1. Brookhaven Science Associates U.S. Department of Energy Gene-Jack Wang, M.D. Brookhaven Center for Translational Neuroimaging Obesity & Addiction: Neuroimaging Studies

2. Brookhaven Science Associates U.S. Department of Energy Obesity Newsday / Walt Handelsman Oct 10, 2002

3. Brookhaven Science Associates U.S. Department of Energy Culture, Genetics, High energy intake, Lowered energy expenditure, Abnormal eating behavior. Factors Contributing to Obesity

4. Brookhaven Science Associates U.S. Department of Energy Extrinsic factors food-related cue & availability Emotional factors Stress, boredom Intrinsic factors Leptin, Insulin, Ghrelin, PYY, Dopamine Hypothalamus Signals that Control Food Intake

5. Brookhaven Science Associates U.S. Department of Energy 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 Habits

6. 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.

7. Brookhaven Science Associates U.S. Department of Energy Cocaine AlcoholHeroin AbuserControl [ 11 C]raclopride Abuser Control Dopamine D2 images of Drug Addiction

8. Brookhaven Science Associates U.S. Department of Energy Non Drug AbuserAddicted Subject DA Reward Circuits DA Dopamine DA Dopamine Low Dopamine (DA) State in Addiction

9. Brookhaven Science Associates U.S. Department of Energy Compulsive overeating shares many of the same characteristics as drug addiction. Obesity Do obese subjects have abnormal dopamine receptors?

10. Brookhaven Science Associates U.S. Department of Energy Control Subjects 2 0 ml/gm Obese Subjects Dopamine Receptors [ 11 C]raclopride Wang et al, Lancet 2001

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

12. Brookhaven Science Associates U.S. Department of Energy 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. Implication

13. Brookhaven Science Associates U.S. Department of Energy movement addiction Reward & well-being Dopamine motivation

14. Brookhaven Science Associates U.S. Department of Energy Eating is highly reinforcing behavior, just like taking drugs and as for drugs it can elicit powerful conditioned responses. Food Are the conditioned responses associated with DA release? That is would DA be released by viewing food without eating it?

15. Brookhaven Science Associates U.S. Department of Energy 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 Stimulation

16. Brookhaven Science Associates U.S. Department of Energy Subjects viewed neutral images and/or were asked to describe in as much detail as possible their family genealogy. Neutral Stimulation

17. Brookhaven Science Associates U.S. Department of Energy Methylphenidate ( MP) block the Dopamine Transporter ( ) DA signal DA signal DA MP enhances weak signals MP

18. Brookhaven Science Associates U.S. Department of Energy Subjects were scanned 4 times with [ 11 C]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 [ 11 C]raclopride PET scan Ritalin (20mg, po) Neutral [ 11 C]raclopride PET scan Study 2 Placebo Neutral [ 11 C]raclopride PET scan Ritalin (20mg, po) Food [ 11 C]raclopride PET scan 60 min. A B CD Study Design

19. Brookhaven Science Associates U.S. Department of Energy Brain Dopamine Response to Food Stimulation DA D2 Receptor Availability (Bmax/Kd) 2.5 3 3.5 4 Placebo/NeutralPlacebo/FoodMP/NeutralMP/Food p < 0.11 p < 0.02 p < 0.005 1.5 0 ml/g Sum images of 10 normal weight subjects ([ 11 C]raclopride) Volkow, Wang, et al, Synapse 2002

20. Brookhaven Science Associates U.S. Department of Energy 051015202530 -2 0 2 4 6 8 10 Hunger -2 0 2 4 6 8 10 05 15202530 Desire for Food % Change Bmax/kd Extracellular DA vs Self-report of Hunger & Desire for Food + Ritalin r = 0.76 p < 0.01 Volkow, Wang, et al, Synapse 2002

21. Brookhaven Science Associates U.S. Department of Energy These results support the role of DA neurotransmission in dorsal striatum in mediating food motivation in human brain. Implication

22. Brookhaven Science Associates U.S. Department of Energy Food Presentation Neutral Presentation Right 85 0 µmol/100g/min Brain Metabolic Response to Food Stimulation Wang et al, Neuroimage 2004 18 FDG

23. Brookhaven Science Associates U.S. Department of Energy Statistical Parameter Map of Metabolic Changes between Food and Neutral stimulation R Wang et al, Neuroimage 2004 n Twelve normal weight subjects. n Insula is a brain region modulating emotional responses to appetitive stimuli. n Orbitofrontal cortex is a brain region involved with salience attribution.

24. Brookhaven Science Associates U.S. Department of Energy Metabolism in orbitofrontal cortex during food stimulation % Changes of feeling of hunger r = 0.84, p = 0.001 Wang et al, Neuroimage 2004 n 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”.

25. Brookhaven Science Associates U.S. Department of Energy 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.

26. Brookhaven Science Associates U.S. Department of Energy Neutral Theme Interview Cocaine Theme Interview 85 0 µmole/100g/min Brain Activation during Cocaine Theme Interview 18 FDG Orbitofrontal Activation Wang et al, Life Science 1999

27. Brookhaven Science Associates U.S. Department of Energy Cocaine Craving & Insular Metabolism Wang et al, Life Science 1999 l- Right Insula, p < 0.01 O - Left Insula, p < 0.008 p < 0.0002

28. Brookhaven Science Associates U.S. Department of Energy 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. Prospective

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

30. Brookhaven Science Associates U.S. Department of Energy Would obese subjects have an enhanced sensitivity in the brain regions involved with sensory processing of the food? Obesity

31. Brookhaven Science Associates U.S. Department of Energy 55 0 µmol/100g/min Control subjects Obese subjects R L Averaged FDG images What brain regions differ? Wang et al, NeuroReport 2002

32. Brookhaven Science Associates U.S. Department of Energy Enhanced Somatosensory Cortex Metabolism in Obese Subjects n Ten obese subjects (n = 10, BMI > 40) and 25 lean subjects (BMI < 25). n At baseline condition after fasting for 14-16 hours. n 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

33. Brookhaven Science Associates U.S. Department of Energy 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. Implication

34. Brookhaven Science Associates U.S. Department of Energy Biology Genes Addiction Environment Drug or Behavior Addiction

35. Brookhaven Science Associates U.S. Department of Energy Scientists 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) Support Staff 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) Post Doctoral/Fellow Nelly Klein (psychologist) Kim Lindsey (pharmacologist) Igor Izrailtyan (anesthesiologist) Daryn Moeller (anesthesiologist) Alex Morgan (physician) Lisa Cotton (psychologist) Brookhaven PET Group

36. Brookhaven Science Associates U.S. Department of Energy Support Department of Energy (Office of Biology & Environmental Research) National Institute on Drug Abuse Office of National Drug Control Policy