F. Gerard Moeller, M.D. Department of Psychiatry UTHSC-Houston

1. Neurobiological Changes Related to Impulsivity as a Consequence of and Added Risk Factor for Psychostimulant Abuse F. Gerard Moeller, M.D. Department of Psychiatry UTHSC-Houston

2. What is Impulsivity? • Key concepts associated with impulsivity: • Action • Lack of planning • Immediate or Rapid • Potential for self-harm

3. What is Impulsivity?A Bio-Psycho-Social Definition • A predisposition toward rapid, unplanned reactions to internal or external stimuli without regard to the negative consequences of these reactions to themselves or others (Moeller et al., Am J Psychiatry, 2001).

4. What Is Impulsivity? • Definition implies: • Predisposition (pattern of behavior) but can fluctuate. • Rapid (seconds to minutes). • Unplanned (different than poor judgment). • Without regard to risk (different than sensation seeking). • Act not performed for secondary gain.

5. Two Main Ways to Measure Impulsivity • Self-report (questionnaire) Measures • Barratt Impulsiveness Scale • Eysenck Impulsiveness Questionnaire

6. Two Main Ways to Measure Impulsivity • Behavioral Laboratory Measures • Punishment/Extinction Paradigms • Impulsivity is defined as the perseveration of a response which is punished or not reinforced • Reward-Directed Paradigms • Impulsivity is defined as preference for a smaller-sooner reward over a larger-later reward • Rapid-Decision Paradigms • Impulsivity is defined as either making premature or disinhibited responses Dougherty et al., 2003

7. Are Stimulant Abusers More Impulsive? • Cocaine Dependent • Increased questionnaire measured impulsivity relative to non-drug using controls • Rosenthal et al., 1990 • Moeller et al., 2001 • Patkar et al., 2002 • Moeller et al., 2002 • Coffey et al., 2003

8. Are Stimulant Abusers More Impulsive? • Cocaine Dependent • Behavioral laboratory measured impulsivity • Moeller et al., 2002 (Delayed-reward) • Fillmore and Rush, 2002 (Stop Signal Paradigm) • Coffey et al., 2003 (Hypothetical Delayed Discounting)

9. Are Stimulant Abusers More Impulsive? • Amphetamine, Methamphetamine, MDMA • Morgan et al., 2002 (MFFT) • Moeller et al., 2002 (IMT/DMT) (BIS-11)

10. Impulsivity, Antisocial Personality, and Aggression • 49 Cocaine Dependent Subjects • 25 Controls • Examined relationship between impulsivity, aggression, and Antisocial Personality

11. Measures • Barratt Impulsiveness Scale (BIS-11) Questionnaire • Delayed reward behavioral laboratory measure of impulsivity Choose between short-delay smaller monetary reward and longer-delay larger monetary reward • Life History of Aggression

12. Impulsivity is Increased in Cocaine Users Independent of ASPD Group Controls Non-ASPD Cocaine Users ASPD Cocaine Users LHA Aggression Score *, *** 8.0 + 5.6 11.5 + 5.5 17.5 + 5.4 BIS-11 Total Score *, **, *** 59.6 + 12.19 72.4 + 12.0 80.5 + 11.7 Short-delay (Impulsive) Choices *, **, *** 24.9 + 13.6 33.6 + 13.45 34.7 + 13.1 • (Moeller et al., Drug and Alcohol Dependence 2002)

13. Other Behavioral Laboratory Measures in Cocaine Dependent Subjects Iowa Gambling Task • Subjects Choose from 5 “decks” of cards • Total of 100 choices from decks • Two decks large short-term gain, long-term loss • Two decks smaller short-term gain, long-term gain • Patients with ventromedial prefrontal cortical lesions show altered pattern of response • Antoine Bechara 2000

14. Bechara et al., 2000

15. Iowa Gambling Task in Cocaine Users • 65 Subjects with current cocaine dependence • 20 non-drug using controls

16. Group effect p = 0.037

17. “Rapid Decision” Type Behavioral Paradigm Immediate and Delayed Memory Task Difficult version of the Continuous Performance Test (CPT) Measure of attention, memory, and impulsivity (Dougherty et al., 2002)

18. DMT IMT 25684 58914 25684 12345 39668 12345 58914 12345 Target match 56914 58914 Immediate & Delayed Memory Task • 22 minute session • series of 5-digit numbers appearing for 500 msec once per second • Respond when the number is identical to the preceding number • Immediate Memory Task • Delayed Memory Task Target match Novel no-match Catch trial Dougherty et al., 2000

20. MDMA Users Also Show Increased Impulsivity

21. Impulsivity is Elevated in Stimulant Abusers • Increased questionnaire measured and behavioral laboratory measured impulsivity • Both cocaine and MDMA abusers show increased impulsivity Is the increased impulsivity a precursor or a consequence of stimulant abuse?

22. Impulsivity in children and adolescence is associated with substance abuse. • Recent review of 22 studies of comorbidity • 60% of youths with substance abuse or dependence had comorbid diagnosis • Conduct disorder & oppositional defiant disorder most commonly associated with substance use or dependence. Armstrong and Costello, 2002

23. Conduct Disorder and Behavioral Laboratory Measured Impulsivity • Inpatients with conduct disorder and Oppositional Defiant Disorder (20 subjects) • Compared with healthy controls (20 subjects) • Immediate and Delayed Memory Task (IMT/DMT) as a behavioral laboratory measure of impulsivity

24. 0.7 0.6 0.5 0.4 Commission Errors/Correct Detections 0.3 0.2 0.1 0 Group Group Controls Patients DBD Conduct Disorder and Impulsivity DMT IMT Dougherty et al., 2003

25. Is Impulsivity a Consequence of Stimulant Abuse? • Acute effects of stimulants • Acutely stimulants increase DA and 5-HT • Several studies show decreased impulsivity in behavioral laboratory studies in animals and humans. • Stimulants decrease impulsive behavior in ADHD, CD

26. Is Impulsivity a Consequence of Stimulant Abuse? • Chronic effects of stimulants • Cocaine • Alters structure of neurons in prefrontal cortex and accumbens • Depletes brain 5-HT • Decreased D2 receptor availability • Is associated with ischemic and hemorrhagic strokes • High dose MDMA • Degenerates brain 5-HT nerve terminals

27. Is Impulsivity a Consequence of Stimulant Abuse? • Animal Studies Show Differential Behavioral Effect of Stimulants Based on: • Dose (Richards, Sabol, and de Wit, 1999) • Pattern of Administration (Chronic and Intermittent) (Jentsch et al., 2002, Taylor and Jentsch, 2001, Richards Sabal and de Wit, 1999) • Drug (Taylor and Jentsch, 2001)

28. Evidence that Stimulant Abuse Affects Brain Function

29. Behavioral Output Executive Control Brain stem Effectors Prefrontal Cortex GP-SN Affect N.Acc Amygdala VTA Enhanced Reinforcement of Cond. Stimulus Raphe Adapted from Jentsch et al., 1999 and Robbins and Everitt, 2002

30. Behavioral Output Executive Control Brain stem Effectors Prefrontal Cortex MDMA GP-SN Affect N.Acc Amygdala VTA Enhanced Reinforcement of Cond. Stimulus Raphe COCAINE Adapted from Jentsch et al., 1999 and Robbins and Everitt, 2002

31. Functional Magnetic Resonance Imaging (fMRI) • Method of examining changes in brain activation related to neuronal activity • Does not use ionizing radiation • Widely accepted tool to examine brain function during cognitive tasks in humans

32. fMRI in MDMA Users • Block Design comparing BOLD activation during Delayed Memory Task to Immediate Memory Task • Random Effects analysis using SPM99 • Hypothesis: MDMA users would show changes in BOLD activation compared to controls.

34. fMRI in MDMA Abusers STATISTICS: volume summary (p-values corrected for entire volume)===============================================cluster cluster cluster voxel voxel voxel voxelp(cor) equivk p(unc) p(cor) T equivZ p(unc) x,y,z {mm}--------------------------------------------------------------------------------0.004 382 0.000 0.998 4.04 ( 3.60) 0.000 9 51 150.000 847 0.000 0.999 4.02 ( 3.59) 0.000 15 -27 60.000 676 0.000 1.000 3.67 ( 3.33) 0.000 -27 -33 -3

35. fMRI in MDMA Users • Random Effects analysis showed MDMA users have increased BOLD activation during working memory task in: • Medial Superior Frontal Gyrus in vicinity of Broadman’s areas 9,10 • Pulvinar in thalamus extending into Putamen • Hippocampus

36. fMRI in MDMA Users

37. fMRI in MDMA Users

38. fMRI in MDMA Users

39. fMRI in MDMA Users • Increased BOLD fMRI activation seen in some previous studies in drug users (Lee et al., 2003) but not others (Kaufman et al., 2003). • Interpreted as possibly being due to: • Greater difference between resting blood flow and blood flow during task • Inefficient brain processing (Lee et al., 2003).

40. Impulsivity as a Consequence of Stimulant Abuse • Stimulant Abusers show increased impulsivity compared to non-drug using controls • Stimulants are known to affect areas of the brain which could have an impact on impulsivity • Stimulant abusers show changes in brain function on imaging studies What experimental evidence exists showing stimulants increase impulsivity?

41. MDMA and “Set Shifting” in Rats • Male Sprague Dawley rats trained to respond for food pellets in an operant task. • Initially, rats trained to respond on a signaled DRL (differential reinforcement of low rates) schedule.

42. MDMA and “Set Shifting” in Rats • After being trained, rats administered MDMA (8 mg/kg daily X4) or 1 ml/kg saline, followed by, a second regimen of MDMA (16 mg/kg daily X3) or saline • Finally, rats were tested for acquisition of unsignaled DRL performance.

43. MDMA and “Set Shifting” in Rats • Results: • Signaled DRL performance of MDMA and saline treated rats was not significantly different • When required to perform the task without external signal, MDMA rats showed a significant deficit in acquiring the unsignaled DRL • Appeared to be related to diminished withholding of premature responses

46. Summary • Impulsivity is increased in cocaine and MDMA abusers. • Impulsivity appears to be a risk factor for development of stimulant abuse. • Impulsivity is associated with changes in brain function, possibly related to chronic effects of stimulants • High dose MDMA causes long-term changes in brain function and behavior in rats

47. Questions that Remain • How much of the increased impulsivity seen in stimulant abusers is secondary to stimulant abuse? • Is MDMA use specifically related to changes in brain function and behavior in MDMA abusers? • What treatments can be used for impulsivity and associated stimulant abuse?

48. Environment Genetic Impulsivity Stimulant Abuse Craving

49. Impulsivity Ernest S. Barratt, Ph.D. Donald M. Dougherty, Ph.D. Alan C. Swann, M.D. Animal Studies Peter B. Silverman, Ph.D. Serotonin Measurement Louis Van de Kar, Ph.D. Brain Imaging Joel L. Steinberg, M.D. Ponnada Narayana, Ph.D. Khader Hasan, Ph.D. Perry Renshaw, M.D., Ph.D. Larry Kramer, M.D. Christian Fischer, M.D. Research Team, Collaborators and Funding

50. Treatment and Assessment John Grabowski, Ph.D. Joy M. Schmitz, Ph.D. Angie Stotts, Ph.D. John Overall, Ph.D. Howard Rhoades, Ph.D. Anthony Zamudio, R.N. Michelle Fingeret, M.S. Vivian Gonzales, M.S. Vanessa Salazar Research Team, Collaborators and Funding • Funded By: • National Institute on Drug Abuse • R01-DA08425, R01-DA15345, K02-00403 (FGM) • R01-MH61927, Dana Foundation Grant (JLS)