Transcript J. Neurosci - Charles R. Drew University of Medicine and Science

Impulsivity: Causes and
Consequences
J. David Jentsch, PhD, Associate Professor
Departments of Psychology and
Psychiatry & Biobehavioral Sciences
University of California, Los Angeles
Cognitive Control


“Learning” and “memory” reflect the acquisition and
persistence of experience-dependence modifications
in behavior; however, these mechanisms are often not
sufficient to permit adaptive, flexible behavior
Cognitive control is rubric that describes another set
of processes that contribute the ability to voluntarily
modulate behavior, either in the service of future
plans, changing conditional rules or complex and
variable contextual influences
Cognitive Control

Requires multiple domains of cognitive function,
including:

Working memory (ability to maintain internal
representations of distant goals)
Ability to update the contents of our internal
representations as contingencies shift
Contributes to our ability to execute planned behavior

Inhibitory control of pre-potent responding
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Implications of Poor Cognitive Control
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Inability to delay gratification, integrate complex
outcomes in decision making, stop reward-directed
behavior (addiction)

Generally, the impulsive aspects of substance abuse
can be thought of as a loss of the ability to maintain
internal representations of future goals and to inhibit
immediately gratifying behavior
Questions

What are the determinants of individual variation in
cognitive control and impulsivity?

What neuropharmacological targets emerge as
important mechanisms for the modulation of
cognitive control?
Pathways to Deconstructing a Complex
Phenotype

Recent studies from Lynn Fairbanks (UCLA) have
identified impulsive approach and aggression as a
heritable trait in non-human primates

Heritability supports search for genetic mechanisms that
may be common to those driving the phenotype in humans
Trait Impulsivity
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Rapid, unplanned, inflexible
approach to novelty (social or
non-social) or to rewards;
exploratory (image right) or
aggressive (highly risky) in
nature
Orthogonal to anxious aspects
of temperament, leading to at
least 4 categories of
phenotypic responses to
challenge
Impulsivity: A Stable Indicator of
Temperament
Males (n=70)
r=0.83
Females (n=56)
r=0.89
Impulsivity
Data represent two challenge tests separated by 16 months
Fairbanks et al. (2004) Biol. Psychiatry, 55: 642-7
Genetic Determinants?
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48-basepair, exon 3 variable number tandem repeat
polymorphism in the DRD4 (dopamine D4 receptor) gene
In humans, 4 and 7 repeats are the most common alleles
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7-repeat allele associated with greater risk for ADHD and higher
impulsivity/novelty-seeking
Vervets carry 5 or 6 repeats, with the 5-repeat version
being associated with greater impulsivity
This polymorphism accounts for 13% of the variance in
impulsive responding in the impulsivity tests (Bailey et
al. 2007; Psychiatric Genetics, 17: 23-7)
Is Impulsivity an Indicator of
Poor Cognitive Control in
Monkeys?
Experimental Design
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Common DRD4 allele (DRD4.6)/low impulsivity
Common DRD4 allele (DRD4.6)/high impulsivity
Rare DRD4.5 allele
120
100
80
60
40
20
0
60
**
***
Novelty-Seeking Score
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Social Impulsivity Score
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Adolescent (4 year old) male vervet monkeys, living in social groups
Drawn into the study according to the following criteria:
ore
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60
50
40
30
20
10
0
Low impulsivity/DRD4.6
High impulsivity/DRD4.6
DRD4.5
Spatial Delayed Response

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Maintenance of information in
working memory
Relies upon DLPFC (amongst other
circuits)
Curtis and D’Esposito (2004) Cog. Affec. Behav. Neurosci., 4: 528-39
%C
*
40
Chance
Low impulsivity/DRD4.6
20
High impulsivity/DRD4.6
DRD4.5
Spatial Delayed Response Performance
% Correct (Long delay)
0
100
60
20
r=-0.76, p=0.0003
Low impulsivity/DRD4.6
High impulsivity/DRD4.6
DRD4.5
~0
Middle
Delay
Long
Delay
James et al. (2007) J. Neurosci.,
27(52):14358-64.
60
0
20
40
60
80
100
120
*
20
g delay)
40
Social Impulsivity Score
Chance
80
Long
Delay
60
*
40
0
Middle
Delay
80
0
% Correct (Long delay)
% Correct
80
~0
80
60
40
20
0
r=-0.69, p=0.04
30
35
40
45
50
Novelty-Seeking Score
55
60
DRD4 and Working Memory
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These studies that DRD4 genotype modulates
working memory in the hypothesized direction (rare
allele associates with high impulsivity and poor
working memory)
This genotype contributes in a non-unique fashion as
compared with the as-of-yet unknown genotypes also
driving this super-phenotype that spans the
temperamental and cognitive domains
What about other genes?
Pedigree-wide assessment for working
memory (and other cognitive controlrelated processes) for whole-genome
linkage analyses
What about other aspects
of cognitive control?
Executive control over behavior
(reversal learning)
Reversal Learning and Cognitive
Control
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Subjects (rodents, monkeys or
humans) learn a discrimination
based upon positive and negative
feedback, alone
Once learned, the contingencies
change, and behavior must be
flexibly altered in order to obtain
desired outcomes
Reversal, as compared with
acquisition, selectively measures
the ability to change or inhibit a
conditioned response
Reversal Learning and the
Orbitofrontal Cortex
Dias et al. (1996) Nature, 380: 69-72
# of Errors
Impulsivity and Discrimination
Learning and Reversal
50
45
40
35
30
25
20
15
10
5
0
High Impulsivity
Low Impulsivity
Acquisition Errors
Retention Errors
Perseverative
Reversal Errors
Neutral Reversal
Errors
Subjects were n=12 juvenile (~2 ½ year old subjects)
Impulsivity
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In young subjects (juveniles and adolescents),
impulsive temperament is a strong predictor of
working memory maintenance and flexible
responding, two key aspects of cognitive control
The impulsive youngster exhibits a spectrum of
cognitive control impairments that depend upon
variation in AD/HD risk genes…
Genomic/neurochemical
determinants?
Catecholamine Mechanisms
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Role for the DRD4 gene in modulating impulsivity and
cognitive control suggests that catecholamine
mechanisms, generally, remain important targets for
neuropharmacological interventions
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We know D1-like receptors play a critical role in working
memory
What about other dimensions of cognitive control, such as
the ability to update behavior in response to reinforcement
shifts (reversal learning?)
D1/D5 Mechanisms Do Not Modulate
Reversal Learning Performance
SCH 23390 = D1-like antagonist
Dose = 0.03 mg/kg
Lee et al. (2007) Neuropsychopharmacol., 32(10):2125-34
D2/D3 Mechanisms Selectively Modulate
Reversal Learning Performance
Raclopride = D2-like antagonist
Dose = 0.03 mg/kg
Lee et al. (2007) Neuropsychopharmacol., 32(10):2125-34
Dopaminergic Mechanisms
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Differently from working memory (maintenance of
central representations), reversal learning (flexible
responding) depends more on D2-like than D1-like
receptors
We propose that D1- and D2-like receptors
dissociably contribute to the maintenance vs.
updating of central representations and behavior
New emphasis on D2-like mechanisms in cortex for
cognitive control is needed
Cortical D2 Receptors and Cognitive
Control
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Ideal strategies include mechanisms that selectively
increase, in an activity-dependent manner, extracellular levels of dopamine, which then can act on
D1-like and D2-like receptors to facilitate working
memory and executive control over behavior
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Inhibition of the noradrenaline transporter??
Atomoxetine Improves Reversal
Learning in Monkeys
Acquisition
Disc 2
(15 trial)
(15 trial)
A+B-C-
D+E-F-
10
Reversal
Retention
Disc 2
Block 1
(20 trial)
D+E-F-
Disc 2
(10 trial)
D+E-F-
Retention
(20 trial)
9
Saline
8
Atomoxetine (1 mg/kg, p.o.)
7
6
5
4
3
2
1
A-B+CBlock 2
(20 trial)
A+B-C-
Disc 1
Between -sessions
Block 2
Block 1
Disc 1
Perseverative Errors
Disc 1
(10 trial)
D-E+F-
Within session
0
*
Conclusions
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Progress on the genetics of individual variation in
cognitive control in experimental animals
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Including the identification of subjects that naturally
exhibit a range of psychiatric disorder-related symptoms
and endophenotypes
Pharmacological studies reveal a critical role for
dopamine D2-like and alpha-adrenergic mechanisms
in flexible responding
Collaborators and Students
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Lynn Fairbanks (primatology)
Nelson Freimer (genetics)
Eydie London (molecular imaging)
Emanuele Seu (post-doc), Alex James (graduate
student), Stephanie Groman (graduate student)
Acknowledgements
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National Institute on Drug Abuse
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National Institute of Mental Health
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P20-DA22539 (Methamphetamine Abuse, Inhibitory Control:
Treatment Implications)
P50-MH77248 (CIDAR: Translational Research to Enhance Cognitive
Control)
RL1-MH83270 (Translational Models for Memory and Cognitive
Control)
Tennenbaum Center for the Biology of Creativity at UCLA