Dana M Small, PhD Alain Dagher, MD

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. Small et al., 2001, Brain 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

4. 0 -10 -5 5 10 Eating more would make me sick awful I do not want to eat any more Unpleasant neutral Another piece would be nice pleasant I really want another piece delicious Choc 6

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

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

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activation in the NAc and/or amygdala and ratings of craving, hunger or satiety in lean subjects (Pelchat et al., unpublished observations; Small et al., 2001 Brain; Small et al., in preparation; Kringlebach et al., 2003; Tatarrani et al., 1999 PNAS; Gautier et al., 2001).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. Leyton et al., 2002, Neuropsychopharm Boileau et al., 2003 Synapse Small et al., 2003, Neuroimage Amphetamine Alcohol Food Fig 1. T-maps of the change in [11C]-Raclopride BP for the three experiments T-value 3.5 7 3.5 7 3.0 6.5

10. Labar et al., 2001 Behav Neurosci show amygdala responds more to viewing pictures of donuts > tools only when subjects are hungry 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 What is the role of the NAc/amygdala in feeding in humans?

11. 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 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.

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

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

15. blue green red blue yellow red green red Goldstein et al., 2001 Neuroreport 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.

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