Obesity: Is It A Neuropsychological Disease?

Juan J Fumero-Perez MDPsychiatrist

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H O N O R A R Y NOT R E C E I V E D F O R

T H I S P R E S E N T A T I O N

Juan J. Fumero-Perez, MD

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

neurons drive the anorexic response NTS, nucleus tractus solitarius

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 what’s wrong with obese people?

BMI = weight (kg)/height (m)2

-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, Bardet-Biedl or Alstrôm

30

30

BMI body mass index(IMC indice de masse corporelle)

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?

Juan J Fumero-Perez MDPsychiatrist

High Rates of Obesity in Mental illness• High rates of obesity in schizophrenia, Bipolar

disorder,MDD, binge eating & other disorders1-5

• 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 is not an artifact 8-11

1.Bipolar Disorder 2005;7:424-4302.J Clin Psychchiatry 2002;63:207-2133.Int J Neuropsychopharmacology;2005;8:59-634. J Clin Psychchiatry 2005;66:167-1735.Am J Psychiatry 2001;158:1455-1460

6. Am J Psychiatry 2003;160:112-1177. Biol Psychiatry 2007;62:321-3268. Biol Psychiatry 2007;61:348–358. 9. Psychosom Med 2008;70:288–297.10. J Obes 2008;32:192–200. 11. Arch Gen Psychiatry 2006;63:824–830.

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;61:348–358. 2. J Obes 2008;32:192–200. 3. Arch Gen Psychiatry 2006;63:824–830. 4. Ann Epidemiol 2008;18: 458–466.5. Can J Psychiatry 2006; 51:274–280.

.

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;14:1802–1815.2. http://www.endotext.com.

Brookhaven Science AssociatesU.S. Department of Energy

Body Weight & Drug Treatment

•Drugs (stimulants: e.g. amphetamine, 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.

• 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.12–14

Similarities

1. Am J Psychiatry 2007;164: 708–710.2. Neuroimage 2008;42:1537–1543. 3. Nat Neurosci 2005;8:555–560.

Common Brain Mechanisms in

ADDICTION andOBESITY

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

Function Brain regionMotivation nucleus accumbens

Learning/habits Amygdala/striatum

 Reward value orbitofrontal cortex

 Emotional reactivity amygdala

Behavioural control prefrontal cortex

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

Adapted from Kenny 2011

• 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

Brain Reward Activation

Drugs Activate:• Palatability (& senses)

– Involves both endogenous

• Endocannabinoid• Opioid

– Via dopamine increase• Glucose• Insulin concentration

Food Activates thru:• Via direct

pharmacologic effects directly or indirectly thru modulation – Gaba– Nicotine– Opiate– Cannabinoids

Volcow & Wise 2005

Implicated Brain Regions

Volkow et al. (2007b)

Mejía 200826

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

Circuits having interdependent and overlapping roles in

addiction

ventral pallidum

Reward-pleasure

Memory-Learning

Motivation

anterior cingulate gyrus

cognitive control, in charge of restraining cravings

Brookhaven Science AssociatesU.S. Department of Energy

Non Drug Abuser

Addicted Subject

DA

DA

DA

DA DA DA

DA

Reward CircuitsReward Circuits

DA

DA

DA

DA Dopamine

DA

DA DA DA DA

DA

Dopamine

Low Dopamine (DA) State in Addiction

Dopamine D2 Receptors are Lower in Addiction

DA

D2

Rec

epto

r A

vaila

bilit

y

Cocaine

Alcohol

Heroin

Meth

control addicted Volkow et al., Neurob Learning Memory 2002.

1.5

2

2.5

3

3.5

4

4.5

15

20

25

30

35

40

45

50

DA

D2

Rec

epto

rs(R

atio

Inde

x)20 25 30 35 40 45 50

1.6

1.8

2

2.2

2.4

2.6

2.8

3

3.2

Bm

ax/K

d

Normal ControlsCocaine Abusers

Control Subjects2.99 (Sd 0.41)

2

0ml/gm

Obese Subjects2.47 (Sd 0.36)

Dopamine D2 Receptors[11C]raclopride

Wang et al, Lancet 2001P < 0.008

Brookhaven Science AssociatesU.S. Department of Energy

p < 0.002 • Obese subjectso Control subjects

Dopamine Receptor and BMI

Dopamine Receptor Concentration

BMIp = 0.3

Wang et al, Lancet 2001

Dopamine Neurotransmission

VTA/SNnucleus accumbens

frontalcortex

0100200300400500600700800900

10001100

0 1 2 3 4 5 hrTime After Amphetamine

% o

f Bas

al R

elea

se AMPHETAMINE

0

50

100

150

200

0 60 120 180Time (min)

% o

f Bas

al R

elea

seEmptyBox Feeding

Di Chiara et al.

FOOD

NAcc

VP

REWARD& Pleasure

Hipp

AmygMEMORY/LEARNING

Philipps et al Nature 422, 614-618.

In training the cue was paired with cocaine

In training the cue was not paired with cocaine

Memory Circuit in AddictionMemory Circuit in Addiction and in Obesityand in Obesity

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

Here we tested if conditioned stimuli increase DA in addicted subjects and its relationship to drug craving

DA

Rel

ease

NA

c

Auditory cue

Brookhaven Science AssociatesU.S. Department of Energy

Brain Dopamine Response to Food Stimulation

DA

D2

Rece

ptor

Av

aila

bilit

y(B

max

/Kd)

2.5

3

3.5

4

Placebo/NeutralPlacebo/Food MP/Neutral MP/Food

p < 0.11 p < 0.02

p < 0.005

1.5

0ml/g

Sum images of 10 normal weight subjects ([11C]raclopride)

Volkow, Wang, et al, Synapse 2002

DA

DA

DAD

ADA DA

DA

signal

Motivation & Executive Control Circuits ACG

OFCSCCINHIBITORY

CONTROL

EXECUTIVEFUNCTION

PFC

MOTIVATION/DRIVE

• 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).

DA D2 Receptors

Metabolism

Correlations Between D2 Receptors in Striatum

& Brain Glucose Metabolism

StriatumCG

PreF

OFC

OFC

3035404550556065

u

mol

/100

g/m

in

r = 0.7, p < 0.001

Cocaine Abusers

DA D2 Receptors (Ratio Index)

2.2 2.4 2.6 2.8 3 3.2 3.41.8 230

40

50

60

70

80

90

2.9 3 3.1 3.2 3.3 3.4 3.5 3.6

OFC

umol

/100

gr/m

in

DA D2 Receptors(Bmax/kd)

r = 0.7, p < 0.005

METHAbusers

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

Relationship Between DAD2Receptors (D2R) & Brain

Metabolism in Obese Subjects

p < 0.005

3.0 3.5 4.0 4.5 5.040455055606570

D2R (Bmax/Kd)

Medial Orbitofrontal

3.0 3.5 4.0 4.5 5.040455055606570 Cingulate

Gyrus

Mol

/100

g/m

in

Low D2R in obese subjects is associated in with reduced metabolism in cingulate gyrus and medial orbitofrontal cortex

% Changes of feeling of hunger

r = 0.84, p = 0.001

85

0

µmole/100g/min

Neutral Stimuli

Food Stimuli

Wang et al, Neuroimage 2004

Orbitofrontal Activation

Brain Activation with Food Stimuli

Mejía 200737

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

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

Strength of inhibitory control is weakened (blue), setting up the stage for an unrestrained motivation (green) resulting in compulsive drug taking without regard to potentially catastrophic consequences.

Addiction as the result of impaired information processing within the reward network.

FOOD

What Provides the Specificity?

Drugs

Brookhaven Science AssociatesU.S. Department of Energy

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

Wang et al, NeuroReport 2002

Brookhaven Science AssociatesU.S. Department of Energy

• 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.

Implication

workfamilyfriendscommunitynature

foodSexsportsmusicDanceArt

drugs

GlucosePeptidesNeurohormonesAmino acidsFatty acids

OrgansTissuesCellsMolecules

food intake

HYP

Source: Volkow ND et al., in review, 2012. (Modified with permission from an unpublished presentation,

courtesy of Dr. John Doyle)

Dopamine mediates behavioral responses in the Brain

workfamilyfriendscommunitynature foodSexsportsMusicdanceartdrugs

VTA/SN

DOPAMINE

PFCNAcAmygdalaHippocampusDorsal StriatumMotor Complex

Reward Motivation Action System (incentive, salience, learning, perseverance)

workfamilyfriendscommunitynature

foodsextool-makingsportsmusicdancecraftsart

drugs

Obesity: Is It A Neuropsychological Obesity: Is It A Neuropsychological Disease?Disease?

Juan J Fumero-Perez MDPsychiatrist

Gracias Por Su Atencion.

Juan J Fumero-Perez MDwww.jfbrainwellness.com

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