INFORMATION TO USERS

This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of cornputer printer.

The quality of this reproduction is dependent upon the quality of the copy subrnitted. Broken or indistinct print, coiored or poor quality illustrations and photographs, pnnt bleedthrough, substandard margins. and improper alignrnent can adversely affect reproduction.

In the unlikely event that the author did not send UMI a cornplete manuscript and there are rnissing pages, these will be noted. Also, if unauthorized copyright materiaf had to be rernoved, a note will indicate the deletion.

Oversize materials (e-g., maps, drawings, charts) are reproduœd by sedioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book.

Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appeanng in this copy for an additional charge. Contact UMI directly to order.

Bell & Howell Information and Leaming 300 North Zeeb Road, Ann Arbor, MI 481064346 USA 800-521-0600

Effects of Modafd on Physiological and Perceptual Responses During Exercise

Peter Dinich

A thesis submittea in conformity with the requirements for the degree of Master of Science in the Exercise Sciences Programme Graduate Department of Commu~tyHealth, University of Toronto

O Copyright by Peter Dinich, 1998 National Library Bibliothéque nationale du Canada Acquisitions and Acquisitions et Bibliographie Services senices bibliographiques 395 Wellington Street 395, me Wellington Ottawa ON K1A ON4 Ottawa ON KIA ON4 Canada canada

The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or sell reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfichellZh, de reproduction sur papier ou sur format électronique.

The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fkom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Effects of Modafhil on Physiobgical and Perceptual Responses During Exercise Master of Science, 1998 Peter Dinich Graduate Department of Community Health University of Toronto

Abstract

Modafinil (M) belongs to a new class of dmgs which elicit "arousal" properties similar to amphetamines, but with less potent side-effects. One aim of this study was to corKim that acute treatment with M (4mg-kg-') would have an ergogenic effect on high intensity exercise performance. Eight males cycled to exhaustion at 85% VOz max after both M and placebo (P) treatments, using a double-blind experimental design. M prolonged time to exhaustion by 10-15%. The mechanism responsible for this effect is most likely related to a mechanisrn of action in the CNS that enhanced the level of arousal and vigilance. A second objective was to assess whether M would cause an overconfidence effect (i.e. a self- appraised overestimation of actual performance abilities) and enhanced cognitive performance. Seventeen subjects who participated in this experiment were randomly treated with M and P after familiarization trials. M did not cause an overconfidence effect, nor show any disturbance in self-monitoring ability. Moreover, M significantly shortened reaction time and consequently enhanced cognitive efficiency. In conclusion, M was well tolerated and had positive effects on physical and cognitive performance. To Vesna, Branko and Saslta with love Table of Contents

Abstract ...... i

List of Figures and Tables ...... v List of Abbreviations ...... vi

Chapter 1. Introduction ...... -1

Chapter 2. Literature Review ...... -4 2.1. Central Fatigue ...... -4 2.1.1 Perception of Fatigue ...... 5 2.1.2 Role of Neurotransmitters in Exercise Fatigue ...... 8 2.1.3 Brain Catecholamines and CNS fatigue...... 9 2.1 -4 Brain Serotonin and CNS fatigue ...... -11 2.2. Modafïinil...... 14 2.2.1 Pharrnacokinetic Profile of Modafiil ...... 17 2.2.2 Dosage and Toxicity ...... 17 2.2.3 Mechanism of Action ...... 18 2.2.4 Modafinil and Cognitive Performance ...... -23 2.2.5 Self-Monitoring of Cognitive Performance...... -27 2.2.6 Overconfidence effect ...... 29

Chapter 3 . Study Objectives and Hypotheses ...... 32 3.1. Objectives ...... -32 3.2 Hypotheses...... -32 Chapter 4. Materials and Methods ...... 33 4.1. Subjects...... 33 4.2. Experimental Protocol ...... 34 4.2.1 Endurance Ride to Exhaustion ...... 34 4.2.2 Production Protocol Ride ...... 35 Measurements made during trials ...... -38 Heart Rate ...... -38 Blood ...... 38 Metabolic ...... -38 Rating of Perceived Exertion ...... 39 Line Cornparison Task and Overconfidence effect ...... 39 Blood Metabolite and Neurotransrnitter determinations... 40 Data Analyses ...... 43 4.4.1 Analysis of Variance (ANOVA) ...... 43 4.4.2 Power Analysis ...... 43

Chapter 5. Results ...... -44 5.1 Endurance Ride to Exhaustion ...... -44 5.2 Production Protocol Ride ...... 49

Chapter 6 . Discussion...... 56 6.1. Review of Objectives and Hypotheses ...... 56 6.2. Main Findings ...... 56 6.3. Overconfidence Effect ...... 58 6.4. Indicators of Cognitive Performance ...... 60 6.5. Subjective effects and Individual variations ...... 61 6.6. Compantive Studies ...... 62 iv Chapter 7 . Limitations ...... 66 Conciusions...... 66 Recommendations for Future Study ...... -67 Aclaiowledgements...... -69

References ...... -70

Appendices A: Letter of Approval from the University of Toronto ...... 88 B : Approved Expenmental Protocol ...... -89 C: Raw Data ...... 102 List of Figures and Tables

Figures

Figure 2.1 . Chernical Structure of Modafïnil...... 15 Figure 4.la . Time Line for Experimental Protocol for ER ...... 35 Figure 4- 1b . Time Line for Experirnental Protocol for PPR ...... 35 Figure Time to Exhaustion during Exercise at 85% VOz max ...... 44 Figure Effect of Order of Trial During ER ...... 45 Figure Heart Rate during ER ...... 45 Figure VOz, VE and RQ during ER ...... 46 Figure RPE during ER ...... 47 Figure Plasma Lactate during ER ...... 47 Figure Plasma Glucose and FFA during ER ...... -48 Figure Average Watts at Various RPE ...... 50 Figure Actual Exercise Time in Watts selected...... 51 Figure 5-10 . Reaction Time during Line Cornparison Task ...... 53 Figure 5-1 1 . Plasma Serotonin during ER and PPR ...... 54 Figure 5-12 . Changes in E. NE. and DA during ER ...... 55

Tables Table 5- 1. Means Table for Time to Exhaustion ...... 44 Table 5.2 . Means Table for Resting HR ...... 49 Table 5-3 . Means Table for Resting Systolic BP...... 49 Table 5.4 . Means Table for ERmax ...... 49 Table 5.5 . Watts selected for Exhaustive Exercise for 2.5 min ...... -50 Table 5.6 . PCORR, PRECONF, POSTCONF, PREDIFF and POSTDIFF Data for Line Cornparison Task ...... 52 List of Abbreviations

ARA Ascending Reticular Activating System C-CP Creatine - Phosphocreatine CFS Chronic Fatigue Syndrome CN Line Cornparison Cognitive Task CNS Central Nervous System DA Dopamine DCEM Defence and Civil Institute for Environmental Medicine E EAA Excitatory Amino Acid EEG Electroencephalogram ER Endurance Ride FFA Free Fatty Acid f-TRP Free Triprophan GABA Gamma Aminobuteric Acid HPA-axis Hypothalamic Pituitary Adrenal-axis 5-HT 5-Hydroxytryptarnine (Serotonin) HR Heart Rate IAA Xnhibitory Amino Acid IL- 1 Interleuch I M Modafinil NE Norepinephrine P Placebo PCORR Percent of the Correct Answers PO Power Output PPR Production Protocol Ride PR Production Protocol for Rating of Perceived Exertion vii POSTCONF Post Task POSTDIFF Post Task Confidence - Percent of the Correct Answers PRECONF Pre Task Confidence PREDIFF Pre Task Confidence - Percent of the Correct Answers RPE Rating of Perceived Exertion RS Response Protocol RQ SD Sleep Deprivation t1/2 Elimination half life TRIP Triptophan VE Minute Ventilation vo2 Rate of Consumption VOz max Maximum Oxygen Uptake Rate

viii Chapter

Introduction

The term ergogenic is derived from the Greek words ergon (work) and genncin (to produce). Hence, an ergogenic aid usually refers to something that produces or enhances work (physical or mental performance). In recent years, increases in research in the areas of nutrition, , biomechanics and pharmacology have led to the development of virtually hundreds of purported ergogenic aids aimed at overcorning limitations to human performance (Williams, 1998). The performance of physical work, be it on the athletic field, in a job setting, or for rnilitary personel engaged in combat, requires the confluence of physiological and psychological processes. Many of these processes and related factors can be viewed as potential targets for performance enhancement through ergogenic aids. In addition, impaired dertness chronically affects tens of millions of people (because of narcolepsy, aging, jet-hg, shift-work and other disorders of sleep or circadian timekeeping) and is a major cause of accidents and death in modem society (Edgar and Seidel, 1997). Although physical strength and endurance are only rninimally affected by sleep deprivation, complex mental functions, such as the ability to perceive and understand changing situation, adapt to change and plan alternative strategies, are significantly decreased. Hence, fatigue from even low intensity sustained activity is a major factor that cm lead to performance degradation. In addition, since a psychological boundary precedes the physiological limit (physical fatigue is usually modifiable by incentive), it seems likely that even local muscular fatigue, may have strong central components and may often be a function of decreased alertness or vigilance, which could be restored through an appropriate level of arousal. There are few pharmacological therapies available that can selectively enhance waking, irnprove altered perception and prevent impending fatigue. Drugs like amphetamines, are considered effective centrally mediated therapies to trcat impaired alertness and enhance physicd performance, but they have intractable side effects that lirnit their general use. Caffeine, widely used to enhance vigilance, is also not without side effects such as irritability, and tremor (Kaplan et al., 1997). ~odafinip(diphenylmethyl-sulfinyl-2acetdde) is a relatively new stimulant synthesized in the Lafon Labs of Maison-Alfort, France, with several remarkable features that distinguish it from amphetamines. Modafinil, like amphetamines, has been shown to improve vigilance in sleep-depnved subjects (Lyons and French, 1991; Pigeau et al., 1995). However, unlike amphetamines it does not interfere with normal sleep, nor does it appear to be addictive, or associated with the dangerous cardiovascular side-effects attributed to amphetarnines (Warot et al., 1993). Modafinil has been clinically used for the last 10 years, in the treatment of narcolepsy and idiopathic hypersomnia (Laffont et al., 1995; Bastuji and Jouvet, 1988). However, it is not yet known whether Modafinil has ergogenic properties similar to those of arnphetarnines. Professor Michel Jouvet, an international authority on sleep, has claimed that Modafinil could keep an army on its feet and fighting for three days and nights with no major side-effects (B astuji and Jouvet, 1988). Unfortunately, there are few studies in the scientific literature to support these claims. Pigeau et al. (1995) reported that Modafinil reduced the extent of cognitive performance impairment, caused by sleep deprivation, without the side effects associated with the use of amphetamines. Moreover, Jacobs and Bell (1997) in the only study done so far about the effect of Modafinil on physical performance, reported that acute ingestion of Modafinil prolongs exercise time to exhaustion at - 85% V02 rnax, with significantly lower subjective ratings of perceived exertion at submaximal exercise intensities. Modafmil in these studies does not show peripheral action, which could explain fewer side effects (from arnphetarnines and caffeine). On the other hand, it seems that without affecting energy substrate Modafinil express his mode of action through altenng exclusively mechanism of central fatigue. Of concem, however, was the observation of Baranski and Pigeau (1997), who reported that Modafinil had a disruptive effect on the ability to self-monitor one's own cognitive capabilities, inducing a reliable "overconfidence" effect (i.e., when one overestimates one's own actual cognitive performance). This observed effect was particularly marked 2-4 hours after Modafïnil ingestion. It has been speculated that Modafinil would enhance physical work capacity, similar to amphetamines, but without si,pificant side-effects. Nevertheless, there is concern that the previously reported "overcor~fidence" phenornenon may negatively affect decision processes, caused irnpaired judgment, and even physical performance under certain conditions. Therefore, a more comprehensive unders tanding of the relationship between the perceptual (subjective) and physical perforrnance (physiological) effects of Modafinil, is of great importance before it cm be recomrnended as a safe and reliable fatigue countermeasure.

Thus, the purpose of the present study was to evaluate the effects of Modafinil on physical and cognitive performance, in non-sleep deprived subjects. An additional purpose of this study was to investigate the previously reported "overconfidence" effect of Modafinil. Chapter 2

Literature Review

2.1. Central Fatigue

Fatigue is the inevitable consequence of sustained activity. Central nervous system (CNS) fatigue has been defined as a central inhibition that exists despite the subject's full motivation or, more objectively, as a gnerated by voluntary muscular effort that is less than that produced by electrical stimulation (Asrnussun, 1979). Although, it has been documented for over a century that "psycho1ogica1 factors" (motivational level, alertness and mood) cm affect exercise performance, investigations of CNS components of fatigue have been limited primarily because of a lack of objective measures. It is generally thought that a reduction in CNS drive to the motor neuron can be a result of afferent feedback from the muscle (changes in muscle metabolites) andor a reduction in corticospinal (descending) impulses mediated by alterations in neurotransmitters (dopamine, norepinephrine serotonin, and acetylcholine) (Chaouloff, 1989). In fact, the inability to generate and maintain adequate CNS drive to the working muscle is the most likely explanation of "fatigue" in most people during normal daily activities. Since maintaining maximal CNS motor drive is very difficult and unpleasant, under most circumstances people do "let off" centrally. Thus, the fist indication that fatigue may be imminent is an increased perception of effort at thr same absolute workload (Enoka and Stuart, 1992; B igland et al., 1986). However, the sense in which the word "fatigue7' is used by many authors rnight better be called perceived fatigue, since it may or rnay not correlate with physiological indicators. 2.1.1. Perception of Fatigue

Although people have dways more or Less identified and classified work of different degrees of strain, using words like "light" "moderate" or "hard", no real quantification of the subjective intensity of exertion existed. In the fifties with the introduction of the new psychophysics methods (Stevens and mach, 1959), methods were developed for studying the variation of perceptual intensity with stimulus intensity. In general, psychophysical techniques have been used to examine precise relationships between physical (workload) intensities and perceived intensities by determining the exponents of psychophysical functions. These new methods made it possible to quantify the subjective intensity in the modality of subjective effort and exertion (Stevens and Mach, 1959). Since the work of Borg in the early 1960s' it has been suggested that the overall perception of exertion during physical exercise represents an individual's integration of various nonspecific physiological sensations, that may corne from "local cues" from working muscles (sensations from mechanoreceptors and tendon organs) and "central cues" (strain arising from heart and lungs) (Borg, 1973; Edwards et al., 1972). The significant advancement in this field was also the introduction of the tree effort continua concept by Borg (1973). According to this concept there are a number of psychological and physiological variables (factors) that can affect an individual's response. The tree main continua are the perceptual continuum, the performance continuum and the physiological continuum. For the perceptual continuum, a corresponding performance continuum and physiological continuum exist, and vise versa. This mode1 further stirnulated a number of new psychophysiological studies on exercise performance, showing a high degree of correlation between perceived exertion and a number of physiological variables (from heart rate to energy substrate availability and fibre composition). Pandolf et al., (1975) proposed the use of differentiated Ratings of Perceived Exertion (RPE) Le., local, central and overall ratings. Smutok et al., (1980) evaluated the efficacy of the subjective regulation of exercise intensity by RPE and reported that the prescription of exercise by RPE produced safe and reliable heart rate (HR) but only above 150 b/min (80% HR max), while below these levels use of the RPE for exercise prescription produced inacurate and unreliable responses. Morgan (1973) demonstrated the significant impact of various psychological States and traits on the perception of effort (extraversion-intraversion, - stability, stait and trait , depression, task aversion and motivation). He suggests that one third of the variance (- 33%) in RPE may be related to the psychological factors, and that two thirds of the variance can be attributed to various physiological responses . More recent studies indicate that the central drive or feedforward (corticospinal) impulses are modulated by peripheral feedback, including peripheral receptor sensory input, spinal reflexes, inhibitory interneurons in the spinal cord, synaptic and neurotransmitter modulation (Cafarelli, 1982). It is also known that psychological factors, like alterations of emotional state and motivation may affect the overall cognitive processing of sensory information and the perception of effort during physical exercise. However, the complexity of human behavior and the number of interacting variables (eg., individual, social and environmental variations) make it impossible to determine the exact impact of psychology on the interpretation of sensory cues and perception of effort during exercise. Some exercise scientists (physiologists and psychologists) have studied effort sensation for different types of exercise, duration and intensity, or different exercise situations involving a variety of clinical and industrial applications. Some have tried to evaluate the influence of age, sex and physical training on exertional estimates (Pandolf, 1983). The rnajority of these investigations have employed either psychophysical techniques (to deterrnine the exponents of psychophysical functions), or a category rating scales (form of sensory scde) that allowed direct interindividual comparisons (Kinsman and Weiser, 1976). Thus, category rating rnethods, such as RPE, appear more appropriate for studies concerning simple perceptual-level comparisons between various exercise tasks andor individuds for most applied studies. Four classes of scales are cornmonly used to study sensory processes. They have been referred to as nominal, ordinal, interval, and ratio scales (Stevens and Mach, 1959). The most widely used rating methods involve ordinal or interval scales. Nonetheless, with development of psychophysiology and biological psychology, it becomes increasingly evident that virtually al1 behaviors and perceptions have a biological basis at the molecular, synaptic and neural system levels, that are integrated into behavioral adaptation to environmental challenge i.e. exercise stress. In this regard, it may be even possible to explore the cellular basis of the sense of effort and to determine the relative roles of the cerebral cortex, basal ganglia and cerebellum, with their different receptors, in the control of movement and force failure during fatigue. This evaluation would also involve an evaluation of the effects of subject alertness, motivation and mood, the intensity and duration of the activity, and the extent to which the activity is continuously sustained (Dunn and Dishaman, 199 1). Weil-established techniques in electrophysiology, biochemistry and nuclear magnetic resonance that are now available, can be used to study suprasegmental (CNS) aspects of fatigue. Further elucidation of how the CNS influences affect fatigue is relevant for achieving optimal (maximal) performance in athletics, as well as, in everyday iife and in several fatigue related disorders (various mental disorders, depression, and chronic fatigue syndrome) (Stokes et al., 1988). In patients suffering from the "chronic fatigue syndrome" (CFS), there is evidence suggesting an abnorrnality in the perception of fatigue. CFS patients have higher perceived exertion ratings in relation to heart rate during exercise and tend to stop early, well before the normal physiological limit is reached (Chaouloff, 1989). There is also recent evidence that CFS patients demonstrate a ~ig~cantreduction in 24-h basal levels of the norepinephrine metabolite and an elevation in the mean basal plasma level of the serotonin metabolite, when compared with normal individuals. In addition, possible up-regulation of hypothalarnic serotonin receptors in these patients has also been reported (Sothmann et al., 1996).

2.1.2. Role of Neurotransmitters in Exercise Fatigue

The major amines found in the brain are norepinephrine (NE), dopamine (DA) and serotonin, Le., 5-hydroxytryptamine (5-HT). NE and DA are called catecholamines, while serotonin is an indoleamine; al1 three are monoarnines. Neurons that secrete these monoarnines originate pnmarily in the stem of the brain in and around the reticular formation, a structure involved in arousal and attention. Those which secrete NE or 5-HT project to the hyothalarnus, the limbic system and other structures, while the dopaminergic neurons project pnmady to the basal ganglia. The basal ganglia, limbic system, and hypothalamus have been found to play a role in motor behaviors, emotional and motivational States, respectively (Chaouloff, 1989). In addition, these three monoarnines have been implicated to play a role in: motor function, motivation and arousal (DA neurons); sleep, analgesic responses, stress-related aggression, pituitary hormone release and cardiovascular function (NE neurons); and pain, appetite, fatigue and penodicity of sleep (5-HT neurons). More hypotheses that involve serotonin and dopamine, and studies that evaluate the merits of each of them are beginning to appear (Enoka and Stuart, 1992; Davis et al., 1993) 2.1.3. Brain Catecholamines and CNS Fatigue

Dopamine (DA) was the first neurotransrnitter to be investigated for its potential role in deterrnining CNS fatigue. This was probably the case because of the previously established role of DA in controlling movement and the pnor use of arnphetamine by athletes to improve performance (Freed and Yamamoto, 1985). Increases in whole brain DA metabolism following running activity were first documented by Bliss and Ailion (1971). Indeed, on the basis of the higher DA levels that were found in mice submitted to either swirnrning, foot shocks or restraint, the authors have concluded that activity and emotionality are both activators of DA synthesis . In patients with Parkinson's disease, loss of doparninergic neurons leads to dopamine depletion in the brain and drastically reduced voluntary movement. Treatment with the dopamine precursor L-dopa can increase the dopamine and restore motor function (Ahlenius and Hillegart, 1986). While it is clear that amphetarnine administration can improve endurance performance, the mechanisms underlying this effect still remain unknown (Knapp et al., 1974; Chandler and Blair, 1980). It is possible that in addition to a stimulative effect on catecholamines production and release, amphetarnine increases endurance by means of inhibition of the serotonergic system. Stimulation by arnphetamine (particularly after large doses) is often followed by a "rebound period" of mental depression and fatigue. These observations rnay reflect a temporary depletion of norepinephrine stores available for continued release (Chaouloff et al., 1987). While many observations suggest that amphetarnine may potentiate the effects of catecholamine release, there is also evidence that amphetamine rnay as well exert a direct action at DA and 5-HT receptors (Knapp et al., 1974; Bailey and Davis, 1993). From some of the results provided by Chaouloff at al. (1985, 1989), it appears reasonable to hypothesize that increased brain doparninergic activity may be beneficial owing to its ability to inhibit brain 5-HT synthesis and metabolism. It is also possible that when dopaminergic activity is reduced during prolonged exercise (suppression in certain catecholarnine-synthesizing enzymes when exhaustion is reached), fatigue is precipitated by a loss of coordination (i.e., reduced efficiency) and/or a reduction in motivation. Epinephrine (adrenaline) is synthesized from NE in the adrenal medula. Activity of phenylethanarnine-N-methyltramsferase, the enzyme involved in this reaction, has been shown to be enhanced by adreno-cortical steroids and activation of hypothalamic-pituitary-adrenal-axis (HPA-axis) (Chaouloff, 1989). The blood- brain barrier effectively prevents the entry of epinephrine into the brain, except possibly in the region of the hypothdamus. On the other hand, NE does not appears to cross the blood-brain barrier to an appreciable extent. Thus, because of this inherent limitation, it is unlikely that the brain can be a significant source of circulating NE (Chaouloff et al., 1985; Dunn and Dishaman, 199 1). Nonetheless, data on the urinary excretion of NE and metabolites are of interest, since biochemical changes in catecholamine metabolism in the periphery may reflect similar changes occumng centrally (Moore, 1982). Thus, an increase in peripheral sympathetic (epinephrine) activity (for instance with exercise) may reflect increased central NE activity (B aldesserini, 1989). With this in regard, Pagliarï et al. (1994) examined the effect of exercise on the in vivo cerebral release and turnover of NE in trained rats running on a treadmill for 60 minutes. They used a chronic probe implantation in the frontal cortex and found that NE turnover and release increased dunng exercise and even further increased when exercise time was prolonged to 2 hours of running, similarly to changes in epinephrine on the periphery. This finding is of great importance for establishing a relation between mode, intensity, duration and frequencies of exercise and clinical improvernent from depression, since it was hypothesized that chronic physical activity alters the brain NE system in a way qualitatively sirnilar to pharmacotherapy for major depression (B aldesserini, 1989). 2.1.4. Association Between hcreased Brain Serotonin and Fatigue

Of the many proposed causes of CNS fatigue, the role of brain serotonin (5-HT) has generated the most interest. This indoleamine transrnitter is synthesized from the amino acid tryptophan. The rate-lirniting enzyme, tryptophan hydroxilase, is not fully saturated under normal physiological conditions, and its activity depends on the arnount of available L-tryptophan (TRP) which, in turn, is controlled by a variety of factors, including its concentration in plasma and its rate of uptake into the brain through blood/brain barrier (DUM and Dishaman, 1991). There are apparently two regulatory and complementary mechanisms that govern 5- HT synthesis, the first is linked to precursor (TRP) availability, and the second (intrinsic) to the TRP-hydroxylase activity. Investigators have begun to test the validity of these mechanisms in experiments involving: the effects of exercise on brain 5-HT synthesis and turnover, the effects of 5-HT agonist and antagonist hgs on exercise fatigue, and the influence of nutritional strategies that alter the plasma f-TRP ratio (Blomstrand et al., 1989; Chaouloff et al., 1986a; Young, 1990). The "Central Fatigue Hypothesis" suggests that increased of brain 5-HT cm impair CNS function during prolonged exercise and thus cause a detenoration in exercise performance (Ramanovski and Grabiec, 1984). With this in regard Davis et al. (1993) showed the effects of both moderate and fatiguing exercise on 5-HT and DA in various regions of the rat brain. These data show a good association between increased brain 5-HT and fatigue dunng prolonged exercise. Altematively, brain DA, which has been linked with increased arousal, motivation, muscular coordination, and increased endurance performance, actually decreased towards the end of prolonged exercise as fatigue developed. The si-~ficanceof this apparent inverse relationship between brain 5-HT and DA as fatigue develops was also confiied by Chaouloff et al. (1986b). Their results have shown that the increase in 5-HT during 90 min of exercise could be attenuated by prior administration of amphetamine, suggesting that the exercise- induced increases in brain 5-HT may be attenuated by increases in DANE activity. The above mentioned studies in both rats and humans appear to provide good evidence that brain 5-HT activity increases during prolonged exercise and that this may cause CNS fatigue by attenuation of DA synthesis and reduction of arousal. However, any statement that singles out DA, NE, or 5-HT as the crucial amine may be premature and oversimplified. Dynamic and constant interaction between several other neurotransmitters (including Glycine, gamma aminobuteric acid-GABA, and some other inhibitory or excitatory arnino acid, like Glutamate) and neuromodulators (IL-1, TNF), including their receptors, rnay also under some circumstances significantly affect the release or reuptake of NE and 5-HT (Blomstrand et al., 1989; Blomstrand et al., 1988; Gemma et al., 199 1). Nevertheless, this will continue to be questioned until methods are available to measure more directly CNS fatigue during dynamic exercise in humans and until more is known about the specific physiological mechanisms for such an effect. With the development of more specific pharmacological agents (doparninergic and serotonegic agonist and antagonist) and in vivo measurement of extracellular neurotransmitter levels (brain microdialysis and voltammetry), as well as induction techniques (push-pull cannulation), it appears that this area is ready for more mechanistic research (Moore, 1982; Wilson and Maughan, 1992). Another question of importance is the functional significance of various neurotransrnitter receptors: subtypes, density, bindings and sensitivity, since single neurotransmitters can have both inhibitory and excitatory effects (Chaouloff et al., 1985). With many layers of regulations within the different (stimulatory or inhibitory) types of neurons and synapses, neurotransrnitters becomes only one of these target sites that within this complex cascade, or circuit of various solubile factors involved, regulates brain function (Blomstrand et al., 1989). Only having in mind multifactorial underlying mechanism and functional interaction (multidimensional integration) in o continziurn be~eencentral neurotransmission and the peripheral processes during exercise, including the immune and neuro-endocrine system involvement (HPA-axis), we cm better comprehend al1 complexity of the different processes that happen in the brain during exercise.

It can be concluded that brain neurotransmission is influenced by exercise and that exercise induced physiological and behavioral (psychological) adaptations through changes in neurotransmission, can have feedback effect on physical and mental performance. However, many more physiological and psychological studies must be performed to determine the validity of this hypothesis and the complexity of the suggested relationship. Impaired alertness chronically affects tens of millions of people (because of narcolepsy, aging, jet-lag, shift-work and other disorders of sleep or circadian timekeeping) and is a major cause of accidents and death in modem society (Edgar and Seidel, 1997). Therefore, sleep depnvation is a major overlying factor that can lead to performance degradation. This problem has long been recognized by the military as well, and thus, has been the focus of considerable laboratory and field research. According to Pigeau and Naitoh (1995), the ability to do useful mental work declines by 35 % after the Fust 24 hours awake, particularly under conditions of continuous work. Although physical strength and endurance can also be affected by sleep deprivation, complex mental functions, such as the ability to perceive and understand changinp situation, adapt to change and plan alternative strategies are significantly decreased. It is remarkable, therefore, that there are few pharmacological therapies available that can selectively enhance waking. Drugs like amphetamines, that facilitate catecholamine release and/ or block their re-uptake, are comrnonly used to treat impaired alertness in severe disorders, such as narcolepsy, but have intractable side effects (cardiovascular side effects, interference with sleep, psychiatrie disturbances and addiction) that lirnit their general use (Simon et al., 1995; Buguet et al., 1995). Caffeine, widely used by aircrew to enhance vigilance, is also not without side effects, such as irritability, diuresis and tremor (Kaplan et al., 1997). A novel stimulant calIed Modafïnil (diphenylmethyl-sulfinyl-2-acetarnide) has been developed (synthesised) in the Lafon Labs of Maisons-Alfort, France. Modafinil (Modiodalo) apparently has several remarkable features that distinguish it from amphetamine. Modafinil in a single dosage (200-400mg) improves vigilance in sleep-deprived subjects (Lyons and French, 199 1). However, unlike amphetamines, it does not interfere with normal sleep (there is no sleep rebound or change in sleep architecture), nor does it appear to be associated with the dangerous cardiovascular side-effects attributed to amphetamines (Buguet et al., 1995).

Fig. 2- 1. Chernical structure of Modafiil.

Modafinil (M), therefore, does not exhibit a peripheral action, which could explain the fewer observed side effects. In addition, M (300 mg) does not possess the abuse potential of amphetamines since it does not induce euphona or improved sense of well-being, which are often associated with dmg dependence (Warot et al., 1993; Chandler and Blair, 1980). M has been clinically used since 1973 for the treatrnent of narcolepsy and idiopathic hypersomnia (LafTont et al., 1995; Bastuji and Jouvet, 1988). M has been used in the Persian Gulf War by the French military dunng sustained rnilitary operations and as a countermeasure for a circadian desynchronosis, apparently with great effectiveness. No evidence has been found of intolerance regarding subjective or laboratory sips and liver function in particular (Ferrer et al., 1995) Application of M (in therapeutic doses of 300 mg, twice a day) in sleep deprive subjects (for three days), indicate satisfactory level of vigilance, both subjective and objective, with absence of rnicrosleep episodes whch gradually occuned under placebo condition. Electroencephalogram (EEG) results showed an increased level of high frequency alpha activity and a decreased level of delta and theta activity, an effect consistent with increased alertness (Laffont et dl., 1995). In addition, comparative spectral EEG analysis of subjects treated with M in the same study, differs from the results obtain from the subjects treated with other psychostimulants (caffeine, amphtamine and tabernanthine), suggesting thât M appears to be an unique molecule whose effect on the EEG spectrum differs from any of the currently used psychostimulants. Besides being a major therapeutic advance in treatment of narcolepsy and excessive day tirne sleepiness, and valuable pharmacological tool for studies on the wake-sleep cycle (countermeasure against sleepiness due to sleep loss) (Akerstedt et al., 1997), M has been reported to have protective effects in: experimental (Lagarde et al., 1993), ischemic injury (Ueki et al., 1993), Parkinson's disease (Fuxe et al., 1992), depression and early phase of withdrawal of alcoholic patients (Mitchell, 1995). There is also recent evidence of a neuroprotective effect of M against organophosphate intoxication (Lallement et al., 1997). Moreover, Laffont (1996) indicates that M, by increasing alpha EEG activity, may have beneficial effect on age-related defects in alertness regulation systems. Unfortunately, the effect of M on alertness in the elderly, has not yet been tested using an objective measurement tools such as: visual analogue scale for alertness, a multiple sleep latency test, and spectral analysis of variations in thetalalpha ratio in EEG (Laffont, 1996). With its mild effect (closer to that of caffeine than other stronger psychostimulant dmgs), enhanced vigilance, increased sensation of energy and intellectual efficiency (feeling more energetic, but not overly anxious), and very good tolerance, M appears to be very well accepted by the subjects and patients who now generally show a preference for M over previous stimulant medications (Akerstedt and Ficca, 1997; Lafont, 1997; Broughton et al., 1997). Presently, the use of M in Canada is lirnited to scientific and/or clinical investigations. 2.2.1. Pharrnacokinetic Profile of Modafïnil

The pharmacokinetics of M (Moachon et al., 1996; ~odiodal@,1994) show, that after oral administration (single dose of 200-400 mg), M reaches a peak concentration in human plasma in 2-4 h after dosing (with inter-individuai absorption variations of 21%), and has an elimination half life (t %) of 10-13 h (with inter-individual variations of t '/2 of 35%). This means that it takes approximately 3 ?hdays for complete clearance (washout, or Wear out period). However, most subjective effects pdually disappear within first 12 h of absorption. Therefore, a t % of 10-13 h, which is not dose-dependent, allows a once or twice-daily administration. M distribution showed that M levels in plasma and brain are similar and that there are no distribution differences between

0oenders (~odiodal~,1994). The major metabolites of My indentified as the acidic and sulfonic derivatives, are excreted through urinary, fecal and biliary elimination (7096, 6% and 17-32% respectively). Since there is considerable involvement of urinary and hepatic (biliary) routes in M excretion, in subjects, or patients, with chronic hepatic or renal disease, dose reduction is recommended, due to modified kinetics (~odiodal~,1994). Food intake did not modify M pharmacokinetics (extent of absorption), but there is a delay in drug absorption when M is taken after a meal. Moreover, administration of high doses of ethanol was found to reduce the elimination capacity of M (~odiodal",1994; Moachon et al., 1996).

2.2.2. Dosage and Toxicity

Trying to establish dose-response curve, one study examining 75 narcolepsy patients showed that even 200 mg daily dose of M was effective in treatment of excessive daytime sleepiness (Broughton et al., 1997). The 400 mg daily dose was not significantly more effective than the 200 mg dose, but it tended to increase the frequency of headache, dizziness, and dry mouth. In a study of dose-related effects of M on alertness and cognitive performance during 60 h of sleep deprivation, Cian et al. (1997) found that doses of 300 mg/24 h effectively maintained cognitive performance, 150 mg/24 h showed some maintenance of performance, and 50 mg124 h was not substantively different from placebo. On the other hand, Saletu et al. (1986) reporting on M toxity, indicate no side effects with dosages up to 600 mg and only insomnia at 700 mg. Even in a case of an attempted overdose (> 4500 mg), M produced only tachycardia, excitation and insomnia.

2.2.3. Mechanisni of Action

Although M mechanism of action is still not fully understood numerous studies have concluded that M behavioral (Bastuji and Jouvet, 1988; Buguet et al., 1995), subjective (Pigeau et al., 1995; Warot et al., 1993) and pharmacological properties (Duteil et al., 1990), are clearly distinct from that of amphetamine (Rambert et al., 1990; De Sereville et al., 1994; Simon et al., 1995). One of the many comparative studies with arnphetamines (Engber et al., 1998) showed that in brain regions in which amphetamine increased c-fos-like imrnunoreactivity (frontal cortex, striatum and lateral habenula), M had no effect. On the other hand, neuronal targets for M in the brain (nuclei of the hypothalamus and amygdale, responsible also for the generation of sleep-wake circadian rhythm) are not affected with amphetamines. Moreover, unlike arnphetamines, methylphenidate, and cocaine, M exhibits only a weak affinity for the dopamine uptake carrier site (Lin et al., 1996; Mignot et al., 1994), and does not stimulate striata1 dopamine release in conjunction with dopaminergic behaviors (stereotyped and increased locomotor activity and anxiety). Some occasionally induced mild increase in locomotor activity with M (at doses above 500 mg), in highly responsive subjects, is still not accompanied by anxiety, stereotyped behaviour, or increases in dopamine release, which again atests to the absence of dependence (De Serville et al., 1994). Furthemore, dopamine receptor btockade with haloperïdol, or tyrosine hydroxylase inhibition with a-methylparatyrosine, block the stimulating effects of amphetamine, but not M, in cats and rnice (Lin et al., 1992; Simon et al., 1995). In addition, the beta antagonist propranolol and the alpha antagonist phentolarnine attenuate the EEG-wake-promoting effect of M, but do not block amphetarnine stimulation in cats (Lin et al., 1992). On the other hand, some studies (Ferraro et al., 1996a; Mignot et al., 1994) show that M to some (lower) extent, may increase dopamine release, which is postulated to exert its rewarding "uplifting" action (in the region of the nucleus accumbens), without initiating excessive dopaminergic behaviors and dmg abuse potential. In addition, the dopamine releasing action of M will also have a distinct pathway (different from other psychostirnlants) and cm be secondary to its ability to reduce local GABAergic transmission, which than leads to a reduction of GABA receptor signaling on the dopamine terminals (Ferraro et al., 1996a). There is a large body of evidence for M central al-adrenergic agonist effect. In fact, the stimulant-like effects of M in cats, rnice and monkeys are prevented by pre-treatment with the al-antagonist prazosin (Lin et al., 1992; Simon et a1.,1996). In addition, most of the evidence for M receptor binding characteristics seems to support the compound's effect on central adrenergic receptors. For example, repeated dosing with M increases the number of prazosin binding sites in rat brain suggesting al-adrenergic up regulation (Rambert et al., 1987). This suggests that the action of M arises from central post-synaptic al-adrenergic activation, or an increased tonus of al-adrenergic neurons (Akaoka et al., 199 1; Bastuji and Jouvet, 1988; De ServilIe et al., 1994; Duteil et al., 1990; Rarnbert et ai., 1990). Unfortunately, no other data are currently available for the receptor specificig of M, and human studies particularly are rather limited to uncontrolled studies and limited number of patients. In addition, although M promotes waking in narcoleptic dogs (Shelton et al., 1995), it is ineffective in blocking cateplexy, a symptom that is usually responsive to modulators of adrenergic transmission (Mignot et al., 1994). Therefore, it seems plausible that M may also facilitate waking through some indirect mechanisms, perhaps through decreased gama- aminobuteric acid (GABA) and increased glutamatergic transmission (Tanganelli et al., 1995; Ferraro et al., 1996a; Ferraro et al., 1996b; Lin et al., 1996). Recent findings (Fenaro et al., 1997) indicate that the ability of M to increase wakefulness may be related to a reduction of GABAergic transmission in sleep-related brain areas (posterior hypothalamus and media1 preoptic area) through reduction of GABA synthesis from glutamine, and/or through involvement of local serotonergic (5-HT3) receptors mecahanisms. Since regulation of cortical GABA, as a main inhibitory arnino acid (IAA), seems to be dependent on the equilibrium between serotonergic and al-adrenergic central neurotransrnission, M-induced reduction of cortical GABA release cm be related as well, to an inhibition of serotonergic transmissions. Ferraro et al. (1997) showed that an increase in glutamate release (disturbance in glutamate/GABA ratio) in sleep-related brain areas may be relevant to the vigilance enhancing effect of M. They found an increase in excitatory arnino acids (EAA) and a decrease in inhibitory arnino acid (GABA) function. This is confirrned in another microdialysis study (Pierard et al., 1997) with intrathalamic application of EAA (glutamate) antagonist which produced a strong sleep-prornoting action. Although a transient rise in EAA storage with M application may favour the hypothesis of an activated re-uptake of EEA, rather than a decline in their release or supply, EAA (mainly glutamate and aspartate, which act via receptors well characterized) cm certainly play a determining role on the regulation of the release of brain neurotransrnitters (Lagarde et al., 1996). Moreover, it has been observed (Vogel, 1975) that sleep depnvation increases neuronal excitability and decreases the threshold for seizures in epileptic models. This suggests that at least some neurons may become more sensitive to the excitatory effects of glutamate. Thus, a substantial net synthesis of glutamate (decrease in GABA) would be consistent with a general excitation of glutamatergic neurons due to sleep deprivation or accumulated fatigue (Ferraro et al., 1997). Thus, M may act by two synergistic mechanisms: 1) on post-synaptic al- adrenergic, and 2) on excitatory amino acid (EAA) receptors (Pierard et al., 1997). Furthemore, these possibilities are in line with previous metabolic evidence (Pierard et al., 1995), showing that M dose-dependently induces a si,~ficant increase in aspartate, glutamate-glutamine, inositol and creatine-phosphocreatine (C-CP) pools in the rat brain. Therefore, the observed shift in the ratio of GABA to glutamate transmission in these thalamic subregions could represent an additional mechanism that underlies (by metabolic activation) the vigilance enhancing effect of M. In this regard, an M-induced increase in the storage of EAA, together with an increased C-CP pool in nerve endings and glial cells, may enhance not only excitatory neurotransmission, but also enhance the brain's cellular production of energy. In brain tissue, which contains high levels of creatine-kinase (Walker, 1981) and where the Iargest changes in energy metabolism occur, this cm further have neuroprotective effect in some pathological situations with a cellular energetic deficiency such as: hypoxia, ischemia and Parkinson disease (Pierard et al., 1995; Pierard et al., 1997). In addition, Pellerin (1997) showed that M modulates glycogen metabolism (stimulating glycogenolysis through inhibition of glycogen resynthesis) in the astrocytes of the brain. This glycogenolytic effect is consistent with an array of evidence indicating a relationship between cerebral energy metabolism and the sleeplwake cycle. Long ago, it was hypothesized that the sleep/waking cycle may be metabolic in origin. It has been suggested that prolonged waking induces an accumulation of brain metabolites, responsible for both excessive sleepiness and sleep rebound. Several authors have attempted to establish a relationship between the sleep/waking cycle, sleep deprivation or rebound and the amino acid content in different cerebral structures, including cortex. (Davis et al., 1969; Karadzic et al., 1971; Himwich et al., 1973). Unfortunately, because the diversity of the methods used, the different duration of deprivation employed, and the lack of appropriate controls, the published data are not always consistent. It is generally considered that brain ammonia content increases during prolonged and intense cerebral activity (Cooper et al., 1987; Guezeennec et al., 1998), and this might explain the apparently increased synthesis of glutamate. Sorne available data (Touret et al., 1994) would suggest that stress by itself may increase brain uptake of large amino acids, but there is no evidence that it may affect glutamate metabolism. Nevertheless, glutamate infusion was found to interfere with sleep-promoting factor S (isolated from CSF and brain stems of sleep deprived animals) in a way to cause hyperactivity. Therefore, 99% of glutamate has to be removed from brain concentrate for purifing factor S (Touret et al., 1994). Bettendorf et al. (1996) in their study on sleep deprived rats found increased glutamate and glutamine levels in the cerebral cortex compared with control animals. He further speculated about the origin of this increase, and considered three mechanisms: 1) they can be taken up from the blood, which is unlikely in the case of glutamate, because acidic amino acids are practically not taken up by the brain (Pardridge, 1983), but glutamine cm cross the blood-brain barrier to some extent (Smith et al., 1987); 2) their synthesis in the brain may be increased; and 3) their degradation cm be slowed down. In addition, M altered plasma corticosterone Ievel in this study. Bettendorf et al. (1996) concluded that the CNS appears to be able to respond to changes of brain tissue homeostasis during the sleep/waking cycle by appropriate metabolic regulation, the mechanism of which is still largely unknown, and that M may have its own unique effects on glutamate and glutamine transport through the glial cells. Future studies will need to measure (in-vivo, since postmortem analysis rnay lead to inaccurate determination of GABA) and compare individual changes in cerebral metabolic effects (C-CP, glutamate-glutamine pools), in order to determine more accurately the effects of changes in energy metabolism involved in the vigilance enhancing effects of M. In this regard, it is interesting to hypothesize how certain nutritional manipulations (certain amino acid supplementation) rnight affect changes in CNS related to fatigue. It is already known that hypothalamus contain some glucose sensitive neurons (Karnovski et al., 1980). Another way of andyzing modifications of brain amino acid neurotransrnitter rnetabolism during the sleep/waking cycle, sleep deprivation and fatigue, is to study the enzymes involved in their metabolism. Therefore, in order to establish the exact mechanism of action of M, more rnicromethods such as microdialisis and receptor binding studies (for different receptors) are needed.

2.2.4. Modafinil and Cognitive Performance

Cognitive psychology is the study of al1 processes by which sensory input is transformed, reduced, elaborated, stored, recovered and used. Although it may be approached from several points of view, the study of cognitive performance is frequently viewed from an information-processing standpoint (Reed, 1982). Thus, it is assumed that information is variously processed through a series of identifiable stages, each of which performs a unique function that then passes information on to another stage for further processing. These stages include: perception, attention, pattern recognition, memory, imagery, language, problem solving and decision making (Reed, 1982). The frequent problem in constmcting information-processing models is the identification of the stage at which a performance limitation occurs. The arousal response of the Ascending Reticular Activating System (ARAS) seerns to be essential for the maintenance of a conscious alerted state of the organism. The "reticulo-cortical loop" connecting the cortex to the ARAS, regulate through a neural feedback mechanism, the level of arousal of the cortex, and hence, the general efficiency of information processing (Reed, 1982). If arousal deviates from the optimal (pleasant arousal tone), the person is motivated to avoid or seek arousal to remit to the most pleasant, moderate level. This need to maintain a moderate level of arousal may affect the person's behavior during task performance. If the task provides low levels of stimulation and tends to reduce arousal, people may arouse thernselves by increasing their response rate (Foikard, 1983). On the other hand, over activation of the brain stem reticular systern (overly awake andor anxious) cm result in the loss of selective awareness and discrimination. This can be further related to the beneficial effects of sorne psychotropic drugs (benzodiazepines) in reducing tensiodanxiety level and increasing calmness in highly stressed individuals, which in tum, rnay have beneficial consequences for performance (Wesnes and Warburton, 1983). Vigilance can be defined as the process of maintaining attention (Stroh, 1971). Although attention shifts constantly, the shifting is not random; it is guided by certain definite conditions of the extemal and internal environment. The internal environment can be affected by: level of fatigue, motivation, mood, personality type, mental state (attitude toward the task), and age; while the external environment can be result of: characteristic of the stimulus (maagitude, frequency, distribution), task complexity and environmental stress (macro and microstressors from noise, heat, etc.) (Strohy 1971). Moreover, motivation and mood can also be affected by declines in the level of arousal. Some evidence suggests that incentive (intrinsic and extrinsic motivation) can be regarded as an arouser (Eysenck, 1983). While on one hand, some investigators have argued that performance is always positively related to motivational strength, Yerkes and Dodson have claimed that there is a curvilinear relationship between arousal, motivation and performance, and that an intermediate level of arousal andor motivation is optimal for performance. This is known as " the inverted-U hypothesis" or Yerkes-Dodson law (Eysenck, 1983). According to the Yerkes-Dodson law, performance is best at intermediate levels of arousal. The durability of the Yerkes-Dodson law lies in its 'ccornmonsense" appeal. However, while there is general support for the positive limb of the relationship, the detrimental effects of "over-arousal" have been assumed, rather than shown to occur by the results of experiment. However, it seems obvious that while a little motivation will clearly improve our efficiency, one can be "too keyed-up" or "not relaxed enough" for some jobs andor optimal performance. For example, younger more neurotic people are normally operating at a level of arousal which is too high for optimum performance. As arousal level decreases, these people approach their optimal operating level (Eysenck, 1983). It has becomes usual to think of performance changes under stress as the result of a change in the level of arousal. The amount of stress (with noise, rapid changes in , sleep deprivation, sustained attention, or high informational content presented to individual) is related to stress hormone release (corticosteroid and catecholamine release) and the level of electrocorticai arousal. In addition, corticosteroids will activate both noradrenergic and serotonin neurons, and these neurochemical changes may influence the individual's sense of effort and onset of fatigue (Wesnes and Warburton, 1983). The primary neurochemical action of a psychostimulative drug is to increase the activity in the ascending reticular pathways, which hieghtens attzntional efficiency which is believed (through improved psychological cornpetence), to enable individuals to cope with stressful situations (Wesnes and Warburton, 1983). Some of these drugs seems to block serotonergic function, and therefore, decreases the experience of anxiety; others increase noradrenergic function, which apparently induces euphoria and causes addiction (Ferrer et al., 1995; Kaplan et al., 1997). The relation between cortical electrogenesis and the state of arousal (consciousness) is evident (Wesnes and Warburton, 1983). The potential role of different neurotransrnitters and neuromodulators in maintainhg this optimal (moderate) level of arousd is still largely unknown and appears to be of great interest for future research on CNS fatigue. Therefore, it is apparent that increases in arousal cm result in either improved or inferior performance, depending upon the situation and the individual (personality type, age, etc.). A prolonged task time, a lack of feedback (as incentive), monotonous stimulus conditions from both the task and the work environment, will al1 enhance problems of suboptimal and declining performance, through altering optimal (moderate) level of arousal.

There is no doubt that cognitive performance cm be maintained at a higher level, and for a longer duration, with stimulating dmgs than without. The relatively benign psycho-pharmacological properties make M a good candidate for reducing or arneliorating the cognitive impairment during prolonged sleep loss under continuous workload conditions. Since 1994, the Human Factors Division of DCIEM undertook an extensive investigation of the effectiveness of M (as compared to d-amphetamine, and placebo) in a simulated sustained operations environment (Sleep Deprived-SD conditions) involving normal healthy adults (Buguet et al., 1995; Pigeau et al., 1995). Generafiy, the findings concerning M were quite encouraging. The dmg was reported to be as effective as d- amphetamine, but with less potent side effects (fewer cardiovascular disturbances, better recovery sleep, lower susceptibility to addiction, and wider ratio between usehl and toxic doses j. Many fundamental cognitive abilities are known to display circadian rhythms and progressive deterioration with increasing sleep deprivation (SD). According to the study of Pigeau et al. (1995), M and amphetamine can raise body temperature and thus disrupt (suppressed andlor elevate) the natural circadian rhythm, improving the mood and performance, compared to the placebo group. On the other hand, Bourdon et al. (1994) demonstrated that the ingestion of a single dose of M has no significant acute effect on thermal balance in neutral conditions and on thermoregulation in non-sleep deprived subjects exposed to cold. Stivalet at al. (1997) reported that the administration of M prevented the slowing down of the attentive/serial processes during SD, and reduced error rates (increase accuracy of visual detection) to one-half those seen with a placebo. However, as with any stimulant, M induces subjective effects. In this regard, it is important to understand the extent to which the SD individual cmquantify and articulate these cognitive performance deficits, and the extent to which stimulating dmgs, such as M, can affect the relationship between subjective and objective (real) performance effects.

2.2.5. Self-Monitoring of Cognitive Performance

It is well known that subjective reports of fatigue or sleepiness are correlated with cognitive performance decrements during SD (Pigeau et al., 1995; Gillberg et al., 1994; Pigeau and Naitoh, 1995). Thus, the subjective estimate of how one feels cm provide a prelirninary indication that mental performance is (or may soon be) sub-optimal. Although by proper intrinsic andor extrinsic motivation (Wilmore, 1968), it may be possible to reduce the vigilance decrement, in the often extreme situational demands of certain occupations (e.g., rnilitary personnel, police, medical professionals) individual may disregard the subjective assessment of fatigue or sleepiness. If this occurs, then the decision to actively pursue fatigue countermeasures (e-g., take a nap, stimulant, or withdraw frorn the relevant activity) will be based on either interna1 or external evidence concerning actual performance (Baranski et al., 1994). In some situations, feedback from the environment may not be available and an accurate assessment of one's own performance (by "intemal-feedback") provides the only means by which to indentify a potentially life-threatening state. Thus, in the absence of explicit feedback from the environment, subjects apparently have access to a fairly reIiable "intemal-feedback" about their declining performance. This mechanism appears to be pretty accurate during the normal state, as well as during SD stress (Baranski et al., 1994; Baranski and Pigeau, 1997). In addition, according to the study of Shek and Pigeau (1995), the measurement of arousal using subjective scales and performance measures seem to correlate well with biochemical changes (level of salivary cortisol). On the other hand, Gaillard (1993) suggests that some psychological estirnates of stress (eg, mood or fatigue scales) can be distinguished from subjective perceptions (estimates) of workload. Therefore, one view of physiological stress is that it is a function of arousal. Then it follows that the use of M and amphetamine will alleviate the performance decrements due to sleep loss; however, the question remailis: "wiIl the subjective estimate of performance (workload) be affected by such substances?" Several studies have shown that amphetamine produces a heightened arousal feelings of euphoria and well-being, a decrease in appetite and fatigue, without having an antagonistic effect on the subjective jud,oment of one's own performance in non-SD subjects (Weiss and Laties, 1962; Smith and Beecher, 1964). In addition, in study of Warot et al. (1993) M has shown no evidence of euphoric subjective effects in non-SD individuals. Findings from the study by Pigeau et al. (1995) and Baranski and Pigeau (1997) indicate that M and d-amphetamine work equally well in terms of their ability to arneliorate the effects of SD stress of cognitive performance. However, d-amphetamine did not disrupt the ability to self-monitor performance, whereas M (although with fewer mood changes) induced exaggerated (Le. overconfident) self-assessments of performance, 2 hours after drug ingestion, particularly in post- task estimates of the perceptual cornparison task and the mental addition task. These findings suggest that M may actually have a negative effect on performance, making individuals more confident about their decisions than they rnight othenvise be (Baranski, 1995). 2.2.6. Overconfidence Effect

Self-monitoring refers to the ability to assess accurately one's own performance in a specific environment. Perfect self-assessrnent or self-efficacy judgment is indicated when subjective estimates of confidence match response accuracy. Underconfidence is denoted by estimates that fa11 below response accuracy, and Overconfidence is denoted by estimates that exceed the percentage of correct responses (Baranski et al., 1994). If accuracy of self-efficacy judgement is consistent with overt performance (abiiity to perforrn), then there is much to benefit in terms of increased performance and productivity. On the other hand, if subjective effects are not consistent with overt performance, then the potential for human error (from pour judgement, planning and overly risky decision making) necessarily increases (Baranski, 1995). Interestingly enough, Keren (1980) considered the possibility that, unlike our intellectual knowledge, our accurate sensory systems rnight not be vulnerable to the phenornenon of overconfidence. He confirrned that overconfidence occured on a difficult knowledge task, but not on perceptual tasks. In addition, Winman and Juslin (1993) suggested that perceptual judgements will not show overconfidence or a difficulty effect, and consequently, that "the nature of confidence in sensory discriminations is different from the nature of confidence in cognitive judgements". On the other hand, Baranski and Petrusic (1994) provided evidence of a calibration difficulty in expenments involving confidence evaluation in human judgements and argued against fundarnentally different basis for the judgement of confidence in perceptual and non-perceptual tasks (Baranski and Petnisic, 1995). According to these authors, the general knowledge and perceptual cornparison tasks have very similar properties of confidence judgements if the levels of judgement difficulty are appropriately matched. To date, the self-monitoring of performance has been studied at two levels. The first concems the validity of subjective (confidence) assessments made on a trial-by-trial basis during a specific task (Baranski and Petrusic, 1995). In terms of the effect of SD stress on the validity of confidence judgments, Baranski et al. (1994) found that trial-by-trial self-monitoring was unaffected by 64 hours of SD despite pronounced circadian and SD effects on primary task performance (Le. mental addition task). This finding provided prelirninary evidence of a reliable "intemal-feedback" mechanisrn during SD stress. In contrast to self-monitoring at the level of the individual trial, the second level of self-monitoring involves an zssessment of the validity of more global subjective (frequency) estimates of performance made irnmediately before andor immediately after a specific cognitive task (Stone, 1994; Treadwell and Nelson, 1996). Hence, the relation between the pre-task evaluation and the actual performance provides an index of how well individuals can anticipate a SD- induced change in cognitive performance (i.e., prospective self-monitoring). Conversely, the relation between the post-task evaluation and the actual performance provides an index of how well individuals can detect a SD-induced change in cognitive performance once it has occurred (i.e., retrospective self- monitoring) . It is noteworthy that in terms of self-monitoring task performance, Pigeau et al. (1995) and Baranski and Pigeau (1997) found that al1 groups display a clear overconficlence in the pre-task estimate that precedes session 1 (i.e., before beginning the task). This initial (first impression) overconfidence, made on cornplex cognitive tasks, although related also to personality type (impulsiveness) and mood, have been confied also by Stone (1994). His results suggests that there is a tendency toward overestimation of personal ability in comection to overly positive expectations (sirnilarly to overly negative expectations), which may have a de-motivational effect on individual behavior (attitude toward the task), decreasing the effort and putting less attention to strategy how to perform the task. On the other hand, mildly negative expectations ("healthy scepticism") may improve performance, since it will increase the effort with more time being placed on planning, which is essential for cognitive function of problem solving and goal-directed decision making. Therefore, even without physiological side effects, M as any stimulant may (dose-dependently) induce undesirable subjective effects. Reported overconfidence phenomenon may negatively affect the decision process (cause impaired judgment) and even affect physical performance under certain conditions. Finally, fatigue is a subjective state with both physiological and psychological aspects (Borg, 1977). According to Borg (1977), maybe we should consider perception of exertion as a unique class of sensation, that has a unique (one or more) sense organ(s) and a separate path from the sense organ(s) to the brain. We may also speculate upon the importance of having a good perceptual system that will be able to regulate effort precisely to the right intensity, without misjudging how hard one could exercise. Although vigilance must be studied in more cornplex and operationally valid environments (real-world vigilance tasks), evidently, a more comprehensive understanding of M mode of action, and the relationship between subjective and performance (physiological) enhancing effects is needed, before M can be recommended as a safe and reliable fatigue countermeasure. Chapter 3

Study Objectives and Hypotheses

3.1. Objectives The only study done so far about the effect of M on physical performance, was the study of Jacobs and Bell (1997), who reported that acute ingestion of M prolongs exercise time to exhaustion at - 85% V02 max, with significantly lower subjective ratings of perceived exertion. Of concern, however is the reported overconfidence effect (Baranski and Pigeau, 1997), which may negatively affect the decision processes, causing irnpaired cognitive (intellectual) and sensory judgement (i.e., mask the effect of fatigue) by lowering EZPE dunng exercise. Thus, the objectives of this study were:

1. to confiirm the ergogenic effects of M on physical performance in non-sleep deprived subjects. . Il. to determine if M will alter the individual self-monitoring ability and particularly RPE during exercise. ... 111. to evaluate the effect of M on cognitive performance.

3.2. Hypotheses

The hypotheses tested in this snidy were as follows:

1. M will significantly prolong time to exhaustion during high intensity submaximal exercise. . Il. M will cause an ovevconfdence effect demonstrated by a change in the relationship of perceived and actual exercise intensity and by overestimation of the actual cogritive abilities. Chapter 4

Materials and Methods

This study was carried out at the Defence and Civil Institute of Environmental Medicine (DCIEM) from Novernber 1997 to May 1998. The study was approved by Institutional Ethics Cornmittees both at DCIEM and at the University of Toronto. The approved experimental protocol and Ethics Cornmittee letter of approval are attached as Appendix A.

4.1. Subjects

Volunteer subjects consisted of civilian and military personnel from DCIEM, students from York University, the University of Toronto and individuals recruited from local fitness clubs. Seventeen healthy, moderately active, male subjects, 18-40 years of age participated in this study. On the first visit, the experimental protocol was explained to each of the subjects individually. They were given the opportunity to ask questions about the protocol and potential nsks involved in the study, before they completed and signed informed consent and invasive procedures consent forms. Subjects were required to complete a medical screening questionnaire and were exarnined by a physician to assure their suitability to participate in the study. They were also required to abstain from consumption of coffee and alcohol 24 h pnor to any testing session, and any other stimulative substances during the time of the study. In addition, they were instructed to maintain their normal exercise regime, but to avoid any hard exercise 24 h prior to each visit. Al1 subjects were non-smokers. The lowest individual VOz max was 40 mL - kg-'- min' and the highest V02 rnax was 54.6 mL - kg-'- min". 4.2. Experimental Protocol

The experiment was divided in two separated parts: 1) Endurance Ride to Exhaustion (ER) and 2) Production Protocol Ride (PPR). Al1 testing was perfomed on an electronically controlled cycle ergometer that maintained a constant power output irrespective of pedaling rate (Sensormedics Ergo-metrics 800s). The cycle ergometer seat height was measured on the fist visit, in the knee extended position for each subject and than kept the sarne throughout the study.

4.2.1. Endurance Ride to Exhaustion

In the first part of the expenment, eight subjects perfomed the Endurance Ride to exhaustion (ER) at 85% V02max. The ER consisted of a 5 minute warm- up exercise at 50% V02 max, followed by exercise at 85% V02max to exhaustion or until the subject canot maintain the pedaling cadence above 60 rpm. Since the aim of this part of the study was to confithe previous findings of Jacobs and Bell (1997), the same protocol was used as in their study. On the first visit, V02 rnax and submax test were perfomed. The V02 max test consisted of pedaling at 60-80 revolutions per minute (rpm), with the exercise intensity starting at 60 W and increasing in steps of 30 W-min-', until the subject can no longer maintain the pedaling frequency of 60 rpm. After 45 min of rest, the submaximal test was perfomed at fixed intensities of - 60, 70, 80, and 90% of V02max dunng 5 min intervals of exercise, separated with 5 min intervals of rest. From these two tests, the relationship between the rate of oxygen consumption and Power Output (PO) equivalents of 50 and 85% V02 rnax were determined (using a regression line) and were applied for al1 subsequent performances of the ER (Fig. 4-la). Each subject performed: one familiarization, one control and two treatment trials with a minimum of five days intervening between the trials. During the ER, indicators of aerobic fitness (time to exhaustion, HR, V02, and Ventilation, as wel as RPE) were monitored and recorded at: 5, 11, 17, 23 min - point of exercise, and at the exhaustion.

A Blood I

Food A 1

Cogitive Test

PPR

Figure 4- la and Figure 4- 1b: Time line for experimental pro toc01 for ER and PPR.

4.2.2. Production ProtocoI Ride

The second part of the expenrnent was the Production Protocol Ride (PPR)' designed to test overconfidence effect. Seventeen subjects (eight from the first part plus nine new subjects) participated in this part of the study. In an atternpt to test overconfidence effect with more precision, the less common approach to the Rating of the Perceived Exertion (RPE) was used, by application of the Production (PR) instead of more traditional Response (RS) protocol. The difference between these two protocols is that in the PR protocol, the investigator selects the RPE values and the subject adjust his power output (using a hand-held control) on a device, such as a cycle ergorneter, whereas in the more traditional RS protocol, the subject exercises at a power output selected by the investigator and responds by rating the intensity as a RPE value on the same Borg scale. The comparison of RS and PR protocols for assessing perceived exertion in the study of Myles and Maclean (1986) showed that the relationship between RPE and power output (the regression coefficient, the slope and intercept of the regression line) was the same for both protocols. However, the PR protocol has the advantage of greater safety for the subject when it is used in laboratory settings to monitor progress in training or rehabilitation (Noble, 1982). In addition, a subject who is instmcted to exercise to a specific RPE, will increase his exercise intensity as his level of fitness or alertness irnproves, or decrease it on a day when he feels unwell (Myles and Maclean, 1986). Therefore, administration of both protocols can provide an opportunity to assess the subject's perception of exercise intensity from two different perspectives, thereby increasing the reliability of any conclusion drawn from the data. Since overconfdence is normally expected to affect the subjects perception of exercise intensity, judgement of the appropriate intensity for the same levels of RPE should be in the case of overconj?dence overrated. Therefore, we assume that an overconfident subject, when they have a chance to pick their own exercise intensity, will overload themselves and thus shorten their time to exhaustion. During the PPR, the control panel on the cycle ergorneter was turned away so that the subject could not see the power output settings. The dock was removed from the exercise laboratory so that the only feedback available to the subject was his own sense of effort. After farniliarization with a ten-point Borg scale, the subject's were given three different RPE values: light (2), heavy (5), and very heavy (8), according to the Borg scale. These RPE values are presented in the same order on al1 sessions (i.e., 2, 5 and 8). For each RPE value, the subject was given 15 s at the beginning of each minute, to adjust the power output to an appropriate level, by means of a handheld control with an unmarked dial. The selected power outputs were recorded at the end of each minute. Each RPE (5 min) interval, was followed by a 5 min recovery period, during which the subject remain seated on the cycle, pedaling at a workload of 50 W. At the end of the last recovery period, the subjects where asked to set the highest possible intensity (with two adjustment opportunities: during the Fust 30 s and between 60 and 75 s of exercise), that they think they will be able to sustain for 2.5 min without any further adjustments (this is presented as a gray area on the Time Line for the expenmental protocol - Fig. 4- 1b). Each subject for the PPR visited the laboratory on at least five occasions, having one farniliarization, one control and two dmg trials. However, some of the subjects in order to establish the maximum intensity that they would be able to sustain for 2.5 min (accepted time variation was between 1.5 to 3.5 min) required one or two practice sessions more. The start time for each of four different levels of PPR was when the subjects began pedaling at 50 W with a rate of pedaling exceeding 60 rprn. A verbal confirmation would be made to the subject that the test, or the certain level (2, 5, 8, or max) had started so that the subject could set the PO within the time for adjustment, and following the RPE value of the Borg scale (posted in front of him) that he was perceiving at that moment with his whole body. The subjects exercising at the highest possible intensity were not stopped after 2.5 min, but would continue to exercise till exhaustion. The point of voluntary exhaustion was determined as the point when the subject could no longer maintain a pedaling rate of 60 rpm. A verbal confirmation that the test was complete was made and the time noted. The power output was then reduced to the starting 50 W and the subject was instructed to continue pecialing to cool down for a minimum 5 min. The time to exhaustion at maximal intensity (2.5 min) was measured separately and was expected to be shorter in case of overconfidence. Furthemore, we assumed that the total load and average load values for 5 min RPE intervals (Le., 2, 5, and 8) would be higher for overconfident subjects. In addition, during the drug trials after each RPE (2, 5, and 8) level of exercising (during 5 min recovery period) and after exhaustion at max. intensity exercise, the subjects where asked to self-evaluate their performance in tems of load (how much they think that was higher or lower), tirne (how long they think they last at max. intensity), and to compare it with the control trial. These answers were used as response criteria for assessing the subjective ratings of perceived exertion and maintenance of their self-monitoring ability. During each visit for PPR subjects also perforrned three sessions of Line Comparison Cognitive Task (CT) as depicted in Fig. 4-1 b. Moreover, each subject was tested at the same time of day to avoid diumal variations in cognitive performance. A small standardized meal without caffeine (juice and muffin) was provided in al1 trials, two hours before ER or PPR, as depicted in Fig. 4-la and 4-lbb. Care was taken to ensure that the subjects could not see or hear any signs of elapsed time dunng the exercise. The subjects were not informed of their elapsed tirne for any drug trial until dl the trials for ER or PPR had been completed. The order of treatments was counter bdanced arnong the subjects to avoid any order effect. During the treatment trials, capsules with M (4mgkg-l) or Placebo (metamucil) were consumed 3 h before the ER or PPR, using a double-blind expenmental design. In order to monitor training effect and considering that eight subjects who participate in both experiments have up to 13 exercise sessions, in addition to five days minimum interval between the sessions, we repeated V02max test after each expenment.

4.3. Fol10 wing measurements were made dunng trials:

4.3.1. Heart Rate (HR) was monitored continuously during each ER and PPR with a transmitter / telernetry unit (Polar Electro PE3000). 4.3.2. Blood Pressure (BP) was measured before each exercise session while subject was sitting on the cycle-ergorneter, with a standing device for rneasuing BP- Trimline (mm Hg calibrated, Somerville N.J. USA) 4.3.3. Metabolic gus exchange. i.e., oxygen uptake (V02), carbon dioxide production (VCO*), and minute ventilation (VE), were measured during each ride to exhaustion with an autornated metabolic cart (AMETEK Applied Oxygen Analyzer System, Model S-3A/1 and AMATEK CD-3A Carbon Dioxide Analyzer) using open circuit spirometry. Before each measurement, the analyzers were calibrated with a standardized precision gas of containing 15.00% O2 and 5.00% COz. Expired gases were collected in a rnixing charnber and sampled at breath by breath intervals. Ventilation was rneasured from the expired side of a two way valve using an air flow transducer (Model K520, K.L. Engineering, Northridge CA.). These measures were integrated using a PC and DCIEM written software with standard metabolic equation. Time averaged values were calculated for VE (L/rnin), V02 (La min-' and mL min-'. kg-'), VC02 (L- min-') and the Respiratory Quotient (RQ) every 30 s during the testing period and stored for later analyses. 4.3.4. Rating of Perceived Exertion (RPE) - The subjects were asked to score their Rating of Perceived Exertion (RPE) on the 10 point Borg Scale (Borg, 1982). This scale was constnicted to use simple verbal expressions as anchors for numbers, with the arrangement of these expressions and numbers in a format compatible with the properties of ratio scaling. Thus, a score of O (essential in ratio scaling) was equal to a rating of the amount of effort being "Nothing at dl" and a score of 10 being "Very, Very Strong". With ratio properties, this category (interval) rating scale allows inter-mode1 and inter-individual cornparisons of perceived exertion (Borg, 1982). The subjects were asked to assess their perceived exertion by pointing to two numbers on the scale. The first number selected was 1 unit and the second was a tenth of 1 unit. Extra attention was placed on familiarization with the Borg scale for PPR. Since the original Borg RPE values were associated with the descriptive phrases, each subject was provided with an additional information sheet to provide a better understanding of their meaning. 4.3.5. Line Cornparison Cognitive Task and Overconfidence rneasurements - For this testing, the subjects worked alone in 3 X 4m experimental rooms, which was equipped with an DBM PC, monitor, keyboard, table, chair and desk lamp. The Line Cornparison Cognitive Task (CT) was controlled by the main computer and the task was displayed on the subject's monitors. The CT was perform at the same time twice before and once after exercise (during PPR-farniliarization trials), before treatment with M, or P, and both pre- and post exercise (during PPR- treatment trials) (Fig. 4-lb). The duration of the CT was constant among visits (approximately 15 min), and each session included the line comparison task and subjective questionnaires for fatigue, motivation, mood and performance evaluation. This CT has already been used in the study of Baranski and Pigeau (1997). Each of the subjects had minimum of nine CT practice sessions before the dmg trials, which provided enough training for leveling performance and avoiding any additional learning effect during application of the hg. CT was also used for measuring the overconfidence effect. On each trial of the Line comparison task, the subjects were required to deterrnined the "LONGER" or "SHORTER of two horizontal line lengths presented on the video monitor. They indicated their response by depressing the left or right button on the mouse. Imrnediately following the response, they were presented with a choice of 6 confidence levels (50%, 60%, 70%, 80%, 90%, and 100%), where 50% represented a guess and 100% indicated absolute certainty. The subjects were asked to select the level that best represented their confidence in the correctness of their answer and then click the appropriate mouse button. In addition, they were asked to make pre (how well they think they will do the task) and posr (how well they think they did the task) assessrnent of their performance.

4.3.6. Biochemical Assays for Metabolite and Nezcrotransmitter Deteminations

Blood Sampling and Collection Blood was drawn through a Teflon catheter (Deseret Medical Inc., Sandy, UT) inserted into an antecubital vein. The catheter was kept patent with a heparin lock; 0.25 mL of heparin (IO units - mL1) was injected into the catheter, filling it to the tip. Venous blood samples (10 mL) were collected in 2 vacutainer tubes (one for the determination of glucose and Free Fatty Acids (FFA), and the other one pre-cooled heparinized/gIutathione tube for determination of catecholamines and M). These tubes were kept in crushed ice during the time of the experiment. The blood samples were taken as depicted on the time line of events during the treatment trials of ER and PPR (Fig. 4-la and 4-lb). An aliquot of the blood sample was immediately deproteinized in cold perchloric acid for subsequent determination of lactate concentration. The rernaining blood was centrifüged at 3500 g at 10°C within 15 min, and the plasma (divided in conics (Id) for glucose and FFA, or to a clean Polystyrene tube (5 mL) for catecholamines and M was stored at -70°C until assayed. The plasma samples from the eight subjects who participated in the ER were assayed for: glucose, free fatty acids, lactate, serotonin, dopamine, norepinephrine, epinephrine and Modafinil. For the PPR, the Modafinil assay was done for al1 seventeen subjects at one time point (3 h after ingestion of M), and the concentration of catecholamines were done for the eight subjects at three points of time in the experimental protocol (before hg,before the run - 3 h after ingestion, and at the exhaustion). Blood Metabolite and Neurotransmitter Determinations The plasma glucose samples were analyzed in duplicate using an automated spectrophotorneter (Mode1 3500, Gliford Instruments Lab. Inc., Oberlin, OH) by the GOD-PAP method of Trinder. P. (Ann. Clin. Biochem. 6:24. 1969.). The assay was camied out using a glucose kit (Cat. No. 166391) supplied by Boehringer, London. The conversion of glucose and oxygen to gluconic acid and hydrogen peroxide forms the basis for this glucose determination method. The liberated hydrogen peroxide is reduced to water. The concentration of glucose in the sample corresponding to the measured fluorescence was calculated from a previously prepared standard curve. The plasma samples were assayed for FFA in duplicate using the WAKO NEFA C test kit (CODE No. 990-75401, Wako Pure Chernical Industries Ltd., Osaka, Japan). This enzymatic colorimetric method relies on the acylation of Coenzyme A (Coa) by the fatty acids in the presence of Acyl-CoA synthetase. The Acyl-CoA thus formed is oxidized by the added Acyl-CoA oxidase with the production of hydrogen peroxide. The latter, in the presence of peroxidase, perrnits the oxidative condensation of 3-methyl-N-P-aniline with 4- aminoantipyrine to form a purple colored product, which was then measured colorimetricdly at 550 nm (Model 3500, Gilford Instruments Lab. Inc., Oberlin, OH). The amount of FFA in the sarnple corresponding to the measured absorbante was calculated from a previously prepared standard curve (range: 0.50 to 1.97 mmol L-~). The blood samples were assayed in duplicate for lactate concentration after deproteinization (Maughan, 1982). The conversion of lactate to pyruvate in the presence of lactate dehydropenase and excess NAD+ forms the basis of this method. The NADH which is forrned in stoichiometric quantities during the reaction was measured fluorometrically (Perkin-Elmer Model 650-10A, Nonvalk, CT). Hydrazine was added in the reaction medium to react with the formed ketone and remove it from the . The amount of lactate in the sample corresponding to the measured fluorescence was calculated from a previously prepared standard curve. Plasma epinephrine (E), norepinephrine (NE), dopamine (DA), serotonin (5-HT) and Moddinil level were measured by gas chromatography-mass spectrometry with electron capture negative ion chernical ionization (GC-MS EC- NCI) using a 5% ammonidmethane mixture as a reagent gas. The assay has a high specificity and its sensitivity was sufficient to measure resting concentrations of biogenic amines in only 0.1 mL of blood plasma. This method is based on work of Martin et al. (1982), with additional modifications being made by Zarnecnik (1997). Al1 catecholarnines and M assays were performed by trained technicians. 1.4. Data Analyses

4.4.1. Analysis of Variance (ANOVA) All ANOVAs were performed using statistical software (Super ANOVA v 1.1 1 (199 1), Abacus Concepts Inc., Berkeley California or Super ANOVA SAS@ Statistics, Version 5 by SAS Institute Inc. Cary, NC, U.S.A.) on a Macintosh 6 100/60 personai cornputer. A repeated measures one-way analysis of variance design was used to deterrnine the significance of changes between M and P trials for al1 dependent variables. Time dependent variables were analyzed with two "within" factors (trial and time), while the variables measured at exhaustion with no time factor were considered using one "within" (trial) factor. For al1 repeated measures analyses, an a priori significance was set at p = 0.05. For significant interactions of main effects, the Super ANOVA software application was used to compute analyses of means cornparisons to determine significant differences within the interaction. Data are presented as mean values IT standard deviation (SD).

4.4.2. Power Analysis An a priori statistical power analysis for time to exhaustion was performed. An estimation of the required number of subjects to achieve a power of 0.8 was carried out following the power calculations. The required number of subjects for the power of 0.8 was - 70. With 16 subjects, the calculated power was - 0.7. Chapter 5

RESULTS

5.1. Endurance Ride to Exhaustion (ER)

Time fo Exhaustion Time to exhaustion during exercise at 85% V02 max was siWcantly longer (pcO.01) during M than during control or placebo trials (Table 5-1, and Fig. 5-1). Table 5-1: Time to Exhaustion in minutes for al1 subjects with mem and SD values.

Time ta Exhaustion Subject control placebo madafinil I 1 MC 23.260 25.61 0 29.260 2 N.C. 25.1 00 25.950 26.71 0 3 M.A. 21.800 20.680 25.750 4 ICB 20.930 17.350 20.200

Figure 5-1: Time to Exhaustion during exercise at 85% VO, max. Values are in mean ISD. The asterisk (*) within the figure indicates significant difference between the trials.

control Order effect No significant "order effect" was found among days for exercise to exhaustion, (Fig. 5-2). The "day 1" trial was always the control trial, while the placebo and M trials were either on "day 2" or "day3".

Figure 5-2: Effect of order of trial and time to exhaustion. Values are in mean ISD.

day 1 day 2

He& rate, Oxygen Uptake, Ventilation and Respiratory Exchange Ratio There were no significant differences among trials during the ER or at exhaustion for any of these variables, with the exception of HR, which was significantly higher for the M trial, cornpared to both the control and the placebo, but only at the 5 min point of exercise. Figure 5-3: HR during ER. Values are in mean a SD. The * within the figure indicates significant difference among the trials.

wntrol placebo madafinil a rn Figure 5-4: V02, VE and RQ during ER. Values are in the mean ISD.

conml modafinil placebo

conml placabo modafinil

contriol placebo modafinil Rate of Perceived Exertion dunng the Endurance Ride There was no si,pificant effect of M on the subjective ratings of perceived exertion. However, there was a trend for lower RPE values during M trials cornparhg with placebo (pc0.09). The RPE data for the control trials has not been presented because of poor farniliarization with RPE scde initially, which did not provide valid data from the subjects during the control trials. Figure 5-5: RPE during ER. RPE is shown as the mean -c SD. 1 r I 11 , r

CS 11 1 11 7 tend Blood Lactate rime (min) Blood lactate concentration was similar during the ER in both the M and P trial, with the exception of the values at exhaustion. The values at exhaustion were significantly higher for the M trial. The higher values are expected because of the longer duration of exercise during M trial. Figure 5-6: Blood lactate during ER. Values are shown as the mean + SD. The asterisk (*) indicate significant difference between M and P trial. Plasma Glucose and Free Fatty Acids There was a significant increase in plasma glucose during the M trial, which was most pronounced at the end of the exercise. On the other hand, the changes in FFA showed no difference between trials. Figure 5-7: Plasma Glucose and FFA during ER Values are in mean + SD. The * within the figure indicates significant difference between M and P trial.

placebo rnodafinil

I I T 1 before dnig befom run 10 min end of run lime 5.2. Production Protocol Ride (PPR)

Resting Heart Rate and Blood Pressure during PPR There were si@cant differences between the M and P, and between the M and C trials in the resting HR and systolic blood pressure (BP), with no differences in diastolic BP. The P trial values for al1 these variables were not significantly different from C. Table 5-2: Mean values for resting heart rate. * Indicates significant difference from placebo and control trials.

Courrt Mean Std. Dev. Std. Enor control 17 71 -706 10.067 1 2.442 placebo 17 76.765 11.718 2.842 modafinil 17 86.882 12.067 2.927

Table 5-3: Mean values for resting systolic blood pressure. * Indicates significant difference from placebo and control triais.

Count Mean Std. Dev. Std. Error controI 17 120.882 7.582 1.839 1 placebo 17 118.941 7.207 1.748 modafinit 17 ' 125.941 7.420 1 .a00

Marimal Heart Rate There was significant difference between M and P, and M and C trials in HR max, at the end of PPR.

Table 5-4: Means Table for max. * Indicates significant difference from placebo and controi triais.

Count Mean Std. Dev. Std. Error control 17 183.882 10.770 1 2.61 2 placebo 17 186.118 10.505 1 2.548 modafinil 17 ' 190.118 1 0.228 1 2.481 Average Watts at Vanous RPE Levels During the PPR, the subjects chose power levels corresponding to three specific RPE values (2, 5, and 8 according to the 10-point Borg scale). There were no differences between the trials in the average Power Output (W) watts selected (during each 5 rnin interval).

Figure 5-8: Average Power Output (W) at various RPE levels (mean 2 SD).

control placebo

Watts Selected for Exhaustive Exercise for 2.5 min The subjects were asked to pick the highest intensity that they thought they could sustain for 2.5 min. Table 5-5 shows that the PO did not change significantly across trials.

Table 5-5: Power Output (W) selected for Exhaustive Exercise for 2.5 rnin.

Count Mean Std.ûev. Std. Error controf 17 319.706 65.227 15.820 Pmb 17 338.235 70.754 17.160 madafinil 17 345.588 69.370 16.825 Actual Exercise Time at Watts Selected Actual iimes to exhaustion during the exercise chosen by the subjects to induce exhaustion &ter 2.5 min are shown in Figure 5-9. There were no significant differences between trials.

Figure 5-9: Actual Exercise Time at watts selected (mean ISD).

I I control placebo madafinil Tnal

Overconjidence Effect and Line Cornparison Task In the study of Baranski and Pigeau (1997) with sleep deprived subjects, M induced a significant "overcoPzfdence effect", as reflected by the difference between the pre- and post-task estimates of performance and the actual proportion of correct responses in the Line Cornparison Task. Doing the sarne task in this study the seventeen subjects were asked to make pre-task (how weil they think they will do the task) and post-task (how well they think they did the task) estimates by selecting their confîdence level from 50400%. It was emphasized that 100% denoted that al1 trials were (would be) answered correctly, and because there were only two choices on each trial ("longer" or ccshorter'~of two horizontal Line lengths) 50% correct could be achieved by chance responding.

The results from fourteen subjects showed that PREDIFF (PRECONF - PCORR) and POSTDIFF (POSTCONF - PCORR) were not significantly different between drug conditions and sessions, indicating no overconfidence effect.

Line Comparison Task - Accuracy, Reaction Tirne and Confidence Accuracy (PCORR) in Line Comparison Task did not change significantly with Modafinil among the sessions, but Reaction Time was siadcantly shorter (pc0.05)after M ingestion (during session 2) and showed a trend toward a shorter reaction time during session 3 (p

Figure 5-10: Reaction Time during Line Cornparison Task in mean t SD. Asterisk (*) indicates significant difference between M and P trial.

O Placebo II Modafinil

Session Epinephrine, Norepinephtine, Dopamine and Serotonin during ER and PPR

Evaluation of plasma catecholamines (E, NE, DA) and serotonin were done for the seven subjects who performed both the ER and PPR. Only the following samples were analyzed: before hg, before exercise, and at exhaustion. Nevertheless, what may be beneficial for findings is that with these two experiments we did repeated measurements for the placebo and Modafinil trial, at the same point in time and for the sarne subjects twice.

Exercise to exhaustion in ER and PPR caused a significant increase in the plasma level of E, NE, and DA, without significantly changing plasma serotonin level (Fig. 5-1 1). However, the only significant effect of M was that E was higher at the end of the ER (Fig. 5-12), albeit not for the PPR. Therefore, on the basis of these data, it can be said that M did not cause any significant changes in the plasma level of catecholarnines and serotonin-

Figure 5-1 1: PIasma serotonin during ER and PPR (rnean k SD).

PPR

bdom drug before exer. end of exiar- before drug before exer. end of exer. Time Figure 5-12: Changes in E, NE, and DA in mean 2 SD during ER. The * indicates si-cant difference between P and M txial.

Placarn Modafinil

Placebo Modafinil

betore druq before exer. end of exer. Chapter 6

Discussion

6.1. Review of Objectives and Hypotheses

The objectives of this study were to determine whether M would have an enhancing (ergogenic) effect on physical and cognitive performance in non-sleep depnved subjects and whether M would have a disniptive effect on the ability to self-assess capabilities. There were two hypotheses tested in this study. The fist hypothesis stated that M would significantly prolong time to exhaustion dunng high intensity exercise (85% V02 max) was confirmed. Secondly, it was hypothesized that M would cause an overconfidence effect (i.e. an overestimation of actual abilities), as was observed in the study of Baranski and Pigeau (1997) conceming the effects of M on cognitive performance dunng sustained operations (in sleep deprived subjects). Considering that M is a ïelatively new and prornising stimulant, with a wide range of possible applications in rnilitary and other job setting situations, we found that a more comprehensive understanding of the effect of M on physical performance, and any associated overconfidence effect, would be of great importance before M can be recommended as a safe and reliable fatigue counterrneasure.

6.2 Main Findings The main finding from the first part of Our study was that M significantly prolonged time to exhaustion by 1045% (Fig. 5-1 and Table 5-l), conf'lrming previous findings of Jacobs and Bell (1997). In contrast to caffeine and amphetamines, M in our study appears to have no effect on physiological variables, such as maximal hem rate, oxygen uptake minute ventilation and respiratory exchange ratio (Fig. 5-3 and 5-4). In addition, there were no differences in FFA concentration (Fig. 5-7), glucose, or lactate (Fig. 5-6), other than the increase of glucose and lactate at exhaustion, which can be attributed to the prolonged time of exercise. Although the possibility of peripheral effects and associated metabolic changes cm not be completely excluded, it is more plausible that the increased work with M (prolong time to exhaustion) was mediated by an enhanced effect on vigilance and a decreased perception of effort, possibly through alterations in central neurotransmitter function. In this case, a longer duration of exercise at the same relative intensity (85% of V4max) would lead to the increase in plasma lactate concentration, at the end of the M trial. Althouph in Our ER to exhaustion, the subjective ratings of perceived exertion were not significantly different from those of the M trial, compared to the placebo, there was an obvious trend towards a decreased perception of effort (Fig. 5-5). The lower subjective rating of perceived exertion during the M-trial may have led to an improvement in performance by allowing subjects to work at a higher intensity, while perceiving it as being the same. However, the results must be viewed in light of al1 individual variations and general difficulties to attain more accurate measures of these subjective responses. The resting blood pressure and heart rate data from the PPR, measured dunng 3 min pre-exercise rest period are shown in Tables 5-2 and 5-3, and the maximal HR data at the end of the PPR are presented in Table 5-4. There is significant increase in the resting HR and systolic BP, as well as in maximal HR at the end of the exercise in PPR. Although, these differences in resting HR (average +10 beats between M and P mals), and systolic BP (average -7 mm Hg between M and P trials), may not have physiological significance in relation to a possible hgeffect, one must consider the methods used to evaluate these variables, and the extemal factors that may affect them besides the dmg. It may also be possible that the increased HR and BP at rest indicated a heightened arousal of the subjects (CNS stimulation) before cornmencing exercise (which will bring arousal more close to the optimal level of arousal), and thus suggests that a prolonged time to exhaustion, as well as the increase in resting HR and BP, was due to a CNS and not a peripheral metabolic effect. The increase in maximal HR at the end of the PPR ride during the M-trial can be explained by the higher load andlor longer duration of the exercise (on the same RPE value), rather than by any peripheral catecholarnines effect of the drug, which however was not confirrned in this part of the experiment. In both experiments (ER and PPR), there were no changes in plasma catecholarnines and serotonin levels between the treatment trials. For epinephrine and norepinephrine, it is known that they cross blood brain barrier in very limited amount, and serotonin is even more exctusively produced in the brain. Therefore, plasma levels of neurotransmitters can hardly reflect changes in neurotransmitters on the central level (in the brain), due to the very selective permeability of the blood brain barrier. A progressive increase in plasma catecholamines concentration, during high intensity submaximal exercise to exhaustion, would reflect therefore, more penpheral changes in the catecholarnine production by the adrenal glands. This would also support Our belief that an evaluation of central biogenic amines (their synthesis, elimination and turnover rates) must be done not in the plasma, but in the brain, within certain target areas and during ongoing activities, which would require more sophisticated techniques from these we have available in Our experiments.

6.3. Overconjïdence effect

The second hypothesis that M would lead to an overconfdence effecr was not supported. This over-estimation of the actual ability to perform (exaggerated subjective estimate of performance) was reported by Baranski (1995) and Baranski and Pigeau (1997) 2 hours following the ingestion of M, in cognitive performance of sleep deprived subjects. The difference between the pre- and post-task estimates of performance in the Line Cornparison Task and the actual proportion of correct responses provided an index of the altered self-monitoring ability (Le., overconfidence eflect). An increase in overconfidence cm occur in two ways: performance declines, but the estimate of it do not (i.e., the person does not realize that they are doing worse), or the estimate increases, but the performance does not (Le., the persons thinks they are doing better than they actually are). Our results from fo-rteen subjects (the data from three subjects were excluded from the analyses, because their performance rernained at approximately 50% correct throughout the study) revealed that the subjects in both dnig trials displayed generally accurate assessments of performance. The cognitive test sessions were perforrned: before ingestion of the dmg, 2 hours post-dose, and after the exercise run (3 hours post-dose), which reaches a maximum of 4 hours post-dose when observed (immediate but short lived) overconfidence effect of M in the study of Baranski and Pigeau had returned to baseline. Our findinps show (Table 5-6) that the percentage of correct responses and pre- and post-task estirnates imrnediately before [and after] each session about the proportion of trials they thought they would answer [had answer] correctly were not different between dmg conditions and sessions. This was consistent with their subjective feeling of well maintained self-monitoring ability. Another complementary approach to measuring over-confidence effect was made through production protocol run (PPR) for assessing perceived exertion. The effect of M on power output at the various levels of perceived exertion (RPE values 2, 5, 8, and max. intensity for 2.5 min) during the 30 min of variable-resistance cycling exercise, showed no sign of disturbance in self-monitoring ability. There were no differences between the groups in the average or total power output selected during the 5min intervals (Fig. 5-8), or in the self selected power outputs during exercise at the highest possible intensity for 2.5 min (Table 5-5). The time to exhaustion for 2.5 min exercise at the maximal intensity was also not significantly altered (Fig. 5-9). This confirmed that M (4 mg - kg-') in our study didn't produce an overconfidence effect, as demonstrated by a change in the relationship of perceived and actual exercise intensity. Thus, the self-monitoring ability, which refers to the ability to assess accurately one's own performance in a specific environment was not altered, but was remarkably accurate throughout the study. In addition to the performance measurements, the subjects were asked to quantify and articulate their power outputs (for RPE values of 2, 5, 8, and max.) in terms of: how much higher or lower (in percentage) they think they set their power outputs comparing with the previous (drug or control) time. They were also asked to evaluate their time at the maximum intensity ("how long they thought they could last"). These responses also showed that their estimates for the selected power outputs, or elapsed time, didn't differ more than i 5% from the real values. Therefore, the stimulating effect of M didn't affect the relationship between the subjective and overt performance measures in our study. The interna1 biofeedback mechanism on which the body normally depends in the absence of any external (environmental) feedback was not affected by the application of the dmg.

6.4. Indicators of Cognitive Performance

To evaluate effect of M on sorne aspects of cognitive performance, we analyzed the data for accuracy and reaction time in the Line Comparison Task. Without changing the accuracy (percentage of correct answers), M shortened reaction time (Fig. 5-10) and consequently enhanced intellectual efficiency on the boiven task after the drug (session 2 and 3). Although cognitive performance is a complex and integral function of the brain that cannot be simply measured (with sufficient precision) by any single cognitive test battery, we feel confident to conclude that in Our experiment the increased subjective sensation of energy and intellectual efficiency was associated with enhancement of some objective measures (indicators) of cognitive performance. This is in line with the large body of evidence about the effect of M on cognitive performance in sustained operational settings and studies with sleep deprived subjects.

6.5. Subjective effects and Individual variations

Modafinil in a dose of 4 mg - kg-' produced several favorable subjective effects. Improvements in physical and cognitive performance was related to an elevated but desirable (pleasant), level of arousal and vigilance, without any unfavorable increase in anxiety level. The subjects reported feeling more energetic, awake and "ready to go" before the mn, without any sign of nervousness, excitement, tension, or imtability. Dunng and after the run, although depending on their sensitivity to the drug, personality type (level of impulsiveness), and previously learned (accepted) behavior type, most of the subjects felt less tired when they were on M. Overall, they described their experience with Modafinil as pleasantly invigorating and not disturbing for their cornposure or self control. Seven out of the eight subjects that participated in the ER, and 14 out of the 17 subjects that participated in the PPR, were able to accurately identify when they had received M and when placebo. The subjects who were "not sure" when they were, or had been, under the influence of M exhibited little or no sensitivity to the drug (low or no-responders). When the values for the 3 subjects with low responsiveness to M were separated from the others, the M-sensitive subjects (Le., highly responsive to M) exhibited an increased mean work output that was even higher after M ingestion, while the M-insensitive subjects improved very little on M compared with placebo. The subject's perception that they had in fact ingested the M during the M trial may have led to a "Hawthorn Effect", i.e., when subjects tend to comply with the intentions of the experirnenter, confounding the physiological effect of the dmg. It is unlikely, however, that performance results were caused by a Hawthom Effect because the subjects were not asked the question about their treatment until after exercise was completed. Taken together with the double blind design, 1 feel that the experïment was adequately controlled to avoid the Hawthorn Effect. Therefore, if the subjects felt more awake and consequently performed better, that would be more for the reason of physiological effect of the drug related primarily to feelings of increased arousal, than for any other psychological effect, which however, in this type of study can never be completely discounted.

6.6. Comparative studies

The mechanism of action for amphetamines and caffeine, as the most investigated psychostimulants, are still partially unknown. Amphetarnines Amphetarnines in the study of Chandler and Blair (1980) proved to significantly increase anaerobic capacity, knee extension strength, pre-exercise and maximum HR, and time to exhaustion during the V02max test (presumably due to higher lactic acid tolerance). Many aspects of arnphetamine research are still full of conflicting results. However, with its chemical characteristics and central nervous system responses (presumably by increasing dopamine release, which makes it highly addictive), the effect of amphetamines on selected physiological components of athletic performance and specifically endurance activities show a great deal of variations in regard to dosage, subjects, dmg-subject interaction (susceptibility), environmental and physiological conditions (Chandler and Blair, 1980). The significant increase in lactate concentrations after maximal exercise, the unchanged V02 max values, and the significantly increased time to exhaustion, indicates that the subjects while under influence of the amphetamines were able to maintain exercise longer under anaerobic conditions. La Cava (1961) stated that: "Adequate doses of amphetamine may suppress the sensation of fatigue, but do not eliminate fatigue itself or its toxins". This conclusion is supported by the wamings issued by many authors who state that amphetamines do not prevent fatigue, but rather mask the effects of fatigue and interfere with the body's fatigue-alarm system, which could lead to disastrous results, especially under extreme environmental conditions. As demonstrated by the significant effects on pre-exercise and maximum HR, this drug was shown to exhibit a marked influence on the cardiovascular system, which could also lead to less than desirable consequences. Lastly, because significant subjectheatment interaction, this drug has no consistent effect for al1 people, nor consistent effects when adrninistered to the sarne individual on separate occasions (Akerstedt and Ficca, 1997). Caffeine On the other hand, several mechanisms by which caffeine may improve athletic performance have been proposed. Apparently there is evidence for both a central (through altering perception of effort) and metabolic (through altering substrate use) effect. Caffeine ingestion has been shown to decrease reliance on muscle glycogen stores (Esig et al., 1980), increase serum FFA and glycerol concentrations (Ivy et al., 1979; Flin et al., 1990) and increase reliance on fat metabolism as determined from respiratory exchange ratio (Costill et al., 1978; Esig et al., 1980). These indications of a shift in metabolisrn are even more conclusive when it is noted that they occur at a higher exercise intensity (as measured by VOz values), especially when a shift towards carbohydrate oxidation (usage) is expected. In addition, it was hypothesized that the effect of caffeine on perception may depend upon the intensity of the exercise. To test this hypothesis, the work outputs during the chosen levels of exertion were compared in a study of Cole et al. (1996). Although significantly more work was performed following caffeine ingestion, the effect of caffeine did not appear to be intensity dependent, as no difference was found between the responses at each of three chosen intensity levels (Cole et al. 1996). Therefore, they concluded that caffeine may decrease perception of effort (RPE values) regardless of submaximal intensity level, and that the increase in work production (power output) are likely a result of caffeine's metabolic and central neuronal effects (decreased perception of effort, through alterations in central neurotransmitters function). Several snidies done with amphetamines or caffeine (Kaplan et al., 1992; Hasenfratz and B attig, 1994) suggest that while favorable subjective and performance-enhancing stimulant effects occur at low to interrnediate drug (caffeine) doses, the unfavorable subjective and somatic effects, as well as performance disruption can occur at the high doses. In a study of Kaplan et al. (1997) done on volunteers who, in pneral were habitua1 users of caffeine, at lower dose (< 250 mg) caffeine produced a significantly greater increases in favorable subjective measures of elation, peacefulness and pleasantness, while the higher dose (z 500 mg) produced greater increase in anxiety measures (irritability, tenseness, nervousness, excitement, restlessness and agitation). Low to intermediate doses of caffeine (Kaplan, 1997), since they were associated with favorable effects on alertness and mood, have stimulant effect on cognitive and motor tasks (increasing arousal, alertness, concentration, and sense of well-being). On the other hand, high doses having aversive somatic effects (nausea, sweating, palpitations, tremors), cause a disruption of attention, learning and performance. Higher doses of caffeine (10 mg kg-') have been shown to induce an even greater anxiogenic effects in individuals with generalized anxiety or disorder (Bruce et al., 1992).

Therefore, it cm be concluded that M improves physical performance during high intensity submaximal exercise (i.e., prolongs time to exhaustion at - 85% VO? max). Moreover, a greater work output at the same perceived exertion indicate that M cm be considered as an effective ergogenic aid for many individuals. The mechanism responsible for this effect is most likely related to M central mechanism of action and changes in brain neurotransmitters Ievel, thcit highten the level of arousal and vigilance. The effectiveness of moderate vigilance enhancement effect of M is also consistent with the Yerkes-Dodson Law (vigilance-performance relationship), which explain why optimal performance is usually at the medium level of arousal. This is lcnown as "the inverted-U hypothesis" (Eysenck, 1983). In this regard, according to Yerkes-Dodson law, it seems a conceivable explanation that maintaining a medium (favorable) level of arousal can improve performance, while any over-stimulation of vigilance can induce an increase in anxiety, and subsequently have a more dismptive effect on performance. Therefore, any psycho-stimulating dmg in dose-response manner and depending on its specific biochemical actions (related to more central or peripheral effect) cm be beneficial in returning declining CNS activity to its optimal (favorable) level of arousal. This moderate (optimal) level of arousal is than associated with increased, energy, alertness and attentiveness. Good tolerance of the dmg (absence of aversive somatic and dysphoric effects) and moderate stimulativ effect can apparently grant this favorable subjective effects and performance enhacement. Modafinil (4 mgkg-') in our study, prove to have both of these characteristics. In addition, an enhancernent of physical working capacity for 10- 15 % appears to be more realistic increment for performance measures, since it is better tolerated frorn the body, than the effects of some stronger psychostimulative dmgs (or higher doses) in healthy well-rested individuals. This is as well in line, with the general conclusion of U.S Committee for Military Nutrition Research (1994, p.48), who stated that: 'The military science and technology objective of enhancing performance by 10- 15% is more realistic in short term enhancement of performance under stress, than to obtain super performance from troops in a well-fed, well-rested state"). Moreover, since subjective effects are consistent with overt performance, potential for human error from this aspect of dmg effect can be eliminated and there is much to benefit in terms of increased performance and productivity. Chapter

7.1. Limitations

The several factors have limited interpretation of the results of this study:

1. The small number of subjects in each experiment reduced the power of the statistical design. 2 Problem in recruiting a sufficient number of subjects willing to participate fully in al1 aspects of the study, force us also te widen Our entering criteria regarding their fitness level what consequently made Our groups less homogenous.

7.2. Conclusions

1. Modafinil significantly improves endurance performance during high intensity submaximal exercise (Le., prolongs time to exhaustion at - 85% V02 max). The mechanism responsible for this effect is closely related to still not completely known Modafinil mechanisrn of action in the CNS that enhance the level of arousal and vigilance. 2. Modafinil did not cause an overconfdence effect (Le., an overestimation of actual performance), or show any disturbance in self-monitoring ability. 3. The good tolerance of the drug and moderate stimulativ effect, associated with higher but not overly exaggerated level of arousal, provide favorable subjective and performance enhancing effects which confirrns its good ergogenic potential for sustained operations. 7.3. Recommendations for Future Study

Directions for future study should include the following:

1. Modafïnil mechanism of action in the CNS still requires further elucidation. The central nervous system appears to be able to respond to changes in brin tissue homeostasis by appropriate metabolic regulation (adaptation). It is generally considered that brain arnmonia content increases during prolong and intense cerebral activity (Cooper and Plum, 1987; Guezennec et al. 1998). This may explain the apparently increased synthesis of glutamate concomitant with some other excitatory amino acids, and their region interactions with other main neurotransmitters (DA, NE and 5-HT) during exercise. Another possibility is that M which interferes with catecholaminergic neurotransmission rnay have its own unique effects on glutamate and glutamine transport through the membrane of nerve cells. Using more direct measures and methods that allows to monitor in vivo, these changes in different brain regions (particularly in ascending reticular pathways responsible for state of general arousal) rnay provide better explanation for M arousal properties during accumulated fatigue. In addition, since human brain is conditioned to a carbohydrate environment the important role of circulating glucose and even muscle glycogen, with brain creatine-phosphocreatine and glutamate-glutamine pool, merit further attention. Thus, application of radioisotope tracers for metabolic research at this central level may be equally important as changes in specific receptor types and neurons. Moreover, studies designed to measure simultaneously blood flow in target areas of the brain can also provide useful information.

2. The effect of M on increased alertness or vigilance should be tested using more objective measurement tools such as: visual analogue scale for alertness andor spectral analysis of variations in thetahlpha ratio in EEG (Laffont, 1996). Furthemore, whether endurance time is a valid and applicable measure of increased performance is equivocal. The measurable increase in the ability to sustain endurance exercise, measured as increased time to exhaustion, show substantial variability among subjects of average fitness (McLellan et al., 1995). Therefore, time to exhaustion should not be the only dependent measure used to evaluate treatment effects dunng subrnaximal exercise. In addition, the power of the experimental design should be strengthened by the addition of more subjects on each of the treatment groups.

3. The results of pharrnacological and nutritional manipulations indicate that CNS fatigue during prolonged exercise cm be diminished. This will continue to inspire abundance of new pharmacological and nutritional strategies in order to push the lirnits for human (maximai) performance on athletic or rnilitary field, as well as in every day jobs or life settings. Apart from using pharmacological tools of good specificity, Safety must be practiced as a condition sine q~tunon, in al1 those attempts, since there is a high risk for alteration in physiological balance with short and particularly long term side effects.

Finally, a greeater emphasis on al1 types of research on the CNS fatigue is needed for establishinp more causal relationships in this communications between the brain and muscle function, since such interaction is of great importance for the health of the organisrn. Many people assisted directly or indirectly accomplishment of this thesis. 1 would Iike firstly to sincerely thank Dr. ira Jacobs for his supervision and guidance, and also for giving me the opportunity to pursue and ultimately complete this degree. A special thanks to Mr. Doug Bell whose counsel was invaluable during my expenmental work on this thesis. As well, 1would like to thank Dr. Valerie Gil for her immense help on c~~gnitivepart of this study. 1 would like to acknowledge and th& the staff and technician of the Defence and Civil Institute of Environmental Medicine who assisted me during the testing sessions of the study. In particular Mr. Rejean Bordeleau and Mr. Jan Pope, and Mrs. Ingrid Smith and Mrs. Debbie Kerrigan-Brown for their assistance in the biochemistry lab. Thank you al1 for you help, patience and understanding. Last but certainly not least I would like to thank al1 my friends and family, near and far, who are never far from my heart. References

Ahlenius, S. and V. Hillegart (1986). Involvement of extrapyramidal motor mechanisms in the suppression of locomotor activity by antipsychotic drugs. Pharmacol. Bioch. Behav. 24: 1409- 1415.

Akaoka, H., B. Roussel, J.S. Lin, G. Chouvet and M. Jouvet (1991). Effect of Modafinil and amphetamine on the rat catecholarninergic neuron activity. Neurosci. Letters 123 : 20-22.

Akerstedt, T. and G. Ficca (1997). Alertness-enhancing drugs as a countermeasure to fatigue in irregular work hours. Chronobiology International, 14(2): 145-158.

Asmussun, E. (1979). Muscle fatigue. Med. Sci. Sports 11 : 3 13-32 1.

Bailey, S.P. and J.M. Davis (1993). Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue. J. Appl. Physiol. 74: 3006-3012.

Baldeserini, R.J. (1989). status of antidepressants: clinical phannacology and therapy. J. Clin. Psych. 50: 117-126.

Bastuji, H. and M. Jouvet (1988). Successful treatment of idiopathic hypersomnia and narcolepsy with Modafinil. Prog. Neuro-Psychopharmacol. Biol. Psychiat. l2:695-7OO. Baranski, J.V., R.A. Pigeau and R.G. Angus (1994). On the ability to self-monitor cognitive performance dunng sleep deprivation: a calibration study. J. Sleep Res. 3:36-44.

Baranski, J.V. and W.P. Petrusic (1994). The calibration and resolution of confidence in perceptual judgements. Perc. Psychophys. 55:4 12-428.

Baranski, J.V. (1995). Evidence for a modafinil induced "overconfidence" effect during sustained operations. Paper presented at the 37th Annual Conference of the International Military Testing Association, Toronto, Ontario.

Baranski, J.V. and W.M. Petrusic (1995). On the calibration of knowledge and perception. Can. J. Exp. Psych. 49: 397-407.

Baranski, J.V. and R. Pigeau (1997). Self-monitoniig cognitive performance during sleep deprivation: effects of rnodafinil, d-amphetamine and placebo. J. Sleep Res., 6, 84-91.

Bettendorff, L., M. Sallanon-Moulin, M. Touret, P. Wins and E. Schoffeniels (1996). Paradoxical sleep deprivation increases the content of glutamate and Glutamine in rat cerebral cortex. Sleep. 19 (1): 65-7 1.

Bliss, E.L. and J. Ailion (1971). Relation of stress and activity on brain dopamine and homovanillic acid. Life Sci. 10: 1 16 1-1 169.

Blomstrand, E., F. Celsing, and E.A. Newsholme (1988). Changes in plasma concentration of aromatic and branch-chain amino acids during sustained exercise in man and their possible role in fatigue. Acta Phys. Scand. 133: 115-121. Blomstrand, E., M. Perrett, M. Parry-Billings and E.A. Newsholrne (1989). Effect of sustained exercise on plasma amino acid concentrations and on 5-HT metabolism in six different brain regions in the rat. Acta. Phys. Scand. 136: 473-48 1.

Bigland, B ., F. Furbsh and J.J. Woods (1986). Fatigue of intermittent submaximal voluntary contractions: central and peripheral factors. J. Appl. Phys. 6 1: 42 1-429.

Borg, G. (1973). Perceived exertion: A note on "history" and methods. Med. Sci. Sports 5: 90-93.

Borg, G. (1977). General Introduction: Psychophysiological Studies of the Three Effort Continua. In: Physical Work and Effort, edited by G. Borg. Oxford: Pergarnon Press, hc., 1977, p. 1-10.

Borg, G.A.V. (1982). Psychophysical bases of perceived exertion. Med. Sci. Sports. 14: 377-38 1.

Bourdon, L., A. Jacobs, and A. Vallerand (1994). The effects of rnodafhil on thermoregulation during cold air exposure. Aviat. Space Environ. Med. 65: 999- 1004.

Broughton, R.J., J.A.E. Fleming, C. George and W.F. Murphy (1997). Randornized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology, 49: 444-45 1. Bruce, M., N. Scott, P. Shine and M. Lader (1992). Anxiogenic effects of caffeine in patients with anxiety disorders. Arch. Gen. Psych. 49: 867-869.

Buguet, A., A. Montmayeur, R. Pigeau and P. Naitoh (1995). Modafinil, d- amphetamine and placebo during 64 hours of sustained mental work. II Effects of two nights of recovery sleep. I. Sleep. Res. 4: 229-241.

Cafarelli, E. (1982). Peripheral contributions to the perception of effort. Med. Sci. Sports 14: 382-389.

Chandler, J. and S .N. Blair (1980). The effects of amphetamines on selected physiological components related to athletic success. Med.. Sci. Sports. Exerc. 12: 65-69.

Chaouloff, F., J.L. Elghozi, Y. Guzennec and D. Laude (1985). Effect of conditioned running on plasma, liver and brain triptophan and on brain 5-HT metabolism of the rat. Br. J. Phann. 86: 33-41.

Chaouloff, F., G.A. Kenett, D. Marino and G. Curzon (1986a). Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in the rat. J. Neurochem. 46: 1647-1650.

Chaouloff, F., D. Laude and Y. Guzennec (1986b). Motor activity increases tryptophan, 5-hydroxyindoleacetic acid and homovanillic acid in ventricular cerebrospinal fluid of the conscious rat. J. Neurochem. 46: 1313-13 16. Chaouloff, F., D. Laude and D. Meringo (1987). Amphetamine and alpha-rnethyl- p-tyrosine effect the exercise induced imbalance between the availability of tryptophan and synthesis of serotonin. Neuropharm. 26 (8): 1099-1 106.

Chaouloff, F. (1989). Physical exercise and brain monoamines: a review. Acta Physiol. Scand. 137: 1-13.

Chaouloff, F., D. Laude and J.L. Elghozi (1989). Physical exercise: evidence for differential consequences of tryptophan on 5-HT synthesis and metabolism in central serotonergic ce11 bodies and terminais. J. Neur. Transrn. 78: 121-130.

Cian, C., J. Baranski, D. Esquivie and C. Raphel(1997). Effets de differents dosages de modafinil sur la vigilance et les performances cognitives au cours d'une privation de sommeil de 60 heures. Trav. ScientNo. 18: 255-257.

Cole, J.K., D.L. Costill, R.D. Starling, B.H. Goodpaster and J. Frink (1996). Effect of caffeine ingestion on perception of effort and subsequent work production. Int. J. Sport Nutrit. 6:14-23.

Cornmittee on Military Nutrition Research (1994). Food Components to Enhance Performance. National Academy Press, Washington, D.C. p. 48.

Cooper, J.L. and F. Plum (1987). Biochemistry and physiology of brain arnrnonia. Physiol. Rev. 67: 440-523.

Costill, D.I., G.P. Dalskyand and W.J. Fink (1978). Effects of caffeine ingestion on metabolism and exercise performance. Med. Sci. Sports 10: 155- 158. Davis, J. M., W.A. Himwich and M. Stout (1969). Cerebral amino acids during deprivation of paradoxical sleep. Biol. Psychiatry 1: 387-390.

Davis, J.M., S.P. Bailey and D. Jackson (1993). Serotonergic production affect endurance performance in the rat. Intern. J. Sports Med. 14 (6): 330-336.

De Sereville, J.E., C. Boer, F.A. Rambert and J. Duteil (1994). Lack of pre-synaptic dopaminergic involvement in rnodafinil activity in anaesthetized mice: In vivo voltamrnetry studies. Neuropharmacology 33: 755-76 1.

Duteil, I., F.A. Rambert, J. Pessonnier, J. Hermant and A. Assous (1990). Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil: Studies with experimental animals. Eur. J. Pharmacol. l80:49-58.

Dunn, L.A. and R.K. Dishaman (1991). Exercise and the neurobiology of depression Exerc. Sport Sci. Rev. 19:41-97.

Edgar, M.D. and W.S. Seidel (1997). Modafinil induces wakefulness without intensifying rnotor activity or subsequent rebound hypersomnolence in the rat. The Journal of Pharmacology and Experimental Therapeutics 283(2): 757-769.

Edwards, R.H., A. Melcher, C.M. Hesser and L.G. Ekelund (1972). Physiological correlates of perceived exertion in continuous and intermittent exercise with the sarne average power output. Eur. J. Clin. Invest. 2: 108-1 14.

Engber, T.M., E.J. Koury, S.A. Dennis, M. Miller, P. Contreras and R. Bhat (1998). Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent rnodafinil. Neuroscience Letters, 241 : 95-98. Enoka, M. R. and S.G. Stuart (1992). Neurobiology of muscle fatigue. J. Appl. Physiol. 72 (5): 163 1-1648.

Essig, D., D.I. Costill and P.J. Van Handel (1980). Effects of caffeine ingestion on utilization of muscle glycogen and lipid during leg ergometer cycling. Int. J. Sports Med. 1: 86-90.

Eysenck, M. (1983). Anxiety and Individual Differences. In: Stress and Fatigue in Human Performance, edited by R. Hockey. John Wiley & Sons. p. 273-295.

Ferraro, L., S. Tanganelli, W.T. O'Connor, T. Antonelli and K. Fuxe (1996a). The vigilance promoting dmg modafinil increases dopamine release in the rat nucleus accumbens via the involvment of a local GABAergic mechanism. European Journal of Pharmacology 306: 33-39.

Ferraro, L., S. Tanganelli. W.T. O'Connor, T. Antonelli and K. Fuxe (1996b). The vigilance promoting drug modafinil decreases GABA release in the media1 preoptic area and in the posterior hypothalamus of the awake rat: possible involvernent of the serotonergic 5-HTs receptor. Neurosc. Letters 220: 5-8.

Ferraro, L., T. Antonelli, W. T. O'Connor and K. Fuxe (1997). The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus. Neuro Report 8 (13): 2883-2887.

Ferrer, C. F., R.U. Bisson and J. French (1995). Circadian rhythm desynchronosis in rnilitary deployments: A review of current strategies. Aviation, Space, and Environmental Medicine 66(6): 57 1-578. Flinn, S., J. Gregory, L.R. McNaughton, S. Tristram and P. Davies (1990). Caffeine ingestion prior to incremental cycling to exhaustion in recreational cyclists. Int. J. Sports Med. 11: 188-193.

Fokard, S. (1983). Diumal Variation. Ln: Stress and Fatigue in Human Performance, edited by R. Hockey. John Wiley & Sons p. 245-269.

Freed, C.R. and B.K. Yamamoto (1985). Regional brain dopamine metabolism: a marker for speed, direction, and posture of moving anirnals. Science 229: 62-65.

Fuxe, K., A.M. Janson, L. Rosen, M. Goldstein and L. Agnati (1992). Evidence for a protective action of the vigilance promoting drug Modafinil on the MPTP- induced degeneration of the nigrostriata1 dopamine neurons in the black mouse: an imrnunocytochemical and bichernical analysis. Exp. Brain Res. 88: 117- 130.

Gaillard, A.W. K. (1993). Comparing the concepts of mental Ioad and stress. Ergonomies, 36(9): 99 1- 1005.

Gemrna, C., P. Ghezzi and M.G. De Sirnoni (1991). Activation of the hypothalamic serotoninergic system by central interleukin-1 . Eur. J. Pharmacol. 209: 139- 140.

Gillberg, M., G. Kecklund and T. Akerstedt (1994). Relations between performance and subjective ratings of sleepiness during a night awake. Sleep, 17: 236-241.

Guezennec, C.Y., A. Abdelmaki, B. Serrurier, D. Merino and M. Peres (1998). Effects of Prolonged Exercise on Brain Ammonia and Amino Acids. Int. J. Sports Med. 19: 323-327. Hasenfratz, M. and K. Battig (1994). Acute dose-effect relationship of caffeine and mental performance, EEG, cardiovaskular and subjective parameters. Psychophm. 114: 28 1-287.

Himwich, W.A., M.J. Davis and M. Stout (1973). Cerebral amino acids of rats deprived of paradoxical sleep. Biol. Psychiatry 6: 37-44.

Ivy, J.L., D.L. Costill, W.J. Fink and R.W. Lower (1979). Influence of caffeine and carbohydrate feedings on endurance performance. Med. Sci. Sports 11 : 6- 11.

Jacobs, 1. and DG. Be11 (1977). Modafinil prolongs time to exhaustion during high intensity submaximal exercise. Med. Sci. Sports Exerc. Vol. 29, No. 5: S 39.

Kaplan, G.B., D.J. Greenblatt, M.A. Kent and R.I. Shader (1992). Caffeine-induced behavioral stimulation is dose-dependent and associated with A 1 adenosine receptor occupancy. Neuropsychopharmacology 6: 145- 153.

Kaplan, G.B ., D.J. Greenblatt, B .L. Ehrenberg, J.E. Goddard and R.I. Shader (1997). Dose-dependent phmacokinetics and psychomotor effects of caffeine in humans. J. Clin. Pharm.37 (8): 693-703.

Karadzic, V., D. Micic and L. Rakic (197 1). Alteration of free arnino acid concentration in cat brain induced by rapid eye movement sleep deprivation. Experentia 27: 509-5 11.

Karnovski, M.L., B.L. Bunows and M.A. Zoccoli (1980). Cerebral glucose-6- phosphatase and the movement of 2-deoxyglucose during slow wave sleep. Cerebral metabolisn and neural function. Baltimore and London: Williams & Wilkins, p. 59-70. Keren, G. (1988). On the ability of monitoring non-vendical perceptions and uncertain knowledge: Some calibration studies. Acta Physiol. 67: 95- 1 19.

Kinsman, R.A. and P. C. Weiser (1976). Subjective simptomatology during work and fatigue, Springfield, IL. Charles C. Thomas, Publisher, p. 336-405.

Knapp, S., A.J. Mandell, and M.A. Geyer (1974). Effects of arnphetarnines on regional tryptophan-hydroxylase activity and synaptosomal conversion of wtophan to 5-HT in rat brain. J. Exp. Pharm. 189: 676-689.

LaCava, G. (1961). The use of drugs in cornpetitive sport. J. Sports Med. Phys. Fitness. 1: 49-5 1.

Lagarde, D. (1990). Effects of modafinil on the nocturnal activity and behavioural sleep of rhesus monkeys. Med. Sci. Res. 18: 397-399.

Lagarde, D., S. Trocherie, T. Morlet, J. Mothel and P. Van Beers (1993). Evaluation of the effects of modafinil in hypobaric hypoxia in Rhesus monkeys. Med, Sci. Res. 21: 633-636.

Lagarde, D., D. Batejat, P. Van Beers, D. Sarafian and S. Pradella (1995). Interest of modafinil, a new psychostimulant, during a sixty-hour sleep deprivation experiment. Fundarn Clin. Pharmacol. 9: 27 1-279.

Lagarde, D., S. Giraull, D. Le Ray and C. Pierard (1996). Modulation of the stimulating effect of modafinil by glutamate agonists and antagonists. MedSci. Res. 24: 687-690. LafTont, F., N. Agar, G. Mayer and M. Minz (1995). Effect du modafinil chez des patients narcoleptiques. Etudes electophysiologique et psycometrique. Neurophysiol. Clin. 25: 84-95.

Laffont, F. (1996). Clinical Assessrnent Of Modafinil. Dmgs Of Today, 32(Suppl. 1): 35-44.

Laffont, F. (1997). Troubles du sommeil. Medicine Generale, Tome Il, No. 369.

Lallement, G., C. Pierard, C. Masqueliez, D. Baubichon and D. Lagarde (1997). Neuroprotective effect of modafinil against soman-induced hippocampal Lesions. Med. Sci. Res. 35: 437-440.

Lin, J.S., B. Roussel, H. Akaoka, P. Fort, G. Debilly and M. Jouvet (1992). Role of catecholamine in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Research 59 1: 3 19-326.

Lin, J.S., Y. Hou and M. Jouvet (1996). Potential brain neuronal targets for amphetamine, methylphenidate and modafinil-induced wakefulness, evidences by c-fos immunocytochemistry in the cat. Neurobiology, 93 : 14 128- 14133.

Lyons, J. and J. French (1991). Modafinil: The unique properties of a new stimulant. Aviat. Space and Environ. Med. 62:432-435.

Martin, J.T., J.D. Barchas and K.F. Faul(1982). Fused silica capillary gas chromatograph yhegative chemical ionization mass spectrometry for determination of catecholamines and their O-methylated metabolites. Anal. Chem. 54: 1806- 181 1. Maughan, J.R. (1982). A simple, rapid method for the determination of glucose, lactate, pyruvate, alanine, 3-hydroxybutyrate and acetoacetate on a single 2-pl blood sample. Clinica Chernica Acta. 122: 23 1-240.

McLellan, M.T., S.S. Cheung and 1. Jacobs (1995). Variability of Time to Exhaustion During Submaximal Exercise. Cm. J. Appl. Physiol. 20(1): 39-5 1.

Mignot, E., S. Nishino, C. Guillerninault and W.C. Dement (1994). Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep, 17 (5):436-437.

Mitchell, B .P. (1995). Novel Antidepressants Report. Psychopharmacology Bulletin 31(3): 3-12.

Moachon, G., 1. Kanmacher, M. Clenet and D. Matinier (1996). Pharmacokinetic profile of modafinil. Dnigs Of Today 32(Suppl.I): 23-33.

~odiodal@(Modafinil) (1994). Dossier d'Information Medicale et Pharmaceutique. L. Lafon Laboratory. Deltacom Report # 484.

Moore, M (1982). Bioamines and exercise: a puzzling relationship. Phys. Sports Med. 10: 11 1-1 14.

Morgan, K.P. (1973). Psychological factors influencing perceived exertion. Med. Sci. Sports 5: 97-103.

Myles, W.S. and D. Maclean (1986). A cornparison of response and production Protocols for assessing perceived exertion. Eur. J. Appl. Physiol. 55: 585-587. Pagliar-i, R., L. Peyrin and S. Milano (1994). Effect of submaximal physical exercise in norepinephrine release in the rat frontal cortex: a study with microdialysis. Med. Sci. Sports Exerc. 26 (5):S23-S27.

Pandolf, K.B., R.L. Burse and R.F. Goldman (1975). Differentiated ratings of perceived exertion during physical exercise. Percept. Mot. Skills 40: 563-574.

Pandolf, K.B. (1983). Advances in the study and application of perceived exertion. Exer. Sort Sci. Rev. 11: 1 11-158.

Pardridge, W.M. (1983). Brain metabolism: a perspective from the blood-brain barrier. Physiol. Rev. 63: 148 1-1535.

Pellerin, L., O. Sorg, 1. Allaman, L. Bene1 and P.J. Magistretti (1997). Modafinil, An awakening drug, selectively modulates energy metabolism in astrocytes. Neuroscience 23 12.

Pierard, C., P. Satabin, D. Lagarde, B. Barrere, and M. Peres (1995). Effects of a vigilance-enhancing drug, modafinil, on rat brain metabolism: a 2D COSY H-NMR snidy. Brain Research 693: 25 1-256.

Pierard, C., D. Lagarde, B. Barrere, P. Duret, C. Cordeiro and M. Peres (!997). Effects of a vigilance enhancing drug, modafinil, on rat brain cortex arnino acids: a microdialysis study. Med. Sci. Res. 25: 51-54.

Pigeau, A. R., P. Naitoh, A. Buguet, C.McCann, J. Baranski, M. Taylor (1995). Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work: Effects on rnood, fatigue, cognitive performance, and body temperature. Jour. Sleep Research, 4(4), 212-228. Pigeau, R. and P. Naitoh (1995). The effect of mod&nil and amphetamine on core temperature and cognitive performance during 64 hours of sustained mental work. Paper presented at the 80th Ann. Sympos. Aerospace Med. Panel on Neur. Limit. Aircr. Oper. Human Performance Implications, Koin, Germany.

Rambert, F.A., G. Moachon, M.F. Multon and J. Duteil (1987). Correlation of Modafinil plasma levels to pharmacological activity in rnice. Proceedings of the Meeting of the 5th International Congress of Sleep Research. Copenhagen : European Sleep Research Society, June28-July 3: 124.

Rambert, F., J. Pessonnier and J. Duteil (1990). Modafinil, amphetamine, and methylphenidate induced hyperactivities in mice involve different mechanisms Eur. J. Pharrn. 183: 455-456.

Reed, K.S. (1982). Cognition. Theory and Application. Brooks/Cole Publishing Company, Montrey, California. p. 2-9.

Romanovski, W. and S. Grabiec (1984). The roIe of serotonin in the mechanism of central fatigue. Acta Physiol. Scand. 25: 127- 134.

Saletu, B., J. Grunberger, L. Linzmayer and H. Stohr (1986). Pharmaco-EEG, psychometric and plasma level studies with two novel Alpha-adrenergic stimulants CRL 40476 and 40028 (adrafinil) in elderlies. In: Pancheri P, ed. New Trends in Experimental and Clinical Psychiatry, Vol. II, 1: 5-3 1.

Sheck, Y. and R. Pigeau (1995). The effects of modafinil, d-amphetamine, and placebo on physiological and psychological stress during sleep deprivation. Paper presented at the 37LhAnn. Conf. Inter. Mil. Test. Assoc. Toronto, Ont. Shelton, J., S. Nishino, J. Vaught, W.C. Dement and E. Mignot (1995). Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs. Sleep 18: 8 17-826.

Simon, P., C. Hemet, C. Rarnassamy and J. Costentin (1995). Non-amphetarninic mechanism of stimulant locornotor effect of modafinil in mice. European Neuropsychopharmacology 5: 509-5 14.

Simon, P., C. Hemet, and J. Costentin (1996). Analysis of stimulant locomotor effects of modafinil in various strains of mice and rats. Clin. Pharmacol. 10: 431-435.

Smith, G.M. and H.K. Beecher (1964). Dmgs and Judgement: Effects of amphetamine and secobarbital on self-evaluation. J. Psychol. 58: 397-405.

Smith, Q.R., S. Momma, M. Aoyagi and S.I. Rapoport (1987). Kinetics of neutral arnino acid transport across the blood-brain barrier. J. Neuroch. 49: 1651-1658.

Smutok, M.A., G.S. Skrnar and K.B. Pandolf (1980). Exercise intensity: Subjective regulation by perceived exertion. Arch. Phys. Med. Rehabil. 6 1569-574.

Sothmann, M., S.J. Buckworth, R.P. Claytor and R.K. Dishman (1996). Exercise and the cross-stressor adaptation hypothesis. Exer. Sport Sci. Rev. 24: 267-287.

Stevens, J.C. and J.D. Mach (1959). Scales of apparent force. J. Exp. Psychol. 58: 405-4 13. Stivalet, P., D. Esquivie, P.A. Bmaud, D. Leifflen and C. Raphel(1997). Effects du Modafinil sur les processus attentionnels au cours d'une privation de sommeil de 60 heures. Trav. Scient. No.18: 253-255.

Stokes, M. J., R.G. Cooper and R.H. Edwards (1988). Normal muscle strength and fatigability in patients with effort syndromes. Br. Med. J. 297: 10 14- 10 1%

Stone, ND. (1994). Overconfidence in initial self-efficacy judgements: effects on decision processes and performance. Org. Behav. & Hum. Dec. Proc. 59:

Stroh, M.C. (197 1). Vigilance: The problem of sustained attention. Oxford: Pergarnon Press, Inc., p. 1-37.

Tanganelli, S., M. Perez, L. Ferraro and K. Fuxe (1995). Modafinil and cortical gamma-aminobutyric acid outfiow. Modulation by 5-hydroxytryptamine neurotoxins. Eur. J. Pharmacol. 273: 63-71.

Touret, M., M. Sallanon-Moulin, and C. Fages (1994). Effects of modafinil-induced wakefulness on glutamine synthetase regulation in the rat brain. Molecular Brain Research 26: 123- 128.

Touret, M., M. Sallanon-Moulin and M. Jouvet (1995). A wakening properties of modafinil without paradoxical sleep rebound: comparative study with amphetamione in the rat. Neuroscience Letters 189: 43-46.

Treadwell, J. and T.O. Nelson (1996). Availability of information and the aggregation of confidence in prior decisions. Org. Behav. & Hum. Dec. Proc. 68: 13-27. Ueki, A., L. Rosen, B. Andbjer, and K. Fuxe (1993). Evidence for a preventive action of the vigilance-promoting dmg modafinil against sh5atal ischemic injury induced by endothelin-l in the rat. Exp. Brain Res. 96: 89-99.

Vogel, W.G. (1975). A review of REM sleep depnvation. Arch. Gen. Psychiatry 32: 749-761.

Walker, J.B. (198 1). Creatine: biosynthesis, regulation and function. Advances in Enzymology and Related Areas of Molecular Biology, John Wiley and Sons. p.144-171.

Warot, D., E. Comble, C. Payan, I.S. Weil and A.J. Puech (1993). Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine. caffeine and placebo. Eur. Psychiatry 8: 201-208.

Weiss, B. and V. Laties (1962). Enhancement of human performance by caffeine and the amphetamines. Pharmacol. Rev. 14: 1-36.

Wesnes, K. and D. Warburton (1983). Stress and Drugs. In: Stress and Fatigues in Human Performance, edited by R. Hockey. John Wiley & Sons. p:203-235.

Williams, H.M. (1998). The Ergogenic Edge: pushing the lirnits of sports performance. Human Kinetics, P.O. Box. 5076. p. 1-5 1.

Wilmore, J.H. (1968). Influence of motivation on physical work capacity and performance. J. Appl. Physiol. 24(4): 459-463. Wilson, W.M. and R.J. Maughan (1992). Evidence for a possible role of 5-HT in the genesis of fatigue in man: administration of paroxetine, a 5-HT re-uptake inhibitor, reduces the capacity to perform prolonged exercise. Exp. Phys. 77: 921-924.

Winrnan, A. and P. Juslin (1993). Calibration of sensory and cognitive judgments: Two different accounts. Scandinavian Journal of Psychology, 34: 135- 148.

Young, S.N. (1990). The clinical psychofarmacology of tryptophan. In: Nutrition and the Brain. Neuropharm. 17: 703-709.

Zamecnic, J. (1997). Quantitation of Epinephrine, Norepinephrine, Dopamine, Metanephrine and Normetanephrine in human plasma using negative ion chernical ionization GC-MS. Canad. J. Anal. Sci. Spect. 42 (4): 106- 112. Appendix A: Letter of Approvai from the University of Toronto University of Toronto

-- OFFICE OF RESEARCH SEWICES

Dr. 1. Jacobs Defince and Civil Tnstitutt af E.m&mmmtEtl~Medicine 1133 Shqpard Avenue Wrn P.O. Box 2000 Norrh York Onfario MM3B9

brou& ta the -on of tht ûfEœ of Research Sdcu.

Best wiuk for thc maxdùl cumplerion of your

cc: Dr. H. S'W Appendix B: Approved Ethics Proposal Information to Subjects

Modafinil, Exercise and Cognitive Performance Protocol # L-188 Principal Investigator: Dr. 1. Jacobs Co-Investigators: P. Dinich, Dr. J.V. Baranski, Dr. V. Gil, Mr. D.G. Bell

Background DCIEM is evaluating ergogenic aids that may enhance the physical performance of specid operations personnel. Amphetamines are effective centrally mediated ergogenic aids, due to their masking of perceptual responses that would otherwise cause fatigue (Chandler and Blair, 1980). There is history of rnilitary use of amphetamines, but high doses are associated with dangerous side-effects. Modafîî (M) is a relatively new, promising stimulant, with a mechanism of action that is not yet established (although it appears comected to central alpha adrenoceptor stimulation). M, like amphetamines, has been shown to improve vigilance in sleep-deprived subjects (Lyons and French, 1991; Pigeau et ai., 1995). However, unlike amphetamines, M does not interfere with normal sleep (Buguet et al. 1995), nor does it appear to be addictive, or associated with the dangerous side-effects attributed to amphetamines. M has been used clinically for up to 3 years in the treatment of narcolepsy and idiopathic hypersomnia (Laffont et al. 1995; Bastuji and Jouvet, 1988). However, it is not yet known whether M has ergogenic properties similar to those of amphetamines. Moreover, M has been shown to have a disruptive effect on the ability to self-monitor one's own cognitive capabilities, inducing a reliable "overconfdence" effect (Le., an overestimation of actual cognitive performance), which was particularly marked 2-4 hours post-dose (Baranski and Pigeau, 1997). Therefore, a more comprehensive understanding of the relation between subjective (attitude change) and performance (physiological) enhancing effects of M, is of great importance before M can be recommended as a safe and reliable fatigue countermeasure during sustained military operations. M has been used previously at DCIEM in several studies such as: a) Cornparison of the effects of M vs. amphetamine on sustained cognitive performance, sleepiness and recovery sleep (Pigeau et al., DCIEM Ethics Committee protocol #L58,05 Oct 93); b) Effect of M on heat production and regdation of body in cold-exposed humans (Burdon et al. DCIEM Ethics Committee protocol #LAO, 25 Nov 92); c) Effect of M on time to exhaustion during high intensity sub-maximal exercise (Jacobs and Beii DCIEM Ethics Committee protocol #L136, 17 Jan 96). Investigative New Drug (IND) approval was obtained fiom Heaith Protection Branch (HPB)of Heaith and Welfare Canada for di these studies. In these studies little or no side effects of M were noted. Moreover Pigeau et al. (1995) reported that M reduced the extent of cognitive performance impairment, caused by sleep deprivation, without the side effects associated with the use of amphetamine; and Jacobs and Bell (1997) reported that acute ingestion of M prolongs exercise tïme to exhaustion at -85% VO7-, with significantly lower subjective rahgs of perceived exertion . We speculate that M may enhance physical work capacity, like amphetamines, but without signüîcant side- effects. However there is concern that the previously reported "overconfidence" phenomenon may negatively affect decision processes (cause impaired judgment) and even physical performance under certain conditions. Therefore, the aim of this study is to evaliiate the enhancing effect of M on aerobic and cognitive performance, in non-sleep deprived subjects.

OBJECTIVE This experiment is designed to: - 1) Test the hypothesis that ModaGnil will improve physical work capacity, and specXcally with this more extensive investigation, confirm the previous findings of Jacobs and Bell (1997). 2) Test the hypothesis that Modafd will cause an "overcon.dence" effect.

Subiects: 15 to 20 healthy, male volunteers, not being treated with any medication for acute or chronic illness, will be used for this study. They will be My informed of the detaiis, discornforts and nsks, associated with the experimental protocol and written informed consent will be obtained . The subjects will be between 18 and 40 years of age, accustomed to regular physical exercise, and will not be trained cornpetitive athletes. Participation in the study will be subject to the examination and approval of a DCIEM physician. Subjects will be told that they may voluntarily withdraw from the study at any tune. Participation will be restrïcted to males because special warfare units, the target populatioo for the eventual application of the resuits of this study, consist of only mdes. Approximate Time Involvement: The tirne cornmitment required on the part of the subjects wili range from 3 to 5 hours per visit. Total time cornmiment for each subject will be approximateIy 36 hours. Reimbursement of Subiects: Subjects are entitied to stress allowance for DND experiments as outhed in Memorandum 7200-2 mSD)Dec. 92.

Experimental Desi-: Subjects will be required to visit the laboratory on nine occasions as follows:

Visit 1 - Medical screeninp, VO-, ma..test and Subma. Test. After medical screening, V02 max. will be determined on a bicycle ergorneter. This test consists of pedaling at 60-80 revolutions per minute (rprn), with the exercise intensity starting at 60 watts and increasing in steps of 30 watts every minute, until the subject cm no longer maintain the pedaling cadence. Verbal encouragement will be provided during the later stages of this test Individual maximal heart rates will also be measured during this test with a transmitter/telemetry unit (Polar Electro PE 3000). After 45 min of rest, Submaximal testing will be performed at Gxed intensities of - 60, 70, 80, and 90% of VO?,, during 5mui intervals of exercise. separated with 5 min intervals of rest. Total time required for Visit 1 will be between 3 to 4 hours.

Visit 2 - Familiarization trial -Endurance ride to exhaustion. The Endurance ride to exhaustion (ER) will consist of a 5 minute warm-up exercise at 50% V02 max, followed by exercise at 85% VOz ma, until the subject cannot maintain the pedaluig cadence above 60 rprn. Total thne for Visit 2 will be approximately 3 to 4 hours, and this trial will occur no eariier thm one week after Visit 1. Visit 3 - FWarization trial - ER plus blood smling. Before commencing the ER, a catheter will be inserted in to a forearm vein. The subject will then perfom the ER. The blood samples will be drawn from the catheter before, during (at 10 min. point) and at the end of the ER. Total tirne for Visit 4 will be approximateIy 3 houn and this niai wdl occur no earlier than one week after Visit 2.

Visit 4 and 5 - ER Treatment trials. The treatment nids consist of blood samphg foilowed by either ingestion of placebo (P), or the Mod~~(M). This will then 6e followed an hour later by a srnail standardized rneal without caffeine (juice with muffin or toast). The same meal will be provided in all familiarization trials (Visit:2,3, and 6,7) two hours before ER or PPR. Two hours after the meal, another blood sample will be taken and then subsequentiy during the ER additional blood samples will be taken, as it is depicted on the time line of events during the treatment trials (Fig. la). The total amount of blood taken will be 40 ml. The blood samples wilI be analyzed for the concentration of: Modafinil, catecholamines, lactate, fkee fatty acids, glycerol, glucose, serotonin and dopamine. The order of treatments will be balanced among the subjects to avoid any order effect. The total time required for each treaîment triai will be approximately 4 hours. The minimum 72 h will intervene between the Qeatments, and this trial will

- occur no earlier than one week after Visit 3.

Visit 6 - Familiarization trial - Production protocol ride (PPR) for assessing perceived exertion and familiarization with cosmitive test batterv. . The control panel on the cycle ergometer for the Production protocol will be hmed away so that the subject can not see the power output settings. After farniliarization with the Borg scale (a ten-point numerical scale with associated descriptive phrases of the perceived exertion) the subjects will be given three different Rates of Perceived Exertion (RPE) values [light (2), heavy (3,and very heavy (8)], according to the Borg scale. For each RPE value, the subject will be given 15 sec at the beghmhg of each minute, to adjust the power output to an appropriate level, by means of a handheld control with an unmarked diai. The selected power outputs wili be recorded by the investigator at the end of each minute. RPE values will be presented in the same order on al1 sessions (i.e. 2, 5, and 8). Each RPE (5 min) interval, wiU be foilowed by a 5min recovery period. during which the subject wiU remaui seated on the cycle- pedaling at workload of 50 watts. At the end of the last recovery period, the subjects will be asked to set the highest possible intensity (with adjustment opportunities: during fist 30 sec and between 60 and 75 sec of exercise), that they rhink they wiU be able to sustain for 2.5 min. without any Meradjustments (gray 'area on Fig. 1b). Total time for Visit 6, with three practice session for cognitive test battery, will be approximately 4 hours.

Visit 7 - Familiarizaiion trial - PPR plus blood sarnpling plus familiarization with CO-gnitivetest battery. Before starting PPR, a catheter will be inserted into a foream vein. The blood samples wiU be taken: before first, and then after each 5 min exercise interval, prior to and following the maximum exercise (lasting about 2.5 min. after 2 adjustment by the subject). Total Ume for Visit 7 will be approximately 4 hours, and this trial will occur no earlier than one week after Visit 6.

Visit 8 and 9 - PPR Treatment trials. The treatment ai& for PPR consist of blood sampling followed by either ingestion of placebo (P), or the Modafinil (M). Two houn after the meal, another blood sample will be taken and then, dunng the PPR additional blood samples will be taken , as it is depicted on the iine of events during the treatrnent trials (Fig. lb). The total amount of blood taken will be 70 ml and blood samples will be analyzed for the concentration of: Madafinil, catecholamines, lactate, fiee fatty acids, glycerol, glucose, serotonin and dopamine. The order of treatments will be balanced arnong the subjects to avoid any order effect. The total time required for treatment trial will be approximately 5 hours. The heart rate, rate of oxygen consumption, minute ventilation, and respiratory exchang ratio will be monitored regularly during the: VO1mLK.test, Subma. test. ER and PPR. The subjective RPE Gom a 10-point scde will be evaluated durÎng the Subrn~u.test and ER.

min. -180 -120 -60 O 5 LO end

Food

Cognitive Test

Theline for experimental protocol for: ER to exhaustion(1a); and PPR for assessing RPE(1b).

Double -Blind: Neither the experimenter nor the subject will know what dmg is being ingested on any given trial. A technician, not involved with acmai testing, will assign the eeatment order to the subjects, and give the subjects their treatment capsules. The treatment order will only be revealed once aiI data collection is cornpleted.

Exercise: During Visit 1, the subjects will perform a VO? mx- and Subrnax test. on a bicycle ergorneter. From these two tests, the reiaticnship berneen the rate of oxygen consurnption and power output for eacch subject wiU be determined, and used to derive the power output equivalents of 50 and 85% VO? max, which are the exercise intensities used for dl subsequent performances of the ER , described above. For Visits #2,3,4,5,6,7,8, and 9, the subjects will arrive at the laboratory for testing in a fasted state, i.e.without having consumed any food or drink, with the exception of wnter. for the pst 12 hours. Fuaher the subject will not have perfomed any hard exercise for the past 24 hours. Blood Sam~ling:Durin; Visit 3,4,5,7,8, and 9, smail quantities, Le.. tom1 of blood will be drawn: 3 times (Visit 3); 4 times (Visit 4 and 5); 6 times (Visit 7); and 7 times (Visit S and 9). The total amount of biood drawn over the 9 weeks will be 3 10 ml. Coonitive Test Battenr (CTBI: For this testing subjects will work alone in 3 x 4 rn experimental rooms, which are equipped with a IBM PC, monitor, keyboard, table, chair. and desk lamp. Cognitive ta& will be controlled by the computer and displayed on the rubject's monitors. The CTB will be perform at the same time: before and after exercise (during PPR- farniliarization trials), before treatment with LM,or P and pre adpost exercise (during PPR- treatment trials) (Fig. Ib). The duration of CTB is constant among visits (appro,uimately 45 min.) and each session include the following tasks: serial reaction time, line cornparison, addition, logical reasoning, synwork and subjective questio~airesfor fatigue, motivation, mood and performance evaluation. This Cognitive Test battery has afready been used in the study of Baranski and Pigeau, (1997) and was approved by the DCIEM erhics committee (for details see: Baranski and Pigeau 1997). Drug and Placebo Administration: HPB approval for the use of an IND wiU be obtained for M before commencing this study. Standard 100 mg M tablets will be powdered and a dose of 4 mg --kge'body of MM,or the placebo, will be placed in opaque gelaiin capsules. They wiU be consumed approximately 3 hours before the ER or PPR. The placebo WU consist of approximately the same number of capsules containing Metamucil Le., a dietary fiber. Data AnaI~sis:A repeated measures analysis of variance will be used to compare the changes in the dependent variables across treatments and time.

POSSIBLE SlDE EFFECTS AND

Drug Ingestion: In humans blood concentration of LM at the dosage proposed for use in this study peaks between 2 to 4 hours after ingestion (Modiodal, 1994) and causes maximal vigilance enhancing properties 4 hours after a dose of 200 mg (Saletu et al ., 1986). To make it relative to body mas, a 4 mgkg-'body weight will be used which equates to approximately 280 mg for a 70 kg penon. This level has been approved by our ethics cornmittee previously[ see protocol #L58 Oct. 5 1993, Pigeau et al.]. Pigeau at al., (1995) used dosages of 300 mg and reported side effects of increased urination and marginally higher incidence of headaches cornpared to placebo controls in their sleep deprivation smdy. Saletu et al. (1986) reported no side effects with dosages up to 600 mg and only insomnia at 700 mg. in a case of attempted overdose, 4500 mg of modafini7 produced ody tachycardia, excitation and insomnia (Lyons and French, 199 1). Stoa~a~eof Trials as a Result of Dmo Reaction: If any ?indue discornfort or side effects of modannil ingestion are reported by the subjecr before or during cxercise, the trial will be discontinued and the subjects wîlI be referred to the aending physician. Exercise Tests: There is a risk of 1/10,000 of a cdac arrest. associated with a maximal exercise test (Gibbons et al., 1989). During the exercise tests there is a risk of muscle strain, muscle soreness and /or joint sprains. AU risks will be minimized by employing appropriate warm up techniques prior to all exercise tests and training sessions. The subjects will have a history of engaging in regular physical exertion. This history of re,oulax physical activity and the age limitation siwcantly reduce, the aiready small nsks of injury or hem attack; that are associated with hard exercise. However, all subjects WU be screened by a physician prior to participaàng in the study. In addition, before each trial subjects WU be questioned about any changes ta health status since their Iast visit The investigators are certified in basic CPR techniques. Also in case of ernergency, resuscitation equiprnent and supplies are available in a "crash cart" in the exercise laboratory. Venous Catheterisation: Bruising, feeling of stiffuess, infection in the puncture site, or fainting, are the ody sideeffects that has been reported with similar experiments at DCIEM involvuig thousands of venous blood sampies. The sampling will be performed by a technician trained in phlebotomy.

DCXEM is part of an international scientSc collaborative effort to evaluate the effects of ergogenic aids of potential benefit to specid warfare persounel (TTCP U-TP8). Based on a review of the Literanire, Modafinil was proposed by TTCP U-TPS, as an ergogenic aïd candidate that may be applicable to a military environment. The proposed investigation addresses some of the questions which must be answered, before such an aid cm be recommended for use by such personnel. MEDICAL OFFICER REQULREMENTS The presence of a medical oEcer in the exercise physiolog laboratory is noc required during these experiments. AU experiments will occur during regular working hours and DCEl\1 physician will be on caU ail the time during the experiment. Basruji. H. and M. Jouvet. Succcssful muncnt of idiopathic hypcnomnia and narco lepsy with Modafinil. Prog. Neun>-Psychophamami. Biol. Psychiat 1 2: 695-700. 1988.

Barans ki, J. and R Pigeau. Self-monitoring axgitive performance during sieq deprivation: effecn of modafuiil, d-amphetamine and piaczbo. J. Sletp Res.. 6.84-9 1, 1997.

Bourdon, L., 1. Jmbs, A: Vallerand The effkîs of moda5nil on thermoregdation during coid air exponneAviat Space Environ Md65: 999-1004, !994.

Buguet A, A Monmiayeur, R Pi gzîu anci P. Naitoh. Modafinil, d-amphetamine and placebo during 64 houn of sustained mental wwk IL on two nigh ofgrecwery sleep. J. Sleep Ftes., 4 219-241. 1995.

Chandler, J. and S. Blair. The &ects ofamohcgmines on seiecred physioiogical cornponenn nlared to athietic nicçs. MdSci Sporis Exerc. 12: 6549,1980.

Gibbons, L.. S. Blair, K Kohl and K The sdqof maximal detsting.

Jacobs, 1. and D. &IL Modafinil plongr timr to dnustion d- hi& immSiry submaximal exucisehîed. Sci Spom EId ( SuvpL) VOL 29, No. 5: S 39,1997.

Laffon~F., N. Agar, G. Mayer and M Minr Ena du modafinil cher des patmts narcoieptiques. Etudes dedophysiologique et psyamr&que. NemphysioLClin 25: 84- 95,1995.

Modiodal (Modafinil) Dossier d71nfoimationMedïcaie d Pharmdque. L Lafm Laboratory. Deltacorn Repo~:! 484, pg 137- 141,1994.

Lyons, J. and J. French Modafinil : The unique propenies of a new simulant Avia(ion, Space and EnvirornenraI Medicine 62: 432-335, 199 1.

Pigeau. R. et al. MoMnil ,d-amphebmine and plac-boduring 64 hours of sunaincd rnentai work:Eff&s on mood . fazigue . cognïnve perfomance and body temperature. J Slce? Rcscarch 3: 312-21 8 I995.

Snlcru. B. et al. Pharmaco-EEG. psychomanc and plasma level studies wirh rwo novd alpha-adrcncryic stsrnulanis CRL 40476 and 40028 ( adnfmii in eidcriics. in New - '1 rcnds in I:spcnmcntal and Clinical Psvchtatry. Vol. 1 1. 1. Panchem. Editor. 1986. p.>- .; .; 1 VOLUNTEER CONSEXT FORM

ModakiLExercise and Cognitive ?dormance Protocol 5 Prinauai Invesrioator: Dr. Ira Jacobs Co-lnvestirzitors: P-Dinich, Dr. J.V. Banmi& Dr. V. a,Mr. D.G. Beil

3. 1 am aware thar die &aiment invohies nine visirs to the laboratory, =ch visir iasting up IO 5 nours with exercise tesring indudd 1 am awarc tfrar 1 wiU be asked to aracise to voiuntary exhausnon on =ch ocasion . I am aware that dtrring triais 3.4.5.7.8 and 9 up to 70 mL ofblood wiIl be taka and thover the 9 weeks of this sûldy 3 20 mL of blood may bc ta- 1bave bew made aware of the discomfbrr invoived wRh this procedm~and the asçociated ri* 1 am aware th1 mut si- a separare invasive. medical procedure mnsexxt fbrm consemimg to t)iil;t pmcah~~

6. 1 hereby ansent ro the medical sokniiig assessrnent &ed in the protocal and agrre to pmnde responses ro questions tbar are to the bsr of my Iniowledp mnhîul and cornplne. Funhermore 1 agre to advise the invaiopron of any health auus hgasina my initiai assessrnent (includins but not limired ro viral il Inesses. new prescription or *O--the-coma" rncdic&ons). 1 have bem advid rhar the medical information 1 reveai and the expairnad daxa conaming me will be udas confidemd and not revealed io anvone orha than the investiq~orrwithout rny cmsent, acqr as dara uniùentified as ro sourco. i am awarc that a physician will be ai-cd1 in DCIEM auring dl cime af die expmmenr. In the hiçhi>~unlikely evenr. rhar i becorne inupacitatd during rny participation. I herebv consenr to whaiever emergencv medical intemention deemed nesePuy by the attending medial personnel. -I I undenrand thar 1 am tic to rerüçe ta parricipare and may withdraw mv consenr without p-udicc or hard feriings ar my tirne. Siiouia i wi~harawnu consent, iny pr;icipation fi a subjec: cease irnmediateiv - uniess the Invesrigaror(s) derermine thar such acion wouid be dangerous ûr impossiole (in winch case rny paraclpatron wiil cese as soon as it IS saxe ro ao so). i isd undentand tbar the Invesigatois), kir designale, or the pitysician(s) responsible for the experiment may renninate rny parucipzuon ar any ïirne. rqarciless of rny wisbes.

Print 'lame Date

Subjetx fn to participate as assessed 'by Physician Dare

For miliw ~ersanneicm owmanent meneth at Cm: Approval in principie by Commanding Oficer is gven in Memorandum 3700- i (CO Cr"c"'viEi. !S .kg 94; tiowtvg, mcmbers must d obtain th& Smor Head's signanue desi- approval to participate- - in this puticuiar experIrna CF pasonnd are considerd to be on chry kr discipiinary. ;Idminrnranve adParsion Act purposes dutnig tiieir participarion in tbis experiment

Sectoi Head's / Comding ûfiica's Sigamc:

CO'S unir Projcct Title: Modafinil. Excrcise and Cognitive Performance

Pr,?cipi Invesigaor Dr. L J'âcobs Co-bvrstigiton: P. Dinick Dr. J.V. Baranski, Dr. V. Gii, MT.'D.G. Be!l

Venous Blood Samoiinq A smdl ndeis used to pi- the slrui overiying a vein This venipuncme is used to obtain a blood sample: prior to, during ,and îfter the exefciS5 as detailed in the nibject mform;dion package. Either a phyncian or a properly qrralined and

ïhs procedm and possible cornplicarions have been explaineci to me m my satisfaction by the Investigator, and 1 have had the opportun if^ to ask guestions both of the Iiivestigmr and of a phpician.

Subject's Signature: Date:

Wimess: Dater Appendix C:Raw Data Endurance Ride to Exhaustion (ER)

i rime to Exhaustion in min Subject control 1 olaceba 1 madafinil 1 1 M.C. 1 23.260 1 25.6 10 1 29.260 1 2 1 N.C. 25.100 1 25.950 1 26.71 0 3 M.A. 21 -800 20.680 25.750 4 KB 20.930 7 7.350 20 -200 5 M.K. 20 -430 22.880 zr.ztoT

8 A.W. 18 -520 18.ô50 20 .GO 9 Mean 21.529 21.266 23.734 2. 1 O S.D. 1.978 3.278 3.248

Order-€3

dav 1 1I day 2 1 dav 3 1 1 M.C. 1 23.260 1 29.260 1 25.61 0

- 3M.K 20.430 22.880 21.21 O 6 1 ARC. 21 A50 20.750 23.31 0

Pf-a qt.mm& 3taaeo 1 maaatlnil ~iomaniq 1 nrn miom amq !auam ;un 10mn dot.w U.C. I .sso j t .sa0 1 s.050 I .sa0 I .aao 4.370 ( s.aso 1 N.C. i 1.330 ( 2.140 I 3.;ao 1 .7so I 1 .a90 3.300 I 9.!60 I A. 1 .as0 l t .zoo l s.300 l 3 580 u 250 ( aso l a.aso I 7 0.350 i K3 1 1.290 ( 1.250 ! 5.240 ( .a60 1 .780 1 5.530 1 !:.?a0 1 M.K i .a20 1 r ,020 1 5.~301 .sa0 I 1 .ooo 1 7.310 I 10.r30 I ARC. l 1.1ao 1 1 .ro1 7.010 t 10.790 1 I .os0 1 i.rto 6.170 I i i .zoo 1 J-C. 1 1.210 1 1 .90O 1 7.970 1 9.870 ] 1.200 1 I -590 1 7.370 1 10.570 1 A.W. 1 a60 1 370 I j.950 I a.380 1 730 1 ïsa 1 5.360 1 3.510 -I ER-Eoinepnnne Ipg/mL) ! i Sublect Pracebo Moaaf in:l before drug before exerc. end of exerc. before drug 1 before exerc. 1 end af axerc. N.C. 59.000 28.000 a26.000 41 .O00 1 J2.000 1 73.000 M.A. 16.000 59.000 1 :46.000 8 1 .O00 2*16.000 K.6 22.000 16.000 442-000 15.000 1227.000 M.K- 68.000 237.000 440.000 48.000 d0.000 ! --737.000 A.RC. 10 .O00 27.000 ( 587-000 95.000 1 19.000 ( 587.000 J-C. I 75.000 71 .O00 1 104.000 65.000 1 71 .OOO I I1 13.~~oj X.W. JJ.000 t 13,000 1 796.000 ‘U.000 1 3Ï 1100 1 360.000 1

I ER-Noreuinephrine (pqmL) 1 Subiect P!acaoo Modafinil before dmg before exer. 2nd of exer. before dmg t before axer. j and of exer. N.C. 334.000 d63.000 4392.000 28S.000 1 603.000 4553-0007 MA. 336.000 366.000 5206.000 300.000 7 391 .O00 56 18.000 1 KB 270.000 961 .O00 5929.000 M.K. 628.000 474.000 1888.000 6360.000 i ARC. 1 101 .O00 326.000 3755 .O00 234.000 )! 509.000 3755.000 J.C. 1A1.000 431 .O00 1327.000 179.000 ; 431 .O00 1 1 168.000 &W. 482.000 628.000 4930.000 1 482.000 1 590.000 1 3092.300 1

Oooarnine (pqmU Subjec: Place00 Madafinil belore dnig ( before exer. 1 end of exer. before dmg before axer. 1 end of exar. MC. 70.000 1 84.000 1 248.000 ] 33.000 ! 42.000 1 89.000 1 M.A. 1 32.000 28.0001 72.000 40.000 ! *7.000 ! 9S.000 1 K.8 18 .O00 20.000 1 i 29.000 1 25.000 ( 20.000 1 78.000 1 M .K. 1 28.300 26.000 i 65.000 59.000 1 27.000 t tir .ooo ! ARC. 36.000 39.000 1 00.000 40.000 36.000 1 75.000 ; J-C. 28 .O00 34.000 31 .O00 30.000 34.000 1 os.000 i 57.000 46.000 80.000 57.000 68.000 1 94.000 * A.W.

ER-Serotonin (ng/mC) I Subject Placeba Madafinil + before dmg befare exer. 1 end of exer. before dmg 1 before exer. 1 end of exer. N.C. 19.000 27.000 1 49.000 1 1.O00 48.000 71 .O00 M.A. 54.000 3.000 8.000 115.000 29.000 70.000 iCB 114.000 7.000 15.000 62.000 1.O00 3.000 M.K. 69.000 41 .O00 20.000 1 5.000 1 10.000 9.000 1 ABC. \ 31 .O00 28.000 1 77.000 42.000 ) 32.000 7.000 J.C. 1 59.000 49.000 1 22.000 ZO.000 1 49.000 26.000 A.W. 122.000 73.000 ) 35.000 1 58.000 26.000 1 7 000

H.R. rest for PPR HR mw PPR name I I l1 controi 1 aiacoca I moaatinit i mnrroi 1 ûla=bo ( moaarinii 1 M-CS. 77.000 1 77.0CO - 85.000 1 189.000 188.000 1 :91 .O00 N.C. 57 000 1 50.000 1 ô6.CIOO 1 157.000 7 60.000 1 161.000 K.B. 87.000 1 81.000 1 108.000 200.000 198.000 203.000 J-C. ïs.ooo ao-ûoo I 75.000 1~0.000 i84.000 190.a00 A.'N- 68.000 77.000 1 99.000 1 :83.000 1 187.000 7 87.000 MX- 65.000 96.000 1 90.000 i 195.000 1 192.000 1 193.000 IM.A. I a6 -000 97 000 1 90.000 i r9ï.000 195.000 1 200.000 ARz. 73.000 1 70.000 1 42.000 180.000 197.000 1 2!30.000 A.& 34.000 1 S6.000 1 91 000 1 178.000 ;75-000 / 178.000 G.?. 76.000 1 7J.aOO ) 91 -000 ) 186.000 1 i85.000 1 7 92.000 1

- -- 7 2 1 TT-C- 1 53.000 1 55.000 1 64.000 1 1 76.000 1 173-000 185.000 1 3 1 J.L. 69.900 1 70.000 1 34.000 i 179.000 180.000 187.000 T * i C.P. I 79.000 I a2.000 ) 98.000 186.000 181 -000 188.000 i 5 1 J-9. I 51 .ooo 1 76.oao I ao.000 ! 197.000 201 .ooo 1 20 1.ooo

B.P. syst PPR B.P. diast PPFl name contrai 1 ~lacew 1 nadafinil .:zn t:ol I r I giaceoo .nocarinil i 1 m. 1 120.000 1zo.000 tao.ooo 1 ao-ooo t as.ooo as.000 2 N.C. 117.000 120.000 120.000 1 75.00a 1 75.000 80.000 3 K.B. 1 t 35.000 120.000 12S.000 } 80.000 1 75.000 80.000 J J-C. 120.000 130.000 13o.000 1 7S.000 1 85.000 ao.ooo s A.W. 120.000 110.000 13o.000 1 7s.ooo 1 ao-000 9o.ooo 6 M.K. r zo.ooo i 20.000 t3o.000 so.ooo 1 90.000 ao.000 I 7 ' M.A. 1 120.000 t 15.ooo r30.000 I 7s.000 I :s.ooo 1 ao.ooo I a A-RZ. 120.000 120.000 130.000 ao.000 90.000 85.000 9 A.B. 130.000 130.000 ) 120.000 9o.ooo 30.000 ao.000 1 O G-P. 130.000 Il 5.000 1 120.000 80.000 80.000 80.000 i r GG i30.000 1 130.000 1 136.000 85.000 90.000 a2.000 12 M.C. i 13.000 ) 120.000 1 120 -000 75.000 f 77.000 I 78 .ooo 1 3 J.L. 110.000 1 108.000 \ 120.000 75.000 1 75.000 1 80.300 14 C.P. 11s.000 1 120.000 1 t4o.000 1 as.000 1 ss.ooo l 87.000. 15 J.B. 130.000 1 120.000 ) 130 .O00 / 80.000 1 80.900 1 85.000 i 1 6 1 H.J. 115.000 120.000 1 120.000 1 80.000 1 75.000 ( 82.000 i PPR-hoamme ipg/mL) t Suc~ec: ?lace00 Modatinil Defore dmg before exer. 1 end of exer. before dmg berare exer. ) ana ot exer. N.C. 33.000 32.iJOO 1 ô 1-000 J7.000 50.000 1 124.000 IM.A. 18.000 31 .O00 32.000 16.000 35.000 1 5J.300 1 f K.0 22.000 52.000 145.000 27.000 29.000 ( 68.000 1M.K- 23.000 22.000 90.000 1 74.000 2i4.000 1 07.000 A.RC. 37.000 32.000 6S.000 1 39.000 28.000 1 ô t .O00 J-C. 1 33 .a00 32.000 1 57.000 1 25.000 1 35.000 / 54.300 / fi. 56.000 1 35.000 1 65.000 00.000 1 52.000 1 0s.000 !

PPR-EPIN€PHR!NE (pg/rnL) il Subject PIaceba C Modafinil l \ 1 oefore dmg 1 before exer. 1 end of axer. 1 before dmg 1 before axer. 1 ofla of exer- N.C. 1 18.000 1 24.000 1 214.000 1 19 000 1 23.000 1 439.000 1 . . --.--- - b ica t 5oa.000 24.000 2058.000 94000 i ss.ooo i a67 .ooo

M.K. 1 0.000 6 1 .O00 383.000 54.000 * 2592.000 353.000 A.RC. 1472.000 351 .O00 !523.000 20.000 36.000 1227.000 1 J-C. 04.000 1 58.000 368.000 56.000 1 97-000 1 370.000 i A.W. 35.000 1 59.000 393.000 28.000 5.000 1 393.000 :

- PPR-Norepineuhrine (pqfmt) Subjeu placebo 1 Madafini1 befam dnia 1 before exer. I end of exer. 1 before umq- before exer. 1 end af exer. I 1 b NC. 228.000 503.000 1852.000 469.000 1 402-000 3740-000 MA 207.000 392.000 370 1 .O00 471 .O00 )) 466.000 781 -000 K.8 280.000 271 .O00 5369.000 147.000 1 376.000 5402.003 M.K. 251 .O00 443 .O00 4230.000 148.000 ' 5309.000 3972.000 i A-RC. 26.000 313.000 1247.000 26.000 31 9.000 3341 .O00 J-C. 138.000 493.000 36 13.000 185.000 560.000 1 41 ~4.000 A.W. t 79.000 1 468 .O00 4289.000 292.000 467.000 1 J289.000

Subiect Placebo Modafinil .2nd of exer. before dnig 1 befare exer. and of exer. before drug before exer. N.C. 12.000 1 t 0,000 38.000 48.000 , 12.000 17.000 1 MA. 66.000 1 3.000 4.000 21 .go0 1 4.000 7.000 ICB 1 13.000 7.000 20.000 28.000 1 2.000 9.900 MX. J0.000 10.000 49.000 r 9.000 1 22.000 :t .O00 ARC. 12.000 9.000 9.000 12.000 k 4,000 ) 22.000 J-C. 19.000 24.000 1 10.000 19.000 1 24.000 ! 10.000 A.W. 38.000 1 6.000 1 13.000 31 .O00 11 : 1 .O00 1 25.300 Line Comparison Task

S ;- C~gnrnveSesi~n ; Pie-T& Co&dence (PRECOm D I = Placebo S2 - Cqniuve Session I !X = XadaEmi Percet of the correcz answers !PCORRl SZ - Cclqickre Session 3

POEX-TaskC~af?&xe (POSTCONF) POSTDFr = POSTCONF -PCORR

OBS s1J&lCODE JAE- DlS1 D1S2 D1S3 D2SI D2S2 D2S3 P=cxrof die comcr answen in [ne txk (PCORR)

OBS SVBCC3DE ,W, 91Si 31S2 31S3 DSSI

Ca? Gre Uaj jr;a JOE .Th nev Pac NEI ace aga mic

pid

. - OBS SûBTCODE >VAMEVAME DlSl D2S1 D2S3

CONE 54 -7059 51.7460 51.7568 cm 61.2371 60.4878 60.8602 CONF 75 - 8696 71.2821 67.6289 cm 82.6126 75 -9664 83 - 0081 CONF 66.3636 65.6452 64 -9038 CONF 69.6154 66.2069 67.3016 cm 61.3158 62.0482 02.7523 cm 58. aïço 61.î789 60,5063 C3NF a0 -4839 70.60'67 78.6207 C3NF 74 - 3333 73.3655 a0 -5310 CONF 39-4366 60.3065 60. 2564 CCNF 58 -3626 58 .O000 57.0149 CONF 54.5570 ça. 3099 ça. ~043 CONE 73.7647 71.2222 73 - 0196 0- OVUN OVCTN OVUN OVUN om OW OVUN OVUN ovm OWN OvON ûVUN om

V02 max (Umin) Subjen 1 Before 1 After

1 ô 1 H.J. 3.360 1 3.570 ' 17! P.V. 3.210 1 3.220 i