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Impaired Inhibitory Control Precursor or Consequence of Drug Abuse

Impaired Inhibitory Control Precursor or Consequence of Drug Abuse. Edythe D. London, Ph.D. elondon@mednet.ucla.edu , C8-528. Why Talk About Inhibitory Control in the Context of Drug Addiction?. I-RISA Syndrome of Drug Addiction. R.Z. Goldstein and N.D. Volkow, Am. J. Psychiatry 2002;159:1642.

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Impaired Inhibitory Control Precursor or Consequence of Drug Abuse

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  1. Impaired Inhibitory ControlPrecursor or Consequence of Drug Abuse Edythe D. London, Ph.D. elondon@mednet.ucla.edu, C8-528

  2. Why Talk About Inhibitory Control in the Context of Drug Addiction?

  3. I-RISA Syndrome of Drug Addiction R.Z. Goldstein and N.D. Volkow, Am. J. Psychiatry 2002;159:1642

  4. Circuits of Addiction reward prediction & core substrates of pleasure learning & memory main substrates of conditioning motivation, drive & salience cognitive control

  5. PART I • What do we mean by “inhibitory control deficits”? Impulsivity? • How are inhibitory control deficits related to impulsivity?

  6. Impulsivity: Inability to control behavior Personality Measure Related to Inhibitory Control ● psychopathic personality ● sociopathic personality ● ADHD● conduct disorder Measures: Barratt Impulsivity Scale Relevant scales of Personality Inventories: TPQ, Eysenck extroversion, venturesomeness, sensation-seeking

  7. Deficits in Inhibitory Control Operationally: Inability to Inhibit Pre-potent Responses ● motor control: (Go/No GO tasks, SST) ** ● cognitive control allocation of cognitive resources: focusing of attention (Stroop task) sustaining attention (CPT) ** shifting set (reversal learning, WCST) ** ●emotional control conscious & unconscious: reappraisal techniques (CBT) labeling tasks **animal tests possible

  8. Deficits in Inhibitory Control Risky Decision-Making ● Gambling Task ● Rogers Task ● Balloon Analogue Risk Task Delay Discounting

  9. O X Press the key shown on the display.

  10. O Stop Signal: Do not press key if a tone is heard.

  11. SSRT Stop-Signal Reaction Time Uninhibited RT 0 s 0.5 s 1 s

  12. What Circuitry Mediates Inhibitory Control?Effect of Lesions on Stop Signal Reaction Time Right VLPFC A. Aron et al. (2004): Trends Cogn Sci. 8:170.

  13. “Hyperdirect” Pathway Connects IFC and STN and Links to preSMA for Basal Ganglia Control A.R. Aron et al., J. Neurosci 2007;27:3743.

  14. SSRT is Related to D2/D3 Dopamine Receptors r = 0.592p = 0.033 r = 0.640p = 0.019 Ventral striatum Binding Potential for [F-18]Fallypride in Ventral Striatum Buyean Lee et al., unpublished

  15. SSRT is Correlated with Impulsivity aImpulsivity subscale of Extraversion Scale, Eysenck Personality Inventory ** p<0.01 (two-tailed) G.D. Logan et al. 1997; Psychol. Sci. 6:63.

  16. Stroop Task ZEBRA EYE HORSE PIN BUSH MOON ROPE KOALA PACK DOG PAT LAMB BALL TRAIN CAT APPLE FISH HAND Color naming without interference

  17. Stroop Task GREEN BLUE RED GREEN GREEN YELLOW YELLOW GREEN RED YELLOW GREEN RED YELLOW RED BLUE BLUE YELLOW GREEN Reading Color naming Incongruent/Interference

  18. Brain Activity Incongruent Minus Congruent

  19. Regulate negative emotions by activating PFC. PFC exerts inhibitory control.down-regulating amygdala activation Orbital PFC (green) Ventromedial PFC (red) Dorsolateral PFC Anterior Cingulate Amygdala Adapted from Davidson RJ et al., Science, 2000

  20. Conscious Emotion Control K. Baicy et al., Abstr. Soc. Neurosci, 2006

  21. PFC Modulates Amygdala Activation Amygdala activation while viewingevocative stimuli IFG activation during reappraisal t DECREASE > LOOK LOOK negative > neutral

  22. Please pick a card. A B C D

  23. You get $100! A B C D

  24. You must pay$125 A B C D

  25. BRAIN ACTIVATION BY GAMBLINGTASK OFC OFC + Amygdala -

  26. Visual Picture Discriminationand Reversal Learning Acquisition WGTA Retention Reversal

  27. Reversal Learning Set-Up

  28. Raclopride Impairs Reversal Learning Role of D2 Dopamine Receptors Reversal Errors Trials to Reach Criterion Perseverative Errors * vehicle raclopride vehicle raclopride vehicle raclopride vehicle raclopride B. Lee et al. Neuropsychopharmacology 2007

  29. PART Il What evidence indicates that addicted humans have deficits in inhibitory control? ● cognitive assessments ● structural brain imaging ● functional brain imaging

  30. Impairment on the Stop-Signal Task controlnonsmoker control smoker METH users Deficit in motor control is related to METH use. J. Monterosso et al., Drug Alcohol Depend., 2005

  31. Gray Matter Deficit in Lateral Cortex Deficit in right ventrolateral PFC in METH Abuse PM Thompson et al., J. Neurosci. 2004

  32. Affect Matching Task Which of the two bottom pictures matches the emotion shown on top?

  33. Methamphetamine Dependence Heightened Activation: Dorsal ACC METH > control Blunted Activation: Right Ventrolateral PFC Control > METH t t 3 4 3 2 2 1 1 0 0 P<.005, 10 voxel extent Dorsal ACC activity correlated with: ● hostility ● interpersonal sensitivity (n = 12/group) D Payer et al., manuscript in review 2007

  34. Negative Correlation of Right VLPFC and Dorsal ACC Activity r = -.516, p<.001 Control Dorsal ACC METH Right Ventrolateral PFC

  35. Drug Abusers Make a Higher Percentage of Risky ChoicesCorrelated with Activation of Right OFC While Making Risky Choices F= 4.4: p<.05 Percentage of Risky choices Control Drug Abuse DH Fishbein et al., Cogn. Brain Res. 2005; 23: 119:

  36. Drug Abusers have Structural as well as Functional Differences In PFC 90 Control Drug abuse 80 70 Volume (cm3) 60 50 Left (p < 0.001) Right (p < 0.005) 40

  37. Brain Structure is Genetically Controlled P. Thompson, UCLA, 2001

  38. PART IIIWhat came first? ● Animal studies: effects of drugs of abuseon inhibitory control ● Human studies: vulnerability to addiction

  39. Chronic PCP Produces Enhanced Responding for a Conditioned Reinforcer F (1,10)=10.70 **p = .01 ** Mean Lever Responses CR Lever NCR Lever CR Lever NCR Lever Saline PCP J.D. Jentsch & J. Taylor, Neuropsychopharmacology 2001;24:66

  40. AMPH Changes Dendritic Morphology in Nonhuman Primate PFC Layers II/Superficial III peak density along apical dendritic trunk AMPH-naïve Intermittent AMPH escalating dose, 6 or 12 wk 0.1-1 mg/kg, bid L.D. Selemon et al., Neuropsychopharmacology 2007;32:919

  41. Some Childhood Disorders Predict Substance Abuse ADHD Conduct Disorder 25 % No Conduct Disorder 75 % Substance Abuse 79 % No Substance Abuse 21 % Substance Abuse 40 % No Substance Abuse 60 % Biederman et al., 1995

  42. Adolescents with Behavior Disorders Show Impaired GT Performance ADULTS ADOLESCENTS

  43. Conclusion MoodDisorder  anxiety  depression Cognitive Deficits decision-makingresponse inhibition Inhibitory Control Problems Drug Abuse Inhibitory Control Problems (Impulsivity)

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