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Opportunities in Neuroscience for Future Army Applications 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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Opportunities in Neuroscience for Future Army Applications tral nervous system (CNS) and peripheral (muscle) factors contribute to the onset of fatigue during prolonged physical exertion. However, the neurophysiological basis of CNS fatigue is not understood. There has been little systematic neuroscience research into the causes of CNS fatigue and potential countermeasures to it. Given the ever-increasing mental demands on today’s warfighter, along with emerging evidence showing the potential for nutrition to reduce CNS fatigue during sustained periods of physical and mental exertion, there is much to be gained by applying neuroscience research to improve warfighter performance. At a minimum, the tools should include functional magnetic resonance imaging (fMRI), transcranial magnetic stimulation, more sophisticated behavioral studies in humans, and basic neurochemical and physiological assessments in rodents.2 Good evidence is emerging to suggest that CNS fatigue may be caused, in part, by reduced availability of glucose, the main energy source for the brain, and/or an imbalance of neurotransmitters/neuromodulators, including serotonin, dopamine, adenosine, and ammonia. Under some circumstances, an increase of inflammatory cytokines and elevated brain temperature could also play a role (Bautmans et al., 2008; Miller, 2009). Carbohydrate and/or caffeine feedings during exercise are the most well-established nutritional strategies used to delay both physical and mental fatigue. Less information is available on promising new nutritional strategies such as tyrosine supplementation, which has been shown to benefit mental performance in military-specific situations, and novel food and spice extracts and phytochemicals derived from traditional medicines like quercetin and curcumin. Phytochemicals may work by virtue of their antioxidant and anti-inflammatory activity as well as their ability to provide sustained energy within the brain and muscle. Although claims of enhanced mental performance during long periods of physical or mental stress are made for a range of nutritional supplements, including branched-chain amino acids (BCAAs), ginseng, ginkgo biloba, and choline, there is little scientific support for these claims. The development of fatigue during sustained periods of physical and mental stress is a complex and poorly understood phenomenon. During prolonged exercise, many factors contribute to the production and onset of fatigue. These factors can operate peripherally—that is, in the muscles—most importantly through depletion of the intramuscular carbohydrate stores and/or through inhibition of adenosine triphosphate (ATP) hydrolysis due to the accumulation of metabolic waste products such as phosphates and hydrogen ions (Davis and Fitts, 1998). They also act centrally in the brain, but the physiological mechanisms of CNS fatigue are just now beginning to be unraveled. Good evidence is emerging that demonstrates how important a role the CNS plays in the processes of fatigue. Unfortunately, advances in understanding fatigue and its consequences for performance have been held back because physiologists almost exclusively study peripheral factors in fatigue (e.g., those that involve muscle, heart, or blood) in isolation from CNS involvement, whereas psychologists study mental factors (e.g., cognition, mood, vigilance, sleepiness) in isolation from peripheral interactions. Although mind and body are inextricably linked in the onset and consequences of fatigue, there has been very little focus on the neurophysiological basis of the complex interactions between the brain and peripheral factors. Nowhere is an understanding of the biological mechanisms by which the CNS and peripheral factors in fatigue interact more important than in sustaining today’s soldiers. The increased speed, complexity, and lethality of modern warfare make it even more important than in the past to understand how to sustain or enhance physical and cognitive performance. It is also important to maintain mood and motivation as the foundation of both physical and mental performance. Without such an understanding, it will be difficult to move past outdated strategies such as nutrition and exercise training to offset muscle-specific fatigue or caffeine to maintain wakefulness. This section presents a working model of the factors associated with fatigue during sustained periods of physical and mental exertion. It then briefly reviews emerging evidence of the neurobiological basis of fatigue. This new understanding, along with the likelihood that nutrition can play an important role in mitigating CNS fatigue, can provide the foundation for what should become an area of emphasis in neuroscience research and applications relevant to soldier performance. A working model of the factors involved in fatigue is shown in Figure 5-1. Fatigue results from mental and physical factors that ultimately increase the conscious perception of fatigue and the impairment of mental and physical performance. Physical performance requires not only the capacity of muscle to maintain its force production but also adequate motivation or effort, mental alertness, clarity of thought, decision-making ability, and mood (Davis and Bailey, 1997; Davis, 2000). Neural processes, including higher-level cognitive processing, are important components of the fatigue state, whose symptoms at onset include decreased energy, motivation, arousal, and vigor, as well as increased tiredness, perception of effort, and force sensation. These feelings of fatigue almost always occur before the muscle actually loses the ability to maintain the required force or power output (Hampson et al., 2001). Although highly trained individuals (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 perform as well in a fatigued state as when well rested is not borne out by objective measures of cognitive performance. 2 Animal studies are necessary to gain understanding of neurobiological mechanisms of fatigue to a degree that is not possible using human trials.
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Opportunities in Neuroscience for Future Army Applications FIGURE 5-1 Schematic diagram illustrating the likely interactions between central and peripheral components of fatigue. SOURCE: Committee-generated. As fatigue approaches, concentration and decision-making abilities often become impaired. There is also good evidence of direct impairments in central drive to the muscles and of impairments of motor coordination (Gandevia, 2001; Smith et al., 2007; Reis et al., 2008). All these factors are particularly important for today’s soldiers, who must have good decision making, vigilance, mood, and motivation for mission success. Maintaining these factors for extended periods of time in harsh environments and at high levels of physiological and psychological stress is essential for soldiers to perform optimally despite these stressors. New evidence from fMRI and transcranial magnetic imaging have begun to provide a better understanding of the neural correlates of fatigue (Gandevia, 2001; Cook et al., 2007; van Duinen et al., 2007; Reis et al., 2008). However, these studies have not been applied to whole-body exercise during sustained periods of physiological and psychological stress. Neurophysiological Basis of CNS Fatigue Very little neuroscience research has focused on the possible biological basis of CNS fatigue. However, recent evidence suggests testable hypotheses about the factors underlying CNS fatigue. These factors include (1) an inadequate supply of energy (glucose), (2) an imbalance among several neurotransmitters/neuromodulators, and (3) elevated brain temperature. One hypothesis is that CNS fatigue occurs during prolonged periods of intense physiological and psychological stress as a result of increased metabolic and oxidative stress in highly active brain regions, decreased availability of glucose, either delivered by the blood or derived from brain glycogen, and increased levels in the brain of 5-hydroxytryptamine (5-HT), coupled with a decrease in brain dopamine and increases in brain adenosine and ammonia. Under certain circumstances, CNS fatigue could also come from increased inflammatory cytokines and elevated brain temperature (Bautmans et al., 2008). Carbohydrate: Fuel for the Brain The brain is protected by the blood-brain barrier, which selectively allows transport of important nutrients into the brain. However, glucose is essentially the brain’s only fuel source. The exercise-induced reduction in blood glucose and in muscle and liver glycogen can contribute greatly to muscle-specific fatigue, but carbohydrate depletion is an even greater problem for the brain, which stores very little glycogen (Evans and Amiel, 1998). Although glucose availability has traditionally been thought to remain relatively constant throughout the brain under most conditions when adequate blood glucose is maintained (Robinson and Rapoport, 1986), recent research suggests that the brain’s glucose supply is compartmentalized. As glucose supply and demand change, concentrations change frequently in some areas but not in others (McNay et al., 2001).
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Opportunities in Neuroscience for Future Army Applications Altering brain glucose availability can affect both physical and mental performance. For example, Koslowski et al. (1981) showed that glucose infusion into the carotid artery delayed fatigue in dogs during treadmill exercise. McNay et al. (2000) found that performance of demanding cognitive tasks reduced tissue glucose availability in a specific region of the brain (hippocampus) that is very active during mental functions, even though blood glucose was well maintained. They also showed that intravenous infusion of glucose blocked the decrease in glucose in the hippocampus and improved performance of the cognitive task. Evidence from human studies also shows important benefits of carbohydrate supplementation for mental function, including perceived exertion, vigilance, and mood (Lieberman et al., 2002; Nybo, 2003). Recent elegant studies in humans provide direct evidence for the important role cerebral carbohydrate availability and energy turnover play in physical performance during prolonged exercise (Nybo et al., 2003a, 2003b). Adenosine, Ammonia, and Dopamine Increased metabolic stress and decreased glucose availability can lead to an increase in brain levels of adenosine and ammonia. Adenosine is a product of the breakdown of ATP, the body’s most important energy molecule. Increased levels of adenosine in the brain have been linked to tiredness and sleep (Huston et al., 1996; Porkka-Heiskanen et al., 1997; Porkka-Heiskanen, 1999). Plasma ammonia concentration can become markedly elevated during prolonged strenuous exercise. Ammonia can easily penetrate the blood-brain barrier and is toxic to the brain. It has been proposed that increased levels of circulating ammonia may play a role in CNS fatigue (Banister and Cameron, 1990; Davis and Bailey, 1997). Direct evidence of exercise-induced increases in brain ammonia and impaired brain function was shown in rats by Guezennec et al. (1998) and, more recently, in humans by Nybo et al. (2005). The latter study found a good association between arterial ammonia concentration, brain uptake of ammonia, cerebral spinal fluid (CSF) ammonia concentration, and perceived exertion during prolonged exercise in human subjects. A high concentration of brain dopamine is associated with energetic mood, arousal, motivated behaviors, and movement initiation. Control of dopamine is responsible for the effects of many stimulants such as caffeine and ephedrine (Davis, 2000). Dopamine levels in the brain initially increase during endurance exercise and then decrease at the point of fatigue (Bailey et al., 1993). Through various modulatory interactions, increases in serotonin and adenosine play roles in decreasing dopamine levels (Fredholm et al., 1999; Davis, 2000). Brain Inflammation, Interleukin-1β, and Fatigue Cytokines are an important link between the immune system inflammatory responses and CNS fatigue. During times of inflammation, this cross-talk enables the development of behavioral changes whose goal is to hasten recovery. Interleukin-1β, a potent proinflammatory cytokine and one of the first cytokines upregulated during an inflammatory response, can initiate a host of sickness symptoms, known as sickness behavior, which include poor appetite, changes in sleeping patterns, reduced interest in environment, and, most important, profound fatigue (Dantzer and Kelley, 1989). Fatigue may be initiated by interleukin-1β produced by toxins or disuse damage in the peripherial system, but it is now known that these cytokines are also expressed in the brain (Allan et al., 2001). And it is in the brain that they produce their potent behavioral effects (Kent et al., 1992). Whether peripherally released interleukin-1β enters the brain or transmits its inflammatory signal to the brain via afferent nerves (e.g., the vagus nerve) to initiate fatigue is still under investigation. However, in various inflammatory models, including exercise-induced muscle damage, interleukin-1β-induced behavioral effects, including fatigue, can be blunted by a brain-administered interleuken-1 receptor antagonist, which indicates that the brain is the origin of interleukin-1β-induced fatigue (Bluthe et al., 1997; Carmichael et al., 2006). Nutritional Measures to Counter the Effects of Fatigue An interesting and exciting aspect of this understanding of CNS fatigue is the growing scientific evidence that suggests nutrition may be effective in preventing or at least delaying these responses in the brain. Branched-Chain Amino Acids Newsholme et al. (1987) laid the foundation for one of the first nutritional strategies to delay CNS fatigue. He reasoned that dietary supplementation of the BCAAs valine, leucine, and isoleucine could delay CNS fatigue by offsetting the increase in the ratio of free tryptophan (another amino acid) to BCAA, thereby preventing the typical increase in uptake of tryptophan by the brain during exercise. Limiting tryptophan access would decrease 5-hydoxytryptamine (5-HT) synthesis. Although administration of BCAA in rats prolonged the time to exhaustion (Yamamoto and Newsholme, 2000), positive effects of BCAA ingestion on exercise performance in humans are largely unsubstantiated (van Hall et al., 1995; Strüder et al., 1996; Davis et al., 1999; Davis, 2000; Lieberman, 2003; Cheuvront et al., 2004). Although physical performance in humans is apparently not influenced by BCAA ingestion, a few studies have reported benefits for cognitive performance and mood. These benefits include improved effort during postexercise psychometric testing (Strüder et al., 1998), improved postexercise Stroop Colour-Word test scores (Hassmèn et al., 1994; Blomstrand et al., 1997), maintained performance in postexercise shape-rotation and figure-identification tasks (Hassmèn et al., 1994), and less perceived exertion during exercise (Blomstrand et al., 1997). However, Cheuvront
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Opportunities in Neuroscience for Future Army Applications et al. (2004) reported no significant differences in mood, perceived exertion, or cognitive performance with BCAA supplementation. Similarly, infusion of a saline solution containing BCAA had no effect on perceived exertion during 90-minute treadmill runs (Strüder et al., 1996). The committee believes that there is not enough evidence so far to recommend BCAA supplementation to delay brain fatigue. An important concern here is the well-characterized increase in ammonia production and the brain dysfunction that can occur when large BCAA doses are ingested during exercise (van Hall et al., 1995). In addition, acute tryptophan depletion produces mood and cognitive disturbances in individuals with a history of depression or a heritable variant of the serotonin transporter (Neumeister et al., 2006). Carbohydrate Supplementation It is well established that carbohydrate supplementation during prolonged, intense exercise delays fatigue. The majority of research to understand this effect of carbohydrate feedings has focused on peripheral mechanisms such as maintaining blood glucose levels and sparing muscle glycogen stores (Coggan and Coyle, 1991). More recently, research has demonstrated the beneficial effects of carbohydrate supplementation on CNS fatigue. Carbohydrate beverages have been shown to benefit CNS function in both sport and military settings. In the late stages of exercise designed to mimic the demands of soccer and basketball, carbohydrate beverages enhanced performance of gross motor skills, decreased sensitivity to physical force, improved mood (both reported and observed), increased vigor, and reduced perception of fatigue/tiredness. All of these effects were seen in addition to enhanced physical performance, including faster sprint times and higher average jump heights (Welsh et al., 2002; Winnick et al., 2005). Lieberman et al. (2002) also showed a dose-related improvement in vigilance (sustained attention) in a U.S. Army Special Operations unit with carbohydrate supplementation during sustained physical activity designed to mimic a typical combat operation. In addition to improvements in physical performance, volunteers who received carbohydrate supplementation also reported increased vigor and decreased confusion. Even as little as 25 g of glucose can increase cognitive functioning and decrease subjective feelings of mental fatigue (Reay et al., 2006). The neurobiological mechanisms of the benefits of carbohydrate beverages on CNS function remain speculative. One hypothesis is that carbohydrate beverages provide energy in the form of glucose, along with an increase in dopamine and reductions in brain 5-HT, adenosine, ammonia, and brain temperature. The extra energy supplied by sustaining blood glucose levels presumably lessens the metabolic stress in the brain during exercise, leading to a smaller increase in brain adenosine. The relationship between prolonged exercise, brain adenosine, and tiredness/sleep has recently been demonstrated in rats (Dworak et al., 2007). More glucose can also lessen the increase in brain ammonia, which is toxic to the brain (Nybo et al., 2005). Greater glucose availability in the blood lessens the concentration of fatty acids in the blood, which in turn blunts the typical increase in free tryptophan available for transport into the brain and presumably attenuates the increase in brain serotonin that is typically associated with tiredness, lethargy, depression, and low arousal (Davis et al., 1992; Bequet et al., 2002; Blomstrand et al., 2005). Lowered serotonin and adenosine combine to combat the drop in brain dopamine as exercise progresses (Davis et al., 2003b) and, along with the reduced levels of brain ammonia, help delay brain fatigue (Davis, 2000; Nybo et al., 2005). Finally, carbohydrates are typically consumed during exercise as sports drinks that provide fluid to offset dehydration and reduce the risk of elevated body temperature—and therefore brain temperature, which is another factor in exercise-induced central fatigue (Nybo, 2008). Caffeine Caffeine is the most widely consumed nervous system stimulant in the world. It has long been reported to increase wakefulness, subjective feelings of energy, vigilance, mood, and mental and physical performance. All of these effects are due to an increase in dopamine activity and are opposite to those produced by adenosine (Fredholm et al., 1999). Caffeine competes with adenosine for binding to adenosine receptors in the brain, so if caffeine displaces some adenosine molecules, the negative effects of adenosine discussed previously will be reduced (Garrett and Griffiths, 1997). The primary outcome of blocking adenosine receptors with caffeine is a large increase in the release of dopamine in the brain (Fredholm et al., 1999). This hypothesis was confirmed in a recent study by Davis et al. (2003b) of rats during prolonged treadmill running to fatigue. Caffeine use to improve cognitive functioning during sustained military operations has been extensively researched (NRC, 2001). In a review by Lieberman (2003), it was reported that caffeine improves vigilance in rested and sleep-deprived individuals, improves target detection speed without adversely affecting rifle-firing accuracy, improves decision response (choice reaction) time, improves learning and memory, and improves mood, including perceptions of fatigue and sleepiness. Benefits were seen with as little as 100-200 mg caffeine (~1.4-2.8 mg/kg body weight). Although optimal caffeine doses vary widely among individuals, caffeine can improve cognition and mood in both habitual caffeine users and nonusers (Haskell et al., 2005). Ephedrine as a Dietary Supplement Ephedrine is another commonly used stimulant that has demonstrated ergogenic properties. Ephedra, which is an extract from the Chinese ma huang plant (an herb in the genus Ephedra), contains ephedrine and related alkaloids and is used as a dietary supplement. It has been reported that there is an additive ergogenic effect when ephedrine is used with caffeine, with
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Opportunities in Neuroscience for Future Army Applications the performance enhancement being greater than when either stimulant is used alone (Magkos and Kavouras, 2004), and, indeed, most commercial ephedrine-containing products also contain caffeine. A supplement containing 375 mg of caffeine and 75 mg of ephedrine improved run times (Bell and Jacobs, 1999), and Bell et al. (2000) demonstrated that lower doses of caffeine plus ephedrine (4 mg caffeine per kilogram body weight and 0.8 mg ephedrine per kilogram body weight) were just as ergogenic as higher doses but with fewer adverse side effects. Caffeine, ephedrine, and similar stimulants are associated with adverse side effects, and responses to these drugs are highly individualized. Minor side effects can include insomnia, anxiety, irritability, mild diuresis, headaches, and gastrointestinal distress. More severe side effects can include severe diuresis and dehydration, tachycardia, arrhythmia, hypertension, dependence, seizures, coma, or death. Caution must be taken when using caffeine and/or other stimulants. Sometimes it is difficult to determine that a product contains caffeine or other stimulants because they are not specifically listed as such on the label. For instance, guarana is a popular constituent of many commercial energy products, but it is not widely known that the main active component of guarana is, in fact, caffeine. Tyrosine Tyrosine is the amino acid precursor of the neurotransmitter dopamine, which has been associated with energetic mood, arousal, motivated behaviors, and movement initiation and control (Davis, 2000). There is promising but preliminary evidence that tyrosine supplementation may have beneficial effects on cognitive functioning and mood, especially under prolonged stress. Chinevere et al. (2002) showed in a study of prolonged and intense cycling that tyrosine lessened perceived exertion. In addition, tyrosine supplementation, when tested in subjects in prolonged stressful environments such as military operations, improved vigilance, choice reaction time, pattern recognition, map and compass reading capabilities, working memory, and mood, including perceptions of fatigue, confusion, and tension (Lieberman, 2003; Magill et al., 2003; Lieberman et al., 2005; Mahoney et al., 2007). Supplemental dietary tyrosine increases plasma concentrations of the amino acid (Davis and Bailey, 1997), but the mechanism by which this affects brain activity to produce the observed performance benefits is uncertain. For the central catecholamine neurotransmitters—norepinephrine, dopamine, and epinephrine—the rate-limiting step in their synthesis is the activity of the enzyme tyrosine hydroxylase. This enzyme is fully saturated with its tyrosine substrate even under dietary starvation conditions (Cooper et al., 2003). This point argues against a simple mass effect of increased plasma tyrosine on dopamine production. Increased plasma tyrosine may be acting by some other mechanism. For example, it may compete with the amino acid tryptophan for the transporters required to move these amino acids across the blood-brain barrier. A decreased uptake of tryptophan may decrease brain serotonin; the resultant change in the ratio of brain serotonin to dopamine might improve performance when subjects are experiencing CNS fatigue. At present, however, this and other hypotheses for how tyrosine supplementation works remain speculative. Although the evidence is limited, tyrosine supplementation is a promising nutritional intervention that may have significant effects on the CNS, but more studies are needed before specific recommendations can be made. Herbal Derivatives: Quercetin and Curcumin Herbal remedies for fatigue, both physical and mental, have been used in traditional medicine for centuries. The biologically active components of these remedies are receiving increased attention in the biomedical literature as dissatisfaction grows with the cost and efficacy of conventional Western pharmacological interventions for general ailments. Two of these herbal derivatives that may in time prove to have positive effects on both the mental and physical components of fatigue are quercetin and curcumin. Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a flavonoid3 found in many fruits and vegetables such as apples, onions, red grapes, berries, and black tea. Preliminary evidence suggests that the effect of quercetin on CNS fatigue is like the effect of caffeine as an adenosine antagonist with resulting increase in dopamine activity. Perhaps the most important and exciting aspect of quercetin supplementation is its effects on brain and muscle mitochondrial biogenesis, which would be expected to increase energy availability. Davis et al. (2007a) found that 7 days of quercetin feedings in mice subjected for 3 days to a treadmill run to fatigue (about 140 minutes) increased markers of mitochondrial number and function in muscle and brain compared with untreated controls; they also observed improved running performance in the quercetin-fed mice in both run to fatigue and voluntary wheel-running activities. In human subjects, quercetin feedings increased the maximum aerobic capacity (VO2 max) and ride time to fatigue on a bicycle as measured by an ergometer (Chen et al., 2008). However, the specific importance of increased brain mitochondria has not been determined in this context. Another potential application for quercetin in mitigating CNS fatigue involves its powerful antioxidant and anti-inflammatory activity. Quercetin has strong anti-inflammatory properties by virture of its ability to modulate enzymes and transcription factors within pathways essential for inflammatory signaling, including those that are involved in the interleukin-1β signaling cascade (Comalada et al., 2005, 2006; Dias et al., 2005). Quercetin has been shown to reduce the expression of pro-inflammatory cytokines (Huang 3 The term “flavonoid” refers to a class of secondary plant metabolites often cited for their antioxidant properties. Chemically, a flavonoid is an aromatic compound that has two substituted benzene rings connected by a chain of three carbon atoms and an oxygen bridge.
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Opportunities in Neuroscience for Future Army Applications et al., 2006; Min et al., 2007; Sharma et al., 2007) and other inflammatory mediators such as COX-2 and NF-κB from many types of cells, including astrocytes,4 following treatment with various inflammatory agents (O’Leary et al., 2004; Martinez-Florez et al., 2005). Quercetin is generally known to have a much wider safety margin when administered for extended periods (Harwood et al., 2007; Lakhanpal and Rai, 2007) than do anti-inflammatory pharmaceuticals, which are sometimes used for off-label medical indications. In short, based on the literature cited above, quercetin may mitigate CNS fatigue during sustained operations and incidentally provide some protection from other stressors such as injury, infection, and toxic exposures. Understanding the role of inflammation in fatigue is important when examining the possible benefits of another nutritional countermeasure, curcumin. Curcumin (diferuloylmethane) is an anti-inflammatory component of turmeric, an east Asian plant root familiar as a spice in curries but also a traditional herbal medicine used to treat inflammations of arthritis, heartburn and stomach ulcer, and gallstones (NCCAM, 2008). In recent research, curcumin hastened recovery to baseline performance after exercise-induced muscle damage partly because it attenuated the inflammatory response in muscle and presumably also in the brain (Davis et al., 2007b). However, the specific role of curcumin in brain inflammation, interleukin-1β, and fatigue requires further study. Herbal Products Herbals are a relatively new area of research, and the mechanisms of their actions remain unclear. Ginseng is by far the most studied of the herbal products. Reay et al. (2005) showed that a single 200-mg dose of Panax ginseng was associated with improved cognitive performance and lower subjective feelings of mental fatigue on a visual analog scale. In a follow-up study, Reay et al. (2006) tested the possible interaction between P. ginseng and a carbohydrate drink. Both the carbohydrate drink and P. ginseng showed improvements on some of the cognitive tests and lowered subjective feelings of mental fatigue, but there was no additive effect by P. ginseng and glucose on any of the cognitive outcomes measured. It should be noted, however, that ingestion of P. ginseng often reduces blood glucose levels, which could be detrimental to cognitive performance. Because studies of the potential beneficial effects of ginseng on physical exercise performance often involve long-term vs. sporadic/occasional ginseng supplementation, their results are equivocal. Without a reasonable mechanism of action, the evidence that ginseng ingestion can improve exercise performance is not convincing. Guarana (whose active component is caffeine) in commercial supplements is often found in combination with P. ginseng. Few studies have assessed the effects of guarana on cognitive and behavioral measures in humans. Haskell et al. (2005) evaluated guarana extract given in doses of 37.5 mg, 75 mg, 150 mg, and 300 mg. Increased secondary memory performance and increased mood (alertness and content) were seen, with the two lower doses showing more beneficial cognitive outcomes than the higher doses. Kennedy et al. (2004) gave subjects single doses of 75 mg guarana extract, 200 mg P. ginseng, or a guarana/ginseng mixture (75 mg/200 mg). Guarana supplementation led to improvements in attention tasks, a sentence verification task, and a serial subtraction task. The combination of guarana and ginseng also led to improvements on a speed-of-memory task. A few studies examined the effects of ginkgo biloba on cognitive effects in healthy young volunteers. Acute administration of ginkgo (120 mg) improved sustained attention and pattern recognition memory but had no effects on mood, planning, mental flexibility, or working memory (Elsabagh et al., 2005). However, 6-week chronic administration of ginkgo biloba (120 mg) had no effect on any of the cognitive or mood variables measured (Elsabagh et al., 2005; Burns et al., 2006). Some studies have shown slight positive cognitive effects of higher doses (360 mg) of ginkgo (Kennedy et al., 2002) and combination ginkgo/ginseng mixtures (Kennedy et al., 2001, 2002). Choline Supplements Choline serves as the dietary precursor to the neurotransmitter acetylcholine. One study reported that plasma choline levels dropped in marathon participants, and the authors suggested that choline supplementation before or during exercise might improve endurance performance (Conlay et al., 1992). However, there is insufficient evidence to support claims that choline supplementation improves physical or mental performance outcomes. Warber et al. (2000) studied the effects of choline citrate ingestion during a treadmill run to exhaustion, with subjects carrying a load of 34.1 kg. They found that choline supplementation had no effect on time to exhaustion, squat tests, or ratings of perceived exertion. In a similar treadmill test while carrying a load, Deuster et al. (2002) found that choline supplementation (50 mg per kilogram body weight) had no effects on physical or cognitive performance, including tests of reaction time, logical reasoning, vigilance, spatial memory, and working memory. Summary of CNS Fatigue Countermeasures 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 good mental functioning—for instance, to maintain alertness, clarity of thought, decision-making ability, and mood. 4 Astrocytes are star-shaped, nonneuronal glial cells. Glial cells constitute the essential supporting tissue, or glia (meaning “glue”), of the brain, which is essential for the health and functioning of the neurons (nerve cells).
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Opportunities in Neuroscience for Future Army Applications Both brain and body contribute to the onset of fatigue during endurance exercise. Nutritional strategies designed to enhance CNS function are likely to also improve physical performance. CNS fatigue may be caused in part by reduced glucose availability or by an imbalance between serotonin, dopamine, and adenosine, along with an increase in circulating ammonia, inflammatory cytokines, and—sometimes—elevated brain temperature. The levels of these transmitters as such do not directly change the effectiveness of the neurons that use them. For example, the neuronal circuits that use these transmitters could become unbalanced, but the brain’s adaptive systems go to great lengths to maintain equilibrium. What can change in the short term and later drive metabolic compensations is the activity of the neurons that use these transmitters. Even though our understanding of possible mechanisms for CNS fatigue is severely limited, the evidence has risen to a level that supports development of testable hypotheses and justifies a recommendation to increase systematic neuroscience research into the neurobiological basis of CNS fatigue and possible nutritional countermeasures in both animal and human models. The most promising nutritional strategies involve carbohydrate and caffeine supplementation, which can increase glucose and dopamine while decreasing serotonin and adenosine. Tyrosine supplementation might have some benefits in certain situations, possibly by increasing brain dopamine. Perhaps the most exciting new supplements that deserve more research are quercetin and curcumin. These supplements may work via their antioxidant and anti-inflammatory activity, along with an increase in mitochondrial biogenesis (quercetin only). To summarize, neuroscience approaches are already being used to examine the effects of commonly used nutritional supplements on brain functioning. These efforts are just the beginning of research on the effects of various candidate nutritional supplements on brain functioning and performance. Although there is ongoing research sponsored or conducted by the Army into the practical effects of nutritional supplements, virtually nothing is known about how or where they affect brain function and which specific aspects of brain functions are improved (or impaired). Therefore, a concerted effort by neuroscience laboratories to support Army-relevant research would help the Army to identify and test potentially useful nutritional supplements. These efforts would probably yield important results within the next 5 years. Brain Response to Metabolic Stressors The Army medical community has long sponsored research on the effects of stress, pain, and sleep deprivation on soldier abilities. Neuroscience research has already demonstrated its potential to revolutionize understanding in these areas. For its weight, the brain has an extraordinarily high demand for glucose and oxygen supplied via the general circulation. Although it accounts for only 2-3 percent of total body mass, for an individual in a resting state the brain accounts for 20 percent of blood glucose utilization. The brain exhibits non-insulin-dependent glucose uptake. Glucose is transported from the blood compartment to the astrocytic end feet surrounding the vascular endothelial cells by glucose transport molecules (Dwyer, 2002). Although in the embryonic state the neuronal elements and glial cells contain an abundance of glycogen (a storage form of glucose), the neurons and glia of postnatal humans and adults contain very low levels of glycogen, thus making the brain dependent on vascular sources of energy. Under conditions of glucose deprivation, the brain can use ketone bodies from the breakdown of fats, but a well-fed individual depends almost totally on glucose to fuel the metabolic processes that produce ATP, the intermediary that provides the chemical energy for neuronal processes such as synthesis of macromolecules and cellular repolarization after axonal discharge. To provide the brain with sufficient metabolic resources, the distance between the small capillaries comprising the vascular bed in the brain approximates 0.1 mm, making the brain one of most highly vascularized organs in the body. Blood glucose levels are regulated by the release of glucose from the liver, where it is produced from glycogen, and by serum insulin levels that are controlled by pancreatic beta cells. Maintaining a functional metabolic state for decision making and other cognitive tasks—including perceptual discrimination, memory recall and new-memory consolidation, rule-based moral judgment, and multiple task performance—that are accomplished through neuronal information processing is thus critically dependent on the supply of energy-producing substrates for ATP synthesis. A variety of neurotransmitters and growth factors affecting neural development and function (for example, thyroxin, galanin [an insulin-like growth factor], estrogen, and corticosteroids) have a measurable effect on glucose uptake and metabolism. As discussed in the preceding section on countermeasures to fatigue, quercetin is one of the dietary flavonoids under active investigation as a fatigue countermeasure. Quercetin is also of interest as a dietary supplement to sustain brain function and cognition generally. In addition to its antioxidant and anti-inflammatory characteristics, described above, quercetin may have other mechanisms of action (Nieman et al., 2007). It also has a binding affinity to the adenosine A-1 receptor 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 attenuate the deterioration associated with aging or ethanol intake. By interacting with the adrenergic adenosine A1 receptor, quercetin may improve neural function (Patil et al., 2003; Singh et al., 2003; Naidu et al., 2004). Various technologies are being studied to enable soldiers to retain complex decision-making capabilities during continuous operations lasting 72 hours. Transcranial
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Opportunities in Neuroscience for Future Army Applications electrical stimulation, enhanced contrast iconography, and flashing icons representing threat (red force) on Force XXI Battle Command Brigade and Below video displays are examples of such technologies. In addition, pharmaceutical supplements are in development to sustain complex decision-making capabilities for extended operations. Sleep Deprivation Sleep is not the mere absence of wakefulness. It is an active state that is finely regulated and that undoubtedly plays multiple important roles in brain function. While it is accepted that sleep deprivation degrades performance and impairs vigilance, there are other positive functions of sleep that may be degraded when soldiers are deprived of adequate sleep (Van Dongen et al., 2004b). Current military doctrine is based on operational activities for ground forces continuing for periods up to 72 hours. A persistently high operations tempo places coalition forces in a dominant position with respect to their adversary. However, also associated with 72 hours of sustained operation is sleep deprivation and concomitant reductions in capabilities for decision making and complex cognitive functioning while performing several tasks. The pioneering studies of Gregory Belenky at Walter Reed Army Institute of Research have demonstrated that whereas overlearned sharpshooting capabilities are retained after 40 hours of sleep deprivation, the decision-making ability required for differentiating specific targets from neutral images deteriorates markedly. These and similar observations show that different facets of attention and decision making decay at different rates as sleep deprivation accumulates. Research over the past two decades indicates that sleep is essential for consolidating memory and promoting synaptic plasticity. Sleep affects the two major types of memory: declarative memory, which involves retention of facts, and procedural memory, which refers to acquisition of complex skills. Declarative memory is encoded, at least initially, in the hippocampus, whereas procedural memory appears to be localized primarily in the frontal cortex (Marshall and Born, 2007). Electrophysiologic studies of place cells (neurons that fire when an animal is in a specific place in a maze) in the hippocampus reveal that the series of place cells activated in the maze during the acquisition of a spatial learning task is reactivated in precisely the same sequence when the animal is in slow-wave sleep but several times more rapidly. Rapid eye movement (REM) sleep, in contrast, appears to benefit the consolidation of procedural memory (Euston et al., 2007). Investigators speculate that sleep gets the brain off-line so that it can engage the diverse cortical circuitry in memory consolidation. Sleep deprivation severely compromises the ability of humans to respond to stimuli in a timely fashion. The observed deficits have often been attributed to failures of vigilant attention, which many investigators believe is the foundation of the more complex components of cognition. David Dinges at the University of Pennsylvania has exploited the psychomotor vigilance test (PVT)—a high-signal-load, reaction-time test—to characterize the neurocognitive effects of sleep deprivation. As the amount of normal sleep time 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 extended periods of sleep deprivation, interactions between the circadian and homeostatic sleep drives contribute to the lapses in performance (Lim and Dinges, 2008). Chee et al. (2008) used fMRI to study subjects performing the PVT who were either well rested or sleep deprived. They found that lapses occurring with sleep deprivation, compared with lapses after normal sleep, were associated with a reduced ability of frontal and parietal regions to raise activation, dramatically reduced visual sensory cortex activation, and reduced thalamic activation. Notably, correct performance under both conditions elicited comparable levels of frontoparietal activation. Thus, sleep deprivation produces periods of apparently normal neural activation interleaved with periods of depressed cognitive control, visual perceptual function, and arousal. Another finding was that most subjects have poor insight into the degree of their own impairment due to sleep deprivation. There are substantial traitlike differences among individuals in terms of their vulnerability to neurobehavioral deficits as the amount of lost sleep increases. Three categories have been identified, with Type 1 individuals being highly tolerant of sleep deprivation (cognitive performance near normal on the tests used). Type 2 individuals are those around the mean performance deficit, and Type 3 individuals are substantially more vulnerable to sleep deprivation than the norm (Van Dongen et al., 2004a). These responses to sleep deprivation are highly stable over time for a particular individual, consistent with the response patterns being stable traits with a high genetic component. Identifying reliable biomarkers5 for these behavioral types is a high priority for the field of sleep research. Screening with the PVT or another suitable biomarker could be useful to the Army in selecting individuals with optimal resistance to sleep deprivation for missions or assignments where sleep time is likely to be below normal for a sustained period. For soldiers deployed in combat operations, there are profound effects of sleep deprivation on brain glucose utilization (Spiegel et al., 2005). Positron emission tomography studies have demonstrated that sleep deprivation reduces glucose uptake by the brain. Sleep deprivation also affects release of insulin from the pancreas, which affects the levels of circulating blood glucose. The diurnal levels of hormones that respond to food intake (e.g., leptin and ghrelin) are also modified by sleep deprivation. The 28-amino-acid gastric 5 See Chapter 2 for the committee’s definition of “biomarker” and 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 responses (Sibilia et al., 2006). This pain suppression effect has not yet been correlated with glucose metabolism. The van Cauter group reported that suppression of slow-wave sleep patterns (non-REM sleep) in healthy subjects alters normal glucose homeostasis (Tasali et al., 2008). Aside from its interest in prolonging wakefulness, the Army would benefit from following the research on the benefits of sleep. It has recently been suggested that short bouts of sleep can facilitate memory consolidation (Lahl et al., 2008). In the future, it may be possible to improve sleep efficiency so that the necessary physiological processes accomplished during sleep could be done much more rapidly or without the loss of consciousness. For example, birds are able to engage in slow-wave sleep in one hemisphere at a time so that they can remain vigilant and even fly. Marine mammals (cetaceans) also experience slow-wave, symmetric sleep in one hemisphere at a time, while the other hemisphere shows wakeful activity (Pillay and Manger, 2004; Lyamin et al., 2008). The homeostatic facet of sleep-wake regulation is keeping track of changes in “sleep propensity” (or “sleep need”), which increases during wakefulness and decreases during sleep. Increased sleep propensity following extended prior wakefulness (sleep deprivation) is counteracted by both prolonged sleep duration and enhanced non-REM sleep intensity, as measured by electroencephalography. There is compelling and convergent evidence that adenosinergic neurotransmission plays an important role in non-REM sleep homeostasis. Adenosinergic mechanisms modulate individual vulnerability to the detrimental effects of sleep deprivation on neurobehavioral performance. Sleep deprivation increases the levels of extracellular adenosine and of the adenosine A1 receptor in the cholinergic zone of the basal forebrain. Caffeine, an A1 receptor antagonist, prolongs wakefulness and sleep latency by interfering with the rise of sleep propensity during wakefulness, as revealed by the buildup of theta-wave activity over the frontal lobes. A functional polymorphism in the adenosine-metabolizing enzyme adenosine deaminase contributes to the high interindividual variability in deep slow-wave sleep duration and intensity (Rétey et al., 2005). Additionally, the circadian gene PERIOD 3 has been shown to correlate with differential vulnerability to cognitive deficits resulting from total sleep deprivation (Viola et al., 2007; Groeger et al., 2008). Moreover, caffeine greatly attenuates the electroencephalography markers of non-REM-sleep homeostasis during both sleep and wakefulness. Whereas the homeostatic process determines sleep needs, the timing of sleep is determined by the circadian process, endogenous cycles of gene expression, and physical activity. The circadian secretion of melatonin from the pineal gland plays an important role in determining sleep onset, and this effect of melatonin has been exploited to manipulate sleep onset in shift workers, for example. A family of genes, known as “clock” genes, has been identified that comprise a “molecular clock.” They are expressed in many cell types throughout the body as well as in the neurons of the brain. Notably, clock genes are overexpressed in the cerebral cortex with sleep deprivation, indicating that they also play a role in sleep homeostasis (Tafti and Franken, 2007). Recent genetic studies reveal a significant role for heritability in sleepiness, usual bedtime, and usual sleep duration. Several genetic loci, including the clock genes, have been identified that mediate this behavior (Gottlieb et al., 2007). These genetic studies point to endogenous, interindividual differences in sleep homeostasis that may need to be identified to optimize selection of soldiers for specific tasks. They also point to potential targets for pharmacologically manipulating sleep in vulnerable individuals. PHARMACEUTICAL COUNTERMEASURES TO NEUROPHYSIOLOGICAL STRESSORS Over the past two decades, neuroscience has made remarkable advances in understanding the neural circuitry of memory, drive, mood, and executive function. Furthermore, the neurochemical features that mediate neurotransmission for components of these circuits have largely been characterized. This knowledge has provided the pharmaceutical industry with targets for developing drugs that perturb specific neurotransmitters, with the potential for treating disorders in which these neural systems have been implicated, such as schizophrenia, Alzheimer’s disease, severe mood disorders, and critical behaviors affected by specific neuropsychiatric disorders. Prospective neuropharmacological agents that act on wholly novel targets include a nicotinic acetylcholine receptor modulator to improve attention and executive function in attention deficit disorder, N-methyl-D-aspartic acid (NMDA), a receptor-positive modulator to enhance memory consolidation, and a metabotropic glutamate receptor agonist to treat psychosis (Patil et al., 2007). Over the next 5 to 10 years, it is highly likely that many new classes of drugs will be developed that mitigate symptoms and deviant behaviors associated with neuropsychiatric disorders. Beyond their approved therapeutic indications, these new medications have the potential for sustaining or optimizing the performance of soldiers. In addition, some of them are likely to alleviate the adverse neuropsychological consequences of combat and other extreme stressors, including major depression and stress-related disorders such as post-traumatic stress disorder (PTSD). As the Army debates using pharmaceuticals that have been approved by the Food and Drug Administration (FDA) for off-label uses such as sustaining or optimizing performance, it needs to consider a number of issues. First, drugs that affect the CNS by acting on a specific neurotransmitter are likely to affect multiple neural circuits, as a particular neurotransmitter is generally used in several functionally distinct circuits, such as dopamine in the striatum modulating
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Opportunities in Neuroscience for Future Army Applications 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. 1See Web 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, it is essential that specificity of action be demonstrated by the development of tools to measure stress on other baseline states desired. Box 5-1 illustrates the challenge of coming up with a tool to measure stress. Second, one must be concerned about unforeseen or delayed side effects, particularly when medical indications may be present for which the drug has not been formally approved. Cost-benefit analyses must be undertaken using tools to measure baseline states and which aspects of performance are being enhanced and to obtain clinical measures of overall effects, detrimental or positive. It is possible that some components of performance might be degraded even as others are improved. Used in this context, “benefit” refers to enhanced performance—for example, superior ability to withstand sleep deprivation, faster response times, and the overall improvement in carrying out the military mission. It may include a greater likelihood of survival. “Cost” refers not only to dangerous immediate side effects, but also to long-term side effects or even the potential for the enhanced abilities to lead to unacceptably risky behavior or other poor decisions. Currently, there are a few examples of the use of FDA-approved drugs to sustain behavior or prevent degradation of performance. Modafinil is prescribed to pilots in the Air Force who are tasked to fly prolonged missions. Sertraline hydrochloride (Zoloft, Lustral) is often prescribed to troops who have sustained repeated combat exposure to reduce the consequences of persistent stress and the risk of depression. Nonetheless, the committee has significant concerns about the potentially inappropriate use of performance-enhancing drugs by the military, particularly with respect to whether the benefits outweigh the risks. Still, it may be worthwhile to continue research into the use of neuropharmacological agents to mitigate degraded performance in unique military circumstances when the benefits of the agents outweigh the risks. To succeed in the area of neuropharmacological countermeasures to performance deficits due to stressors in operational environments, the Army needs to leverage its relationships with entities whose missions are focused on, or at least involve, developing new drugs—these entities include the pharmaceutical industry, the National Institutes of Health, and the university biomedical and pharmacological research communities. The Army should aim to build on the clinical findings of these entities to determine whether a therapeutic, preventive, or optimizing effectiveness purpose of an agent has been established for conditions relevant to Army operations and whether proper administration of a proven-effective agent is both technically feasible and advisable. The Army should use the full range of neuroscience methods to determine the mechanisms of action for a pharmaceutical’s proposed use beyond its approved medical indications and to ensure the specificity and selectivity of the proposed intervention. Finally, pharmacogenetics has revealed substantial 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 how widely such drugs are used for any purpose other than their FDA-approved therapeutic indications. Box 5-2 describes an example of predicting drug effects. Although these approaches are in their infancy, nevertheless they point toward unprecedented opportunities to selectively and specifically manipulate the brain to alter decision making. BRAIN INJURY As noted in Chapter 1, the committee was tasked to focus its study on nonmedical applications in light of the numerous studies of medical neuroscience research and applications. Nevertheless, biomedical and neurophysiological knowledge of combat-related brain injury and stress disorders is a prerequisite for assessing opportunities for mitigating these effects of combat, whether through preventive strategies or by prompt and efficient treatment after a soldier has experienced a potentially injurious event. Accordingly, the section begins with a brief overview of the most salient aspects of current biomedical understanding of brain injuries. The Iraq war has increased awareness and programmatic emphasis on mitigating, preventing, treating, and protecting against neurological damage. This war has seen a marked increase in the risk for traumatic brain injury (TBI) because of the high proportion of soldiers who have been injured by strong explosions due to improvised explosive devices (IEDs) and who have survived because they received prompt medical care. Blasts from IEDs may cause a unique type of brain damage compared with the more typical penetrating injuries of combat (Stuhmiller, 2008). It is also uncertain whether the number and duration of repeated deployments for the same soldiers have contributed to the prevalence of stress-related disorders in veterans of the Iraq and Afghanistan wars. Neuroscience research has improved our understanding of the brain’s response to stress, the pathophysiology of 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 Excellence for Psychological Health and Traumatic Brain Injury in 2008. Stress Disorders, Including PTSD Several studies and reviews have examined the risk for developing PTSD and allied stress-related disorders, such as panic attacks, emotional dyscontrol, and substance abuse (Hoge et al., 2008; Schneiderman et al., 2008; Smith et al., 2008). A recently released RAND study based on a representative sample of nearly 2,000 individuals deployed for Operation Enduring Freedom in Afghanistan and Operation Iraqi Freedom found that 18.5 percent of all returning service members met criteria for PTSD, depression, or both, whereas 19.5 percent reported experiencing a probable TBI during deployment. About a third of those experiencing a TBI had a concurrent mental disorder (RAND, 2008). Neuroscience research reveals that a complex interaction involving the brain, the adrenal glands, the peripheral automatic nervous system, and the immune system underlies this kind of mental stress (McEwen, 2007). Whereas the
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Opportunities in Neuroscience for Future Army Applications acute fight-or-flight response of the stress axis is protective, persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis can have noxious effects on the brain. McEwen coined the term “allostatic overload” to refer to persistent, excessive stress responses. He found that the powerful interaction between high anxiety and impaired sleep (since sleep deprivation causes increased blood pressure) increased levels of cortisol, insulin, and proinflammatory cytokines (McEwen, 2007). Several experimental paradigms have also shown that sleep deprivation inhibits neurogenesis in the hippocampus, which accounts for concurrent subtle cognitive impairments. Developmental studies of both animals and humans indicate that high levels of stress during human childhood, such as physical or sexual abuse or neglect, can markedly increase vulnerability to stress in adulthood (Heim and Nemeroff, 2002; Kaffman and Meaney, 2007). Stress early in life results in persistent blunting of the HPA axis, which is mediated by a down-regulation of glucocorticoid receptor expression due to methylation of the DNA in the promoter region of the gene (Meaney et al., 2007). Heritable factors such as allelic variants of the gene for the serotonin transporter, which inactivates serotonin at the synapse, can render individuals more vulnerable to stress early in life and at greater risk for depression in adulthood (Lesch and Gutknecht, 2005; Roy et al., 2007). Brain neurons express the glucocorticoid receptors, which are responsive to mineralocorticoids as well as to glucocorticoids. The hippocampus, a brain structure critically involved in learning and memory, expresses high levels of these corticoid receptors. Thus, it is not surprising that there is a complex relationship among brain glucocorticoid receptor occupancy, behavior, and cognition. The hippocampus, one of the most malleable structures in the brain, exhibits both functional and structural plasticity, including neurogenesis. Chronic stress or chronic treatment with exogenous glucocorticoids is associated with impairments of hippocampal-dependent memory tasks and with reduction in the volume of the hippocampus (Sapolsky, 2003). Persistent stress and elevated corticosteroids suppress neurogenesis and expression of brain-derived neurotrophic factor in the hippocampus. In this regard, quantitative morphometric studies consistently reveal reduced hippocampal volume in patients suffering from PTSD; the degree of atrophy correlates significantly with the degree of cognitive impairment (Bremner, 2006). It is not yet clear whether the reduced hippocampal volume is a predisposing factor in the development of PTSD or a consequence of traumatic injury. Many young adults (military or civilian) enter their early twenties with neurological change resulting from automobile accidents, football or other athletic injuries, febrile episodes from infection, or drug taking. An abundance of literature attests to the prevalence of all these factors in the U.S. young adult population. Before one can decide whether an individual’s small hippocampus was caused by injury incurred during military service and that the injury led to PTSD or whether the small hippocampus predisposed him or her to PTSD, carefully designed studies of the relevant conditions before and after deployment must be conducted. Resolution of this issue has substantial consequences for care delivery, for the value of preventive measures for susceptible individuals, and for compensation related to military service. Another brain structure that figures prominently in stress-related mood and anxiety disorders is the amygdala. Research by Yehuda and LeDoux (2007) and by Davis et al. (2003a) has established the neuronal pathways that mediate conditioned fear. Conditioning results when information from the conditioned stimulus (a neutral stimulus such as light or sound) converges with information from the unconditioned stimulus (such as pain or a feared object). Processing of feared experience in the lateral nucleus of the amygdala is a critical step in circuitry through which the release of catecholamines, adrenocorticotropic hormone, and cortisol is regulated. Administration of an α-adrenergic receptor antagonist into the amygdala attenuates the development of conditioned fear, whereas administration of exogenous cortisol exacerbates it (Roozendaal et al., 2006). Although catecholamine metabolites increase in subjects with chronic PTSD, most studies indicate lower levels of corticosteroids and a blunted response to stress (Yehuda and LeDoux, 2007). The central role of the amygdala in conditioned fear in experimental animals has been extended to humans via functional brain imaging studies. Exposure to fear-inducing stimuli leads to functional activation of the amygdala. Furthermore, PTSD patients generally demonstrate increased activation of the amygdala in response to a threatening stimulus or even a neutral stimulus, as compared to untraumatized controls or even to traumatized individuals without PTSD (Rauch et al., 2006). Extinction of conditioned fear may suggest potential treatments for PTSD. Repeated presentation of the conditioned stimulus to an experimental animal without the unconditioned stimulus results in the gradual extinction of conditioned fear. This active process involves new learning and requires the activation of the NMDA subtype of glutamate receptors in the amygdala. When conditioned fear exists, both animal and human studies point to a loss of inhibitory control over the relevant nuclei of the amygdala by the medial prefrontal cortex. Indeed, prolonged stress alters the circuitry linking the medial prefrontal cortex to the amygdala. Davis et al. (2006) demonstrated that the extinction of conditioned fear in experimental animals through repeated exposure to the conditioned stimulus is significantly facilitated by concurrent treatment with a single dose of D-cycloserine, a partial agonist at the glycine modulatory site on the NMDA receptor, which enhances NMDA receptor responses to glutamate. Controlled clinical trials indicate that reviewing the traumatic experience in a supportive setting (exposure therapy) can be an effective treatment for chronic PTSD, analogous
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Opportunities in Neuroscience for Future Army Applications to exposing an experimental animal to the unconditioned stimulus without the conditioned stimulus. Recent studies demonstrate that, analogous to laboratory results with rats, the administration of a single dose of D-cycloserine robustly and persistently enhances the response to cognitive-behavioral therapy (desensitization) in subjects with acrophobia (Ressler et al., 2004). This robust enhancement persists for at least 3 months and involves memory consolidation. Ongoing studies are examining the use of virtual environments that recall soldiers’ experiences in a controlled, graded fashion for desensitizing them, coupled with administration of D-cycloserine (Rizzo et al., 2008).6 These outcomes, along with neuropsychological research connected with recovery/treatment for traumatic brain injuries, are likely to continue as a source of future neuroscience opportunities. As noted above, sleep deprivation can reinforce the negative cognitive-emotional features of PTSD. An insidious component of PTSD is that anxiety dreams repeatedly awaken some individuals suffering from it. Increased activity of brain noradrenergic neurons may contribute to the pathophysiology of PTSD as well as to the nighttime sleep disturbances and nightmares that accompany the disorder. Increased noradrenergic activity interferes with normal REM sleep and could interfere with the normal cognitive processing of traumatic events. A recent study examined the effects of prazosin, a centrally active alpha-1-adrenergic antagonist. Compared with placebo in a blinded clinical trial, prazosin increased total sleep time by 90 minutes, on average, increased REM sleep duration, reduced trauma-related nightmares, and significantly improved overall clinical symptoms (Taylor et al., 2008). Not all individuals exposed to trauma develop PTSD. The type of trauma is important; an interpersonal trauma such as rape or combat appears to be more salient than an accident trauma. Other risk factors include lower intelligence quotient, childhood adversity, avoidant personality, and poor social supports. As noted above, reduced hippocampal volume is robustly associated with PTSD, but it is unclear whether it antedates the traumatic events, thereby being an additional risk factor, or is a consequence of trauma and stress. The higher concordance of PTSD in identical twins compared to fraternal twins supports the involvement of heritable risk factors. Several putative risk genes for PTSD have been identified. In a small study, a polymorphism in the untranslated region of the dopamine transporter gene was associated with greater risk for PTSD in trauma survivors (Segman et al., 2002). The glucocorticoid receptor genotype was found to affect basal cortisol levels in a subgroup of patients with PTSD (Bachmann et al., 2005). Kilpatrick et al. (2007) found interaction between a polymorphism in the serotonin transporter gene, the severity of the trauma, and the level of emotional support when they studied the development of PTSD after a hurricane. This polymorphism has also been associated with increased risk for depression in the context of stressful life events, including childhood abuse (Kaufman et al., 2004). Binder et al. (2008) recently reported that four single-nucleotide polymorphisms of the FKBP5 gene interacted with the severity of childhood abuse as a predictor of adult PTSD symptoms. FKBP5 is part of the mature glucocorticoid receptor heterocomplex, which provides face validity for an association. Major Depressive Disorder in the Military Context Aside from the experience of IED events, there are a number of other factors related to military service that predispose individuals to clinical depression. Among them are separation from support networks and family, loss or death of close colleagues, divorce or family instability, economic distress, and untoward responses to medication. U.S. soldiers, who are separated from their families for nominal 15-month deployments, are likely to experience all or most of these factors in some form, independent of having received any TBI. Stress and disruption of the HPA axis are central to the pathophysiology of major depressive disorder. Stressful life events have been associated with the onset of affective illness. A majority of individuals with an episode of major depressive disorder exhibit dysregulation of the HPA axis with resistance to dexamethasone, a potent glucocorticoid receptor agonist. A major depressive disorder is also highly comorbid in patients suffering from chronic PTSD (Scherrer et al., 2008). Most animal models of depression that are used to screen for antidepressant efficacy are in fact based on acute or recurrent stress. For example, the Porsolt task is one of the most robust predictors of antidepressant efficacy. The duration of swimming when mice or rats are repeatedly placed in a vat of cool water decreases progressively; effective antidepressants restore prolonged swimming. Chronic administration of corticosterone to rats produces a number of signs and symptoms consistent with major depressive disorder, including increased anxiety, shorter latency on the Porsolt test, and impairments in working memory. Thus, although major depressive disorder can occur spontaneously without evident precipitants, in the military context depression may more often be related to persistent stress and trauma. Resilience 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 psychological and neurophysiological underpinnings of resilience should be of considerable interest to the Army because it 6 Personal communication between Michael Davis, Robert W. Woodruff Professor, Emory University School of Medicine, and Joseph Coyle, committee member.
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Opportunities in Neuroscience for Future Army Applications identifies strategies to enhance resilience, as well as potential indicators of naturally resilient individuals (Haglund et al., 2007). As noted above, research on experimental animals and in humans unequivocally demonstrates that severe stress in childhood such as abuse or neglect renders the individual much more vulnerable to stress in adulthood (Heim et al., 2000; McCormack et al., 2006). However, the experience of modest, controllable stress in childhood results in greater ability to regulate stress responses in adulthood. This phenomenon, known as “stress inoculation,” has been demonstrated in experimental animals and humans (Rutter, 1993). Studies in monkeys indicate that infant monkeys subjected to stress inoculation (e.g., in childhood, separation from the mother for an hour every week) display lower levels of anxiety later in life. They have lower basal cortisol levels and enhanced prefrontal cortex-dependent cognition than controls not subject to the stress inoculation (Parker et al., 2004, 2005). Small-molecule markers for resilience have also been identified. Dehydroepiandrosterone (DHEA) is an endogenous steroid that elevates mood and counteracts the effects of high cortisol. Soldiers subjected to the stress of survival training, who exhibit superior performance, have a higher ratio of DHEA to cortisol (Morgan et al., 2004). In animal experiments, the neuropeptide Y (NPY) has anxiety-decreasing effects and counteracts the behavioral effects of corticotrophin-releasing hormone. Consistent with these results in animals, serum NPY levels of soldiers subject to the stress of survival training correlated positively with performance, suggesting that NPY may be involved in enhanced stress resilience in humans (Morgan et al., 2000). Studies have identified several attitudes and behaviors that foster psychological resilience to stress, including optimism, active coping, cognitive flexibility, moral compass, physical exercise, and social support (Haglund et al., 2007). Twin studies indicate that temperamental features such as optimism or neuroticism (tendency toward neurotic responses and behavior) are substantially heritable (Wray et al., 2008). Furthermore, neurophysiological research suggests mechanisms that may explain the protective features of behaviors that foster resilience, such as the finding that physical exercise promotes expression in the brain of brain-derived neurotrophic factor (Cotman and Berchtold, 2002). Similarly, social support appears to modulate the HPA axis (Heinrichs et al., 2003). Longer-Term Performance Deficits Linked to Traumatic Brain Injury As noted by Hoge et al. (2008), TBI has been labeled the signature injury of the wars in Iraq and Afghanistan, with 15 percent of soldiers deployed to these theaters reporting blast injuries sufficiently severe to result in loss of consciousness or altered mental status. The risk of comorbid PTSD with CNS symptoms was three to four times greater in these soldiers than in those with no history of blast injury. The presence of PTSD and depression are robust predictors of poor physical health and persistent impairment. Yet the biological basis for this association remains poorly understood. It is simplistic to conclude that the co-occurring PTSD is “a psychological response.” Neuroscience should provide some leads about the underlying pathology of blast-induced TBI and opportunities for prevention and treatment. Box 5-3 introduces a new area of neuroscience that may help in following up on such leads. There is debate about whether brain injury as a consequence of blast waves differs from brain injury due to penetrating wounds (Bhattacharjee, 2008). Indeed, it appears that some penetrating brain injuries may reduce the risk for PTSD (Koenigs et al., 2008; Sayer et al., 2008). Research on depression that occurs after a stroke may be particularly relevant to thinking about TBI. Many clinicians believed that post-stroke depression was a predictable psychological response to disability, although studies indicated that comparable levels of disability from other causes did not result in equally high rates of depression. Furthermore, left anterior lesions pose greater risk for persistent depression than right posterior lesions. Comorbid depression with stroke was a robust predictor of poor outcome, especially death. Both central noradrenergic and serotonergic neuronal systems have figured prominently in the pathophysiology of major depression, as they are the targets of action of effective antidepressants. Robinson and Coyle (1980) demonstrated that because of the peculiar trajectory of these fine, unmyelinated aminergic fibers, which project in an anterior to posterior orientation in the cortex, a stroke lesion in the anterior cortex denervates the rostral cortex of their aminergic innervation. Treating post-stroke depression with antidepressants ameliorates the depression and improves the clinical outcome. Multiple sclerosis is another disorder associated with a high risk of comorbid depression. The multifocal lesions in the case of multiple sclerosis may have devastating effects on the fine aminergic intracortical axons, as demonstrated by the observation that the severity of depression correlates inversely with the CSF levels of 5-hydroxyindoleacetic acid, a metabolite of serotonin. Given the evidence that exposure to explosion increases the risk for PTSD in the absence of an acute alteration in mental state, the sport of boxing is germane to the discussion of TBI. Markers of cellular damage are increased in the CSF of boxers with no evidence of concussion. The absence of structural magnetic resonance imaging changes in boxers demonstrates that it may be an insensitive index of damage. For example, only 14 percent of 49 professional boxers subjected to structural magnetic resonance imaging showed abnormalities. In contrast, diffusion tensor imaging revealed robust differences between boxers and matched controls, with reduced diffusion and anisotropy, consistent with disruption of axon terminals. Similar findings have
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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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Opportunities in Neuroscience for Future Army Applications been obtained in a small study of adolescents with mild TBI who demonstrated an increased anisotrophy and decreased diffusivity at 6 days after an incident. Little is known about intrinsic risk factors that may affect the outcome of TBI. Apo E4 status robustly predicts neurological deficits in boxers and is linked to poor neurological outcome after TBI from any cause (Jordan et al., 1997; Zhou et al., 2008). Recently, Chan et al. (2008) examined whether polymorphism in the serotonin transporter gene, previously linked to increased risk for depression after psychological trauma, affected the risk for depression and TBI, but they found no association. Prospective Interventions While the long-term treatment of PTSD and the consequences of TBI may not be the primary responsibility of the Army, it is in the Army’s interest to understand the pathophysiology of these conditions sufficiently to develop effective preventive interventions or acute treatments that mitigate a trauma. Such interventions could include physical training, psychological methods, or pharmaceuticals. Continued research on the identification of risk factors for the development of PTSD could inform interventions that mitigate a risk for PTSD and related stress disorders, thereby lessening the risk of performance deficits and disabilities. Understanding the neuropathology of TBI should aid in developing better types of body armor to lessen, to the extent possible, the specific types of trauma associated with blast injury. These interventions could hasten recovery after blast exposure and the more rapid return of soldiers to mission. 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