J. David Jentsch, PhD, Associate Professor

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Impulsivity Causes and Consequences

• J. David Jentsch, PhD, Associate Professor
• Departments of Psychology and
• Psychiatry Biobehavioral Sciences
• University of California, Los Angeles

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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

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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

• 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

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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?

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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

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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

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Impulsivity A Stable Indicator of Temperament
Males (n70)
Females (n56)
r0.83
r0.89
Impulsivity
Data represent two challenge tests separated by
16 months Fairbanks et al. (2004) Biol.
Psychiatry, 55 642-7
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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)

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Is Impulsivity an Indicator of Poor Cognitive
Control in Monkeys?
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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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Spatial Delayed Response

• Maintenance of information in working memory
• Relies upon DLPFC (amongst other circuits)

Curtis and DEsposito (2004) Cog. Affec. Behav.
Neurosci., 4 528-39
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Spatial Delayed Response Performance
James et al. (2007) J. Neurosci., 27(52)14358-64.
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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

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What about other genes?

• Pedigree-wide assessment for working memory (and
  other cognitive control-related processes) for
  whole-genome linkage analyses

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What about other aspects of cognitive control?

• Executive control over behavior (reversal
  learning)

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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

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Reversal Learning and the Orbitofrontal Cortex
Dias et al. (1996) Nature, 380 69-72
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Impulsivity and Discrimination Learning and
Reversal
Subjects were n12 juvenile (2 ½ year old
subjects)
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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

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Genomic/neurochemical determinants?
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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?)

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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
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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
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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

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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??

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Atomoxetine Improves Reversal Learning in Monkeys

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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

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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)

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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