Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 14, Number 32, 2008


Contents

Neurobiology of Sleep Disorders
Executive Editor: Luigi De Gennaro


Editorial: Pp. 3384-3385


The Genetic Basis of Sleep Disorders Pp. 3386-3395
Y. Dauvilliers and M. Tafti
[Abstract] [Purchase Article]


Genotype-Dependent Differences in Sleep, Vigilance, and Response to Stimulants Pp. 3396-3407
H.-P. Landolt
[Abstract] [Purchase Article]


The Role of Cytokines in Sleep Regulation Pp. 3408-3416
J.M. Krueger
[Abstract] [Purchase Article]


Functional Neuroimaging of Sleep Disorders Pp. 3417-3429
E.A. Nofzinger
[Abstract] [Purchase Article]


Neurobiology of Sleep Disturbances in Neurodegenerative Disorders Pp. 3430-3445
J.-F. Gagnon, D. Petit, V. Latreille and J. Montplaisir
[Abstract] [Purchase Article]


Quantitative Electroencephalogram (EEG) in Insomnia: A New Window on Pathophysiological Mechanisms Pp. 3446-3455
C. Marzano, M. Ferrara, E. Sforza and L. De Gennaro
[Abstract] [Purchase Article]


Intermittent and Long-Term Use of Sedative Hypnotics Pp. 3456-3465
M. Perlis, P. Gehrman and D. Riemann
[Abstract] [Purchase Article]


Cardiovascular Morbidity and Mortality in Obstructive Sleep Apnea Pp. 3466-3473
P. Lavie and L. Lavie
[Abstract] [Purchase Article]


Neurobiology of Sleep Fragmentation: Cortical and Autonomic Markers of Sleep Disorders Pp. 3474-3480
S. Janackova and E. Sforza
[Abstract] [Purchase Article]




Abstracts


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Editorial: Neurobiology Wakes Up for Research on Sleep Disorders: An Integration of Basic and Clinical Research

On average we spend one third of our lives asleep, and we have little idea why. Similarly, despite the high prevalence of sleep disorders and their negative impact on waking functions and life quality, which significantly contribute to healthcare costs, most basic pathophysiological mechanisms are still unknown.

Knowledge accumulated in recent years about the identification of susceptibility genetic determinants, about biochemical mechanisms of sleep regulatory substances, and about initiation of sleep at circumscribed local neural networks level, has led to a new integration between findings of basic and clinical research. Hopefully, these will also have an impact on a better understanding of pathogenesis of sleep disorders, on an assessment of the risk for diseases, and on new drug development to treat and to prevent the underlying conditions.

In basic sleep research, the consolidated evidence of a robust and reliable marker of sleep need, the amount of electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (NREM) sleep, provided the best working model of sleep regulation [1]. According to the 2-process model of sleep regulation, SWA depends on the duration of previous wakefulness, and represents a marker of NREM sleep intensity; manipulations of sleep pressure lead to clear homeostatic recovery processes [1, 2]. Recent research, however, has shown that these recovery processes are mainly local and do not involve the entire cerebral cortex [3, 4]. Furthermore, experience-dependent plasticity in specific neural circuits during wakefulness induces localized changes in SWA during subsequent sleep [5, 6], supporting the idea that sleep regulation is a locally regulated process. This emerging notion of sleep as a local process could help to shift the focus of clinical sleep research from structural to functional characteristics of sleep disorders. We strongly believe that the extension of the theoretical framework of “local sleep” to the study of sleep disorders has a great heuristic potential. Likewise, the growing body of evidence pointing to (a) genetic determinants of normal and pathological sleep, in humans and in animals [7], which may be also responsible for the large individual differences in normal sleep [8], are candidates for a similar heuristic potential.

Thanks to Prof Banks invitation to edit a special issue of Current Pharmaceutical Design, I was able to assemble an outstanding panel of experts, each addressing a different segment of the wide spectrum of neurobiological mechanisms of sleep disorders.

This issue consists of 9 carefully selected peer-reviewed articles prepared by some of the leading experts in the field of sleep and its disorders. I trust this issue will be of great interest to the readers of Current Pharmaceutical Design and will expose them to the exciting field of sleep and its disorders.

Drs. Dauvilliers and Tafti [8] reviewed the role of genetic basis in the key sleep disorders. Recent linkage, genome-wide and candidate gene association studies resulted in the identification of gene mutations, gene localizations, or evidence for susceptibility genes and/or loci in several sleep disorders. These identified susceptibility genetic determinants will provide clues to a better understanding of the pathogenesis of sleep disorders, to assess not only the risk for diseases but also to develop therapeutic agents for treating and preventing the underlying conditions. With similar aims, Dr. Landolt’s [9] review focused on the molecular mechanisms underlying the trait-like, inter-individual variation in sleep regulation, with a special attention to the role of adenosine in sleep homeostasis and its implications for the neurobiology of sleep-wake disorders and their pharmacological treatment. This is followed by Dr. Krueger’s [10] that shows that sleep is a local use-dependent process influenced by cytokines and their effectors’ molecules such as nitric oxide, prostaglandins and adenosine. The article opens a new avenue to explain physiological sleep, and sleep disturbances within the context of the brain cytokine network.

Dr. Nofzinger [11] reviews the functional neuroimaging findings in patients with sleep disorders, and studies addressing the pharmacology of sleep disorders. These findings may be helpful in clarifying pathophysiology, aiding in differential diagnosis, in assessing treatment response, guiding new drug development, and monitoring treatment response.

Little is known about the neural basis of sleep disturbances or EEG abnormalities in neurodegenerative disorders. For this reason, Drs. Gagnon et al. [12] present sleep disturbances and their underlying pathophysiology in three categories of neurodegenerative disorders namely tauopathies, synucleinopathies, and prion-related diseases. The evaluation of sleep disturbances in these pathologies may be useful to make a diagnosis and to assess the efficacy of pharmacotherapy. Furthermore, sleep disturbances may serve as a groundwork to study the efficacy of neuroprotective agents to prevent or delay the development of the full-blown neurodegenerative disorder, since sleep disruption may occur early in the course of neurodegeneration.

Drs. Marzano et al. [13] discuss the use of quantitative EEG analysis in the investigation on the neurophysiological characteristics of insomnia and on the effects of non-pharmacological and pharmacological interventions. The article underlines the several methodological limitations that make it difficult to reach an unequivocal interpretation of the main findings in the field. Their extension of recent findings from basic sleep research to the study of insomnia could provide new insights on the underlying pathophysiological mechanisms. Within the framework of the treatment of chronic insomnia, Drs. Perlis et al. [14] critically evaluate the evidence for intermittent and long-term treatment with hypnotics. They discuss future prospects for intermittent dosing (with or without placebos), suggesting that the use of placebos in an intermittent dosing regimen presages the use of partial reinforcement principles to enhance the safety and efficacy of the approach.

Drs. Lavie and Lavie [15] focus their review on the pathophysiology of cardiovascular morbidity in sleep apnea, on the long-term outcomes of the sleep apnoea syndrome, on the effects of treatment, and on the underlying mechanisms linking it with pathophysiological mechanisms responsible for cardiovascular morbidity and mortality. The clinical significance of sleep fragmentation and altered sleep continuity on daytime functioning, cardiovascular consequences and cognitive sequelae is reviewed in the ninth article by Drs. Janackova and Sforza [16].


References

[1] Borbély AA, Achermann P. Concepts and models of sleep regulation: an overview. J Sleep Res 1992; 1: 63-79.

[2] Tobler I, Franken P, Trachsel L, Borbély AA. Models of sleep regulation in mammals. J Sleep Res 1992; 1: 125-7.

[3] Oleksenko AI, Mukhameto LM, Polyakova IG, Supin AY, Kovalzon VM. Unihemispheric sleep deprivation in bottlenose dolphins. J Sleep Res 1992; 1: 40-4.

[4] Ferrara M, De Gennaro L, Curcio G, Cristiani R, Corvasce C, Bertini M. Regional differences of the human sleep electroencephalogram in response to selective slow-wave sleep deprivation. Cereb Cortex 2002; 12: 737-48.

[5] Huber R, Esser SK, Ferrarelli F, Massimini M, Peterson MJ, Tononi G. TMS-induced cortical potentiation during wakefulness locally increases slow wave activity during sleep. PLoS ONE 2007; 2 (3): e276 doi:10.1371/journal.pone.
0000276.

[6] De Gennaro L, Fratello F, Marzano C, Moroni F, Curcio G, Tempesta D, et al. Cortical plasticity induced by transcranial magnetic stimulation (TMS) during wakefulness affects EEG activity during sleep. PLoS ONE 2008; 3(6): e2483 doi:10.1371/journal.pone.0002483.

[7] Dauvilliers Y, Maret S, Tafti M. Genetics of normal and pathological sleep in humans. Sleep Med Rev 2005; 9: 91-100.

[8] Dauvilliers Y, Tafti M. The genetic basis of sleep disorders. Curr Pharm Des 2008; 14(32): 3386-3395.

[9] Landolt H-P. Genotype-dependent differences in sleep vigilance, and response to stimulants. Curr Pharm Des 2008; 14(32): 3396-3407.

[10] Krueger JM. The role of cytokines in sleep regulation. Curr Pharm Des 2008; 14(32): 3408-3416.

[11] Nofzinger EA. Functional neuroimaging of sleep disorders. Curr Pharm Des 2008; 14(32): 3417-3429.

[12] Gagnon J-F, Petit D, Latreille V, Montplaisir J. Neurobiology of sleep disturbances in neurodegenerative disorders. Curr Pharm Des 2008; 14(32): 3430-3445.

[13] Marzano C, Ferrara M, Sforza E, De Gennaro L. Quantitative electroencephalogram (EEG) in insomnia: a new window on pathophysiological mechanisms. Curr Pharm Des 2008; 14(32): 3446-3455.

[14] Perlis M, Gehrman P, Riemann G. Intermittent and long-term use of sedative hypnotics. Curr Pharm Des 2008; 14(32): 3456-3465.

[15] Lavie P, Lavie L. Cardiovascular morbidity and mortality in obstructive sleep apnea. Curr Pharm Des 2008; 14(32): 3466-3473.

[16] Janackova S., Sforza E. Neurobiology of sleep fragmentation: cortical and autonomic markers of sleep disorders. Curr Pharm Des 2008; 14(32): 3474-3480.


Luigi De Gennaro
Department of Psychology
University of Rome “Sapienza”
Via dei Marsi, 78
00185 Rome
Italy
E-mail: luigi.degennaro@uniroma1.it


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The Genetic Basis of Sleep Disorders
Y. Dauvilliers and M. Tafti

The contribution of genes, environment and gene-environment interactions to sleep disorders is increasingly recognized. Well-documented familial and twin sleep disorder studies suggest an important influence of genetic factors. However, only few sleep disorders have an established genetic basis including four rare diseases that may result from a single gene mutation: fatal familial insomnia, familial advanced sleep-phase syndrome, chronic primary insomnia, and narcolepsy with cataplexy. However, most sleep disorders are complex in terms of their genetic susceptibility together with the variable expressivity of the phenotype even within a same family. Recent linkage, genome-wide and candidate gene association studies resulted in the identification of gene mutations, gene localizations, or evidence for susceptibility genes and/or loci in several sleep disorders. Molecular techniques including mainly genome-wide linkage and association studies are further required to identify the contribution of new genes. These identified susceptibility genetic determinants will provide clues to better understand pathogenesis of sleep disorders, to assess the risk for diseases and also to find new drug targets to treat and to prevent the underlying conditions. We reviewed here the role of genetic basis in most of key sleep disorders.


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Genotype-Dependent Differences in Sleep, Vigilance, and Response to Stimulants
H.-P. Landolt

To better understand the neurobiology of sleep disorders, detailed understanding of circadian and homeostatic sleep-wake regulation in healthy volunteers is mandatory. Sleep physiology and the repercussions of experimentally-induced sleep deprivation on sleep and waking electroencephalogram (EEG), vigilance and subjective state are highly variable, even in healthy individuals. Accumulating evidence suggests that many aspects of normal sleep-wake regulation are at least in part genetically controlled. Current heritability estimates of sleep phenotypes vary between approximately 20-40 % for habitual sleep duration, to over 90 % for the spectral characteristics of the EEG in nonREM sleep. The molecular mechanisms underlying the trait-like, inter-individual variation are virtually unknown, and the human genetics of normal sleep is only at the beginning of being explored. The first studies identified distinct polymorphisms in genes contributing to the endogenous circadian clock and neurochemical systems previously implicated in sleep-wake regulation, to modulate sleep architecture and sleep EEG, vulnerability to sleep loss, and subjective and objective effects of caffeine on sleep. These insights are reviewed here. They disclose molecular mechanisms contributing to normal sleep-wake regulation in humans, and have potentially important implications for the neurobiology of sleep-wake disorders and their pharmacological treatment.


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The Role of Cytokines in Sleep Regulation
J.M. Krueger

Interleukin-1 beta (IL1) and tumor necrosis factor alpha (TNF) promote non-rapid eye movement sleep under physiological and inflammatory conditions. Additional cytokines are also likely involved but evidence is insufficient to conclude that they are sleep regulatory substances. Many of the symptoms induced by sleep loss, e.g. sleepiness, fatigue, poor cognition, enhanced sensitivity to pain, can be elicited by injection of exogenous IL1 or TNF. We propose that ATP, released during neurotransmission, acting via purine P2 receptors on glia releases IL1 and TNF. This mechanism may provide the means by which the brain keeps track of prior usage history. IL1 and TNF in turn act on neurons to change their intrinsic properties and thereby change input-output properties (i.e. state shift) of the local network involved. Direct evidence indicates that cortical columns oscillate between states, one of which shares properties with organism sleep. We conclude that sleep is a local use-dependent process influenced by cytokines and their effector molecules such as nitric ox-ide, prostaglandins and adenosine.


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Functional Neuroimaging of Sleep Disorders
E.A. Nofzinger

Functional neuroimaging methods provide a means to understand brain function in patients with sleep disorders. This paper summarizes functional neuroimaging findings in sleep disorders patients, and studies addressing the pharmacology of sleep and sleep disorders. Areas in which functional neuroimaging methods may be helpful in sleep medicine, and in which future development is advised, include: 1) clarification of pathophysiology; 2) aid in differential diagnosis; 3) assessment of treatment response; 4) guiding new drug development; and 5) monitoring treatment response.


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Neurobiology of Sleep Disturbances in Neurodegenerative Disorders
J.-F. Gagnon, D. Petit, V. Latreille and J. Montplaisir

This review presents sleep disturbances and their underlying pathophysiology in three categories of neurodegenerative disorders namely tauopathies, synucleinopathies, and Huntington’s disease (HD) and prion-related diseases. Sleep abnormalities are a major and early feature of neurodegenerative disorders, especially for synucleinopathies, HD and prion-related diseases, in which the sleep-related brainstem regions are severely altered and impaired sooner than in most of the tauopathies. In synucleinopathies, HD and prion-related diseases, specific sleep disturbances, different from those observed in tauopathies, are considered as core manifestations of the disease and in some cases, as preclinical signs. For this reason, the evaluation of sleep components in these neurodegenerative disorders may be useful to make a diagnosis and to assess the efficacy of pharmacotherapy. Since sleep disruption may occur early in the course of neurodegeneration, sleep disturbance may serve as groundwork to study the efficacy of neuroprotective agents to prevent or delay the development of a full-blown neurodegenerative disorder. The cause of sleep disturbances in neurodegenerative disorders may be attributed to several factors, including age-related modifications, symptoms of the disease, comorbid conditions and the neurodegenerative process itself.


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Quantitative Electroencephalogram (EEG) in Insomnia: A New Window on Pathophysiological Mechanisms
C. Marzano, M. Ferrara, E. Sforza and L. De Gennaro

In the last two decades quantitative electroencephalogram (EEG) analysis has been widely used to investigate the neurophysiological characteristics of insomnia. These studies provided evidence in support of the hypothesis that primary insomnia is associated with hyperarousal of central nervous system and altered sleep homeostasis. However, we have here underlined that these results have intrinsic methodological problems, mainly related to constraints of standard assessment in clinical research. We have proposed that future studies should be performed on larger samples of drug-free patients, using within-subjects designs and longitudinally recording patients adapted to sleep laboratory. All these methodological improvements will allow to partial out the contribution of individual differences, pharmacological influences and first-night effects on EEG frequencies. Moreover, we have discussed the potential relevance of recent findings from basic research concerning local changes during physiological sleep, which could be extended to the study of insomnia. We have suggested that, if normal sleep exhibits specific regional characteristics, also disorders in initiating and maintaining sleep should be characterized by local changes. The extension of this theoretical framework to the study of insomnia could provide new insights on the underlying pathophysiological mechanisms. As a first step toward the integration of knowledge from basic and clinical research focused on local sleep changes, here we showed some preliminary data from sleep onset recordings of patients with paradoxical insomnia. This approach supports the heuristic potential of our proposal, pointing to a local functional impairment in the process of synchronization in insomniac patients compared to normal subjects, the former exhibiting more beta and less delta and sigma power on anterior scalp locations than the latter.


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Intermittent and Long-Term Use of Sedative Hypnotics
M. Perlis, P. Gehrman and D. Riemann

In this review, the context and evidence base for intermittent and long term dosing with hypnotics is critically evaluated. The context provided includes addressing two questions: “why has long term or maintenance therapy not been a standard for practice for the treatment of chronic insomnia?”; and “why is intermittent dosing thought to represent a potential solution for the problem of chronic insomnia?”. The data from the systematic review suggests, over all, that: 1) while intermittent dosing can be conducted without resulting in rebound insomnia on non-med nights, there is insufficient data to show that the strategy is equal, or superior, to nightly dosing on a long term basis; 2) long term therapy (up to 6 months) with intermittent or nightly dosing appears viable to the extent that clinical outcomes are stable over time and occur in the absence of dose escalation or increased adverse events. The discussion section of the review includes: an analysis of the future prospects for intermittent dosing (with or without placebos); the suggestion that the use of placebos in an intermittent dosing regimen presages the use of partial reinforcement principles to enhance the safety and efficacy of the approach; finally the discussion contains a challenge to re-think, from first principles, whether the underlying approach to the medical management of insomnia is rational. It is suggested that a more rational approach is possible and that medical therapy for insomnia needs to be re-assessed for it’s curative (vs palliative) potential.


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Cardiovascular Morbidity and Mortality in Obstructive Sleep Apnea
P. Lavie and L. Lavie

Obstructive sleep apnea syndrome (OSA) is a highly prevalent breathing disorder in sleep affecting at least 2-4% of the adult population. A large number of studies have demonstrated that OSA is an independent risk factor of cardiovascular morbidity and mortality. Sleep apnea was shown to be associated with hypertension, ischemic heart disease, stroke, pulmonary hypertension, cardiac arrhythmia, and cardiovascular mortality. The association of OSA with subclinical signs of cardiovascular morbidity such as endothelial dysfunction and vasculature remodeling on the one hand, and with oxidative stress, activation of inflammatory pathways and increased leukocytes/endothelial cells adhesion on the other, implicate that atherogenesis plays a major role in cardiovascular sequela of OSA. Results demonstrating that effective treatment of the syndrome can abort and even reverse the atherogenic process suggest that OSA should be diagnosed and treated as early as possible in order to prevent cardiovascular sequlea.


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Neurobiology of Sleep Fragmentation: Cortical and Autonomic Markers of Sleep Disorders
S. Janackova and E. Sforza

New insights into the physiopathological correlates of arousal and sleep fragmentation have recently been gained through experimental and clinical studies in healthy individuals and in patients with sleep disorders. The development of new analyses of autonomic system during sleep, has enriched the knowledge of sleep fragmentation derived from electroencephalographic analysis and has made possible the characterization of other phasic events arising from sleep, such as autonomic arousals. All of these studies provide evidence in support of the hypothesis that autonomic activations without cortical involvement are an epiphenomena of sleep fragmentation and altered sleep continuity, similar to that induced by cortical activation. This review begins by describing the latest findings on type of arousal response, with regards to the effect of arousing stimuli on the brain and the autonomic system. It then focuses on the hotly debated issue on experimental and clinical physiopathology of the arousals without cortical activation, highlighting the results of novel studies on the neural substrates mediating these response. Finally, we address the current question on clinical significance of sleep fragmentation to understand if arousal per se, cortical or autonomic, has an impact on daytime functioning, cardiovascular consequences and cognitive sequelae.