Sleep Deprivation, Stimulant Medications, and Cognition provides a review, synthesis and analysis of the scientific literature concerning stimulant medications and neurobehavioral performance, with an emphasis on critically evaluating the practical utility of these agents for maintaining cognitive performance and alertness in sleep-deprived (but otherwise healthy) individuals. The book explores the nature of sleep loss-induced cognitive deficits, neurophysiologic basis of these deficits, relative efficacy and limitations of various interventions (including non-pharmacological), and implications for applying these interventions in operational environments (commercial and military). Readers of this volume will gain a working knowledge of:Mechanisms contributing to sleep loss-induced cognitive deficits Differential effects of stimulant compounds on various aspects of cognitionConsiderations (such as abuse liability) when applying stimulant interventions in operational settingsCurrent state and future directions for including stimulants in comprehensive fatigue-management strategies. This text is key reading for researchers and trainees in sleep and psychopharmacology.
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The logic behind sleep deprivation studies is basically sound. The first problem is that sleep is a process that not only occurs in the brain, but is also a process that undoubtedly confers unique benefits to the brain itself. In the parlance familiar to those who are afflicted with a degree in experimental psychology and have thus been subjected to a course in "The Philosophy of Science", the scientific paradigm under which sleep deprivation research is conducted contains some conceptual gaps. The difficulty is as follows: extended continuous wakefulness is an antecedent condition that leads to a predictable, observable outcome: decremented performance. Results from studies conducted to determine the effects of sleep loss on various neurocognitive abilities have proven useful for informing policy, and decision-making in a variety of operational and regulatory environments, and the utilitarian value of such studies for testing work/rest schedules and drug effects remains high.
This chapter discusses how the effects of sleep deprivation on the brain can be studied using functional magnetic resonance imaging (fMRI). Most contemporary functional brain imaging experiments are conducted using fMRI. This technique measures changes in blood oxygenation level dependent (BOLD) signal in capillaries and venules adjacent to neuronal clusters whose firing rate is modulated by task performance. Inference is most straightforward when the activated brain region participates in a circumscribed set of cognitive functions. For example, state related modulation of amygdala activity in response to affective pictures can be reasonably related to changes in emotional processing. Results of many fMRI experiments conducted on sleep-deprived subjects have consistently shown reduced superior parietal and lateral occipital activation during task performance. Results of more recent studies involve making decisions under uncertainty have shown that sleep-deprived persons tend toward riskier options, mirroring the behavior of patients with medial frontal damage.
This chapter focuses on the neurotransmitter and neuromodulator systems involved in the regulation of wakefulness and sleep as well as the neurochemical responses to sleep loss. Wakefulness, rapid eye movement (REM), and non-REM (NREM) states were originally defined in mammals using measures of skull surface electrical brain activity, skeletal muscle activity, and eye movements. The two primary factors that determine the degree of human vigilance and sleepiness are the duration of prior wakefulness and circadian influences. Increases in homeostatic sleep need are associated with subjective sleepiness, objective sleepiness, diminished neurocognitive function, as well as neurochemical and neurophysiological changes. The ascending reticular activating system (ARAS) is comprised of the brainstem reticular formation and its ascending projections responsible for cortical activation and wakefulness. Electrophysiological and neurochemical data indicate that highest levels of orexinergic activity occur during active wakefulness, and greatly reduced activity is seen during NREM and REM sleep.
This chapter presents results from studies showing strong evidence for pronounced heritability of waking and rapid eye movement (REM) and non-REM sleep electroencephalographic (EEG) activity. Genes regulate the expression and function of the neurobiological systems that modulate sleep and wakefulness. The most commonly employed method for identifying genes involved in some aspect of physiological or behavioral regulation is the candidate gene approach. In this approach, individuals with genetic polymorphisms thought to be involved in sleep-wake regulation or neurobehavioral vulnerability to sleep loss are subjected to sleep loss in the laboratory, and neurobehavioral measures are assessed throughout. The chapter determines whether functional polymorphisms of the catechol-O-methyltransferase (COMT) gene moderate responsivity to other psychostimulants that also act via dopaminergic signaling. Genetic variations also appear to control individual responsivity to stimulants. Evidence indicates that the COMT Val158Met polymorphism controls individual responsivity to the stimulant modafinil during sleep loss.
This chapter focuses on the extent to which modafinil sustains/restores various aspects of cognitive performance during sleep deprivation in normal healthy adults. The earliest published studies of modafinil's effects in humans were conducted by Saletu and colleagues, and involved non-sleep-deprived young adult and elderly volunteers. The first published study of modafinil's dose-response effects on cognitive performance during sleep loss was performed at the Defense Research and Development Canada (DRDC) laboratory. The focus of an increasing number of studies is the effect of sleep loss on tasks of executive functioning. Executive functions encompass a wide range of mental abilities including critical reasoning, planning, flexible thinking, and effective judgment. Deficits in one or more of these abilities due to sleep loss and circadian factors are thought to be the underlying cause of mishaps such as Three Mile Island.
This chapter focuses on studies in which the interaction of sleep loss and caffeine on a variety of cognitive tests was examined. Caffeine effects on cognitive performance are dependent upon both the dose and the method used to deliver the caffeine. A variety of outcome measures have been used to assess the efficacy of caffeine during sleep loss. The commonly used measures are subjective and objective sleepiness. Short-term memory has been examined during sleep loss using several types of tasks including the Digit-Symbol Substitution Test (DSST), coding, short-term memory recall, and digit span. Numerous additional cognitive tests have been examined during sleep deprivation. The effects of caffeine during sleep loss have been examined over a large dose range. Administration of caffeine typically produces both physiological effects and mood changes. If caffeine use is terminated once tolerance develops, withdrawal (which includes symptoms such as headache, fatigue, and sleepiness) may occur.
This chapter begins with a brief discussion of caffeine metabolism and mechanism of action. The half-life of caffeine in the circulatory system varies substantially between individuals, and is influenced by health, lifestyle, and genetic factors. In cigarette smokers, caffeine's half-life is approximately 3 hours. Caffeine is metabolized in the liver by a complex series of reactions. Genetic variation accounts for some inter-individual differences in caffeine metabolism. Caffeine is structurally similar to adenosine, an inhibitor of neuronal activity in the central nervous system (CNS) with sedative-like properties. Under normal physiological conditions, the behavioral and ergogenic effects of caffeine are due to competitive antagonism at central adenosine receptor sites. Caffeine's effects during sustained marksmanship tasks in rested personnel have been investigated in both laboratory and field studies. The effects of caffeine during severe operational stress and sleep deprivation were examined in a field study conducted with US Navy SEAL trainees.
This chapter reviews pharmacological options that may improve the impaired wakefulness associated with shift work disorder (SWD) and available data regarding the use of stimulant therapy. It begins with a brief discussion of shift work and SWD. Night shift workers are at a greater risk for workplace accidents than day shift workers. Research into the negative physical and mental effects of shift work is accumulating, and available evidence indicates that shift work is associated with greater risk of psychiatric problems, cardiovascular disorders, cancer, and accidents, and it represents a serious occupational health problem. A variety of countermeasures have been proposed and studied for the treatment of sleepiness and daytime sleep disturbances associated with shift work. These countermeasures range from basic nonpharmacological and behavioral strategies for improving sleep quality and quantity to pharmacological interventions for improving alertness during the work period or for improving sleep during the sleep period.
This chapter reviews the relative abuse liability of the various stimulant medications used to treat impairments associated with chronic sleep deprivation and how the drugs' potential for abuse impacts their medical usefulness. The abuse liability of a drug is an important consideration during the drug development process, when estimating risk: benefit ratios for approving drugs, and ultimately in the prescription and utilization of a drug by physicians and patients. The physicochemical properties of a drug determine how it may be administered and its pharmacokinetic profile. The mesolimbic dopamine system has been identified as a key pathway involved in mediating the properties of drugs that are responsible for their addictive nature. The behavioral effects of drugs evaluated in abuse liability studies include reinforcing effects and discriminative stimulus effects. Amphetamine is readily self-administered and discriminated by animals, and often used as a positive control drug in studies of abuse liability.
This chapter reviews the evidence concerning the efficacy of psychostimulants as cognitive enhancers in healthy and non-clinical individuals. Cognitive operations are the mental processes whose outcomes affect mental content in one or more areas of cognition. Cognitive functions are typically modulated by non-cognitive factors such as mood, level of energy, motor function, impulsivity, and motivation. Cognitive enhancement is an intervention that improves or augments one or more cognitive domains, such as learning, memory, or attention. Psychostimulant is a behavioral description for drugs that elevate mood, increase motor activity, increase alertness, allay sleep, and increase the brain's metabolic activity. Psychostimulants are a large class of drugs with broadly overlapping neuropharmacological properties, mechanisms of action, and therapeutic effects. The class of psychostimulants most commonly reported for use as cognitive enhancers is that of amphetamines. Amphetamines influence both dopaminergic and noradrenergic systems.
Histamine (HA) is a biogenic amine, providing a number of functional roles throughout the body. HA release triggers inflammatory responses as a protective reaction against foreign pathogens. Released from basophils and mast cells in the periphery, HA causes increased vascular permeability and dilation of blood vessels to allow increased fluid infiltration into tissues which in turn induces swelling. Research designed to test the role of HA in mediating central nervous system (CNS) activity demonstrated that HA immunoreactive brain neurons actively fire action potentials and release HA during the wake phase but are essentially silent during sleep, supporting the hypothesis that increased HA tone is related to levels of wakefulness. Results of experiments investigating the effects of HA in the CNS, either through direct injection of HA or through pharmacological inhibition of its synthesis, show that increases in HA are positively correlated with amounts of wakefulness.