F. Gerard Moeller

Two models of impulsivity: relationship to personality traits and psychopathology

BACKGROUND Impulsivity is prominent in psychiatric disorders. Two dominant models of impulsivity are the reward-discounting model, where impulsivity is defined as inability to wait for a larger reward, and the rapid-response model, where impulsivity is defined as responding without adequate assessment of context. We have compared the role of these models of impulsivity in human psychopathology, based on the hypothesis that rapid-response impulsivity would be more strongly related to other aspects of psychopathology and to impulsivity as described by questionnaires. METHODS We investigated relationships between personality and laboratory measures of impulsivity, and between these measures and clinical characteristics, in parents of adolescent subjects with disruptive behavioral disorders (DBDs) and matched control subjects. Diagnoses were rendered using the Structured Interview for DSM-IV. The Barratt Impulsiveness Scale (BIS) was used as a trait measure of impulsivity. Rapid-response impulsivity was assessed using a form of the Continuous Performance Test, the Immediate Memory-Delayed Memory Task (IMT/DMT). Reward-delay impulsivity was measured using two tasks where subjects could choose between smaller immediate or larger delayed rewards. RESULTS Rapid-response, but not reward-delay impulsivity, was significantly higher in subjects with lifetime Axis I or Axis II diagnoses. Scores on the BIS were elevated in subjects with Axis I diagnoses and correlated significantly with both rapid-response and reward-delay tests, but more strongly with the former. Multiple regression showed that rapid-response, but not reward-delay performance or intelligence quotient, contributed significantly to BIS scores. Correlations were similar in parents of control subjects and of DBD subjects. CONCLUSIONS These data suggest that measures of rapid-response impulsivity and of reward-delay impulsivity are both related to impulsivity as a personality characteristic. The relationship appears stronger, however, for rapid-response impulsivity, as measured by the IMT/DMT. Laboratory and personality measures of impulsivity appear to be related to risk of psychopathology.

Studies of violent and nonviolent male parolees: II. Laboratory and psychometric measurements of impulsivity

Male parolees were recruited into a laboratory study to determine the relationship between their previous aggression history, psychometric measures of aggression, and behavioral measures of aggressive responding using a laboratory methodology: the Point Subtraction Aggression Paradigm. Subjects were assigned to a violent or nonviolent group based upon their criminal history. Subjects participated in sessions in which they were given three response options defined as: (1) nonaggressive responding which earned money, (2) aggressive responding which ostensibly subtracted money from another fictitious person, (This responding was defined as aggressive since it resulted in the ostensible delivery of an aversive stimulus (subtraction of money) to another person), and (3) escape which protected the subjects earnings from subtractions initiated by the other person. Results indicated that the violent subjects emitted significantly more aggressive responses than subjects in the nonviolent group. The number of aggressive responses parolees emitted was significantly correlated with most psychometric measures of aggression. This study provides external validity for our laboratory measurement of human aggressive responding, since aggressive responding was directly related to violent criminal histories.

Dextroamphetamine for cocaine-dependence treatment : A double-blind randomized clinical trial

A properly implemented agonist treatment regimen should improve retention and reduce illicit drug use. Cocaine-dependent subjects (N = 128) were enrolled in a 12-week randomized, double-blind, placebo-controlled trial. In the multistage dosing design, subjects initially received placebo (PBO) or 15 to 30 mg of dextroamphetamine sulfate, sustained-release capsules. At week 5, the dose doubled to 30 mg or 60 mg for active groups. Subjects attended the clinic twice a week, provided urine samples, obtained medication, and had one behavioral therapy session a week. Retention was best for the 15-to 30-mg group, whereas the proportion of benzoylecgonine-positive urine screens was, from lowest to highest, 30 to 60 mg, 15 to 30 mg, and PBO at study end. Dosing must be refined. The results provide support for additional examination of the agonist model in psychostimulantdependence treatment.

New developments in human neurocognition: clinical, genetic, and brain imaging correlates of impulsivity and compulsivity

Impulsivity and compulsivity represent useful conceptualizations that involve dissociable cognitive functions, which are mediated by neuroanatomically and neurochemically distinct components of cortico-subcortical circuitry. The constructs were historically viewed as diametrically opposed, with impulsivity being associated with risk-seeking and compulsivity with harm-avoidance. However, they are increasingly recognized to be linked by shared neuropsychological mechanisms involving dysfunctional inhibition of thoughts and behaviors. In this article, we selectively review new developments in the investigation of the neurocognition of impulsivity and compulsivity in humans, in order to advance our understanding of the pathophysiology of impulsive, compulsive, and addictive disorders and indicate new directions for research.

P300 event-related potential amplitude and impulsivity in cocaine-dependent subjects.

Previous studies report reduced amplitude of the P300 event-related potential in cocaine-dependent individuals. Cocaine dependence is also associated with increased impulsivity, possibly due to deficits in cognitive function that are associated with reduced P300 amplitude. In the current study, the relationship between cocaine dependence, impulsivity, and P300 amplitude were examined. An auditory oddball event-related potential task along with self-report (Barratt Impulsiveness Scale version 11) and behavioral laboratory (Immediate and Delayed Memory Task) measures of impulsivity were assessed in healthy controls (n = 14) and subjects who met DSM-IV criteria for current cocaine dependence (n = 17). P300 amplitude was reduced and self-reported and behavioral laboratory impulsivity scores were elevated among the cocaine-dependent group compared to controls. There was a positive correlation between the questionnaire and behavioral laboratory measures of impulsivity, and a negative correlation between impulsivity measures and P300 amplitude. The correlation between self-reported impulsivity scores and P300 amplitude remained after taking into account the number of childhood conduct disorder symptoms. This study supports the hypothesis that the basic neurophysiology responsible for the P300 amplitude in cocaine-dependent individuals is associated with impulsivity independent of a history of childhood conduct disorder symptoms.

Antisocial Personality Disorder and Alcohol‐Induced Aggression

This study compared the effects of alcohol on aggressive responding between subjects with antisocial personality disorder (ASPD) and subjects without ASPD. Eighteen alcohol drinking subjects (10 subjects without ASPD and 8 subjects with ASPD) underwent testing on a laboratory measure of aggression, the Point Subtraction Aggression Paradigm, after consumption of placebo and three doses of alcohol (0.25 g/kg, 0.5 g/kg, and 1.0 g/kg). There was a significant difference in the effect of alcohol on aggressive responding on the Point Subtraction Aggression Paradigm between subjects with ASPD and subjects without ASPD. Subjects with ASPD had a greater increase in aggressive responding after alcohol, compared with non-ASPD subjects. There was no difference between the two groups in the effect of alcohol on monetary-reinforced responding.

Choice impulsivity: Definitions, measurement issues, and clinical implications

Impulsivity critically relates to many psychiatric disorders. Given the multifaceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity. The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species. Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, and steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings. The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures.

Selective serotonin 5-HT2C receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues

Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT(2C) receptor (5-HT(2C)R) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT(2C)R agonist, WAY 163909, in cocaine and sucrose self-administration and reinstatement assays employing parallel experimental designs in free-fed rats. WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID(50) = 1.19 mg/kg) and sucrose (ID(50) = 0.7 mg/kg) as well as reinstatement (ID(50) = 0.5 mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues. The ID(50) of WAY 163909 predicted to decrease the reinforcing efficacy of cocaine or sucrose as well as reinstatement upon exposure to cocaine-associated cues was ∼5-12-fold lower than that predicted to suppress horizontal ambulation (ID(50) = 5.89 mg/kg) and ∼2-5-fold lower than that predicted to suppress vertical activity (ID(50) = 2.3 mg/kg). Thus, selective stimulation of the 5-HT(2C)R decreases the reinforcing efficacy of cocaine and sucrose in freely-fed rats, but differentially alters the incentive-salience value of cocaine- vs. sucrose-associated cues at doses that do not impair locomotor activity. Future research is needed to tease apart the precise contribution of 5-HT(2C)R neurocircuitry in reward and motivation and the learning and memory processes that carry the encoding for associations between environmental cues and consumption of rewarding stimuli. A more complete preclinical evaluation of these questions will ultimately allow educated proof-of-concept trials to test the efficacy of selective 5-HT(2C)R agonists as adjunctive therapy in chronic health maladies including obesity, eating disorders and drug addiction.

Acute Yohimbine Increases Laboratory-Measured Impulsivity in Normal Subjects

BACKGROUND State-dependent changes in impulsivity may be related to norepinephrine. To examine possible relationships between norepinephrine and acute changes in impulsivity, we measured effects of yohimbine, which increases norepinephrine release by blocking alpha-2 noradrenergic receptors, on laboratory-measured impulsivity in healthy subjects without psychiatric or substance-use disorders. METHODS Impulsivity was assessed using the Immediate and Delayed Memory Tasks (IMT-DMT), derived from the Continuous Performance Test, before and after placebo or two doses of yohimbine, given 4 days apart. Blood pressure was monitored, and psychiatric symptoms were measured using self-rated visual analog scales. RESULTS Yohimbine was associated with a dose-related increase in impulsive IMT commission errors, with an increase of > 50% relative to baseline at the higher dose. The activation factor of the Internal State Scale was increased at the same dose. CONCLUSIONS These results are consistent with increased impulsivity in normal subjects given yohimbine, possibly related to increased norepinephrine.

Personality traits and vulnerability or resilience to substance use disorders

Clear evidence supports a genetic basis for substance use disorders (SUD). Yet, the search to identify individual gene contributions to SUD has been unsuccessful. Here, we argue for the study of endophenotypes within the frame of individual differences, and identify three high-order personality traits that are tied to specific brain systems and genes, and that offer a tractable approach to studying SUD. These personality traits, and the genes that moderate them, interact dynamically with the environment and with the drugs themselves to determine ultimately an individuals vulnerability or resilience to developing SUD.