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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
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