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NeuroImage 21 (2004) 1790–1797

Exposure to appetitive food stimuli markedly activates

the human brain

Gene-Jack Wang,a,* Nora D. Volkow,a,1 Frank Telang,a Millard Jayne,a Jim Ma,a Manlong Rao,b

Wei Zhu,b Christopher T. Wong,a Naomi R. Pappas,a Allan Geliebter,c and Joanna S. Fowlerd

aMedical Department, Brookhaven National Laboratory, Upton, NY 11973, USAbDepartment of Applied Mathematics and Statistics, S.U.N.Y., Stony Brook, NY 11794, USAcSt. Luke’s/Roosevelt Hospital, New York, NY 10025, USAdChemistry Department, Brookhaven National Laboratory, Upton, NY 11973, USA

Received 22 September 2003; revised 18 November 2003; accepted 20 November 2003

Objective: The increased incidence of obesity most likely reflects

changes in the environment that had made food more available and

palatable. Here we assess the response of the human brain to the

presentation of appetitive food stimuli during food presentation using

PET and FDG. Method: Metabolic changes in response to food

presentation were done in 12 healthy normal body weight subjects

who were food deprived before the study. Results: Food presentation

significantly increased metabolism in the whole brain (24%, P < 0.01)

and these changes were largest in superior temporal, anterior insula,

and orbitofrontal cortices. The increases in the right orbitofrontal

cortex were the ones that correlated significantly with the increases in

self-reports of hunger and desire for food. Discussion: The marked

increase in brain metabolism by the presentation of food provides

evidence of the high sensitivity of the human brain to food stimuli. This

high sensitivity coupled with the ubiquitousness of food stimuli in the

environment is likely to contribute to the epidemic of obesity. In

particular, the activation of the right orbitofrontal cortex, a brain

region involved with drive, may underlie the motivation to procure

food, which may be subjectively experienced as ‘‘desire for food’’ and

‘‘hunger’’ when exposed to food stimuli.

D 2004 Elsevier Inc. All rights reserved.

Keywords: PET; FDG; Food; Orbitofrontal cortex; Insula; Motivation

Introduction

The incidence of obesity in the United States and in the world

has reached epidemic proportions and continues to rise (i.e.,

approximately 30% of adults in the United States are obese)

(Flegal et al., 2002). The increased morbidity and mortality

associated with obesity places a sense of urgency to understand

the processes that have contributed to this epidemic. Of particular

1053-8119/$ - see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.neuroimage.2003.11.026

* Corresponding author. Fax: +1-631-344-5260.

E-mail address: gjwang@bnl.gov (G.-J. Wang).1 N.D. Volkow’s current affiliations are NIDA and NIAA, 6001

Executive Dr., Bethesda MD 20892-9581.

Available online on ScienceDirect (www.sciencedirect.com.)

relevance is the environment, which has made food not only

widely available but also increasingly more varied and palatable.

Although many signals that regulate food intake originate from

internal sources that control caloric and nutrient intake (i.e., leptin,

insulin, ghrelin, PYY), variables other than caloric intake and

satiety have profound effects on food intake. These include the

pleasurable sensory responses from food (i.e., palatability), emo-

tional variables (i.e., stress, depression), and environmental factors

(i.e., food availability, food related cues, alternative reinforcers)

(Patel and Schlundt, 2001). Disruption in the sensitivity of the

brain to these other variables could result in excessive eating and

obesity. A particularly relevant variable is the sensory appeal and

the conditioned responses that the food conveys to the subject. In a

prior study with PET and [11C]raclopride, we showed that striatal

dopamine release was associated with the desire for food during

presentation of palatable food stimuli (Volkow et al., 2002a). This

response was consistent with dopamine’s (DA) role in motivation

for food (Martel and Fantino, 1996). However, DA’s role is to

regulate the activity of brain regions, which in turn are the ones that

are likely to modulate the motivation for food consumption

(nucleus accumbens, dorsal striatum, orbitofrontal cortex, and

insula) (Bassareo et al., 2002; Chikama et al., 1997). Here we

assessed the brain circuits activated by the presentation of food

stimuli using the experimental paradigm that we had used to show

DA increases in striatum with exposure to palatable food stimuli

(Volkow et al., 2002a).

Methods

Twelve healthy right-handed subjects (seven female and five

male subjects, age 28 F 5 years old) were recruited for the study.

Subjects with body mass index greater than 30 kg/m2, history of

eating disorders, surgical/medical treatment for weight control,

dependence on alcohol or other drugs of abuse (except for caffeine

<5 cups/day or nicotine <1 pack/day), neurological or psychiatric

disorder, use of prescription (nonpsychiatric) medication(s) that

can affect brain function in the past 2 weeks, medical conditions

G.-J. Wang et al. / NeuroImage 21 (2004) 1790–1797 1791

that may alter cerebral function, cardiovascular disease and

diabetes, and head trauma with loss of consciousness of more

than 30 min were excluded from the study. Urine screening tests

for psychoactive drugs (including PCP, cocaine, amphetamine,

opiates, barbiturates, benzodiazepine, and THC) were performed

to corroborate lack of drug use. Written informed consents were

obtained after the experimental procedure was explained and after

the subjects had read the consent form. The protocol was

approved by the Institutional Review Board at Brookhaven

National Laboratory.

Subjects were scanned with 2-deoxy-2[18F]fluoro-D-glucose

(FDG) using a Siemens HR + positron emission tomography

(PET) scanner. Details on procedures for positioning of the sub-

jects, arterialized venous and venous catheterization, quantification

of radiotracer, and transmission and emission scans have been

published (Wang et al., 2003). Briefly, one emission scan (20 min)

was taken 35 min after an intravenous injection of 4–6 mCi 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. Subjects were scanned twice with FDG in two

different days under the following conditions. (1) Day A: Food

presentation started 15 min before FDG injection and continued for

a total of 45 min. (2) Day B: Neutral intervention started 15 min

before FDG injection and continued for a total of 45 min. The

sequence was randomized so that for half of the subject the first

day was day A, while for the other half it was day B.

The subjects were asked to fill out a questionnaire, which

contained the following information on the day of screening: a

rating of the subject’s overall interest in food; what the subject’s

favorite foods were; what food smells stimulated the subject’s

appetite; what food smells diminished the subject’s appetite; and to

rate a list of foods for their preferences on a scale from 1 to 10, 10

being the highest. The food items with the highest ratings were

Fig. 1. Transaxial FDG-PET brain images of a subject during food presentation and

cortex, insula, and orbitofrontal cortex. The metabolic images for both scans are sc

neutral intervention and presented using the rainbow scale, where red represents

then selected to be presented to the subject during the food

stimulation condition.

For the food stimulation condition, the subjects were asked to

describe their favorite foods and how they like to eat them while

they were presented with foods that they had reported as among

their favorite ones. The food was warmed to enhance the smell and

the subjects were presented with it so that they could view it and

smell it. A cotton swab impregnated with the food was placed in

their tongues so they could taste it. A given food item was

presented for 5 min and then it was exchanged for a new one.

For the neutral intervention, subjects were asked to describe in as

much detail as possible their family genealogy while they were

presented with nonfood related items (paper photographs of nature

scenes, of humans, and of animals), which they were allowed to

smell, and a cotton swab impregnated with water was placed in

their tongues and lips as was done for the food condition. The food

and the neutral interventions were started 15 min before radiotracer

injection and were continued for a total of 45 min. Subjects were

asked to have their last meal at 7 PM the evening before the day of

the study and were studied between 17 and 19 h after the last meal.

During the PET studies, participants were instructed to orally

respond to each descriptor using a whole number between 1 and 10

for the self-report of ‘‘hunger’’ and ‘‘desire of food’’, which were

obtained before the food presentation and then at 5-min intervals

for a total of 45 min.

Regions of interest (ROI) in orbitofrontal cortex, anterior

insula, parietal cortex, temporal cortex, caudate, putamen, and

thalamus were obtained using a template, which we had previously

published (Wang et al., 2003). We also computed a value for global

metabolism by averaging the activity in the 63 planes scanned. To

minimize the effects of overall changes in brain metabolism on the

regional measures, we normalized them using the ratio of the

region to the global metabolic measures (‘‘relative’’ measures).

during neutral intervention at levels of postcentral gyrus, superior temporal

aled with respect to the maximum absolute metabolic value obtained on the

the highest value and dark violet represents the lowest value.

G.-J. Wang et al. / NeuroImage 21 (2004) 1790–17971792

Differences in metabolism between the measures obtained in

the food presentation and neutral intervention conditions were

tested with paired samples t tests. Pearson product moment

correlations were used to assess the relationship between the

changes in metabolism and the change in the behavioral measures

between the food and neutral interventions.

Differences in metabolism between the two conditions were

also tested on the voxel level using the software package for

Statistical Parametric Mapping (SPM99 Software, 1999). Before

the analysis, each subject’s PET image was mapped onto the

Montreal Neurological Institute template, which closely resembles

the Talairach brain and smoothed via a Gaussian kernel with full

width half maximum (FWHM) at 16 mm. The relative (normal-

ized) metabolic image was obtained by dividing the signal level of

each voxel with the global mean, which is the average signal level

of all voxels in the PET image. The analysis, which was

essentially a paired samples t test performed on each voxel, was

Fig. 2. Absolute brain metabolic changes between food presentation and neutral i

right somatosensory cortex; LIN: left insula; RIN: right insula; LST: left superior

cortex; ROF: right orbitofrontal cortex; LOC: left occipital cortex; ROC: right oc

thalamus; RTH: right thalamus. A, P < 0.005; B, P < 0.01; C, P < 0.05.

performed using both the absolute and the relative metabolic

images. Multiple-test correction was performed via the random

field theory less conservative than the traditional approach such as

the Bonferroni method (Worsley et al, 1996). Pixels that were

significantly different from those in the neutral presentation (P <

0.05) were identified with respect to the Talairach and Tournoux

stereotactic coordinates (Talairach and Tournoux, 1988) and dis-

played on the axial MR images. The threshold for the cluster size

was set at 100 voxels. Only regions with corrected P values <

0.05 at the cluster level were considered significantly activated or

deactivated.

Results

The body weight of the subjects was between 110 and 210 lb

(average: 147.5 F 32.4 lb). The averaged body mass index of the

ntervention conditions. GLO: global; LSS: left somatosensory cortex; RSS:

temporal cortex; RST: left superior temporal cortex; LOF: left orbitofrontal

cipital cortex; LBG: left basal ganglia; RBG: right basal ganglia; LTH: left

G.-J. Wang et al. / NeuroImage 21 (2004) 1790–1797 1793

subjects was 24 F 2.6 (range: 20–29). The favorite food items

most frequently selected by the subjects were bacon–egg–cheese

sandwich, cinnamon bun, pizza, hamburger with cheese, fried

chicken, lasagna, Bar-Be-Que rib, ice cream, brownie, and choc-

olate cake.

Compared to the neutral intervention condition (36 F 2 Amol/

100g/min), the food presentation (45F 9 Amol 100 g�1 min�1, P <

0.01) significantly increased whole brain metabolism (+24F 21%).

The absolute regional metabolic measures were also significantly

higher for all brain regions (except in the occipital cortex) for the

food than the neutral condition (Figs. 1 and 2). Normalization by

whole brain metabolism (relative metabolic measures) revealed that

(Fig. 3) the largest increases were in the left and right postcentral

gyrus (left: +14.9 F 11.6%, P < 0.0001; right: +8.5 F 7.9%, P <

0.012), left superior temporal (+11.2 F 9.2%, P < 0.002), left

anterior insula (+9.6 F 14.6%, P < 0.03), and left orbitofrontal

cortex (+8.9 F 12.3%, P < 0.015).

The SPM analyses of the absolute metabolic values at a

significance level of P < 0.0001 (voxel level) showed a large

Fig. 3. Relative brain metabolic changes between food presentation a

contiguous cluster (72,865 voxels) in bilateral cortical (inferior

frontal, parietal, temporal, occipital, and cerebellar regions) and

subcortical structures with food presentation. The results from

SPM with the relative metabolic measures (Fig. 4) corroborated

the findings obtained using the ROI method. The SPM analyses

yielded a large contiguous cluster (8339 voxels) in the left

parietotemporal cortices and two smaller clusters: one in the right

parietotemporal cortex (1679 voxels) and one in the left orbito-

frontal cortex (499 voxels) with food presentation. The large

cluster in the left parietotemporal cortices encompassed three

subclusters that included the posterior central gyrus (Brodmann’s

areas 1): (�42,�26, 30); the left insula: (�44,�6, 2); and the left

superior temporal gyrus: (�60,�30,�2). The significance of this

cluster was P < 0.004 (corrected at the cluster level). The

significance for the cluster in the right parietotemporal cortex

(62, �16, 20) was P < 0.05 (uncorrected at the cluster level).

The cluster in the left orbitofrontal cortex was not significant at the

cluster level; however, there were two voxel-level significant

regions (�38, 44, 4, P < 0.01; �38, 56, 2, P < 0.02).

nd neutral intervention conditions. A, P < 0.005; B, P < 0.05.

Fig. 4. SPM images showing the areas with higher metabolism in food presentation than in neutral intervention condition. Color-coded SPM results displayed

in a transaxial plane with a superimposed with brain MR images (grayscale). The results (T value) are presented using the color scale, where white represents

the high value and red represents the low value. SS: somatosensory cortex; In: insula; ST; superior temporal cortex; OF: orbitofrontal cortex.

Fig. 5. Time sequence of self-report ratings of hunger and desire for food

during food presentation condition. The subjects reported increases in the

ratings of hunger (+25%) and desire for food (+28%) as compared to the

baseline (0 min).

Fig. 6. Correlation between changes in right orbitofrontal metabolism and

self-report rating of hunger was significant (r = 0.84, P = 0.001).

G.-J. Wang et al. / NeuroImage 21 (2004) 1790–17971794

G.-J. Wang et al. / NeuroImage 21 (2004) 1790–1797 1795

The food presentation condition resulted in significant increases

in the ratings of hunger (25 F 26%, P = 0.006) and desire for food

(28 F 27%, P = 0.007, Fig. 5). The correlation analyses showed a

significant association between relative metabolic changes in the

right orbitofrontal cortex and the self-reports of hunger (r = 0.84,

P = 0.001, Fig. 6) and desire for food (r = 0.77, P = 0.006). No

significant correlations were found between the behavioral meas-

ures and the metabolic changes in the insula, postcentral gyrus, and

superior temporal regions.

Discussion

This study shows that presentation of food stimuli to fasting

subjects resulted in marked increases in whole brain metabolism

(24%). The increases in metabolism were largest in left cortical

regions (postcentral gyrus, superior temporal cortex, insula, and

orbitofrontal cortex). There is no conclusive evidence regarding a

lateralized representation for processing of chemosensory stimuli

in the brain. Indeed, some studies have reported right hemisphere

dominance (Small et al., 1999), while others reported bilateral

(Faurion et al., 1999) or left hemispheric (Del Parigi et al., 2002)

activation in response to chemosensory stimulation. In our study,

the predominant activation in the left hemisphere could reflect the

experimental conditions used for the food and the neutral

stimulations.

Food stimulation resulted in activation of the postcentral region

on the lateral surface of the parietal cortex, which is where the

somatosensory map of the tongue is located and is an area involved

with taste perception (Heimer, 1995). Thus, its activation is consis-

tent with its known role in the somatosensory perception of food.

The reward associated with the taste of food (influenced by palat-

ability) is distinctively different from that associated with food

ingestion (influenced by hunger/satiety). Palatability increases food

intake through a positive-feedback reward mechanism that involves

opioid and GABA/benzodiazepine systems (Cooper, 1989; Yeo-

mans and Gray, 2002). We had previously observed during non-

stimulation conditions (resting state) enhanced brain activity in this

somatosensory region in morbidly obese subjects when compared to

normal-weight subjects (Wang et al., 2002). This led us to postulate

that enhanced activity in this region could make an individual more

sensitive to the rewarding properties of food related to palatability

and could be one of the variables contributing to excess food

consumption. Similarly, in obese women, cerebral blood flow in

parietal cortex was found to be significantly higher than in normal-

weight subjects (Karhunen et al., 1997).

The anterior insula showed activation during the food presen-

tation, which is consistent with its role as a primary gustatory

cortex (O’Doherty et al., 2001; Yaxley et al., 1990; Zald et al.,

1998). The activation of the insula has been observed with fasting

(Morris and Dolan, 2001; Tataranni et al., 1999) and during

activation with unpleasant and aversive food-eating conditions

(O’Doherty et al., 2001; Zald et al., 1998). The anterior insular

region has also been implicated in the processing of visceral

sensations (Allen et al., 1991; Small et al., 1999). Indeed, insular

activation has been reported during temperature and pain percep-

tion (Casey et al., 1996).

The OFC has been identified as a secondary gustatory cortex

(Rolls et al., 1990). It is believed that the OFC is involved with the

rapid learning of visual, olfactory, and taste associations (Rolls,

1997). The OFC receives projections from the insula, striatum, and

amygdala. These connections place the OFC in a position to

process information about the motivational value of gustatory

stimuli. Neurons in the OFC are modulated by the motivational

state of the animal, which respond to the sight or taste of food

when the animal is hungry but do not respond when the animal is

satiated (Rolls, 1989). The neurons in the OFC respond selectively

to rewards or aversive stimuli and process the relative preference

for food rewards (Tremblay and Schultz, 1999). The OFC is also

involved in processing tastes that have both positive and negative

affective valence (O’Doherty et al., 2001). Primate studies have

shown not only taste but also smell-responsive cells throughout the

posterior OFC (Rolls et al., 1999). The present study showed

increased metabolic activity in the left posterior OFC in response to

the food presentation, which included tasting and smelling of food.

Thus, its activation, which was not associated with the subjective

perception of hunger or desire of food, is likely to reflect its

involvement in processing the valence of the flavors and of the

smells from the stimuli. In contrast, the right OFC was significantly

associated with the perception of hunger and desire for food. A

similar correlation had previously been reported by a PET study

that showed a positive correlation between increases in cerebral

blood flow in right posterior OFC and hunger ratings during

presentation of food items (Morris and Dolan, 2001). This associ-

ation is consistent with the known role of the OFC in processing

expectation of food reward (Watababe, 1996). Wanting food (or

appetite) is modulated by DA pathways in part by modulating

activity in the OFC (Berridge, 1996; Spanagel and Weiss, 1999).

Indeed, imaging studies have shown that metabolic activity in the

OFC is in part regulated by DA activity (Volkow et al., 1993,

2002b).

Using the same food-stimulation paradigm, we previously

showed DA increases in the striatum during food stimulation that

were also associated with the ‘‘desire for food’’ and with the

perception of ‘‘hunger’’ (Volkow et al., 2002b). Thus, the current

studies suggest that the enhanced OFC activation by the food

stimulation may reflect downstream effects from DA stimulation

and that DA’s involvement in the drive for food consumption in

human subjects is in part mediated by its effects in the OFC. The

results could explain the deleterious effects of constant exposure to

food stimuli (e.g., advertisements, candy machines, food channels,

stores) in overeating (Coon and Tucker, 2002). It also raises the

possibility that being a food management professional (e.g., chef)

may pose a risk for overeating particularly in those at higher

genetic risk for obesity similar to the higher risk for drug abuse and

addiction in anesthesiologists who as part of their work are

constantly exposed to psychoactive drugs with abuse potential

(Tirrell, 1994). In nonhuman primates, lesions of the OFC produce

abnormal eating behavior (Baylis and Gaffan, 1991). The OFC is a

brain region that has been implicated in the compulsive behaviors

characteristic of drug addictive states (Volkow and Fowler 2000).

Indeed, activation of the right OFC cortex was shown to be

associated with cocaine craving induced by stimulant administra-

tion in cocaine-addicted subjects (Volkow et al. 1999). Markedly

increased metabolic activity in the OFC was also reported during

cue-induced cocaine craving in drug-addicted subjects (Bonson et

al., 2002; Grant et al., 1996; Wang et al., 1999). This suggests that

the same brain region, which is linked with the desire for natural

stimuli (food), is also linked with drug craving in drug-addicted

subjects. Thus, disrupted OFC activity could also possibly underlie

the compulsiveness and lack of control in the eating behaviors of

morbidly obese subjects.

G.-J. Wang et al. / NeuroImage 21 (2004) 1790–17971796

Although no studies have demonstrated abnormalities in the

OFC in obese subjects, we have reported decreases in DA D2

receptors in obese individuals (Wang et al., 2001). Since our

previous studies in drug-addicted subjects showed an association

between decreases in DA D2 receptors and metabolism in OFC

(Volkow et al., 1993, 2001), further studies are warranted to

assess if indeed there are abnormalities in the OFC in obese

subjects.

Conclusion

The marked activation of brain metabolism by the presentation

of food provides evidence of the high sensitivity of the human

brain to the presence of food stimuli. This high sensitivity coupled

with the ubiquitousness of food stimuli in the environment is likely

to contribute to the epidemic of obesity. In particular, the activation

in the right orbitofrontal cortex, a brain region involved with drive,

may underlie the motivation to procure food, which may be

subjectively experienced as ‘‘desire for food’’ and ‘‘hunger’’.

Acknowledgments

This research was carried out at Brookhaven National

Laboratory (BNL) under support by the U.S. Department of

Energy OBER (DE-ACO2-76CH00016) and by the National

Institute on Drug Abuse (DA 7092-01 and DA00280). We thank

David Schlyer and Michael Schueller for Cyclotron operations;

Donald Warner and David Alexoff for PET operations; Richard

Ferrieri, Colleen Shea, Youwen Xu, Victor Garza, and Payton King

for radiotracer preparation and analysis; Karen Apelskog for study

protocol preparation; and Noelwah Netusil, Pauline Carter, and

Naomi Pappas for patient care and recruitment.

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