# Presentation: 584397

## 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*

## Internal State

**Internal State**
**Hunger, fullness**
**craving**
**Individual differences**
**Experience**
**Context**

**Sensory inputs**
**Taste **
**Smell**
**Sight**
**Texture**
**Temperature**
**Sound**

**Notes:**
There are many different factors that will determine whether or not the mouse will risk it all for the cheese. Many of these factors are also relevant to drug addiction. In the next 19 minutes or so I am going to highlight some of the similarities and differences in brain response to food and addictive drugs elucidated by neuroimaging studies and informed by work in done in non human animals.

## 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**

**Notes:**
My relationship with food reward and neuroimaging began with chocolate. The goal of this study was to change the reward value of a food by having subjects eat that food to beyond satiety.  I chose chocolate because it is one of the most craved foods and I thought it would be easy to find subjects who really liked it and who would agree to eat a lot.  Then I would ask them to eat more than they wanted to and in this way I could have subjects experience the same stimulus under different affective conditions. In doing so I could correlated brain activity with ratings of pleasantness and motivation to eat the chocolate and identify regions of the brain sensitive to food reward independent from the sensory attributes of the stimulus – which are held constant.

## Choc 6

**Choc 6**

**Notes:**
This is the PET protocol. Each of these bars represents a 60- second scan during which the subject wood take a single square of lindt chocolate and let it melt in their mouths.  Immediately following the scan they rated the pleasantness of the chocolate and their motivation to eat another piece using this scale.  During the “feed” periods they were given more squares to eat and rate until their ratings dropped by at least two points. The ratings are shown in this graph. You can see that as intended the chocolate goes from being highly pleasant and desired to being quit unpleasant and really undesired.

**Notes:**
The most significant correlation with pleasantness and neural activity was within subcallosal region.  More recent data from my lab suggests a specific role for this region in the experience of hunger, which decreased over the course of the chocolate experiment. In the newer study, which I am going to refer to as the peanut butter study, we capitalized on the fact that some people have very strong preferences for crunchy vs smooth peanut butter. By interspersing scans of crunch vs smooth we were able dissociated pleasantness, which is related to the type texture from hunger and satiety, which decreased linearly over time. What we found is that hunger but not pleasantness predicted activation of the subcallosal region. This result is in accordance with data from De Aruajo et al who showed that activity in this region correlated with thirst This same region of subcallosal cortex has also been implicated in drug (Breiter et al., 1997 and Kilts et al., 2001) and alcohol craving (Tapert et al., 2004). Here you see a figure from Kilts et al 2001 illustrating activation in the subcallosal area in when addicts imagined dosing on drug vs imaging a neutral scene.

## Positive correlation with Pleasantness and motivation to eat

**Positive correlation with Pleasantness and motivation to eat**

**Notes:**
Other Key regions in which blood flow correlated with pleasantness and desire to eat included the midbrain, medial OFC, dorsal striatum, and insula. The insular region corresponded to the area identified as the primary gustatory cortex in humans. The modulation of this early sensory cortical area highlights the close relationship between sensory and affective aspects of the gustatory sense and food. Just prior to this study Tataranni and colleagues had reported that the dorsal striatum, medial OFC and the insular cortex are activated more when hungry compared to when full. Involvement of the caudate and the insula in the desire for  food reward is also in accordance with unpublished observations of Pelchat and colleagues who showed that these regions were preferentially activated when subjects viewed pictures of craved food after being on a monotonous diet.  Many of these regions are key parts of the network thought to underlie drug abuse (dorsal striatum, midbrain, OFC).

## Slide 7

**Notes:**
However, two key regions that are frequently reported as important in drug reward are the amygdala and nucleus accumbens.  For example, Grant and colleagues reported that activation in the amygdala correlates with degree of craving; a result which contrasts with the findings of Pelchat and colleagues.  Breiter and colleagues also found a relationship between both NAC and amygdala in drug craving relative to the “rush” associated with the drug. No study of satiety/hunger/craving in lean subjects has shown sensitivity in either of these regions. Instead in healthy lean subjects it is the dorsal striatum that appears to be preferentially sensitive to changes in food reward associated with satiety.

## 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). 

## Slide 9

**Notes:**
This notion is also in line with studies using radiolabeled raclopride, a dopamine receptor antagonist to measure dopamine release. In each column you see regions of color that indicate significant da release with amphetamine, alcohol and food. The striking difference is that with amphetamine and alcohol release is in the ventral striatum whereas with food the da release occurs in the dorsal striatum. This result is also in accordance with the work of Wang and colleagues about which you were likely hear of in the next talk. So in food reward in healthy lean subjects the evidence points towards the dorsal striatum and not the ventral striatum, marking an important difference in the neural correlates of food and drug reward.

## What is the role of the NAc/amygdala in feeding in humans?

**What is the role of the NAc/amygdala in feeding in humans?**

**Notes:**
However, we know from many studies in nonhuman animals that the Nac and amygdala are important in feeding behavior. So what is the role of this region in feeding? All of the studies discussed so far probed for relationships to receipt of food reward or changes in food reward related to internal state. O’Doherty and colleagues found that these areas were more responsive to pictures predicting the arrival of a taste and Arana and colleagues show higher amygdala activation in hungry subjects ordering food of high vs low incentive value. And Labar and colleagues have shown that the amygdala responds to pictures of food items when hungry vs when full. Taken together these results suggest that the NAC and amygdala are important in either anticipation of taste or in processing incentive salience of a food item rather than in receipt of a food reward or drive state (hunger and craving). In this respect, we have concordance with the very influential incentive-salience proposed by Berridge and colleagues (A lesson from addiction research!). 

## 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.

**Notes:**
Now we come to the real reason why I have chosen to focus upon these two areas. Gautier and colleagues measured rCBF in lean and obese subjects after fasting and after a liquid meal. They found that both the Nac and the amygdala were active in hungry>full in obese but not lean subjects – as shown in this figure taken from their study.  As per slide for the rest.

## Slide 12

**Notes:**
Another important aspect of feeding is satiety and the decision to stop eating. 

## Negative correlation with Pleasantness and motivation to eat

- Gautier et al., 2001 Obesity Research: show greater increases with satiety here in obese > lean subjects.

**Negative correlation with Pleasantness and motivation to eat**

**Notes:**
Negative correlations with pleasantness and desire to eat included were found in several regions of prefrontal cortex including the ventrolateral PFC and lateral orbitofrontal cortex (among others).  This lateral activation contrasts with the medial OFC activation which correlates positively with pleasantness. This sort of valence-specific dissociation between medial and lateral OFC has since been replicated by many groups with both simple and abstract rewards (eg. O’Doherty et al, 2001; Small et al., 2003)). Gauthier and colleagues show greater increases with satiety in these regions in obese compared to lean

## Ventral lateral PFC

- -12

- -4

- Increases with satiety in obese

- Decreases with satiety in obese

- Response to hunger and satiety in Obese

**Notes:**
Here we see increases with satiety in blue and decreases with satiety in yellow in obese subjects from the study by Gautier and colleagues. On the right I have displayed the brain at the same level in the axial plane so that you can see the close correspondence between our results. Guatier and colleagues have also proposed that this increased activation reflects increased need to inhibit paralimbic circuitry (such as the nac and amygdala), which are more active in obese as well. This suggestion is in accordance with a wealth of evidence showing that the frontal cortical regions are important in inhibiting inappropriate behaviors. 

## 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.

## 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.  **

## David Zald

**Robert Zatorre**

**Me**

**Alain Dagher**

**Alan Evans**

**Michael Petrides**

**Marilyn **
**Jones-Gotman**

**David Zald**

**Katharine Simmons**

**Y Erica Mak**

**Francis McGlone**