The Office of Nonproliferation & National Security

The Office of Nonproliferation & National Security

Obesity & Addiction: Neuroimaging Studies Gene-Jack Wang, M.D. Brookhaven Center for Translational Neuroimaging Brookhaven Science Associates U.S. Department of Energy Obesity Brookhaven Science Associates U.S. Department of Energy Newsday / Walt Handelsman Oct 10, 2002 Factors Contributing to Obesity

Brookhaven Science Associates U.S. Department of Energy Culture, Genetics, High energy intake, Lowered energy expenditure, Abnormal eating Signals that Control Food Intake Emotional factors Intrinsic

factors Leptin, Insulin, Ghrelin, PYY, Dopamine Stress, boredom Hypothalamus Extrinsic factors food-related cue & availability Brookhaven Science Associates U.S. Department of Energy Eating Habits 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. Brookhaven Science Associates U.S. Department of Energy 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. Brookhaven Science Associates U.S. Department of Energy

Dopamine D2 images of Drug Addiction Cocaine Control Abuser Alcohol Heroin Control Abuser Control Abuser Brookhaven Science Associates U.S. Department of Energy [11C]raclopride Low Dopamine (DA) State in Addiction DADA

DADA DA Dopamine DA DA DA DA DA DA DA DADA DA Dopamine DA DA Reward Circuits Reward Circuits Non Drug Brookhaven

Science Associates Abuser U.S. Department of Energy Addicted Subject y Compulsive overeating shares many of the same characteristics as drug addiction. Do obese subjects have abnormal dopamine receptors? Brookhaven Science Associates U.S. Department of Energy Dopamine Receptors [11C]raclopride 2 0

ml/gm Control Subjects Obese Subjects Brookhaven Science Associates U.S. Department of Energy Wang et al, Lancet 2001 Dopamine Receptor and BMI p < 0.002 Obese subjects o Control subjects BMI p = 0.3 Dopamine Receptor Concentration Brookhaven Science Associates U.S. Department of Energy

Wang et al, Lancet 2001 Implication 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. Brookhaven Science Associates U.S. Department of Energy moveme nt motivation Dopami

ne addiction Brookhaven Science Associates U.S. Department of Energy Reward & wellbeing d Eating is highly reinforcing behavior, just like taking drugs and as for drugs it can elicit powerful conditioned responses. Are the conditioned responses associated with DA release? That is would DA be released by viewing food without eating it? Brookhaven Science Associates U.S. Department of Energy Food Stimulation 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. Brookhaven Science Associates U.S. Department of Energy Neutral Stimulation Subjects viewed neutral images and/or were asked to describe in as much detail as possible their family genealogy.

Brookhaven Science Associates U.S. Department of Energy block the Dopamine Transporter ( ) DA DA DA DA DA DA DA DA DA DA signal

Brookhaven Science Associates MP U.S. Department of Energy DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA MP signal enhances weak signals Study Design

Ritalin (20mg, po) Study 1 Placebo [11C]raclopride [11C]raclopride PET scan PET scan 60 min. A Neutral C Food [11C]raclopride

Ritalin (20mg, [11C]raclopride po) PET scan PET scan Study 2 Placebo B Food D Neutral 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

Brookhaven Science Associates U.S. Department of Energy Brain Dopamine Response to Food Stimulation Sum images of 10 normal weight subjects ([11C]raclopride) 4 0 Availability (Bmax/Kd) DA D2 Receptor 1.5 3.5 p < 0.11 ml/g p < 0.02

p < 0.005 3 2.5Placebo/Neutral Placebo/Food MP/Neutral Brookhaven Science Associates U.S. Department of Energy MP/Food Volkow, Wang, et al, Synapse 2002 Extracellular DA vs Self-report of Hunger & Desire for Food + Ritalin r = 0.76 p < 0.01 10 Desire for Food

10 Hunger 8 6 4 2 0 -2 0 5 10 15 20 25 30 8 6 4 2 0 -2 0

5 10 15 20 25 30 % Change Bmax/kd Brookhaven Science Associates U.S. Department of Energy Volkow, Wang, et al, Synapse 2002 Implication These results support the role of DA neurotransmission in dorsal striatum in mediating food motivation in human brain. Brookhaven Science Associates U.S. Department of Energy Brain Metabolic Response to Food Stimulation

85 Food Presentation 0 mol/100g/ min 18 Right Neutral Presentation Brookhaven Science Associates U.S. Department of Energy Wang et al, Neuroimage 2004 FDG Statistical Parameter Map of Metabolic Changes between Food and Neutral stimulation

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. Brookhaven Science Associates

U.S. Department of Energy R SS In ST OF Wang et al, Neuroimage 2004 Metabolism in orbitofrontal cortex during food stimulation 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. Brookhaven Science Associates U.S. Department of Energy 25 r = 0.84, p = 0.001 20 % Metabolic Changes 15 10 5 0

-5 -10 -10 0 10 20 30 40 50 60 70 % Changes of feeling of hunger Wang et al, Neuroimage 2004 80 Implication 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. Brookhaven Science Associates U.S. Department of Energy Brain Activation during Cocaine Theme Interview Neutral Theme Interview 85

Orbitofronta l Activation Cocaine Theme Interview 0 mole/100g/min 18 FDG Brookhaven Science Associates U.S. Department of Energy Wang et al, Life Science 1999 35 30 25 20

15 10 5 0 -5 -10 -15 -2 p < 0.0002 - Right Insula, p < 0.01 % Pulse rate changes mol/100g/min Cocaine Craving & Insular Metabolism 30 O - Left Insula, p < 0.008

25 20 15 10 5 0 2 4 6 8 Craving (0-10) Brookhaven Science Associates U.S. Department of Energy 10 12 0 -40 -20 0 20 40 60 80 100120140160 % Metabolic changes Wang et al, Life Science 1999 Prospective

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. Brookhaven Science Associates U.S. Department of Energy Obesit y VS Drug Abuse What makes obese subjects different from drug abusers? Brookhaven Science Associates

U.S. Department of Energy Obesit y Would obese subjects have an enhanced sensitivity in the brain regions involved with sensory processing of the food? Brookhaven Science Associates U.S. Department of Energy Averaged FDG images Control subjects Obese subjects 55 0 mol/100g/min R What brain regions differ?L Brookhaven Science Associates

U.S. Department of Energy Wang et al, NeuroReport 2002 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 Brookhaven Science Associates U.S. Department of Energy Wang et al, NeuroReport 2002 Implication 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. Brookhaven Science Associates U.S. Department of Energy Addiction Biology Environment Drug or Genes Behavior Addiction Brookhaven Science Associates U.S. Department of Energy Brookhaven PET Group Scientists Support Staff Joanna 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) Karen 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) Brookhaven Science Associates U.S. Department of Energy Post Doctoral/Fellow Nelly Klein (psychologist) Kim Lindsey (pharmacologist) Igor Izrailtyan (anesthesiologist) Daryn Moeller (anesthesiologist) Alex Morgan (physician) Lisa Cotton (psychologist) Support 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

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