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

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

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

Wed Thursday FridaySaturday Sunday Training Sleep 5 In-Residence Sleep Deprivation Studies General Study Design

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

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

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

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

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

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

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

13 Total $$$: 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. Iowa Gambling Task

14 Risk Taking and Judgment WIN $100 Net: +$100 Total $$$: Iowa Gambling Task

15 Risk Taking and Judgment WIN $75 Total $$$: Iowa Gambling Task

16 Risk Taking and Judgment WIN $75 LOSE $50 Net: +$25 Total $$$: Iowa Gambling Task

17 Risk Taking and Judgment WIN $300 Net: +$300 Total $$$: Iowa Gambling Task

18 Risk Taking and Judgment WIN $500 Total $$$: Iowa Gambling Task

19 Risk Taking and Judgment WIN $500 LOSE $1200 Net: -$700 Total $$$: Iowa Gambling Task

20 Goal: Learn to choose good decks & avoid bad ones Risk Taking and Judgment NetLoss Good Decks Bad Decks NetWin NetWin NetLoss Iowa Gambling Task

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

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

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

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 Good Choices 49 Hours of Sleep Deprivation Mimics VMPFC Damage 24 Killgore et al., Journal of Sleep Research (2006) Iowa Gambling Task N = 34

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 Sleep deprived performance was very similar to that seen in patients with actual brain lesions to VMPFC Good Choices 49 Hours of Sleep Deprivation Mimics VMPFC Damage 25 Killgore et al., Journal of Sleep Research (2006) Iowa Gambling Task N = 34

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 Killgore et al., Aviation Space and Environmental Medicine (2007) 26 Iowa Gambling Task

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

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

Baseline: Normal Learning 23 Hrs Awake: Mild Impairment 46 Hrs Awake: Moderate Impairment Across 4 Test Sessions 46 Hours Sleep Deprived + Drug 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) 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) Iowa Gambling Task

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

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

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

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

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

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

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

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

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

Walter Reed Army Institute of Research Collaborators: Thomas J. Balkin Nancy J. Wesensten Gary H. Kamimori Nancy L. Grugle 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 McLean Hospital Harvard Medical School

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43 Future Directions / Challenges 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).

Humor Appreciation 44 Humor appreciation is one of the most complex cognitive capacities Goel & Dolan (2001) Ventromedial Prefrontal Cortex Thomas et al., 2000 Active Joke is “Funny” Sleep Deprived Inactive

Humor Appreciation 45 Cartoons Newspaper Headlines What’s so Funny… Killgore et al., Sleep (2006)

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

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

Wed Thursday FridaySaturday Sunday Training Sleep Minor Lapses (0.5 to 3 seconds) Killgore et al., Journal of Sleep Research (2008) 48

Wed Thursday FridaySaturday Sunday Training Sleep Major Lapses (≥ 3 seconds) Killgore et al., Journal of Sleep Research (2008) 49

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

Self Control Danger SeekingEnergy Impulsivity Invincibility * * Interaction: F 2,22 = 5.19, P =.01 Placebo: Main Effect, P =.006 Caffeine: Main Effect, P =.04 Evaluation of Risks Scale—EVAR