The neurobiology of appetite

The neurobiology of appetite
(Insights from brain imaging)
Alain Dagher MD
Montreal Neurological Institute
McGill University
Acknowledgements
Saima Malik
Deborah Tang
Francis McGlone
Dana Small
CIHR, NIDA, FRSQ
Nothing in Biology Makes Sense Except in the Light of
Evolution.
- Theodosius Dobzhansky (1900-1975)
Nothing in the Brain Makes Sense Except in the Light of
Eating.
Is hunger an addiction?
•
Homeostasis
•
•
Thirst determined by
internal state
Homeostasis does not fully
explain hunger
•
Calories can be stored
•
Water can’t be stored
•
Obtained through effort
•
Water doesn’t induce
craving
•
Food can induce craving even
•
when satiated *
Easily available
•
Hunger is learned *
* Features of addiction
Is hunger an addiction?
• DO Hebb (1949)
– “Salted peanuts” paradox.
– Hunger and learning:
Anxiety
Reward
• Initial effect of hunger is disruptive.
• Infant learns that eating relieves
unpleasant effects (e.g. stomach
contractions).
• Eventually hunger becomes an
organized behaviour
Empty
Full
•
RA Wise (1978)
– Dopamine blockade reduces the
reinforcing and rewarding effects
of food.
– Addictive drugs act on brain
circuitry that originally developed
to serve feeding behaviour.
stomach
Feeding
When is it an addiction? (DSM-IV)
• A maladaptive pattern of substance use, leading to
clinically significant impairment or distress, as
manifested by three (or more) of the following,
occurring at any time in the same 12-month period:
– Tolerance
– Withdrawal
– Loss of control
• Taken in larger amounts than intended
• Persistent desire or unsuccessful efforts to cut down
– Preoccupation
– Important social, occupational, or recreational activities are
given up or reduced
– Continued use despite knowledge of adverse consequences
1881: Angelo Mosso (Turin)
1890: Redistribution of blood flow as index of
mental activity
1890: Roy & Sherrington
‘…the chemical products of cerebral metabolism […]
can cause variations of the calibre of the cerebral
vessels: […] vascular supply can be varied locally in
correspondence with local variations of functional
activity’
fMRI Experimental Set-Up
Odors / liquids
back projection screen
scanner hardware
magnet
mirror
LCD projector
surface coil
1.3m
RGB video
SGI
1.6m
Subject feedback
fMRI Activation Experiment
on
stimulus
off
time
image acq
time
ROI
14
2800
2780
10
2760
2
Signal
2740
6
2720
2700
2680
2660
-2
t-value
2640
2620
2600
0
20 40 60 80 100 120 140 160 180
Time (s)
fMRI studies of food reward
I shouldn’t, but I’m going to have the garbage
Brain response to “food cues”
• Event-related fMRI
• Images displayed 5s, 15s apart.
hunger
•Time since last meal
•Energy balance (e.g.
leptin, glucose)
•Gut peptides (e.g.
insulin, ghrelin)
•Stress (acute, chronic)
•Cognitive factors (e.g. selfcontrol)
•Personality / Eating style
time
fMRI activation
(“incentive salience”)
1
4
+++
2
3
Stimuli
5
+++
1.
2.
3.
4.
5.
OFC
Amygdala
Visual areas
Insula
Lateral PFC
Why study cues?
• Cues cause relapse
• Cues increase consumption
• Neural response to cues predicts consumption
and relapse
• Cues are in the environment
– Obesogenic environment
– Role of public smoking regulations
• Cues are Pavlovian conditioned stimuli
• All foods are conditioned stimuli …
A: Dopamine and conditioning
1
2
Reward
(drug, food)
Reward
(drug, food)
Conditioned
stimulus
3
4
Conditioned
stimulus
Conditioned
stimulus
sensitization
DOPAMINE
Incentive Salience
DOPAMINE
Incentive Salience
DOPAMINE
Incentive Salience
DOPAMINE
Incentive Salience
Approach
(wanting, craving)
Approach
(wanting, craving)
Approach
(wanting, craving)
Approach
(wanting, craving)
B: Conditioning to food
Food
Flavor
Flavor
Flavor
Sight, smell
Fuel sensing
DOPAMINE
DOPAMINE
DOPAMINE
Approach
(wanting, craving)
Approach
(wanting, craving)
Approach
(wanting, craving)
A Dagher, Trends Endo Metab, In Press
The Appetitive Network
•Cognitive control
•Execution
•Sensory
specific satiety
•Link cues to
rewards
•Assign value to
stimuli & actions
•Memory
PFC / ACC
•Ingestive cortex
•Incentive
learning
•Role in drug
craving
Insula
Amygdala
OFC
Striatum
•Reward
learning
•Punishment
learning
•Transform
motivation into
action
Smoking and food cues activate the appetitive network
Food
Amygdala
OFC
Insula
Striatum
Smoking Smoking (craving)
Effect of ghrelin on cue response
Ghrelin or
Saline
Malik et al., Cell Metab 2008
Ghrelin responsive areas
Amygdala
(-18 -10 -16)
Fusiform Gyrus
(-50 -66 -10)
Insula
(-34 20 8)
Pulvinar
(-18 -34 0)
OFC
(-28 30 -10)
Malik et al. Cell Metab 2008
Food cues and fMRI
• Appetitive network cue response is greater in the hungry
state.
• Appetitive network response is modulated by homeostatic
factors: ghrelin, PYY, leptin, insulin, glycemia.
• Greater cue responsiveness in obese adults (N=5) and
obese or at-risk children (N=3).
• Reduced activation to food (milkshake) in obese – reward
deficiency?
A Dagher, Trends Endo Metab, In Press
Reward deficiency
Stice et al. Science 2008
Reward (like taste) comes with predictions
Anticipation
Internal Cues
Consumption
External Cues
Motivation
Reward Prediction
Internal Cues
T=0
External Cues
Satiety
Reward Prediction Error
Consumer spending / GDP
Marketing can overcome homeostasis
• Hydration for health, an organization that promotes
drinking water, has a mission to include drinking enough
water as an integral part of public health nutritional
guidelines and routine patient counseling so that patients
can make informed choices.
Neuroeconomics of obesity
• In the developed world, obesity correlates somewhat with
socio-economic status
• Unhealthy energy-dense foods are cheaper than healthy
foods, and energy density predicts palatability
• Food consumed during a meal is determined at the
planning stages.
• Correlation between energy content of supermarket food
purchases and daily caloric intake.
• 40% of the recent increase in weight in America can be
attributed to reduced food prices secondary to agricultural
innovation and policy.
Drewnowski and Eichelsdoerfer 2010
A new thrifty
hypothesis
• Thrifty gene selected
in agricultural
societies.
• Cues signal
abundance (low cost).
• Low cost should
trigger increased
consumption.
• Opportunity cost.
• Consumption matched
to cost.
Prentice et al. Int J Obes 2008
Neuroeconomics of obesity
How much would you pay for this item?
$0
$1
$2
$3
$4
$5
Bid as a function of price and caloric density
Bid vs caloric density
ghrelin
saline
Price vs caloric density
Ghrelin Increased Bidding for Food
Participant Bids
*
{
2.5
* P < 0.05
2
{
*
1.5
$
Saline
Ghrelin
1
0.5
0
Food
Trinket
Overall
vmPFC computes value
Plassmann et al. J Neurosci 2007
2 Way Repeated Measures ANOVA
Factors
• Condition
– Ghrelin/Saline
• Run
– 1, 2, 3, 4, 5, 6
F-map (Main effect of
condition for food*bid)
Ghrelin
• Increases response to food cues in brain areas
involved in motivation, hedonic
evaluation, memory.
• Increases willingness to pay for food.
• Effect seen in the OFC/vmPFC area that
computes value.
• “Incentive salience”.
Hunger and drugs
• The development of feeding behaviour has similarities to
drug addiction.
– It is a learned behaviour
– Not homeostatic
• Food and drug cues activate brain areas involved in
motivation, reward and attention.
• Pharmacological treatments of obesity have a risk of
causing psychiatric/mood side-effects.
• Can lessons from tobacco be applied to obesity?
• Does obesity represent an addiction to food?
Lessons from tobacco
• Smoking incidence
– 90% after WW I
– < 15% today (California)
• Effective Measures
–
–
–
–
–
–
Cost increase
Prohibition
Cue elimination
Behavioral Therapy
Replacement therapy (nicotine gum, patch)
Drugs acting on the reward system (Zyban,
rimonabant)
Pitfalls and limitations of fMRI of appetite
• States vs Traits
• No one pathway to obesity
• Stress and negative affect during MRI
• Reward vs reward prediction errors
• Signal loss in critical areas (OFC)
• Inability to interpret negative findings
– (no control of false negative rate)
“Food addiction”
Pro
• Shared neural circuitry
• Dopamine
• Conceptual similairty
• Shared risk factors
– Genetic
– Endophenotypes
• Hints for effective
treatments
Con
• Addiction has no formal
definition
• Drug addiction has a wide
spectrum
• Loaded term
• Is “food addiction” really a
cause of obesity?