1. Obesity and Impulsivity
Examining the role of diet-induced obesity on dopamine transporter function, and effects in adolescents

2. What is obesity?
Abnormal or excessive fat accumulation that can impair health – World Health Organization
Determined with Body Mass Index (BMI)
>25 = overweight
>30 = obese
Causes:
Imbalance between calories expended/consumed
Excessive consumption of energy dense foods
Sedentary lifestyle
Genetics(?)
Consequences:
Risk factor for: cardiovascular disease, diabetes, cancer, death

3. Worldwide Obesity

4. Worldwide Obesity 1.4 billion overweight people worldwide (2008)
500 million of those are obese (2008)
Today, roughly 10% of worlds population
Now major problem in developing countries
Increased access to processed, high calorie foods
Changes in lifestyle and lack of access to medical services

6. Obesity in America 35.7% of American adults are obese
Doubled since 1980
17 % of American adolescents are obese
Tripled since 1980
Radical differences in prevalence by race, socioeconomic status

7. Obesity in Adolescents
Youth obesity in America recently saw a slight decline
Childhood obesity associated with premature death, disability
Linked to enhanced reward sensitivity and reduced impulse control during food processing

8. Obesity and Impulsivity
What is the relationship?
Both are kind of murky concepts
Obesity: A disease which is tangentially related to genetic predisposition, cultural and socioeconomic factors
Fundamentally: Caused by eating too much
Is that impulsive?
From Cliff’s Presentation, Phenotypic Impulsivity is:
Negative consequences
Risky Behavior
Repetitive*
Not able to discern want from need
Underdeveloped PFC
less feedback from PFC to limbic
impatience
make choices even recognizing the negative consequences for that choice

9. Obesity and Impulsivity
Assuming over-eating is impulsive behavior…
Previous studies suggest that over-eating may be a result of reduced sensitivity to food reward in the dorsal striatum
Reduced sensitivity = compensatory eating
Links obesity to other impulsive behaviors - drug use
However, in obese people, over-eating itself leads to down-regulation of D2 receptors
Leading to reduced sensitivity to food reward
Leading to more over-eating
So does impulsivity predict obesity, or is it an outcome of it?

10. Obesity and Reward Response
Stice et al.
Rats: Overweight = ↓ basal DA, ↓ D2 receptor availability, ↓ induced DA release in dorsal striatum, NAc, mPFC
Humans: Obese = ↓ D2 receptor availability in striatum, ↓ striatal response to food intake
But ↑ response to food cues (anticipation)

11. Obesity and Reward Response
Stice et al.
Proposes three theories to explain conflicting findings
Individuals at risk experience ↓ reward from eating, leading to compensatory over-eating and hyper-responsivity of reward circuitry via conditioning – Reward Deficit Theory
Individuals at risk initially show ↑ responsivity to reward value of food cues, leading to over-eating and a reduction in DA signaling in response to food intake – Reward Surfeit Theory
Individuals at risk initially experience ↑ reward from eating, leading to overeating that reduces DA signaling in response to food intake and hyper-responsivity of reward circuitry to food cues, both of which may drive further overeating - Synthesis

12. Obesity and Reward Response
Stice et al. experimental design
60 lean human youths
35 at high risk for obesity (both parent’s BMI > 30)
25 at low risk for obesity (both parent’s BMI < 25)
fMRI
Anticipation/Receipt of Food Reward – Tasteless Solution
Receipt of Food Reward – Tasteless Solution
First academic paper to contain milkshake recipe
Anticipation/Receipt of Monetary Reward
Winning Money/ Possibly Winning Money/Neutral Response

13. Stice et al. Experiment

14. Stice et al. Results
High Risk/Low Risk found the milkshake equally pleasant
High Risk group showed greater activation in right caudate/right frontal operculum
For both milkshake receipt/tasteless solution receipt
No difference in unpaired cue test for food reward
High Risk group showed greater activation in putamen in response to winning money/reward neutral display
No difference in anticipatory response for winning money/reward neutral display

15. Figure 2. A–D, Greater activation in the right caudate (A: 6, 9, 24; Z3.14; p0.04, FDR; k3; B: 6, 9, 30; Z3.23, p0.04, FDR; k3), right frontal operculum (C: 39, 21, 21; Z3.44, p0.02, FDR; k5), and left parietal operculum (D:54, 15, 21; Z3.36; p0.02, FDR; k2) in the high-risk versus low-risk group during milkshake receipt–tasteless receipt, with the bar graphs of parameter estimates from those peak voxels.

16. Figure 3. A–D, Greater activation in high-risk versus low-risk group in response to the win–neutral display in the right putamen (A, square: 18, 0, 9; Z3.44; p0.018, FDR; k3), left putamen (circle:18, 0, 12; Z3.74, p0.007, FDR, whole brain; k5) with bar graphs of the parameter estimates from those regions (B, right putamen; C, left putamen) and in the right orbitofrontal cortex (D: 45, 33,6; Z5.61, p0.001, FDR; k16) with bar graphs of the parameter estimates from that voxel.

17. Obesity and Reward Response
Normal weight, high risk adolescents showed greater response in dorsal striatum to food receipt
Elevated sensitivity to food reward may be a cause of obesity
↓ striatal response, ↓ D2 receptor availability in obese people is then a consequence, not a cause of over-eating
High risk adolescents also showed greater striatal response to monetary reward
Suggests initial hyper-responsivity to various reward types in people at risk for obesity
… impulsivity?

18. Obesity and Impulsivity
Moreno-Lopez et al.
Why are some people susceptible to obesity, and others not?
Demonstrated by high-risk, low-risk groups in previous paper
Does the structure of the brain correlate with impulsive behavior? Obesity? Both?
Previous evidence:
Reduced GM in orbital frontal cortex in obese vs. lean adoloscents
Volumetric changes to GM in striatum
Obese adolescents show greater trait disinhibition, poorer cognitive control

19. Obesity and Impulsivity
Moreno-Lopez et al. experimental design
52 adolescent humans
16 normal weight
16 overweight
20 obese
Tests
SPSRQ – 48 item questionnaire to assess reward/punishment sensitivity
UPPSP – 59 item inventory to assess facets of impulsive behavior
Sensation seeking, lack of perseverance, lack of premeditation, negative urgency, positive urgency
Stroop Test – Measures inhibitory control
MRI to show structural correlates

20. Moreno-Lopez et al. Results
No significant differences between groups for any of the measurements assessed
Regional differences in GM between normal weight, overweight groups
↑ volume of right hippocampus in excess weight individuals
Structural correlates between ROI and behavioral test scores showed differences only in normal weight individuals
Reward sensitivity, positive urgency negatively associated with GM volume in left somatosensory cortex

21. Figure 1. Clusters of significant gray matter volume increase in excess weight compared with normal weight subjects. Peak coordinates were located in the right hippocampus (x, y, z_ 38, 213, 218; t = 4.21; pFWE-SVC,0.05). Results are overlaid on coronal and sagittal sections of a normalized brain, and the numbers correspond to the ‘y’ and ‘x’ coordinates in MNI space. Color bar represents t value. For demonstration purposes the images are displayed at p,0.001 (uncorrected, k.50). doi: /journal.pone g001

22. Figure 2. Between-group interaction between regional gray matter volume and reward sensitivity. A. Voxel-wise correlations between regional gray matter volume and reward sensitivity score specifically observed in normal weight subjects. Peak coordinate was located in the left secondary somatosensory cortex (SII, Brodmann area 43) (x, y, z =260, 27, 11; t = 4.51; pFWE-SVC,0.05). Results are overlaid on coronal (left) and axial (right) sections of a normalized brain, and the numbers correspond to the ‘y’ and ‘z’ coordinates in MNI space, respectively. Color bar represents t value. For demonstration purposes the images are displayed at p,0.001 (uncorrected, k.100). B. Plot of the correlation between gray matter volume at the peak coordinate and the reward sensitivity score. Normal weight group (filled circles, solid line) showed a significant correlation between these two measures (r =20.750; p,0.005), while in the excess weight group the correlation was not significant (r = 0.284; p.0.05).

23. Figure 3. Between-group interaction between regional gray matter volume and positive urgency. A. Voxel-wise correlations between regional gray matter volume and positive urgency (UPPS-P) score specifically observed in normal weight subjects. Peak coordinate was located in the left secondary somatosensory cortex (SII, Brodmann area 43) (x, y, z =263, 27, 15; t = 4.89; pFWE-SVC,0.05). Results are overlaid on coronal (left) and axial (right) sections of a normalized brain, and the numbers correspond to the ‘y’ and ‘z’ coordinates in MNI space, respectively. Color bar represents t value. For demonstration purposes the images are displayed at p,0.001 (uncorrected, k.100). B. Plot of the correlation between gray matter volume at the peak coordinate and the positive urgency score. Normal weight group (filled circles, solid line) showed a significant correlation between these two measures (r =20.856; p,0.0005), while in the excess weight group the correlation was not significant (r = 0.058; p.0.05).

24. Figure 4. Between-group interaction between regional gray matter volume and response inhibition. A. Voxel-wise correlations between regional gray matter volume and the Stroop response inhibition score specifically observed in normal weight subjects. Peak coordinate was located in the left dorsolateral prefrontal cortex (Brodmann area 9) (x, y, z =261, 6, 24; t = 5.01; pFWE-SVC,0.05). Results are overlaid on coronal (left) and axial (right) sections of a normalized brain, and the numbers correspond to the ‘y’ and ‘z’ coordinates in MNI space, respectively. Color bar represents t value. For demonstration purposes the images are displayed at p,0.001 (uncorrected, k.100). B. Plot of the correlation between gray matter volume at the peak coordinate and the Stroop response inhibition score. Normal weight group (filled circles, solid line) showed a significant correlation between these two measures (r = 0.769; p,0.005), while in the excess weight group the correlation was not significant (r =20.327; p.0.05).

25. Moreno-Lopez et al. Results
↑ volume of right hippocampus in excess weight individuals
Region associated with motivational signals for appetite
So there are structural differences in obese/normal weight brains
Structural correlates between ROI and behavioral test scores showed differences only in normal weight individuals
Excess weight individuals didn’t show significant correlations, and scored no differently than normal weight on the tests
So there are structural correlations with impulsivity, but these are not linked to obesity (at least not according to this test)

26. Obesity and Impulsivity
Obesity and impulsivity linked by brain function, not structure
Adolescents who are at risk of obesity are more sensitive to reward
But adolescents who are actually obese are not more impulsive
So what’s the connection?
Stice et al:
Individuals at risk initially show ↑ responsivity to reward value of food cues, leading to over-eating and a reduction in DA signaling in response to food intake – Reward Surfeit Theory

27. Obesity, Impulsivity, & Dopamine
Is the reward surfeit theory viable?
↑ reward sensation (impulsivity)
→overeating
→Diet induced obesity (DIO)
↓ DA function
↓ impulsivity
Seems illogical on the surface
Let’s get some hard evidence for this stuff
I’m talkin’ Animal Models! Oh Yeah!!!
(His brain was dissected and analyzed)

28. Obesity, Impulsivity, & Dopamine
Narayanaswami et al.
Used rat model to study DAT function, impulsivity and motivation as outcomes/predictors of obesity
Narayanaswami’s definition of impulsivity:
“…a multifaceted behavioral construct involving urgent actions, lack of premeditation and perseverance, and increased sensation-seeking behaviors”
Asserts that cognitive and motivational factors of impulsivity are linked to obesity via inability to resist excessive eating
Thanks, Captain Picard

29. Narayanaswami et al. Experiment
Experiment One – Outcomes of obesity
32 rats used to generate DIO model
24 on High Fat Diet (HF) for 8 weeks
Split into Obesity Prone and Obesity Resistant based on weight gain
8 on Low Fat Diet (LF) for 8 weeks
Impulsivity evaluated with Delayed Discounting task
Sucrose pellets
Food motivation evaluated with reinforcers (HF and LF pellets)
First using Fixed Ratio (FR) schedule
Then a Progressive Ratio (PR) schedule with the alternate reinforcer

30. Narayanaswami et al. Experiment
Experiment Two – Predictors of Obesity
22 rats used to test for predictors
All fed standard chow
Impulsivity evaluated with Delayed Discounting task
Sucrose pellets
Food motivation evaluated with reinforcers (HF and LF pellets)
First using Fixed Ratio (FR) schedule
Then a Progressive Ratio (PR) schedule with the alternate reinforcer
After testing, HF diet introduced for 8 weeks
Split into OP and OR (n=6)
Correlations between neurobehavioral measures and weight

31. Fig 1

32. Narayanaswami et al. Experiment
Striatal D2-receptor density/affinity
Shift in control from NAc to striatal DA pathways →habitual behaviors
Striatal involvement in food motivation
∆Fos B overexpressed in rats with high PR breakpoint
D2 receptor density decreased in obese individuals
Maximal velocity/affinity of VMAT2
With DAT, regulates extracellular dopamine
DAT-deficient mice have ↑ extracellular DA, ↑ food consumption
Likely plays a role in regulating binge eating

33. Fig 2

34. Obesity, Impulsivity, & Dopamine
Effects of DIO
OP rats exhibited:
↓striatal D2 receptor density compared with OR
↓ maximal velocity of uptake at DAT compared with OR
↑ extracellular dopamine in striatum compared to OR
Predictors of DIO
No correlation between delay for reinforcer and weight gain
Positive correlation between PR breakpoint for HF reinforcers in OP compared to OR
BUT there were no differences in dopamine concentration

35. Fig 3

36. Fig 4

37. Fig 5

38. Fig 6

39. Narayanaswami Results
Motivation to obtain HF foods predicts obesity
Not impulsivity (according to this test)
↓ in striatal DAT function is an outcome of DIO
Upon development of DIO:
Motivation to obtain HF foods was maintained in OP
Impulsivity decreased in OP after DIO (compared to OR)

40. The Big Picture Where do we stand on obesity and impulsivity?
They’re linked, but we’re not sure how
Do the models used accurately illustrate impulsivity?
Probably not
How do we explain conflicting results?
With great effort, although…
Reward Surfeit theory does a good job (IMO):
Individuals at risk of obesity are more sensitive to reward (and maybe more impulsive)
Eventual onset of obesity leads to reduced DAT/D2 function
This leads to maintenance of over-eating (impulsive?) but a decrease in other forms of measured impulsivity