PowerPoint Presentation

Plan for Today

Nuts and Bolts Plan for TodayLecture

Today, well start with depression and substance use

But mainly focus on reward and depression

Next time, well focus on substance use and related impulsivity disorders

Take-home critical thinking questions

PSYC 210:

E/PE: Biological Bases and Implications for Understanding Depression

(Pleasure, Reward & Inhibition Part 1 of 2)

AJ Shackman5 May 20153Conceptual RoadmapHow are T&P, on the one hand, and depression, on the other, related to one another?

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

How are Extraversion & Positive Emotionality (Grays BAS) organized in the brain?

Is Reward a process or a set of processes?

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

How are Extraversion & Positive Emotionality (Grays BAS) organized in the brain?

Is Reward a process or a set of processes?

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

How are Extraversion & Positive Emotionality (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?Section 0:

Why Bother?

(Show me the epidemiological data!)http://www.adaa.org/about-adaa/press-room/facts-statistics & http://www.nimh.nih.gov/Statistics/index.shtml

Burden: MDD is the leading disorderhttp://www.adaa.org/about-adaa/press-room/facts-statistics & http://www.nimh.nih.gov/Statistics/index.shtml

Burden: MDD is the leading disorder

DALY = disability-adjusted life-year; Collins et al Nature 2011; NIDA.govBurden: SUDs are common & costlyDALY = disability-adjusted life-year; Collins et al Nature 2011; NIDA.govBurden: SUDs are common & costly

Global Disease Burden>30M life-years lost world-wide to Disability, illness, and deathBurden: SUDs are common & costly

Global Disease BurdenAnnual Cost in the US: ~$600B/Year)DALY = disability-adjusted life-year; Collins et al Nature 2011; NIDA.gov

Section 1: How are these disorders related to T&P

Section 1: Developing some hypotheses

Aberrant responses to reward

Suggests a potential role for E/PE (BAS)

Students - what is common to depression (MDD) and substance use disorders (SUDs)?Section 1: Developing some hypothesesAberrant responses to reward andpleasurable stimuli

Suggests a potential role for E/PE (BAS)Extraversion / Positive Emotionality (E/PE)

Zentner et al. 2012; cf. Caspi et al 2005000000Extraversion / Positive Emotionality (E/PE)

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

000000

Zentner et al. 2012; cf. Caspi et al 2005Nave Preliminary Hypothesis

Depression = Too Little E/PE/BAS

SUDs = Too Much E/PE/BASExtraversion / Positive Emotionality (E/PE)

000000

Nave Preliminary Hypothesis

Depression = Too Little E/PE/BAS

SUDs = Too Much E/PE/BAS

Goldilocks & The 3 Bears Porridge (too cold, too hot)Extraversion / Positive Emotionality (E/PE)

000000How well does our hypothesis actually map onto the formal criteria for MDD?

DSM-IV-TR: Major Depressive DisorderDSM-IV-TR: Major Depressive Disorder

DSM-IV-TR: Major Depressive Disorder

Anhedonia- lack of pleasure- reduced liking of rewarding stimuli

Abulia (Avolition)- lack of motivation, drive, or interest in obtaining reward- reduced wantingDSM-IV-TR: Major Depressive Disorder

Anhedonia- lack of pleasure- reduced liking of rewarding stimuli

Abulia (Avolition)- lack of motivation, drive, or interest in obtaining reward- reduced wantingDSM-IV-TR: Major Depressive Disorder

Anhedonia- lack of pleasure- reduced liking of rewarding stimuli

Abulia (Avolition)- lack of motivation, drive, or interest in obtaining reward- reduced wantingDepression may reflect

1. Decreased consummatory pleasure (liking)

2. Decreased appetitive motivation (wanting)

3. Both

Kringelbach 2015Section 2:

Show me the (epidemiological) data!

Are trait-like differences in E/PErelated to MDD?

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

High N/NE and Low Conscientiousness were nonspecifically associated with anxiety, depression, and SUD

Many disorders were associated with Low E/PE, with larger effects for depression/dysthmia

The 'disinhibition' facet of C/SC was specifically associated with SUD

N = Neuroticism; E = Extraversion; D = Disinhibition; C = ConscientiousnessDistress = MDD + GAD; Fear = Panic and PhobiasAmong broad-band superfactors,MDD risk is associated with

High N/NE (though this is not specific to MDD)

2. Low E (also not specific)

Surprisingly strong relationship with C/SC

N = Neuroticism; E = Extraversion; D = Disinhibition; C = ConscientiousnessDistress = MDD + GAD; Fear = Panic and PhobiasAmong broad-band superfactors,MDD risk is associated with

High N/NE (though this is not specific to MDD/Distress)

2. Low E (also not specific)

Surprisingly strong relationship with C/SC

N = Neuroticism; E = Extraversion; D = Disinhibition; C = ConscientiousnessDistress = MDD + GAD; Fear = Panic and PhobiasAmong broad-band superfactors,MDD risk is associated with

High N/NE (though this is not specific to MDD/Distress)

2. Low E (also not specific)

Surprisingly strong relationship with C/SC

N = Neuroticism; E = Extraversion; D = Disinhibition; C = ConscientiousnessDistress = MDD + GAD; Fear = Panic and PhobiasAmong broad-band superfactors,MDD risk is associated with

High N/NE (though this is not specific to MDD/Distress)

2. Low E (also not specific)

Surprisingly strong relationship with C/SCFor now, ignore N/NE and C/SC

Focus on E/PESection 3a:

Do depressed individuals show reduced liking in the lab?

Show me the behavioral data!

Depressed IndividualsShow Blunted Liking

Depressed IndividualsShow Blunted LikingMDD is characterized by reduced reactivity to both positive and negative stimuli (e.g., film clips)

The effect is twice as large for positive (d=.53) vs. negative (d=.25) stimuli

This is true for self-reported experience, expressive behavior (e.g., facial expressions), and peripheral physiology

Depressed IndividualsShow Blunted LikingMDD is characterized by reduced reactivity to both positive and negative stimuli (e.g., film clips)

The effect is twice as large for positive (d=.53) vs. negative (d=.25) stimuli

This is true for self-reported experience, expressive behavior (e.g., facial expressions), and peripheral physiology

Depressed IndividualsShow Blunted LikingMDD is characterized by reduced reactivity to both positive and negative stimuli (e.g., film clips)

The effect is twice as large for positive (d=.53) vs. negative (d=.25) stimuli

This is true for self-reported experience, expressive behavior (e.g., facial expressions), and peripheral physiology

Section 3b:

Do depressed individuals show evidence of reduced wanting or effort in the lab?

Students

Have we discussed any biological measures that are sensitive to wanting?

Left > RightFrontal EEG Asymmetry moreover, in a very interesting recent study by John Allens group at Arizona, its been shown that you can train individuals to regulate frontal asymmetyry directly using neurofeedback techniques. And when you train them to achieve a more leftward asymmetry you can actually reduce the amount of anxiety and negative affect elicited by subsequent provocations. This is important because it indicates that whatever region or regions of the brain are responsible for generating this pattern of activity on the scalp are making a CAUSAL contribution to trait anxiety BUT 43L > R has been linked to Wanting (appetitive drive) During the anticipation of monetary reward in unselected Ss

During the anticipation of smoking in nicotine deprived smokers

During the anticipation of moms return following brief separation in young children

Depressed (anhedonic) Pps show reduction at baseline more about this later!

Left > Right

frontal EEG asymmetry and wanting

moreover, in a very interesting recent study by John Allens group at Arizona, its been shown that you can train individuals to regulate frontal asymmetyry directly using neurofeedback techniques. And when you train them to achieve a more leftward asymmetry you can actually reduce the amount of anxiety and negative affect elicited by subsequent provocations. This is important because it indicates that whatever region or regions of the brain are responsible for generating this pattern of activity on the scalp are making a CAUSAL contribution to trait anxiety BUT 44L > R has been linked to Wanting (appetitive drive) During the anticipation of monetary reward

During the anticipation of smoking in nicotine-deprived smokers

During the anticipation of moms return following brief separation in young children

Depressed (anhedonic) Pps show reduction at baseline more about this later!

Left > Right

frontal EEG asymmetry and wanting

moreover, in a very interesting recent study by John Allens group at Arizona, its been shown that you can train individuals to regulate frontal asymmetyry directly using neurofeedback techniques. And when you train them to achieve a more leftward asymmetry you can actually reduce the amount of anxiety and negative affect elicited by subsequent provocations. This is important because it indicates that whatever region or regions of the brain are responsible for generating this pattern of activity on the scalp are making a CAUSAL contribution to trait anxiety BUT 45Students

So what might we expect to find in patients diagnosed with depression?Depressed IndividualsShow Reduced L150% normative levelsSelectively increases wanting (working harder, faster, and longer to obtain palatable rewards)Does not enhance hedonic reactions to food rewards

Pharmacologically raising dopamine levels (amphetamine)Increases wanting of reward Completely fails to increase hedonic liking reactions to the same rewardI

In sum, dopamine is neither necessary nor sufficient for pleasure

Dopamine = WantingDecrease Dopamine Selectively disrupt wantingPharmacological blockade of the dopamine system in rats Selectively disrupts wanting (bar pressing) and eatingBUT: Spares liking expressions when you directly inject yummy solutions into the mouth

Genetic elimination (knock-out) of dopamine spares liking in mice

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 DopamineGenetically increasing dopamine neurotransmission in mice (gene knock-in) to >150% normative levelsSelectively increases wanting (working harder, faster, and longer to obtain palatable rewards)Does not enhance hedonic reactions to food rewards

Pharmacologically raising dopamine levels (amphetamine)Increases wanting of reward Completely fails to increase hedonic liking reactions to the same rewardI

In sum, dopamine is neither necessary nor sufficient for pleasure

Dopamine = WantingDecrease Dopamine Selectively disrupt wantingPharmacological blockade of the dopamine system in rats Selectively disrupts wanting (bar pressing) and eatingBUT: Spares liking expressions when you directly inject yummy solutions into the mouth

Genetic elimination (knock-out) of dopamine spares liking in mice

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 DopamineGenetically increasing dopamine neurotransmission in mice (gene knock-in) to >150% normative levelsSelectively increases wanting (working harder, faster, and longer to obtain palatable rewards)Does not enhance hedonic reactions to food rewards

Pharmacologically raising dopamine levels (amphetamine)Increases wanting of reward Completely fails to increase hedonic liking reactions to the same rewardI

In sum, dopamine is neither necessary nor sufficient for pleasure

Dopamine = WantingDecrease Dopamine Selectively disrupt wantingPharmacological blockade of the dopamine system in rats Selectively disrupts wanting (bar pressing) and eatingBUT: Spares liking expressions when you directly inject yummy solutions into the mouth

Genetic elimination (knock-out) of dopamine spares liking in mice

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 Selectively boosts wanting without altering likingGenetically increasing dopamine neurotransmission in mice (gene knock-in) to >150% normative levelsSelectively increases wanting (working harder, faster, and longer to obtain palatable rewards)Does not enhance hedonic reactions to food rewards

Pharmacologically raising dopamine levels (amphetamine)Increases wanting of reward Completely fails to increase hedonic liking reactions to the same reward

In sum, dopamine is neither necessary nor sufficient for pleasure

Dopamine = WantingDecrease Dopamine Selectively disrupt wantingPharmacological blockade of the dopamine system in rats Selectively disrupts wanting (bar pressing) and eatingBUT: Spares liking expressions when you directly inject yummy solutions into the mouth

Genetic elimination (knock-out) of dopamine spares liking in mice

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 Selectively boosts wanting without altering likingGenetically increasing dopamine neurotransmission in mice (gene knock-in) to >150% normative levelsSelectively increases wanting (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 wanting of reward Completely fails to increase hedonic liking reactions to the same reward

In sum, dopamine is neither necessary nor sufficient for pleasure

Dopamine = WantingDecrease Dopamine Selectively disrupt wantingPharmacological blockade of the dopamine system in rats Selectively disrupts wanting (bar pressing) and eatingBUT: Spares liking expressions when you directly inject yummy solutions into the mouth

Genetic elimination (knock-out) of dopamine spares liking in mice

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 Selectively boosts wanting without altering likingGenetically increasing dopamine neurotransmission in mice (gene knock-in) to >150% normative levelsSelectively increases wanting (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 wanting of reward Completely fails to increase hedonic liking reactions to the same reward

In sum, dopamine is neither necessary nor sufficient for pleasure

Dopamine = WantingDecrease Dopamine Selectively disrupt wantingPharmacological blockade of the dopamine system in rats Selectively disrupts wanting (bar pressing) and eatingBUT: Spares liking expressions when you directly inject yummy solutions into the mouth

Genetic elimination (knock-out) of dopamine spares liking in mice

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 Selectively boosts wanting without altering likingGenetically increasing dopamine neurotransmission in mice (gene knock-in) to >150% normative levelsSelectively increases wanting (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 wanting of reward Completely fails to increase hedonic liking reactions to the same reward

In sum, dopamine is neither necessary nor sufficient for pleasure

Dopamine = WantingDecrease Dopamine Selectively disrupt wantingPharmacological blockade of the dopamine system in rats Selectively disrupts wanting (bar pressing) and eatingBUT: Spares liking expressions when you directly inject yummy solutions into the mouth

Genetic elimination (knock-out) of dopamine spares liking in mice

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 Selectively boosts wanting without altering likingGenetically increasing dopamine neurotransmission in mice (gene knock-in) to >150% normative levelsSelectively increases wanting (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 wanting of reward Completely fails to increase hedonic liking reactions to the same reward

In sum, dopamine is neither necessary nor sufficient for pleasure

Science is Self-Correcting!

Today few neuroscientistsassertthat dopamine causes pleasureFor example Wisewas quoted [as saying], I no longer believe that the amount of pleasure felt is proportional to the amount of dopamine floating around in the brain, and pleasure is not a necessary correlate of dopamine elevations

Berridge & Kringelbach Neuron 2015

Wanting = Mesolimbic DA SystemWanting = Mesolimbic DA System

Wanting = Mesolimbic DA SystemAnalyses of the rodent dopamine experiments strongly implicate the mesolimbic dopamine (DA) system in wanting

Dopamine projection neurons sitting in the midbrain VTA that project to ventral striatal regions, particularly the nucleus accumbens, via the MFB

What About Liking?

Students:

How might we identifythe brainshedonic hotspots ?Search for regions where micro-stimulation amplifies hedonic expressionswithout altering wanting+likingHedonic Hotspots in NAcc ShellHedonic Hotspots in NAcc ShellThe nucleus accumbens (Nacc) can be split into core and shell regions

Hedonic Hotspots in NAcc ShellStimulation of a small region of the medial shell quadruples hedonic liking reactions

Hedonic Hotspots in NAcc ShellHotspot is sensitive to endogenous opioids (cf. Heroin, Oxy/Vicodin) and canabinoids (cf. THC/Marijuana)

Hedonic Hotspots in NAcc ShellConsistent with this, opioid reduction in humans selectively reduces liking of pleasant tastes (Arbisi et al Appetite 1999)

Systemic administration of the opioid antagonist naltrexone; Arbisi et al Appetite 1999 Section 5a:

Does Ventral Striatal (VS) activity correlate with wanting, positive affect, and E/PE?

Show me the (human brain) data!

VS/NAcc Activation

Knutson & Greer Philo Trans Royal Sci B 2008Ventral Striatum and WantingVentral Striatum and Wanting

vs. Pun Ant.vs. Rew DeliveryVS/NAcc ActivationIncreases during reward anticipation (wanting) vs. punishment anticipation; and vs. reward delivery (liking)

Correlates with positive arousal ratings (excitement)

Predicts reward-motivated behavior (selecting desirable products, high-risk/high-reward gambles)Knutson & Greer Philo Trans Royal Sci B 2008; Venkatraman et al J Marketing Research 2015Knutson & Greer Philo Trans Royal Sci B 2008; Venkatraman et al J Marketing Research 2015Ventral Striatum and Wanting

vs. Pun Ant.vs. Rew DeliveryVS/NAcc ActivationIncreases during reward anticipation (wanting) vs. punishment anticipation; and vs. reward delivery (liking)

Correlates with positive arousal ratings (excitement)

Predicts reward-motivated behavior in life (selecting desirable products, high-risk/high-reward gambles)Wu et al NI 2014Ventral Striatum and E/PE;BAS

VS Activation During Reward Anticipation

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

Related to dispositional E/PE/BASWu et al NI 2014Ventral Striatum and E/PE;BAS

VS Activation During Reward Anticipation

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

Related to dispositional E/PE/BASWu et al NI 2014Ventral Striatum and E/PE;BAS

Other groups have reported similar effectsFood: Beaver et al., 2006; Erotica: Costumero et al., 2013; Money: Braams et al J Neuro 2015Ventral Striatum and BAS

Yummy food imagesErotic imagesSection 5b:

fMRI is correlative,not mechanistic (causal)

What would happen ifwe directly manipulated activity in the human VS?

Neurofeedback ApproachGreer et al. NI 2014Neurofeedback ApproachInstruct subjects to increase or decrease fMRI signal (activation) in the VS/Nacc; not told how to do it.

Greer et al. NI 2014Neurofeedback ApproachInstruct subjects to increase or decrease fMRI signal (activation) in the VS/Nacc; not told how to do it.

Greer et al. NI 2014

Neurofeedback ApproachThe increasing cue indeed leadsto amplified activation in the VS/Nacc

Greer et al. NI 2014

Neurofeedback ApproachSubjects report that in order to increase activation, they were imagining engaging in different kinds of high arousal, positive activities.

Greer et al. NI 2014

Neurofeedback ApproachSubjects report that in order to increase activation, they were imagining engaging in different kinds of high arousal, positive activities.

And those who experienced the most intense positive affect showed the largest increases in VS/NAcc activationconsistent with the idea that VS/NAcc activity causally contributes to approach-related positive affect [increased activity] and depression [decreased activity]

Greer et al. NI 2014

Neurofeedback ApproachSubjects report that in order to increase activation, they were imagining engaging in different kinds of high arousal, positive activities.

And those who experienced the most intense positive affect showed the largest increases in VS/NAcc activationconsistent with the idea that VS/NAcc activity causally contributes to approach-related positive affect

Greer et al. NI 2014

What about drug manipulations?DA Pharmacological ApproachesNugent et al Bipolar Dis 2014DA Pharmacological ApproachesIncreasing 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-effort reward optionTreadway & Zald Curr Dir Psychol Sci 2013

DA Pharmacological ApproachesIncreasing 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-effort reward option, suggesting mediationTreadway & Zald Curr Dir Psychol Sci 2013

Section 6a

What About Treating Patients with Depression?

DA Pharmacological ApproachesNugent et al Bipolar Dis 2014DA Pharmacological ApproachesKetamine rapidly (