Impaired Inhibitory Control

Precursor or Consequence of Drug Abuse

Edythe D. London, Ph.D.elondon@mednet.ucla.edu, C8-528

Why Talk About Inhibitory Control in the Context of Drug

Addiction?

I-RISA Syndrome

of Drug Addiction

R.Z. Goldstein and N.D. Volkow, Am. J.

Psychiatry 2002;159:1642

Circuits of Addiction

reward prediction & core substrates of pleasure learning & memory main substrates of conditioning

motivation, drive & salience

cognitive control

PART I

• What do we mean by “inhibitory control deficits”? Impulsivity?

• How are inhibitory control deficits related to impulsivity?

Impulsivity: Inability to control behavior

extroversion, venturesomeness, sensation-seekingextroversion, venturesomeness, sensation-seeking

● ● ADHDADHD● ● conduct conduct disorderdisorder

● ● psychopathic psychopathic personality personality

● ● sociopathic sociopathic personality personality

Measures: Barratt Impulsivity ScaleMeasures: Barratt Impulsivity Scale Relevant scales of Personality Inventories: TPQ, Eysenck Relevant scales of Personality Inventories: TPQ, Eysenck

Personality Measure Related to Inhibitory Control

Deficits in Inhibitory Control

● ● motor control:motor control: (Go/No GO tasks, SST) (Go/No GO tasks, SST) ****● ● cognitive controlcognitive control allocation of cognitive resources: allocation of cognitive resources: focusing of attention (Stroop task) focusing of attention (Stroop task) sustaining attention (CPT) sustaining attention (CPT) **** shifting set (reversal learning, WCST) shifting set (reversal learning, WCST) ****●● emotional controlemotional control conscious & unconscious: conscious & unconscious: reappraisal techniques (CBT) reappraisal techniques (CBT) labeling taskslabeling tasks

Operationally: Inability to Inhibit Pre-potent ResponsesOperationally: Inability to Inhibit Pre-potent Responses

**** animal tests possibleanimal tests possible

Deficits in Inhibitory Control

Risky Decision-MakingRisky Decision-Making

● ● Gambling TaskGambling Task

● ● Rogers TaskRogers Task

● ● Balloon Analogue Risk TaskBalloon Analogue Risk Task

Delay DiscountingDelay Discounting

OXPress the key shown on the

display.

OStop Signal: Do not press

key if a tone is heard.

Stop-Signal Reaction Time

0 s 0.5 s 1 s

UninhibitedRT

SSRT

What Circuitry Mediates Inhibitory Control? Effect of Lesions on Stop Signal

Reaction Time

A. Aron et al. (2004): Trends Cogn Sci. 8:170.

Right VLPFC

“Hyperdirect” Pathway Connects IFC and STN and Links to preSMA for Basal Ganglia

Control

A.R. Aron et al., J. Neurosci 2007;27:3743.A.R. Aron et al., J. Neurosci 2007;27:3743.

SSRT is Related to D2/D3 Dopamine Receptors

Ventral Striatum

r = 0.592p = 0.033

r = 0.640p = 0.019

Buyean Lee et al., unpublished Buyean Lee et al., unpublished

Ventral striatum Binding Potential for [F-18]Fallypride in Ventral Striatum

Impulsivity a

Go TaskMean RT -036 (073)

Stop-signal delay -131 (-060)

Stop-signal RT 315 **

a Impulsivity subscale of Extraversion Scale, Eysenck Personality Inventory

** p<0.01 (two-tailed)G.D. Logan et al. 1997; Psychol. Sci. 6:63.

SSRT is Correlated with Impulsivity

Stroop Task

BALL

TRAIN

CAT

APPLE

FISH

HAND

ROPE

KOALA

PACK

DOG

PAT

LAMB

ZEBRA

EYE

HORSE

PIN

BUSH

MOON

Color naming without interferenceColor naming without interference

Stroop Task

YELLOW

RED

BLUE

BLUE

YELLOW

GREEN

YELLOW

GREEN

RED

YELLOW

GREEN

RED

GREEN

BLUE

RED

GREEN

GREEN

YELLOW

Reading Color naming Incongruent/Interference

Brain Activity Incongruent Minus Congruent

Amygdala

Regulate negative emotions by activating PFC. PFC exerts inhibitory control.

down-regulating amygdala activation

Adapted from Davidson RJ et al., Science, 2000

DorsolateralPFC

Anterior Cingulate

Orbital PFC (green) Ventromedial PFC (red)

Conscious Emotion Control

K. Baicy et al., Abstr. Soc. Neurosci, 2006K. Baicy et al., Abstr. Soc. Neurosci, 2006

PFC Modulates Amygdala Activation

t

LOOK negative > neutral

DECREASE > LOOK

IFG activation IFG activation during reappraisalduring reappraisal

AmygdalaAmygdala activation while viewingactivation while viewing

evocative stimulievocative stimuli

A B C D

Please pick a card.

A B C D

You get $100!

You must pay$125

A B C D

OFC

OFC

Amygdala

+

-

01020304050607080

Ne

t S

co

re

1-100 101-200 201-300

Card Number

8120 Net Score(Good - Bad Cards)

BRAIN ACTIVATION BY GAMBLING TASK

Acquisition

Retention

Reversal

Visual Picture Discriminationand Reversal Learning

WGTA

Reversal Learning Set-Up

Raclopride Impairs Reversal Learning

Role of D2 Dopamine Receptors

B. Lee et al. Neuropsychopharmacology 2007

*vehicle raclopridevehicle raclopride vehicle raclopride vehicle raclopride

Trials to Reach Criterion

Reversal Errors Perseverative Errors

PART Il What evidence indicates that addicted

humans have deficits in inhibitory control?

● cognitive assessments

● structural brain imaging

● functional brain imaging

Impairment on the Stop-Signal Task

J. Monterosso et al., Drug Alcohol Depend., 2005

controlsmoker

METHusers

Deficit in motor control is related to METH use.

controlnonsmoker

Gray Matter Deficit in Lateral Cortex

PM Thompson et al., J. Neurosci. 2004

Deficit in right ventrolateral PFC in METH AbuseDeficit in right ventrolateral PFC in METH Abuse

Affect Matching Task

Which of the two bottom pictures matches the emotion shown on top?

Methamphetamine Dependence

P<.005, 10 voxel extent(n = 12/group)

D Payer et al., manuscript in review 2007

Dorsal ACC activity correlated withDorsal ACC activity correlated with: : ● ● hostility hostility ● ● interpersonal sensitivityinterpersonal sensitivity

t

Heightened Activation: Dorsal ACC

METH > control t33

22

11

00

44

33

22

11

00

Blunted Activation:Right Ventrolateral PFC

Control > METH

PFC/ ACC Activation (Cons)

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

-2 -1 0 1 2 3 4 5RVLPFC

dA

CC CON

MA

Negative Correlation of Right VLPFC and Dorsal ACC

Activityr = -.516, p<.001

METHControl

Do

rsa

l AC

C

Right Ventrolateral PFC

Drug Abusers Make a Higher Percentage of Risky ChoicesCorrelated with Activation of Right OFC

While Making Risky Choices

15

25

35

45

55

Control Abusers

Pe

rce

nta

ge

of R

isky

ch

oic

es

F= 4.4: p<.05

Control Drug Abuse Control Drug Abuse

DH Fishbein et al., Cogn. Brain Res. 2005; 23: 119:DH Fishbein et al., Cogn. Brain Res. 2005; 23: 119:

Drug Abusers have Structural as well as Functional Differences In PFC

Left (p < 0.001)Left (p < 0.001) Right (p < 0.005)Right (p < 0.005)

ControlControl

Drug abuseDrug abuse

Vo

lum

e (

cm3)

Vo

lum

e (

cm3)

7070

4040

5050

6060

8080

9090

Brain Structure isBrain Structure is Genetically Controlled Genetically Controlled

P. Thompson, UCLA, 2001

PART IIIWhat came first?

● Animal studies: effects of drugs of abuse

on inhibitory control● Human studies: vulnerability to

addiction

Chronic PCP Produces Enhanced Responding for a Conditioned

Reinforcer

0

20

40

60

80

100

120

Me

an

Le

ver

Re

spo

nse

s

**F (1,10)=10.70

**p = .01

CR Lever

NCR Lever

J.D. Jentsch & J. Taylor, Neuropsychopharmacology 2001;24:66Saline PCPPCP

CR Lever

NCR Lever

AMPH Changes Dendritic Morphology in Nonhuman Primate PFC

Layers II/Superficial III

AMPH-naïve Intermittent AMPH escalating dose, 6 or 12 wk 0.1-1 mg/kg, bid

peak densitypeak density along apical along apical

dendritic trunkdendritic trunk

L.D. Selemon et al., Neuropsychopharmacology 2007;32:919L.D. Selemon et al., Neuropsychopharmacology 2007;32:919

Some Childhood Disorders Predict Substance Abuse

ADHDADHD

No ConductDisorder

75 %

No ConductDisorder

75 %

SubstanceAbuse79 %

SubstanceAbuse79 %

No SubstanceAbuse21 %

No SubstanceAbuse21 %

SubstanceAbuse40 %

SubstanceAbuse40 %

No SubstanceAbuse60 %

No SubstanceAbuse60 %

ConductDisorder

25 %

ConductDisorder

25 %

Biederman et al., 1995

Adolescents with Behavior Disorders Show Impaired GT Performance

ADULTS ADOLESCENTSADULTS ADOLESCENTS

Conclusion

Cognitive Deficits decision-making

response inhibition

Inhibitory Control Problems (Impulsivity)

Mood Disorder anxiety

depression

Inhibitory Control Problems

Drug AbuseDrug Abuse