impulsivity: causes and consequences

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

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Low impulsivity/DRD4.6

High impulsivity/DRD4.6

DRD4.5

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Soc

ial I

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-See

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Sco

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r=0.45, p=0.06

Social Impulsivity Score

Nov

elty

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king

Sco

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*****

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

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~0 MiddleDelay

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DRD4.5



% C

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Novelty-Seeking Score

% C

orre

ct (

Lon

g de

lay)

r=-0.69, p=0.04

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r=-0.76, p=0.0003

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~0 MiddleDelay

LongDelay

DRD4.5



% C

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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

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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

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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

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Atomoxetine (1 mg/kg, p.o.)

(20 trial)

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Retention

(20 trial)

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Reversal

(20 trial)

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(10 trial)

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(10 trial)

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(15 trial)

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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

impulsivity: causes and consequences

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