Preface

Changes in daily living circumstances over several decades have significantly affected sleep quality, propelling two revolutions in health care: a treatment revolution, which has been directed to the care of sleep disturbances, chiefly through pharmacological methods, and a research revolution, which has produced a novel understanding of the role of sleep in cognition. High-paced social and employment practices, for instance, have notably combined to make insomnia a major dysfunction affecting both physical and mental health, with nearly 30%–40% of the adult population suffering from its mild to severe forms.

The need to treat insomnia and other sleep disorders has been the stimulus for developing pharmacologic interventions that, historically, have pursued an empiric approach. This approach has yielded drug candidates capable of alleviating sleep disturbances, but often with accompanying undesirable effects. Benzodiazepines, the first group of sleep medications developed, exhibited significant adverse effects like cognitive and psychomotor impairment, anterograde amnesia, nextday hangover, and rebound insomnia. Because of these adverse effects, the use of benzodiazepines for treatment of insomnia became controversial. In their place the non-benzodiazepine drugs like zolpidem, zaleplon, and zopiclone that followed all had high affinity and selectivity for the a1-subunit of the GABAA receptor complex, which improved sleep maintenance shortly after administration but lost this effect, however, at later sleep stages. These drugs too had adverse effects, which included daytime drowsiness, dizziness, headache, and nausea. In like manner, empirical approaches have yielded other drug candidates such as the orexin blockers with their own suite of advantages and disadvantages. Following this empirical progression has thus altogether yielded an extensive, proliferating, and somewhat bewildering variety of sleep medications, with the current pharmacopeia now exhibiting a broad range of biological properties affecting sleep.

Coincident with the revolution in sleep pharmacotherapy there has been a parallel revolution in the understanding of the nature of sleep. While motivated chiefly by the health needs of increasing numbers of individuals suffering sleep disturbances, the study of the physical reality of sleep also presented itself as a strikingly interesting, universal feature of cognition. All known mammalian species notably exhibit sleep. This universal physical feature led to numerous studies that attempted to explain sleep's biophysical basis. Dominating the hypothetical landscape was the fact that sleep's defining feature entailed a sensory disconnection from afferent input. Addressing the why and how of this feature has now yielded key insights into the nature of sleep with a growing body of data coalescing around several models. These models point to a global influence in the modulation of the neuroplastic events of cognition and thus of an influence likely to be exerted on neurological functions throughout the brain.

The text presented here is a recognition of these twin revolutions, which have been driven by the need to address a common and increasingly prevalent class of health and social impairments.

This text, however, is also a recognition that the revolutions in pharmacological medications and in the understanding of the physical basis of sleep are windows into a broader view of systemic dysfunction within the brain and so of the cross-cutting relevance of sleep for the practice of medicine in numerous neurological domains. This is to say that both the understanding of sleep and the methodology evolved for its treatment have reached a point of synergy that represents a plateau with broader implications for therapeutic intervention in cognitive dysfunction.

Consistent with this view, several studies have reported that sleep and psychiatric disorders are comorbid, such as depression or anxiety, suggesting that sleep disturbances may constitute etiological factors contributing to psychiatric impairments. Indeed, the identification of comorbidities ranging from psychoses and addiction to neurological dysfunction and the like is a significant indicator that processes like sleep that operate on global scales are likely to have wide-ranging functional effects.

Accordingly, this book presents an up-to-date portrait of these revolutions, demonstrating the success achieved in pharmacological therapy and the insights acquired through research exploration. However, the text is also intended to link these findings to efforts to chart a trajectory that will reveal the cross-cutting relevance of sleep pharmacotherapy not only for the medical management of its disorders but also for the practice of medicine in a wider range of neurological issues.

To present these themes, the chapters are anchored by an introductory discussion on the contemporary understanding of the biological and physical basis of sleep and the implications that this understanding has about cognition and the physiological mechanisms that are themselves affected by sleep. These mechanisms are then discussed from the vantage of pharmacological tools that are capable of modulating sleep events and therapeutically resolving its disturbances. A final section considers the therapeutic terrain beyond sleep disturbances, the neurological domain of sleep-induced, system dysfunction.

Current models of sleep situate it within the sphere of biophysical phenomena and often characterize it as adhering strictly to fundamental physical principles. The bodily processes that govern sleep and establish its rhythms are therefore themselves constrained to accommodate these principles within the architecture shaping sleep behavior. The biochemical medium underpinning this behavior is taken up in Chapter 2. Included in its discussion is a comprehensive compendium of the many small regulatory molecules involved in sleep and circadian rhythms. Their roles in brain systems physiology, hypothalamic and pituitary hormone influences in sleep, neuropharmacological agents, and changes during psychiatric disease are presented, an organization that assists not only in relating their molecular contribution to brain systems physiology but that is also helpful in understanding how they are likely to interact with each other in normal and pathological circumstances.

The disruption of sleep regulatory mechanisms constitutes the most visible aspect of sleep disturbances, their biochemical, electrophysiological, and behavioral features having motivated the progressive evolution in the present pharmacopeia. Chapters 3 and 4 consider two well-known symptomatic consequences of failures in sleep regulation mechanisms: narcolepsy and the parasomnias.

Narcolepsy is one of the most common causes of chronic sleepiness, occurring in nearly one of every 2000 individuals with significant impact on quality of life

**V**

(Chapter 9).

and employment. Chapter 3 by Jose et al. highlights current pharmacotherapeutic practice for narcolepsy, which has a stated intention of managing but not curing the disease. Its discussion addresses first- and second-line treatments, combined therapies, kinetic profiles, and other details of the chief pharmaceuticals now available for medical management of narcolepsy, a compendium that should be useful for the physician not frequently accustomed to treating this class of patients. Parasomnias are unusual motor and/or behavioral events that occur while falling asleep, during sleep, or arousal, which may appear in rapid eye movement (REM) or non-REM (NREM) phases of sleep. In pediatric populations, they can be highly prevalent, as in NREM parasomnias, attaining nearly 40%. Chapter 4 by Carter reviews the principal parasomnia classes, sleep-related movement disorders, REM and NREM parasomnias, and arousal disorders, their symptomatology, and contraindications. The discussion considers not only pharmacokinetics, bioavailability, receptor physiology, and system influences, but also provides a wealth of physical molecular features (e.g., the presence of single vs double rings, receptor binding site interactions, affinity constants, etc.) that distinguishes compound classes as considered effects of their biological action. Included are such major players as the benzodiazepines; melatonin; antidepressants; alpha delta, voltage-gated, calcium

channel blockers; dopamine agonists; and opioids.

breadth offered by supplementary disciplines.

dysfunction affecting normal health.

providing for personal medical needs.

Beyond the symptomatic expression of direct regulatory dysfunction, sleep disturbances encompass ancillary symptoms whose modalities significantly, but indirectly, impinge on secondary systemic wellbeing. Chapters 5 and 6 consider the special case of apnea, with Chapter 5 exploring the significance of a risk indicator in a previously unassessed, cultural setting, Taiwan, and Chapter 6 the diagnostic

Chapter 5 explores the link between snoring and obstructive sleep apnea (OSA), a predisposing risk factor causative for cardiovascular disease and associated dysfunctions, including hypertension, arrhythmia, coronary heart disease, and stroke. The author's focus on variables relating to altered suprachiasmatic nuclear function is useful for relating apnea to a neurological basis. Chapter 6 takes up the symbiotic and growing intersection between the medical dental disciplines and the clinical specialties associated with sleep and disorders of the upper respiratory airway, notably OSA. As the authors state, the intersection between disciplines is comprehensive, including diagnosis, therapy, and medical management. This is a significant evolution in two previously disparate approaches to upper airway

The remaining three chapters chart territory that moves beyond sleep processes themselves to the effects of sleep dysfunction in the public health arena (Chapter 7), circadian rhythmic alterations and their effects on health and wellbeing (Chapter 8), and influences on maternal wellbeing and bodily development during pregnancy

Chapter 7 takes up the very significant issue of the difficult balance required for navigation between threats to traffic safety and sleep dysfunctions harmful to drivers. Compounding this difficult balance has been the proliferation in pharmacological products affecting sleep, often obtained in over-the-counter formulations. The authors of the chapter address this situation by discussing the legal and medical framework that has evolved in Switzerland for preserving public safety while also

and employment. Chapter 3 by Jose et al. highlights current pharmacotherapeutic practice for narcolepsy, which has a stated intention of managing but not curing the disease. Its discussion addresses first- and second-line treatments, combined therapies, kinetic profiles, and other details of the chief pharmaceuticals now available for medical management of narcolepsy, a compendium that should be useful for the physician not frequently accustomed to treating this class of patients. Parasomnias are unusual motor and/or behavioral events that occur while falling asleep, during sleep, or arousal, which may appear in rapid eye movement (REM) or non-REM (NREM) phases of sleep. In pediatric populations, they can be highly prevalent, as in NREM parasomnias, attaining nearly 40%. Chapter 4 by Carter reviews the principal parasomnia classes, sleep-related movement disorders, REM and NREM parasomnias, and arousal disorders, their symptomatology, and contraindications. The discussion considers not only pharmacokinetics, bioavailability, receptor physiology, and system influences, but also provides a wealth of physical molecular features (e.g., the presence of single vs double rings, receptor binding site interactions, affinity constants, etc.) that distinguishes compound classes as considered effects of their biological action. Included are such major players as the benzodiazepines; melatonin; antidepressants; alpha delta, voltage-gated, calcium channel blockers; dopamine agonists; and opioids.

Beyond the symptomatic expression of direct regulatory dysfunction, sleep disturbances encompass ancillary symptoms whose modalities significantly, but indirectly, impinge on secondary systemic wellbeing. Chapters 5 and 6 consider the special case of apnea, with Chapter 5 exploring the significance of a risk indicator in a previously unassessed, cultural setting, Taiwan, and Chapter 6 the diagnostic breadth offered by supplementary disciplines.

Chapter 5 explores the link between snoring and obstructive sleep apnea (OSA), a predisposing risk factor causative for cardiovascular disease and associated dysfunctions, including hypertension, arrhythmia, coronary heart disease, and stroke. The author's focus on variables relating to altered suprachiasmatic nuclear function is useful for relating apnea to a neurological basis. Chapter 6 takes up the symbiotic and growing intersection between the medical dental disciplines and the clinical specialties associated with sleep and disorders of the upper respiratory airway, notably OSA. As the authors state, the intersection between disciplines is comprehensive, including diagnosis, therapy, and medical management. This is a significant evolution in two previously disparate approaches to upper airway dysfunction affecting normal health.

The remaining three chapters chart territory that moves beyond sleep processes themselves to the effects of sleep dysfunction in the public health arena (Chapter 7), circadian rhythmic alterations and their effects on health and wellbeing (Chapter 8), and influences on maternal wellbeing and bodily development during pregnancy (Chapter 9).

Chapter 7 takes up the very significant issue of the difficult balance required for navigation between threats to traffic safety and sleep dysfunctions harmful to drivers. Compounding this difficult balance has been the proliferation in pharmacological products affecting sleep, often obtained in over-the-counter formulations. The authors of the chapter address this situation by discussing the legal and medical framework that has evolved in Switzerland for preserving public safety while also providing for personal medical needs.

The lack of synchrony between an individual's internal, circadian rhythm and locally experienced, environmental time can significantly impair quality of life. Chapter 8 identifies the chief rhythmic dysfunctions that are observed clinically, provides a diagnostic guide for the screening and evaluating of these dysfunctions, and introduces basic treatment strategies that can be applied by non-sleep medicine clinicians. The chapter also discusses the effect of these daily rhythm disorders on the functioning of other organ systems.

Sleep and circadian rhythm dysfunction can also impact development by affecting pregnancy symptoms and outcomes, as discussed in Chapter 9. A widely replicated observation, for example, is the change seen in the Pittsburgh Sleep Quality Index. Maternal effects introduced by these dysfunctions can extend to the foetus, who lacks intrinsic circadian mechanisms and must depend on their maternal origin to function. Small birth weights, growth retardation, and the subsequent evolution of high blood pressure are among the significant effects on secondary systems that are experienced by the foetus. Chapter 9 discusses the unique medical management of sleep required for disorders during pregnancy, which is complicated by the potential for harm to the foetus from pharmaceutical compounds used to treat sleep dysfunction of the mother, as well as numerous secondary effects occurring in both mother and child.

It is my hope that readers of this text will come to appreciate the medical significance of sleep therapy not solely for treating sleep disturbances but also for the care of other neurological symptoms for which the influence of sleep is only beginning to be understood.

> **Denis Larrivee** Mind and Brain Institute, University of Navarra Medical School, Pamplona, Spain

> > Department of Arts and Sciences, Loyola University Chicago, Chicago, USA

Section 1
