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Walter Reed Army Institute of Research (WRAIR) McLean Hospital, Harvard Medical School

The Effects of Stimulant Countermeasures on Executive Functioning and Decision-Making During Sleep Deprivation. William D. S. Killgore, Ph.D. Walter Reed Army Institute of Research (WRAIR) McLean Hospital, Harvard Medical School. Hypotheses.

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Walter Reed Army Institute of Research (WRAIR) McLean Hospital, Harvard Medical School

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  1. The Effects of Stimulant Countermeasures on Executive Functioning and Decision-Making During Sleep Deprivation William D. S. Killgore, Ph.D. Walter Reed Army Institute of Research (WRAIR) McLean Hospital, Harvard Medical School

  2. Hypotheses Reduced metabolic activity will lead to deficits in “executive functioning” including planning, judgment, and decision-making Modified from Thomas et al. (2000)

  3. Hypotheses Reduced metabolic activity will lead to deficits in “executive functioning” including planning, judgment, and decision-making Stimulants may “activate” these areas and “reverse” these deficits Modified from Thomas et al. (2000) 3

  4. Hypotheses Reduced metabolic activity will lead to deficits in “executive functioning” including planning, judgment, and decision-making Stimulants may “activate” these areas and “reverse” these deficits or Stimulants may activate other areas involved in alertness, while leaving prefrontal areas and associated executive functions degraded Modified from Thomas et al. (2000) 4

  5. Sleep Sleep General Study Design In-Residence Sleep Deprivation Studies Sunday Friday Saturday Thursday Wed Training 2400 2400 2400 2400 1200 1200 1200 1200

  6. Sleep Sleep Executive Function Test Battery Dorsolateral Prefrontal Cortex 44 HOURS Caffeine 600 mg D-AMPH 20 mg Modafinil 400 mg Placebo 3:00 AM Sunday Friday Saturday Thursday Wed Training 2400 2400 2400 2400 1200 1200 1200 1200 6 Killgore et al., Journal of Sleep Research (2008)

  7. Wisconsin Card Sorting Test Match each card to the appropriate “key” card: WRONG! RIGHT! Concept Formation, Set Shifting, & Mental Flexibility

  8. Wisconsin Card Sorting Test Perseverative Errors (T-Score) Better Age Norm Worse Modafinil significantly improved WCST performance (i.e., reduced perseveration during sleep deprivation) relative to other stimulants or placebo. Killgore et al., Sleep (2009)

  9. Tower of Hanoi Number of Moves Time to Solve Planning & Sequencing

  10. Tower of London Goal Your Tower Number of Moves beyond Optimal Time Before Each Move Total Time Planning & Sequencing

  11. Stimulant Effects: TOH & TOL Tower of London Tower of Hanoi p < .05 Below Average Impaired Below Average Average Average Total Moves Total Moves Mean Pickup Time Mean Pickup Time Killgore et al., Sleep (2009)

  12. Two Different Executive “Brain Systems” Dorsolateral vs. Ventromedial Ventromedial Dorsolateral Behavioral Inhibition Planning Working Memory Mental Control Attention Set-Shifting Affective Processing Reward/Punishment Learning 12

  13. Iowa Gambling Task Total $$$: -300 -100 300 500 400 -200 0 100 200 Choose cards from any deck and switch as often as you like. Try to win as much money as possible. Some decks are “worse” than others. You will win the game if you avoid the worst decks.

  14. Iowa Gambling Task Total $$$: -300 -100 300 500 400 -200 0 100 200 WIN $100 Net: +$100 Risk Taking and Judgment

  15. Iowa Gambling Task Total $$$: -300 -100 300 500 400 -200 0 100 200 WIN $75 Risk Taking and Judgment

  16. Iowa Gambling Task Total $$$: -300 -100 300 500 400 -200 0 100 200 WIN $75 LOSE $50 Net: +$25 Risk Taking and Judgment

  17. Iowa Gambling Task Total $$$: -300 -100 300 500 400 -200 0 100 200 WIN $300 Net: +$300 Risk Taking and Judgment

  18. Iowa Gambling Task Total $$$: -300 -100 300 500 400 -200 0 100 200 WIN $500 Risk Taking and Judgment

  19. Iowa Gambling Task Total $$$: -300 -100 300 500 400 -200 0 100 200 WIN $500 LOSE $1200 Net: -$700 Risk Taking and Judgment

  20. Iowa Gambling Task Goal: Learn to choose good decks & avoid bad ones Net Loss Net Loss Net Win Net Win Bad Decks Good Decks Risk Taking and Judgment 20

  21. Iowa Gambling Task Damage to Ventromedial Prefrontal Cortex Impairs Emotional Decision Making Ventromedial Prefrontal Lesion (n = 5) Normal Controls (n = 13) Good Decks Bad Decks Bad Decks Good Decks Bechara et al., 1999 Bechara, Damasio, & Damasio, 2000

  22. Bechara, Damasio, & Damasio, 2000 Thomas et al., 2000 VMPFC Lesions Sleep Deprivation Iowa Gambling Task Similar Impairment? We predict a similar pattern of impaired decision-making performance… 22

  23. Iowa Gambling Task 49 Hours of Sleep Deprivation Mimics VMPFC Damage Good Choices At rested baseline, participants learn to avoid risky choices Bad Choices N = 34 23 Killgore et al., Journal of Sleep Research (2006)

  24. Iowa Gambling Task 49 Hours of Sleep Deprivation Mimics VMPFC Damage Good Choices At rested baseline, participants learn to avoid risky choices When sleep deprived, these same participants failed to learn to avoid risky choices—actually preferring to choose from the worst decks Bad Choices N = 34 24 Killgore et al., Journal of Sleep Research (2006)

  25. Iowa Gambling Task 49 Hours of Sleep Deprivation Mimics VMPFC Damage Good Choices At rested baseline, participants learn to avoid risky choices When sleep deprived, these same participants failed to learn to avoid risky choices—actually preferring to choose from the worst decks Sleep deprived performance was very similar to that seen in patients with actual brain lesions to VMPFC Bad Choices N = 34 25 Killgore et al., Journal of Sleep Research (2006)

  26. Iowa Gambling Task 49 Hour Study (n = 34) 75 Hour Study (n = 23) Sleep loss affects emotional decision making in a dose-dependent manner Less sleep = poorer decisions 26 Killgore et al., Aviation Space and Environmental Medicine (2007)

  27. Iowa Gambling Task Caffeine (n = 12) vs. Placebo (n = 11) 75 Hours Awake 51 Hours Awake Caffeine was not significantly better than placebo at enhancing decision-making, suggesting that it may have little effect on VMPFC regions 27 Killgore et al., Aviation Space and Environmental Medicine (2007)

  28. Iowa Gambling Task Caffeine (600 mg), D-AMPH (20 mg), Modafinil (400 mg), vs. Placebo Across 4 Test Sessions Baseline: Normal Learning 28 Killgore et al., Sleep (2006)

  29. Iowa Gambling Task Caffeine (600 mg), D-AMPH (20 mg), Modafinil (400 mg), vs. Placebo Across 4 Test Sessions Baseline: Normal Learning 23 Hrs Awake: Mild Impairment 29 Killgore et al., Sleep (2006)

  30. Iowa Gambling Task Caffeine (600 mg), D-AMPH (20 mg), Modafinil (400 mg), vs. Placebo Across 4 Test Sessions 46 Hours Sleep Deprived + Drug Baseline: Normal Learning 23 Hrs Awake: Mild Impairment 46 Hrs Awake: Moderate Impairment Sleep deprivation impaired decision making abilities. These deficits were not reversed by dextroamphetamine, caffeine, or modafinil at doses sufficient to restore alertness and vigilance. 30 Killgore et al., Sleep (2006)

  31. Iowa Gambling Task Caffeine (600 mg), D-AMPH (20 mg), Modafinil (400 mg), vs. Placebo Across 4 Test Sessions Post Recovery: Normal Learning 31 Killgore et al., Sleep (2006)

  32. 5 Balloon Analog Risk Task—BART Win money for each pump…but don’t pop the balloon: Risk Taking and Judgment

  33. 5 Balloon Analog Risk Task—BART Win money for each pump…but don’t pop the balloon: Risk Taking and Judgment 33

  34. 5 Balloon Analog Risk Task—BART Win money for each pump…but don’t pop the balloon: Risk Taking and Judgment

  35. 5 Balloon Analog Risk Task—BART Win money for each pump…but don’t pop the balloon: Risk Taking and Judgment

  36. 5 Balloon Analog Risk Task—BART Win money for each pump…but don’t pop the balloon: POW Risk Taking and Judgment

  37. 5 Balloon Analog Risk Task—BART Win money for each pump…but don’t pop the balloon: Risk Taking and Judgment

  38. Correlates with: Sensation Seeking Impulsivity Disinhibition Risk Taking Addictive Behavior Balloon Analog Risk Task—BART Win money for each pump…but don’t pop the balloon: $0.10 $0.05 $4.65 $6.55 $5.20 $2.25 $0.30 $3.80 $7.95 $1.50 $0.90 5 Risk Taking and Judgment

  39. Balloon Analog Risk Task—BART Release of Inhibition? More Risk • Placebo: • No effect of sleep loss at 51 hours • Significant disinhibition at 75 hours P = .01 • Caffeine: • No significant difference from placebo at 51 hours P = .02 • Performance sustained across 51 and 75 hours of wakefulness Less Risk Differs from IGT – Suggests an “unfolding” of behavioral processes: Decision-Making Impaired Early – Inhibition Impaired Later Inhibition Sustained by Caffeine Killgore et al., Sleep (2009)

  40. Conclusions Does Sleep Deprivation Impair Executive Functioning/Decision Making? Do Stimulants Reverse the Deficits? Conclusion Yes—On Some Tasks Sometimes— Sleep Loss May Affect some Prefrontal Systems More than Others All Stimulants were Effective for PVT Particularly those involving Ventromedial PFC Systems (IGT; BART) Stimulants may restore some aspects of functioning while leaving others impaired Not Effective for Emotion Based Ventromedial Tasks Minimal Effects on Dorsolateral PFC Systems (WCST; TOH; TOL) Differential Effects on Dorsolateral Tasks 40

  41. Walter Reed Army Institute of Research McLean Hospital Harvard Medical School Collaborators: Thomas J. Balkin Nancy J. Wesensten Gary H. Kamimori Nancy L. Grugle Email: killgore@mclean.harvard.edu The opinions expressed are those of the author and do not reflect the official position of the U.S. Army, DoD, or any of the institutions with which the author may be affiliated. 41

  42. Sleep Deprivation and Judgment/Decision-Making: How does sleep loss affect the ability to control/modulate affect? Stimulant Countermeasures: Are there novel stimulants or combinations of stimulants that might prove more effective at reversing deficits in judgment and decision-making? Individual Differences: Role of social stimulation and its interaction with individual traits (e.g., introversion/extraversion) on the ability to resist sleep loss Individual differences in baseline levels of brain chemistry that might be predictive of the ability to resist sleep loss (e.g., GABA, glutamate). Future Directions / Challenges

  43. Thomas et al., 2000 Humor Appreciation Joke is “Funny” Goel & Dolan (2001) Active Ventromedial Prefrontal Cortex Sleep Deprived Inactive Humor appreciation is one of the most complex cognitive capacities

  44. Humor Appreciation Cartoons Newspaper Headlines What’s so Funny… Killgore et al., Sleep (2006)

  45. Verbal Norm Visual Norm Caffeine (600 mg) was ineffective at restoring humor appreciation after 49.5 hours of sleep deprivation Killgore et al., Sleep (2006)

  46. Sleep Sleep Sleep Psychomotor Vigilance Psychomotor Vigilance Speed (1/RT*1000) Sunday Friday Saturday Thursday Wed Training 2400 2400 2400 2400 1200 1200 1200 1200 47 Killgore et al., Journal of Sleep Research (2008)

  47. Sleep Sleep Sleep Minor Lapses (0.5 to 3 seconds) Sunday Friday Saturday Thursday Wed Training 2400 2400 2400 2400 1200 1200 1200 1200 48 Killgore et al., Journal of Sleep Research (2008)

  48. Sleep Sleep Sleep Major Lapses (≥ 3 seconds) Sunday Friday Saturday Thursday Wed Training 2400 2400 2400 2400 1200 1200 1200 1200 49 Killgore et al., Journal of Sleep Research (2008)

  49. Balloon Analog Risk Task—BART Scoring Method: COST / BENEFIT RATIO COST = % of Popped Balloons (Lost Opportunity) (10 Pops / 30 Balloons) = 33% BENEFIT = % of Max Possible Money Won ($45 Won / $94.50 Possible) = 48% = .69 33% Cost / Benefit Ratio = /48%

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