impulsivity: causes and consequences

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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 Presentation

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  • J. David Jentsch, PhD, Associate ProfessorDepartments of Psychology and Psychiatry & Biobehavioral SciencesUniversity of California, Los AngelesImpulsivity: Causes and Consequences

  • Cognitive ControlLearning and memory reflect the acquisition and persistence of experience-dependence modifications in behavior; however, these mechanisms are often not sufficient to permit adaptive, flexible behaviorCognitive 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 ControlRequires 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 shiftContributes to our ability to execute planned behavior

    Inhibitory control of pre-potent responding

  • Implications of Poor Cognitive ControlInability 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

  • QuestionsWhat 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 PhenotypeRecent studies from Lynn Fairbanks (UCLA) have identified impulsive approach and aggression as a heritable trait in non-human primatesHeritability supports search for genetic mechanisms that may be common to those driving the phenotype in humans

  • Trait ImpulsivityRapid, unplanned, inflexible approach to novelty (social or non-social) or to rewards; exploratory (image right) or aggressive (highly risky) in natureOrthogonal to anxious aspects of temperament, leading to at least 4 categories of phenotypic responses to challenge

  • Impulsivity: A Stable Indicator of TemperamentMales (n=70)Females (n=56)Data represent two challenge tests separated by 16 months

    Fairbanks et al. (2004) Biol. Psychiatry, 55: 642-7r=0.83r=0.89Impulsivity

  • Genetic Determinants?48-basepair, exon 3 variable number tandem repeat polymorphism in the DRD4 (dopamine D4 receptor) geneIn humans, 4 and 7 repeats are the most common alleles7-repeat allele associated with greater risk for ADHD and higher impulsivity/novelty-seekingVervets carry 5 or 6 repeats, with the 5-repeat version being associated with greater impulsivityThis 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 DesignAdolescent (4 year old) male vervet monkeys, living in social groupsDrawn into the study according to the following criteria:Common DRD4 allele (DRD4.6)/low impulsivityCommon DRD4 allele (DRD4.6)/high impulsivityRare DRD4.5 allele

  • Spatial Delayed Response Maintenance of information in working memoryRelies upon DLPFC (amongst other circuits)Curtis and DEsposito (2004) Cog. Affec. Behav. Neurosci., 4: 528-39

  • Spatial Delayed Response PerformanceJames et al. (2007) J. Neurosci., 27(52):14358-64.

  • DRD4 and Working MemoryThese 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 ControlSubjects (rodents, monkeys or humans) learn a discrimination based upon positive and negative feedback, aloneOnce learned, the contingencies change, and behavior must be flexibly altered in order to obtain desired outcomesReversal, as compared with acquisition, selectively measures the ability to change or inhibit a conditioned response

  • Reversal Learning and the Orbitofrontal CortexDias et al. (1996) Nature, 380: 69-72

  • Impulsivity and Discrimination Learning and ReversalSubjects were n=12 juvenile (~2 year old subjects)

    Chart4

    22.331666666722.11166666674.50852704456.488322031

    0.9451.88833333330.18152593940.7635374545

    41.943333333330.72333333336.14788943014.4262713177

    13.118.61166666673.81402237362.1039794306

    High Impulsivity

    Low Impulsivity

    # of Errors

    Sheet1

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    B16 WHigh108High80HighHigh36.8High47High5.3311812.6711.675431220.334613

    B16 BHigh77High38HighMixed29Low46High16.33334.6718.330.6714.67437.338.335.3370.6725

    B16 NHigh94High53HighLow24Low28Low297.3348.6719.670.3314.3342611.336.675820.67

    B16 ULow63Low0LowMixed39High22Low26.678.674922.330.331.334.33424.676.6710.6746.6715.33

    B16 XLow72Low10LowMixed31Low36.5High23.33248.33254.672.3311.336.6725.331024.6749.3314

    B16 YLow68Low1LowLow29Low0Low8.67219.67112.332.3374.6725.671.339.3343.3316.33

    B16 SLow32Low0LowLow0Low9Low19.33438.6719.330.671.334.674289.67747.6722.33

    B16 VMixed103High7LowMixed32.6High0Low21.3324321.671.671.336.334.6748.333010.33117.3339

    B16 LMixed58Low51HighHigh37.7High50.17High49.672.3388.3338.673.3329.33652.6717897.3327.67

    B16 AMixed95High1LowMixed32.6High31Low37.673.6765.6728115.334.3368.3314.338.33109.6727

    B16 1Mixed62Low65HighHigh38.6High34High541490144287105318

    101.3333333333High32.483333333322.33166666673.333333333342.001666666719.61166666670.9451.16666666675.27666666674.333333333341.943333333313.1112.053333333380.44525.39

    59.1666666667Low29.216666666722.11166666673.83333333334320.88833333331.88833333331.726.77666666674.8930.72333333338.611666666711.611666666756.221666666718.9433333333

    7.3333333333High2.29323885464.50852704450.88564728376.4173896132.07877915560.18152593940.11418308880.31497795340.17234977366.14788943013.81402237362.861097303111.54801360993.5069702023

    5.7874385046Low6.08979565436.4883220311.039729665710.83705925674.38448736390.76353745450.23417941841.23066829180.47697658924.42627131772.10397943062.66784484398.32332001732.1042523085

    Acquisition ErrorsRetention ErrorsPerseverative Reversal ErrorsNeutral Reversal Errors

    TF - trials to first correct choice

    CC - number of correct choices

    TC - trials to criterion

    NR - neutral responses

    PR - pers responses

    IC - incorrect choices

    Sheet1

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    High Impulsivity

    Low Impulsivity

    # of Errors

    Sheet2

    Sheet3

  • ImpulsivityIn young subjects (juveniles and adolescents), impulsive temperament is a strong predictor of working memory maintenance and flexible responding, two key aspects of cognitive controlThe impulsive youngster exhibits a spectrum of cognitive control impairments that depend upon variation in AD/HD risk genes

  • Genomic/neurochemical determinants?

  • Catecholamine MechanismsRole for the DRD4 gene in modulating impulsivity and cognitive control suggests that catecholamine mechanisms, generally, remain important targets for neuropharmacological interventionsWe know D1-like receptors play a critical role in working memoryWhat 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 PerformanceLee et al. (2007) Neuropsychopharmacol., 32(10):2125-34 SCH 23390 = D1-like antagonistDose = 0.03 mg/kg

  • D2/D3 Mechanisms Selectively Modulate Reversal Learning PerformanceRaclopride = D2-like antagonistDose = 0.03 mg/kgLee et al. (2007) Neuropsychopharmacol., 32(10):2125-34

  • Dopaminergic MechanismsDifferently from working memory (maintenance of central representations), reversal learning (flexible responding) depends more on D2-like than D1-like receptorsWe propose that D1- and D2-like receptors dissociably contribute to the maintenance vs. updating of central representations and behaviorNew emphasis on D2-like mechanisms in cortex for cognitive control is needed

  • Cortical D2 Receptors and Cognitive ControlIdeal 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*

    Chart1

    6.2530.86602540381

    Saline

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

    Perseverative Errors

    Sheet1

    GUA 0.5mg/kg- MPH 0.3mg/kg- ATO 1mg/kg

    RETENTION

    Tot errorsTime retention (min)

    Monkey1234meanSEDsal atoMonkey1234mean

    005111.751.32287

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