impulsivity: causes and consequences
DESCRIPTION
J. David Jentsch, PhD, Associate Professor Departments of Psychology and Psychiatry & Biobehavioral Sciences University of California, Los Angeles. Impulsivity: Causes and Consequences. Cognitive Control. - PowerPoint PPT PresentationTRANSCRIPT
J. David Jentsch, PhD, Associate Professor
Departments of Psychology and
Psychiatry & Biobehavioral Sciences
University of California, Los Angeles
Impulsivity: Causes and Consequences
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
Implications of Poor Cognitive Control
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 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) Females (n=56)
Data represent two challenge tests separated by 16 months
Fairbanks et al. (2004) Biol. Psychiatry, 55: 642-7
r=0.83 r=0.89
Impulsivity
Genetic Determinants? 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
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
Adolescent (4 year old) male vervet monkeys, living in social groups Drawn into the study according to the following criteria:
Common DRD4 allele (DRD4.6)/low impulsivity Common DRD4 allele (DRD4.6)/high impulsivity Rare DRD4.5 allele
0
20
40
60
80
100
120
Low impulsivity/DRD4.6
High impulsivity/DRD4.6
DRD4.5
0
10
20
30
40
50
60
Soc
ial I
mpu
lsiv
ity
Sco
re
Nov
elty
-See
king
Sco
re
0
10
20
30
40
50
60
0 20 40 60 80 100 120
r=0.45, p=0.06
Social Impulsivity Score
Nov
elty
-See
king
Sco
re
*****
Spatial Delayed Response
Maintenance of information in working memory
Relies upon DLPFC (amongst other circuits)
Curtis and D’Esposito (2004) Cog. Affec. Behav. Neurosci., 4: 528-39
0
20
40
60
80
100
~0 MiddleDelay
LongDelay
DRD4.5
High impulsivity/DRD4.6
Low impulsivity/DRD4.6
% C
orre
ct
Chance
*
*
% C
orre
ct (
Lon
g de
lay)
Social Impulsivity Score
0
20
40
60
80
30 35 40 45 50 55 60
Novelty-Seeking Score
% C
orre
ct (
Lon
g de
lay)
r=-0.69, p=0.04
0 20 40 60 80 100 1200
20
40
60
80
r=-0.76, p=0.0003
0
20
40
60
80
100
~0 MiddleDelay
LongDelay
DRD4.5
High impulsivity/DRD4.6
Low impulsivity/DRD4.6
% C
orre
ct
Chance
*
*
% C
orre
ct (
Lon
g de
lay)
Social Impulsivity Score
0
20
40
60
80
30 35 40 45 50 55 60
Novelty-Seeking Score
% C
orre
ct (
Lon
g de
lay)
r=-0.69, p=0.04
0 20 40 60 80 100 1200
20
40
60
80
r=-0.76, p=0.0003
Spatial Delayed Response Performance
James et al. (2007) J. Neurosci., 27(52):14358-64.
DRD4 and Working Memory 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 control-related processes) for whole-genome
linkage analyses
What about other aspects of cognitive control?
Executive control over behavior (reversal learning)
Reversal Learning and Cognitive Control
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
Impulsivity and Discrimination Learning and Reversal
0
5
10
15
20
25
30
35
40
45
50
Acquisition Errors Retention Errors PerseverativeReversal Errors
Neutral ReversalErrors
# of
Err
ors
High Impulsivity
Low Impulsivity
Subjects were n=12 juvenile (~2 ½ year old subjects)
Impulsivity 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 Role for the DRD4 gene in modulating impulsivity and
cognitive control suggests that catecholamine mechanisms, generally, remain important targets for neuropharmacological interventions 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
Lee et al. (2007) Neuropsychopharmacol., 32(10):2125-34
SCH 23390 = D1-like antagonistDose = 0.03 mg/kg
D2/D3 Mechanisms Selectively Modulate Reversal Learning Performance
Raclopride = D2-like antagonistDose = 0.03 mg/kg
Lee et al. (2007) Neuropsychopharmacol., 32(10):2125-34
Dopaminergic Mechanisms 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
Ideal strategies include mechanisms that selectively increase, in an activity-dependent manner, extra-cellular levels of dopamine, which then can act on D1-like and D2-like receptors to facilitate working memory and executive control over behavior
Inhibition of the noradrenaline transporter??
Atomoxetine Improves Reversal Learning in Monkeys
0
1
2
3
4
5
6
7
8
9
10
1
Per
seve
rativ
e E
rror
s
Saline
Atomoxetine (1 mg/kg, p.o.)
(20 trial)
A+B-C-
Blo
ck
1B
loc
k 2
Disc 1 Disc 2
Retention
(20 trial)
D+E-F-
Disc 1 Disc 2
Reversal
(20 trial)
A-B+C-
(10 trial)
D+E-F-
(10 trial)
D-E+F-
Bet
wee
n -s
essi
ons
Within -session
Retention
(15 trial)
A+B-C-
Disc 1 Disc 2
Acquisition
(15 trial)
D+E-F-B
loc
k 1
Blo
ck
2
*
Conclusions Progress on the genetics of individual variation in
cognitive control in experimental animals 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 Lynn Fairbanks (primatology) Nelson Freimer (genetics) Eydie London (molecular imaging)
Emanuele Seu (post-doc), Alex James (graduate student), Stephanie Groman (graduate student)
Acknowledgements National Institute on Drug Abuse
P20-DA22539 (Methamphetamine Abuse, Inhibitory Control: Treatment Implications)
National Institute of Mental Health 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