Plan

for Today

Nuts and Bolts Plan for Today

Lecture

- Today, well start with depression and substance use
- But mainly focus on reward and depression
- Next =me, well focus on substance use and related
impulsivity disorders

Take-home cri=cal thinking ques=ons

PSYC 210:


E/PE: Biological Bases and
Implica=ons for Understanding Depression

(Pleasure, Reward & Inhibi=on Part 1 of 2)


AJ Shackman
5 May 2015

Conceptual Roadmap
How are T&P, on the one hand, and depression,
on the other, related to one another?

Conceptual Roadmap
How are T&P, on the one hand, and depression,
on the other, related to one another?

How are Extraversion & Posi8ve Emo8onality
(Grays BAS) organized in the brain?

Is Reward a process or a set of processes?

Conceptual Roadmap
How are T&P, on the one hand, and depression,
on the other, related to one another?

How are Extraversion & Posi8ve Emo8onality
(Grays BAS) organized in the brain?

Is Reward a process or a set of processes?

Conceptual Roadmap
How are T&P, on the one hand, and depression,
on the other, related to one another?

How are Extraversion & Posi8ve Emo8onality
(Grays BAS) organized in the brain?

Is Reward a process or a set of processes?

Are there Pleasure Centers in the brain? Is
dopamine The Substrate for pleasure?

Sec8on 0:


Why Bother?

(Show me the epidemiological data!)

Burden: MDD is the leading disorder

h2p://www.adaa.org/about-adaa/press-room/facts-staBsBcs & h2p://www.nimh.nih.gov/StaBsBcs/index.shtml

Burden: MDD is the leading disorder

h2p://www.adaa.org/about-adaa/press-room/facts-staBsBcs & h2p://www.nimh.nih.gov/StaBsBcs/index.shtml

Burden: SUDs are common & costly

DALY = disability-adjusted life-year; Collins et al Nature 2011; NIDA.gov

Burden: SUDs are common & costly

Global Disease Burden

>30M life-years lost world-wide to

Disability, illness, and death

DALY = disability-adjusted life-year; Collins et al Nature 2011; NIDA.gov

Burden: SUDs are common & costly

Global Disease Burden

Annual Cost in the US: ~$600B/Year)

DALY = disability-adjusted life-year; Collins et al Nature 2011; NIDA.gov

Sec=on 1:
How are these disorders related to T&P

Sec=on 1: Developing some hypotheses

Sec=on 1: Developing some hypotheses

Aberrant responses to reward

Suggests a poten=al role for
E/PE (BAS)
Students - what is common to depression
(MDD) and substance use disorders (SUDs)?

Aberrant responses to reward and

pleasurable s=muli




Suggests a poten=al role for
E/PE (BAS)

Extraversion / Posi=ve Emo=onality (E/PE)

00

00

00

Zentner et al. 2012; cf. Caspi et al 2005

Extraversion / Posi=ve Emo=onality (E/PE)

00

00

00

Zentner et al. 2012; cf. Caspi et al 2005

Extraversion / Posi=ve Emo=onality (E/PE)

00

00

00

Nave Preliminary Hypothesis

1. Depression = Too Li_le E/PE/BAS
2. SUDs = Too Much E/PE/BAS

Zentner et al. 2012; cf. Caspi et al 2005

Extraversion / Posi=ve Emo=onality (E/PE)

00

00

00

Nave Preliminary Hypothesis

1. Depression = Too Li_le E/PE/BAS
2. SUDs = Too Much E/PE/BAS

Goldilocks & The 3 Bears Porridge (too cold, too hot)

How well does our hypothesis actually

map onto the formal criteria for MDD?

DSM-IV-TR: Major Depressive Disorder

DSM-IV-TR: Major Depressive Disorder

DSM-IV-TR: Major Depressive Disorder

Anhedonia
- lack of pleasure
- reduced liking of rewarding sBmuli

Abulia (Avoli=on)
- lack of moBvaBon, drive, or interest in obtaining reward
- reduced wanBng

DSM-IV-TR: Major Depressive Disorder

Anhedonia
- lack of pleasure
- reduced liking of rewarding sBmuli

Abulia (Avoli=on)
- lack of moBvaBon, drive, or interest in obtaining reward
- reduced wanBng

DSM-IV-TR: Major Depressive Disorder

Anhedonia
- lack of pleasure
- reduced liking of rewarding sBmuli

Abulia (Avoli=on)
- lack of moBvaBon, drive, or interest in obtaining reward
- reduced wanBng

Depression may reect

1. Decreased consummatory pleasure (liking)

2. Decreased appe88ve mo8va8on (wan8ng)

3. Both

Kringelbach 2015

Sec=on 2:


Show me the (epidemiological) data!

Are trait-like dierences in E/PE
related to MDD?

 Meta-analysis of 175 studies (n=75,229)

High N/NE and Low Conscien=ousness were
nonspecically associated with anxiety, depression,
and SUD
Many disorders were associated with Low E/PE, with
larger eects for depression/dysthmia
The 'disinhibi=on' facet of C/SC was specically
associated with SUD

Among broad-band superfactors,

MDD risk is associated with

1. High N/NE (though this is not
specic to MDD)

2. Low E (also not specic)

3. Surprisingly strong rela=onship
with C/SC

N = NeuroBcism; E = Extraversion; D = DisinhibiBon; C = ConscienBousness

Distress = MDD + GAD; Fear = Panic and Phobias

Among broad-band superfactors,

MDD risk is associated with

1. High N/NE (though this is not
specic to MDD/Distress)

2. Low E (also not specic)

3. Surprisingly strong rela=onship
with C/SC

N = NeuroBcism; E = Extraversion; D = DisinhibiBon; C = ConscienBousness

Distress = MDD + GAD; Fear = Panic and Phobias

Among broad-band superfactors,

MDD risk is associated with

1. High N/NE (though this is not
specic to MDD/Distress)

2. Low E (also not specic)

3. Surprisingly strong rela=onship
with C/SC

N = NeuroBcism; E = Extraversion; D = DisinhibiBon; C = ConscienBousness

Distress = MDD + GAD; Fear = Panic and Phobias

Among broad-band superfactors,

MDD risk is associated with

1. High N/NE (though this is not
specic to MDD/Distress)

2. Low E (also not specic)

3. Surprisingly strong rela=onship
with C/SC

N = NeuroBcism; E = Extraversion; D = DisinhibiBon; C = ConscienBousness

Distress = MDD + GAD; Fear = Panic and Phobias

For now, ignore N/NE and C/SC

Focus on E/PE

Sec=on 3a:

Do depressed individuals show
reduced liking in the lab?


Show me the behavioral data!

Depressed Individuals
Show Blunted Liking

Depressed Individuals
Show Blunted Liking


MDD is characterized by reduced reacBvity to both
posiBve and negaBve sBmuli (e.g., lm clips)
The eect is twice as large for posiBve (d=.53) vs.
negaBve (d=.25) sBmuli
This is true for self-reported experience, expressive
behavior (e.g., facial expressions), and peripheral
physiology

Depressed Individuals
Show Blunted Liking


MDD is characterized by reduced reacBvity to both
posiBve and negaBve sBmuli (e.g., lm clips)
The eect is twice as large for posiBve (d=.53) vs.
negaBve (d=.25) sBmuli
This is true for self-reported experience, expressive
behavior (e.g., facial expressions), and peripheral
physiology

Depressed Individuals
Show Blunted Liking


MDD is characterized by reduced reacBvity to both
posiBve and negaBve sBmuli (e.g., lm clips)
The eect is twice as large for posiBve (d=.53) vs.
negaBve (d=.25) sBmuli
This is true for self-reported experience, expressive
behavior (e.g., facial expressions), and peripheral
physiology

Sec=on 3b:

Do depressed individuals show
evidence of reduced wan8ng
or eort in the lab?

Students

Have we discussed any biological
measures that are sensi8ve to
wan8ng?

Frontal EEG
Asymmetry

Lei > Right


frontal EEG asymmetry and wan=ng

een linked to Wan=ng (appe==ve drive)

L > R has b
During the anBcipaBon of monetary reward in
unselected Ss
During the anBcipaBon of smoking in nicoBne deprived
smokers
During the anBcipaBon of moms return following brief
separaBon in young children
Depressed (anhedonic) Pps show reducBon at baseline
more about this later!


Lei > Right


frontal EEG asymmetry and wan=ng

een linked to Wan=ng (appe==ve drive)

L > R has b
During the anBcipaBon of monetary reward
During the anBcipaBon of smoking in nicoBne-deprived
smokers
During the anBcipaBon of moms return following brief
separaBon in young children
Depressed (anhedonic) Pps show reducBon at baseline
more about this later!

Lei > Right

Students

So what might we expect to nd in
pa8ents diagnosed with depression?

Depressed Individuals
Show Reduced L<R

Frontal EEG

Asymmetry
26 studies and N = 1,673 adults
Consistent, moderate eect (meta-analyBc R = .26)

Depressed Individuals
Show Reduced L<R

Frontal EEG

Asymmetry
26 studies and N = 1,673 adults
Consistent, moderate eect (meta-analyBc R = .26)

Depressed Individuals
Show Reduced L<R

Frontal EEG

Asymmetry
26 studies and N = 1,673 adults
Consistent, moderate eect (meta-analyBc R = .26)

How can we behaviorally measure Wan8ng?

Willingness to Work or Expend Resources for Reward

- or -
The Ability of Reward to Alter Behavior

Students?

Zald

Treadway

Pizzagalli

How can we behaviorally measure Wan8ng?

Willingness to work or expend resources for reward

- or -
Rewards ability to alter or modulate behavior

Students?

Willingness to Work for Reward

Treadway et al PlosOne 2009

Willingness to Work for Reward

Eort Expenditure for
Rewards (EefRT) Task

Treadway et al PlosOne 2009

Willingness to Work for Reward

Eort Expenditure for
Rewards (EefRT) Task

Treadway et al PlosOne 2009

Willingness to Work for Reward

Eort Expenditure for
Rewards (EefRT) Task

More Depression,
Less EefRT

Treadway et al PlosOne 2009

Behavioral Sensi=vity to Reward

Pizzagalli et al Biol Psychiatry 2005

Behavioral Sensi=vity to Reward

Reward-responsiveness = propensity to
modulate behavior in response to reward

75% of reward feedback for one of the 2
correct responses (e.g., short mouth)

Goal is to produce a response bias and test
whether depressed individuals are less biased
(responsive to reward)

Pizzagalli et al Biol Psychiatry 2005

Behavioral Sensi=vity to Reward

Reward-responsiveness = propensity to
modulate behavior in response to reward

75% of reward feedback for one of the 2
correct responses (e.g., short mouth)

Goal is to produce a response bias and test
whether depressed individuals are less biased
(responsive to reward)

Pizzagalli et al Biol Psychiatry 2005

Behavioral Sensi=vity to Reward

Reward-responsiveness = propensity to
modulate behavior in response to reward

75% of reward feedback for one of the 2
correct responses (e.g., short mouth)

Goal is to produce a response bias and test
whether depressed individuals are less biased
(responsive to reward)

Pizzagalli et al Biol Psychiatry 2005

Behavioral Sensi=vity to Reward

Reward-responsiveness = propensity to
modulate behavior in response to reward

75% of reward feedback for one of the 2
correct responses (e.g., short mouth)

Goal is to produce a response bias and test
whether depressed individuals are less biased
(responsive to reward)

Controls Develop a Reward Bias

Pa8ents Do Not

Pizzagalli et al 2005, 2008

Sec=on 3c:


Is reduced Reward Responsiveness
an endophenotype for depression?

Students


Whats an endophenotype?

Reduced Reward Responsiveness (RR):

Endophenotype for Depression

ProspecBvely predicts depressive symptoms 1 year later

Predicts which paBents will fail to get be2er following 8 weeks of Tx
Like E/PE, behavioral measures of RR are moderately
Trait-like (38-day test-retest, R = .56)
Persists following remission of an acute depressive episode
Heritable (h2 = 46%)
Behavioral measures of RR avoid the kinds of biases, distorBons, and
arBfacts that can inuence introspecBve measures (Strauss & Gold Amer J
Psychiatry 2012)

Berghorst & Pizzagalli 2010; Pizzagalli Ann Rev Clin Psychol 2014

Reduced Reward Responsiveness (RR):

Endophenotype for Depression

Reduced Reward Responsiveness (RR)

ProspecBvely predicts depressive symptoms 1 year later

Predicts which paBents will fail to get be2er following 8 weeks of Tx
Like E/PE, behavioral measures of RR are moderately
Trait-like (38-day test-retest, R = .56)
Persists following remission of an acute depressive episode
Heritable (h2 = 46%)
Behavioral measures of RR avoid the kinds of biases, distorBons, and
arBfacts that can inuence introspecBve measures (Strauss & Gold Amer J
Psychiatry 2012)

Berghorst & Pizzagalli 2010; Pizzagalli Ann Rev Clin Psychol 2014

Reduced Reward Responsiveness (RR):

Endophenotype for Depression

Reduced Reward Responsiveness (RR)

ProspecBvely predicts depressive symptoms 1 year later

Predicts which paBents will fail to get be2er following 8 weeks of Tx
Like E/PE, behavioral measures of RR are moderately
Trait-like (38-day test-retest, R = .56)
Persists following remission of an acute depressive episode
Students
2
Heritable (h = 46%)
What does this suggest?
Behavioral measures of RR avoid the kinds of biases, distorBons, and
arBfacts that can inuence introspecBve measures (Strauss & Gold Amer J
Psychiatry 2012)

Berghorst & Pizzagalli 2010; Pizzagalli Ann Rev Clin Psychol 2014

Reduced Reward Responsiveness (RR):

Endophenotype for Depression

Reduced Reward Responsiveness (RR)

ProspecBvely predicts depressive symptoms 1 year later

Predicts which paBents will fail to get be2er following 8 weeks of Tx
Like E/PE, behavioral measures of RR are moderately
Trait-like (38-day test-retest, R = .56)
Persist following remission of an acute depressive episode
Heritable (h2 = 46%)
Behavioral measures of RR avoid the kinds of biases, distorBons, and
arBfacts that can inuence introspecBve measures (Strauss & Gold Amer J
Psychiatry 2012)

Berghorst & Pizzagalli 2010; Pizzagalli Ann Rev Clin Psychol 2014

Reduced Reward Responsiveness (RR):

Endophenotype for Depression

Reduced Reward Responsiveness (RR)

ProspecBvely predicts depressive symptoms 1 year later

Predicts which paBents will fail to get be2er following 8 weeks of Tx
Like E/PE, behavioral measures of RR are moderately
Trait-like (38-day test-retest, R = .56)
Persist following remission of an acute depressive episode
Heritable (h2 = 46%)
Behavioral measures of RR avoid the kinds of biases, distorBons, and
Students
arBfacts that can inuence
introspecBve measures (Strauss & Gold Amer J
Psychiatry 2012)

What does this suggest?

Berghorst & Pizzagalli 2010; Pizzagalli Ann Rev Clin Psychol 2014

Reduced Reward Responsiveness (RR):

Endophenotype for Depression

Reduced Reward Responsiveness (RR)

ProspecBvely predicts depressive symptoms 1 year later

Predicts which paBents will fail to get be2er following 8 weeks of Tx
Like E/PE, behavioral measures of RR are moderately
Trait-like (38-day test-retest, R = .56)
Persist following remission of an acute depressive episode
Heritable (h2 = 46%)
Behavioral measures of RR avoid the kinds of biases, distorBons, and
arBfacts that can inuence introspecBve measures (Strauss & Gold Amer J
Psychiatry 2012)

Berghorst & Pizzagalli 2010; Pizzagalli Ann Rev Clin Psychol 2014

Consistent with Daily Diary Data

DAILY DIARY SAME TECHNIQUE USED IN THE GABLE STUDY DISCUSSED IN CLASS

Hopko et al BRT 2003

Consistent with Daily Diary Data

LOW
DAILY DIARY SAME TECHNIQUE USED IN THE GABLE STUDY DISCUSSED IN CLASS

HIGH
Hopko et al BRT 2003

Consistent with Daily Diary Data

Underinvest in
Hi-Rew Ac8vity

Overinvest in
Lo-Rew Ac8vity

LOW
DAILY DIARY SAME TECHNIQUE USED IN THE GABLE STUDY DISCUSSED IN CLASS

HIGH
Hopko et al BRT 2003

Consistent with Experience Sampling

Brown et al JNMD 2011

Consistent with Experience Sampling

Underinvest in
Hi-Reward Social Ac8vity

Brown et al JNMD 2011

Consistent with Clinical Experience

Consistent with Clinical Experience

Consistent with Clinical Experience

Behavioral Ac=va=on Therapy

PaBents are coached to engage in more
frequent, more rewarding acBviBes
Focus on behavioral change, not
thoughts, feelings, or moods
Large eect
Causal evidence that low RR is a key
acBve ingredient in depression

Consistent with Clinical Experience

Behavioral Ac=va=on Therapy

PaBents are coached to engage in more
frequent, more rewarding acBviBes
Focus on behavioral change, not
thoughts, feelings, or moods
Large eect
Causal evidence that low RR is a key
acBve ingredient in depression

Sec=on 3d:


Wait a minute!

What about blunted liking?

In prac8ce, how easy is it to cleanly

dissociate Liking from Wan8ng
(willingness to work or expend resources)?

Meh

Grocery Store Sushi

SupercalafragalisBcexpealidociuous

Exclusive Tokyo Sushi Bar Sushi

Students?

In prac8ce, how easy is it to cleanly

dissociate Liking from Wan8ng
(willingness to work or expend resources)?

Grocery Store Sushi

Exclusive Tokyo Sushi Bar Sushi

Students?

liking and wanBng are highly entangledmost eaBng manipulaBons (e.g., hunger, saBety)
are characterized by conjunct changes in food liking and wanBng

[But the situaBon is not hopeless!!]

Fruitless [no pun intended] debates on whether this or that task is measuring true food
wanBng, or liking, or a bit of both can be avoided by reporBng precisely that what
everyone agrees on the task or test is measuring.

[For example] In the case of a progressive raBo of food reinforcement task,
one can measure moBvaBon or the eort one is prepared to invest in obtaining a given food

liking and wanBng are highly entangledmost eaBng manipulaBons (e.g., hunger, saBety)
are characterized by conjunct changes in food liking and wanBng

[But the situaBon is not hopeless!!]

Fruitless [no pun intended] debates on whether this or that task is measuring true food
wanBng, or liking, or a bit of both can be avoided by reporBng precisely that what
everyone agrees on the task or test is measuring.

[For example] In the case of a progressive raBo of food reinforcement task,
one can measure moBvaBon or the eort one is prepared to invest in obtaining a given food

liking and wanBng are highly entangledmost eaBng manipulaBons (e.g., hunger, saBety)
are characterized by conjunct changes in food liking and wanBng

[But the situaBon is not completely hopeless!!]

Fruitless [no pun intended] debates on whether this or that task is measuring true food
wanBng, or liking, or a bit of both can be avoided by reporBng precisely that what
everyone agrees on the task or test is measuring.

[For example] In the case of a progressive raBo of food reinforcement task,
one can measure moBvaBon or the eort one is prepared to invest in obtaining a given food

liking and wanBng are highly entangledmost eaBng manipulaBons (e.g., hunger, saBety)
are characterized by conjunct changes in food liking and wanBng

[But the situaBon is not completely hopeless!!]

Fruitless [no pun intended] debates on whether this or that task is measuring true food
wanBng, or liking, or a bit of both can be avoided by reporBng precisely that what
everyone agrees on the task or test is measuring.

[For example] In the case of a progressive raBo of food reinforcement task,
one can measure moBvaBon or the eort one is prepared to invest in obtaining a given food
[with the understanding that it probably reects a combinaBon of liking AND wanBng]

Put simply, behavioral and self-report

measures (considered in isola8on)
cannot tease apart
Liking from Wan8ng

Students - What is another approach?

Put simply, behavioral and self-report

measures (considered in isola8on)
cannot tease apart
Liking from Wan8ng

Students - What is another approach?

What if we had a labeled brain map?

Liking
Circuits

Wan=ng
Circuits

What if we had a labeled brain map?

Liking
Circuits
Kringelbach & Berridge Sci Amer 2012

Sec=on 4:


Show me the (rodent brain) data!


Focus on Berridge & Robinson

Self-S=mula=on (SS) of the MFB

Self-S=mula=on (SS) of the MFB

MFB: medial forebrain bundle (complex bundle of axons; main pathway for ascending dopamine bers; relays informaBon from VTA
to accumbens; rewarding eect of SS reects acBvaBon of the mesocorBcolimbic dopamine system; Carlezon Nature Prot 2007

Self-S=mula=on (SS) of the MFB

Rodents learn to robustly SS (e.g.,

bar press) within a minuteup to
2000x/hour

Impervious to anxiety or saBaBon,

unlike many natural rewards (food,
sex)
Rodents will engage in SS for hours
or, if allowed, even days, oven to
the exclusion of every other
behavior
Rats will choose SS over access to
food or heat in a subfreezing
environment, despite lethal
Details Are
Not Important
consequences
MFB: medial forebrain bundle (complex bundle of axons; main pathway for ascending dopamine bers; relays informaBon from VTA
to accumbens; rewarding eect of SS reects acBvaBon of the mesocorBcolimbic dopamine system; Carlezon Nature Prot 2007

Medial Forebrain Bundle (MFB)

MFB: medial forebrain bundle (complex bundle of axons; main pathway for ascending dopamine bers); relays informa=on from VT
to accumbens; rewarding eect of SS reects ac=va=on of the mesocor=colimbic dopamine system;
Carlezon N
ature
Prot
2007
Schlaepfer
et
al Biol
Psych
2013

Self-S=mula=on (SS) of the MFB

Rodents learn to robustly SS (e.g.,

bar press) within a minuteup to
2000x/hour

Impervious to anxiety or saBaBon,

unlike many natural rewards (food,
sex)
Rodents will engage in SS for hours
or, if allowed, even days, oven to
the exclusion of every other
behavior
Rats will choose SS over access to
food or heat in a subfreezing
environment, despite lethal
consequences
MFB: medial forebrain bundle (complex bundle of axons; main pathway for ascending dopamine bers; relays informaBon from VTA
to accumbens; rewarding eect of SS reects acBvaBon of the mesocorBcolimbic dopamine system; Carlezon Nature Prot 2007

Self-S=mula=on (SS) of the MFB

Rodents learn to robustly SS (e.g.,

bar press) within a minuteup to
2000x/hour

Impervious to anxiety or saBaBon,

unlike many natural rewards (food,
sex)
Rodents will engage in SS for hours
or, if allowed, even days, oven to
the exclusion of every other
behavior
Rats will choose SS over access to
food or heat in a subfreezing
environment, despite lethal
consequences
MFB: medial forebrain bundle (complex bundle of axons; main pathway for ascending dopamine bers; relays informaBon from VTA
to accumbens; rewarding eect of SS reects acBvaBon of the mesocorBcolimbic dopamine system; Carlezon Nature Prot 2007

SS was a scien8c home run and

captured the acen8on (and
imagina8on) of scien8sts and the
public alike

Sci Am 1956; see also Horgan Sci American 2005; video clip @ h2ps://www.youtube.com/watch?v=de_b7k9kQp0

Dopamine = Pleasure (Liking) ?

Dopamine
Release Tracks
Reward
Work
to Understand
MFB-SS
Dopamine Release Tracks Reward

triggered
encounters
with
Release of the neurotransmi2er dopamine is tis
riggered
by bey ncounters
with
rugs
of adbuse,
SS, and secondary oreinforcers
(e.g., and
food, sex, adll
major
rugs oef lectrical
abuse [psychosBmulants,
piates, ethanol,
money) electrical SS, and secondary reinforcers (e.g., money)
nicoBne],
A kind of common currency

Dopamine Blockade

Radically a2enuates behaviors aimed at earning or consuming reward

Wises Inuen=al Anhedonia Hypothesis: Dopamine Mediates Pleasure

Aver the administraBon of dopamine antagonists, all of lifes pleasures

the pleasures of primary reinforcement and the pleasures of their
associated sBmulilose their ability to arouse the animal
the dopamine juncBons represent a synapBc way staBon . . . where.
sensory inputs are translated into the hedonic messages we experience as
pleasure, euphoria or yumminess

Note: Roy Wise later rejected the hypothesis; Berridge & Robinson Brain Res Rev 1998; Berridge Psychopharm 2007

Dopamine = Pleasure (Liking) ?

Work to Understand MFB-SS Dopamine Release Tracks Reward

Release of the neurotransmi2er dopamine is triggered by encounters with

food, sex, all major drugs of abuse [psychosBmulants, opiates, ethanol, and
nicoBne], electrical SS, and secondary reinforcers (e.g., money)
A kind of common currency

Dopamine Blockade

Radically a2enuates behaviors aimed at earning or consuming reward

Wises Inuen=al Anhedonia Hypothesis: Dopamine Mediates Pleasure

Aver the administraBon of dopamine antagonists, all of lifes pleasures

the pleasures of primary reinforcement and the pleasures of their
associated sBmulilose their ability to arouse the animal
the dopamine juncBons represent a synapBc way staBon . . . where.
sensory inputs are translated into the hedonic messages we experience as
pleasure, euphoria or yumminess

Note: Roy Wise later rejected the hypothesis; Berridge & Robinson Brain Res Rev 1998; Berridge Psychopharm 2007

Dopamine = Pleasure (Liking) ?

Work to Understand MFB-SS Dopamine Release Tracks Reward

Release of the neurotransmi2er dopamine is triggered by encounters with

food, sex, all major drugs of abuse [psychosBmulants, opiates, ethanol, and
nicoBne], electrical SS, and secondary reinforcers (e.g., money)

Dopamine Blockade

Radically a2enuates behaviors aimed at earning or consuming reward

Wises Inuen=al Anhedonia Hypothesis: Dopamine Mediates Pleasure

Aver the administraBon of dopamine antagonists, all of lifes pleasures

the pleasures of primary reinforcement and the pleasures of their
associated sBmulilose their ability to arouse the animal
the dopamine juncBons represent a synapBc way staBon . . . where.
sensory inputs are translated into the hedonic messages we experience as
pleasure, euphoria or yumminess

Note: Roy Wise later rejected the hypothesis; Berridge & Robinson Brain Res Rev 1998; Berridge Psychopharm 2007

Dopamine = Pleasure (Liking) ?

Work to Understand MFB-SS Dopamine Release Tracks Reward

A kind of common currency

Dopamine Blockade

Dopamine release in the ventral striatum

Release of the neurotransmi2er dopamine is triggered by encounters with

food, sex, all major drugs of abuse [psychosBmulants, opiates, ethanol, and
nicoBne], electrical SS, and secondary reinforcers (e.g., money)

Radically a2enuates behaviors aimed at earning or consuming reward

Wises Inuen=al Anhedonia Hypothesis: Dopamine Mediates Pleasure

Aver the administraBon of dopamine antagonists, all of lifes pleasures

the pleasures of primary reinforcement and the pleasures of their
associated sBmulilose their ability to arouse the animal
the dopamine juncBons represent a synapBc way staBon . . . where.
sensory inputs are translated into the hedonic messages we experience as
pleasure, euphoria or yumminess
Scale is reversed

Note: Roy Wise later rejected the hypothesis; Berridge & Robinson Brain Res Rev 1998; Berridge Psychopharm 2007

Dopamine = Pleasure (Liking) ?

Work to Understand MFB-SS Dopamine Release Tracks Reward

Release of the neurotransmi2er dopamine is triggered by encounters with

food, sex, all major drugs of abuse [psychosBmulants, opiates, ethanol, and
nicoBne], electrical SS, and secondary reinforcers (e.g., money)
Dopamine release in the ventral striatum

Point:
A kind of Larger
common
currency


The balance of evidence suggests rather
Dopamine Blockade
massive overlap between neural systems that
Radically mediate
a2enuates
behaviors
aimed
at e arning or consuming reward
rewards
of dierent
types.

The oAverlap
is far mHore
extensive tD
han
many Mediates Pleasure
Wises Inuen=al
nhedonia
ypothesis:
opamine
have expected
ased onsubjecBve
Aver the might
administraBon
of dbopamine
antagonists, all of lifes pleasures
dierences
i
n
e
xperiences
the pleasures of primary reinforcement and the pleasures of their
sBmulilose their ability to arouse the animal
associated
Berridge & Kringelbach Neuron 2015

the dopamine
juncBons represent a synapBc way staBon . . . where.

sensory inputs are translated into the hedonic messages we experience as

pleasure, euphoria or yumminess
Scale is reversed

Note: Roy Wise later rejected the hypothesis; Berridge & Robinson Brain Res Rev 1998; Berridge Psychopharm 2007

Dopamine = Pleasure (Liking) ?

Work to Understand MFB-SS Dopamine Release Tracks Reward

Release of the neurotransmi2er dopamine is triggered by encounters with

food, sex, all major drugs of abuse [psychosBmulants, opiates, ethanol, and
nicoBne], electrical SS, and secondary reinforcers (e.g., money)
A kind of common currency

Dopamine Blockade

Radically a2enuates behaviors aimed at earning or consuming reward

Wises Inuen=al Anhedonia Hypothesis: Dopamine Mediates Pleasure

Aver the administraBon of dopamine antagonists, all of lifes pleasures

the pleasures of primary reinforcement and the pleasures of their
associated sBmulilose their ability to arouse the animal
the dopamine juncBons represent a synapBc way staBon . . . where.
sensory inputs are translated into the hedonic messages we experience as
pleasure, euphoria or yumminess

Note: Roy Wise later rejected the hypothesis; Berridge & Robinson Brain Res Rev 1998; Berridge Psychopharm 2007

Dopamine = Pleasure (Liking) ?

Work to Understand MFB-SS Dopamine Release Tracks Reward

Release of the neurotransmi2er dopamine is triggered by encounters with

food, sex, all major drugs of abuse [psychosBmulants, opiates, ethanol, and
nicoBne], electrical SS, and secondary reinforcers (e.g., money)
A kind of common currency

Dopamine Blockade

Radically a2enuates behaviors aimed at earning or consuming reward

Wises Inuen=al Anhedonia Hypothesis: Dopamine Mediates Pleasure

Aver the administraBon of dopamine antagonists, all of lifes pleasures

the pleasures of primary reinforcement and the pleasures of their
associated sBmulilose their ability to arouse the animal
the dopamine juncBons represent a synapBc way staBon . . . where.
sensory inputs are translated into the hedonic messages we experience as
pleasure, euphoria or yumminess

Note: Roy Wise later rejected the hypothesis; Berridge & Robinson Brain Res Rev 1998; Berridge Psychopharm 2007

Dopamine = Pleasure (Liking) ?

Work to Understand MFB-SS Dopamine Release Tracks Reward

Release of the neurotransmi2er dopamine is triggered by encounters with

food, sex, all major drugs of abuse [psychosBmulants, opiates, ethanol, and
nicoBne], electrical SS, and secondary reinforcers (e.g., money)
A kind of common currency

Dopamine Blockade

Radically a2enuates behaviors aimed at earning or consuming reward

Wises Inuen=al Anhedonia Hypothesis: Dopamine Mediates Pleasure

Aver the administraBon of dopamine antagonists, all of lifes pleasures

the pleasures of primary reinforcement and the pleasures of their
associated sBmulilose their ability to arouse the animal
the dopamine juncBons represent a synapBc way staBon . . . where.
sensory inputs are translated into the hedonic messages we experience as
pleasure, euphoria or yumminess

Note: Roy Wise later rejected the hypothesis; Berridge & Robinson Brain Res Rev 1998; Berridge Psychopharm 2007

Dopamine = Pleasure (Liking) ?

Work to Understand MFB-SS Dopamine Release Tracks Reward

Release of the neurotransmi2er dopamine is triggered by encounters with

food, sex, all major drugs of abuse [psychosBmulants, opiates, ethanol, and
nicoBne], electrical SS, and secondary reinforcers (e.g., money)
A kind of common currency

Dopamine Blockade

Radically a2enuates behaviors aimed at earning or consuming reward

Wises Inuen=al Anhedonia Hypothesis: Dopamine Mediates Pleasure

Aver the administraBon of dopamine antagonists, all of lifes pleasures

the pleasures of primary reinforcement and the pleasures of their
associated sBmulilose their ability to arouse the animal
the dopamine juncBons represent a synapBc way staBon . . . where sensory
inputs are translated into the hedonic messages we experience as pleasure,
euphoria or yumminess

Note: Roy Wise later rejected the hypothesis; Berridge & Robinson Brain Res Rev 1998; Berridge Psychopharm 2007

But not all of the data quite t

Humans also have a MFB

MFB: medial forebrain bundle (complex bundle of axons; main pathway for ascending dopamine bers); relays informaBon from VTA
to accumbens; rewarding eect of SS reects acBvaBon of the mesocorBcolimbic dopamine system; CSchlaepfer
arlezon Nature
Prot
007 2013
et al B
iol P2sych

Humans also have a MFB

Human Self-S=mula=on Research
Aords opportuniBes for tackling quesBons that
cant be addressed by animal research



Students
What kinds of ques8ons?

MFB: medial forebrain bundle (complex bundle of axons; main pathway for ascending dopamine bers; relays informaBon from VTA
to accumbens; rewarding eect of SS reects acBvaBon of the mesocorBcolimbic dopamine system; CSchlaepfer
arlezon Nature
Prot
007 2013
et al B
iol P2sych

Humans also have a MFB

Human Self-S=mula=on Research
Aords opportuniBes for tackling quesBons that
cant be addressed by animal research



Students

What kinds of ques8ons?

MFB: medial forebrain bundle (complex bundle of axons; main pathway for ascending dopamine bers; relays informaBon from VTA
to accumbens; rewarding eect of SS reects acBvaBon of the mesocorBcolimbic dopamine system; CSchlaepfer
arlezon Nature
Prot
007 2013
et al B
iol P2sych

Is MFB S=mula=on Really About

Liking and Hedonic Pleasure?
Heaths Subject B-19
voraciously self-sBmulated (never sated)

Never u2ered exclamaBons of delight

or said that SS caused pleasure thrills

Reported that SS simply evoked desire to
sBmulate again and a strong desire to
engage in sex

* Another MFB paBent said SS made him feel
as if he were building up to orgasm BUT lev
him unable to achieve the end point
which was frustraBng and produced a
nervous feeling

MFB SS does not appear to produce
Pleasure and paBents did not report liking it
per se
Smith/Berridge et al 2008

Is MFB S=mula=on Really About

Liking and Hedonic Pleasure?
Heaths Subject B-19
voraciously self-sBmulated (never sated)

Never u2ered exclamaBons of delight

or said that SS caused pleasure thrills

Reported that SS simply evoked desire to
sBmulate again and a strong desire to
engage in sex

* Another MFB paBent said SS made him feel
as if he were building up to orgasm BUT lev
him unable to achieve the end point
which was frustraBng and produced a
nervous feeling

MFB SS does not appear to produce
Pleasure and paBents did not report liking it
per se
Smith/Berridge et al 2008

Is MFB S=mula=on Really About

Liking and Hedonic Pleasure?
Heaths Subject B-19
voraciously self-sBmulated (never sated)

BUT never u2ered exclamaBons of delight

or said that SS caused pleasure thrills

Reported that SS simply evoked desire to
sBmulate again and a strong desire to
engage in sex

* Another MFB paBent said SS made him feel
as if he were building up to orgasm BUT lev
him unable to achieve the end point
which was frustraBng and produced a
nervous feeling

MFB SS does not appear to produce
Pleasure and paBents did not report liking it
per se
Smith/Berridge et al 2008

Is MFB S=mula=on Really About

Liking and Hedonic Pleasure?
Heaths Subject B-19
voraciously self-sBmulated (never sated)
BUT never u2ered exclamaBons of delight
or said that SS caused pleasure thrills

Reported that SS simply evoked desire to
sBmulate again and a strong desire to
engage in sex

Another MFB paBent said SS made him
feel as if he were building up to orgasm BUT
lev him unable to achieve the end point
which was frustraBng and produced a
nervous feeling

MFB SS does not appear to produce
Pleasure and paBents did not report liking it
per se
Smith/Berridge et al 2008

Is MFB S=mula=on Really About

Liking and Hedonic Pleasure?
Heaths Subject B-19
voraciously self-sBmulated (never sated)
BUT never u2ered exclamaBons of delight
or said that SS caused pleasure thrills

Reported that SS simply evoked desire to
sBmulate again and a strong desire to
engage in sex

Another MFB paBent said SS made him
feel as if he were building up to orgasm BUT
lev him unable to achieve the end point
which was frustraBng and produced a
nervous feeling

MFB SS does not appear to produce
pleasure per se and pa=ents did not report
liking itsomething more like craving
Smith/Berridge et al 2008

Perhaps dopamine reects wan8ng

rather than liking?

How can we tease the two apart
behaviorally?

(A prerequisite for
mapping separate brain circuits)

Perhaps dopamine reects wan8ng

rather than liking?

How can we tease the two apart
behaviorally?

(A prerequisite for
mapping separate brain circuits)

Berridge & Robinson

established a clever means of
teasing apart the role of DA
in liking vs. wan=ng
Measured Oro-Facial Emo=onal Expressions
Rats, like humans and other mammals, react to
pleasant (sugar water) and unpleasant (bi2er
quinine soluBons with highly-conserved,
stereotypical facial expressions

These expressions are reexive and automaBc
Direct read-out of liking
Normally, liking displays co-vary with behavioral
Indexes of wanBng (work or eort), as with
the sushi example earlier in the lecture

Berridge & Robinson

established a clever means of
teasing apart the role of DA
in liking vs. wan=ng
Measured Oro-Facial Emo=onal Expressions
Rats, like humans and other mammals, react to
pleasant (sweet) and unpleasant (bi2er)
tastes with highly-conserved,
stereotypical facial expressions

These expressions are reexive and automaBc
Direct read-out of liking
Yum!

Yuck!

Normally, liking displays co-vary with behavioral

Indexes of wanBng (work or eort), as with
the sushi example earlier in the lecture

Berridge & Robinson

established a clever means of
teasing apart the role of DA
in liking vs. wan=ng
Measured Oro-Facial Emo=onal Expressions
Rats, like humans and other mammals, react to
pleasant (sweet) and unpleasant (bi2er)
tastes with highly-conserved,
stereotypical facial expressions

These expressions are reexive and automaBc
Can be measured in response to intra-oral
canula delivery in animals incapable of
voluntary acBon or eort (e.g., eaBng)
Yum!

Yuck!

Direct read-out of hedonic liking and pleasure

Normally, liking displays co-vary with behavioral
indexes of wanBng (work or eort), as with
the sushi example earlier in the lecture

Berridge & Robinson

established a clever means of
teasing apart the role of DA
in liking vs. wan=ng
Measured Oro-Facial Emo=onal Expressions
Rats, like humans and other mammals, react to
pleasant (sweet) and unpleasant (bi2er)
tastes with highly-conserved,
stereotypical facial expressions

These expressions are reexive and automaBc
Can be measured in response to intra-oral
canula delivery in animals incapable of
voluntary acBon or eort (e.g., eaBng)
Yum!

Yuck!

Direct read-out of hedonic liking and pleasure

Normally, liking displays co-vary with behavioral
indexes of wanBng (work or eort), as with
the sushi example

Using measures of Liking

(expressions) and Wan8ng+Liking
(e.g., bar pressing) paired with
tradi8onal neuroscience tools (e.g.,
lesions), we can begin to trace the
relevant circuitry

Liking
Circuits

Wan=ng
Circuits

Dopamine = Wan=ng

Decrease Dopamine
1. Pharmacological blockade of the dopamine system in rats
-
-

selecBvely disrupts wanBng

spares liking expressions

2.

GeneBc eliminaBon (knock-out) of dopamine does not impair liking in mice

3.

In humans, the perceived pleasantness of palatable rewards is not reduced by

the loss of brain dopamine neurons in Parkinsons disease or in response to
dopamine-blocking drugs

Increase Dopamine
1. GeneBcally increasing dopamine neurotransmission in mice (gene knock-in) to
>150% normaBve levels

2.

-
-

SelecBvely increases wanBng (working harder, faster, and longer to obtain palatable rewards)
Does not enhance hedonic reacBons to food rewards

Pharmacologically raising dopamine levels (amphetamine)

-
-

Increases wanBng of reward

Completely fails to increase hedonic liking reacBons to the same rewardI

In sum, dopamine is neither necessary nor sucient for pleasure

Dopamine = Wan=ng

Decrease Dopamine Selec=vely disrupt wan=ng

1. Pharmacological blockade of the dopamine system in rats
-
-

SelecBvely disrupts wanBng (bar pressing) and eaBng

Spares liking expressions when you directly inject yummy soluBons into the mouth

2.

GeneBc eliminaBon (knock-out) of dopamine does not impair liking in mice

3.

In humans, the perceived pleasantness of palatable rewards is not reduced by

the loss of brain dopamine neurons in Parkinsons disease or in response to
dopamine-blocking drugs

Increase Dopamine
1. GeneBcally increasing dopamine neurotransmission in mice (gene knock-in) to
>150% normaBve levels

2.

-
-

SelecBvely increases wanBng (working harder, faster, and longer to obtain palatable rewards)
Does not enhance hedonic reacBons to food rewards

Pharmacologically raising dopamine levels (amphetamine)

-
-

Increases wanBng of reward

Completely fails to increase hedonic liking reacBons to the same rewardI

In sum, dopamine is neither necessary nor sucient for pleasure

Dopamine = Wan=ng

Decrease Dopamine Selec=vely disrupt wan=ng

1. Pharmacological blockade of the dopamine system in rats
-
-

SelecBvely disrupts wanBng (bar pressing) and eaBng

BUT: Spares liking expressions when you directly inject yummy soluBons into the mouth

2.

GeneBc eliminaBon (knock-out) of dopamine does not impair liking in mice

3.

In humans, the perceived pleasantness of palatable rewards is not reduced by

the loss of brain dopamine neurons in Parkinsons disease or in response to
dopamine-blocking drugs

Increase Dopamine
1. GeneBcally increasing dopamine neurotransmission in mice (gene knock-in) to
>150% normaBve levels

2.

-
-

SelecBvely increases wanBng (working harder, faster, and longer to obtain palatable rewards)
Does not enhance hedonic reacBons to food rewards

Pharmacologically raising dopamine levels (amphetamine)

-
-

Increases wanBng of reward

Completely fails to increase hedonic liking reacBons to the same rewardI

In sum, dopamine is neither necessary nor sucient for pleasure

Dopamine = Wan=ng

Decrease Dopamine Selec=vely disrupt wan=ng

1. Pharmacological blockade of the dopamine system in rats
-
-

SelecBvely disrupts wanBng (bar pressing) and eaBng

BUT: Spares liking expressions when you directly inject yummy soluBons into the mouth

2.

GeneBc eliminaBon (knock-out) of dopamine spares liking in mice

3.

In humans, the perceived pleasantness of palatable rewards is not reduced by

the loss of brain dopamine neurons in Parkinsons disease or in response to
dopamine-blocking drugs

Increase Dopamine
1. GeneBcally increasing dopamine neurotransmission in mice (gene knock-in) to
>150% normaBve levels

2.

-
-

SelecBvely increases wanBng (working harder, faster, and longer to obtain palatable rewards)
Does not enhance hedonic reacBons to food rewards

Pharmacologically raising dopamine levels (amphetamine)

-
-

Increases wanBng of reward

Completely fails to increase hedonic liking reacBons to the same rewardI

In sum, dopamine is neither necessary nor sucient for pleasure

Dopamine = Wan=ng

Decrease Dopamine Selec=vely disrupt wan=ng

1. Pharmacological blockade of the dopamine system in rats
-
-

SelecBvely disrupts wanBng (bar pressing) and eaBng

BUT: Spares liking expressions when you directly inject yummy soluBons into the mouth

2.

GeneBc eliminaBon (knock-out) of dopamine spares liking in mice

3.

In humans, the perceived yumminess of palatable rewards is not reduced by

the loss of brain dopamine neurons in Parkinsons disease or in response to
dopamine-blocking drugs

Increase Dopamine
1. GeneBcally increasing dopamine neurotransmission in mice (gene knock-in) to
>150% normaBve levels

2.

-
-

SelecBvely increases wanBng (working harder, faster, and longer to obtain palatable rewards)
Does not enhance hedonic reacBons to food rewards

Pharmacologically raising dopamine levels (amphetamine)

-
-

Increases wanBng of reward

Completely fails to increase hedonic liking reacBons to the same rewardI

In sum, dopamine is neither necessary nor sucient for pleasure

Dopamine = Wan=ng

Decrease Dopamine Selec=vely disrupt wan=ng

1. Pharmacological blockade of the dopamine system in rats
-
-

SelecBvely disrupts wanBng (bar pressing) and eaBng

BUT: Spares liking expressions when you directly inject yummy soluBons into the mouth

2.

GeneBc eliminaBon (knock-out) of dopamine spares liking in mice

3.

In humans, the perceived yumminess of palatable rewards is not reduced by

the loss of brain dopamine neurons in Parkinsons disease or in response to
dopamine-blocking drugs

Increase Dopamine Selec=vely boosts wan=ng without altering liking
1. GeneBcally increasing dopamine neurotransmission in mice (gene knock-in) to
>150% normaBve levels

2.

-
-

SelecBvely increases wanBng (working harder, faster, and longer to obtain palatable rewards)
Does not enhance hedonic reacBons to food rewards

Pharmacologically raising dopamine levels (amphetamine)

-
-

Increases wanBng of reward

Completely fails to increase hedonic liking reacBons to the same reward

In sum, dopamine is neither necessary nor sucient for pleasure

Dopamine = Wan=ng

Decrease Dopamine Selec=vely disrupt wan=ng

1. Pharmacological blockade of the dopamine system in rats
-
-

SelecBvely disrupts wanBng (bar pressing) and eaBng

BUT: Spares liking expressions when you directly inject yummy soluBons into the mouth

2.

GeneBc eliminaBon (knock-out) of dopamine spares liking in mice

3.

In humans, the perceived yumminess of palatable rewards is not reduced by

the loss of brain dopamine neurons in Parkinsons disease or in response to
dopamine-blocking drugs

Increase Dopamine Selec=vely boosts wan=ng without altering liking
1. GeneBcally increasing dopamine neurotransmission in mice (gene knock-in) to
>150% normaBve levels

2.

-
-

SelecBvely increases wanBng (working harder, faster, and longer to obtain palatable rewards)
Does not enhance hedonic expressions to food rewards placed in mouth

Pharmacologically raising dopamine levels (amphetamine)

-
-

Increases wanBng of reward

Completely fails to increase hedonic liking reacBons to the same reward

In sum, dopamine is neither necessary nor sucient for pleasure

Dopamine = Wan=ng

Decrease Dopamine Selec=vely disrupt wan=ng

1. Pharmacological blockade of the dopamine system in rats
-
-

SelecBvely disrupts wanBng (bar pressing) and eaBng

BUT: Spares liking expressions when you directly inject yummy soluBons into the mouth

2.

GeneBc eliminaBon (knock-out) of dopamine spares liking in mice

3.

In humans, the perceived yumminess of palatable rewards is not reduced by

the loss of brain dopamine neurons in Parkinsons disease or in response to
dopamine-blocking drugs

Increase Dopamine Selec=vely boosts wan=ng without altering liking
1. GeneBcally increasing dopamine neurotransmission in mice (gene knock-in) to
>150% normaBve levels

2.

-
-

SelecBvely increases wanBng (working harder, faster, and longer to obtain palatable rewards)
Does not enhance hedonic expressions to food rewards placed in mouth

Pharmacologically raising dopamine levels (amphetamine)

-
-

Increases wanBng of reward

Completely fails to increase hedonic liking reacBons to the same reward

In sum, dopamine is neither necessary nor sucient for pleasure

Dopamine = Wan=ng

Decrease Dopamine Selec=vely disrupt wan=ng

1. Pharmacological blockade of the dopamine system in rats
-
-

SelecBvely disrupts wanBng (bar pressing) and eaBng

BUT: Spares liking expressions when you directly inject yummy soluBons into the mouth

2.

GeneBc eliminaBon (knock-out) of dopamine spares liking in mice

3.

In humans, the perceived yumminess of palatable rewards is not reduced by

the loss of brain dopamine neurons in Parkinsons disease or in response to
dopamine-blocking drugs

Increase Dopamine Selec=vely boosts wan=ng without altering liking

1. GeneBcally increasing dopamine neurotransmission in mice (gene knock-in) to
>150% normaBve levels

2.

-
-

SelecBvely increases wanBng (working harder, faster, and longer to obtain palatable rewards)
Does not enhance hedonic expressions to food rewards placed in mouth

Pharmacologically raising dopamine levels (amphetamine)

-
-

Increases wanBng of reward

Completely fails to increase hedonic liking reacBons to the same reward

In sum, dopamine is neither necessary nor sucient for pleasure

Dopamine = Wan=ng

Decrease Dopamine Selec=vely disrupt wan=ng

1. Pharmacological blockade of the dopamine system in rats
-
-

SelecBvely disrupts wanBng (bar pressing) and eaBng

BUT: Spares liking expressions when you directly inject yummy soluBons into the mouth

-
-

Increases wanBng of reward

Completely fails to increase hedonic liking reacBons to the same reward

2. GeneBc eliminaBon
of dopamine spares liking in mice
Science is (Sknock-out)
elf-CorrecBng!

3. In humans, Today
the perceived
yumminess of palatable rewards is not reduced by
few neuroscien8stsassertthat
the loss of bdopamine
rain dopamine
in Parkinsons
causes npeurons
leasureFor
example disease or in response to
dopamine-blocking
drugs
Wisewas
quoted [as saying], I no longer
believe that the amount of pleasure felt is
Increase Dopamine
Selec=vely
oosts w
without altering liking
propor8onal
to the abmount
of an=ng
dopamine
around
in the bn
rain,
and
1. GeneBcally oa8ng
increasing
dopamine
eurotransmission
in mice (gene knock-in) to
>150% normaBve
levels
pleasure
is not a necessary correlate of
-
SelecBvely
increases
wanBng (working harder, faster, and longer to obtain palatable rewards)
dopamine
eleva8ons
-
Does n
ot enhance hedonic expressions to food rewards placed in mouth

Berridge & Kringelbach Neuron 2015
2. Pharmacologically
raising dopamine levels (amphetamine)

In sum, dopamine is neither necessary nor sucient for pleasure

Wan=ng = Mesolimbic DA System

Wan=ng = Mesolimbic DA System

Wan=ng = Mesolimbic DA System

Analyses of the rodent dopamine experiments strongly implicate the mesolimbic
dopamine (DA) system in wan=ng

- Dopamine projecBon neurons sing in the midbrain VTA that project to
ventral striatal regions, parBcularly the nucleus accumbens, via the MFB

What About Liking?

Students:

How might we iden8fy
the brains
hedonic hotspots ?

Search for regions where

micro-s8mula8on amplies
hedonic expressions
without altering wan8ng+liking

Hedonic Hotspots in NAcc Shell

Hedonic Hotspots in NAcc Shell

The nucleus accumbens (Nacc)

can be split into core and shell
regions

Hedonic Hotspots in NAcc Shell

SBmulaBon of a small region of

the medial shell quadruples
hedonic liking reacBons

Hedonic Hotspots in NAcc Shell

Hotspot is sensiBve to
endogenous opioids (cf. Heroin,
Oxy/Vicodin) and canabinoids (cf.
THC/Marijuana)

Hedonic Hotspots in NAcc Shell

Consistent with this, opioid

reducBon in humans selecBvely
reduces liking of pleasant tastes
(Arbisi et al AppeBte 1999)

Systemic administraBon of the opioid antagonist naltrexone; Arbisi et al AppeBte 1999

Sec=on 5a:


Does Ventral Striatal (VS) ac8vity
correlate with wan8ng, posi8ve aect,
and E/PE?


Show me the (human brain) data!

Ventral Striatum and Wan=ng

VS/NAcc Ac=va=on

Knutson & Greer Philo Trans Royal Sci B 2008

Ventral Striatum and Wan=ng

VS/NAcc Ac=va=on

Increases during reward

anBcipaBon (wanBng) vs.
punishment anBcipaBon;
and vs. reward delivery
(liking)

vs. Pun Ant.

vs. Rew Delivery

Correlates with posiBve

arousal raBngs (excitement)
Predicts reward-moBvated
behavior (selecBng desirable
products, high-risk/high-
reward gambles)
Knutson & Greer Philo Trans Royal Sci B 2008; Venkatraman et al J MarkeBng Research 2015

Ventral Striatum and Wan=ng

VS/NAcc Ac=va=on

Increases during reward

anBcipaBon (wanBng) vs.
punishment anBcipaBon;
and vs. reward delivery
(liking)

vs. Pun Ant.

vs. Rew Delivery

Correlates with posiBve

arousal raBngs (excitement)
Predicts reward-moBvated
behavior in life (selecBng
desirable products, high-
risk/high-reward gambles)
Knutson & Greer Philo Trans Royal Sci B 2008; Venkatraman et al J MarkeBng Research 2015

Ventral Striatum and E/PE;BAS

Wu et al NI 2014

Ventral Striatum and E/PE;BAS

VS Ac=va=on During
Reward An=cipa=on

Trait-like (Test-Retest: ICC
=~ .70 over >2.5 years)

Related to disposiBonal E/
PE/BAS

Wu et al NI 2014

Ventral Striatum and E/PE;BAS

VS Ac=va=on During
Reward An=cipa=on

Trait-like (Test-Retest: ICC
=~ .70 over >2.5 years)

Related to disposiBonal E/
PE/BAS

Wu et al NI 2014

Other groups have

reported similar eects

Ventral Striatum and BAS

Yummy food images

Ero=c images

Food: Beaver et al., 2006; EroBca: Costumero et al., 2013; Money: Braams et al J Neuro 2015

Sec=on 5b:

fMRI is correla8ve,
not mechanis8c (causal)

What would happen if
we directly manipulated ac8vity in the
human VS?

Neurofeedback Approach

Greer et al. NI 2014

Neurofeedback Approach
Instruct subjects to increase or
decrease fMRI signal (ac=va=on) in
the VS/Nacc; not told how to do it.

Greer et al. NI 2014

Neurofeedback Approach
Instruct subjects to increase or
decrease fMRI signal (ac=va=on) in
the VS/Nacc; not told how to do it.

Greer et al. NI 2014

Neurofeedback Approach
The increasing cue indeed leads
to amplied ac=va=on in the VS/
Nacc

Greer et al. NI 2014

Neurofeedback Approach
Subjects report that in order to
increase ac=va=on, they were
imagining engaging in dierent kinds
of high arousal, posi=ve ac=vi=es.

Greer et al. NI 2014

Neurofeedback Approach
Subjects report that in order to
increase ac=va=on, they were
imagining engaging in dierent kinds
of high arousal, posi=ve ac=vi=es.



And those who experienced the most
intense posi=ve aect showed the
largest increases in VS/NAcc
ac=va=onconsistent with the idea
that VS/NAcc ac=vity causally
contributes to approach-related
posi=ve aect [increased ac=vity]
and depression [decreased ac=vity]

Greer et al. NI 2014

Neurofeedback Approach
Subjects report that in order to
increase ac=va=on, they were
imagining engaging in dierent kinds
of high arousal, posi=ve ac=vi=es.



And those who experienced the most
intense posi=ve aect showed the
largest increases in VS/NAcc
ac=va=onconsistent with the idea
that VS/NAcc ac=vity causally
contributes to approach-related
posi=ve aect

Greer et al. NI 2014

What about drug manipula8ons?

DA Pharmacological Approaches

Nugent et al Bipolar Dis 2014

DA Pharmacological Approaches

Increasing dopamine
transmission produces a dose-
dependent increase in
willingness to work for reward
on the EEfRT Task

Individuals with heightened
dopamine release in the
ventral striatum (indexed
using PET) more frequently
choose the high-eort reward
op=on

Treadway & Zald Curr Dir Psychol Sci 2013

DA Pharmacological Approaches

Increasing dopamine
transmission produces a dose-
dependent increase in
willingness to work for reward
on the EEfRT Task

Individuals with heightened
dopamine release in the
ventral striatum (indexed
using PET) more frequently
choose the high-eort reward
op=on, sugges=ng media=on

Treadway & Zald Curr Dir Psychol Sci 2013

Sec8on 6a

What About Trea8ng
Pa8ents with Depression?

DA Pharmacological Approaches

Nugent et al Bipolar Dis 2014

DA Pharmacological Approaches
Ketamine rapidly (<1 hour)
alters both depression ra=ngs
and metabolic ac=vity in the
VS

Ketamine-increased ac=vity in
the VS/Nacc reduced
depression

Nugent et al Bipolar Dis 2014

DA Pharmacological Approaches
Ketamine rapidly (<1 hour)
alters both depression ra=ngs
and metabolic ac=vity in the
VS

Ketamine-increased ac=vity in
the VS/Nacc reduced
depression, sugges=ng a causal
rela=onship

Nugent et al Bipolar Dis 2014

DA Pharmacological Approaches
Ketamine rapidly (<1 hour)
alters both depression ra=ngs
and metabolic ac=vity in the
VS

Ketamine-increased ac=vity in
the VS/Nacc reduced
depression, sugges=ng a causal
rela=onship
.Put another way, that changes in VS/Nacc
ac=vity mediate the impact of drug on mood
Nugent et al Bipolar Dis 2014



What if we directly and more
selec8vely manipulated the
depressed VS using DBS?

Deep Brain S=mula=on (DBS)

N = 10 Mean Response

Bewernick Biol Psychiatry 2010; Neuropsychopharm 2012

Reduces Depression Symptoms

N = 10 Mean Response

Bewernick Biol Psychiatry 2010; Neuropsychopharm 2012

Reduces Depression Symptoms

N = 10 Mean Response

Increases Posi8ve Ac8vi8es

Bewernick Biol Psychiatry 2010; Neuropsychopharm 2012

Reduces Depression Symptoms

N = 10 Mean Response

Increases Posi8ve Ac8vi8es

Bewernick Biol Psychiatry 2010; Neuropsychopharm 2012

DBS of the VS/Nacc seems to drive wan=ng/approach more than

liking/pleasure

DBS can produce sudden feelings of desire to engage in a parBcular acBvity, such as
visiBng a nearby landmark or taking up again an old hobby

In one case, when the electrode was sBmulated, the paBent spontaneously reported that
he realized that he was in Cologne (in Germany), that he never visited the famous Cologne
Cathedral, and he planned on doing this in the immediate future, which he indeed did the
day following the operaBon.

Does not seem to produce pleasure, euphoria, or orgasmic states

There were no liking eects during sBmulaBon (p. 372) (Schlaepfer et al., 2008)
Impact on depression is likely to be (loosely) similar to behavioral acBvaBon therapy (CBT)

DBS of the VS/Nacc seems to drive wan=ng/approach more than

liking/pleasure

DBS can produce sudden feelings of desire to engage in a parBcular acBvity, such as
visiBng a nearby landmark or taking up again an old hobby

In one case, when the electrode was sBmulated, the paBent spontaneously reported that
he realized that he was in Cologne (in Germany), that he never visited the famous Cologne
Cathedral, and he planned on doing this in the immediate future, which he indeed did the
day following the operaBon.

Does not seem to produce pleasure, euphoria, or orgasmic states

There were no liking eects during sBmulaBon (p. 372) (Schlaepfer et al., 2008)
Impact on depression is likely to be (loosely) similar to behavioral acBvaBon therapy (CBT)

DBS of the VS/Nacc seems to drive wan=ng/approach more than

liking/pleasure

DBS can produce sudden feelings of desire to engage in a parBcular acBvity, such as
visiBng a nearby landmark or taking up again an old hobby

In one case, when the electrode was sBmulated, the paBent spontaneously reported that
he realized that he was in Cologne (in Germany), that he never visited the famous Cologne
Cathedral, and he planned on doing this in the immediate future, which he indeed did the
day following the operaBon.

Does not seem to produce pleasure, euphoria, or orgasmic states

There were no liking eects during sBmulaBon (p. 372) (Schlaepfer et al., 2008)
Impact on depression is likely to be (loosely) similar to behavioral acBvaBon therapy (CBT)

DBS of the VS/Nacc seems to drive wan=ng/approach more than

liking/pleasure

DBS can produce sudden feelings of desire to engage in a parBcular acBvity, such as
visiBng a nearby landmark or taking up again an old hobby

In one case, when the electrode was sBmulated, the paBent spontaneously reported that
he realized that he was in Cologne (in Germany), that he never visited the famous Cologne
Cathedral, and he planned on doing this in the immediate future, which he indeed did the
day following the operaBon.

Does not seem to produce pleasure, euphoria, or orgasmic states

There were no liking eects during sBmulaBon (p. 372) (Schlaepfer et al., 2008)
Impact on depression is likely to be (loosely) similar to behavioral acBvaBon therapy (CBT)

DBS of the VS/Nacc seems to drive wan=ng/approach more than

liking/pleasure

DBS can produce sudden feelings of desire to engage in a parBcular acBvity, such as
visiBng a nearby landmark or taking up again an old hobby

In one case, when the electrode was sBmulated, the paBent spontaneously reported that
he realized that he was in Cologne (in Germany), that he never visited the famous Cologne
Cathedral, and he planned on doing this in the immediate future, which he indeed did the
day following the operaBon.

Does not seem to produce pleasure, euphoria, or orgasmic states

There were no liking eects during sBmulaBon (p. 372) (Schlaepfer et al., 2008)
Impact on depression is likely to be (loosely) similar to behavioral acBvaBon therapy (CBT)

How does DBS increase behavioral

ac8va8on / engagement?

DBS increases VS metabolism at rest

FDG-PET; Schlaepfer et al Neuropsychopharm 2008

DBS increases VS metabolism at rest

N = 3 MDD PaBents

FDG-PET; Schlaepfer et al Neuropsychopharm 2008

DBS increases VS ac=va=on during

reward an=cipa=on

OCD PaBents; Figee Nature Neurosci 2013

DBS increases VS ac=va=on during

reward an=cipa=on

OCD PaBents; Figee Nature Neurosci 2013

Conven8onal fMRI
studies of pa8ents with depression
paint a somewhat messier picture

What about conven8onal fMRI

studies in neurologically-intact
pa8ents with less severe depression?

fMRI of Reward in MDD

Pizzagalli AJP 2009; Forbes AJP 2009

fMRI of Reward in MDD

To date, few studies L

Some evidence for blunted
liking




Less evidence for
blunted wanBng


Both signals predict posiBve
aect in daily

Pizzagalli AJP 2009; Forbes AJP 2009

fMRI of Reward in MDD

To date, few studies L

Some evidence for blunted
liking




Less evidence for
blunted wanBng


Both signals predict posiBve
aect in daily

Pizzagalli AJP 2009; Forbes AJP 2009

fMRI of Reward in MDD

To date, few studies L

Some evidence for blunted
liking




Less evidence for
blunted wanBng


Both signals predict posiBve
aect in daily

Pizzagalli AJP 2009; Forbes AJP 2009

fMRI of Reward in MDD

To date, few studies L

Some evidence for blunted
liking




Less evidence for
blunted wanBng


Both signals predict posiBve
aect in daily

Pizzagalli AJP 2009; Forbes AJP 2009

Interim Summary

1.
Wan=ng (MFB-SS, dopamine) and liking (opioids, endocannabinoids)
are neurochemically dissociable
2.

In humans, VS/NAcc ac=va=on is trait-like, predicts individual

dierences in E/PE, and has been linked to both liking and wan=ng,
albeit more strongly with wan=ng and approach-related posi=ve
emo=on

3.

Behavioral and self-report data indicate that depression is associated

with blunted liking and wan=ng; pa=ents are less responsive to
reward (heritable endophenotype)

4.

Manipula=ons (ketamine, DBS) that increase VS/Nacc ac=va=on

ameliorate depression; not clear whether this represents wan=ng,
liking, or both

5.

fMRI studies suggest that depression is associated with reduced

liking-related (i.e. in response to reward) ac=va=on

Interim Summary

1.
Wan=ng (MFB-SS, dopamine) and liking (opioids, endocannabinoids)
are neurochemically dissociable
2.

In humans, VS/NAcc ac=va=on is trait-like, predicts individual

dierences in E/PE, and has been linked to both liking and wan=ng,
albeit more strongly with wan=ng and approach-related posi=ve
emo=on

3.

Behavioral and self-report data indicate that depression is associated

with blunted liking and wan=ng; pa=ents are less responsive to
reward (heritable endophenotype)

4.

Manipula=ons (ketamine, DBS) that increase VS/Nacc ac=va=on

ameliorate depression; not clear whether this represents wan=ng,
liking, or both

5.

fMRI studies suggest that depression is associated with reduced

liking-related (i.e. in response to reward) ac=va=on

Interim Summary

1.
Wan=ng (MFB-SS, dopamine) and liking (opioids, endocannabinoids)
are neurochemically dissociable
2.

In humans, VS/NAcc ac=va=on is trait-like, predicts individual

dierences in E/PE/BAS, and has been linked to both liking and
wan=ng, albeit more strongly with wan=ng and approach-related
posi=ve emo=on

3.

Behavioral and self-report data indicate that depression is associated

with blunted liking and wan=ng; pa=ents are less responsive to
reward (heritable endophenotype)

4.

Manipula=ons (ketamine, DBS) that increase VS/Nacc ac=va=on

ameliorate depression; not clear whether this represents wan=ng,
liking, or both

5.

fMRI studies suggest that depression is associated with reduced

liking-related (i.e. in response to reward) ac=va=on

Interim Summary

1.
Wan=ng (MFB-SS, dopamine) and liking (opioids, endocannabinoids)
are neurochemically dissociable
2.

In humans, VS/NAcc ac=va=on is trait-like, predicts individual

dierences in E/PE/BAS, and has been linked to both liking and
wan=ng, albeit more strongly with wan=ng and approach-related
posi=ve emo=on

3.

Behavioral and self-report data indicate that depression is associated

with blunted liking and wan=ng; pa=ents are less responsive to
reward (heritable endophenotype)

4.

Manipula=ons (ketamine, DBS) that increase VS/Nacc ac=va=on

ameliorate depression; not clear whether this represents wan=ng,
liking, or both

5.

fMRI studies suggest that depression is associated with reduced

liking-related (i.e. in response to reward) ac=va=on

Interim Summary

1.
Wan=ng (MFB-SS, dopamine) and liking (opioids, endocannabinoids)
are neurochemically dissociable
2.

In humans, VS/NAcc ac=va=on is trait-like, predicts individual

dierences in E/PE/BAS, and has been linked to both liking and
wan=ng, albeit more strongly with wan=ng and approach-related
posi=ve emo=on

3.

Behavioral and self-report data indicate that depression is associated

with blunted liking and wan=ng; pa=ents are less responsive to
reward (heritable endophenotype)

4.

Manipula=ons (ketamine, DBS) that increase VS/Nacc ac=va=on

ameliorate depression; appears to represent wan=ng
fMRI studies suggest that depression is associated with reduced
liking-related (i.e. in response to reward) ac=va=on

5.

Interim Summary

1.
Wan=ng (MFB-SS, dopamine) and liking (opioids, endocannabinoids)
are neurochemically dissociable
2.

In humans, VS/NAcc ac=va=on is trait-like, predicts individual

dierences in E/PE/BAS, and has been linked to both liking and
wan=ng, albeit more strongly with wan=ng and approach-related
posi=ve emo=on

3.

Behavioral and self-report data indicate that depression is associated

with blunted liking and wan=ng; pa=ents are less responsive to
reward (heritable endophenotype)

4.

Manipula=ons (ketamine, DBS) that increase VS/Nacc ac=va=on

ameliorate depression; appears to represent wan=ng

5.

fMRI studies suggest that depression is associated with reduced

liking-related (i.e. in response to reward) ac=va=on

LikingWan8ngBoth?


Perhaps this inconsistency or
ambiguity in the human data is not
altogether surprising

Rodents: VS/Nacc contains

wan=ng and liking systems

Liking
Circuits
Kringelbach & Berridge Sci Amer 2012

Reality Check: fMRI Voxels are Huge!

e.g., Nucleus Accumbens: Shell/Core Subdivisions

Just a handful of voxels, each containing a mix

5 mm

Core
Shell
DETAILS ARE NOT IMPORTANT; CLD = Core-Like Division; SLD = Shell-Like Division

Voorn et al Neurosci 1996; Baliki J Neurosci 2013

e.g., Nucleus Accumbens: Shell/Core Subdivisions

Just a handful of voxels, each containing a mix
of shell and core

5 mm

Core
Shell
DETAILS ARE NOT IMPORTANT; CLD = Core-Like Division; SLD = Shell-Like Division

Voorn et al Neurosci 1996; Baliki J Neurosci 2013

This suggests that fMRI studies mix

wan8ng and liking signals

DBS (and drugs) alter many regions

FDG-PET; N = 3 MDD PaBents; Schlaepfer et al Neuropsychopharm 2008

Unknown which region or set of

regions drives decreased anhedonia
in human pa8ents

Reward is complex
there remains much leo to learn

Key Take Home Points

Key Take Home Points

How are T&P, on the one hand, and depression,
on the other, related to one another?

How are Extraversion & Posi8ve Emo8onality
(Grays BAS) organized in the brain?

Is Reward a process or a set of processes?

Are there Pleasure Centers in the brain? Is
dopamine The Substrate for pleasure?

Take Home Cri=cal Thinking Ques=ons

Please pick 2 of the 3 op=ons.

I strongly urge you to do #1 (course
evalua=on), but you are free to refrain.

The numeric/quan=ta=ve por=on of the
evalua=on directly impacts me. The narra=ve/
free-response por=on directly impacts students
enrolled in future classes.

Take Home Cri=cal Thinking Ques=ons

You must complete the rst ques8on (Ques8on 0)




You are free to complete any of the other ques8ons, for a total of two responses

Please pick 2 of the 3 op=ons.

I strongly urge you to do #1 (course
evalua=on), but you are free to refrain.

The numeric/quan=ta=ve por=on of the
evalua=on directly impacts me. The narra=ve/
free-response por=on directly impacts students
enrolled in future classes.

This is the mandatory ques8on

Take Home Cri=cal Thinking Ques=ons

0. In the Fall, I will be teaching an upper-division
version of this class (Psyc 435)

I would like to incorporate some in-class or out-of-class
acBviBes that require more independent thinking on the
part of the students

My preference is to not simply add a term paper

What do you think?

What are some other kinds of blended learning exercises
(group or individual, in or out of class) that would be fun
and challenging?

Take Home Cri=cal Thinking Ques=ons

0. In the Fall, I will be teaching an upper-division
version of this class (Psyc 435)

I would like to incorporate some in-class or out-of-class
acBviBes that require more independent thinking on the
part of the students

My preference is to not simply add a term paper

What do you think?

What are some other kinds of blended learning exercises
(group or individual, in or out of class) that would be fun
and challenging?

Take Home Cri=cal Thinking Ques=ons

0. In the Fall, I will be teaching an upper-division
version of this class (Psyc 435)

I would like to incorporate some in-class or out-of-class
acBviBes that require more independent thinking on the
part of the students

My preference is to not simply add a term paper

What do you think?

What are some other kinds of blended learning exercises
(group or individual, in or out of class) that would be fun
and challenging?

Take Home Cri=cal Thinking Ques=ons

0. In the Fall, I will be teaching an upper-division
version of this class (Psyc 435)

I would like to incorporate some in-class or out-of-class
acBviBes that require more independent thinking on the
part of the students

My preference is to not simply add a term paper

What do you think?

What are some other kinds of blended learning exercises
(group or individual, in or out of class) that would be fun
and challenging?

Please choose any

one of the following
for your second ques8on

Take Home Cri=cal Thinking Ques=ons

1. In addiBon to blunted liking and RR decits (facets of E/PE;
BAS), depression is associated with massively elevated N/NE
(and elevated amygdala reacBvity) and somewhat a2enuated
C/SC. Briey comment on one or both of these eects...you can
focus more on T&P or psychopathology as you prefer. For
instance, how might increased stress reacBvity (N/NE)
contribute to decreased RR (E/PE; BAS)? Or, what is your
intuiBon about the role of self-control in MDD? Might it play a
role in emoBon regulaBon decits?

Take Home Cri=cal Thinking Ques=ons

1. In addiBon to blunted liking and RR decits (facets of E/PE;
BAS), depression is associated with massively elevated N/NE
(and elevated amygdala reacBvity) and somewhat a2enuated
C/SC. Briey comment on one or both of these eects...you can
focus more on T&P or psychopathology as you prefer. For
instance, how might increased stress reacBvity (N/NE)
contribute to decreased RR (E/PE; BAS)? Or, what is your
intuiBon about the role of self-control in MDD? Might it play a
role in emoBon regulaBon decits?

Take Home Cri=cal Thinking Ques=ons

2. Deep brain sBmulaBon (DBS) is increasingly being used for the treatment of Parkinson's disorder.

h2p://www.ninds.nih.gov/disorders/deep_brain_sBmulaBon/deep_brain_sBmulaBon.htm

There is a growing interest in using DBS as a therapeuBc intervenBon for psychiatric disorders, e.g.,

h2p://www.nyBmes.com/2006/04/02/magazine/02depression.html?pagewanted=all&_r=0

But like other novel therapeuBc approaches, this work is not without its limitaBons and problems

h2p://neurocriBc.blogspot.com/2014/01/broaden-trial-of-dbs-for-treatment.html

And an earlier generaBon of research into human brain sBmulaBon was fraught with controversy and ethical
concerns (e.g., over mind-control),
h2p://www.sciencechannel.com/tv-shows/dark-ma2ers-twisted-but-true/videos/professor-creates-remote-
control-people.htm

h2p://www.scienBcamerican.com/arBcle/a-sex-chip/

Heaths work at Tulane was notably ethically challenged
h2p://blog.ketyov.com/2011/08/self-sBmulaBng-brain-for-heterosexual.html

What do you think? Briey describe your perspecBve on the opportuniBes and challenges facing DBS for
psychiatric disorders, such as depression and addicBon, based on what we discussed in class and one or more of
the links shown here.

Take Home Cri=cal Thinking Ques=ons

2. Deep brain sBmulaBon (DBS) is increasingly being used for the treatment of Parkinson's disorder.

h2p://www.ninds.nih.gov/disorders/deep_brain_sBmulaBon/deep_brain_sBmulaBon.htm

There is a growing interest in using DBS as a therapeuBc intervenBon for psychiatric disorders, e.g.,

h2p://www.nyBmes.com/2006/04/02/magazine/02depression.html?pagewanted=all&_r=0

But like other novel therapeuBc approaches, this work is not without its limitaBons and problems

h2p://neurocriBc.blogspot.com/2014/01/broaden-trial-of-dbs-for-treatment.html

And an earlier generaBon of research into human brain sBmulaBon was fraught with controversy and ethical
concerns (e.g., over mind-control),
h2p://www.sciencechannel.com/tv-shows/dark-ma2ers-twisted-but-true/videos/professor-creates-remote-
control-people.htm

h2p://www.scienBcamerican.com/arBcle/a-sex-chip/

Heaths work at Tulane was notably ethically challenged
h2p://blog.ketyov.com/2011/08/self-sBmulaBng-brain-for-heterosexual.html

What do you think? Briey describe your perspecBve on the opportuniBes and challenges facing DBS for
psychiatric disorders, such as depression and addicBon, based on what we discussed in class and one or more of
the links shown here.

Take Home Cri=cal Thinking Ques=ons

2. Deep brain sBmulaBon (DBS) is increasingly being used for the treatment of Parkinson's disorder.

h2p://www.ninds.nih.gov/disorders/deep_brain_sBmulaBon/deep_brain_sBmulaBon.htm

There is a growing interest in using DBS as a therapeuBc intervenBon for psychiatric disorders, e.g.,

h2p://www.nyBmes.com/2006/04/02/magazine/02depression.html?pagewanted=all&_r=0

But like other novel therapeuBc approaches, this work is not without its limitaBons and problems

h2p://neurocriBc.blogspot.com/2014/01/broaden-trial-of-dbs-for-treatment.html

And an earlier generaBon of research into human brain sBmulaBon was fraught with controversy and ethical
concerns (e.g., over mind-control),
h2p://www.sciencechannel.com/tv-shows/dark-ma2ers-twisted-but-true/videos/professor-creates-remote-
control-people.htm

h2p://www.scienBcamerican.com/arBcle/a-sex-chip/

Heaths work at Tulane was notably ethically challenged
h2p://blog.ketyov.com/2011/08/self-sBmulaBng-brain-for-heterosexual.html

What do you think? Briey describe your perspecBve on the opportuniBes and challenges facing DBS for
psychiatric disorders, such as depression and addicBon, based on what we discussed in class and one or more of
the links shown here.

Take Home Cri=cal Thinking Ques=ons

2. Deep brain sBmulaBon (DBS) is increasingly being used for the treatment of Parkinson's disorder.

h2p://www.ninds.nih.gov/disorders/deep_brain_sBmulaBon/deep_brain_sBmulaBon.htm

There is a growing interest in using DBS as a therapeuBc intervenBon for psychiatric disorders, e.g.,

h2p://www.nyBmes.com/2006/04/02/magazine/02depression.html?pagewanted=all&_r=0

But like other novel therapeuBc approaches, this work is not without its limitaBons and problems

h2p://neurocriBc.blogspot.com/2014/01/broaden-trial-of-dbs-for-treatment.html

Indeed, an earlier generaBon of research into human brain sBmulaBon was fraught with controversy and ethical
concerns (e.g., over mind-control),
h2p://www.sciencechannel.com/tv-shows/dark-ma2ers-twisted-but-true/videos/professor-creates-remote-
control-people.htm

h2p://www.scienBcamerican.com/arBcle/a-sex-chip/

Heaths work at Tulane was parBcularly ethically challenged
h2p://blog.ketyov.com/2011/08/self-sBmulaBng-brain-for-heterosexual.html

What do you think? Briey describe your perspecBve on the opportuniBes and challenges facing DBS for
psychiatric disorders, such as depression and addicBon, based on what we discussed in class and one or more of
the links shown here.

Take Home Cri=cal Thinking Ques=ons

2. Deep brain sBmulaBon (DBS) is increasingly being used for the treatment of Parkinson's disorder.

h2p://www.ninds.nih.gov/disorders/deep_brain_sBmulaBon/deep_brain_sBmulaBon.htm

There is a growing interest in using DBS as a therapeuBc intervenBon for psychiatric disorders, e.g.,

h2p://www.nyBmes.com/2006/04/02/magazine/02depression.html?pagewanted=all&_r=0

But like other novel therapeuBc approaches, this work is not without its limitaBons and problems

h2p://neurocriBc.blogspot.com/2014/01/broaden-trial-of-dbs-for-treatment.html

Indeed, an earlier generaBon of research into human brain sBmulaBon was fraught with controversy and ethical
concerns (e.g., over mind-control),
h2p://www.sciencechannel.com/tv-shows/dark-ma2ers-twisted-but-true/videos/professor-creates-remote-
control-people.htm

h2p://www.scienBcamerican.com/arBcle/a-sex-chip/

Heaths work at Tulane was parBcularly ethically challenged
h2p://blog.ketyov.com/2011/08/self-sBmulaBng-brain-for-heterosexual.html

What do you think? Briey describe your perspecBve on the opportuniBes and challenges facing DBS for
psychiatric disorders, such as depression and addicBon, based on what we discussed in class and one or more of
the links shown here.

Take Home Cri=cal Thinking Ques=ons

3. The public health and economic burden of mental illness is enormous!

Take Home Cri=cal Thinking Ques=ons

3. The public health and economic burden of mental illness is enormous!

Take Home Cri=cal Thinking Ques=ons

3. The public health and economic burden of mental illness is enormous!

Europe spends more on brain disorders than on cardiovascular disease and cancer combined

Europe spends 798B/Year on neurological and psychiatric condiBons, 192B on cardiovascular disease, and 150-250B on
cancer.

The most costly group of brain disorders was mood disorders, including major depression and bipolar disorders (113B/
Year)

Take Home Cri=cal Thinking Ques=ons

3. The public health and economic burden of mental illness is enormous!

Take Home Cri=cal Thinking Ques=ons

3. What do you think?

Briey comment on the implicaBons of these data for the economy and for the public funding
of scienBc research aimed at understanding the mechanisms that underlie the development,
maintenance, and recurrence of major depression.

Take Home Cri=cal Thinking Ques=ons

4. Watch this short interview of Kent Berridge:
















What do you think?
Briey comment on what you found most interesBng or thought-provoking about the interview

The End

Material to Consider
Using in Future Terms

Assigned reading for fall 2014?

Assigned reading for fall 2014?

Assigned reading for fall 2014?

Reverse Transla=on of Diegos RR

Task

Like humans, rats developed a

response bias toward the more
frequently reinforced sBmulus

Reward responsiveness can be
bidirecBonally modulated
(increased/decreased) by
pharmacological manipulaBons
that increase (amphetamine) or
block striatal dopamine
transmission.

Alex these next few slides actually

make the point that MDD and SAD are
really really similar, which belongs in
one of the earlier ppts

the fun-seeking data are kind of
disturbingsuggest that MDD is more
about PE than appeBBve moBvaBon

Regarding Weak MDD-E Rela=ons

Regarding Weak MDD-E Rela=ons

Low PE is supposed to be the facet that
dis=nguishes depression from the anxiety disorders

Low
E/PE

High
N/NE

Tripar=te Model: Clark & Watson JAP 1991; Watson et al JAP 1995a, b

Regarding Weak MDD-E/PE Rela=ons

Low PE is supposed to be the facet that
dis=nguishes depression from the anxiety disorders

Low
PE

High
N/NE

Tripar=te Model: Clark & Watson JAP 1991; Watson et al JAP 1995a, b

Regarding Weak MDD-E Rela=ons

Weak rela=ons may reect the use of a broadband
measure of Extraversion, rather than a more specic
measure of Posi=ve Emo=onality

Regarding Weak MDD-E Rela=ons

Weak rela=ons may reect the use of a broadband
measure of Extraversion, rather than a more specic
measure of Posi=ve Emo=onality

Collected mul=ple measures of each facet of E/PE

Results revealed that

1) E/PE = 4 Facets = Sociability, PE, ExhibiBonism/Dominance, and Fun-Seeking

2) Depression, but not anxiety, was strongly and selecBvely related to low PE

Extra Slides

2012

Stop Success OFC Network

Stop Success
Right Frontal Network

N = 1,896 14-year olds

2012

OFC Cause: Risk reects impulsivity and is

characterized by hypoacBvity in the OFC

R PFC Compensa=on: Drug use eects related
to impulsivity are characterized by
hyperacBvity in R PFC, reecBng the increased
diculty that users experience when
exercising inhibitory control.

Increased
Right Frontal

Reduced OFC

N = 1,896 14-year olds

VS DBS May Alleviate Addic=on

N/NE

Among broad-band
superfactors,
C/SC
SUD risk is associated with

1. High N/NE (though this is not
specic to SUDs)
2. Low C/SC (High DisinhibiBon,
Low ConscienBousness)
C/SC

3. Surprisingly weak rela=onship
with Extraversion
Indeed, a core dening characterisBc of SUD is that of li2le interest for rewards other than the
drug. When not engaged in drug-related behavior, [paBents] show low disposiBon toward
posiBve emoBons and a low degree of incenBve moBvaBon (Belcher et al TiCS 2014)
N = NeuroBcism; E = Extraversion; D = DisinhibiBon; C = ConscienBousness
Distress = GAD + MDD; Fear = Panic and Phobias

Equinality:

There are dierent pathways
(causes or e8ologies) to the same
phenotype (disorder)

Frac=ona=ng Reward into

Wan=ng & Liking

The major components of reward and their subdivisions include:

Liking: the actual pleasure component or hedonic impact of a reward.
Pleasure comprises two levels: (1) core liking reacBons that need not
necessarily be conscious; (2) conscious experiences of pleasure, in the
ordinary sense of the word, which may be elaborated out of core
liking reacBons by cogniBve brain mechanisms of awareness (see A
glossary of reward deniBons below for more detail on deniBons).
WanBng: moBvaBon for reward, which includes both (1) incenBve
salience wanBng processes that are not necessarily conscious and (2)
conscious desires for incenBves or cogniBve goals. Learning:
associaBons, representaBons, and predicBons about future rewards
based on past experiences. Learned predicBons include both (1)
explicit and cogniBve predicBons and (2) implicit knowledge as well as
associaBve condiBoning, such as basic Pavlovian and instrumental
associaBons.



Kennis, M., Rademaker, A. R., Geuze, E. (2013). Neural correlates of
personality: An integraBve review. Neuroscience and Biobehavioral
Reviews, 37, 73-95.


Schneider, S., Peters, J., Bromberg, U., Brassen, S., Miedl, S. F.,
Banaschewski, T., ... &
Bchel, C. (2012). Risk taking and the adolescent reward system: a
potenBal common
link to substance abuse. American Journal of Psychiatry, 169(1), 39-46.
Scho2, B.