Gastric stimulation in obese subjects activates the
hippocampus and other regions involved in brain
Gene-Jack Wang*†‡, Julia Yang*, Nora D. Volkow§, Frank Telang§, Yeming Ma§, Wei Zhu¶, Christopher T. Wong*,
Dardo Tomasi*, Panayotis K. Thanos§, and Joanna S. Fowler*†
*Medical Department, Brookhaven National Laboratory, Upton, NY 11973;†Department of Psychiatry, Mount Sinai School of Medicine, New York, NY
10029;§National Institute on Alcohol Abuse and Alcoholism?National Institute on Drug Abuse, Rockville, MD 20857; and¶Department of Applied
Mathematics and Statistics, State University of New York, Stony Brook, NY 11794
Edited by Michael I. Posner, University of Oregon, Eugene, OR, and approved August 21, 2006 (received for review March 10, 2006)
The neurobiological mechanisms underlying overeating in obesity
are not understood. Here, we assessed the neurobiological re-
sponses to an Implantable Gastric Stimulator (IGS), which induces
stomach expansion via electrical stimulation of the vagus nerve to
identify the brain circuits responsible for its effects in decreasing
food intake. Brain metabolism was measured with positron emis-
sion tomography and 2-deoxy-2[18F]fluoro-D-glucose in seven
obese subjects who had the IGS implanted for 1–2 years. Brain
metabolism was evaluated twice during activation (on) and during
deactivation (off) of the IGS. The Three-Factor Eating Question-
naire was obtained to measure the behavioral components of
eating (cognitive restraint, uncontrolled eating, and emotional
eating). The largest difference was in the right hippocampus,
where metabolism was 18% higher (P < 0.01) during the ‘‘on’’ than
‘‘off’’ condition, and these changes were associated with scores on
‘‘emotional eating,’’ which was lower during the on than off
condition and with ‘‘uncontrolled eating,’’ which did not differ
between conditions. Metabolism also was significantly higher in
the on condition. These findings corroborate the role of the vagus
hippocampus in modulating eating behaviors linked to emotional
eating and lack of control. IGS-induced activation of regions
previously shown to be involved in drug craving in addicted
subjects (orbitofrontal cortex, hippocampus, cerebellum, and stri-
atum) suggests that similar brain circuits underlie the enhanced
motivational drive for food and drugs seen in obese and drug-
addicted subjects, respectively.
brain activation ? obesity
stood. The regulation of food intake is a complex balance
between excitatory and inhibitory processes. The excitatory
processes arise from the body’s needs for nutrients and calories.
The inhibitory processes arise from satiety signals (i.e., electrical
and chemical) after food consumption (1). The vagus nerve is
one of the ways by which satiety signals are conveyed to the
brainstem (2). Gastric and duodenal vagal afferents increase
their firing in response to the mechanical pressure from the
ingested nutrients and in response to food-induced release of a
variety of brain gut peptides (i.e., cholecystokinin and ghrelin).
In addition, several neurotransmitters (e.g., serotonin, dopa-
mine, norepinephrine, and opiates) and peptides (i.e., cholecys-
tokinin and corticotrophin releasing factor) are also involved in
feeding behaviors (1). It is also recognized that in addition to
food’s role in fulfilling nutrient requirements, eating also may
serve to mitigate stress (comfort food) (3). Disruption in the
sensitivity of the brain to these signals could lead to obesity.
Recently, the Transcend Implantable Gastric Stimulator
(IGS) system, which generates electric signals to induce the
he cerebral mechanisms underlying the behaviors that result
in pathological overeating and obesity are poorly under-
expansion of the fundus, has been shown to produce increased
satiety, which leads to decreased food intake and reduced body
weight in obese subjects (4). It is hypothesized that electrical
stimulation by the IGS triggers the gastrointestinal system to
release satiety signals equivalent to those conveyed after a meal
by the vagus nerve. The purpose of this study was to measure
brain glucose metabolic responses to the IGS by using positron
emission tomography (PET) and 2-deoxy-2[18F]fluoro-D-
glucose (FDG) to assess brain circuits mediating its effects on
food intake. Inasmuch as vagal stimulation affects the activity of
regions involved with emotional regulation such as hippocampus
(5), orbitofrontal cortex (6), and striatum (7), we hypothesized
that the therapeutic benefits from IGS in obesity would involve
activation of these brain regions.
The body mass index of the subjects was 46.0 ? 6.2 kg?m2(range
36.7–52) before the implantation of the IGS. The subjects had
because of the implantation 1–2 years prior. Six subjects had
maintained ?5% of the weight loss at the time of the study.
Evaluation of eating behaviors by using the Three-Factor Eating
Questionnaire-Eating Inventory revealed small but significant
(P ? 0.04) decreases on the scores on emotional eating during
the on relative to the off condition (21% lower) and no differ-
ences on the scores for cognitive restraint or uncontrolled eating
Statistical parametric mapping (SPM) analysis of the brain
metabolic images (absolute measures) showed significantly
higher activity in the on than off conditions in the right hip-
pocampal region and in right anterior cerebellum (P ? 0.01)
(Fig. 1). Similar findings were obtained for the SPM analysis
done on the normalized brain metabolic images (relative mea-
sures), which also showed significantly higher metabolism in the
right hippocampal region and in right cerebellum but, in addi-
tion, revealed higher metabolism in right orbitofrontal cortex
(OFC) and right striatum (P ? 0.01) (Fig. 1 and Table 2). The
SPM comparison for the off ? on was not significant.
Author contributions: G.-J.W., J.Y., N.D.V., P.K.T., and J.S.F. designed research; F.T. per-
formed research; G.-J.W., N.D.V., Y.M., W.Z., C.T.W., D.T., and P.K.T. analyzed data; G.-J.W.
wrote the paper; and N.D.V. and J.S.F. revised the manuscript.
Conflict of interest statement: J.Y. was an employee of Transneuronix, Inc. (Mt. Arlington,
NJ) at the time of the experiment; however, the company did not provide funding for the
This article is a PNAS direct submission.
Freely available online through the PNAS open access option.
Abbreviations: DA, dopamine; FDG, 2-deoxy-2[18F]fluoro-D-glucose; IGS, Implantable Gas-
tric Stimulator; OFC, orbitofrontal cortex; PET, positron emission tomography; ROI, region
of interest; SPM, statistical parametric mapping.
‡To whom correspondence should be addressed. E-mail: email@example.com.
© 2006 by The National Academy of Sciences of the USA
October 17, 2006 ?
vol. 103 ?
no. 42 ?
The regions of interest (ROI) analysis corroborated that
during the on condition, metabolism was significantly higher in
right hippocampus, right striatum (putamen and ventral stria-
tum), and right orbitofrontal cortex (Brodmann area 11), but the
difference was not significant in right cerebellum (Table 3).
However, failure to corroborate the cerebellar effect is likely to
reflect the fact that the ROI quantified metabolic activity in a
much greater volume (whole right cerebellum) that the relatively
small cerebellar volume detected by SPM. Note also that
ventral striatum, putamen, and orbitofrontal cortex, the SPM on
the absolute metabolic image did not (Fig. 1). This apparent
discrepancy has to do with the threshold used to report signif-
icance for SPM, which was P ? 0.01, versus that used for the
individual ROI comparisons, which was P ? 0.05. Indeed, if we
bring significance for the SPM analysis to P ? 0.03, this result
reveals the differences in right ventral striatum, putamen, and
Changes in regional metabolism in right hippocampus were
correlated significantly (P ? 0.01) with the scores on emotional
eating for the scores obtained both during the on and off
conditions (Fig. 2) and with the scores on uncontrollable eating
obtained both during the on (r ? 0.81, P ? 0.02) and off
conditions (r ? 0.77; P ? 0.05). Changes in right ventral striatum
also were correlated with scores on emotional eating during the
on condition (P ? 0.01) and showed a trend for the off condition
(P ? 0.08) (Fig. 2). Cognitive control was not associated with any
of the regional metabolic changes. Neither the correlations
between the metabolic changes and the changes in the scores of
emotional eating (difference between the on and off) nor the
correlations between metabolic changes and body mass index
reductions were significant.
Here, we show that chronic IGS induced significant changes in
regional brain metabolism. Specifically, the SPM done on the
absolute and normalized metabolic images revealed significantly
higher metabolism in the right hippocampus and the right
cerebellum during IGS stimulation (on condition). In addition,
the SPM on the normalized images and the ROI analyses on the
absolute measures also revealed increases in right orbitofrontal
cortex and right striatum.
The right hippocampal region was the brain area that was the
most sensitive to the effects of IGS (18% increases in metabo-
lism). This result is consistent with prior preclinical and clinical
studies showing that vagal stimulation changed hippocampal
activity (reviewed in ref. 5). Moreover, therapeutic response to
chronic vagal nerve stimulation in epileptic patients was asso-
ciated with hippocampal changes in GABAAreceptor density
(8). In addition, with chronic IGS, we also show significant
activation of other limbic regions, namely right OFC and right
striatum as well as activation of the right anterior cerebellum.
IGS stimulation is believed to mimic the response of the vagus
nerve to meal-related signals, which it transmits to the nucleus
tractus solitarius in the brainstem from where signals are con-
veyed to various cortical and subcortical regions, including
hippocampus and OFC (2, 9, 10). The pattern of activation
obtained in our study with chronic IGS differed from that
previously reported with gastric distention (balloon inflation
method), which also simulates vagal nerve and activated brain-
stem, inferior frontal gyrus, insula, and subgenual anterior
that the IGS stimulation we used was chronic, whereas the
balloon inflation procedure was an acute intervention. Thus, the
response to the IGS is likely to reflect the pattern of activation
linked with continuous, as opposed to transient, vagal stimula-
tion. Vagal nerve stimulation has been used for other indications
(e.g., epilepsy, depression, and Alzheimer’s disease) (12). Im-
aging studies to evaluate the pattern of activation observed when
vagal nerve stimulation is used for these therapeutic purposes
have shown effects in some of the same brain regions reported
in this study (i.e., hippocampus and OFC) but also in other brain
regions (reviewed in ref. 5). The sensitivity of the hippocampus
and the OFC to vagal stimulation, regardless of the disease
condition for which it was used, suggests that these two regions
may be some of the main targets conveyed by the vagus nerve
through the nucleus tractus solitarius. On the other hand, the
differences in regional effects between studies are likely to
reflect differences in the location of nerve stimulation, param-
eters used (i.e., frequencies and intensity), and the unique
neuropathology of the disease.
The hippocampal region, which was the region with the largest
change induced by IGS activation, traditionally has been asso-
ciated with learning and memory (13). However, this brain
region also is involved in sensorimotor processing (14) and
studies that the hippocampus is involved with eating behaviors
because hippocampal damage can result in hyperphagia (16).
Moreover, it has been postulated that the hippocampus partic-
ipates in a specific type of memory inhibition function that could
pus also is likely to contribute to eating behaviors by processing
satiety signals such as those produced by cholecystokinin (18),
ghrelin (19), and motilin (20) and by its involvement in incentive
and with the normalized (Lower) images (ratio of pixel to whole brain).
Threshold corresponds to P ? 0.01 (uncorrected), T ? 3.14, and k ? 20 voxels.
Table 1. The results of Three-Factor Eating Questionnaire when
the IGS was activated (on) and deactivated (off)
Questionnaire IGS onIGS off
13.4 ? 4.4
9.7 ? 3.0
6.1 ? 3.0
14.6 ? 4.6
10.0 ? 3.0
7.7 ? 3.2
www.pnas.org?cgi?doi?10.1073?pnas.0601977103Wang et al.
motivation (21) and on behavioral control (22). The hippocam-
pus modulates dopamine (DA) release in the ventral striatum
(23), which is a means by which the saliency of stimuli is
modulated (24). It also regulates activity in prefrontal regions
involved with inhibitory control (25, 26). Imaging studies have
shown that the desire to eat a specific food was associated with
activation of the hippocampus, which was interpreted to reflect
the involvement of this region in the memories of the desired
food (27). A recent study showed that tasting a liquid meal
resulted in decreased activity in posterior hippocampus in obese,
and previously obese but not in lean, subjects, implicating the
hippocampus in the neurobiology of obesity (28). The effects of
gastric stimulation on the hippocampus therefore could contrib-
of food reward memories, decreasing saliency, and?or strength-
ening inhibitory control. The association between IGS-induced
eating and uncontrolled eating support this hypothesis.
The OFC is a brain region involved in the integration of
food-related sensory, visceral, and reinforcing information (29).
Visceral and other satiety-related signals reach the OFC (from
the nucleus tractus solitarius via thalamic relays) and there
modulate the representation of food resulting in an output that
reflects the reward or appetitive value of each food (19). Studies
using functional MRI (30) and PET-FDG (31) showed that OFC
activation was associated with the perception of hunger and
desire for food. Moreover, a decrease in OFC activation when
the food was eaten to satiety (32) suggests that the saliency value
of the food is represented in the OFC. The DA system has a
recognized role in reinforcing and motivating feeding behavior.
Specifically, mesolimbic DA projections into striatum are hy-
pothesized to regulate food intake by modulating appetitive
motivational processes (33). We previously had shown that
changes in extracellular DA in striatum in response to food
stimulation were significantly correlated with subjective reports
of hunger and with the desire for food (34). Mesencephalic DA
cells also regulate the function of the OFC both by direct and
indirect striato-cortical projections (35). The enhanced OFC
activation previously reported with food stimulation may reflect
downstream effects from DA stimulation, which would imply
that DA’s involvement in the motivation for appetitive behaviors
in part is mediated through the OFC that, in turn, also is
modulated by vagal nerve stimulation. Thus, it is possible that
IGS-induced weight loss reflects, in part, the decreased moti-
vational value of food that is mediated through the OFC and the
The right cerebellum, which was the only nonlimbic brain
region activated by chronic IGS also receives projections from
the vagus nerve (36). In addition to its involvement in motor
control, it also participates in visceroception (37) and learning
(38). The cerebellum also has been implicated in modulating
food responses, specifically those when food is consumed to
satiety (39). Moreover, as for the results with the hippocampus,
these responses were more accentuated in obese than in lean
subjects, implicating an involvement of the cerebellum in the
neurobiology of obesity.
The brain regions activated by IGS have all been associated
with the responses to drugs and to drug-associated cues in
addicted subjects. Specifically, activation of the OFC and the
striatum has been linked with the craving and desire for the drug
(drug priming and conditioned cues) (40), and activation of the
cerebellum and hippocampus have been linked with mnemonic
processes associated with prior drug experiences (38). Thus,
results from this study corroborate the similarities in the neu-
robiological substrates underlying the intense wanting triggered
by drugs and drug cues in addiction and by food in obesity. The
overlapping substrates between these disorders could explain
been shown to decrease drug intake in animal models of
addiction (i.e., cannabinoid 1 antagonist, corticotrophin-
releasing factor antagonist, and GABA-enhancing agents) (41).
Metabolic changes induced by IGS were not associated with
the difference in behavioral scores; instead, it was the scores
themselves obtained either on the on or off conditions for
emotional eating and for uncontrolled eating that were associ-
ated with metabolic changes in hippocampus and ventral stria-
tum. This association would suggest that the sensitivity of the
right hippocampus and ventral striatum to vagal stimulation
might underlie the vulnerability to emotional eating and sensi-
tivity in the hippocampus to uncontrollable eating. In this study,
the IGS resulted in increased activation in limbic brain regions
and cerebellum in the absence of food stimulation. Future
studies comparing responses to food stimulation between the on
versus the off IGS conditions could allow researchers to deter-
mine whether chronic vagal stimulation blunts the limbic re-
sponses to food or to food-conditioned stimuli. The fact that
Table 2. Coordinates for regions that differed significantly between the on and off IGS
conditions obtained in the SPM comparisons of the normalized metabolic images
Activated regions (on ? off)
Rt. anterior cerebellum
Rt. orbitofrontal (BA 47)
Rt. orbitofrontal (BA 11)
Significance set at P ? 0.01 (uncorrected), T ? 3.14, and k ? 20 voxels. Z value represents peak voxel statistical
significance. Rt., right.
Table 3. Regional brain metabolic measures (micromoles per 100
g per min) obtained by using ROI when the IGS was activated
(on) and deactivated (off)
ROIIGS on IGS off
Right ventral striatum
Left ventral striatum
Right orbitofrontal cortex
Left orbitofrontal cortex
56.9 ? 5.4
56.7 ? 8.4
50.3 ? 7.0
49.8 ? 8.5
41.7 ? 1.8
44.6 ? 4.2
39.2 ? 5.2
37.1 ? 5.8
40.8 ? 6.0
41.6 ? 5.3
51.0 ? 3.0
53.7 ? 4.3
43.7 ? 4.2
47.8 ? 6.3
37.8 ? 3.1
38.8 ? 3.3
33.1 ? 5.3
33.1 ? 5.1
45.7 ? 4.7
45.2 ? 3.2
Boldface numbers represent statistical significance (P ? 0.005).
Wang et al.
October 17, 2006 ?
vol. 103 ?
no. 42 ?
in the neurocircuitry that underlies the responses mediated by
vagal stimulation in obese subjects and those mediated by
conditioned drug cues in addicted subjects. Because IGS stim-
ulation is effective in decreasing food intake, this phenomenon
raises the possibility that it also may interfere with drug admin-
istration. Preclinical studies to assess this hypothesis merit
A limitation for this study was the small number of subjects.
These were very difficult subjects to recruit; we required that
they be medically healthy and we excluded subjects with hyper-
tension, diabetes, or cardiovascular disease because we wanted
to minimize confounds from these conditions. In this study, we
did not have a balanced randomization (six of the seven subjects
had the on scan first), and we did not have a control group that
underwent FDG scans on a test-retest condition with no inter-
vention. However, previous studies from our group measuring
in metabolic measures for hippocampus, OFC, striatum, or
These findings provide insight into the brain circuits involved
in processing the satiety signals that originate from the stomach
of obese subjects. The brain regions activated by gastric stimu-
lation overlap with those reported during craving responses in
addicted subjects, supporting the commonalities in the neuro-
circuitry that underlie compulsive food intake and compulsive
Subject Eligibility. We studied six female obese subjects and one
male obese subject (47.8 ? 6.3 years of age; range, 37–55 years
mass index ?30 kg?m2at the time of IGS implantation were
included. The exclusion criteria were as follows: urine positive
for psychoactive drugs, dependence on alcohol or other drugs of
abuse (except for caffeine ?5 cups per day or nicotine ?1 pack
per day), neurological disorder of central origin or major psy-
chiatric disorder, use of anorexic medications for weight loss in
the past 6 months, use of medications in the past 1 month that
can affect brain function, uncontrolled cardiovascular disease
(e.g., hypertension), uncontrolled endocrinological disease (in-
cluding diabetes), and acute or chronic medical illness that may
affect brain function.
The Institutional Review Boards at Brookhaven National
Laboratory and State University of New York–Stony Brook
approved the protocol, and written informed consent was ob-
tained from all subjects.
Study Design. Each subject was tested two times with PET-FDG
scan on 2 separate days within 2 weeks. Subjects were asked to
fast for ?14–16 h before the PET scans. The referring physicians
screened subjects for eligibility at Transneuronix clinical study
sites (such as in New York, Atlanta, Kansas City, and Boston)
and activated (remained on) or deactivated (turned off) the IGS.
The subjects were blinded to the status of the IGS (remained
1, the IGS remained activated (on), and for study Arm 2, the IGS
remained deactivated (off) for the 2 weeks before the first PET
scans. For six of the subjects, the on scan was done first, and for
one of the subjects, the on scan was done second.
Scanning. Subjects were scanned with FDG by using an HR?
Siemens (Iselin, NJ) tomograph by using the 3D acquisition
mode. Details on procedures for positioning of the subjects,
arterialized venous and venous catheterization, quantification of
radiotracer and transmission and emission scans have been
published in ref. 43. Briefly, one emission scan (20-min duration)
was taken starting at 35 min after an i.v. injection of ?185 MBq
of FDG. During the study, subjects were positioned supine in the
PET camera with their eyes open; the room was dimly lit, and
noise was kept to a minimum.
Behavioral Assessment. The Three-Factor Eating Questionnaire-
Eating Inventory was obtained on the day that the scans were
Fig. 2.Correlation between changes in metabolism (from off to on) and the scores on the emotional eating obtained during the on and off conditions.
www.pnas.org?cgi?doi?10.1073?pnas.0601977103 Wang et al.
performed. This questionnaire measures three aspects of eating Download full-text
Image and Data Analysis. Differences between the IGS on and off
conditions were tested by using the software package for Sta-
tistical Parametric Mapping (SPM99) (45). Before the analysis,
each subject’s PET image was mapped onto the Montreal
Neurological Institute template and smoothed via a Gaussian
kernel with full width half maximum at 16 mm. Pixels signifi-
cantly different between the IGS on and the IGS off were
identified with respect to the Talairach and Tournoux stereo-
tactic coordinates and displayed on the axial MR images. To
ensure that the regional differences were not driven predomi-
nantly by subjects with either very high or very low whole-brain
the normalized metabolic images. The normalized (relative)
image was obtained by dividing the signal level of each voxel with
the global mean, which was the average signal level of all voxels
in the PET image. The level of significance was set at P ? 0.01,
uncorrected, cluster threshold ?20 voxels.
In parallel, we also obtained ROI for the right and left
orbitofrontal cortex, anterior cingulate, anterior insula, caudate,
putamen, ventral striatum, thalamus, hippocampus, and cere-
bellum by using a template, which we had published in ref. 33.
Differences in the behavioral components of eating behavior
and in the ROIs between the on and off conditions were tested
by using the paired t test, two-tailed. To assess the associations
between changes in metabolism induced by IGS and the behav-
ioral scales, we measured the correlations between the regions
for which absolute metabolic measures were affected signifi-
cantly by IGS and the behavioral scores obtained during the on
and the off conditions as well as the differences between on and
off. P values ?0.05 were considered significant if they were
corroborated by the association with both the on and the off
conditions or P ? 0.01 if they were observed in only one
condition or in the difference between conditions.
We thank all of the subjects who participated in this study; M. Bessler,
J. Champion, S. Champion, A. Daud, A. Melanson, I. Sarosiek, and S.
Shikora for subject referrals; K. Torres for Institutional Review Board
correspondence and study compliance; D. Schlyer and M. Schueller for
Cyclotron operations; D. Alexoff, P. Vaska, and D. Warner for PET
operations; R. Ferrieri, C. Shea, Y. Xu, and P. King for radiotracer
care; K. Pradhan and M. Michaelides for data analysis; and A. Ruggiero
for manuscript submission. This work was supported by U.S. Department
of Energy Office of Biological and Environmental Research Grant
DE-ACO2-98CH10886, National Institute on Drug Abuse Grants
DA6891 and DA6278, National Institute on Alcohol Abuse and Alco-
holism Grants AA9481 and Y1AA3009, and the General Clinical
Research Center at University Hospital Stony Brook (National Institutes
of Health Grant M01RR 10710).
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vol. 103 ?
no. 42 ?