1. Converging and Diverging Neurobiological Features of Feeding and Drug Self- Administration in Humans Dana M Small, PhD Alain Dagher, MD The John B Pierce Laboratory and Yale University McGill University

2. Internal State Hunger, fullness craving Individual differences Experience Context Sensory inputs –Taste –Smell –Sight –Texture –Temperature –Sound

3. Food Reward in Healthy Lean Subjects Goal: –Change the reward value of a food by feeding subjects to beyond satiety Correlate brain activity with ratings of pleasantness and motivation to eat the chocolate Small et al., 2001, Brain

4. 0 -10-5105 neutralAnother piece would be nice pleasant I do not want to eat any more Unpleasant I really want another piece delicious Eating more would make me sick awful Choc 6

5. thirst De Araujo et al., 2003 J Neurophys Kilts et al., 2001 Arch of Gen Psych Subcallsum/OFC – 1, 25, -19 t = 11.4

6. Dorsal Striatum –29, 1, 6 t = 4.4 and 15, 20, 9 t = 3.2 Positive correlation with Pleasantness and motivation to eat Midbrain 3, -28, -13 (t = 4.4) Subcallsum/OFC – 1, 25, -19 t = 11.4 taste Small et al., 1999 NeuroReport Gustatory Area: 36, 1, 15 t = 6.1, -43, -4, 13 t = 4.3

7. Grant el al., 1996 PNAS: Report amygdala activity correlated with craving. Breiter et al., 1997 Neuron: Differentiate regions responsive to “rush” vs craving. Childress et al., 1999 Am J Psych, reported amygdala activation when addicts watched a cocaine related video

8. No study has as yet reported a relationship between activation in the NAc and/or amygdala and ratings of craving, hunger or satiety in lean subjects (Pelchat et al., unpublished observations; Small et al., 2001 Brain; Small et al., in preparation; Kringlebach et al., 2003; Tatarrani et al., 1999 PNAS; Gautier et al., 2001).

9. Fig 1. T-maps of the change in [ 11 C]-Raclopride BP for the three experiments 3.57 T-value 3.576.53.0 AmphetamineAlcoholFood Leyton et al., 2002, Neuropsychopharm Boileau et al., 2003 Synapse Small et al., 2003, Neuroimage

10. O’Doherty et al., 2002 Neuron show amygdala/Nac respond to anticipation but not receipt of a taste reward. Arana et al., 2003 JNS show higher amygdala activation when hungry subjects order food of high vs low incentive value Labar et al., 2001 Behav Neurosci show amygdala responds more to viewing pictures of donuts > tools only when subjects are hungry What is the role of the NAc/amygdala in feeding in humans?

11. Therefore, the NAc and amygdala are not sensitive to receipt of food reward or to hunger or craving in lean subjects, but are sensitive to drug craving in drug abusers and to hunger in the obese. This strongly suggests that modifications of processing within these areas are important correlates of unhealthy consumptive behaviors as would be predicted by the incentive sensitization theory of addiction proposed by Robinson and Berridge. Gautier and colleagues (2001) compared rCBF in lean and obese subjects before and after a meal and found that both the amygdala and NAc were active only in the obese subjects. Increases with satiety Decreases with satiety

13. Gautier et al., 2001 Obesity Research: show greater increases with satiety here in obese > lean subjects. Negative correlation with Pleasantness and motivation to eat PFC Right lateral (44,27,-15) Orbitofrontal cortex

14. Ventral lateral PFC -12-4 Increases with satiety in obese Decreases with satiety in obese Response to hunger and satiety in ObeseResponse to eating chocolate to beyond satiety in lean -12-4

15. I-RISA Impaired Response Inhibition and Salience Attribution Proposed by Goldstein and Volkow, 2002 Am J Psychiatry. - which posits that one of the critical changes in addiction is a deficit in inhibitory control that relies on PFC circuitry. Goldstein et al., 2001 Neuroreport greenblueredblueyellowred green

16. Summary There is evidence for considerable convergence of the neurophysiological substrates of food and drug reward: –Midbrain, OFC, insula, subcallosal region are all recruited during administration of food or drug reward and subcallosal region may have a specific role in representing drive states related to food and drugs. –PFC/OFC likely play important roles in feeding termination and dysfunction of these regions appears to result in decreases in ability to inhibit food and drug consumption. Important divergences have also been identified: –The amygdala and NAc do not appear to mediate satiety/hunger/craving in healthy lean subjects. However, significant evidence suggests that these regions mediate drug craving and satiety/hunger in obese subjects.

17. Robert Zatorre Me Alain Dagher Alan Evans Michael Petrides Marilyn Jones-Gotman David Zald Katharine SimmonsY Erica Mak Francis McGlone