Obesity: Is It A

Neuropsychological
Disease?
Juan J Fumero-Perez MD
Psychiatrist

Juan J. Fumero-Perez, MD

SPEAKER/CONSULTANT FOR:

Merck
Sunovion

MEMBER OF:
SEA VIEW HOSPITAL
San Juan Capestrano Faculty
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H O N O R A R Y NOT R E C E I V E D
THIS

PRESENTATION

FOR

A simplified version
of homeostatic
regulation of food
intake; focus on
signals from the
digestive system
(ghrelin, CCK, PYY),
adipose tissue
(leptin) and the
pancreas (insulin)

ghrelin signals
hunger (orexigen,
stimulates food
intake), whereas
leptin, insulin,
CCK and PYY
signal satiety
(anorexigen,
inhibit food
intake).
Their targets are
neurons in the
arcuate nucleus,
of which
POMPC/CART
provide an orexic
signal and
AgRP/NPY
NTS, nucleus tractus solitarius
neurons drive the

With respect to regulation, a general distinction is

made between homeostatic (metabolite input) and
hedonic regulation (reward input)
*

Regulation of food intake; a complex circuitry

between different areas of the brain

So whats wrong with obese people?

30

30
BMI = weight (kg)/height (m)2
BMI body mass index
(IMC indice de masse corporelle)

-In most cases a polygenic

disorder which still has to
be understood further
-In some (severe) cases a
lack of MC4-R signalling, an
excess of ghrelin, a lack of
leptin or a dysfunctioning of
insulin signalling
-In some cases a disorder
associated with a syndrome
such as Prader-Willi, BardetBiedl or Alstrm

Context
It is necessary to consider:
Obesity research encompasses work of:

Economics
Sociology
Nutrition
Biology
Psychology
Epidemiology

Beyond the scope of this lecture.

Obesity: Is It A
Neuropsychological Disease?
JuanJFumeroPerezMD
Psychiatrist

High Rates of Obesity in Mental

illness
High rates of obesity in schizophrenia, Bipolar
disorder,MDD, binge eating & other disorders 15

Evidence support that obesity negatively

impacts illness course and response to
treatment6-7
Epidemiological studies have found
association between obesity & several forms
of mental illness in the general population
indicating
that comorbidity
is2003;160:112-117
not an artifact 81.Bipolar
Disorder 2005;7:424-430
6. Am J Psychiatry
2.J Clin
11Psychchiatry 2002;63:207-213
3.Int J
Neuropsychopharmacology;2005;8:59
-63
4. J Clin Psychchiatry 2005;66:167173

7. Biol Psychiatry 2007;62:321-326

8. Biol Psychiatry 2007;61:348358.
9. Psychosom Med 2008;70:288297.
10. J Obes 2008;32:192200.
11. Arch Gen Psychiatry 2006;63:824830.

Psychiatric Correlates With

Obesity

Particularly strong for women 4,5 and

in severe obesity (i.e., BMI- 35),1,2
Also some associations between
excess body fat and psychiatric
illness also have been documented in
men3 and in more moderately
overweight individuals.2
1 Biol Psychiatry 2007;61:348358.
2. J Obes 2008;32:192200.
3. Arch Gen Psychiatry 2006;63:824
830.
4. Ann Epidemiol 2008;18: 458466.
5. Can J Psychiatry 2006; 51:274280.

Psychosocial Aspects of
Obesity
Obese individuals are subject to
weight-based stigmatization in a
variety of settings,1
Report poorer quality of life
compared with lean individuals.2

1. Obesity 2006;14:18021815.
2. http://www.endotext.com.

Body Weight & Drug Treatment

(stimulants: e.g. amphetamine,
Drugs
cocaine, methylphenidate) that increase

brain dopamine concentration are

anorexigenic.

Drugs (antipsychotic: e.g. Haloperidol,.. )

that block dopamine D2 receptors
increase appetite and result in significant
weight gain.

Brookhaven Science Associates

U.S. Department of Energy

Similarities
Similarities among:
Obesity,
Drug addiction
Compulsive behaviors
Suggests that a form of obesity
characterized by compulsive food
consumption should be included as a
mental disorder in DSM-V.1214
1. Am J Psychiatry 2007;164: 708
710.
2. Neuroimage 2008;42:15371543.
3. Nat Neurosci 2005;8:555560.

Common Brain Mechanisms in

ADDICTION and
OBESITY
Overlapping Neuronal Circuits

Interaction of homeostatic and hedonic control of food intake.

Van Vugt D A Hum. Reprod. Update 2010;16:276-292

The Author 2009. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
journals.permissions@oxfordjournals.org

Overlap in behavioural features

Substance Dependence Criteria

Corresponding Behaviours for obesity

Tolerance: increasing amounts of drug to reach

intoxication

Tolerance: increasing amounts of food to maintain

satiety

Withdrawal symptoms

Distress and dysphoria during dieting

Larger amounts of drug taken than intended

Larger amounts of food eaten than intended

Persistent desire and unsuccessful attempts to cut

drug use

Persistent desire for food and unsuccessful attempts

to curtail the amount of food eaten

Great deal of time spent on getting the drug, using

the substance

Great deal of time is spent eating

Important activities given up because of substance

abuse

Activities given up from fear of rejection because of

obesity

Substance use continued despite knowledge of

problems caused by the drug

Overeating despite knowledge of problems caused

by excessive food consumption

From Volkow and O'Brien 2007

Common Brain Reward Systems

Activation of brain dopamine systems and
connected circuits by food and drugs underlies
their rewarding effects

Function

Brain region

Motivation

nucleus accumbens

Learning/habits

Amygdala/striatum

Reward value

Adapted from Kenny 2011

orbitofrontal cortex

Emotional reactivity

amygdala

Behavioural control

prefrontal cortex

Brain Reward Activation

Repeated Stimulation is believe to:
Trigger neurobiological adaptations that make
behavior increasingly compulsive leading to a
loss in control over food and drug intake
Plastic changes in
Glutaminergic cortico-striatal pathways resulting in;
Enhance reactivity to drugs and their cues
Poor inhibitory control over consumption (Volkow 2004)

Parallel dopamine stimulation during intoxication

facilitates conditioning strengthening the habit
when exposed to stress or stressors

Brain Reward Activation

In food, similarly after repeated
exposure to certain foods
(Particularly energy dense foods such
as high fats and sugars) (Avena et al
2008)
In vulnerable individuals it may also
result in compulsive food
consumption(genetic or developmental
predisposing factors

Brain Reward Activation

Food Activates thru:

Drugs Activate:

Palatability (&
senses)

Via direct
pharmacologic
effects directly or
indirectly thru
modulation

Involves both
endogenous
Endocannabinoid
Opioid

Via dopamine
increase
Glucose
Insulin concentration

Volcow & Wise 2005

Gaba
Nicotine
Opiate
Cannabinoids

Implicated Brain Regions

Volkow et al. (2007b)

Reward-pleasure
Memory-Learning
Motivation
cognitive control,
in charge of
restraining
cravings

anterior cingulate gyrus

ventral pallidum

Circuits having
interdependent and
overlapping roles in
addiction
26

Trends in Molecular Medicine, Volume 12, Issue 12, December 2006, Pages 559-566

Meja 2008

Low Dopamine (DA) State in Addiction

DADA

DADA

DA

Dopamine

DA
DA
DA DA
DA

DA DA
DADA

Reward Circuits
Non Drug Abuser
Brookhaven Science Associates
U.S. Department of Energy

DA
Dopamine

DA
DA

Reward Circuits

Addicted Subject

Dopamine D2 Receptors are Lower in Addiction

NormalControls
Cocaine
Abusers

4.
5

Meth

Alcohol

3.
5
3
2.
5
2
1.
5 1
3. 5

2
0

2
5

3
0

3
5

4
0

4
5

40

45

5
0

2
3

2.8

Bmax/Kd

DAD2ReceptorAvailability

Cocaine

DAD2Receptors
(RatioIndex)

2.6
2.4
2.2
2
1.8
1.6
20

Heroin
control

addicted

25

30

35

50

Volkow et al., Neurob Learning Memory 2002.

Dopamine D2 Receptors
[11C]raclopride
2

0
ml/gm

Control Subjects
2.99 (Sd 0.41)

Obese Subjects
2.47 (Sd 0.36)
P < 0.008

Wang et al, Lancet 2001

Dopamine Receptor and BMI

65
60

p < 0.002

Obese subjects

55
50

Control subjects

BM I

45

BMI

40
35

p = 0.3

30
25
20
1 .8

2 .2 2 .4 2 .6 2 .8 3 3 .2 3 .4 3 .6 3 .8
B m a x Concentration
/K d
Dopamine Receptor

Brookhaven Science Associates

U.S. Department of Energy

Wang et al, Lancet 2001

frontal
cortex

nucleus
accumbens

REWARD
& Pleasure
N VP
Ac
c

VTA/SN

% of Basal Release

% of Basal Release

Dopamine
Neurotransmission

1100
1000
900
800
700
600
500
400
300
200
100
0

AMPHETAMINE

1
2
3
4
Time After Amphetamine

5 hr

FOOD

200
150
100

Empty
50 Box Feeding
0

60

120

Time (min)

180

Di Chiara et al.

Memory Circuit in Addiction

and in Obesity
In rats when a neutral stimuli is
repeatedly paired with the drug
(conditioned), it elicits DA
increases and reinstates
drug self- administration
DA Release NAc

Hipp

Amyg

MEMORY/
LEARNING

In training the cue was

paired with cocaine

Auditory cue

In training the cue was

not paired with cocaine
Philipps et al Nature 422, 614-618.

HerewetestedifconditionedstimuliincreaseDAin
addictedsubjectsanditsrelationshiptodrugcraving

Brain Dopamine Response to Food Stimulation

Sum images of 10 normal weight subjects ([11C]raclopride)
(Bmax/Kd) DA D2 Receptor Availability

1.5

4
0

3.5

p < 0.11

ml/g
p < 0.02
p < 0.005

2.5 Placebo/Neutral Placebo/Food

Brookhaven Science Associates

U.S. Department of Energy

MP/Neutral

MP/Food

Volkow, Wang, et al, Synapse 2002

Motivation & Executive

Control Circuits

EXECUTIVE
FUNCTION
PFC
ACG

INHIBITORY OFC
SCC
CONTROL

In addicted subjects or in
obese subjects, are the
changes in DA function
linked with disruption of
frontal activity?
Used multiple tracers to
evaluated in the same
subject DA D2 receptors
and brain glucose
metabolism (marker of
brain function).

MOTIVATION/
DRIVE

D
A

D
D ADA
A D
A

D
A

DA D2 Receptors
DA

signal
Metabolism

Correlations Between
D2 Receptors in Striatum
& Brain Glucose Metabolism

Relationship Between DAD2

Receptors (D2R) & Brain
Metabolism in Obese Subjects

PreF

Mol/100g/min

CG

Striatum

OFC

Cocaine
Abusers

90

umol/100gr/min

OFC

umol/100g/min

OFC

65
60
55
50
45
40
35
30

80
70
60

1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4

METH
Abusers
p<
0.005

50

r=0.7,p<0.001 40

DAD2Receptors
(RatioIndex)

70 Cingulate
65
Gyrus
60
55
50
45
40
3.0 3.5 4.0 4.5 5.0
70
Medial
65 Orbitofrontal
60
55
50
45
403.0 3.5 4.0 4.5 5.0

r=0.7,p<0.005

30
2.9 3 3.1 3.2 3.3 3.4 3.5 3.6

DAD2Receptors
(Bmax/kd)

Volkow et al., AJP 158(3):377-382, 2001.

D2R (Bmax/Kd)

Low D2R in obese subjects is

associated in with reduced
metabolism in cingulate gyrus
and medial orbitofrontal cortex

Brain Activation with Food Stimuli

25

85

Neutral
Stimuli

% Metabolic Changes

20

Orbitofrontal
Activation

Food
Stimuli

15
10
5
0
-5

0
mole/100g/min

Wang et al, Neuroimage 2004

r = 0.84,
p = 0.001

-10
-10 0 10 20 30 40 50 60 70 80
%Changesoffeelingofhunger

Compared with the non-addicted state, the salience value of a drug (green) and its associated cues (purple) is
enhanced in the addicted state

Addiction as the result of impaired information

Strength of inhibitory control is weakened (blue), setting up the stage for an unrestrained motivation (green)
processing
within
the
network.
resulting
in compulsive drug
taking without
regardreward
to potentially catastrophic
consequences.
Trends in Molecular Medicine, Volume 12, Issue 12, December 2006, Pages 559-566

37

Meja 2007

WhatProvidestheSpecificity?
Drugs
FOOD

Enhanced Somatosensory Cortex

Metabolism in Obese Subjects

Ten obese subjects (n =

10, BMI > 40) and 25
lean subjects (BMI < 25).
At baseline condition
after fasting for 14-16
hours.
Obese subjects had
higher metabolism than
lean subjects in the
somatosensory areas
where the mouth, lips
and tongue are
represented.
FDG

Brookhaven Science Associates

U.S. Department of Energy

Wang et al, NeuroReport 2002

Implication

The enhanced activation in somatic parietal

areas for mouth, tongue and lips in obese
subjects suggests that enhanced
sensitivity in regions involved in the
sensory processing of food may make food
more rewarding and may be one of the
variables contributing to their excess food
consumption.

Brookhaven Science Associates

U.S. Department of Energy

Dopamine mediates behavioral responses in the Brain

food
intake

HYP
Glucose
Peptides
Neurohor
mones
Amino
acids
Fatty
acids

Organs
Tissues
Cells
Molecules

work
family
friends
community
nature

food
Sex
sports
music
Dance
Art

Source: Volkow ND et al., in review, 2012.

drugs

(Modified with permission from an unpublished presentation,

courtesy of Dr. John Doyle)

work
work
family
family
friends
friends
community
community
nature
nature

food
food

sex
Sex
tool-making
sports
sports
Music
music
dance
dance
art
crafts
artdrugs

VTA/SN
DOPAMINE

PFC
NAc
Amygdala
Hippocampus
Dorsal Striatum
Motor Complex

drugs

Reward Motivation Action System

(incentive, salience, learning, perseverance)

Obesity: Is It A
Neuropsychological
Disease?
Juan J Fumero-Perez MD
Psychiatrist

Gracias Por Su
Atencion.
Juan J Fumero-Perez MD
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