Numerious studies conducted over the last 40 years assessing different physiological domains including autonomic nervous system status, whole body and brain metabolic rate, stress and immune system activity suggest that (1) insomnia is a disorder of physiologic hyperarousal present throughout 24-hour sleep-wake cycle, and (2) insomnia and sleep loss are two distinct states. Central nervous system hyperarousal, either as pre-existing and/or induced by psychiatric pathology and worsened by stressful events, as well as aging- and menopause-related physiological decline of sleep mechanisms appears to be at the core of this common sleep disorder. Finally, there is emerging evidence that the levels of physiologic hyperarousal are directly related to the degree of polysomnographically documented sleep disturbance in insomnia patients, suggesting that objective measures of sleep duration in insomnia may be a useful marker of the medical severity of the disorder.
Many complex behavioral phenomena such as sleep can not be explained without multidisciplinary experimental approach, and complementay approaches in the animal models "in vivo" and human studies. Electrophysiological, pharmacological, anatomical and immunohistochemical techniques, and particularly stereotaxically guided local nanovolume microinjection technique, enable us to selectively stimulate and lesion the brain nuclei or their specific neuronal subpopulation, and to reslove the mechanisms of certain brain structure regulatory role, and its afferent-efferent connectivity within the brain. Local stereotaxically guided nanovolume microinjection technique enable us to investigate in animals the brain nulcei functional topography with a resolution of < or = 10 microM, and at a level of 300 microM of effective radius within the brain tissue "in vivo". The advantage of local glutamate or DL- homocysteic acid microinjection stimulation or local excitotoxic (glutamate, ibotenic acid, IgG saporin) microinjection lesion over electrical stimulation/lesion of the same neuronal population are that they reduces the likelihood of activation/lesion of fibers of passage. Much of our knowledge of the sleep neuronal substrates is based on animal studies primarly in cat and rat. Selective pharmacological stimulation of the pedunculopontine tegmentum (PPT) in freely moving rat, using glutamate microinjection, proved that excitation of its cholinergic part is necessary for induction of wakefulness or REM (Datta S, 2001). Local nanovolume glutamate microinjection into PPT of anesthetized rats (Saponjić et al, 2003a) additionally evidenced P-wave and respiratory regulating neuronal subpopulation within the cholinergic compartment of PPT (apneogenic neuronal zone). Local microinjection of serotonin and noradrenaline into cholinergic PPT apneogenic zone evidenced their opposed impact through PPT on breathing, in contrast to their convergent regulatory role in behavioral state control (Saponjić et al., 2005a). Also, selective pharmacological stimulation by microinjection of DL-homocysteic acid defined four neuronal micro-circuitry approximately 500 microm in lenght of breathing-related neurons within the ventral respiratory group of medulla oblongata, which when stimulated produce different effects on respiratory rate, rhythm and amplitude, and on blood pressure. This study was the first high resolution study in order to understand anatomical and functional neuronal system organization (Monnier et al., 2003). Recently, local glutamate microinjection stimulation technique enabled detailed functional topography of respiratory, cardiovascular and pontine-wave responses within the PPT (Topchiy et al., 2010). Discovery of "flip-flop" switch for REM sleep control is based on the experiments in rats using local stereotaxically guided microinjection of excitotoxins (ibotenic acid, IgG saporin), and the anterograde and retrograde tracers for selective lesion, and identifying "REM-off" and "REM- on" regions and their afferent-efferent connections, and for identifying pathways for REM atonia and REM EEG activation (Lu et al., 2006). Recently, selective lesion of SLD part of "REM-on" region in rat established an animal model of RBD, as well as a selective ibotenic acid lesion of PC part of "REM-on" region abolished theta during REM (Lu et al., 200; Anaclet et al., 2010). Selective ablation targeted to pre-Bötzinger complex neurons of ventrolateral respiratory group of medulla in rat induced REM related respiratory disorder up to 10 days, when this respiratory disorder became spreaded to all sleep phases, and even during wakefulness, due to long-lasting intermitent hypoxia, and an increase of the threshold for hypoxia/hypercapnea induced arousal response (McKay et al., 2005). Human development, maturation, healthy aging and many neurological diseases are associated with profound changes in sleep/wake states distribution and with variety of the sleep-related behavioral disorders. Sleep and sleep-related respiratory disorders (insomnia, hypersomnia, parasomnias, excessive nocturnal motor activity, circadian sleep-wake rhythm disturbances, respiratory dysrhythmias, RBD) are very frequently unnoticed in patients with neurodegenerative diseases (Boeve et al., 2007; Whitwell et al., 2007). Alzheimer's and Parkinson's disease (AD, PD) are the most common neurodegenerative diseases, with prevalence of 0.5-1%; increasing to 1-3% for Parkinson, and up to 50% for Alzheimer's disease in ages over 69 (Nussbaum and Christopher, 2003). In spite of a long knowledge of their clinical description and brain pathology (lesions of the NB cholinergic neurons in basal forebrain, dopaminergic neurons in substantia nigra, etc.), they remain incurable with only limited success in temporal amelioration of their symptoms. Clinical symptoms first appear at 65-69 years on average, but there are indications that subclinical features may start many years earlier. Patients with REM-sleep behavior disorder (RBD) face close to a 20% 5-year risk of developing PD or dementia, and that risk rises to more than 40% after 10 years, and exceeds 50% after 12 years. Human studies evidenced that sleep/wake cycle disturbance, as no cognitive symptom of dementia, precedes on average 3 years before the clinical diagnosis of the AD (Simic et al., 2009), and that RBD, precedes as symptom the onset of motor and cognitive disturbances by years or decades. AD and PD involve the selective loss of specific neuronal populations within the brain. RBD in those patients reflects an underlying synucleinopathy, with presence of the alpha-synuclein protein pathology within the REM sleep-related regulatory structures of the dorsal midbrain and pons at the onset of disease, with ascending pattern of neurodegeneration progression from brainstem to basal areas of the brain (Whitwell et al., 2007; Simic et al., 2009: Raggi and Ferri, 2010). On the base of hypothesis that basal forebrain cholinergic system plays an important role in the etiology of the most common neurodegenerative diseases of elderly (AD, PD), the lesion of the nucleus basalis in rat presents the most utilized "in vivo" animal model to study the disorders of cortical cholinergic innervation, and its impact on higher central nervous system functions. Our knowledge of the neural substrates for sleep/wake states and sleep-related behavior disorders regulation in health and the diseases, over more than 50 years of sleep research, is based on animal models, pharmacotherapy, central nervous system lesions, and the neuropathological studies in humans. Today we have many complementary animal models of human sleep pathology, and further work in fundamental multidisciplinary and clinical research between sleep and neurodegenerative disease investigators is promising to enable us understand normal and abnormal sleep, and may provide new insights into preventive or disease-altering approaches for therapy. Obviously counseling and prevention of AD or PD would be highly enriched by the development of a practical, sensitive and reliable methodology of detecting those patients with RBD, or other sleep disorders, who are at risk for developing AD or PD.
The goals of OSAS therapy are to improve daytime symptoms especially excessive sleepiness, prevent neurocognitve, metabolic and cardiovascular consequences and quality of life in patients with sleep apnea. A variety of therapy exist starting from general measures that include weight reduction, change in life style, postional therapy, oral devices, upper airway surgery and pharmacotherapy. However, CPAP has been demonstrated to be the most important and highly effective therapy in these disorders. CPAP therapy dramatically improves symptoms and decreases cadriovascular and metabolic consequences stoping the occurence of the apneas. Hoewer, not all patients tolerate CPAP especially patients with milder forms of the disease. The individualised approach wich pay attention to different phenotypes and genotype could select patients for selecitively acting treatment modalities such us mandibular advancement devices and electical stimulation of the upper airway muscles.
Evolutionary approach to the interpretation of sleep function seems more promising than the contemporary theories which, in nature, are more utilitarian. The basis of biological approach rest first on the existance of neuronal networks opearting in most primitive (even few cells) organisms. Under an evolutionary pressure, multifunctional neuronal networks developed in response to the need to elaborate more complex tasks relevant to the vital functioning of more complex organisms. As an answer to the need to process the sonsory input a state of calm wakefulness, as a precursor state to the primitive sleep, developed. At a certain point of evolution, coincident with the development of focal vision, the sonsory input relevant to the well-being of the organisms overcame the processing capacity of the existant neuronal networks. A new state of vigilance developed corresponding to the state of primitive sleep in which animals withdrew to the security of an ecological niche. With the advance of focal vision and homeothermy a novel state of vigilance corresponding to 'sleep' developed. The enormous amounts of sensory (specially visual) input relevant for the animal, were moved for processing to the newly developed vigilance state of sleep. This sleep state was able to process memory and perform synaptic strengthening within neuronal networks, without coming into collision with the more vital activities performed at wakefulness (like surveillance of the surrounding, flee reaction, preying, etc). Sleep developed in more complex and higher organisms as an answer to the evolutionary pressures to process the sensory input which would otherwise interfere with the processing capacities of the multifunctional neuronal networks in wakefulness.
The common feature that characterized humoral theories of sleep is the production and accumulation of certain substances, usually end-products of metabolism, either in the tissues, in general, or in certain organs, such as the brain. When a definite concentration of such substances has been reached, the activity of the brain is depressed either directly, or through indirect influences, like vasoconstriction or asphyxia. The gradual removal of these substances during sleep leads to a return to the waking state. Humoral sleep theories were popular in the twentieth century. However, none of them lasted for a long time since either their authors or other investigators were not able to repeat them. Thus, this brief review mentions only a few of them. Today, humoral sleep theories are only of historic interest to sleep researchers and illustrate the creativity and the rich imagination of our predecessors.
One of the most important fields in sleep medicine is that of respiratory disorders in sleep. There was a steady progress in a development of new diagnostic methods and procedures, particularly after the introduction of portable apnea screening devices. The review provides update on techniques and procedures in respect to the diagnosis of sleep apnoea. Current trends are discussed, including the increasing role of portable devices and at-home monitoring in the screening and diagnostic process. A comparison between the procedures is discussed, as well as the polysomnographic examples of different types of studies (Type 1 to Type 4, attended v. non-attended).
In the 20th century, the prevalence of obesity has been increasing worldwide at an alarming rate and it is followed by an increase in the diseases for which obesity is major risk factor, like metabolic syndrome, diabetes type 2 and hypertension. These facts has been resulting in explosion of investigation devoted to explanation of pathogenetic mechanisms of this serious social and medical problems with the main idea to find adequate way of prevention as well as of treatment. Together with the observed epidemy of obesity and Type 2 diabetes, it was found parallel tendency for sleep curtailment, that was confirmed in numerous epidemiological studies, that coincide with its beginning and progress with this two epidemies. This facts lead to investigations with the idea to try to explaine possible mechanisms of the association between sleep curtailment, obesity, type 2 diabetes, metabolic syndrome and polycistic ovary syndrome. Having in mind that insulin resistance is one of the fundamental pathogenetic mechanism in these disorders, numerous studies were done with the aim to explain association between sleep curtailment and insulin resistance in obesity, Type 2 diabetes, metabolic syndrome and polycistic ovary syndrome. It was demonstrated that sleep curtailment may affect energy homeostasis of human organism with the effects on body weight increase through three different ways: appetite increase, prolongation of time for food intake and through decrease of energy expenditure. There are several postulated mechanism for the effect of sleep curtailment on development of insulin resistance as well as for predisposition for Type 2 diabetes. Among possible mechanism are included: increase of sympathetic neuronal acitvity, decreased cerebral utilisation of glucose, increase in evening cortisol values, growth hormone increase and disorder of neuroendocrine control of appetite which increases the risk for getting the body weight. Metabolic systems are of particular interest in the discussion of possible mechanisms to account for elevated inflammatory mediators during sleep deprivation, particularly because of the contributory role of insulin resistance in the development of impaired vascular function and increased inflammation.
The review presents current information on how pharmacological compounds influence sleep. Different mechanisms of action were discussed, including sedative and stimulative effect that different medications have on sleep, and also specific changes in sleep architecture, paroxismal events and other sleep parameters. There is a particular emphasis on conventional and alternative hypnotics, with a mention of older and less used medications.
Interrelationship between sleep and epilepsy presents in the best way the delicate konjuction of physiologic and pathologic mechanisms underlying both of the states. In the II century it was Galen who pointed to the detrimental effect of sleep deprivation on the frequency of epileptic attacks. This empiric formulation is important even today in the counceling of patients with epilepsy. The research of the sleep process generated better understanding of the basic mechanisms of epilepsies. Sleep deprivation worsens the control of epileptic attacks which in turn destroy sleep structure and impede the daily functioning of the epileptic patients.
To review the numerous works concerning sleep and epilepsy, this review considers the effects of sleep, firstly on seizures and secondly on paroxysmal interictal EEG activity (PA), in the different types of epilepsy according to the International League against Epilepsy classification. Apart from the exceptions of the definite nocturnal preponderance of seizures in idiopathic rolandic epilepsy and of the mostly nocturnal occurrence of seizures in some types of familial or sporadic frontallobe epilepsy, assessing a seizure according to the time of day it occurs is of no diagnostic or predictive value. In generalised idiopathic epilepsy, as in partial symptomatic or cryptogenic epilepsy, only about 20% of the patients had a sleep increase in PA. This percentage is higher (75%) in idiopathic partial epilepsy. Stereoelectroencephalography demonstrates a relative stability of spiking within the fouus across the states of vigilance and an increase in transmitted discharges during stages 3 and 4. In the Landau and Kleffner syndrome, as in the syndromes of continuous spike-waves during sleep, there is a huge, unexplained increase in PA during sleep. The neuropsychological consequences of this PA have some relationship with their localisation and the patient’s age at the time of occurrence. Sleep PA has also been reported in several groups of non-epileptic subjects. As regards the effect of epilepsy on sleep, sleep may be lighter and abnormally discontinuous in the absence of seizures, particularly in temporallobe epilepsy.
The future of solving the problem of sleep apnea necessitates the systematic organization of activities that would include: 1) increase in the awareness of the significant prevalence of sleep apnea and its influence on health and economic burden in the population via media and educational campaign; 2) establishment of the work groups that will find the answers and set the scientific research according to the needs posed by the sleep diseases; 3) Check the existing and develop new diagnostic and therapeutic methods with special reference to home monitoring with the creation of the national research network which will connect researchers and their programs and research centers; 4) Organization at the national level of educational centers and laboratories that will adequately respond to the needs of the pathology present in the population.
Although majority of skeletal muscles displays reduced tonic activity during sleep it is well known that the body during sleep is not motionless. Studies from the beginning of the past century established that the contractions of the muscle groups and the movements of the body are the consequence of the influence of the afferent stimuli from periphery generated by the sleeper in an endeavor to ensure a better position of the body and a better sleep quality. The number of body movements represent the individual trait of the sleeper. Aside from the contractions of the large muscle groups, sleep can generate short lasting contractions of the distal muscles (fingers, muscles of the face) that could be detected at the beginning of the sleep process or in REM sleep. Though all these movements could be seen in healthy individuals, their existence may be a part of the disease and involuntary movements seen during the process of sleep, and then they differ from normal ones in their frequency, timing and distribution of the affected muscle groups.
Sleep represents organized complex behavior necessary and vital for the survival of the species. It is reversible, internally regulated and homeostatically controlled process. Sleep consists of two separate states designated as NREM and REM sleep. NREM sleep has four sleep states (1 through 4) easily defined by the PSG and EEG components. REM sleep consists of tonic and phasic components. The tonic component of REM sleep by default includes the duration while phasic component consists of clusters of rapid eye movement, muscle twitches and PGO activity. The two states of sleep differ fundamentally both from one another as well as from the state of wakefulness. NREM and REM sleep is organized in sleep cycles with a typical duration between 90 and 110 minutes. Approximately 4 to 6 cycles emerge during the night with the REM episodes being prolonged towards the morning. About 70-80% of sleep process belongs to NREM and 20-25% to REM sleep. Normal aging carries the reduction in slow high-voltage activity (delta sleep) while REM sleep is of the relatively constant duration. Overall, sleep in elderly is characterized by the increase in the number of sleep stage shifts, increase in the number of awakenings and a shift towards the superficial sleep stages.
Epidemiological studies indicate that sleep disturbances in general population are highly frequent. It is estimated that approximately 40 million people in the USA has some kind of problem with sleep. The most frequent sleep complaint is insomnia whose prevalence is around 50% some time in the life. Only a small part of this population refer their sleep problems to the medical doctor with the consequence that only a minority is adequately diagnosed and treated. Sleep problems may appear at any age, and the epidemiological studies indicate the increase of specific prevalence with advancing age, with a special increase in the adults. It is estimated that the prevalence of sleep problems in childhood and adolescence is present in 25-40%. Some of the problems are more frequent in the female population, although not as a rule. The best example for this is the observed prevalence of sleep apnea which is present in 24% of male and only 9% of female population. Sleep problems are often associated with other diseases such as psychiatric or kidney diseases (patients on hemodialysis). However, their frequency may increase in physiologic conditions such as pregnancy. Overall characteristic of sleep diseases is that they may compromise daily functioning by causing deficits in memory, decrease in concentration, depressive mood, irritability, decreased libido or erectile dysfunction, having as a consequence decrease in the quality of life.
High frequency of sleep disturbed breathing in adults is increasingly recognized. Obstructive sleep apnea, defined as the recurring obstruction of the upper airway is documented in 24% of adult males and 9% of females. The highest incidence is in the sixth decade. Snoring accompany 24% of middle aged man and 14% of females of the same age. Sleep apnea with the central origin, defined as the transient and recurrent cessation of breathing during sleep, is less frequent than obstructive sleep apnea. It can be identified in the wide spectrum of patients with medical, neurologic and neuromuscular diseases tightly connected with alveolar hypoventilation.
Parasomnias are defined as unpleasant and undesirable behavioral (in the sense of action) or experiential (in the sense of sensorial or perceptive) phenomena which overwhelmingly or exclusively happen during sleep. Former attitudes that parasomnias are closely related to psychiatric derangement are abandoned and newer polysomnographic research indicates that we are dealing with a number of totally different organically defined states, most of which are easy to diagnose and even cure. The frequency of parasomnias in population is much higher than so far supposed so that they are considered among the most frequent disturbance of the CNS. Another inglorious record tightly connected to parasomnias is that they belong to the most frequently undiagnosed or misdiagnosed diseases. Clinically the most important and intriguing of the parasomnias associated with REM sleep, is REM sleep behavior disorder (RBD). In the last few decades in the field of human and animal sleep, researchers have noticed that RBD represents the omen of the more complex degenerative disorders of the central nervous system--the synucleinopathies and tauopathies. RBD can precede these disorders for decades before the florid clinical picture becomes obvious.
Sleep disorders although relatively new multidisciplinary territory in the field of medicine, have rather well developed classification system and nosology owing to the constant work of the American Academy for Sleep Medicine as well as the European, Japanese and Latin-American societies for sleep research. This collaboration produced the International classification of Sleep Disorders (ICSD) that has recently met its second revision. At the same time the International Classification of Diseases of the World Health Organization gives codes and enables statistical elaboration of a large number of sleep diseases. Differences between these two systems exist reflecting the basic principle used in their work out.
