# Presentation: 102561

## 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

## What is Impulsivity?

- Key concepts associated with impulsivity:
- Action
- Lack of planning
- Immediate or Rapid
- Potential for self-harm

## 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).**

## 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.

## Two Main Ways to Measure Impulsivity

- Self-report (questionnaire) Measures
- Barratt Impulsiveness Scale
-  Eysenck Impulsiveness Questionnaire

## 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

## 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

## 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)

## Are Stimulant Abusers More Impulsive?

- Amphetamine, Methamphetamine, MDMA
- Morgan et al., 2002 (MFFT)
- Moeller et al., 2002 (IMT/DMT) (BIS-11)

## Impulsivity, Antisocial Personality, and Aggression

- 49 Cocaine Dependent Subjects
- 25 Controls
- Examined relationship between impulsivity, aggression, and Antisocial Personality

## 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

- Impulsivity is Increased in Cocaine Users Independent of ASPD

- (Moeller et al., Drug and Alcohol Dependence 2002)

## 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

- 								Bechara et al., 2000

## Iowa Gambling Task in Cocaine Users

- 65 Subjects with current cocaine dependence
- 20 non-drug using controls

- Group effect p = 0.037

## “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)

## 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

## MDMA Users Also Show Increased Impulsivity

## 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?

##  Impulsivity in children and adolescence is associated with substance abuse.

-  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

## 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

## Conduct Disorder and Impulsivity

**IMT**

**DMT**

- Dougherty et al., 2003

## 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

## 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

## 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)

- Evidence that Stimulant Abuse Affects Brain Function

## Behavioral Output

- N.Acc

- VTA

- Prefrontal
- Cortex

- Amygdala

- Raphe

- GP-SN

- Adapted from Jentsch et al., 1999
- and Robbins and Everitt, 2002

- Brain stem Effectors

- Affect

- Enhanced Reinforcement of Cond. Stimulus

- Executive Control

## COCAINE

- N.Acc

- VTA

- Prefrontal
- Cortex

- Amygdala

- Raphe

- GP-SN

- Behavioral Output

- Adapted from Jentsch et al., 1999
- and Robbins and Everitt, 2002

- Brain stem Effectors

- Affect

- Enhanced Reinforcement of Cond. Stimulus

- Executive Control

- MDMA

## 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

## 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.

|  | MDMA | Controls |
| --- | --- | --- |
| N | 15 | 19 |
| Age | 24.7 + 3.4 | 25.4 + 6.0 |
| Gender | 12M   3F | 11M   8F |
| Lifetime MDMA Use | 193.5	+ 239.7 | 0 |
| Monthly MDMA Use | 6.5 + 4.9
 | 0
 |
| Days Since Use | 36.6 + 51.4 |  |

## 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

## 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

## fMRI in MDMA Users

## fMRI in MDMA Users

## fMRI in MDMA Users

## 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).

## 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?

## 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.

## 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.

## 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

## Slide 44

## Slide 45

## 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

## 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?

## Stimulant Abuse

- Genetic

- Environment

- Impulsivity

- Craving

## Research Team, Collaborators and Funding

- 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

- 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

- Funded By:
- National Institute on Drug Abuse
- R01-DA08425, R01-DA15345, K02-00403 (FGM)
- R01-MH61927, Dana Foundation Grant (JLS)