brookhaven science associates u.s. department of energy gene-jack wang, m.d. brookhaven center for...

Brookhaven Science AssociatesU.S. Department of Energy

Gene-Jack Wang, M.D.

Brookhaven Center for Translational Neuroimaging

Obesity & Addiction:

Neuroimaging Studies

Obesity & Addiction:

Neuroimaging Studies


ObesityObesity

Newsday / Walt HandelsmanOct 10, 2002


• Culture, • Genetics,

• High energy intake,• Lowered energy

expenditure,• Abnormal eating

behavior.

Factors Contributing to Obesity

Factors Contributing to Obesity


Extrinsic factors

food-related cue & availability

Emotional factors

Stress, boredom

Intrinsic factors

Leptin, Insulin, Ghrelin, PYY,

Dopamine

Hypothalamus

Signals that Control Food IntakeSignals that Control Food Intake


Many obesity researchers focus on how the body's fuel and fat levels control appetite. But as comfort eaters know, habits and desires often override metabolic need.

Eating HabitsEating Habits


Body Weight & Drug Treatment

Body Weight & Drug Treatment

•Drugs (stimulants: e.g. amphetamine, cocaine, methylphenidate) that increase brain dopamine concentration are anorexigenic.

•Drugs (antipsychotic: e.g. Haloperidol,.. ) that block dopamine D2 receptors increase appetite and result in significant weight gain.


Cocaine Alcohol Heroin

AbuserControl

[11C]raclopride

Abuser AbuserControl Control

Dopamine D2 images of Drug Addiction

Dopamine D2 images of Drug Addiction


Non Drug Abuser

Addicted Subject

DA

DA

DA

DA DA DA

DA

Reward CircuitsReward Circuits

DA

DA

DA

DA Dopamine

DA

DA DA DA DA

DA

Dopamine

Low Dopamine (DA) State in Addiction

Low Dopamine (DA) State in Addiction


•Compulsive overeating shares many of the same characteristics as drug addiction.

ObesityObesity

•Do obese subjects have abnormal dopamine receptors?


Control Subjects

2

0

ml/gm

Obese Subjects

Dopamine ReceptorsDopamine Receptors[11C]raclopride

Wang et al, Lancet 2001


p < 0.002 • Obese subjectso Control subjects

Dopamine Receptor and BMI

Dopamine Receptor and BMI

Dopamine Receptor Concentration

BMIp = 0.3

Wang et al, Lancet 2001


• Dopamine modulates motivation and reward circuits and hence dopamine deficiency in obese subjects may perpetuate pathologic eating as a means to compensate for the decreased activation of reward circuits.

ImplicationImplication


movement

addiction Reward & well-being

DopamineDopamine

motivation


•Eating is highly reinforcing behavior, just like taking drugs and as for drugs it can elicit powerful conditioned responses.

FoodFood

•Are the conditioned responses associated with DA release? That is would DA be released by viewing food without eating it?


1) 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.

2) Food was warmed to enhance the smell and the subjects were presented with it so that they could view it and smell it and a cotton swab impregnated with the food was placed in their tongues so they could taste it.

3) A given food item was presented for 4 minutes and then it was exchanged for a new one.

Food StimulationFood Stimulation


Subjects viewed neutral images and/or were asked to describe in as much detail as possible their family genealogy.

Neutral StimulationNeutral Stimulation


Methylphenidate ( MP) block

the Dopamine Transporter ( )

Methylphenidate ( MP) block

the Dopamine Transporter ( )

DA

DA

DA

DA DA DA

DA

signal

DA

DA

DA

DA DA DA

DA

signal

DA

DA

DA

DADADA DA

DA

DA DA

DA

DA

DA

MP enhances weak signals

MP


Subjects were scanned 4 times with [11C]raclopride over a two day period. Six subjects participated study 1 on the first day and four subjects participated study 2 on the first day of the studies

Study 1

Placebo

Food

[11C]raclopride

PET scan

Ritalin (20mg, po)

Neutral

[11C]raclopride

PET scan

Study 2

Placebo

Neutral

[11C]raclopride

PET scan

Ritalin (20mg, po)

Food

[11C]raclopride

PET scan60 min.

A B

C D

Study DesignStudy Design


Brain Dopamine Response to Food Stimulation

Brain Dopamine Response to Food Stimulation

DA

D2

Recep

tor

Availab

ilit

y(B

max/K

d)

2.5

3

3.5

4

Placebo/NeutralPlacebo/Food MP/Neutral MP/Food

p < 0.11p < 0.02

p < 0.005

1.5

0

ml/g

Sum images of 10 normal weight subjects ([11C]raclopride)

Volkow, Wang, et al, Synapse 2002


0 5 10 15 20 25 30-2

0

2

4

6

8

10

Hu

ng

er

-2

0

2

4

6

8

10

0 5 10 15 20 25 30

Desir

e f

or

Food

% Change Bmax/kd

Extracellular DA vs Self-report of Hunger & Desire for Food + Ritalin

Extracellular DA vs Self-report of Hunger & Desire for Food + Ritalin

r = 0.76p < 0.01

Volkow, Wang, et al, Synapse 2002


These results support the role of DA neurotransmission in dorsal striatum in mediating food motivation in human brain.



Food Presentation

Neutral PresentationRight

85

0µmol/100g/min

Brain Metabolic Response to Food Stimulation

Brain Metabolic Response to Food Stimulation

Wang et al, Neuroimage 2004

18FDG


SS

In ST

OF

Statistical Parameter Map of Metabolic Changes between Food and Neutral

stimulation

Statistical Parameter Map of Metabolic Changes between Food and Neutral

stimulation

R


Twelve normal weight subjects.

Insula is a brain region modulating emotional responses to appetitive stimuli.

Orbitofrontal cortex is a brain region involved with salience attribution.


Metabolism in orbitofrontal cortex during food stimulation

Metabolism in orbitofrontal cortex during food stimulation

% M

etab

olic

Cha

nges

-10

-5

0

5

10

15

20

25

-10 0 10 20 30 40 50 60 70 80

% Changes of feeling of hunger

r = 0.84, p = 0.001


Orbitofrontal cortex is a brain region involved with salience attribution and drive, may underlie the motivation to procure food, which may be subjectively experienced as “desire for food” and “hunger”.


ImplicationImplication• The enhanced orbitofrontal cortex

activation by food stimulation may reflect downstream effects from dopamine stimulation.

• Dopaminergic involvement in the drive for food consumption in humans is in part mediated by its effects in orbitofrontal cortex.

• The results could explain the deleterious effects of constant exposure to food stimuli (e.g. advertisements, candy machines, food channels, stores) in overeating.


Neutral Theme Interview

Cocaine Theme Interview

85

0

µmole/100g/min

Brain Activation during Cocaine Theme InterviewBrain Activation during

Cocaine Theme Interview

18FDG

Orbitofrontal Activation

Wang et al, Life Science 1999


² Craving (0-10)

² µm

ol/1

00g/

min

-15-10

-505

101520253035

-2 0 2 4 6 8 10 12% Metabolic changes

% P

ulse

rat

e ch

ange

s0

5

10

15

20

25

30

-40 -20 0 20 40 60 80 100120140160

Cocaine Craving & Insular Metabolism

Cocaine Craving & Insular Metabolism

Wang et al, Life Science 1999

- Right Insula, p < 0.01

O - Left Insula, p < 0.008

p < 0.0002


Activation of the temporal insula, a brain region involved with autonomic control, and of the orbitofrontal cortex, a brain region involved with expectancy and salience attribution, during the cocaine theme support their involvement with craving in cocaine addicted subjects.

ProspectiveProspective


•What makes obese subjects different from drug abusers?

ObesityObesity

VS

Drug Abuse


•Would obese subjects have an enhanced sensitivity in the brain regions involved with sensory processing of the food?

ObesityObesity


55

0µmol/100g/min

Control subjects Obese subjects

R L

Averaged FDG images

Averaged FDG images

What brain regions differ?Wang et al, NeuroReport 2002


Enhanced Somatosensory Cortex Metabolism in Obese Subjects

Enhanced Somatosensory Cortex Metabolism in Obese Subjects

Ten obese subjects (n = 10, BMI > 40) and 25 lean subjects (BMI < 25).

At baseline condition after fasting for 14-16 hours.

Obese subjects had higher metabolism than lean subjects in the somatosensory areas where the mouth, lips and tongue are represented.

FDG

Wang et al, NeuroReport 2002


• The enhanced activation in somatic parietal areas for mouth, tongue and lips in obese subjects suggests that enhanced sensitivity in regions involved in the sensory processing of food may make food more rewarding and may be one of the variables contributing to their excess food consumption.



BiologyGenes

Addiction

EnvironmentDrug or

Behavior

AddictionAddiction


ScientistsJoanna Fowler (organic chemist)David Alexoff (engineer)Helene Benveniste (anesthesiologist)Anat Biegon (pharmacologist)Stephen Dewey (anatomist)Yu-Shin Ding (organic chemist)Richard Ferrieri (physical chemist)S. John Gatley (pharmacologist)Rita Goldstein (psychologist)Kuo-Shan Lin (organic chemist)Jean Logan (theoretical chemist)Yeming Ma (physical chemist)David Schlyer (inorganic chemist)Michael Schueller (biomedical physicist)Frank Telang (neurologist)Peter Thanos (neuroscientist)Paul Vaska (physicist)Nora Volkow (psychiatrist)Gene-Jack Wang (nuclear med physician)

Support StaffKaren Apelskog (protocol coordinator)Pauline Carter (nurse)Victor Garza (chemist)Barbara Hubbard (nurse)Millard Jayne (nurse)Payton King (Lab Technician)Hai-Dee Lee (Lab Technician)Noel Netusil (nurse)Colleen Shea (chemist)Azael Villanueva (biomedical engineering) Donald Warner (electronics)Youwen Xu (chemist)Lisa Zimmerman (study coordinator)Post Doctoral/FellowNelly Klein (psychologist)Kim Lindsey (pharmacologist)Igor Izrailtyan (anesthesiologist)Daryn Moeller (anesthesiologist)Alex Morgan (physician)Lisa Cotton (psychologist)

Brookhaven PET GroupBrookhaven PET Group


SupportSupport

Department of Energy(Office of Biology & Environmental Research)

National Institute on Drug Abuse

Office of National Drug Control Policy

brookhaven science associates u.s. department of energy gene-jack wang, m.d. brookhaven center for...

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