5
Sustaining Soldier Performance

Recent technological breakthroughs provide quantitative physiological metrics of human attentiveness, performance, and neural functioning to gauge cognitive fitness and degradation to below an individual’s baseline performance optimum. Advances in neuroscientific knowledge, coupled with these technology breakthroughs, are suggesting approaches to counteracting a range of stressors that soldiers confront in operational environments. Among these are: metabolic stressors such as dehydration, sleep deprivation, fatigue, and pain; physiological stressors such as injury and trauma; and psychological stressors such as emotional trauma.1

This chapter discusses neuroscience advances aimed at sustaining soldier performance before, during, and after battle. Two recurring themes emerge from the committee’s presentation here of recent relevant research findings and opportunities for the Army to enhance its current soldier sustainment activities. First, stresses on the soldier affect both mind and body—the brain and the traditional somatic systems and organs. Complex interactions between neurophysiological and conventional physiological responses to a stressor contribute to the degradations of performance that occur during sustained and intense operations. The same brain–body interactivity holds for identifying and using countermeasures to sustain performance despite those stressors.

The second recurring theme covered in this chapter extends a theme found as well in Chapters 3, 4, 6, and 8: the growing importance of individual variability in all of the areas where neuroscience can contribute to Army applications. In this chapter, the insight to take away is that individuals differ markedly in their response to the various stressors described here, just as they differ in their optimal baseline performance, against which degradation due to stressors should be compared. Individuals differ as well in their response to a countermeasure or intervention intended to mitigate a performance deficit, including the extent to which they are helped by a particular intervention or experience undesirable side effects from it.

Finally, parts of the discussion here extend the usual concept of sustainment as it is typically understood in the Army community. That community generally views the time frame for sustainment in terms of the duration of a single extended operation or action—typically up to 96 hours. The performance deficits discussed here often occur during or soon after a single extended operation (the usual time frame for sustainment), but other deficits affect performance over longer time frames of weeks, months, and even years. These longer times are typically associated with Army concepts such as individual soldier resiliency and, at the unit level, recovery and reset. In a sense, then, this chapter covers soldier resiliency and its implications for unit recovery and reset, as well as the sustainment of performance through an entire operation.

MEASURES TO COUNTER PERFORMANCE DEGRADATION

Knowledge of how the body and brain function can serve to counter degradations in performance resulting from physiological and neurophysiolocical stressors. The operational performance of soldiers will benefit from research to develop effective nutritional as well as pharmacological and therapeutic countermeasures to performance degradation from fatigue, sleep deprivation, and other metabolic stressors.

Fatigue

Fatigue is typically described as a failure of performance with time on task; however, its causes are multiple and complex, including muscle overuse, loss of motivation, circadian disruption, poor nutrition, or depression. Both cen-

1

The committee notes that such psychological stressors are discussed as degradations of performance in Chapter 5. In general, however, the committee considers them (as in Chapters 3 and 4) to be psychological factors, without regard to how they may or may not affect performance on either a group-averaged or individual basis.



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5 sustaining soldier Performance Recent technological breakthroughs provide quantitative stressors should be compared. Individuals differ as well in physiological metrics of human attentiveness, performance, their response to a countermeasure or intervention intended and neural functioning to gauge cognitive fitness and degra- to mitigate a performance deficit, including the extent to dation to below an individual’s baseline performance opti- which they are helped by a particular intervention or experi- mum. Advances in neuroscientific knowledge, coupled with ence undesirable side effects from it. these technology breakthroughs, are suggesting approaches Finally, parts of the discussion here extend the usual to counteracting a range of stressors that soldiers confront concept of sustainment as it is typically understood in the in operational environments. Among these are: metabolic Army community. That community generally views the time stressors such as dehydration, sleep deprivation, fatigue, and frame for sustainment in terms of the duration of a single pain; physiological stressors such as injury and trauma; and extended operation or action—typically up to 96 hours. The psychological stressors such as emotional trauma.1 performance deficits discussed here often occur during or This chapter discusses neuroscience advances aimed soon after a single extended operation (the usual time frame at sustaining soldier performance before, during, and after for sustainment), but other deficits affect performance over battle. Two recurring themes emerge from the committee’s longer time frames of weeks, months, and even years. These presentation here of recent relevant research findings and longer times are typically associated with Army concepts opportunities for the Army to enhance its current soldier such as individual soldier resiliency and, at the unit level, sustainment activities. First, stresses on the soldier affect recovery and reset. In a sense, then, this chapter covers both mind and body—the brain and the traditional somatic soldier resiliency and its implications for unit recovery and systems and organs. Complex interactions between neuro- reset, as well as the sustainment of performance through an physiological and conventional physiological responses to entire operation. a stressor contribute to the degradations of performance that occur during sustained and intense operations. The measures To couNTer same brain–body interactivity holds for identifying and PerFormaNce deGradaTioN using countermeasures to sustain performance despite those stressors. Knowledge of how the body and brain function can serve The second recurring theme covered in this chapter to counter degradations in performance resulting from physi- extends a theme found as well in Chapters 3, 4, 6, and ological and neurophysiolocical stressors. The operational 8: the growing importance of individual variability in all performance of soldiers will benefit from research to develop of the areas where neuroscience can contribute to Army effective nutritional as well as pharmacological and thera- applications. In this chapter, the insight to take away is that peutic countermeasures to performance degradation from individuals differ markedly in their response to the various fatigue, sleep deprivation, and other metabolic stressors. stressors described here, just as they differ in their optimal baseline performance, against which degradation due to Fatigue Fatigue is typically described as a failure of perfor- 1The committee notes that such psychological stressors are discussed as degradations of performance in Chapter 5. In general, however, the com - mance with time on task; however, its causes are multiple mittee considers them (as in Chapters 3 and 4) to be psychological factors, and complex, including muscle overuse, loss of motivation, without regard to how they may or may not affect performance on either a circadian disruption, poor nutrition, or depression. Both cen - group-averaged or individual basis. 

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 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS tral nervous system (CNS) and peripheral (muscle) factors just now beginning to be unraveled. Good evidence is emerg- contribute to the onset of fatigue during prolonged physical ing that demonstrates how important a role the CNS plays in exertion. However, the neurophysiological basis of CNS the processes of fatigue. fatigue is not understood. There has been little systematic Unfortunately, advances in understanding fatigue and its neuroscience research into the causes of CNS fatigue and consequences for performance have been held back because potential countermeasures to it. Given the ever-increasing physiologists almost exclusively study peripheral factors mental demands on today’s warfighter, along with emerging in fatigue (e.g., those that involve muscle, heart, or blood) evidence showing the potential for nutrition to reduce CNS in isolation from CNS involvement, whereas psychologists fatigue during sustained periods of physical and mental exer- study mental factors (e.g., cognition, mood, vigilance, sleepi- tion, there is much to be gained by applying neuroscience ness) in isolation from peripheral interactions. Although research to improve warfighter performance. At a minimum, mind and body are inextricably linked in the onset and the tools should include functional magnetic resonance imag- consequences of fatigue, there has been very little focus on ing (fMRI), transcranial magnetic stimulation, more sophisti- the neurophysiological basis of the complex interactions cated behavioral studies in humans, and basic neurochemical between the brain and peripheral factors. and physiological assessments in rodents.2 Nowhere is an understanding of the biological mecha- Good evidence is emerging to suggest that CNS fatigue nisms by which the CNS and peripheral factors in fatigue may be caused, in part, by reduced availability of glucose, interact more important than in sustaining today’s soldiers. the main energy source for the brain, and/or an imbalance The increased speed, complexity, and lethality of modern of neurotransmitters/neuromodulators, including serotonin, warfare make it even more important than in the past to dopamine, adenosine, and ammonia. Under some circum- understand how to sustain or enhance physical and cogni- stances, an increase of inflammatory cytokines and elevated tive performance. It is also important to maintain mood and brain temperature could also play a role (Bautmans et al., motivation as the foundation of both physical and mental 2008; Miller, 2009). performance. Without such an understanding, it will be dif- Carbohydrate and/or caffeine feedings during exer- ficult to move past outdated strategies such as nutrition and cise are the most well-established nutritional strategies exercise training to offset muscle-specific fatigue or caffeine u sed to delay both physical and mental fatigue. Less to maintain wakefulness. This section presents a working i nformation is available on promising new nutritional model of the factors associated with fatigue during sustained strategies such as tyrosine supplementation, which has periods of physical and mental exertion. It then briefly been shown to benefit mental performance in military- reviews emerging evidence of the neurobiological basis of specific situations, and novel food and spice extracts and fatigue. This new understanding, along with the likelihood phytochemicals derived from traditional medicines like that nutrition can play an important role in mitigating CNS quercetin and curcumin. Phytochemicals may work by fatigue, can provide the foundation for what should become virtue of their antioxidant and anti-inflammatory activity an area of emphasis in neuroscience research and applica- as well as their ability to provide sustained energy within tions relevant to soldier performance. the brain and muscle. Although claims of enhanced mental A working model of the factors involved in fatigue is performance during long periods of physical or mental shown in Figure 5-1. Fatigue results from mental and physi- stress are made for a range of nutritional supplements, cal factors that ultimately increase the conscious perception including branched-chain amino acids (BCAAs), ginseng, of fatigue and the impairment of mental and physical perfor- ginkgo biloba, and choline, there is little scientific support mance. Physical performance requires not only the capacity for these claims. of muscle to maintain its force production but also adequate The development of fatigue during sustained periods of motivation or effort, mental alertness, clarity of thought, physical and mental stress is a complex and poorly under- decision-making ability, and mood (Davis and Bailey, 1997; stood phenomenon. During prolonged exercise, many fac- Davis, 2000). Neural processes, including higher-level cog- tors contribute to the production and onset of fatigue. These nitive processing, are important components of the fatigue factors can operate peripherally—that is, in the muscles— state, whose symptoms at onset include decreased energy, most importantly through depletion of the intramuscular motivation, arousal, and vigor, as well as increased tiredness, carbohydrate stores and/or through inhibition of adenosine perception of effort, and force sensation. These feelings of triphosphate (ATP) hydrolysis due to the accumulation of fatigue almost always occur before the muscle actually loses metabolic waste products such as phosphates and hydrogen the ability to maintain the required force or power output ions (Davis and Fitts, 1998). They also act centrally in the (Hampson et al., 2001). Although highly trained individuals brain, but the physiological mechanisms of CNS fatigue are (e.g., superathletes) can persevere for longer in a fatigued state through motivation and willpower, more generally an individual’s perception that he or she can persevere and 2Animal studies are necessary to gain understanding of neurobiological perform as well in a fatigued state as when well rested is not mechanisms of fatigue to a degree that is not possible using human borne out by objective measures of cognitive performance. trials.

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 SUSTAINING SOLDIeR PeRfORMANCe COMPONENTS OF FATIGUE Peripheral factors Brain (central) factors Mental fatigue Impaired central drive Metabolic and • Decreased energy, motivation, • Dire ct inhibition of mechanical arousal, and vigor impairments corticospinal output • Impaired motor control • Increased tiredness and depression in muscle • Increased perception of effort • Increased force sensation • Impaired cognitive function: poor concentration, decision making Decreased mental and Decreased Decreased physical performance mental function physical function FIGURE 5-1 Schematic diagram illustrating the likely interactions between central and peripheral components of fatigue. SOURCE: Committee-generated. 5-1 Figure As fatigue approaches, concentration and decision- (3) elevated brain temperature. One hypothesis is that CNS making abilities often become impaired. There is also good fatigue occurs during prolonged periods of intense physi- evidence of direct impairments in central drive to the muscles ological and psychological stress as a result of increased and of impairments of motor coordination (Gandevia, 2001; metabolic and oxidative stress in highly active brain regions, Smith et al., 2007; Reis et al., 2008). All these factors are decreased availability of glucose, either delivered by the particularly important for today’s soldiers, who must have blood or derived from brain glycogen, and increased levels good decision making, vigilance, mood, and motivation in the brain of 5-hydroxytryptamine (5-HT), coupled with a for mission success. Maintaining these factors for extended decrease in brain dopamine and increases in brain adenosine periods of time in harsh environments and at high levels of and ammonia. Under certain circumstances, CNS fatigue physiological and psychological stress is essential for sol- could also come from increased inflammatory cytokines and diers to perform optimally despite these stressors. elevated brain temperature (Bautmans et al., 2008). New evidence from fMRI and transcranial magnetic Carbohydrate: Fuel for the Brain The brain is protected imaging have begun to provide a better understanding of the neural correlates of fatigue (Gandevia, 2001; Cook et al., by the blood-brain barrier, which selectively allows transport 2007; van Duinen et al., 2007; Reis et al., 2008). However, of important nutrients into the brain. However, glucose is these studies have not been applied to whole-body exercise essentially the brain’s only fuel source. The exercise-induced during sustained periods of physiological and psychological reduction in blood glucose and in muscle and liver glycogen stress. can contribute greatly to muscle-specific fatigue, but carbohy- drate depletion is an even greater problem for the brain, which stores very little glycogen (Evans and Amiel, 1998). Although Neurophysiological Basis of CNS Fatigue glucose availability has traditionally been thought to remain Very little neuroscience research has focused on the relatively constant throughout the brain under most conditions possible biological basis of CNS fatigue. However, recent when adequate blood glucose is maintained (Robinson and evidence suggests testable hypotheses about the factors Rapoport, 1986), recent research suggests that the brain’s u nderlying CNS fatigue. These factors include (1) an glucose supply is compartmentalized. As glucose supply and inadequate supply of energy (glucose), (2) an imbalance demand change, concentrations change frequently in some among several neurotransmitters/neuromodulators, and areas but not in others (McNay et al., 2001).

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8 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS Altering brain glucose availability can affect both physi- of behavioral changes whose goal is to hasten recovery. Interleukin-1β, a potent proinflammatory cytokine and one cal and mental performance. For example, Koslowski et al. (1981) showed that glucose infusion into the carotid artery of the first cytokines upregulated during an inflammatory delayed fatigue in dogs during treadmill exercise. McNay et response, can initiate a host of sickness symptoms, known al. (2000) found that performance of demanding cognitive as sickness behavior, which include poor appetite, changes tasks reduced tissue glucose availability in a specific region in sleeping patterns, reduced interest in environment, and, of the brain (hippocampus) that is very active during mental most important, profound fatigue (Dantzer and Kelley, 1989). Fatigue may be initiated by interleukin-1β produced functions, even though blood glucose was well maintained. They also showed that intravenous infusion of glucose by toxins or disuse damage in the peripherial system, but blocked the decrease in glucose in the hippocampus and it is now known that these cytokines are also expressed in improved performance of the cognitive task. Evidence from the brain (Allan et al., 2001). And it is in the brain that they human studies also shows important benefits of carbohydrate produce their potent behavioral effects (Kent et al., 1992). Whether peripherally released interleukin-1β enters the brain supplementation for mental function, including perceived exertion, vigilance, and mood (Lieberman et al., 2002; Nybo, or transmits its inflammatory signal to the brain via afferent 2003). Recent elegant studies in humans provide direct evi- nerves (e.g., the vagus nerve) to initiate fatigue is still under dence for the important role cerebral carbohydrate availabil- investigation. However, in various inflammatory models, including exercise-induced muscle damage, interleukin-1β- ity and energy turnover play in physical performance during prolonged exercise (Nybo et al., 2003a, 2003b). induced behavioral effects, including fatigue, can be blunted by a brain-administered interleuken-1 receptor antagonist, Adenosine, Ammonia, and Dopamine Increased meta- which indicates that the brain is the origin of interleukin- 1β-induced fatigue (Bluthe et al., 1997; Carmichael et al., bolic stress and decreased glucose availability can lead to an increase in brain levels of adenosine and ammonia. 2006). A denosine is a product of the breakdown of ATP, the body’s most important energy molecule. Increased levels Nutritional Measures to Counter the Effects of Fatigue of adenosine in the brain have been linked to tiredness and sleep (Huston et al., 1996; Porkka-Heiskanen et al., 1997; An interesting and exciting aspect of this understand- Porkka-Heiskanen, 1999). ing of CNS fatigue is the growing scientific evidence that Plasma ammonia concentration can become markedly suggests nutrition may be effective in preventing or at least elevated during prolonged strenuous exercise. Ammonia can delaying these responses in the brain. easily penetrate the blood-brain barrier and is toxic to the Branched-Chain Amino Acids Newsholme et al. (1987) brain. It has been proposed that increased levels of circulat- ing ammonia may play a role in CNS fatigue (Banister and laid the foundation for one of the first nutritional strategies Cameron, 1990; Davis and Bailey, 1997). Direct evidence of to delay CNS fatigue. He reasoned that dietary supplementa- exercise-induced increases in brain ammonia and impaired tion of the BCAAs valine, leucine, and isoleucine could delay brain function was shown in rats by Guezennec et al. (1998) CNS fatigue by offsetting the increase in the ratio of free and, more recently, in humans by Nybo et al. (2005). The tryptophan (another amino acid) to BCAA, thereby prevent- latter study found a good association between arterial ing the typical increase in uptake of tryptophan by the brain ammonia concentration, brain uptake of ammonia, cerebral during exercise. Limiting tryptophan access would decrease spinal fluid (CSF) ammonia concentration, and perceived 5-hydoxytryptamine (5-HT) synthesis. Although adminis- exertion during prolonged exercise in human subjects. tration of BCAA in rats prolonged the time to exhaustion A high concentration of brain dopamine is associated (Yamamoto and Newsholme, 2000), positive effects of BCAA with energetic mood, arousal, motivated behaviors, and ingestion on exercise performance in humans are largely movement initiation. Control of dopamine is responsible for unsubstantiated (van Hall et al., 1995; Strüder et al., 1996; the effects of many stimulants such as caffeine and ephedrine Davis et al., 1999; Davis, 2000; Lieberman, 2003; Cheuvront (Davis, 2000). Dopamine levels in the brain initially increase et al., 2004). during endurance exercise and then decrease at the point of Although physical performance in humans is appar- fatigue (Bailey et al., 1993). Through various modulatory ently not influenced by BCAA ingestion, a few studies interactions, increases in serotonin and adenosine play roles have reported benefits for cognitive performance and mood. in decreasing dopamine levels (Fredholm et al., 1999; Davis, These benefits include improved effort during postexercise 2000). p sychometric testing (Strüder et al., 1998), improved postexercise Stroop Colour-Word test scores (Hassmèn et Brain Inflammation, Interleukin-1 β , and Fatigue al., 1994; Blomstrand et al., 1997), maintained performance Cytokines are an important link between the immune system in postexercise shape-rotation and figure-identification tasks inflammatory responses and CNS fatigue. During times (Hassmèn et al., 1994), and less perceived exertion during of inflammation, this cross-talk enables the development exercise (Blomstrand et al., 1997). However, Cheuvront

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9 SUSTAINING SOLDIeR PeRfORMANCe et al. (2004) reported no significant differences in mood, also lessen the increase in brain ammonia, which is toxic to perceived exertion, or cognitive performance with BCAA the brain (Nybo et al., 2005). supplementation. Similarly, infusion of a saline solution Greater glucose availability in the blood lessens the containing BCAA had no effect on perceived exertion during concentration of fatty acids in the blood, which in turn blunts 90-minute treadmill runs (Strüder et al., 1996). The com- the typical increase in free tryptophan available for transport mittee believes that there is not enough evidence so far to into the brain and presumably attenuates the increase in brain recommend BCAA supplementation to delay brain fatigue. serotonin that is typically associated with tiredness, lethargy, An important concern here is the well-characterized increase depression, and low arousal (Davis et al., 1992; Bequet et in ammonia production and the brain dysfunction that can al., 2002; Blomstrand et al., 2005). Lowered serotonin and occur when large BCAA doses are ingested during exercise adenosine combine to combat the drop in brain dopamine as (van Hall et al., 1995). In addition, acute tryptophan deple- exercise progresses (Davis et al., 2003b) and, along with the tion produces mood and cognitive disturbances in individuals reduced levels of brain ammonia, help delay brain fatigue with a history of depression or a heritable variant of the (Davis, 2000; Nybo et al., 2005). Finally, carbohydrates are serotonin transporter (Neumeister et al., 2006). typically consumed during exercise as sports drinks that provide fluid to offset dehydration and reduce the risk of Carbohydrate Supplementation It is well established elevated body temperature—and therefore brain temperature, that carbohydrate supplementation during prolonged, intense which is another factor in exercise-induced central fatigue exercise delays fatigue. The majority of research to under- (Nybo, 2008). stand this effect of carbohydrate feedings has focused on Caffeine Caffeine is the most widely consumed nervous peripheral mechanisms such as maintaining blood glucose levels and sparing muscle glycogen stores (Coggan and system stimulant in the world. It has long been reported to Coyle, 1991). More recently, research has demonstrated the increase wakefulness, subjective feelings of energy, vigi- beneficial effects of carbohydrate supplementation on CNS lance, mood, and mental and physical performance. All of fatigue. these effects are due to an increase in dopamine activity and Carbohydrate beverages have been shown to benefit are opposite to those produced by adenosine (Fredholm et CNS function in both sport and military settings. In the al., 1999). Caffeine competes with adenosine for binding late stages of exercise designed to mimic the demands of to adenosine receptors in the brain, so if caffeine displaces soccer and basketball, carbohydrate beverages enhanced some adenosine molecules, the negative effects of adenosine performance of gross motor skills, decreased sensitivity to discussed previously will be reduced (Garrett and Griffiths, physical force, improved mood (both reported and observed), 1997). The primary outcome of blocking adenosine receptors increased vigor, and reduced perception of fatigue/tiredness. with caffeine is a large increase in the release of dopamine All of these effects were seen in addition to enhanced physi - in the brain (Fredholm et al., 1999). This hypothesis was cal performance, including faster sprint times and higher confirmed in a recent study by Davis et al. (2003b) of rats average jump heights (Welsh et al., 2002; Winnick et al., during prolonged treadmill running to fatigue. 2005). Lieberman et al. (2002) also showed a dose-related Caffeine use to improve cognitive functioning dur- improvement in vigilance (sustained attention) in a U.S. ing sustained military operations has been extensively Army Special Operations unit with carbohydrate supplemen- researched (NRC, 2001). In a review by Lieberman (2003), tation during sustained physical activity designed to mimic it was reported that caffeine improves vigilance in rested and a typical combat operation. In addition to improvements in sleep-deprived individuals, improves target detection speed physical performance, volunteers who received carbohydrate without adversely affecting rifle-firing accuracy, improves supplementation also reported increased vigor and decreased decision response (choice reaction) time, improves learning confusion. Even as little as 25 g of glucose can increase cog- and memory, and improves mood, including perceptions nitive functioning and decrease subjective feelings of mental of fatigue and sleepiness. Benefits were seen with as little fatigue (Reay et al., 2006). as 100-200 mg caffeine (~1.4-2.8 mg/kg body weight). The neurobiological mechanisms of the benefits of Although optimal caffeine doses vary widely among indi- carbohydrate beverages on CNS function remain specula- viduals, caffeine can improve cognition and mood in both tive. One hypothesis is that carbohydrate beverages provide habitual caffeine users and nonusers (Haskell et al., 2005). energy in the form of glucose, along with an increase in dopa- Ephedrine as a Dietary Supplement Ephedrine is another mine and reductions in brain 5-HT, adenosine, ammonia, and brain temperature. The extra energy supplied by sustaining commonly used stimulant that has demonstrated ergogenic blood glucose levels presumably lessens the metabolic stress properties. Ephedra, which is an extract from the Chinese in the brain during exercise, leading to a smaller increase in ma huang plant (an herb in the genus ephedra), contains brain adenosine. The relationship between prolonged exer- ephedrine and related alkaloids and is used as a dietary cise, brain adenosine, and tiredness/sleep has recently been supplement. It has been reported that there is an additive demonstrated in rats (Dworak et al., 2007). More glucose can ergogenic effect when ephedrine is used with caffeine, with

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0 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS the performance enhancement being greater than when either the blood-brain barrier. A decreased uptake of tryptophan stimulant is used alone (Magkos and Kavouras, 2004), and, may decrease brain serotonin; the resultant change in the indeed, most commercial ephedrine-containing products ratio of brain serotonin to dopamine might improve per- also contain caffeine. A supplement containing 375 mg of formance when subjects are experiencing CNS fatigue. At caffeine and 75 mg of ephedrine improved run times (Bell present, however, this and other hypotheses for how tyrosine and Jacobs, 1999), and Bell et al. (2000) demonstrated that supplementation works remain speculative. Although the lower doses of caffeine plus ephedrine (4 mg caffeine per evidence is limited, tyrosine supplementation is a promising kilogram body weight and 0.8 mg ephedrine per kilogram nutritional intervention that may have significant effects on body weight) were just as ergogenic as higher doses but with the CNS, but more studies are needed before specific recom- fewer adverse side effects. mendations can be made. Caffeine, ephedrine, and similar stimulants are associ- Herbal Derivatives: Quercetin and Curcumin Herbal ated with adverse side effects, and responses to these drugs are highly individualized. Minor side effects can include remedies for fatigue, both physical and mental, have been insomnia, anxiety, irritability, mild diuresis, headaches, and used in traditional medicine for centuries. The biologically gastrointestinal distress. More severe side effects can include active components of these remedies are receiving increased severe diuresis and dehydration, tachycardia, arrhythmia, attention in the biomedical literature as dissatisfaction hypertension, dependence, seizures, coma, or death. Caution grows with the cost and efficacy of conventional Western must be taken when using caffeine and/or other stimulants. pharmacological interventions for general ailments. Two of Sometimes it is difficult to determine that a product contains these herbal derivatives that may in time prove to have posi- caffeine or other stimulants because they are not specifically tive effects on both the mental and physical components of listed as such on the label. For instance, guarana is a popular fatigue are quercetin and curcumin. Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a flavo- constituent of many commercial energy products, but it is not noid3 found in many fruits and vegetables such as apples, widely known that the main active component of guarana is, in fact, caffeine. onions, red grapes, berries, and black tea. Preliminary evi- dence suggests that the effect of quercetin on CNS fatigue Tyrosine Tyrosine is the amino acid precursor of the is like the effect of caffeine as an adenosine antagonist with neurotransmitter dopamine, which has been associated with resulting increase in dopamine activity. Perhaps the most energetic mood, arousal, motivated behaviors, and move- important and exciting aspect of quercetin supplementation ment initiation and control (Davis, 2000). There is promis- is its effects on brain and muscle mitochondrial biogenesis, ing but preliminary evidence that tyrosine supplementation which would be expected to increase energy availability. may have beneficial effects on cognitive functioning and Davis et al. (2007a) found that 7 days of quercetin feedings mood, especially under prolonged stress. Chinevere et al. in mice subjected for 3 days to a treadmill run to fatigue (2002) showed in a study of prolonged and intense cycling (about 140 minutes) increased markers of mitochondrial that tyrosine lessened perceived exertion. In addition, tyro- number and function in muscle and brain compared with sine supplementation, when tested in subjects in prolonged untreated controls; they also observed improved running stressful environments such as military operations, improved performance in the quercetin-fed mice in both run to fatigue vigilance, choice reaction time, pattern recognition, map and and voluntary wheel-running activities. In human subjects, compass reading capabilities, working memory, and mood, quercetin feedings increased the maximum aerobic capacity including perceptions of fatigue, confusion, and tension (VO2 max) and ride time to fatigue on a bicycle as measured (Lieberman, 2003; Magill et al., 2003; Lieberman et al., by an ergometer (Chen et al., 2008). However, the specific 2005; Mahoney et al., 2007). importance of increased brain mitochondria has not been Supplemental dietary tyrosine increases plasma concen- determined in this context. trations of the amino acid (Davis and Bailey, 1997), but the Another potential application for quercetin in miti- mechanism by which this affects brain activity to produce gating CNS fatigue involves its powerful antioxidant and the observed performance benefits is uncertain. For the a nti-inflammatory activity. Quercetin has strong anti- central catecholamine neurotransmitters—norepinephrine, inflammatory properties by virture of its ability to modulate dopamine, and epinephrine—the rate-limiting step in their enzymes and transcription factors within pathways essential synthesis is the activity of the enzyme tyrosine hydroxylase. for inflammatory signaling, including those that are involved in the interleukin-1β signaling cascade (Comalada et al., This enzyme is fully saturated with its tyrosine substrate even under dietary starvation conditions (Cooper et al., 2003). 2005, 2006; Dias et al., 2005). Quercetin has been shown to This point argues against a simple mass effect of increased reduce the expression of pro-inflammatory cytokines (Huang plasma tyrosine on dopamine production. Increased plasma 3The term “flavonoid” refers to a class of secondary plant metabolites tyrosine may be acting by some other mechanism. For often cited for their antioxidant properties. Chemically, a flavonoid is an example, it may compete with the amino acid tryptophan for aromatic compound that has two substituted benzene rings connected by a the transporters required to move these amino acids across chain of three carbon atoms and an oxygen bridge.

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 SUSTAINING SOLDIeR PeRfORMANCe et al., 2006; Min et al., 2007; Sharma et al., 2007) and other Guarana (whose active component is caffeine) in com - inflammatory mediators such as COX-2 and NF-κB from mercial supplements is often found in combination with P. many types of cells, including astrocytes,4 following treat- ginseng. Few studies have assessed the effects of guarana ment with various inflammatory agents (O’Leary et al., 2004; on cognitive and behavioral measures in humans. Haskell Martinez-Florez et al., 2005). Quercetin is generally known et al. (2005) evaluated guarana extract given in doses of to have a much wider safety margin when administered for 37.5 mg, 75 mg, 150 mg, and 300 mg. Increased second - extended periods (Harwood et al., 2007; Lakhanpal and Rai, ary memory performance and increased mood (alertness 2007) than do anti-inflammatory pharmaceuticals, which are and content) were seen, with the two lower doses showing sometimes used for off-label medical indications. In short, more beneficial cognitive outcomes than the higher doses. based on the literature cited above, quercetin may mitigate Kennedy et al. (2004) gave subjects single doses of 75 mg CNS fatigue during sustained operations and incidentally guarana extract, 200 mg P. ginseng, or a guarana/ginseng provide some protection from other stressors such as injury, mixture (75 mg/200 mg). Guarana supplementation led to infection, and toxic exposures. improvements in attention tasks, a sentence verification Understanding the role of inflammation in fatigue task, and a serial subtraction task. The combination of i s important when examining the possible benefits of guarana and ginseng also led to improvements on a speed- another nutritional countermeasure, curcumin. Curcumin of-memory task. (diferuloylmethane) is an anti-inflammatory component A few studies examined the effects of ginkgo biloba on of turmeric, an east Asian plant root familiar as a spice in cognitive effects in healthy young volunteers. Acute admin- curries but also a traditional herbal medicine used to treat istration of ginkgo (120 mg) improved sustained attention inflammations of arthritis, heartburn and stomach ulcer, and and pattern recognition memory but had no effects on mood, gallstones (NCCAM, 2008). In recent research, curcumin planning, mental flexibility, or working memory (Elsabagh hastened recovery to baseline performance after exercise- et al., 2005). However, 6-week chronic administration of induced muscle damage partly because it attenuated the ginkgo biloba (120 mg) had no effect on any of the cognitive inflammatory response in muscle and presumably also in or mood variables measured (Elsabagh et al., 2005; Burns et the brain (Davis et al., 2007b). However, the specific role of al., 2006). Some studies have shown slight positive cognitive curcumin in brain inflammation, interleukin-1β, and fatigue effects of higher doses (360 mg) of ginkgo (Kennedy et al., requires further study. 2002) and combination ginkgo/ginseng mixtures (Kennedy et al., 2001, 2002). Herbal Products Herbals are a relatively new area of Choline Supplements C holine serves as the dietary research, and the mechanisms of their actions remain unclear. Ginseng is by far the most studied of the herbal products. precursor to the neurotransmitter acetylcholine. One study Reay et al. (2005) showed that a single 200-mg dose of r eported that plasma choline levels dropped in mara - Panax ginseng was associated with improved cognitive thon participants, and the authors suggested that choline performance and lower subjective feelings of mental fatigue supplementation before or during exercise might improve on a visual analog scale. In a follow-up study, Reay et al. endurance performance (Conlay et al., 1992). However, (2006) tested the possible interaction between P. ginseng there is insufficient evidence to support claims that choline and a carbohydrate drink. Both the carbohydrate drink and supplementation improves physical or mental performance P. ginseng showed improvements on some of the cognitive outcomes. Warber et al. (2000) studied the effects of choline tests and lowered subjective feelings of mental fatigue, but citrate ingestion during a treadmill run to exhaustion, with there was no additive effect by P. ginseng and glucose on subjects carrying a load of 34.1 kg. They found that choline any of the cognitive outcomes measured. It should be noted, supplementation had no effect on time to exhaustion, squat however, that ingestion of P. ginseng often reduces blood tests, or ratings of perceived exertion. In a similar treadmill glucose levels, which could be detrimental to cognitive test while carrying a load, Deuster et al. (2002) found that performance. choline supplementation (50 mg per kilogram body weight) Because studies of the potential beneficial effects of had no effects on physical or cognitive performance, includ- ginseng on physical exercise performance often involve ing tests of reaction time, logical reasoning, vigilance, spatial long-term vs. sporadic/occasional ginseng supplementation, memory, and working memory. their results are equivocal. Without a reasonable mechanism of action, the evidence that ginseng ingestion can improve Summary of CNS Fatigue Countermeasures exercise performance is not convincing. Performance during prolonged periods of physiological and mental stress depends not only on the ability to maintain the physical effort required but also the ability to maintain 4Astrocytes are star-shaped, nonneuronal glial cells. Glial cells constitute good mental functioning—for instance, to maintain alert- the essential supporting tissue, or glia (meaning “glue”), of the brain, which ness, clarity of thought, decision-making ability, and mood. is essential for the health and functioning of the neurons (nerve cells).

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2 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS Both brain and body contribute to the onset of fatigue during eral circulation. Although it accounts for only 2-3 percent endurance exercise. of total body mass, for an individual in a resting state the Nutritional strategies designed to enhance CNS function brain accounts for 20 percent of blood glucose utilization. are likely to also improve physical performance. CNS fatigue The brain exhibits non-insulin-dependent glucose uptake. may be caused in part by reduced glucose availability or by Glucose is transported from the blood compartment to the an imbalance between serotonin, dopamine, and adenosine, astrocytic end feet surrounding the vascular endothelial cells along with an increase in circulating ammonia, inflammatory by glucose transport molecules (Dwyer, 2002). Although in cytokines, and—sometimes—elevated brain temperature. the embryonic state the neuronal elements and glial cells The levels of these transmitters as such do not directly contain an abundance of glycogen (a storage form of glu- change the effectiveness of the neurons that use them. For cose), the neurons and glia of postnatal humans and adults example, the neuronal circuits that use these transmitters contain very low levels of glycogen, thus making the brain could become unbalanced, but the brain’s adaptive systems dependent on vascular sources of energy. Under conditions of go to great lengths to maintain equilibrium. What can change glucose deprivation, the brain can use ketone bodies from the in the short term and later drive metabolic compensations is breakdown of fats, but a well-fed individual depends almost the activity of the neurons that use these transmitters. totally on glucose to fuel the metabolic processes that pro - Even though our understanding of possible mechanisms duce ATP, the intermediary that provides the chemical energy for CNS fatigue is severely limited, the evidence has risen for neuronal processes such as synthesis of macromolecules to a level that supports development of testable hypotheses and cellular repolarization after axonal discharge. and justifies a recommendation to increase systematic neuro- To provide the brain with sufficient metabolic resources, science research into the neurobiological basis of CNS the distance between the small capillaries comprising the fatigue and possible nutritional countermeasures in both vascular bed in the brain approximates 0.1 mm, making animal and human models. The most promising nutritional the brain one of most highly vascularized organs in the strategies involve carbohydrate and caffeine supplemen- body. Blood glucose levels are regulated by the release of tation, which can increase glucose and dopamine while glucose from the liver, where it is produced from glycogen, decreasing serotonin and adenosine. Tyrosine supplementa- and by serum insulin levels that are controlled by pancre- tion might have some benefits in certain situations, possibly atic beta cells. Maintaining a functional metabolic state by increasing brain dopamine. Perhaps the most exciting new for decision making and other cognitive tasks—including supplements that deserve more research are quercetin and perceptual discrimination, memory recall and new-memory curcumin. These supplements may work via their antioxidant consolidation, rule-based moral judgment, and multiple and anti-inflammatory activity, along with an increase in task performance—that are accomplished through neuronal mitochondrial biogenesis (quercetin only). information processing is thus critically dependent on the To summarize, neuroscience approaches are already supply of energy-producing substrates for ATP synthesis. being used to examine the effects of commonly used nutri- A variety of neurotransmitters and growth factors affecting tional supplements on brain functioning. These efforts are neural development and function (for example, thyroxin, just the beginning of research on the effects of various galanin [an insulin-like growth factor], estrogen, and cortico- candidate nutritional supplements on brain functioning and steroids) have a measurable effect on glucose uptake and performance. Although there is ongoing research sponsored metabolism. or conducted by the Army into the practical effects of nutri- As discussed in the preceding section on countermeasures tional supplements, virtually nothing is known about how or to fatigue, quercetin is one of the dietary flavonoids under where they affect brain function and which specific aspects active investigation as a fatigue countermeasure. Quercetin is of brain functions are improved (or impaired). Therefore, also of interest as a dietary supplement to sustain brain func- a concerted effort by neuroscience laboratories to support tion and cognition generally. In addition to its antioxidant and Army-relevant research would help the Army to identify anti-inflammatory characteristics, described above, quercetin and test potentially useful nutritional supplements. These may have other mechanisms of action (Nieman et al., 2007). efforts would probably yield important results within the It also has a binding affinity to the adenosine A-1 receptor next 5 years. similar to the binding affinity of caffeine (Alexander, 2006). Some of quercetin’s reported benefits on brain function and cognition may extend beyond its antioxidant properties, which Brain response to metabolic stressors attenuate the deterioration associated with aging or ethanol The Army medical community has long sponsored intake. By interacting with the adrenergic adenosine A1 recep- research on the effects of stress, pain, and sleep depriva- tor, quercetin may improve neural function (Patil et al., 2003; tion on soldier abilities. Neuroscience research has already Singh et al., 2003; Naidu et al., 2004). demonstrated its potential to revolutionize understanding in Various technologies are being studied to enable sol- these areas. For its weight, the brain has an extraordinarily diers to retain complex decision-making capabilities dur- high demand for glucose and oxygen supplied via the gen- ing continuous operations lasting 72 hours. Transcranial

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 SUSTAINING SOLDIeR PeRfORMANCe electrical stimulation, enhanced contrast iconography, and foundation of the more complex components of cognition. flashing icons representing threat (red force) on Force XXI David Dinges at the University of Pennsylvania has exploited Battle Command Brigade and Below video displays are the psychomotor vigilance test (PVT)—a high-signal-load, examples of such technologies. In addition, pharmaceutical reaction-time test—to characterize the neurocognitive effects supplements are in development to sustain complex decision- of sleep deprivation. As the amount of normal sleep time making capabilities for extended operations. lost increases, there is an overall slowing of responses and an increase in the propensity to lose focus for brief periods (>0.5 sec) as well as to make errors of commission. During sleep deprivation extended periods of sleep deprivation, interactions between Sleep is not the mere absence of wakefulness. It is an the circadian and homeostatic sleep drives contribute to the active state that is finely regulated and that undoubtedly lapses in performance (Lim and Dinges, 2008). plays multiple important roles in brain function. While it is Chee et al. (2008) used fMRI to study subjects perform- accepted that sleep deprivation degrades performance and ing the PVT who were either well rested or sleep deprived. impairs vigilance, there are other positive functions of sleep They found that lapses occurring with sleep deprivation, that may be degraded when soldiers are deprived of adequate compared with lapses after normal sleep, were associated sleep (Van Dongen et al., 2004b). with a reduced ability of frontal and parietal regions to raise Current military doctrine is based on operational activi- activation, dramatically reduced visual sensory cortex activa- ties for ground forces continuing for periods up to 72 hours. tion, and reduced thalamic activation. Notably, correct per- A persistently high operations tempo places coalition forces formance under both conditions elicited comparable levels in a dominant position with respect to their adversary. How- of frontoparietal activation. Thus, sleep deprivation produces ever, also associated with 72 hours of sustained operation is periods of apparently normal neural activation interleaved sleep deprivation and concomitant reductions in capabilities with periods of depressed cognitive control, visual perceptual for decision making and complex cognitive functioning function, and arousal. Another finding was that most subjects while performing several tasks. The pioneering studies of have poor insight into the degree of their own impairment Gregory Belenky at Walter Reed Army Institute of Research due to sleep deprivation. have demonstrated that whereas overlearned sharpshooting There are substantial traitlike differences among indi- capabilities are retained after 40 hours of sleep deprivation, viduals in terms of their vulnerability to neurobehavioral the decision-making ability required for differentiating deficits as the amount of lost sleep increases. Three cat- specific targets from neutral images deteriorates markedly. egories have been identified, with Type 1 individuals being These and similar observations show that different facets highly tolerant of sleep deprivation (cognitive performance of attention and decision making decay at different rates as near normal on the tests used). Type 2 individuals are those sleep deprivation accumulates. around the mean performance deficit, and Type 3 individuals Research over the past two decades indicates that sleep are substantially more vulnerable to sleep deprivation than is essential for consolidating memory and promoting synap- the norm (Van Dongen et al., 2004a). These responses to tic plasticity. Sleep affects the two major types of memory: sleep deprivation are highly stable over time for a particular declarative memory, which involves retention of facts, and individual, consistent with the response patterns being stable procedural memory, which refers to acquisition of complex traits with a high genetic component. Identifying reliable biomarkers5 for these behavioral types is a high priority for skills. Declarative memory is encoded, at least initially, in the hippocampus, whereas procedural memory appears to be the field of sleep research. Screening with the PVT or another localized primarily in the frontal cortex (Marshall and Born, suitable biomarker could be useful to the Army in selecting 2007). Electrophysiologic studies of place cells (neurons that individuals with optimal resistance to sleep deprivation for fire when an animal is in a specific place in a maze) in the missions or assignments where sleep time is likely to be hippocampus reveal that the series of place cells activated in below normal for a sustained period. the maze during the acquisition of a spatial learning task is For soldiers deployed in combat operations, there are reactivated in precisely the same sequence when the animal is profound effects of sleep deprivation on brain glucose utili- in slow-wave sleep but several times more rapidly. Rapid eye zation (Spiegel et al., 2005). Positron emission tomography movement (REM) sleep, in contrast, appears to benefit the studies have demonstrated that sleep deprivation reduces consolidation of procedural memory (Euston et al., 2007). glucose uptake by the brain. Sleep deprivation also affects Investigators speculate that sleep gets the brain off-line so release of insulin from the pancreas, which affects the levels that it can engage the diverse cortical circuitry in memory of circulating blood glucose. The diurnal levels of hormones consolidation. that respond to food intake (e.g., leptin and ghrelin) are also Sleep deprivation severely compromises the ability modified by sleep deprivation. The 28-amino-acid gastric of humans to respond to stimuli in a timely fashion. The observed deficits have often been attributed to failures of 5See Chapter 2 for the committee’s definition of “biomarker” and the vigilant attention, which many investigators believe is the requirements for a reliable biomarker.

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 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS peptide ghrelin also inhibits the pain of inflammatory known as “clock” genes, has been identified that comprise responses (Sibilia et al., 2006). This pain suppression effect a “molecular clock.” They are expressed in many cell types has not yet been correlated with glucose metabolism. The van throughout the body as well as in the neurons of the brain. Cauter group reported that suppression of slow-wave sleep Notably, clock genes are overexpressed in the cerebral cortex patterns (non-REM sleep) in healthy subjects alters normal with sleep deprivation, indicating that they also play a role glucose homeostasis (Tasali et al., 2008). in sleep homeostasis (Tafti and Franken, 2007). Aside from its interest in prolonging wakefulness, the Recent genetic studies reveal a significant role for herita- Army would benefit from following the research on the bility in sleepiness, usual bedtime, and usual sleep duration. benefits of sleep. It has recently been suggested that short Several genetic loci, including the clock genes, have been bouts of sleep can facilitate memory consolidation (Lahl et identified that mediate this behavior (Gottlieb et al., 2007). al., 2008). In the future, it may be possible to improve sleep These genetic studies point to endogenous, interindividual efficiency so that the necessary physiological processes differences in sleep homeostasis that may need to be identi- accomplished during sleep could be done much more rapidly fied to optimize selection of soldiers for specific tasks. They or without the loss of consciousness. For example, birds are also point to potential targets for pharmacologically manipu - able to engage in slow-wave sleep in one hemisphere at a lating sleep in vulnerable individuals. time so that they can remain vigilant and even fly. Marine mammals (cetaceans) also experience slow-wave, symmetric PharmaceuTical couNTermeasures To sleep in one hemisphere at a time, while the other hemisphere NeuroPhysioloGical sTressors shows wakeful activity (Pillay and Manger, 2004; Lyamin et al., 2008). Over the past two decades, neuroscience has made The homeostatic facet of sleep-wake regulation is keep- remarkable advances in understanding the neural circuitry of ing track of changes in “sleep propensity” (or “sleep need”), memory, drive, mood, and executive function. Furthermore, which increases during wakefulness and decreases during the neurochemical features that mediate neurotransmission sleep. Increased sleep propensity following extended prior for components of these circuits have largely been charac- wakefulness (sleep deprivation) is counteracted by both terized. This knowledge has provided the pharmaceutical prolonged sleep duration and enhanced non-REM sleep industry with targets for developing drugs that perturb specific intensity, as measured by electroencephalography. There neurotransmitters, with the potential for treating disorders in is compelling and convergent evidence that adenosinergic which these neural systems have been implicated, such as neurotransmission plays an important role in non-REM schizophrenia, Alzheimer’s disease, severe mood disorders, sleep homeostasis. Adenosinergic mechanisms modulate and critical behaviors affected by specific neuropsychiatric individual vulnerability to the detrimental effects of sleep disorders. Prospective neuropharmacological agents that act deprivation on neurobehavioral performance. Sleep depriva- on wholly novel targets include a nicotinic acetylcholine tion increases the levels of extracellular adenosine and of the receptor modulator to improve attention and executive func- adenosine A1 receptor in the cholinergic zone of the basal tion in attention deficit disorder, N-methyl-d-aspartic acid forebrain. Caffeine, an A1 receptor antagonist, prolongs (NMDA), a receptor-positive modulator to enhance memory wakefulness and sleep latency by interfering with the rise consolidation, and a metabotropic glutamate receptor agonist of sleep propensity during wakefulness, as revealed by the to treat psychosis (Patil et al., 2007). buildup of theta-wave activity over the frontal lobes. Over the next 5 to 10 years, it is highly likely that many A functional polymorphism in the adenosine- new classes of drugs will be developed that mitigate symp- metabolizing enzyme adenosine deaminase contributes to toms and deviant behaviors associated with neuropsychiatric the high interindividual variability in deep slow-wave sleep disorders. Beyond their approved therapeutic indications, duration and intensity (Rétey et al., 2005). Additionally, these new medications have the potential for sustaining or the circadian gene PERIOD 3 has been shown to correlate optimizing the performance of soldiers. In addition, some of with differential vulnerability to cognitive deficits resulting them are likely to alleviate the adverse neuropsychological from total sleep deprivation (Viola et al., 2007; Groeger et consequences of combat and other extreme stressors, includ- al., 2008). Moreover, caffeine greatly attenuates the electro- ing major depression and stress-related disorders such as encephalography markers of non-REM-sleep homeostasis post-traumatic stress disorder (PTSD). during both sleep and wakefulness. As the Army debates using pharmaceuticals that have Whereas the homeostatic process determines sleep been approved by the Food and Drug Administration (FDA) needs, the timing of sleep is determined by the circadian for off-label uses such as sustaining or optimizing perfor- process, endogenous cycles of gene expression, and physical mance, it needs to consider a number of issues. First, drugs activity. The circadian secretion of melatonin from the pineal that affect the CNS by acting on a specific neurotransmitter gland plays an important role in determining sleep onset, and are likely to affect multiple neural circuits, as a particular this effect of melatonin has been exploited to manipulate neurotransmitter is generally used in several functionally sleep onset in shift workers, for example. A family of genes, distinct circuits, such as dopamine in the striatum modulating

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 SUSTAINING SOLDIeR PeRfORMANCe BoX 5-1 is salivary cortisol a reliable Biomarker? The levels of cortisol in salivary samples would appear at first glance to serve as an easily applied, dynamic index of the output of the adrenal cortex and therefore of an individual’s reaction to environmental or internal stress, broadly defined (Smyth et al., 1998). However, the interpretation of cortisol level for a given person in a particular context is a complex matter. Salivary cortisol measurement kits vary significantly in their ability to obtain paralleling plasma cortisol levels (assumably the gold standard). That issue aside, researchers agree that to get an accurate area-under-the-curve measure of daily cortisol, measurements at 1, 4, 9, and 11 hours after the subject wakes up can provide good coverage.1 Single-day assessments are nonetheless very weak approaches to this problem, since cortisol levels are affected by many day-to-day events (Stone et al., 2001). Many factors are thought to be important in cortisol measurement: (1) stable characteristics such as age and gender; (2) state characteristics such as menstrual cycle stage and use of contraceptives and other medications; (3) disease and/or chronic conditions such as liver disease, PTSD, malnutrition or fasting, or lifestyle (e.g., jet lag or shift work); (4) dynamic characteristics such as food intake (e.g., carbohydrates increase cortisol), sleep status (e.g., assess sleep quality and quantity on night prior to cortisol measurement), exercise (e.g., level and timing), and wake-up time; and (5) psychological characteristics such as positive and negative affect, passivity, or coping. In short, before salivary cortisol can be used as a reliable biomarker (in the sense defined in Chapter 2), a standard method for assessing individual cortisol baseline must be validated. As well, the difference between the individual’s baseline cortisol reading and the reading at another time must be validated as a sensitive and specific marker of the biological condition or outcome it is intended to measure. 1SeeWeb site of the MacArthur Network on Socioeconomic Status and Health at http://www.macses.ucsf.edu/Research/Allostatic/notebook/salivarycort.html. Accessed December 1, 2008. movement and in the accumbens mediating reward. Thus, consequences of persistent stress and the risk of depression. it is essential that specificity of action be demonstrated by Nonetheless, the committee has significant concerns about the development of tools to measure stress on other baseline the potentially inappropriate use of performance-enhancing states desired. Box 5-1 illustrates the challenge of coming drugs by the military, particularly with respect to whether up with a tool to measure stress. the benefits outweigh the risks. Still, it may be worthwhile Second, one must be concerned about unforeseen or to continue research into the use of neuropharmacological delayed side effects, particularly when medical indications agents to mitigate degraded performance in unique military may be present for which the drug has not been formally circumstances when the benefits of the agents outweigh the approved. Cost-benefit analyses must be undertaken using risks. tools to measure baseline states and which aspects of perfor- To succeed in the area of neuropharmacological counter- mance are being enhanced and to obtain clinical measures measures to performance deficits due to stressors in opera- of overall effects, detrimental or positive. It is possible that tional environments, the Army needs to leverage its relation- some components of performance might be degraded even ships with entities whose missions are focused on, or at least as others are improved. Used in this context, “benefit” refers involve, developing new drugs—these entities include the to enhanced performance—for example, superior ability to pharmaceutical industry, the National Institutes of Health, withstand sleep deprivation, faster response times, and the and the university biomedical and pharmacological research overall improvement in carrying out the military mission. It communities. The Army should aim to build on the clinical may include a greater likelihood of survival. “Cost” refers findings of these entities to determine whether a therapeu- not only to dangerous immediate side effects, but also to tic, preventive, or optimizing effectiveness purpose of an long-term side effects or even the potential for the enhanced agent has been established for conditions relevant to Army abilities to lead to unacceptably risky behavior or other poor operations and whether proper administration of a proven- decisions. effective agent is both technically feasible and advisable. The Currently, there are a few examples of the use of FDA- Army should use the full range of neuroscience methods to approved drugs to sustain behavior or prevent degradation determine the mechanisms of action for a pharmaceutical’s of performance. Modafinil is prescribed to pilots in the Air proposed use beyond its approved medical indications and Force who are tasked to fly prolonged missions. Sertraline to ensure the specificity and selectivity of the proposed inter- hydrochloride (Zoloft, Lustral) is often prescribed to troops vention. Finally, pharmacogenetics has revealed substantial who have sustained repeated combat exposure to reduce the interindividual variations in drug responses—for example, to

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 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS BoX 5-2 Pharmacoimaging with fmri to Predict drug effects Although there are many gaps in knowledge and challenges in technology that must be bridged before brain imaging can be successfully and routinely applied to monitor soldiers’ performance in the field, current imaging techniques can be applied to laboratory-based research directed at answering key questions about drug efficacy. Several recent results support the use of fMRI as a tool for predicting drug effects (Paulus and Stein, 2007; Phan et al., 2008). To function as a test with predictive validity for new treatment agents, a pharmaco-fMRI technique must meet stringent requirements. The insights gained can, however, be readily applied to predicting performance in extreme conditions or assessing the utility of training interventions. Four steps need to be successfully implemented for pharmaco-fMRI to give valid and useful results: First, one has to identify a brain area that is important for the target process of interest. This area has to be shown to be functionally altered when an individual’s performance changes. Second, one has to identify an experimental paradigm that probes (monitors) this brain area. The experimental paradigm should be sensitive to the behavioral effects of anxiety, show no ceiling or floor effects, and be repeatable with negligible learning effects (i.e., have good test-retest reproducibility). It should be simple and relatively independent of volitional effects, be sensitive to basic pharmacological manipulations, activate areas in the brain that are of relevance for anxiety, and show behavioral effects and/or brain-imaging effects that correlate with ratings of anxiety. Third, one has to determine whether there is a correlation between reduction in performance and the BOLD change in the predicted direction with standard interventions (training, etc.). Fourth, one has to demonstrate that the standard pharmacological intervention affects the brain area in the hypothesized direction. Moreover, this effect should show a dose-response relationship (i.e., larger or more frequent doses of the intervention should have a stronger effect). neuropsychotropic agents. These findings should constrain injuries of combat (Stuhmiller, 2008). It is also uncertain how widely such drugs are used for any purpose other than whether the number and duration of repeated deployments their FDA-approved therapeutic indications. for the same soldiers have contributed to the prevalence of Box 5-2 describes an example of predicting drug effects. stress-related disorders in veterans of the Iraq and Afghani- Although these approaches are in their infancy, nevertheless stan wars. they point toward unprecedented opportunities to selec- Neuroscience research has improved our understand- tively and specifically manipulate the brain to alter decision ing of the brain’s response to stress, the pathophysiology of making. PTSD, and the consequences of TBI. DOD-wide recognition of the importance of neuroscience research in these areas is evidenced by the establishment of the Defense Centers of BraiN iNJury Excellence for Psychological Health and Traumatic Brain As noted in Chapter 1, the committee was tasked to focus Injury in 2008. its study on nonmedical applications in light of the numerous studies of medical neuroscience research and applications. stress disorders, including PTsd Nevertheless, biomedical and neurophysiological knowl- edge of combat-related brain injury and stress disorders is a Several studies and reviews have examined the risk for prerequisite for assessing opportunities for mitigating these developing PTSD and allied stress-related disorders, such effects of combat, whether through preventive strategies or as panic attacks, emotional dyscontrol, and substance abuse by prompt and efficient treatment after a soldier has experi- (Hoge et al., 2008; Schneiderman et al., 2008; Smith et al., enced a potentially injurious event. Accordingly, the section 2008). A recently released RAND study based on a repre- begins with a brief overview of the most salient aspects of sentative sample of nearly 2,000 individuals deployed for current biomedical understanding of brain injuries. Operation Enduring Freedom in Afghanistan and Operation The Iraq war has increased awareness and programmatic Iraqi Freedom found that 18.5 percent of all returning service emphasis on mitigating, preventing, treating, and protecting members met criteria for PTSD, depression, or both, whereas against neurological damage. This war has seen a marked 19.5 percent reported experiencing a probable TBI during increase in the risk for traumatic brain injury (TBI) because deployment. About a third of those experiencing a TBI had of the high proportion of soldiers who have been injured a concurrent mental disorder (RAND, 2008). by strong explosions due to improvised explosive devices Neuroscience research reveals that a complex interac- (IEDs) and who have survived because they received prompt tion involving the brain, the adrenal glands, the peripheral medical care. Blasts from IEDs may cause a unique type of automatic nervous system, and the immune system underlies brain damage compared with the more typical penetrating this kind of mental stress (McEwen, 2007). Whereas the

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 SUSTAINING SOLDIeR PeRfORMANCe acute fight-or-flight response of the stress axis is protective, military service and that the injury led to PTSD or whether persistent activation of the hypothalamic-pituitary-adrenal the small hippocampus predisposed him or her to PTSD, (HPA) axis can have noxious effects on the brain. McEwen carefully designed studies of the relevant conditions before coined the term “allostatic overload” to refer to persistent, and after deployment must be conducted. Resolution of this excessive stress responses. He found that the powerful issue has substantial consequences for care delivery, for the interaction between high anxiety and impaired sleep (since value of preventive measures for susceptible individuals, and sleep deprivation causes increased blood pressure) increased for compensation related to military service. levels of cortisol, insulin, and proinflammatory cytokines Another brain structure that figures prominently in (McEwen, 2007). Several experimental paradigms have also stress-related mood and anxiety disorders is the amygdala. shown that sleep deprivation inhibits neurogenesis in the Research by Yehuda and LeDoux (2007) and by Davis et al. hippocampus, which accounts for concurrent subtle cogni- (2003a) has established the neuronal pathways that mediate tive impairments. conditioned fear. Conditioning results when information Developmental studies of both animals and humans indi- from the conditioned stimulus (a neutral stimulus such as cate that high levels of stress during human childhood, such light or sound) converges with information from the uncondi- as physical or sexual abuse or neglect, can markedly increase tioned stimulus (such as pain or a feared object). Processing vulnerability to stress in adulthood (Heim and Nemeroff, of feared experience in the lateral nucleus of the amygdala 2002; Kaffman and Meaney, 2007). Stress early in life results is a critical step in circuitry through which the release of in persistent blunting of the HPA axis, which is mediated by catecholamines, adrenocorticotropic hormone, and cortisol is regulated. Administration of an α-adrenergic receptor a down-regulation of glucocorticoid receptor expression due to methylation of the DNA in the promoter region of the gene antagonist into the amygdala attenuates the development (Meaney et al., 2007). Heritable factors such as allelic variants of conditioned fear, whereas administration of exogenous of the gene for the serotonin transporter, which inactivates cortisol exacerbates it (Roozendaal et al., 2006). Although serotonin at the synapse, can render individuals more vulner- catecholamine metabolites increase in subjects with chronic able to stress early in life and at greater risk for depression in PTSD, most studies indicate lower levels of corticosteroids adulthood (Lesch and Gutknecht, 2005; Roy et al., 2007). and a blunted response to stress (Yehuda and LeDoux, 2007). Brain neurons express the glucocorticoid receptors, The central role of the amygdala in conditioned fear in exper- which are responsive to mineralocorticoids as well as to imental animals has been extended to humans via functional glucocorticoids. The hippocampus, a brain structure criti- brain imaging studies. Exposure to fear-inducing stimuli cally involved in learning and memory, expresses high levels leads to functional activation of the amygdala. Furthermore, of these corticoid receptors. Thus, it is not surprising that PTSD patients generally demonstrate increased activation of there is a complex relationship among brain glucocorticoid the amygdala in response to a threatening stimulus or even receptor occupancy, behavior, and cognition. The hippo- a neutral stimulus, as compared to untraumatized controls campus, one of the most malleable structures in the brain, or even to traumatized individuals without PTSD (Rauch et exhibits both functional and structural plasticity, including al., 2006). neurogenesis. Chronic stress or chronic treatment with Extinction of conditioned fear may suggest potential exogenous glucocorticoids is associated with impairments of treatments for PTSD. Repeated presentation of the con- hippocampal-dependent memory tasks and with reduction in ditioned stimulus to an experimental animal without the the volume of the hippocampus (Sapolsky, 2003). Persistent unconditioned stimulus results in the gradual extinction of stress and elevated corticosteroids suppress neurogenesis conditioned fear. This active process involves new learn- and expression of brain-derived neurotrophic factor in the ing and requires the activation of the NMDA subtype of hippocampus. In this regard, quantitative morphometric glutamate receptors in the amygdala. When conditioned studies consistently reveal reduced hippocampal volume in fear exists, both animal and human studies point to a loss of patients suffering from PTSD; the degree of atrophy corre- inhibitory control over the relevant nuclei of the amygdala lates significantly with the degree of cognitive impairment by the medial prefrontal cortex. Indeed, prolonged stress (Bremner, 2006). alters the circuitry linking the medial prefrontal cortex to the It is not yet clear whether the reduced hippocampal amygdala. Davis et al. (2006) demonstrated that the extinc- volume is a predisposing factor in the development of tion of conditioned fear in experimental animals through PTSD or a consequence of traumatic injury. Many young repeated exposure to the conditioned stimulus is significantly adults (military or civilian) enter their early twenties with facilitated by concurrent treatment with a single dose of neurological change resulting from automobile accidents, d-cycloserine, a partial agonist at the glycine modulatory football or other athletic injuries, febrile episodes from site on the NMDA receptor, which enhances NMDA receptor infection, or drug taking. An abundance of literature attests responses to glutamate. to the prevalence of all these factors in the U.S. young adult Controlled clinical trials indicate that reviewing the trau- population. Before one can decide whether an individual’s matic experience in a supportive setting (exposure therapy) small hippocampus was caused by injury incurred during can be an effective treatment for chronic PTSD, analogous

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8 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS to exposing an experimental animal to the unconditioned the serotonin transporter gene, the severity of the trauma, stimulus without the conditioned stimulus. Recent studies and the level of emotional support when they studied the demonstrate that, analogous to laboratory results with rats, the development of PTSD after a hurricane. This polymorphism administration of a single dose of d-cycloserine robustly and has also been associated with increased risk for depression persistently enhances the response to cognitive-behavioral in the context of stressful life events, including childhood therapy (desensitization) in subjects with acrophobia (Ressler abuse (Kaufman et al., 2004). Binder et al. (2008) recently et al., 2004). This robust enhancement persists for at least reported that four single-nucleotide polymorphisms of the 3 months and involves memory consolidation. Ongoing fKBP gene interacted with the severity of childhood abuse studies are examining the use of virtual environments that as a predictor of adult PTSD symptoms. fKBP is part of recall soldiers’ experiences in a controlled, graded fashion the mature glucocorticoid receptor heterocomplex, which for desensitizing them, coupled with administration of provides face validity for an association. d-cycloserine (Rizzo et al., 2008).6 These outcomes, along with neuropsychological research connected with recovery/ major depressive disorder in the military context treatment for traumatic brain injuries, are likely to continue as a source of future neuroscience opportunities. Aside from the experience of IED events, there are As noted above, sleep deprivation can reinforce the a number of other factors related to military service that negative cognitive-emotional features of PTSD. An insidious predispose individuals to clinical depression. Among them component of PTSD is that anxiety dreams repeatedly are separation from support networks and family, loss or awaken some individuals suffering from it. Increased death of close colleagues, divorce or family instability, eco- activity of brain noradrenergic neurons may contribute to the nomic distress, and untoward responses to medication. U.S. pathophysiology of PTSD as well as to the nighttime sleep soldiers, who are separated from their families for nominal disturbances and nightmares that accompany the disorder. 15-month deployments, are likely to experience all or most Increased noradrenergic activity interferes with normal of these factors in some form, independent of having received REM sleep and could interfere with the normal cognitive any TBI. processing of traumatic events. A recent study examined Stress and disruption of the HPA axis are central to the effects of prazosin, a centrally active alpha-1-adrenergic the pathophysiology of major depressive disorder. Stressful antagonist. Compared with placebo in a blinded clinical trial, life events have been associated with the onset of affective prazosin increased total sleep time by 90 minutes, on aver- illness. A majority of individuals with an episode of major age, increased REM sleep duration, reduced trauma-related depressive disorder exhibit dysregulation of the HPA axis nightmares, and significantly improved overall clinical with resistance to dexamethasone, a potent glucocorticoid symptoms (Taylor et al., 2008). receptor agonist. A major depressive disorder is also highly Not all individuals exposed to trauma develop PTSD. comorbid in patients suffering from chronic PTSD (Scherrer The type of trauma is important; an interpersonal trauma et al., 2008). such as rape or combat appears to be more salient than an Most animal models of depression that are used to accident trauma. Other risk factors include lower intelligence screen for antidepressant efficacy are in fact based on acute quotient, childhood adversity, avoidant personality, and or recurrent stress. For example, the Porsolt task is one of the poor social supports. As noted above, reduced hippocampal most robust predictors of antidepressant efficacy. The dura- volume is robustly associated with PTSD, but it is unclear tion of swimming when mice or rats are repeatedly placed whether it antedates the traumatic events, thereby being an in a vat of cool water decreases progressively; effective anti- additional risk factor, or is a consequence of trauma and depressants restore prolonged swimming. Chronic adminis- stress. tration of corticosterone to rats produces a number of signs The higher concordance of PTSD in identical twins and symptoms consistent with major depressive disorder, compared to fraternal twins supports the involvement of including increased anxiety, shorter latency on the Porsolt heritable risk factors. Several putative risk genes for PTSD test, and impairments in working memory. Thus, although have been identified. In a small study, a polymorphism in the major depressive disorder can occur spontaneously without untranslated region of the dopamine transporter gene was evident precipitants, in the military context depression may associated with greater risk for PTSD in trauma survivors more often be related to persistent stress and trauma. (Segman et al., 2002). The glucocorticoid receptor geno- type was found to affect basal cortisol levels in a subgroup resilience of patients with PTSD (Bachmann et al., 2005). Kilpatrick et al. (2007) found interaction between a polymorphism in Resilience refers to the ability to successfully adapt to stressors, thereby maintaining psychological well-being in the face of adversity. Recent research focusing on the psycho- 6Personal communication between Michael Davis, Robert W. Woodruff logical and neurophysiological underpinnings of resilience Professor, Emory University School of Medicine, and Joseph Coyle, com - should be of considerable interest to the Army because it mittee member.

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9 SUSTAINING SOLDIeR PeRfORMANCe identifies strategies to enhance resilience, as well as potential in these soldiers than in those with no history of blast injury. indicators of naturally resilient individuals (Haglund et al., The presence of PTSD and depression are robust predictors 2007). As noted above, research on experimental animals of poor physical health and persistent impairment. Yet the and in humans unequivocally demonstrates that severe stress biological basis for this association remains poorly under- in childhood such as abuse or neglect renders the individual stood. It is simplistic to conclude that the co-occurring much more vulnerable to stress in adulthood (Heim et al., PTSD is “a psychological response.” Neuroscience should 2000; McCormack et al., 2006). However, the experience of provide some leads about the underlying pathology of blast- modest, controllable stress in childhood results in greater induced TBI and opportunities for prevention and treatment. ability to regulate stress responses in adulthood. This phe- Box 5-3 introduces a new area of neuroscience that may nomenon, known as “stress inoculation,” has been demon- help in following up on such leads. There is debate about strated in experimental animals and humans (Rutter, 1993). whether brain injury as a consequence of blast waves differs Studies in monkeys indicate that infant monkeys subjected from brain injury due to penetrating wounds (Bhattacharjee, to stress inoculation (e.g., in childhood, separation from 2008). Indeed, it appears that some penetrating brain injuries the mother for an hour every week) display lower levels of may reduce the risk for PTSD (Koenigs et al., 2008; Sayer anxiety later in life. They have lower basal cortisol levels et al., 2008). and enhanced prefrontal cortex-dependent cognition than Research on depression that occurs after a stroke may be controls not subject to the stress inoculation (Parker et al., particularly relevant to thinking about TBI. Many clinicians 2004, 2005). believed that post-stroke depression was a predictable psy- S mall-molecule markers for resilience have also chological response to disability, although studies indicated been identified. Dehydroepiandrosterone (DHEA) is an that comparable levels of disability from other causes did endogenous steroid that elevates mood and counteracts the not result in equally high rates of depression. Furthermore, effects of high cortisol. Soldiers subjected to the stress of left anterior lesions pose greater risk for persistent depres - survival training, who exhibit superior performance, have a sion than right posterior lesions. Comorbid depression with higher ratio of DHEA to cortisol (Morgan et al., 2004). In stroke was a robust predictor of poor outcome, especially animal experiments, the neuropeptide Y (NPY) has anxiety- death. Both central noradrenergic and serotonergic neuronal decreasing effects and counteracts the behavioral effects of systems have figured prominently in the pathophysiology corticotrophin-releasing hormone. Consistent with these of major depression, as they are the targets of action of results in animals, serum NPY levels of soldiers subject to effective antidepressants. Robinson and Coyle (1980) dem- the stress of survival training correlated positively with per- onstrated that because of the peculiar trajectory of these formance, suggesting that NPY may be involved in enhanced fine, unmyelinated aminergic fibers, which project in an stress resilience in humans (Morgan et al., 2000). anterior to posterior orientation in the cortex, a stroke lesion Studies have identified several attitudes and behaviors in the anterior cortex denervates the rostral cortex of their that foster psychological resilience to stress, including aminergic innervation. Treating post-stroke depression with optimism, active coping, cognitive flexibility, moral com- antidepressants ameliorates the depression and improves the pass, physical exercise, and social support (Haglund et al., clinical outcome. 2007). Twin studies indicate that temperamental features Multiple sclerosis is another disorder associated with a such as optimism or neuroticism (tendency toward neurotic high risk of comorbid depression. The multifocal lesions in responses and behavior) are substantially heritable (Wray et the case of multiple sclerosis may have devastating effects al., 2008). Furthermore, neurophysiological research sug- on the fine aminergic intracortical axons, as demonstrated gests mechanisms that may explain the protective features by the observation that the severity of depression correlates of behaviors that foster resilience, such as the finding that inversely with the CSF levels of 5-hydroxyindoleacetic acid, physical exercise promotes expression in the brain of brain- a metabolite of serotonin. derived neurotrophic factor (Cotman and Berchtold, 2002). Given the evidence that exposure to explosion increases Similarly, social support appears to modulate the HPA axis the risk for PTSD in the absence of an acute alteration in (Heinrichs et al., 2003). mental state, the sport of boxing is germane to the discus- sion of TBI. Markers of cellular damage are increased in the CSF of boxers with no evidence of concussion. The longer-Term Performance deficits absence of structural magnetic resonance imaging changes linked to Traumatic Brain injury in boxers demonstrates that it may be an insensitive index As noted by Hoge et al. (2008), TBI has been labeled of damage. For example, only 14 percent of 49 professional the signature injury of the wars in Iraq and Afghanistan, with boxers subjected to structural magnetic resonance imaging 15 percent of soldiers deployed to these theaters reporting showed abnormalities. In contrast, diffusion tensor imaging blast injuries sufficiently severe to result in loss of con- revealed robust differences between boxers and matched sciousness or altered mental status. The risk of comorbid controls, with reduced diffusion and anisotropy, consistent PTSD with CNS symptoms was three to four times greater with disruption of axon terminals. Similar findings have

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0 OPPORTUNITIeS IN NeUROSCIeNCe fOR fUTURe ARMY APPLICATIONS BoX 5-3 connectomics and Neural Pathway degeneration Connectomics, the study of the brain’s neural pathways for information transfer, is an emerging area that addresses fundamental issues in how the brain processes information. The name “connectomics” refers to the concept of considering the entire collection of neural pathways and connections as a whole, analogous to viewing the collection of genes in a human cell nucleus as the genome. An emerging technology known as diffusion tensor imaging is used as an enabling technology for the new field. An example of how research on connectomics could be relevant to the Army is the problem of accounting for the progression of diffuse axonal injury resulting from a blast trauma. The current understanding is that pressure waves produced by the blast propagate across soft tissue interfaces in the brain, creating a shear force that degrades the junctions between white and gray matter. After the immediate physical effect of the blast—and even when no overt signs or symptoms of damage are observed, as in mild TBI—a degenerative pathology often develops over time. The effects of this neural pathway degeneration eventually lead to symptoms that appear months to years after the injury: short-term memory loss, degraded affect, and depression. In extreme cases, patients suffer from Parkinson’s-like tremors like those that boxers develop (Erlanger et al., 1999; Jordan, 2000; Toth et al., 2005). This combination of symptoms, with others, may present as PTSD. If this progressive degeneration occurs because neurons are lost along the neural pathways connecting to the cells or junctions that were damaged directly by the pressure waves from the blast, then connectomics may help to explain how the cell loss spreads from the initial foci of damage to other brain regions. An example of progress in connectomics with long-term relevance for TBI is a recent technique by which researchers can trace individual neural pathways in the brains of transgenic mouse models. While the brain of the mouse embryo is still developing, multiple copies of modified genes are transferred into the cells that will develop into the brain. These genes produce three proteins that fluoresce in yellow, red, or cyan, producing a palate of nearly 100 colors that are randomly distributed. When the mouse is mature, the brain tissue is excised and its neural pathways can be traced by the color coding (Lichtman et al., 2008). This technique is appropriate only for animal models such as these BrainBow mice (see Figure 5-3-1), which are used to learn about the brain’s “wiring diagram” and how it develops. In time, however, this fundamental knowledge should contribute to understanding how the brain normally processes information and what happens when disease or injury progressively degrades the neural pathways. One hypothesis about the long-term effects of TBI is that the white-matter networks are injured. Experiments with BrainBow mice or similar animal models exposed to IED-like blast effects might in the future allow optical measurement of how the injury progresses. Since the immediate effects of a blast trauma can be observed in the field, experiments with blast effects on these animal models might provide proof-of-concept laboratory evidence for whether and how battlefield treatments and neuronal protection technologies could mitigate the immediate blast damage. FIGURE 5-3-1 Neuronal pathways in BrainBow mice. Neurons in the hippocampus, a brain area involved in memory, are labeled in different colors, with their neuronal outgoing projections pointing to the left. This is the first time so many different neurons have been separately visualized on such a large scale. SOURCE: Jean Livet, Joshua R. Sanes, and Jeff W. Lichtman, Harvard University (2008).

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 SUSTAINING SOLDIeR PeRfORMANCe been obtained in a small study of adolescents with mild TBI Bautmans, I., R. Njemini, H. Predom, J.-C. Lemper, and T. Mets. 2008. Muscle endurance in elderly nursing home residents is related to who demonstrated an increased anisotrophy and decreased fatigue perception, mobility, and circulating tumor necrosis factor- diffusivity at 6 days after an incident. alpha, interleukin-6, and heat shock protein 70. Journal of the American Little is known about intrinsic risk factors that may affect Geriatrics Society 56(3): 389-396. the outcome of TBI. Apo E4 status robustly predicts neuro- Bell, D.G., and I. Jacobs. 1999. Combined caffeine and ephedrine ingestion logical deficits in boxers and is linked to poor neurological improves run times of Canadian Forces Warrior Test. Aviation, Space, and Environmental Medicine 70(4): 325-329. outcome after TBI from any cause (Jordan et al., 1997; Zhou Bell, D.G., I. Jacobs, T.M. McLellan, and J. Zamecnik. 2000. Reducing the et al., 2008). Recently, Chan et al. (2008) examined whether dose of combined caffeine and ephedrine preserves the ergogenic effect. polymorphism in the serotonin transporter gene, previously Aviation, Space, and Environmental Medicine 71(4): 415-419. linked to increased risk for depression after psychological Bequet, F., D. Gomez-Merino, M. Berthelot, and C.Y. Guezennec. 2002. trauma, affected the risk for depression and TBI, but they Evidence that brain glucose availability influences exercise-enhanced extracellular 5-HT level in hippocampus: A microdialysis study in exer- found no association. cising rats. Acta Physiologica Scandinavica 176(1): 65-69. Bhattacharjee, Y. 2008. Shell shock revisited: Solving the puzzle of blast trauma. Science 319(5862): 406-408. Prospective interventions Binder, E.B., R.G. Bradley, W. Liu, M.P. Epstein, T.C. Deveau, K.B. Mercer, While the long-term treatment of PTSD and the con- Y. Tang, C.F. Gillespie, C.M. Heim, C.B. Nemeroff, A.C. Schwartz, J.F. Cubells, and K.J. Ressler. 2008. Association of fKBP polymorphisms sequences of TBI may not be the primary responsibility and childhood abuse with risk of posttraumatic stress disorder symp - of the Army, it is in the Army’s interest to understand the toms in adults. Journal of the American Medical Association 299(11): pathophysiology of these conditions sufficiently to develop 1291-1305. effective preventive interventions or acute treatments that Blomstrand, E., P. Hassmèn, S. Ek, B. Ekblom, and E.A. Newsholme. mitigate a trauma. Such interventions could include physi- 1997. Influence of ingesting a solution of branched-chain amino acids on perceived exertion during exercise. Acta Physiologica Scandinavica cal training, psychological methods, or pharmaceuticals. 159(1): 41-49. Continued research on the identification of risk factors for Blomstrand, E., K. Moller, N.H. Secher, and L. Nybo. 2005. Effect of the development of PTSD could inform interventions that carbohydrate ingestion on brain exchange of amino acids during sus- mitigate a risk for PTSD and related stress disorders, thereby tained exercise in human subjects. Acta Physiologica Scandinavica lessening the risk of performance deficits and disabilities. 185(3): 203-209. Bluthe, R.-M., R. Dantzer, and K.W. Kelley. 1997. Central mediation of the Understanding the neuropathology of TBI should aid in effects of interleukin-1 on social exploration and body weight in mice. developing better types of body armor to lessen, to the extent Psychoneuroendocrinology 22(1): 1-11. possible, the specific types of trauma associated with blast Bremner, J.D. 2006. Stress and brain atrophy. CNS & Neurological injury. These interventions could hasten recovery after blast Disorders—Drug Targets 5(5): 503-512. exposure and the more rapid return of soldiers to mission. Burns, N.R., J. Bryan, and T. Nettelbeck. 2006. 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