from AN and BN have a persistence of anxiety, perfectionism, and obsessional
behaviors (particularly symmetry, exactness, and order).
Gender, age, and puberty
AN and BN most commonly develop during adolescence or young adulthood (34) in proximity
to puberty. Adolescence (35) is a time of profound biological, psychological and sociocultural
change, and it demands a considerable degree of flexibility to successfully manage the
transition into adulthood. Psychologically, change may challenge the rigidity of those at risk
for AN and BN, and thus open a window of vulnerability (35). Importantly, biological changes
may significantly enhance the risk of onset of an ED, particularly in women. This latter
possibility is supported by twin studies which found essentially no genetic influence on overall
levels of ED symptoms in 11 year-old twins, but significant genetic effects (>50%) in 17 year
old twins (36). These findings collectively imply that puberty may play a role in the genetic
diathesis for ED symptoms. The changes associated with adolescence differ in males and
females and may therefore contribute to the sexual dimorphism of AN. Menarche is associated
(35) with a rapid change in body composition and neuropeptides modulating metabolism. Little
Kaye Page 3
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
is known about whether the rise in estrogen levels associated with puberty in females is
contributory. Estrogens modulates serotonergic function (37) as well as stress-related
neuropeptides such as cortisol releasing hormone (CRH) (38) via a variety of mechanisms.
Moreover, a major phase of synaptogenesis, pruning and myelination of predominantly frontal
and limbic areas occurs around the time of puberty and adolescence and is thought to have a
functional role in the integration of emotional processing with cognition (39).
Neurobiology
There is growing acknowledgement that neurobiological vulnerabilities make a substantial
contribution to the pathogenesis of AN and BN(3). But we have little understanding of how
such vulnerabilities result in disturbances of brain pathways or what systems are primarily
involved. For example, are there disturbances of pathways related to the modulation of feeding
behaviors, or mood, or temperament, or obsessionality, or impulse control? Are there primary
disturbances of pathways that may modulate some factors related to body proprioception, and
thus result in body image distortions? In the past, answering these questions has been thwarted
by the inaccessibility of the brain. Technology capable of characterizing the complexity of
brain circuits in humans, such as imaging or genetics, have only recently become available.
Still, past studies have been useful in terms of grossly identifying systems that may be involved
in ED. Because these technologies tend to only be able to characterize one molecule at a time,
they cannot answer questions about complex interactions and function.
Neuropeptides
Central nervous system (CNS) neuropeptide dysregulation could contribute to abnormal
function of gonadal hormones, cortisol, thyroid hormones and growth hormone in ED (40,
41). Moreover, mechanisms for controlling food intake involve a complicated interplay (42)
between peripheral systems (including gustatory stimulation, gastrointestinal peptide
secretion, and vagal afferent nerve responses) and CNS neuropeptides and/or monoamines.
Studies in animals show that neuropeptides, such as CRH, leptin, the endogenous opioids (such
as beta-endorphin), and neuropeptide-Y (NPY) modulate feeding behaviors and energy
metabolism (43,44). One of the few strategies capable of assessment of neuropeptides in vivo
in humans is to measure their concentrations in cerebrospinal fluid (CSF). In fact, when
malnourished and underweight, AN individuals have altered concentrations of CRH, NPY,
beta-endorphin, and leptin (Figure 1). However, these disturbances tend to normalize after
recovery (45). This observation can be interpreted to suggest that such disturbances are
consequences rather than causes of malnutrition, weight loss and/or altered meal patterns. It
should be noted that many systems known to modulate feeding and related functions remain
to be explored in ED. For example, genotype studies raise the possibility that altered
melanocortin (46) or cannabinoid (47) systems could play a role in ED.
Serotonin
Much technology has focused on characterizing monoamine function. In part, this is because
many of the medications used to treat psychiatric disorders act on these systems. The
monoamine systems, serotonin (5-HT), dopamine (DA), and norepinephrine (NE), are complex
pathways with multiple receptors, transporters, enzymes, and intracellular cascades, etc.
Consequently, our understanding of the pathophysiology of these systems in psychiatric
disorders is limited. The cell bodies of monoamine neurons are located in the brainstem and
project to cortical and striatal limbic regions (48). Each has multiple receptors, grouped on the
basis of shared genetic sequences and second messengers.
Theoretically, 5-HT disturbances could contribute to appetite dysregulation (49,50), anxious
and obsessional behaviors and extremes of impulse control (51-55). Considerable evidence
suggest that disturbances of the monoamine function occur when people are ill with ED, and
Kaye Page 4
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
persist after recovery from AN and BN. (45,56-59). For example, ill AN subjects have a
significant reduction in CSF 5-hydroxyindoleacetic acid (5-HIAA) compared to healthy
control women (CW) whereas CSF 5-HIAA levels are normal in ill BN subjects (Figure 1;
((33,60-64) Kaye, unpublished data). In comparison, REC AN and BN subjects have higher
than normal concentrations of CSF 5–HIAA, that is about 50% greater than CSF 5-HIAA levels
found in the ill state (Figure 1). In addition, REC AN and BN show altered behavioral responses
to 5-HT challenges (65-68) or other measures, such as platelet binding of paroxetine (69). As
noted above, determining cause and effect is a major methodological confound in this illness.
Thus this review will focus on studies that have been done in people who have REC from AN
and BN.
Diet and brain 5-HT neurotransmission
Tryptophan (TRP), an essential amino acid only available in the diet, is the precursor of 5-HT.
Meal consumption, depending on the proportion of carbohydrate and protein, can enhance
brain 5-HT release (70,71); thereby affecting appetite regulation. In brief, carbohydrate
consumption causes an insulin-mediated fall in plasma levels of the large neutral amino acids
(LNAA; tyrosine; phenylalanine; valine; leucine; isoleucine) which compete with TRP for
uptake into the brain. This elevates the plasma TRP/large neutral amino acid ratio (TRP/
LNAA), and thus brain TRP, which rapidly accelerates brain 5-HT synthesis and release.
Dietary proteins tend to block these effects by contributing large amounts of LNAA to the
blood stream. Considerable amounts of evidence in animals and healthy humans (70-76) show
that a restricted diet significantly lowers plasma TRP, resulting in a decreased plasma ratio of
TRP to neutral amino acids, and, in turn, a reduction in the availability of TRP to the brain.
Thus, restricted diet (and experimentally reduced TRP) decreases brain 5-HT synthesis, down-
regulates the density of 5-HT transporters (77), and produces a compensatory supersensitivity
of postsynaptic receptors in response to reduced 5-HT turnover (78,79) Limited data show that
malnourished and emaciated AN women have a reduction of plasma TRP availability (80). In
addition, these alterations in postmeal amino acid metabolism are only partly reversed by
nutritional rehabilitation (80). It has been speculated (1,12) that there is an anxiety-reducing
character to dietary restraint in people with AN. In fact, we have found that the anxiolytic
effects of dieting in AN were related to a reduction in 5-HT neurotransmission. (66). Moreover
administration of meta-chlorophenylpiperazine (m-CPP), a relatively selective 5-HT drug
(81-85) is associated with a significant reduction in dysphoric mood states in one study(68)
but not in another(86).
Implications for medication
While BN individuals show a response to higher doses of fluoxetine (87), the efficacy of such
medication has been questioned since relatively few individuals abstain from binge and purge
behaviors, and relapse during treatment is common (88). Despite the abundance of data
implicating 5-HT dysregulation in AN, it remains controversial whether SSRIs are effective
in restricting type AN (RAN) individuals (89,90). Our clinical experience (91) suggests that
RAN respond better to fluoxetine than do binge eating-purging type AN (BAN) and that some
BN individuals can be relatively insensitive to high doses of SSRIs. Few control trials of any
therapy have been performed, in part, because it has been difficult to enlist cooperation of
individuals with AN, and in part because psychological and pharmacological strategies that
have been successful in other disorders appear to be less effective in this illness. For severely
emaciated patients, hospitalization for supportive medical care and weight restoration may be
useful or necessary. Still, relapse is common after discharge.
Kaye Page 5
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Dopamine
Altered striatal DA function may contribute to symptoms in AN. Reduced CSF DA metabolites
occur in malnourished individuals with AN (60) and persist after recovery (92). Individuals
with AN have altered frequency of functional polymorphisms of DA D2 receptor genes that
might affect receptor transcription and translation efficiency (93). The anteroventral striatum
(AVS) and dorsal caudate are components of limbic and executive-associative pathways
(94-96). Thus striatal DA dysfunction might contribute to altered reward and affect, decision-
making, and executive control, as well as to stereotypic motor activity (95) and decreased food
ingestion (97) in AN.
Brain Imaging
The past decade has seen the introduction of tools, such as brain imaging, which hold the
promise of being better able to characterize complex neurocircuits and their relationship to
behavior in living humans. In fact, these tools have rapidly advanced knowledge to the point
where we can begin to make educated guesses about the pathophysiology of AN and BN and
start to model mechanisms that may be used to test hypotheses.
Brain imaging studies in AN and BN can be divided into several categories. First, there has
been substantial literature, using computerized tomograph (CT) and more recently magnetic
resonance imaging (MRI) that seeks to determine whether there are brain structural alterations
in individuals with ED. Second, are imaging studies, such as positron emission tomography
(PET) and single photon emission computed tomography (SPECT, that employ a radioligand).
These studies, which may use flurodeoxyglucose (FDG) to study glucose metabolism, or a
ligand that is specific for a serotonin receptor, provide information that is specific for the system
being studied, such as the 5-HT2A receptor. Third, more recent studies have used fMRI or other
technologies to assess blood flow responses to some stimuli, such as pictures of food. Overall,
imaging studies have been relatively consistent, in that many studies show differences in ill
and REC ED individuals in frontal, cingulate, temporal, and/or parietal regions compared to
controls. However, it should be noted that these studies have not consistently identified regions,
pathways, or behavioral correlates. Sample sizes have been small, and imaging technologies
and methods vary widely. Moreover, investigations have tended to assess relatively large
regions of brain that vary widely between studies. Papers to date indicate gross alterations of
brain function. Because brain pathways are highly complex, the neuroanatomy of AN and BN
have only begun to be characterized.
Brain structure
Neuroimaging studies with CT reported cerebral atrophy and enlarged ventricles in ill AN
(98-106). In BN similar but less pronounced structural brain abnormalities were reported
(107) and may have been related to a chronic dietary restriction. Similarly, MRI studies in AN
showed larger CSF volumes in association with deficits in both total grey matter (GM) and
total white matter (WM) volumes (108) as well as enlarged ventricles (109-111). Fewer
neuroimaging studies have been conducted in BN, and those have found decreased cortical
mass (112-114). Whether these abnormalities persist to a lesser degree after weight restoration
is less certain, since some studies show persistent alterations (108) but other studies show
normalization of grey and white matter after recovery in AN and BN {Wagner, 2006 #2829
As noted above, in order to avoid the confounding effects of malnutrition, extremes of food
ingestion and/or weight loss, the review of other imaging studies will focus mostly on studies
of individuals after recovery from an ED.
Kaye Page 6
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Body image distortion
A most puzzling symptom of AN is the severe and intense body image distortion in which
emaciated individuals perceive themselves as fat. Theoretically, body image distortion might
be related to the syndrome of neglect, (217) which may be coded in parietal, frontal, and
cingulate regions that assign motivational relevance to sensory events. It is well known that
lesions in the right parietal cortex may not only result in denial of illness or anosognosia,
somatoparaphrenia, the numerous misidentification syndromes, but may also produce
experiences of disorientation of body parts and body image distortion. Wagner and colleagues
confronted AN patients and age-matched healthy controls with their own digitally distorted
body images as well as images of a different person using a computer-based video-technique
(115). These studies reported a hyper-responsiveness in brain areas belonging to the frontal
visual system and the attention network (BA 9) as well as inferior parietal lobule (BA 40),
including the anterior part of the intraparietal (IPL) sulcus. Bailer (116) reported negative
relationships between 5-HT2A receptor activity and the Eating Disorder Inventory Drive for
Thinness scale in the left parietal cortex and other regions. It is intriguing to raise the possibility
that left hemisphere disturbances of this pathway may contribute to body image distortion. It
has long been recognized that parietal cortex mediates perceptions of the body and its activity
in physical space (117). Recent work extends this concept to suggest that the parietal lobe
contributes to the experience of being an ‘agent’ of one’s own actions (118). The well-known
distortion of body image in individuals with AN may suggest abnormalities of circuits through
the postulated ‘self’ networks. In line with this, left parietal cortical activation has previously
been linked to AN womens’ evaluation of body image (115,116).
Appetitive regulation
Individuals with AN and those who have had lifetime diagnoses of both AN and BN (AN-BN)
tend to have negative mood states and dysphoric temperament. There is evidence that there is
a dysphoria reducing character to dietary restraint (1,12,66) and binge-purge behaviors
(119-121). This would suggest some interaction between pathways regulating appetitive
behaviors and emotions. In fact, functional magnetic resonance imaging (fMRI) studies support
this hypothesis. When emaciated and malnourished AN individuals are shown pictures of food,
they display abnormal activity in the insula and orbitofrontal cortex (OFC) as well as in mesial
temporal, parietal, and the anterior cingulate cortex (122-127). Studies using SPECT, PET-
O15, or fMRI, found that when subjects ill with AN ate food, or were exposed to food, they
had activated temporal regions, and often increased anxiety (122,124-126). Those results could
be consistent with anxiety provocation and related amygdala activation, and the notion that the
emotional value of an experience is stored in the amygdale (128). Uher (129) used pictures of
food and non-food aversive emotional stimuli and fMRI to assess ill and REC AN subjects.
Food stimulated medial prefrontal and anterior cingulate cortex in both REC and ill AN subjects
but lateral prefrontal regions only in the REC group. In REC AN subjects, prefrontal cortex,
ACC and cerebellum were more highly activated after food compared to both control subjects
and those chronically ill with AN. This finding suggested that higher ACC and medial
prefrontal cortex activity in both ill and REC AN women compared to CW may be a trait marker
for AN.
Imaging studies of 5-HT and DA function
The development of selective tracers for the 5-HT system has made in vivo study of 5-HT
receptor function possible using PET brain imaging. In turn, this offers the possibility of better
understanding of 5-HT neurotransmitter activity and dynamic relationships to behavior.
Kaye Page 7
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
5-HT1A receptor
Our group used PET imaging with the radioligand [11C]WAY100635 to assess the binding
potential (BP) of the 5-HT1A receptor. The 5-HT1A autoreceptor is located presynaptically on
5-HT somatodendritic cell bodies in the raphe nucleus, where it functions to decrease 5-HT
neurotransmission (130). High densities of postsynaptic 5-HT1A exist in the hippocampus,
septum, amygdala, and entorhinal and frontal cortex, where they serve to mediate the effects
of released 5-HT. Although the molecular organization for the receptor transduction seems to
be identical in all of the areas where 5-HT1A receptors are expressed, some differences in both
functional and regulatory properties have been reported from area to area (131). Studies in
animals and humans implicate the 5-HT1A receptor in anxiety (132-134) and depression and/
or suicide (55,135,136).
Bailer (137) reported that ill AN individuals had a 50 to 70% increase in [11C]WAY100635
BP in subgenual, mesial temporal, orbital frontal, and raphe brain regions as well as prefrontal,
lateral temporal, anterior cingulate, and parietal regions. Similarly, REC BAN and BN subjects
(138) (Kaye unpublished data) (Figure 2) had a significant 20 to 40% increase in [11C]
WAY100635 BP in these same regions compared to CW (138). In contrast, REC RAN women
showed no difference in [11C]WAY100635 BP compared to controls (138). Increased 5-
HT1A postsynaptic activity has been reported in ill BN subjects (139).
The role of the 5-HT1A receptor in behavior is not certain. 5-HT1A receptor activity has been
reported to play a role in anxiety (133). For example, some, but not all studies, show that 5-
HT1A knockout mice have increased anxiety (140). REC RAN subjects showed positive
relationships between harm avoidance, a trait characterized by anticipatory worry and fear of
uncertainty, and postsynaptic [11C]WAY100635 BP in subgenual cingulate, mesial temporal,
lateral temporal, medial orbital frontal, and parietal cortex. It is not clear why this animal model
and human phenomena appear to be opposite.
As noted above, EDs are frequently comorbid with depression and anxiety disorders. Reduced
[11C]WAY100635 BP has been found in ill (141,142) and REC (143) depressed subjects, as
well as in a primate model for depresion (144). Parsey (145) found no difference in
carbonyl-11C]WAY100635 BP in MDD, although a subgroup of never medicated subjects had
elevated carbonyl-11C]WAY100635 BP. Recent studies have found reduced [11C]
WAY100635 BP in social phobia (146) and panic disorder (147). These findings suggest ED,
mood, and depression share disturbances of common systems but are etiologically different.
There is an extensive literature associating the serotonergic systems and fundamental aspects
of behavioral inhibition (51,148). Reduced CSF 5-HIAA levels are associated with increased
impulsivity and aggression in humans and non-human primates, whereas increased CSF 5-
HIAA levels are related to behavioral inhibition (149,150). Brainstem 5-HT1A receptors inhibit
stress-induced sympathetic activity and inhibit fight-or-flight behavioral responses, supporting
a role for this receptor in behavioral inhibition and self-control (151). Furthermore, recent
animal studies also support 5-HT1A receptors’ modulation of impulse control through effects
on catecholamine systems (152). Other studies have shown that blunted 5-HT1A receptor
number or function is associated with increased aggression (153,154). A recent study (155)
found a significant inverse relationship between dorsal raphe 5-HT1A autoreceptor BP and
bilateral amygdala reactivity. 5-HT1A receptor function could contribute to behavioral
inhibition in BN, although there is no direct evidence for this conjecture. Still other studies
show that various measures of 5-HT activity are related to measures of affective instability and
impulsivity in ill BN subjects (59,156,157).
Kaye Page 8
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
5-HT2A receptor
Our group used PET imaging with the radioligand [18F]altanserin to assess BP of 5-HT2A
receptors. (Figure 2) Post-synaptic 5-HT2A receptors are in high densities in the cerebral cortex
and other regions of rodents and humans (158,159). The 5-HT2A receptor is of interest in ED
because it has been implicated in the modulation of feeding and mood, as well as SSRI response
(116,160-163).
Ill AN subjects had normal [18F]altanserin BP values (137). In comparison, REC RAN
individuals (164) had reduced [18F]altanserin BP in mesial temporal and parietal cortical areas
as well as in subgenual and pregenual cingulate cortex. Similarly, REC BAN (116) women
had reduced [18F]altanserin BP relative to controls in left subgenual cingulate, left parietal,
and right occipital cortex. And REC BN women only had reduced [18F]altanserin BP relative
to controls in the orbital frontal region. Audenaert et al (165) used SPECT and 123I-5-I-R91159
and found that ill AN subjectshad reduced binding of postsynaptic 5-HT2A receptors in the left
frontal, bilateral parietal and occipital cortex.
Brain regions/pathways enervated by 5HT1A/2A receptors
In REC subjects, altered 5-HT1A and 5-HT2A receptor BP shows persistent alterations in
frontal, subgenual cingulate and mesial temporal regions that are part of the ventral limbic
system. The subcaudal cingulate regions play a role in emotion (‘affect component’) and have
extensive connections with the amygdala, periaqueductal grey, frontal lobes, ventral striatum,
etc. They are involved in conditioned emotional learning, vocalizations associated with
expressing internal states and assigning emotional valence to internal and external stimuli
(166). Mesial temporal regions include the amygdala and related regions that play a pivotal
role in anxiety and fear (167) as well in the modulation and integration of cognition and mood.
The amygdala may enable the individual to initiate adaptive behaviors to threat based upon the
nature of the threat and prior experience. Together these findings raise the possibility that
mesial temporal (amygdala) - cingulate 5-HT2A receptor alterations may be a trait shared by
AN subgroups related to anticipatory anxiety and integration of cognition and mood.
Several lines of evidence show that 5-HT1A and 5-HT2A receptors interact in the brain. In rats,
5-HT1A and 5-HT2A receptors interact robustly to regulate the inhibition of exploration of
novel environments produced by either 5-HT1A or 5-HT2A receptor agonists (168). 5-HT2A
and 5-HT1A receptors are highly co-localized in rodent frontal cortex (169). Postsynaptic 5-
HT1A and 5-HT2A receptors mediate, respectively, the direct hyperpolarizing and depolarizing
actions of 5-HT on prefrontal neurons (170), which in turn project to numerous cortical and
subcortical areas. Thus a balance between postsynaptic 5-HT1A and 5-HT2A receptor activity
on neurons may modulate the descending excitatory input into limbic and motor structures.
These data raise the speculation that postsynaptic 5-HT1A and 5-HT2A receptors fine tune
cortical systems that modulate behavioral inhibition and self-control. Mixed 5-HT2A/1A
agonists, e.g. psilocybin, seem to disrupt the 5-HT1A/2A balance (171) by driving 5-HT2A
activity, thus resulting in excessive neuronal output that contributes to extremes of
disinhibition, disorganization, and loss of self-control. In our studies, REC ED subjects had a
relative increase in 5-HT1A receptor activity compared to 5-HT2A receptor binding. While
speculative, this possible imbalance could contribute to behavioral inhibition and over control
commonly seen in ED. As discussed below, we found considerable correlations between
binding of these 2 receptors and harm avoidance. Together these findings raise the possibility
that mesial temporal (amygdala) - cingulate 5HT1A/2A imbalance may also be a trait shared by
AN subgroups related to behavioral inhibition, anticipatory anxiety, or integration of cognition
and mood.
Kaye Page 9
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
5-HT transporter (5-HTT)
Our group (172) used PET imaging with [11C]McN5652 to determine if alterations of 5-HTT
persist after recovery from AN and BN. We compared 11 subjects recoveed (> 1 year normal
weight, regular menstrual cycles, no bingeing or purging) from restricting type AN (REC
RAN), 7 REC from bulimia-type AN (REC BAN), and 10 healthy CW. After correction for
multiple comparisons, we found that the REC RAN had significantly increased [11C]McN5652
BP compared to REC BAN for the dorsal raphe and antero-ventral striatum. It remains
controversial whether SSRIs are effective in RAN individuals. Our clinical experience and
data (89-91) suggest that individuals with RAN respond better to fluoxetine than do those with
BAN. While highly speculative, our findings raise the provocative possibility that decreased
5-HTT function may be related to poor response to SSRI medication whereas individuals with
increased 5-HTT activity may respond to higher SSRI doses. In general, the REC RAN
individuals had elevated 5-HTT binding, suggesting they have relatively greater 5-HT uptake,
and reduced extracellular 5-HT, compared to REC BAN. In support of this possibility, the REC
BAN individuals tend to have higher binding of 5-HT1A post-synaptic receptors and
autoreceptors (138), which may be a compensatory means of downregulating raphe activity
(48,173). Moreover, reduced 5-HTT activity, in terms of genotypes (174), has been associated
with affect dysregulation, which tends to be more common in the bulimic subgroups.
Furthermore, in people with impulsive aggressivity reduced 5-HTT binding was found in the
anterior cingulate cortex, a region involved in affect regulation (175).
DA D2/D3 receptor
A recent study from our group, (176) found that REC AN had increased binding of D2/D3
receptors in the anteroventral striatum (AVS), a region that contributes to optimal responses
to reward stimuli (177-179). In addition, there were positive correlations between DA D2/D3
binding in the dorsal caudate/dorsal putamen and anxiety measures in REC AN (176). The
AVS and dorsal caudate are components of limbic and executive-associative pathways
(94-96). Thus striatal DA dysfunction might contribute to altered reward and affect, decision-
making, and executive control, as well as stereotypic motor activity (95) and decreased food
ingestion (97) in AN.
5-HT, DA, and harm avoidance
The PET imaging studies in ill and REC AN and BN subjects described above have found
significant correlations between harm avoidance and binding for the 5-HT1A, 5-HT2A, DA D2/
D3 receptors in mesial temporal and other limbic regions. Bailer(116) found that REC AN-BN
subjects showed a positive relationship between [18F]altanserin BP in the left subgenual
cingulate and mesial temporal cortex and harm avoidance. For ill AN subjects, [18F]altanserin
BP was positively related to harm avoidance in the suprapragenual cingulate, frontal, and
parietal regions. 5-HT2A receptor binding and harm avoidance were shown to be negatively
correlated in the frontal cortex in healthy subjects (180) and in the prefrontal cortex in patients
that attempted suicide (181).
Clinical and epidemiological studies have consistently shown that one or more anxiety
disorders occur in the majority of people with AN or BN (15,16,182,183). Silberg and Bulik
(184), using twins, found a unique genetic effect that influences liability to early anxiety and
eating disorder symptoms. When a lifetime anxiety disorder is present, the anxiety most
commonly occurs first in childhood, preceding the onset of AN or BN (25,26,28). Anxiety and
harm avoidance remain elevated after recovery from AN, AN-BN, and BN (185), even if
individuals never had a lifetime anxiety disorder diagnosis (15). Finally, anxiety (186) and
Harm Avoidance from the Cloninger (TCI) (187) Temperament and Character Inventory have
been a robust signal in our (WK PI) genetic studies (188). In summary, the premorbid onset
and the persistence of anxiety and harm avoidance symptoms after recovery suggest these are
Kaye Page 10
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
traits that contribute to the pathogenesis of AN and BN. The PET imaging data suggest that
such behaviors are related to disturbances of 5-HT and DA neurotransmitter function in limbic
and executive pathways.
Implications
Phillips (94) has described a ventral limbic system, which includes the amygdale, insula, ventral
striatum, and ventral regions of the anterior cingulate gyrus and prefrontal cortex, which
identifies the emotional significance of a stimulus and the production of an affective state in
response to that stimulus. In addition, these regions are important for automatic regulation and
mediation of autonomic responses to emotional stimuli and contexts accompanying the
production of affective states.
The findings described above offer evidence that individuals with ED have 5-HT and DA
dysregulation within brain regions that constitute limbic circuits. In general, such alterations
tend to be present in the ill state and persist after recovery. Patterns of 5-HT receptor binding
vary by subtype in the REC subjects, raising the possibility that each ED subtype has a unique
pathophysiology. (Table 3) Similar patterns of binding (elevated 5-HT1A and reduced 5-
HT2A) were also found in other temporal, cingulate, and parietal regions suggesting a
widespread distribution involving more that just limbic function. We also found that REC AN
had increased binding of the DA D2/D3 receptors in the AVS.
Drawing inferences about behavior from these 5-HT and DA findings is speculative. Moreover,
no receptor works in isolation in the brain. Monoamine enervation of limbic pathways is
complex, and involves many pathways, receptors, enzymes, intracellular transcription
messengers, other neurotransmitters and molecules. It can be hypothesized that these receptor
findings might reflect the “health” of the 5-HT and DA function within limbic circuits, but not
necessarily be the specific cause of these disorders. The genetic literature suggests that
behavioral disorders are complex, and consist of multiple factors, each of small effect. Finally,
altered 5-HT and DA receptor binding is often found in depression and anxiety, although
patterns of binding tend to be different. Disturbances of affect and impulse regulation may
involve similar pathways, but with very different patterns of molecular disturbances.
Feeding behavior
Within the limbic system are brain regions that contribute to rewarding and sensory aspects of
feeding behavior. That is, a primary taste cortex resides in the rostral insula and adjoining
frontal operculum (189-192). Some studies argue that these regions provide a representation
of food in the mouth that is independent of hunger, and thus is of reward value (193). The
responsiveness of taste neurons in secondary regions, such as the OFC, computes the hedonic
value of food (193-195). Other studies (196) raise the possibility that the insula and OFC
contribute to feeding behavior by encoding changes in the value of food reward in addition to
sensory processing, suggesting overlapping representations of sensory and affective processing
of taste. As described above, previous brain imaging studies have shown pictures of food to
emaciated and malnourished AN individuals. These studies found altered activity not only in
the insula and OFC, but in broad regions including mesial temporal, parietal, and the anterior
cingulate cortex when ill AN subjects were compared to controls (122,125-127,129,197).
Our group (198) is the first to use fMRI to investigate the effect of administration of nutrients
to REC RAN individuals. Compared to CW, the remitted AN subjects had a significantly
reduced fMRI signal response to the blind administration of sucrose or water in the insula,
anterior cingulate and striatal regions (Figure 3). Importantly, REC AN and CW also showed
differences in correlations between experience of pleasant taste and brain activation. For CW,
self-ratings of pleasantness of the sugar taste were positively correlated to the signal response
Kaye Page 11
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
in the insula, anterior cingulate, and ventral and dorsal putamen. In comparison, REC AN
individuals failed to show any relationship in these regions to self-ratings of pleasant response
to a sucrose taste.
In general the anterior, less differentiated half of the insula (199-202) receives the majority of
projections from the amygdala and thalamic taste centers, making it an ideal site for the
formulation of hedonic representations of taste. Consistent with this, anterior portions of the
insula have been shown to be differentially activated to the intensity and valence of pleasant
and unpleasant tastes (196), and are thus important to examine in the eating disordered
population. A large literature shows that the anterior insula and associated gustatory cortex
responds not only to the taste and physical properties of food, but also to its rewarding properties
(196,203,204). Animal models show that fine-tuning of feeding responses to salient food items
is lost after insula lesions. For example, the natural devaluation of food after feeding to satiety
is attenuated in lesioned animals, suggesting that the insula encodes representations of the
incentive value of taste under specific conditions (205). Similarly, appropriate avoidance of
foods previously associated to sickening agents is lost after insula lesions, providing further
evidence that the insula encodes the incentive value of taste in particular circumstances
(206).
Our results in the insula are reinforced by parallel findings in basal ganglia subregions that
receive insular inputs. While the entire striatum receives inputs from the insula as a whole, the
ventral putamen is a specific recipient of inputs from anterior insular regions encompassing
the gustatory cortex (207). The ventral putamen in turn projects to the globus pallidus, another
region with significant alterations in signal. The pattern of relatively decreased signal in these
interconnected structures suggests a circuit-wide disturbance in REC AN. Insular inputs to the
striatum are hypothesized to mediate behaviors involving eating, particularly of highly
palatable, high energy foods. The ventrolateral striatal subregions, including the ventral
putamen, have been especially implicated (208). AN subjects tend to avoid high calorie,
palatable food. In theory, this is consistent with abnormal responses of insula-striatal circuits
that are hypothesized to mediate behavioral responses to the incentive value of food.
The insula and interoceptive awareness
Do individuals with AN have an insular disturbance specifically related to gustatory
modulation, or a more generalized disturbance related to the integration of interoceptive
stimuli? The insula is thought to play an important role in processing interoceptive information,
which can be defined as the sense of the physiological condition of the entire body (209). Aside
from taste, interoceptive information includes sensations such as temperature, touch, muscular
and visceral sensations, vasomotor flush, airhunger and others (210). The role of the insula is
thus focused on how the value of stimuli might affect the body state. Interoception has long
been thought to be critical for self-awareness because it provides the link between cognitive
and affective processes and the current body state. The insula has bidirectional connections to
limbic regions, including the amygdale, nucleus accumbens (211) and OFC (212). Thus the
insular cortex is centrally placed to receive information about the salience (both appetitive and
aversive) and relative value of the stimulus environment and integrate this information with
the effect that these stimuli may have on the body state. The insula plays a key role in
interoceptive monitoring of the sensations that are important for the integrity of the internal
body state and connecting to systems, through dorsolateral striatal pathways that are important
for allocating attention, evaluating context, and planning actions (209,210,213).
Individuals with ED have a complex of puzzling symptoms, for which there has been no
neurobiological explanation. Many of the symptoms commonly found in AN, such as distorted
body image, lack of recognition of the symptoms of malnutrition, could be related to disturbed
interoceptive awareness. In support of this possibility, only the controls, but not the REC RAN,
Kaye Page 12
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
showed a positive relationship between self-ratings of pleasantness and the intensity of the
signal for sugar in the insula, ventral and dorsal putamen as well as anterior cingulate cortex.
In addition, for example, studies have consistently found that AN and BN individuals have
elevated pain thresholds (214), which persists after recovery (215), and is potentially a marker
of altered interoceptive awareness. While more speculative, it is possible that other symptoms,
such as diminished insight and motivation to change, and altered central coherence, could be
related to disturbed interoceptive awareness. Those with AN fail to accurately recognize and
incorporate affective and social stimuli in the environment, as confirmed by laboratory tests
(19,20). Furthermore, individuals with AN have enhanced ability to pay attention to detail or
use a logical/analytic approach, but exhibit worse performance with global strategies (19,22).
Conclusion
We hypothesize that a trait-related disturbance of 5-HT neuronal modulation predates the onset
of AN and contributes to premorbid symptoms of anxiety and inhibition. This dysphoric
temperament may involve an inherent dysregulation of emotional and reward pathways (216)
which also mediate the hedonic aspects of feeding, thus making these individuals vulnerable
to disturbed appetitive behaviors. This 5-HT disturbance contributes to a vulnerability for
restricted eating and dysphoric mood states such as increased harm avoidance. Most
importantly, we think that restricting food intake is powerfully reinforcing because it provides
a temporary respite from dysphoric mood. Several factors may act on these vulnerabilities to
cause AN to start in adolescence. First, puberty-related female gonadal steroids or age-related
changes may exacerbate 5-HT dysregulation. Second, stress and/or cultural and societal
pressures may contribute by increasing anxious and obsessional temperament. We hypothesize
that people with AN may discover that reduced dietary intake, by reducing plasma TRP
availability (80), is a means by which they can crudely modulate brain 5-HT functional activity
and anxious mood (66). People with AN enter a vicious cycle which accounts for the chronicity
of this disorder because caloric restriction results in a brief respite from dysphoric mood.
However, malnutrition and weight loss, in turn, produce alterations in many neuropeptides and
monoamine function, perhaps in the service of conserving energy, but which also exaggerates
dysphoric mood. Thus those with AN pursue starvation in an attempt to avoid the dysphoric
consequences of eating. SSRI administration does not appear to be effective in counteracting
5-HT disturbances in patients will with AN, perhaps because of the extreme changes induced
by malnutrition in the 5-HT1A receptor and extracellular 5-HT concentrations.
References
1. Strober, M. Family-genetic perspectives on anorexia nervosa and bulimia nervosa. In: Brownell, K.;
Fairburn, C., editors. Eating Disorders and Obesity-A Comprehensive Handbook. New York: The
Guilford Press; 1995. p. 212-218.
2. Hoek HW, Bartelds AI, Bosveld JJ, van der Graaf Y, Limpens VE, Maiwald M, Spaaij CJ. Impact of
urbanization on detection rates of eating disorders. Am J Psychiatry 1995;152(9):1272–8. [PubMed:
7653680]
3. Treasure J, Campbell I. The case for biology in the aetiology of anorexia nervosa. Psychol Med 1994;24
(1):3–8. [PubMed: 8208892]
4. Kendler KS, MacLean C, Neale M, Kessler R, Heath A, Eaves L. The genetic epidemiology of bulimia
nervosa. Am J Psychiatry 1991;148(12):1627–37. [PubMed: 1842216]
5. Schweiger, U.; Fichter, M. Eating Disorders: Clinical presentation, classification and etiologic models.
In: Jimerson, DC.; Kaye, WH., editors. Balliere’s Clinical Psychiatry. London: Balliere’s Tindall;
1997. p. 199-216.
6. Lilenfeld LR, Kaye WH, Greeno CG, Merikangas KR, Plotnicov K, Pollice C, Rao R, Strober M, Bulik
CM, Nagy L. A controlled family study of anorexia nervosa and bulimia nervosa: psychiatric disorders
Kaye Page 13
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
in first-degree relatives and effects of proband comorbidity. Arch Gen Psychiatry 1998;55(7):603–
610. [PubMed: 9672050]
7. Strober M, Freeman R, Lampert C, Diamond J, Kaye W. Controlled family study of anorexia nervosa
and bulimia nervosa: evidence of shared liability and transmission of partial syndromes. Am J
Psychiatry 2000;157(3):393–401. [PubMed: 10698815]
8. Klump KL, McGue M, Iacono WG. Genetic and environmental influences on anorexia nervosa
syndromes in a population-based sample of twins. Psychol Med 2001;31:737–740. [PubMed:
11352375]
9. Wade TD, Bulik CM, Neale M, Kendler KS. Anorexia nervosa and major depression: Shared genetic
and environmental risk factors. American Journal of Psychiatry 2000;157(3):469–471. [PubMed:
10698830]
10. Bulik C, Sullivan PF, Tozzi F, Furberg H, Lichtenstein P, Pedersen NL. Prevalence, heritability and
prospective risk factors for anorexia nervosa. Archives of General Psychiatry 2006;63(3):305–312.
[PubMed: 16520436]
11. Bulik CM, Sullivan PF, Kendler KS. Heritability of binge-eating and broadly defined bulimia nervosa.
Biol Psychiatry 1998;44(12):1210–8. [PubMed: 9861464]
12. Vitousek K, Manke F. Personality variables and disorders in anorexia nervosa and bulimia nervosa.
J Abnorm Psychol 1994;103(1):137–147. [PubMed: 8040475]
13. Shroff H, Reba L, Thornton L, Tozzi F, Klump K, Berrettini W, Brandt H, Crawford S, Crow S,
Fichter M, Goldman D, Halmi K, Johnson C, Kaplan A, Keel P, LaVia M, Mitchell J, Rotondo A,
Strober M, Treasure J, woodside D, Kaye WH, Bulik C. Features associated with excessive exercise
in women with eating disorders. Int J Eat Disord 2006;39:454–461. [PubMed: 16637047]
14. Halmi K, Agras WS, Crow S, Mitchell J, Wilson G, Bryson S, Kraemer HC. Predictors of treatment
acceptance and completion in anorexia nervosa. Arch Gen Psychiatry 2005;62:776–781. [PubMed:
15997019]
15. Kaye W, Bulik C, Thornton L, Barbarich N, Masters K, Fichter M, Halmi K, Kaplan A, Strober M,
Woodside DB, Bergen A, Crow S, Mitchell J, Rotondo A, Mauri M, Cassano G, Keel PK, Plotnicov
K, Pollice C, Klump K, Lilenfeld LR, Devlin B, Quadflieg R, Berrettini WH. Comorbidity of anxiety
disorders with anorexia and bulimia nervosa. Am J Psychiatry 2004;161:2215–2221. [PubMed:
15569892]
16. Godart NT, Flament MF, Perdereau F, Jeammet P. Comorbidity between eating disorders and anxiety
disorders: a review. Int J Eat Disord 2002;32(3):253–270. [PubMed: 12210640]
17. Godart N, Perdereau F, Rein Z, Berthoz S, Wallier J, Jeammet P, Flament M. Comorbidity studies
of eating disorders and mood disorders. Critical review of the literature. J Affect Disord 2007;97(13):
37–49. [PubMed: 16926052]
18. Cassin S, von Ranson K. Personality and eating disorders: a decade in review. Clin Psychol Rev
2005;25(7):895–916. [PubMed: 16099563]
19. Strupp BJ, Weingartner H, Kaye W, Gwirtsman H. Cognitive processing in anorexia nervosa. A
disturbance in automatic information processing. Neuropsychobiology 1986;15(2):89–94. [PubMed:
3762904]
20. Kingston K, Szmukler G, Andrewes D, Tress B, Desmond P. Neuropsychological and structural brain
changes in anorexia nervosa before and after refeeding. Psychol Med 1996;26(1):15–28. [PubMed:
8643754]
21. Tchanturia K, Campbell I, Morris R, Treasure J. Neuropsychological studies in anorexia nervosa. Int
J Eat Disord 2005;37:S72–S76. [PubMed: 15852325]
22. Lopez C, Tchanturia K, Stahl D, Booth R, Holliday J, Treasure J. An examination of central coherence
in women with anorexia nervosa. Submitted
23. Fairburn CG, Welch SL, Doll HA, Davies BA, O’Connor ME. Risk factors for bulimia nervosa. A
community-based case-control study. Arch Gen Psychiatry 1997;54(6):509–17. [PubMed: 9193191]
24. Anderluh MB, Tchanturia K, Rabe-Hesketh S, Treasure J. Childhood obsessive-compulsive
personalitiy traits in adult women with eating disorders: defining a broader eating disorder phenotype.
Am J Psychiatry 2003;160(2):242–247. [PubMed: 12562569]
25. Deep AL, Nagy LM, Weltzin TE, Rao R, Kaye WH. Premorbid onset of psychopathology in long-
term recovered anorexia nervosa. Int J Eat Disord 1995;17(3):291–297. [PubMed: 7773266]
Kaye Page 14
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
26. Godart NT, Flament MF, Lecrubier Y, Jeammet P. Anxiety disorders in anorexia nervosa and bulimia
nervosa: co-morbidity and chronology of appearance. Eur Psychiatry 2000;15(1):38–45. [PubMed:
10713801]
27. Bulik CM, Sullivan PF, Fear J, Pickering A. Predictors of the development of bulimia nervosa in
women with anorexia nervosa. J Nerv Ment Dis 1997;185(11):704–7. [PubMed: 9368548]
28. Bulik CM, Sullivan PF, Fear JL, Joyce PR. Eating disorders and antecedent anxiety disorders: a
controlled study. Acta Psychiatr Scand 1997;96(2):101–7. [PubMed: 9272193]
29. Pollice C, Kaye WH, Greeno CG, Weltzin TE. Relationship of depression, anxiety, and obsessionality
to state of illness in anorexia nervosa. Int J Eat Disord 1997;21(4):367–76. [PubMed: 9138049]
30. Casper RC. Personality features of women with good outcome from restricting anorexia nervosa.
Psychosom Med 1990;52(2):156–170. [PubMed: 2330389]
31. Srinivasagam NM, Kaye WH, Plotnicov KH, Greeno C, Weltzin TE, Rao R. Persistent perfectionism,
symmetry, and exactness after long-term recovery from anorexia nervosa. Am J Psychiatry 1995;152
(11):1630–1634. [PubMed: 7485626]
32. Strober M. Personality and symptomatological features in young, nonchronic anorexia nervosa
patients. J Psychosom Res 1980;24(6):353–9. [PubMed: 7205724]
33. Kaye WH, Greeno CG, Moss H, Fernstrom J, Fernstrom M, Lilenfeld LR, Weltzin TE, Mann JJ.
Alterations in serotonin activity and psychiatric symptomatology after recovery from bulimia
nervosa. Arch Gen Psychiatry 1998;55(10):927–935. [PubMed: 9783564]
34. Klein D, Walsh B. Eating disorders. Int Rev Psychiatry 2003;15:205–216. [PubMed: 15276960]
35. Connan F, Campbell I, Katzman M, Lightman S, Treasure J. A neurodevelopmental model for
anorexia nervosa. Physiol Behav 2003;79(1):13–24. [PubMed: 12818706]
36. Klump KL, McGue M, Iacono WG. Age differences in genetic and environmental influences on
eating attitudes and behaviors in preadolescent and adolescent female twins. Journal of Abnormal
Psychology 2000;109(2):239–251. [PubMed: 10895562]
37. Rubinow DR, Schmidt PJ, Roca CA. Estrogen-serotonin interactions: implications for affective
regulation. Biol Psychiatry 1998;44(9):839–50. [PubMed: 9807639]
38. Torpy D, Papanicolaou D, Chrousos G. Sexual dismorphism of the human stress response may be
due to estradiol-mediated stimulation of hypothalamic corticotropin-releasing hormone synthesis. J
Clin Endocrinol Metab 1997;82:982. [PubMed: 9062517]
39. Benes F. Brain development, VII: Human brain growth spans decades. Am J Psychiatry
1998;155:1489. [PubMed: 9812107]
40. Jimerson, DC.; Wolfe, BE.; Naab, S. Anorexia nervosa and bulimia nervosa. In: Coffee, CE.;
Brumback, RA., editors. Textbook of Pediatric Neuropsychiatry. Washington, D.C.: American
Psychiatric Press; 1998. p. 563-578.
41. Stoving RK, Hangaard J, Hansen-Nord M, Hagen C. A review of endocrine changes in anorexia
nervosa. J Psychiatr Res 1999;33:139–152. [PubMed: 10221746]
42. Morton G, Cummings D, Baskin D, Barsh G, Schwartz M. Central nervous system control of food
intake and body weight. Nature 2006;443(7109):289–295. [PubMed: 16988703]
43. Morley JE, Blundell JE. The neurobiological basis of eating disorders: some formulations. Biol
Psychiatry 1988;23(1):53–78. [PubMed: 2892538]
44. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food
intake. Nature 2000;404(6778):661–71. [PubMed: 10766253]
45. Kaye, W.; Strober, M.; Jimerson, D. The neurobiology of eating disorders. In: Charney, DS.; Nestler,
EJ., editors. The Neurobiology of Mental Illness. New York: Oxford Press; 2004. p. 1112-1128.
46. Vink T, Hinney A, van Elburg AA, van Goozen SH, Sandkuijl LA, Sinke RJ, Herpertz-Dahlmann
BM, Hebebrand J, Remschmidt H, van Engeland H, Adan RA. Association between an agouti-related
protein gene polymorphism and anorexia nervosa. Molecular Psychiatry 2001;6(3):325–8. [PubMed:
11326303]
47. Siegfried Z, Kanyas K, Latzer Y, Karni O, Bloch M, Lerer B, Berry E. Association Study of
Cannabinoid Receptor Gene (CNR1) Alleles and Anorexia Nervosa: Differences Between
Restricting and Bingeing/Purging Subtypes. Am J Med Genetics Part B (Neuropsychiatric Genetics)
2004;125B:126–130.
Kaye Page 15
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
48. Cooper SJ. Cholecystokinin modulation of serotonergic control of feeding behavior. Ann N Y Acad
Sci 1996;780:213–222. [PubMed: 8602735]
49. Blundell JE. Serotonin and appetite. Neuropharmacology 1984;23(12B):1537–51. [PubMed:
6152027]
50. Leibowitz SF, Shor-Posner G. Brain serotonin and eating behavior. Appetite 1986;7(Suppl):1–14.
[PubMed: 2874768]
51. Soubrie P. Reconciling the role of central serotonin neurons in human and animal behavior. Beh Brain
Sci 1986;9:319.
52. Cloninger CR. A systematic method for clinical description and classification of personality variants.
A proposal. Arch Gen Psychiatry 1987;44(6):573–88. [PubMed: 3579504]
53. Higley JD, Linnoila M. Low central nervous system serotonergic activity is traitlike and correlates
with impulsive behavior. A nonhuman primate model investigating genetic and environmental
influences on neurotransmission. Ann NY Acad Sci 1997;836:39–56. [PubMed: 9616793]
54. Lucki I. The spectrum of behaviors influenced by serotonin. Biol Psychiatry 1998;44(3):151–62.
[PubMed: 9693387]
55. Mann JJ. Role of the serotonergic system in the pathogenesis of major depression and suicidal
behavior. Neuropsychopharmacology 1999;21(2 Suppl):99S–105S. [PubMed: 10432495]
56. Brewerton, TD.; Brandt, HA.; Lessem, MD.; Murphy, DL.; Jimerson, DC. Serotonin in eating
disorders. In: Coccaro, EF.; Murphy, DL., editors. Serotonin in major psychiatric disorders. Progress
in psychiatry. 21. Washington, DC, US: American Psychiatric Press, Inc; 1990. p. 155-84.
57. Jimerson DC, Wolfe BE, Metzger ED, Finkelstein DM, Cooper TB, Levine JM. Decreased serotonin
function in bulimia nervosa. Arch Gen Psychiatry 1997;54(6):529–34. [PubMed: 9193193]
58. Walsh BT, Devlin MJ. Eating disorders: progress and problems. Science 1998;280(5368):1387–1390.
[PubMed: 9603723]
59. Steiger H, Young SN, Kin NM, Koerner N, Israel M, Lageix P, Paris J. Implications of impulsive
and affective symptoms for serotonin function in bulimia nervosa. Psychol Med 2001;31(1):85–95.
[PubMed: 11200963]
60. Kaye WH, Ebert MH, Raleigh M, Lake R. Abnormalities in CNS monoamine metabolism in anorexia
nervosa. Archives of General Psychiatry 1984;41(4):350–5. [PubMed: 6200083]
61. Kaye WH, Gwirtsman HE, George DT, Jimerson DC, Ebert MH. CSF 5-HIAA concentrations in
anorexia nervosa: reduced values in underweight subjects normalize after weight gain. Biol
Psychiatry 1988;23(1):102–5. [PubMed: 2447961]
62. Kaye WH, Gwirtsman HE, George DT, Jimerson DC, Ebert MH, Lake CR. Disturbances of
noradrenergic systems in normal weight bulimia: relationship to diet and menses. Biol Psychiatry
1990;27(1):4–21. [PubMed: 2297551]
63. Kaye WH, Gwirtsman HE, George DT, Ebert MH. Altered serotonin activity in anorexia nervosa
after long-term weight restoration. Does elevated cerebrospinal fluid 5-hydroxyindoleacetic acid
level correlate with rigid and obsessive behavior? Arch Gen Psychiatry 1991;48(6):556–62.
[PubMed: 1710099]
64. Jimerson DC, Lesem MD, Kaye WH, Brewerton TD. Low serotonin and dopamine metabolite
concentrations in cerebrospinal fluid from bulimic patients with frequent binge episodes. Arch Gen
Psychiatry 1992;49(2):132–8. [PubMed: 1372494]
65. Ward A, Brown N, Lightman S, Campbell IC, Treasure J. Neuroendocrine, appetitive and behavioural
responses to d-fenfluramine in women recovered from anorexia nervosa. Br J Psychiatry
1998;172:351–358. [PubMed: 9715339]
66. Kaye WH, Barbarich NC, Putnam K, Gendall KA, Fernstrom J, Fernstrom M, McConaha CW,
Kishore A. Anxiolytic effects of acute tryptophan depletion in anorexia nervosa. Int J Eat Disord
2003;33(3):257–267. [PubMed: 12655621]
67. Smith KA, Morris JS, Friston KJ, Cowen PJ, Dolan RJ. Brain mechanisms associated with depressive
relapse and associated cognitive impairment following acute tryptophan depletion. Brit J Psychiatry
1999;174:525–9. [PubMed: 10616631]
68. Frank GK, Kaye WH, Weltzin TE, Perel J, Moss H, McConaha C, Pollice C. Altered response to
meta-chlorophenylpiperazine in anorexia nervosa: support for a persistent alteration of serotonin
activity after short-term weight restoration. Int J Eat Disord 2001;30(1):57–68. [PubMed: 11439409]
Kaye Page 16
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
69. Steiger H, Richardson J, Israel M, Ng Ying Kin NM, Bruce K, Mansour S, Marie Parent A. Reduced
density of platelet-binding sites for [3H]paroxetine in remitted bulimic women.
Neuropsychopharmacology 2005;30(5):1028–1032. [PubMed: 15841087]
70. Fernstrom JD, Wurtman RJ. Brain serotonin content: increase following ingestion of carbohydrate
diet. Science 1971;174(13):1023–5. [PubMed: 5120086]
71. Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological regulation by plasma neutral
amino acids. Science 1972;178(59):414–6. [PubMed: 5077329]
72. Biggio G, Fadda F, Fanni P, Tagliamonte A, Gessa GL. Rapid depletion of serum tryptophan, brain
tryptophan, serotonin and 5- hydroxyindoleacetic acid by a tryptophan-free diet. Life Sci 1974;14
(7):1321–9. [PubMed: 4823644]
73. Messing RB, Fisher LA, Phebus L, Lytle LD. Interaction of diet and drugs in the regulation of brain
5- hydroxyindoles and the response to painful electric shock. Life Sci 1976;18(7):707–14. [PubMed:
131230]
74. Gibbons JL, Barr GA, Bridger WH, Leibowitz SF. Manipulations of dietary tryptophan: effects on
mouse killing and brain serotonin in the rat. Brain Res 1979;169(1):139–53. [PubMed: 572256]
75. Young SN, Gauthier S. Effect of tryptophan administration on tryptophan, 5- hydroxyindoleacetic
acid and indoleacetic acid in human lumbar and cisternal cerebrospinal fluid. J Neurol Neurosurg
Psychiatry 1981;44(4):323–327. [PubMed: 6165809]
76. Anderson IM, Parry-Billings M, Newsholme EA, Fairburn CG, Cowen PJ. Dieting reduces plasma
tryptophan and alters brain 5-HT function in women. Psychol Med 1990;20(4):785–91. [PubMed:
2284387]
77. Huether G, Zhou D, Ruther E. Long-term modulation of presynaptic 5-HT-output: experimentally
induced changes in cortical 5-HT-transporter density, tryptophan hydroxylase content and 5-HT
innervation density. J Neural Transm Gen Sect 1997;104(10):993–1004.
78. Goodwin GM, Fairburn CG, Cowen PJ. The effects of dieting and weight loss on neuroendocrine
responses to tryptophan, clonidine, and apomorphine in volunteers. Important implications for
neuroendocrine investigations in depression. Arch Gen Psychiatry 1987;44(11):952–7. [PubMed:
3675135]
79. Goodwin GM, Fairburn CG, Cowen PJ. Dieting changes serotonergic function in women, not men:
implications for the aetiology of anorexia nervosa? Psychol Med 1987;17(4):839–42. [PubMed:
3432460]
80. Schweiger U, Warnhoff M, Pahl J, Pirke KM. Effects of carbohydrate and protein meals on plasma
large neutral amino acids, glucose, and insulin plasma levels of anorectic patients. Metabolism
1986;35(10):938–43. [PubMed: 3531760]
81. Graeff FG, Guimaraes FS, De Andrade TG, Deakin JF. Role of 5-HT in stress, anxiety, and depression.
Pharmacology, Biochemistry & Behavior 1996;54(1):129–141.
82. Thomas DR, Gager TL, Holland V, Brown AM, Wood MD. m-Chlorophenylpiperazine (mCPP) is
an antagonist at the cloned human 5- HT2B receptor. Neuroreport 1996;7(9):1457–1460. [PubMed:
8856697]
83. Willins DL, Meltzer HY. Direct injection of 5-HT2A receptor agonists into the medial prefrontal
cortex produces a head-twitch response in rats. J Pharmacol Exp Ther 1997;282(2):699–706.
[PubMed: 9262333]
84. Hoyer D, Neijt HC, Karpf A. Competitive interaction of agonists and antagonists with 5-HT3
recognition sites in membranes of neuroblastoma cells labelled with [3H]ICS 205-930. J Recept Res
1989;9(1):65–79. [PubMed: 2915346]
85. Kahn RS, Wetzler S. m-Chlorophenylpiperazine as a probe of serotonin function. Biol Psychiatry
1991;30(11):1139–66. [PubMed: 1663792]
86. Hadigan CM, Walsh BT, Buttinger C, Hollander E. Behavioral and neuroendocrine responses to
metaCPP in anorexia nervosa. Biol Psychiatry 1995;37(8):504–11. [PubMed: 7619973]
87. Fluoxetine Bulimia Nervosa Collaborative Study Group. Fluoxetine in the treatment of bulimia
nervosa. A multicenter, placebo-controlled, double-blind trial. Arch Gen Psychiatry 1992;49(2):139–
147. [PubMed: 1550466]
88. Walsh BT, Devlin MJ. Pharmacotherapy of bulimia nervosa and binge eating disorder. Addictive
Behaviors 1995:757–764. [PubMed: 8820528]
Kaye Page 17
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
89. Kaye WH, Nagata T, Weltzin TE, Hsu LK, Sokol MS, McConaha C, Plotnicov KH, Weise J, Deep
D. Double-blind placebo-controlled administration of fluoxetine in restricting- and restricting-
purging-type anorexia nervosa. Biol Psychiatry 2001;49(7):644–52. [PubMed: 11297722]
90. Walsh B, Kaplan A, Attia E, Olmsted M, Parides M, Carter J, Pike K, Devlin M, Woodside B, Roberto
C, Rocket W. Fluoxetine After Weight Restoration in Anorexia Nervosa: A Randomized Controlled
Trial. JAMA 2006;295:2605–2612. [PubMed: 16772623]
91. Kaye WH, Weltzin TE, Hsu LK, Bulik CM. An open trial of fluoxetine in patients with anorexia
nervosa. Journal of Clinical Psychiatry 1991;52(11):464–71. [PubMed: 1744064]
92. Kaye WH, Frank GK, McConaha C. Altered dopamine activity after recovery from restricting-type
anorexia nervosa. Neuropsychopharm 1999;21(4):503–6.
93. Bergen A, Yeager M, Welch R, Haque K, Ganjei JK, Mazzanti C, Nardi I, van den Bree MBM, Fichter
M, Halmi K, Kaplan A, Strober M, Treasure J, Woodside DB, Bulik C, Bacanu A, Devlin B, Berrettini
WH, Goldman D, Kaye W. Association of multiple DRD2-141 polymorphism with anorexia nervosa.
Neuropsychopharm 2005;30(9):1703–1710.
94. Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of Emotion Perception I: The Neural
Basis of Normal Emotion Perception. Biol Psychiatry 2003;54:504–514. [PubMed: 12946879]
95. Yin H, Knowlton B. The role of the basal ganglia in habit formation. Nature Neuroscience Rev 2006;7
(6):464–476.
96. Haber SN, Kim K, Mailly P, Calzavara R. Reward-related cortical inputs define a large striatal region
in primates that interface with associative cortical connections, providing a substrate for incentive-
based learning. J Neurosci 2006;26(32):8368–8376. [PubMed: 16899732]
97. Halford J, Cooper G, Dovey T. The pharmacology of human appetite expression. Curr Drug Targets
2004;5:221–240. [PubMed: 15058309]
98. Heinz ER, Martinez J, Haenggeli A. Reversibility of Cerebral Atrophy in Anorexia Nervosa and
Cushing’s Syndrome. Journal of Computer Assisted Tomography 1977;1(4):415–418. [PubMed:
615219]
99. Nussbaum M, Shenker IR, Marc J, Klein M. Cerebral atrophy in anorexia nervosa. Journal of
Pediatrics 1980;96(5):867–869. [PubMed: 7365589]
100. Zeumer H, Hacke W, Hartwich P. A Quantitative Approach to Measuring the Cerebrospinal Fluid
Space with CT. Neuroradiology 1982;22:193–197. [PubMed: 7057991]
101. Kohlmeyer K, Lehmkuhl G, Poustka F. Computed Tomography of Anorexia Nervosa. AJNR
1983;4:437–438. [PubMed: 6410765]
102. Artmann H, Grau H, Adelmann M, Schleiffer R. Reversible and non-reversible enlargement of
cerebrospinal fluid spaces in anorexia nervosa. Neuroradiology 1985;27(4):304–312. [PubMed:
3876520]
103. Dolan RJ, Mitchell J, Wakeling A. Structural brain changes in patients with anorexia nervosa.
Psychological Medicine 1988;18:349–353. [PubMed: 3399587]
104. Krieg JC, Pirke KM, Lauer C, Backmund H. Endocrine, metabolic, and cranial computed
tomographic findings in AN. Biol Psychiatry 1988;23:377–387. [PubMed: 3342267]
105. Palazidou E, Robinson PS, Lishman WA. Neuroradiological and neuropsychological assessment in
anorexia nervosa. Psychol Med 1990;20(3):521–527. [PubMed: 2236361]
106. Lankenau H, Swigar M, Bhimani S, Luchins D, Quainlan D. Cranial CT scans in eating disorder
patients and controls. Compr Psychiatry 1985;26(2):136–147. [PubMed: 3857156]
107. Krieg JC, Lauer C, Pirke KM. Structural brain abnormalities in patients with bulimia nervosa.
Psychiatry Research 1989;27:39–48. [PubMed: 2922442]
108. Katzman DK, Lambe EK, Mikulis DJ, Ridgley JN, Goldbloom DS, Zipursky RB. Cerebral gray
matter and white matter volume deficits in adolescent girls with anorexia nervosa. Journal of
Pediatrics 1996;129:794–803. [PubMed: 8969719]
109. Swayze VW, Andersen A, Arndt S, Rajarethinam R, Fleming F, Sato Y, Andreasen NC. Reversibility
of brain tissue loss in anorexia nervosa assessed with a computerized Talairach 3-D proportional
grid. Psychol Med 1996;26(2):381–90. [PubMed: 8685294]
110. Golden NH, Ashtari M, Kohn MR, Patel M, Jacobson MS, Fletcher A, Shenker IR. Reversibility of
cerebral ventricular enlargement in anorexia nervosa, demonstrated by quantitative magnetic
resonance imaging. Journal of Pediatrics 1996;128:296–301. [PubMed: 8636835]
Kaye Page 18
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
111. Kornreich L, Shapira A, Horev G, Danzinger Y, Tyano S, Moimouni M. CT and MR Evaluation of
the Brain in Patients with Anorexia Nervosa. American Journal of Neuroradiology 1991;12:1213–
1216. [PubMed: 1763756]
112. Laessle RG, Krieg JC, Fichter MM, Pirke KM. Cerebral atrophy and vigilance performance in
patients with anorexia and bulimia nervosa. Neuropsychobiology 1989;21(4):187–191. [PubMed:
2630934]
113. Hoffman GW, Ellinwood EHJ, Rockwell WJ, Herfkens RJ, Nishita JK, Guthrie LF. Cerebral atrophy
in bulimia. Biol Psychiatry 1989;25(7):894–902. [PubMed: 2720004]
114. Husain MM, Black KJ, Doraiswamy PM, Shah SA, Rockwell WJ, Ellinwood EHJ, Krishnan KR.
Subcortical Brain Anatomy in Anorexia and Bulimia. Biol Psychiatry 1992;31:735–738. [PubMed:
1599990]
115. Wagner A, Ruf M, Braus DF, Schmidt MH. Neuronal activity changes and body image distortion
in anorexia nervosa. NeuroReport 2003;14(17):2193–2197. [PubMed: 14625446]
116. Bailer UF, Price JC, Meltzer CC, Mathis CA, Frank GK, Weissfeld L, McConaha CW, Henry SE,
Brooks-Achenbach S, Barbarich NC, Kaye WH. Altered 5-HT2A receptor binding after recovery
from bulimia-type anorexia nervosa: relationships to harm avoidance and drive for thinness.
Neuropsychopharmacology 2004;29(6):1143–1155. [PubMed: 15054474]
117. Gerstmann J. Fingeragnosie: eine umschriebene Storung der Orientierung am eigenen Korper. Wien
Kinische Wochenschr 1924;37:1010–1013.
118. Farrar C, Franck N, Georgieff N, Frith C, Decety J, Jeannerod M. Modulating the experience of
agency: a positron emission tomography study. Neuroimage 2003;18:324–333. [PubMed:
12595186]
119. Abraham S, Beaumont P. How patients describe bulimia or binge eating. Psychol Med 1982;12(3):
625–635. [PubMed: 6957905]
120. Kaye WH, Gwirtsman HE, George DT, Weiss SR, Jimerson DC. Relationship of mood alterations
to bingeing behaviour in bulimia. British Journal of Psychiatry 1986;149:479–85. [PubMed:
3814933]
121. Johnson C, Larson R. Bulimia: an analysis of mood and behavior. Psychosom Med 1982;44(4):341–
351. [PubMed: 6959174]
122. Nozoe S, Naruo T, Nakabeppu Y, Soejima Y, Nakajo M, Tanaka H. Changes in regional cerebral
blood flow in patients with anorexia nervosa detected through single photon emission tomography
imaging. Biol Psychiatry 1993;34(8):578–80. [PubMed: 8274589]
123. Nozoe S, Naruo T, Yonekura R, Nakabeppu Y, Soejima Y, Nagai N, Nakajo M, Tanaka H.
Comparison of regional cerebral blood flow in patients with eating disorders. Brain Res Bull
1995;36(3):251–5. [PubMed: 7697378]
124. Ellison Z, Foong J, Howard R, Bullmore E, Williams S, Treasure J. Functional anatomy of calorie
fear in anorexia nervosa. Lancet 1998;352(9135):1192. [PubMed: 9777839]
125. Naruo T, Nakabeppu Y, Sagiyama K, Munemoto T, Homan N, Deguchi D, Nakajo M, Nozoe S.
Characteristic regional cerebral blood flow patterns in anorexia nervosa patients with binge/purge
behavior. Am J Psychiatry 2000;157(9):1520–2. [PubMed: 10964876]
126. Gordon CM, Dougherty DD, Fischman AJ, Emans SJ, Grace E, Lamm R, Alpert NM, Majzoub JA,
Rausch SL. Neural substrates of anorexia nervosa: a behavioral challenge study with positron
emission tomography. J Pediatr 2001;139(1):51–57. [PubMed: 11445794]
127. Uher R, Murphy T, Brammer M, Dalgleish T, Phillips M, Ng V, Andrew C, Williams S, Campbell
I, Treasure J. Medial prefrontal cortex activity associated with symptom provocation in eating
disorders. Am J Psychiatry 2004;161(7):1238–1246. [PubMed: 15229057]
128. LeDoux J. The emotional brain, fear, and the amygdala. Cell Mol Neurobiol 2003;23(45):727–738.
[PubMed: 14514027]
129. Uher R, Brammer M, Murphy T, Campbell I, Ng V, Williams S, Treasure J. Recovery and chronicity
in anorexia nervosa: brain activity associated with differential outcomes. Biol Psychiatry
2003;54:934–942. [PubMed: 14573322]
130. Staley J, Malison R, Innis R. Imaging of the serotonergic system: interactions of neuroanatomical
and functional abnormalities of depression. Biological Psychiatry 1998;44(7):534–549. [PubMed:
9787877]
Kaye Page 19
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
131. Lanfumey L, Hamon M. Central 5-HT1A receptors: regional distribution and functional
characteristics. Nuclear Medicine & Biology 2000;27(5):429–435. [PubMed: 10962246]
132. Cervo L, Mocaer E, Bertaglia A, Samanin R. Roles of 5-HT1A receptors in the dorsal raphe and
dorsal hippocampus in anxiety assessed by the behavioral effects of 8-OH-DPAT and S 15535 in
a modified Geller-Seifter conflict model. Neuropharmacology 2000;39(6):1037–43. [PubMed:
10727714]
133. File SE, Kenny PJ, Cheeta S. The role of the dorsal hippocampal serotonergic and cholinergic
systems in the modulation of anxiety. Pharmacol Biochem Behav 2000;66(1):65. [PubMed:
10837844]
134. Olivier B, Pattij T, Wood S, Oosting R, Sarnyai Z, Toth M. The 5-HT1A receptor knockout mouse
and anxiety. Behavioural Pharmacology 2001;12(67):439–450. [PubMed: 11742137]
135. Matsubara S, Arora RC, Meltzer HY. Serotonergic measures in suicide brain: 5-HT1A binding sites
in frontal cortex of suicide victims. Journal of Neural Transmission - General Section 1991;85(3):
181–94. [PubMed: 1834090]
136. Arango V, Underwood MD, Gubbi AV, Mann JJ. Localized alterations in pre- and postsynaptic
serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Research
1995;688(12):121–33. [PubMed: 8542298]
137. Bailer UF, Frank G, Henry S, Price J, Meltzer C, Mathis C, Wagner A, Thornton L, Hoge J, Ziolko
SK, Becker C, McConaha C, Kaye WH. Exaggerated 5-HT1A but normal 5-HT2A receptor activity
in individuals ill with anorexia nervosa. Biol Psychiatry. 2007EPub ahead of Print
138. Bailer UF, Frank GK, Henry SE, Price JC, Meltzer CC, Weissfeld L, Mathis CA, Drevets WC,
Wagner A, Hoge J, Ziolko SK, McConana CW, Kaye WH. Altered brain serotonin 5-HT1A receptor
binding after recovery from anorexia nervosa measured by positron emission tomography and [11C]
WAY100635. Arch Gen Psychiatry 2005;62(2):1032. [PubMed: 16143735]
139. Tiihonen J, Keski-Rahkonen A, Lopponen M, Muhonen M, Kajander J, Allonen T, Nagren K, Hietala
J, Rissanen A. Brain serotonin 1A receptor binding in bulimia nervosa. Biol Psychiatry
2004;55:871. [PubMed: 15050870]
140. Groenink L, van Bogaert M, van der Gugten J, Oosting R. 5-HT1A receptor and 5-HT1B receptor
knockout mice in stress and anxiety paradigms. Behavioural Pharmacology 2003;14:369–383.
[PubMed: 14501251]
141. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET
imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;46(10):1375–87.
[PubMed: 10578452]
142. Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen
PJ. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]
WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000;57
(2):174–80. [PubMed: 10665620]
143. Bhagwagar Z, Rabiner E, Sargent P, Grasby P, Cowen P. Persistent reduction in brain
serotonin1A receptor binding in recovered depressed men mesured by positron emission
tomography with [11C]WAY-100635. Molecular Psychiatry 2004;9:386–392. [PubMed:
15042104]
144. Shively C, Friedman D, Gage H, Bounds M, Brown-Proctor C, Blair J, Henderson J, Smith M,
Buchheimer N. Behavioral depression and positron emission tomography-determined serotonin 1A
receptor binding potential in cynomolgus monkeys. Arch Gen Psychiatry 2006;63(4):396–403.
[PubMed: 16585468]
145. Parsey RV, Oquendo MA, Ogden RT, Olvet D, Simpson N, Huang Y, Van Heertum R, Arango V,
Mann JJ. Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635
positron emission tomography study. Biol Psychiatry 2005;59(2):106–113. [PubMed: 16154547]
146. Lanzenberger R, Mitterhauser M, Spindelegger C, Wadsak W, Klein N, Mien L, Holik A, Attarbaschi
T, Mossaheb N, Sacher J, Geiss-Granadia T, Keletter K, Kasper S, Tauscher J. Reduced
serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry 2007;61(9):1081–1089.
[PubMed: 16979141]
Kaye Page 20
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
147. Neumeister A, Brain E, Nugent A, Carson R, Bonne O, Lucnekbaugh D, Eckelman W, Herschovitch
P, Charney D, Drevets W. Reduced serotinin type 1A receptor binding in panic disorder. Journal
of Neuroscience 2004;24(3):589–591. [PubMed: 14736842]
148. Geyer MA. Serotonergic functions in arousal and motor activity. Behavioural Brain Research
1996;73:31. [PubMed: 8788473]
149. Fairbanks L, Melega W, Jorgensen M, Kaplan J, McGuire M. Social impulsivity inversely associated
with CSF 5-HIAA and fluoxetine exposure in vermet monkeys. Neuropschopharmacology 2001;24
(4):370–378.
150. Westergaard G, Suomi S, Chavanne T, Houser L, Hurley A, Cleveland A, Snoy P, Higley J.
Physiological correlates of aggression and impulsivity in free-ranging female primates.
Neuropsychopharmacology 2003;28:1045–1055. [PubMed: 12700686]
151. Johnson P, Lightman S, Lowry C. A functional subset of serotonergic neruons in the rat ventrolateral
periaqueductal gray implicated in the inhibition of sympathoexcitation and panic. Ann NY Acad
Sci 2004;1018:58. [PubMed: 15240352]
152. Winstanley CA, Theobald DE, Dalley JW, Robbins TW. Interactions between serotonin and
dopamine in the control of impulsive choice in rats: Therapeutic implications for impulse control
disorders. Neuropschopharmacology 2005;30:669.
153. Cleare A, Bond AJ. Ipaspirone challenge in aggressive men shows an inverse correlation between
5HT1A receptor function and aggression. Psychopharmacology (Berl) 2000;148:344. [PubMed:
10928305]
154. Coccaro EF, Gabriel S, Siever LJ. Buspirone challenge: preliminary evidence for a role of 5HT1A
receptors in behavioral irritability in personality disorderd patients. Psychopharmacol Bull
1990;26:285. [PubMed: 2274627]
155. Fischer P, Meltzer C, Ziolko S, Price J, Hariri AR. Capacity for 5-HT1A-mediated autoregulation
predicts amygdala reactivity. Nature Neuroscience 2007;9:1362.
156. Steiger H, Gauvin L, Israel M, LKoerner N, Ng Ying Kin NM, Paris J, Young SN. Association of
serotonin and cortisol indices with childhood abuse in bulimia nervosa. Arch Gen Psychiatry
2001;58(9):837–843. [PubMed: 11545666]
157. Steiger H, Koerner N, Engelberg MJ, Israel M, Ng Ying Kin NM, Young SN. Self-destructiveness
and serotonin function in bulimia nervosa. Psychiatry Res 2001;103(1):15–26. [PubMed:
11472787]
158. Burnet PW, Eastwood SL, Harrison PJ. [3H]WAY-100635 for 5-HT1A receptor autoradiography
in human brain: a comparison with [3H]8-OH-DPAT and demonstration of increased binding in
the frontal cortex in schizophrenia. Neurochem Int 1997;30(6):565–74. [PubMed: 9152998]
159. Saudou F, Hen R. 5-Hydroxytryptamine receptor subtypes in vertebrates and invertebrates.
Neurochem Int 1994;25(6):503–32. [PubMed: 7894328]
160. Bonhomme N, Esposito E. Involvement of serotonin and dopamine in the mechanism of action of
novel antidepressant drugs: a review. J Clin Psychopharmacol 1998;18(6):447–454. [PubMed:
9864076]
161. De Vry J, Schreiber R. Effects of selected serotonin 5-HT(1) and 5-HT(2) receptor agonists on
feeding behavior: possible mechanisms of action. Neurosci Biobehav Rev 2000;24(3):341–53.
[PubMed: 10781694]
162. Simansky KJ. Serotonergic control of the organization of feeding and satiety. Behav Brain Res
1996;73(12):37–42. [PubMed: 8788474]
163. Stockmeier CA. Neurobiology of serotonin in depression and suicide. Ann N Y Acad Sci
1997;836:220–32. [PubMed: 9616801]
164. Frank GK, Kaye WH, Meltzer CC, Price JC, Greer P, McConaha C, Skovira K. Reduced 5-HT2A
receptor binding after recovery from anorexia nervosa. Biol Psychiatry 2002;52:896–906.
[PubMed: 12399143]
165. Audenaert K, Van Laere K, Dumont F, Vervaet M, Goethals I, Slegers G, Mertens J, van Heeringen
C, Dierckx R. Decreased 5-HT2a receptor binding in patients with anorexia nervosa. J Nucl Med
2003;44(2):163–169. [PubMed: 12571204]
Kaye Page 21
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
166. Freedman LJ, Insel TR, Smith Y. Subcortical projections of area 25 (subgenual cortex) of the
macaque monkey. The Journal of Comparative Neurology 2000;421:172–188. [PubMed:
10813780]
167. Charney DS, Deutch A. A functional neuroanatomy of anxiety and fear: implications for the
pathophysiology and treatment of anxiety disorders. Crit Rev Neurobiol 1996;10(34):419–46.
[PubMed: 8978989]
168. Krebs-Thomson K, Geyer MA. Evidence for a functional interaction between 5-HT1A and 5-
HT2A receptors in rats. Psychopharmacology (Berl) 1998;140:69–74. [PubMed: 9862404]
169. Amargos-Bosch M, Bortolozzi A, Puig M, S J, Adell A, Celada P, Toth M, Mengod G, Artigas F.
Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal
neurons of prefrontal cortex. Cerebral Cortex 2004;14:281–299. [PubMed: 14754868]
170. Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F. Expression of serotoinin1A and
serotonin2A receptor in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb
Cortex 2004;1
171. Vollenweider F, Vontobel P, Hell D, Leenders K. 5-HT modulation of dopamine release in basal
ganglia in psilocybin-induced psychosis in man--a PET study with [11C]raclopride.
Neuropsychopharmacology 1999;20(5):424–433. [PubMed: 10192823]
172. Bailer U, Frank G, Henry S, Price J, Meltzer CC, Weissfeld L, Mathis C, Wagner A, Hoge J, Ziolko
SK, McConaha C, Kaye W. Altered serotonin transporter binding after recovery from bulimia-type
eating disorders measured by positron emission tomography and [11C]McN5652.
Psychopharmacology (Berl). In Press
173. Hajos M, Gartside SE, Varga V, Sharp T. In vivo inhibition of neuronal activity in the rat
ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT1A receptors.
Neuropharmacology 2003;45(1):72–81. [PubMed: 12814660]
174. Steiger H, Joober R, Israel M, Young S, Ng Ying Kin NM, Gauvin L, Bruce K, Joncas J, Torkaman-
Zehi A. The 5HTTLPR polymorphism, psychopathological symptoms, and platelet [3H-]
paroxetine binding in bulimic syndromes. Int J Eat Disord 2005;37(1):57–60. [PubMed: 15690467]
175. Frankle W, Lombardo I, New AS, Goodman M, Talbot P, Huang Y, Hwang D, Slifstein M, Curry
S, Abi-Dargham A, Lauruelle M, Siever L. Brain serotonin transporter distribution in subjects with
impulsive aggressivity: a positron emission study with [11C]McN 5652. Am J Psychiatry 2005;162
(5):915–923. [PubMed: 15863793]
176. Frank G, Bailer UF, Henry S, Drevets W, Meltzer CC, Price JC, Mathis C, Wagner A, Hoge J, Ziolko
SK, Barbarich N, Weissfeld L, Kaye W. Increased dopamine D2/D3 receptor binding after recovery
from anorexia nervosa measured by positron emission tomography and [11C]raclopride. Biol
Psychiatry 2005;58(11):908–912. [PubMed: 15992780]
177. Montague R, Hyman S, Cohen J. Computational roles for dopamine in behavioural control. Nature
2004;431:760–767. [PubMed: 15483596]
178. Schultz W. Neural coding of basic reward terms of animal learning theory, game theory,
microeconomics and behavioural ecology. Science 2004;14:139–147.
179. Delgado M, Nystrom L, Fissel C, Noll D, Fiez J. Tracking the hemodynamic responses to reward
and punishment in the striatum. J Neurophysiol 2000;84:3072–3077. [PubMed: 11110834]
180. Moresco FM, Dieci M, Vita A, Messa C, Gobbo C, Galli L, Rizzo G, Panzacchi A, De Peri L,
Ivernizzi G, Fazio F. In vivo serotonin 5HT2A receptor binding and personality traits in healthy
subjects: A positron emission tomography study. NeuroImage 2002;17:1470–1478. [PubMed:
12414286]
181. van Heeringen C, Audenaert K, Van Laere K, Dumont F, Slegers G, Mertens J, Dierckx RA.
Prefrontal 5-HT2a receptor binding index, hopelessness and personality characteristics in attempted
suicide. Journal of Affective Disorders 2003;74:149–158. [PubMed: 12706516]
182. Walters EE, Kendler KS. Anorexia nervosa and anorexic-like syndromes in a population-based
female twin sample. American Journal of Psychiatry 1995;152(1):64–71. [PubMed: 7802123]
183. Kendler KS, Walters EE, Neale MC, Kessler RC, Heath AC, Eaves LJ. The structure of the genetic
and environmental risk factors for six major psychiatric disorders in women. Phobia, generalized
anxiety disorder, panic disorder, bulimia, major depression, and alcoholism. Arch Gen Psychiatry
1995;52(5):374–83. [PubMed: 7726718]
Kaye Page 22
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
184. Silberg J, Bulik C. Developmental association between eating disorders symptoms and symptoms
of depression and anxiety in juvenile twin girls. J Child Psychol Psychiat 2005;46(12):1317–1326.
[PubMed: 16313432]
185. Wagner A, Barbarich N, Frank G, Bailer UF, Weissfeld L, Henry S, Achenbach S, Vogel V,
Plotnicov K, McConaha C, Kaye W, Wonderlich S. Personality traits after recovery from eating
disorders: Do subtypes differ? Int J Eat Disord 2006;39(4):276–284. [PubMed: 16528697]
186. Spielberger, CD.; Gorsuch, RL.; Lushene, RE. STAI Manual for the State Trait Anxiety Inventory.
Palo Alto, CA: Consulting Psychologists Press; 1970.
187. Cloninger, CR.; Przybeck, TR.; Svrakic, DM.; Wetzel, RD. The Temperament and Character
Inventory (TCI): A Guide to its Development and Use. St Louis, MO: Center for Psychobiology of
Personality, Washington University; 1994.
188. Bacanu S, Bulik C, Klump K, Fichter M, Halmi K, Keel P, Kaplan A, Strober M, Treasure J,
Woodside DB, Berrettini W, Kaye W. Linkage analysis of anorexia and bulimia nervosa cohorts
using selected behavioral phenotypes as quantitative traits or covariates. American Journal of
Medical Genetics B, Neuropsychiatric Genetics 2005;139(1):61–68.
189. Faurion A, Cerf B, Van De Moortele PF, Lobel E, Mac Leod P, Le Bihan D. Human taste cortical
areas studied with functional magnetic resonance imaging: evidence of functional lateralization
related to handedness. Neurosci Lett 1999;277(3):189–192. [PubMed: 10626845]
190. Schoenfeld M, Neuer G, Tempelmann C, Schussler K, Noesselt T, Hopf J, Heinze H. Functional
magnetic resonance tomography correlates of taste perception in the human primary taste cortex.
Neuroscience 2004;127(2):347–353. [PubMed: 15262325]
191. Scott TR, Yaxley S, Sienkiewicz Z, Rolls E. Gustatory responses in the frontal opercular cortex of
the alert cynomolgus monkey. J Neurophysiol 1986;56:876–890. [PubMed: 3783223]
192. Yaxley S, Rolls E, Sienkiewicz Z. Gustatory responses of single neurons in the insula of the macaque
monkey. J Neurophysiol 1990;63:689–700. [PubMed: 2341869]
193. Rolls ET. Taste, olfactory, and food texture processing in the brain, and the control of food intake.
Physiol Behav 2005;85(1):45–56. [PubMed: 15924905]
194. Kringelbach ML, O’Doherty J, Rolls E, Andrews C. Activation of the human orbitofrontal cortex
to a liquid food stimulus is correlated with its subjective pleasantness. Cereb Cortex 2003;13:1064–
1071. [PubMed: 12967923]
195. O’Doherty J, Rolls ET, Francis S, Bowtell R, McGlone F, Kobal G, Renner B, Ahne G. Sensory-
specific satiety-related olfactory activation of the human orbitofrontal cortex. Neuroreport 2000;11
(4):893–897. [PubMed: 10757540]
196. Small D, Zatorre R, Dagher A, Evans A, Jones-Gotman M. Changes in brain activity related to eating
chocolate: from pleasure to aversion. Brain 2001;124(9):1720–1733. [PubMed: 11522575]
197. Ellison, AR.; Fong, J. Neuroimaging in Eating Disorders. In: Hoek, HW.; Treasure, JL.; Katzman,
MA., editors. Neurobiology in the treatment of eating disorders. Chichester: John Wiley & Sons
LTd.; 1998. p. 255-269.
198. Wagner A, Aizenstein H, Frank GK, Figurski J, May JC, Putnam K, Bailer UF, Fischer L, Henry
SE, McConaha C, Kaye WH. Altered insula response to a taste stimulus in individuals recovered
from restricting-type anorexia nervosa. Neuropsychopharmacology. 2007Epub ahead of print
199. Carmichael ST, Clugnet MC, Price JL. Central olfactory connections in the macaque monkey. J
Comp Neurol 1994;346(3):403–434. [PubMed: 7527806]
200. Kaada BR, Jansen J, Andersen P. Stimulation of the hippocampus and medial cortical areas in
unanesthetized cats. Neurology 1953;3(11):844–857. [PubMed: 13111345]
201. Mesulam MM, Mufson EJ. Insula of the old world mokey. I. Architectonics in the insulo-orbito-
temporal component of the paralimbic brain. J Comp Neurol 1982;212(1):1–22. [PubMed:
7174905]
202. Mesulam MM, Mufson EJ. Insula of the old world monkey. III Efferent cortical output and comments
on function. J Comp Neurol 1982;212(1):38–52. [PubMed: 7174907]
203. O’Doherty J, Rolls ET, Francis S, Bowtell R, McGlone F. Representation of pleasant and aversive
taste in the human brain. J Neurophysiol 2001;85(3):1315–1321. [PubMed: 11248000]
204. Schultz W, Tremblay L, Hollerman JR. Reward processing in primate orbitofrontal cortex and basal
ganglia. Cerebral Cortex 2000;10(3):272–84. [PubMed: 10731222]
Kaye Page 23
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
205. Balleine B, Dickinson A. The effect of lesions of the insular cortex on instrumental conditioning
evidence for a role in incentive memory. J Neurosci Methods 2000;20(23):8954–8964.
206. Dunn L, Everitt B. Double dissociations of the effects of amygdala and insular cortex lesions on
conditioned taste aversion, passive avoidance, and neophobia in the rat using excitotoxin ibotenic
acid. Behav Neurosci 1988;102(1):3–23. [PubMed: 3281693]
207. Fudge J, Breitbart M, Danish M, Pannoni V. Insular and gustatory inputs to the caudal ventral
striatum in primates. J Comp Neurol 2005;490(2):101–118. [PubMed: 16052493]
208. Kelley AE, Bakshi VP, Haber S, Steininger T, Will M, Zhang M. Opioid modulation of taste hedonics
within ventral striatum. Physiol Behav 2002;76(3):365–377. [PubMed: 12117573]
209. Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body.
Nat Rev Neurosci 2002;3(8):655–666. [PubMed: 12154366]
210. Paulus M, Stein MB. An insular view of anxiety. Biol Psychiatry 2006;60(4):383–387. [PubMed:
16780813]
211. Reynolds S, Zahm D. Specificity in the projections of prefrontal and insular cortex to ventral
striatopallidum and the extended amygdala. J Neurosci 2005;25(50):11757–11767. [PubMed:
16354934]
212. Ongur D, Price JL. Organization of networks within the orbital and medial prefrontal cortex of rats,
monkeys, and humans. Cereb Cortex 2000;10:206–219. [PubMed: 10731217]
213. Chikama M, McFarland N, Amaral D, H SN. Insular cortical projections to functional regions of
the striatum correlate with cortical cytoarchitectonic organization in the primate. J Neurosci 1997;17
(24):9686–9705. [PubMed: 9391023]
214. Papezova H, Yamamotova A, Uher R. Elevated pain threshold in eating disorders: physiological
and psychological factors. J Psychiatr Res 2005;39(4):431–438. [PubMed: 15804394]
215. Stein D, Kaye W, Matsunaga H, Myers D, Orbach I, Har-Even D, Frank G, Rao R. Pain perception
in recoverd bulimia nervosa patients. Int J Eat Disord 2003;34:331–336. [PubMed: 12949924]
216. Kelley AE. Ventral striatal control of appetite motivation: role in ingestive behavior and reward-
related learning. Neurosci Biobehav Rev 2004;27:765–776. [PubMed: 15019426]
217. Wagner A, Greer P, Bailer U, Frank G, Henry S, Putnam K, Meltzer CC, Ziolko SK, Hoge J,
McConaha C, Kaye WH. Normal brain tissue volumes after long-term recovery in anorexia and
bulimia nervosa. Biological Psychiatry 2006d;59:291–293. [PubMed: 16139807]
Kaye Page 24
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Figure 1.
Comparison of CSF concentrations of neuropeptide and monoamine metabolites in individuals
who were ill (underweight) and long-term recovered from AN. CSF values in AN are compared
to healthy control women, where control mean values are set to 0.
Kaye Page 25
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Figure 2.
Compared to CW, values for recovered anorexia and bulimia subjects expressed as a percent
of the control woman values. * indicate difference at P< .05
Kaye Page 26
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Figure 3.
Coronal view of left insula ROI (x=-41, y=5, z=5). Time course of BOLD signal as a mean of
all 16 recovered restricting-type anorexia nervosa and 16 control women for taste-related
(sucrose and water) response in the left insula.
Kaye Page 27
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Kaye Page 28
Table 1
DSM IV, Diagnostic Criteria for Anorexia Nervosa
A Refusal to maintain body weight at or above a minimally normal weight for age and height (e.g., weight loss leading to maintenance of body
weight less than 85% of that expected; or failure to make expected weight gain during period of growth, leading to body weight less than 85%
of that expected.)
B Intense fear of gaining weight or becoming fat, even though underweight.
C Disturbance in the way in which one’s body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or
denial of the seriousness of the current low body weight.
D In postmenarcheal females, amenorrhea, i.e., the absence of at least three consecutive menstrual cycles. (A woman is considered to have
amenorrhea if her periods occur only following hormone, e.g., estrogen, administration.)
Specify Type:
Restricting type: during the current episode of anorexia nervosa, the person has not regularly engaged in binge-eating or purging behavior
(i.e., self-induced vomiting or the misuse of laxatives, diuretics, or enemas)
Binge-Eating/Purging Type: during the current episode of anorexia nervosa, the person has regularly engaged in binge-eating or purging
behavior (i.e., self-induced vomiting or the misuse of laxatives, diuretics, or enemas)
DSM IV, Diagnostic Criteria for Bulimia Nervosa
A Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following
1eating, in a discrete period of time (e.g., within any 2-hour period), an amount of food that is definitely larger than most people
would eat during a similar period of time and under similar circumstances
2a sense of lack of control over eating during the episode (e.g., a feeling that one cannot stop eating or control what or how much
one is eating)
B Recurrent inappropriate compensatory behavior in order to prevent weight gain, such as self-induced vomiting; misuse of laxatives, diuretics,
enemas, or other medications; fasting, or excessive exercise
C The binge eating and inappropriate compensatory behaviors both occur, on average, at least twice a week for 3 months
D Self-evaluation is unduly influenced by body shape and weight
E The disturbance does not occur exclusively during episodes of anorexia nervosa
Specify Type:
Purging type: during the current episode of bulimia nervosa, the person has regularly engaged in self-induced vomiting or the misuse of
laxatives, diuretics, or enemas
Nonpurging Type: during the current episode of bulimia nervosa, the person has used other inappropriate compensatory behaviors, such
as fasting or excessive exercise, but has not regularly engaged in self-induced vomiting or the misuse of laxatives, diuretics, or enemas
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Kaye Page 29
Table 2
Lifetime and Premorbid Rates of Anxiety Disorders (AD)
Study ED N Lifetime AD AD before ED
Deep 25 AN 24 68% 58%
Godart 26 AN 29 83% 62%
Godart 26 BN 34 71% 62%
Bulik 27 AN 68 60% 54%
Bulik 28 BN 116 57% 54%
Kaye 15 AN, BN 672 64% 61%
23% OCD
13% social phobia
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Kaye Page 30
Table 3
Compared to normal control values of receptor and transport binding potential in subjects recovered from anorexia and
bulimia nervosa AN AN-BN BN
ROI Medial orbital frontal, subgenual cingulate, mesial temporal
5-HT1A BP - ↑ ↑
5-HT2A BP ↓ ↓ -
ROI Anterio ventral striatum
5-HTT BP ↑ ↓ -
DA D2/D3 BP ↑ ↑ -
Physiol Behav. Author manuscript; available in PMC 2009 April 22.
