Nuclear Medicine and Biology 32 (2005) 755 – 761
www.elsevier.com/locate/nucmedbio
Positron emission tomography studies in eating disorders:
multireceptor brain imaging, correlates with behavior
and implications for pharmacotherapyB
Guido K. Franka, Walter H. Kayeb,T
a
Department of Child and Adolescent Psychiatry, Center for Eating Disorders Research, School of Medicine,
University of California San Diego, San Diego, CA 92123, USA
b
Department of Psychiatry, Western Psychiatric Institute and Clinic, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Received 6 June 2005; accepted 6 June 2005
Abstract
Modern imaging techniques that visualize disease-specific organ neurotransmitter or protein receptor sites are increasingly able to define
pathological processes on a molecular level. One of those imaging modalities, positron emission tomography (PET), for the assessment of
brain neuroreceptor binding has revolutionized the in vivo assessment of biologic markers that may be related to human behavior. Such
studies may help identify chemical targets that may be directly related to psychiatric pathology and, thus, opportunities for pharmacological
intervention. In this review, we describe results from PET studies in eating disorders (EDs). Eating disorders are frequently debilitating
illnesses that are quite homogeneous in their presentation. Those studies that identified particular serotonin and dopamine receptor alterations
can distinguish recovered ED subjects from controls as well as ED subgroups. Furthermore, correlations of receptor binding with behavioral
constructs, such as harm avoidance or novelty seeking, could be found. These recognized receptors may now help us to move away from
rather nonspecific treatment approaches in psychiatric research and clinic to the possibility of more syndrome- and symptom-specific
treatment approaches.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Receptor; Imaging; Serotonin; Dopamine; Positron emission tomography; Eating disorder
1. Introduction
Molecular imaging, which is the visualization of
molecular information that is pertinent to a specific disease,
has been receiving increasing attention [1]. Using advanced
neuroimaging techniques such as positron emission tomography (PET) and single photon emission tomography
(SPECT), disorders such as depression, schizophrenia or
eating disorders (EDs) can now be studied on the level of
receptors that are involved in regional brain neurotransmission. Those receptors may be related to depressive
feelings and anxiety, agitation or changes in the ability to
eat or sleep.
B
This study was supported by NIMH MH46001, MH42984, K05MD01894 and T32-MH18399.
T Corresponding author. Tel.: +1 412 647 9845; fax: +1 412 647 9740.
0969-8051/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.nucmedbio.2005.06.011
Similar to other psychiatric disorders, the conceptual
framework of the pathophysiology and etiology of the EDs
has undergone significant changes in the past decades with
the advent of modern neuroscience research. The etiology
of EDs is still unknown. However, several lines of research
have raised the possibility that trait disturbances of brain
neurotransmitters may contribute to the pathogenesis of
ED. These neurotransmitter systems include serotonin and
dopamine pathways as well as a number of neuropeptides
[2]. A major reason for our lack of understanding of brain
and behavior in the past was that tools for measuring
neurotransmitter activity and brain pathways have been
limited to indirect measures of brain function such as
concentrations of neurotransmitters in cerebrospinal fluid
(CSF) or hormonal responses to drug challenges. Brain
imaging techniques now give us the opportunity to assess
regional brain activity and neuroreceptor function in vivo
in humans and, thus, may help us understand how neuronal circuits are related to behavior and pathophysiology.
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G.K. Frank, W.H. Kaye / Nuclear Medicine and Biology 32 (2005) 755 – 761
Table 1
Summary of PET findings in EDs using serotonin and dopamine ligands
Author
Imaging
technology
Frank et al. [7]
Audenaert et al. [6]
Bailer et al. [8]
Goethals et al. [39]
Kaye et al. [16]
Bailer et al. [40]
Bailer et al. [40]
Henry et al., submitted
for publication
Tiihonen et al. [20]
Tauscher et al. [21]
Bailer et al., submitted
for publication
Bailer et al., submitted
for publication
Frank et al. [13]
PET 5-HT2A
SPECT 5-HT2A
PET 5-HT2A
SPECT 5-HT2A
PET 5-HT2A
PET 5-HT1A
PET 5-HT1A
PET 5-HT1A
Recovered
subjects
n
Frontal
cortex
Cingulate
cortex
Mesial
temporal
cortex
Parietal
cortex
AN
nl
A
nl
nl
A
nl
z
z
A
A
nl
nl
nl
z
z
A
nl
A
nl
nl
nl
z
z
nl
BN
AN
AN-BN
BN
16
15
10
10
9
13
12
10
A
nl
nl
nl
z
z
z
z
nl
nl
AN-BN
8
10
5
PET 5-HTT
BN
8
nl
PET DA D2/D3
AN, AN-BN
10
PET 5-HT1A
SPECT 5-HTT
PET 5-HTT
Ill subjects
AN
AN-BN
BN
BN
BN
An example of visualization of now commonly studied
pre- and postsynaptic neuroreceptors in the living human
brain with specific radioligands is shown in Fig. 1. Those
studies open the opportunity to develop disease-specific
targets for pharmacological intervention. In this review, we
show evidence that we can start to bridge the gap between
basic research and applied human behavioral research.
This involves the comprehensive study of receptor systems
in healthy controls and psychiatric disorders, and the
A
Basal
ganglia
Midbrain
raphe
A
A
A
z
development of maps of normal and pathological neuroreceptor distribution.
2. Anorexia nervosa
Anorerxia nervosa (AN) is a disorder that usually
begins during adolescence in females and is associated
with an intense fear of gaining weight, feeling fat,
emaciation and amenorrhea. There are thought to be two
Fig. 1. Available receptors for PET imaging. Note the different receptor distribution for various receptor types: serotonin 5-HT1A receptor with presynaptic
binding in the midbrain raphe nuclei and cortical post synaptic binding; 5-HT2A receptor binding that is exclusively postsynaptic; 5-HTT with mid brain,
cortical and basal ganglia presynaptic binding; dopamine D2/D3 receptor binding localized in the basal ganglia. [11C] and [18F] radiopharmaceuticals indicate
receptor-specific ligand types.
G.K. Frank, W.H. Kaye / Nuclear Medicine and Biology 32 (2005) 755 – 761
subtypes: restricting type AN (AN-R) and binge-eating/
purging AN (AN-B/P) [3]. Comorbid obsessive–compulsive disorder (OCD) is common, as are depression and
anxiety [4].
Neurotransmitters such as serotonin or dopamine are
distributed throughout the brain via specific neuronal
pathways. Their influence on behavior is believed to be
through action on specific receptors that tend to be located
postsynaptically and, for some receptor types, also presynaptically in regions such as the midbrain. Radioligands exist
for several of the serotonin receptor types. One of the most
commonly assessed receptor type is the 5-HT2A receptor
frequently studied using [18F]altanserin binding. This
receptor type is involved in the regulation of feeding, mood
and anxiety, and in antidepressant action [5]. Three studies
have assessed 5-HT2A receptor binding in ill and recovered
AN women. Ill subjects [6] showed reduced receptor
binding in the left frontal, bilateral parietal and occipital
cortex. Recovered AN-R [7] subjects also had reduced
[18F]altanserin binding, most strongly in mesial temporal
and parietal cortical areas as well as in the cingulate cortex.
In another study, women recovered from AN-B/P had
reduced [18F]altanserin binding relative to controls in the
left subgenual cingulate, left parietal and right occipital
cortex [8]. In that study, 5-HT2A binding was positively
related to harm avoidance and negatively to novelty seeking
in cingulate and temporal regions, with negative relationships between 5-HT2A binding and drive for thinness.
Recent studies have been assessing the 5-HT1A receptor
with [11C]WAY100635 as the radiotracer in AN and bulimia
nervosa (BN). Recovered AN-B/P subjects had significantly
increased [11C]WAY100635 binding in cingulate, lateral and
757
mesial temporal, lateral and medial orbital frontal, parietal
and prefrontal cortical regions and in the dorsal raphe
compared to control women [8]. No differences were found
for recovered AN-R subjects relative to controls. For AN-R,
the increased [11C]WAY100635 postsynaptic receptor binding in mesial temporal and subgenual cingulate regions was
positively correlated with harm avoidance.
Those findings (Table 1) now suggest that AN subgroups
may be identified by assessing 5-HT1A and 5-HT2A receptor
binding. Furthermore, those findings highlight the possibility of disturbances of the anterior cingulate cortex and
mesial temporal cortex in AN. Since these disturbances
persist after recovery, it is possible they are trait disturbances. The anterior cingulate cortex receives afferents from
the amygdala and has direct projections to the premotor
frontal cortex and other limbic regions. It plays a crucial
role in initiation, motivation and goal-directed behaviors
[9], as well as reward [10]. The amygdala mediates the
interpretation of fear and the representation of emotional
stimuli values [11]. It is possible that AN have disturbed
processing of emotional stimuli valence, resulting in poor
flexibility in reevaluating actual danger of those stimuli and
reduced adaptation to new situations. Future studies will
need to determine whether relationships between 5-HT2A
and 5-HT1A receptor activity and measures for anxiety such
as harm avoidance can be replicated. This could be an
exciting avenue for the link of neurochemistry and
behavior. The implication of such findings may be
tremendous. If it is possible to reliably identify a network
of neurotransmission that is involved in an aspect of
anxious response to stimuli, which is an integral part of a
disease process, then pathological behavioral response
Fig. 2. Exemplary increased [11C]raclopride binding in an anorexic woman compared to an age-matched control woman [13].
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G.K. Frank, W.H. Kaye / Nuclear Medicine and Biology 32 (2005) 755 – 761
might be specifically intervened with, for instance, a
particular receptor agonist or antagonist. Imaging techniques such as PET may help to assess drug–neuroreceptor
binding in relation to treatment response.
The dopamine (DA) receptor system has received some
attention in the past regarding its involvement in the
pathophysiology of AN with one study [12], showing low
CSF levels of the DA metabolite homovanillic acid (HVA).
Most recently, we found in a group of subjects who
recovered from both AN-R and AN-B/P an increased DA
D2/D3 receptor binding in the anteroventral striatum, which
includes the nucleus accumbens, an area involved in reward
and learning [13] (Fig 2). 5-HT and DA neurotransmission
is closely intertwined, and future in vivo studies will have to
assess behavioral consequences of receptor expression and
the interaction of various receptor systems. 5-HT and DA
receptor activation may act on other central neurotransmitter
systems such as glutamatergic neurotransmission via the
NMDA receptor [14].Thus, there is a variety of possible
implications of 5-HT and DA receptor alterations. The DA
system has been receiving increased attention in addiction
as well as obesity research. It might be possible that AN and
subjects with various forms of addictive behaviors are at
opposite extremes, and the study of chemical pathways that
are involved could give us clues for intervention research.
Most available therapeutic drugs in psychiatry are acting on
several receptor types or are somewhat nonspecific, such as
reuptake inhibitors. With the new knowledge about disorder-specific disturbances, it will eventually be possible to
develop more specific drugs for intervention. That includes
development of more substances that bind more specifically
to particular receptor sites guided by neuroimaging, as well
as assessment of central receptor availability prior to, during
and after treatment.
3. Bulimia nervosa
Bulimia nervosa is characterized by recurrent binge
eating followed by behaviors to counteract weight gain,
such as self-induced vomiting. Individuals with BN often
maintain a normal weight but present with a fear of gaining
weight and food and body weight-related preoccupations.
Bulimia nervosa is usually associated with increased
depressive and anxious feelings. Impulsive behaviors and
cluster B behaviors are common [3]. The 5-HT system has
consistently been shown to be disturbed in BN as well as in
AN [15]. However, BN, after recovery, had higher CSF
5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA)
compared to AN after recovery, and during the ill phase,
BN CSF 5-HIAA was inversely correlated with bingeeating/purging episode frequency.
Serotonin receptor alterations may have specific implications on behavior. Kaye et al. [16] found reduced
orbitofrontal 5-HT2A receptor binding in recovered BN.
Orbitofrontal alterations could reflect behavioral disturbances in BN that include impulsiveness and altered emotional
processing [17]. Altered orbitofrontal activity, as found in
borderline personality disorder [18], could indicate a
common area for impulse control disturbance. In addition,
BN women failed to show common correlations of age and
5-HT2A binding. This finding raises the possibility that BN
women may have alterations of developmental mechanisms
of the 5-HT system. Reduced 5-HT2A activity after recovery
could reflect a trait disturbance involved in alterations of
mood, anxiety and impulse control. 5-HT receptor imaging
before and during active drug treatment may now help shed
light on the question why BN subjects need higher doses of
SSRIs compared to depressed subjects [19]. In contrast to
reduced 5-HT2A binding in BN, increased 5-HT1A receptor
binding in ill BN subjects was reported by Tiihonen et al.
[20] using PET in all studied brain regions, but most
prominently in prefrontal, cingulate and a parietal cortex
area. Data from our own group support those findings with
generalized increased postsynaptic 5-HT1A binding in
recovered BN subjects (Henry at al submitted). Furthermore, the finding of increased 5-HT1A binding in recovered
bulimic type AN [8] suggest that increased 5-HT1A binding
might be a trait disturbance for bulimic type ED disturbance,
but not for restrictor type AN (Table 1).
Other studies have found reduced 5-HT transporter
(5-HTT) [21] binding in thalamus and hypothalamus in ill
BN. Bailer et al. [8] found reduced 5-HTT binding in
recovered AN-B/P in raphe and mesial temporal regions, but
normal 5-HTT binding in recovered BN subjects. Recent
studies [22,23] using platelet 5-HTT binding raise the
possibility that disturbed 5-HTT function may be related to
mood instability or failure to respond to SSRIs in BN
subjects. Thus, although it is likely that a 5-HTT alteration
occurs in bulimia, the exact nature of this dysfunction
remains uncertain. Still, it is likely that with a comprehensive biological assessment that includes neuroreceptor
imaging, genotype and assessment of the drug-metabolizing
P450 liver enzyme system, it will be possible to determine
prior to treatment drug response likelihood and chance for
experiencing of significant side effects.
4. Healthy subjects
Many studies have found that CSF levels of 5-HIAA
are inversely related to impulsivity and aggression in
humans and nonhuman primates [24,25]. Thus, high
concentrations of CSF 5-HIAA, which can be assumed
to reflect increased extracellular 5-HT, are associated with
inhibited behaviors in nonhuman primates, whereas low
concentrations of CSF 5-HIAA are associated with
impulsive temperament in man and monkey. Recently,
brain imaging studies have found negative relationships
among 5-HT1A receptor binding and aggression [26], selftranscendence [27] and anxiety [21] in frontal, temporal
and cingulate cortical regions. Our group (Kaye, submitted
for publication) has replicated these studies by finding that
frontal, cingulate and temporal postsynaptic and brainstem
G.K. Frank, W.H. Kaye / Nuclear Medicine and Biology 32 (2005) 755 – 761
11
autoreceptor raphe [ C]WAY100635 binding potential was
significantly and inversely related to novelty seeking and
self-transcendence in healthy control women. Little is
known about the relationship between CSF 5-HIAA levels
and 5-HT1A receptors. Nevertheless, it would make sense
to assume that increased extracellular 5-HT would synergistically interact with 5-HT1A receptor activity. These
accumulating data raise the question of whether increased
5-HT1A binding is related to some phenomenon common
to novelty seeking, aggression and self-transcendence. One
possibility is that each of these symptoms reflects some
aspect of behavioral inhibition and self-control. These
findings may shed light on temperament and personality.
That is, people with increased 5-HT1A receptor function
tend to be more inhibited and restrained, whereas people
with low levels of 5-HT1A receptor function tend to be
more stimuli seeking and uninhibited.
5. Implications
Imaging of molecular targets that are involved in disease
is a rapidly growing field with a wide range of applications
from cancer, to joint disease and to psychiatric disorders [1].
Positron emission tomography imaging of 5-HT and DA as
well as other targets has enormous potential for understanding how medication works in the brain of humans with
psychiatric disorders. In the past, treatment has tended to be
empirical because there have been no methods of predicting
which drug to use or what dose to choose, or an
understanding why some people do not respond to a
medication. Positron emission tomography imaging with
these radioligand tools has begun to be used to understand
medication response, for example, 5-HTT transporter function after SSRI blockade, or effects of atypical antipsychotic
drugs on dopamine and 5-HT receptors [28-30]. Receptor
occupancy varies significantly across various compounds at
the clinically recommended doses, and the treatment effect in
relation to binding has yet to be determined in may cases
[31]. Nevertheless, many pharmaceutical companies have
recognized opportunities to understand the effects of
available drugs, as well as test the effects of new compounds
using external imaging [32,33].
As an example, SSRI medications are not effective
when AN patients are malnourished and underweight, and
have limited efficacy in BN. SSRIs block 5-HTT-mediated
reuptake of 5-HT in the synapse, which results in increased
extracellular 5-HT, which in turn gradually desensitizes
and possibly down-regulates the 5-HT1A autoreceptor [34].
It is not known whether some individuals fail to respond to
SSRIs because of aberrant 5-HTT function and/or some
inability to desensitize highly elevated somatic dendritic 5HT1A autoreceptor activity. Moreover, it is not known
whether SSRI effects on specific postsynaptic 5-HT1A and
5-HT2A receptor activity in frontal, cingulate and temporal
regions are associated with specific symptom reduction
such as less harm avoidance. However, one study suggests
759
that treatment with the SSRI paroxetine may reduce harm
avoidance scores in a group of generalized anxiety disorder
patients [35]. Positron emission tomography imaging with
radioligands now provides a tool capable of answering
questions for the research community together with the
pharmaceutical industry regarding mechanisms that are
part of the disease process as well as therapeutic intervention with psychotropic drugs. In addition, it is possible that
such imaging tools may also prove to be useful in the near
future as a clinical tool for understanding why some
individuals with depression or schizophrenia are not
responsive to medication. That is, in some individuals,
PET imaging with radioligands could determine whether
such people have abnormal 5-HTT or 5-HT1A function,
which in turn might help the treating physician to use
alternative treatment options.
It is worthwhile noting that conventional methods of
characterizing pathological behavior [e.g., using the Diagnostic and Statistical Manual of Mental Disorders (DSM-VITR) [36] are based on relatively broad clinical syndromes,
such as depression. In fact, it is possible that depressed
mood is related to disturbances of brain neurocircuits
modulating mood, and there may be many different causes
of depression, each related to a different loci of pathology
within these neurocircuits. Moreover, the way the brain
encodes behavior may not reflect conventional diagnosis,
for example, as described above, relationships between
5-HT1A receptors and impulse control, which is found in
both healthy subjects and people with EDs. Positron
emission tomography imaging with radioligands offers the
opportunity to understand relationships between receptors,
circuits and behavior.
Few studies have been done in EDs in comparison to
depressive disorders or OCD. The overlap and comorbidity
of both major depression and OCD with EDs require studies
that will directly compare those disorders. Studies comparing psychiatric disorders will help to find common pathways
and distinct areas of disturbance that may identify targets for
successful drug interventions. It is important to note that
neuronal activity is an integration of many factors such as
neuronal firing, synaptic transmitter release and reuptake,
metabolism of neurotransmitters, receptor sensitivity, second messenger systems and other intracellular mechanisms,
and the relationship with other neuronal pathways. Positron
emission tomography neuroimaging with radioligands offers
the opportunities to understand the complexities and
interactions of these components in vivo. It may be that
the pattern of dysfunction of components making up 5-HT
functional activity is different in ED, anxiety disorders and
depression, although the end result is a compromise of 5-HT
functional activity that may share common symptoms. In
fact, subjects with major depression had reduced 5-HT1A
receptor binding [37] as did a group of panic disorder
patients [38], whereas our studies suggest increased 5-HT1A
binding in, for instance, bulimic ED subjects who have
frequent comorbid depression or anxiety disorders.
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G.K. Frank, W.H. Kaye / Nuclear Medicine and Biology 32 (2005) 755 – 761
6. Conclusion
The emergence of brain imaging techniques raises the
possibility to assess brain function in vivo and assess
human behavior in conjunction with biological correlates.
The EDs AN and BN are relatively homogeneous disorders
on one hand but with high comorbidity of affective and
anxiety disorders on the other hand. This offers the
opportunity to study the expression of various pathologies
and their relationship with biologic pathology. The
systematic research of neurotransmitter systems, such as
the 5-HT and DA pathways, led to the successful
identification of ED subtypes on a biologic basis and
may now offer targets for the development of disease and
symptom-specific pharmacological treatment. We expect
that those new imaging methods give hope to the prospect
of identifying biologic markers across the psychiatric
spectrum. Psychiatric disorders can be viewed within the
medical chronic disease model. New imaging techniques
define what changes during the ill state persist after
recovery and how pharmaceuticals may be able to
intervene in the disease process and for relapse prevention
in terms of receptor binding and associated behavior
change. Improving the available pharmacological intervention strategies will greatly improve quality of life of the
affected individuals.
Acknowledgments
We thank Roxanne Rockwell for her editorial assistance.
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