1. Modulators of Orbitofrontal Activation in Response to Food Stimuli Deborah A. Yurgelun-Todd, Ph.D. Cognitive Neuroimaging Laboratory Brain Imaging Center, McLean Hospital May 21, 2007 Insights on Obesity and Drug Addiction from Brain Imaging 2007 Science of Addiction: Translating New Insights Into Better Psychiatric Practice APA/NIDA Meeting “Insights on Obesity and Drug Addiction from Brain Imaging”

2. It has been hypothesized that addictive drugs activate the same brain reward pathways involved in the control of normal appetitive behavior. It has been hypothesized that addictive drugs activate the same brain reward pathways involved in the control of normal appetitive behavior. Food is inherently rewarding. Food is inherently rewarding. Rewarding properties of food are determined by: Rewarding properties of food are determined by: -body’s nutritional needs -physical properties of food (appearance) -inherited traits -Other factors ? Introduction

3. To clarify the neurobiological mechanisms by which body weight, mood and age may influence appetitive response. To clarify the neurobiological mechanisms by which body weight, mood and age may influence appetitive response. We presented healthy, normal-weight adolescent and adult females with color photographs of foods differing in fat-content/calorie-density (i.e., high- reward or low-reward) while they underwent blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). We presented healthy, normal-weight adolescent and adult females with color photographs of foods differing in fat-content/calorie-density (i.e., high- reward or low-reward) while they underwent blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). Objective

4. Overview I.Adult fMRI Study of Food  Orbitofrontal activation and Affect  Orbitofrontal activation and BMI II.Adult vs. Adolescent fMRI Study of Food  Orbitofrontal activation and Age

5. Food Study: Adults

6. Clinical Scales and Measurements Structured Clinical Interview for DSM-IV (SCID) Positive and Negative Affect Schedule (PANAS) Body Mass Index (BMI) ((Weight (lbs) / Height (in) x Height in) x 703) Study Design Subjects 15 Healthy normal weight adult women 16 Healthy normal weight adolescent females.

7. Challenge Paradigm Subjects were scanned between 1500 - 1900 hr. Total calorie consumption on scan day was determined for each subject. Subjects were asked to view visual stimuli and told to remember them. Conditions: 1.High Fat Food Items 2.Low Fat Food Items 3.Food-related Utensils 4.Non-food Items

9. Activation 1 Activation 2 Baseline Recovery 1 Recovery 2 TIME (sec) 0 30 60 90 120 150 fMRI Paradigm

10. Activation in Adults: High Calorie Foods Activation for high calorie food compared to control condition includes dorsolateral and medial PFC, thalamus and hypothalamus. Killgore et al., 2003

11. Activation in Adults: Low Calorie Foods Activation in Adults: Low Calorie Foods Activation for low calorie food compared to control condition includes superior temporal gyrus, parahippocampal gyrus and orbitofrontal gyrus. Killgore et al., 2003

12. Activation in Adults: High and Low Calorie Conjunction Activation in Adults: High and Low Calorie Conjunction Activation in common for both high and low calorie food perception includes amygdala, anterior hippocampus and medial PFC. Killgore et al., 2003

13. Activation in Adults: High – Low Calorie Foods Activation in Adults: High – Low Calorie Foods Activation differentiating high calorie and low calorie food includes DLPFC and medial PFC, basolateral thalamus, hypothalamus, and cerebellum. Killgore et al., 2003

14. Our results demonstrated significant activation within the limbic system, particularly the hippocampus and parahippocampal gyri, in response to images of food, regardless of the calorie content. Our results demonstrated significant activation within the limbic system, particularly the hippocampus and parahippocampal gyri, in response to images of food, regardless of the calorie content. Prefrontal regions were activated when viewing high-fat calorie-rich foods (high reward). Prefrontal regions were activated when viewing high-fat calorie-rich foods (high reward). Adult Study of Food

15. The orbitofrontal cortex is critical to appetitive behavior in humans and shows changes in activity that correlate with hunger and satiety. The orbitofrontal cortex is critical to appetitive behavior in humans and shows changes in activity that correlate with hunger and satiety. It receives afferent projections from a variety of feeding-related areas, including the lateral hypothalamus and multimodal sensory regions. It receives afferent projections from a variety of feeding-related areas, including the lateral hypothalamus and multimodal sensory regions. These interoceptive and exteroceptive sources of information converge within the orbitofrontal cortex and are evaluated for their reward potential. These interoceptive and exteroceptive sources of information converge within the orbitofrontal cortex and are evaluated for their reward potential. Orbitofrontal Cortex

16. ROI Analysis: Orbitofrontal Cortex x = -5 y = 40 z = -16 Killgore & Yurgelun-Todd, 2005 Orbitofrontal Cortex medial orbitofrontal cortex: inferior, middle, superior gyrus rectus olfactory cortex anterior cingulate gyrus insular cortex

17. Food Study: Effects of Mood

18. Fluctuations in affect are often associated with changes in food-cravings, but the neural basis for these phenomena is not well-established. Fluctuations in affect are often associated with changes in food-cravings, but the neural basis for these phenomena is not well-established. We examined the relationship between affective state and orbitofrontal brain response to images of food in healthy normal-weight adult women. We examined the relationship between affective state and orbitofrontal brain response to images of food in healthy normal-weight adult women. Effects of Mood

19. When viewing high-calorie foods (high-reward), higher ratings of negative affect were associated with greater activity within medial orbitofrontal cortex. When viewing high-calorie foods (high-reward), higher ratings of negative affect were associated with greater activity within medial orbitofrontal cortex. When viewing high-calorie foods (high-reward), higher ratings of positive affect were associated with greater activity within lateral regions of the orbitofrontal cortex. When viewing high-calorie foods (high-reward), higher ratings of positive affect were associated with greater activity within lateral regions of the orbitofrontal cortex. Effects of Mood

20. Positive Affect (PA) Negative Affect (NA) AP L AP High Calorie Foods Low Calorie Foods Medial Prefrontal Cortex “Hunger” Regions Lateral Prefrontal Cortex “Satiation” Regions High Calorie Foods Low Calorie Foods Lateral Prefrontal Cortex “Satiation” Regions Medial Prefrontal Cortex “Hunger” Regions L Killgore & Yurgelun-Todd, 2006

21. Positive Affect Negative Affect HighCalorie/Fat LowCalorie/Fat LateralOrbitofrontalCortex PosteriorInsula PosteriorInsula LateralOrbitofrontalCortex MedialOrbitofrontalCortex Medial Orbitofrontal Cortex/ Anterior Cingulate AnteriorInsula Killgore & Yurgelun-Todd, 2006 Effects of Mood

22. There was an interaction between affective state and the calorie/fat-content of the food images on the pattern of brain activity in appetite-related regions, including the orbitofrontal cortex. There was an interaction between affective state and the calorie/fat-content of the food images on the pattern of brain activity in appetite-related regions, including the orbitofrontal cortex. These findings suggest orbitofrontal response may be associated with the commonly reported increase in cravings for calorie-dense foods during heightened negative emotions. These findings suggest orbitofrontal response may be associated with the commonly reported increase in cravings for calorie-dense foods during heightened negative emotions. Effects of Mood

23. Food Study: Body Mass Index

24. Most studies examining the relationship between food-related cues and activity changes in the orbitofrontal cortex in humans have compared groups that fall outside the normal range for weight or body mass. Most studies examining the relationship between food-related cues and activity changes in the orbitofrontal cortex in humans have compared groups that fall outside the normal range for weight or body mass. We examined the relationship between weight status and reward-related brain activity in normal weight women. We examined the relationship between weight status and reward-related brain activity in normal weight women. Effects of Body Mass

25. There was a negative correlation between body mass index (BMI) and activation in the orbitofrontal ROI for both high-fat and low-fat conditions. There was a negative correlation between body mass index (BMI) and activation in the orbitofrontal ROI for both high-fat and low-fat conditions. It was reversed during the food-absent utensil control condition provides further support for the specificity of the findings to visual images of food. It was reversed during the food-absent utensil control condition provides further support for the specificity of the findings to visual images of food. Effects of Body Mass

26. Body Mass Index (BMI) R 2 = 0.75 -0.40 -0.20 0.00 0.20 18202224262830 Body Mass Index (kg/m 2 ) Adjusted fMRI Response L R P A Killgore & Yurgelun-Todd, 2005 Right Inferior Orbitofrontal CortexHighCalorie/Fat LowCalorie/Fat Anterior Cingulate/Orbitofrontal Cortex R 2 = 0.57 -0.40 -0.20 0.00 0.20 18202224262830 Adjusted fMRI Response Body Mass Index (kg/m 2 )

27. With greater body mass, activity was reduced in brain regions important for evaluating and modifying learned stimulus- reward associations.With greater body mass, activity was reduced in brain regions important for evaluating and modifying learned stimulus- reward associations. This suggests a relationship between weight status and responsiveness of the orbitofrontal cortex to rewarding food images.This suggests a relationship between weight status and responsiveness of the orbitofrontal cortex to rewarding food images. Effects of Body Mass

28. Food Study: Adolescents

29. To examine developmental brain changes in reward processing, we measured BOLD signal in healthy adults and adolescents viewing images of high- and low-calorie foods. To examine developmental brain changes in reward processing, we measured BOLD signal in healthy adults and adolescents viewing images of high- and low-calorie foods. Objective

30. Activation in Adolescents: High Calorie Food High-Calorie Inferior OFG Hippocampus Fusiform Gyrus Subgenual Cingulate Mid-Temporal Gyrus 543210543210 SPM {t} Killgore & Yurgelun-Todd, 2005

31. Activation in Adolescents: Low Calorie Food Low-Calorie Inferior OFG Fusiform Gyrus 4321043210 SPM {t} Killgore & Yurgelun-Todd, 2005

32. Activation in Adolescents: High and Low Calorie Conjunction 32103210 Conjunction Inferior OFG Hippocampus Fusiform Gyrus SPM {t} Killgore & Yurgelun-Todd, 2005

33. High-Calorie Adults > Adolescents Adolescents > Adults Adult versus Adolescent Differences in Activation: High Calorie Food Differences in Activation: High Calorie Food Killgore & Yurgelun-Todd, 2005

34. LR Effects of Age Killgore & Yurgelun-Todd, 2005 Orbitofrontal Activation Increase with Age

35. Utensils High Fat Low Fat Recognition Memory Performance: Percent Correct Adolescents Adults 959085807570 Killgore & Yurgelun-Todd, 2005

36. Prefrontal activation seen in adults in response to high-calorie food was absent in adolescents.Prefrontal activation seen in adults in response to high-calorie food was absent in adolescents. Age-related increases in orbitofrontal activation were seen for high-calorie but not low-calorie images.Age-related increases in orbitofrontal activation were seen for high-calorie but not low-calorie images. Regions important in reward evaluation and response inhibition show age-related increases in activation.Regions important in reward evaluation and response inhibition show age-related increases in activation. Effects of Age

37. MR study samples are small and include selective samples of populations (female). MR study samples are small and include selective samples of populations (female). Cultural influences on diet preference. Cultural influences on diet preference. Signal intensity changes are small, susceptibility effects can cause signal drop out and distortion. Signal intensity changes are small, susceptibility effects can cause signal drop out and distortion. Analyses were focused on selected brain regions. Analyses were focused on selected brain regions. Limitations

38. These results indicate that mood state, body mass and development of the brain circuitry may moderate the reinforcing capacity of rewarding stimuli. These results indicate that mood state, body mass and development of the brain circuitry may moderate the reinforcing capacity of rewarding stimuli. These findings have important implications for clarifying models underlying reward response and for the development of more effective therapies of eating disorders and drug addiction. These findings have important implications for clarifying models underlying reward response and for the development of more effective therapies of eating disorders and drug addiction. Implications

39. Cognitive Neuroimaging Laboratory McLean Hospital/Harvard Medical School

40. Cognitive Neuroimaging Laboratory McLean Hospital/Harvard Medical School Piotr Bogorodzki, Ph.D. Christina Cintron, B.S. Kate Dahlgren, B.A. Staci Gruber, Ph.D. Robert Irvin, M.D. W. Scott Killgore, Ph.D. Alexandra McCaffrey, B.A. Srinivasan Pillay, M.D. Margaret Riccuitti, B.A. Jadwiga Rogowska, Ph.D. Amy Ross, Ph.D. Isabelle Rosso, Ph.D. Simona Sava, M.D., Ph.D. Marisa Silveri, Ph.D Jennifer T. Sneider, Ph.D. Deborah Yurgelun-Todd, Ph.D.