**2. Sleep physiology and polysomnogram, physiopathology and symptomatology in sleep medicine**

#### **2.1 Sleep physiology and polysomnogram in sleep medicine**

Sleep is a physiological and behavioral process that an individual requires to carry out his daily functions. This process is completed in a regular and continuous manner every night. As a part of biological rhythm, human brain has a healthy functioning by differentiating dark and day hours of the day. From controlling hormone levels to muscle tone, from regulating pace of breathing to contents of our thought; sleep influences all bodily and mental functions. It is not surprising that sleep can make these changes happen in the body because sleep causes significant changes in the electrical activity of the brain as a whole [1]. Sleep characterizes itself by not responding to one's surroundings and by drifting away from perception; yet it is a reversible behavior. During 1940–1950, physiologists believed that sleep was initiated as a result of tiredness that developed during the day and by a slowing down in the activation of the fore brain from

**5**

*Sleep Physiology and Polysomnogram, Physiopathology and Symptomatology in Sleep Medicine*

weakening in the activation of the reticular activating system. Later, based on transection studies, brain stem was shown to be responsible for generating sleep especially studies in cats; where total sections performed on pontine tegmentum induce sleeplessness. Physiologist Nathaniel Kleitman was working at Chicago University and he discovered REM sleep together with his colleague Dement in 1959 leading to a revolution in the field of sleep medicine. Two colleagues demonstrated the nature of sleep and the relation of eye movements with sleep by recording spontaneous whole night sleep. During their observations, it was understood for the first time that sleep consisted of 90–120 minutes cycles, it first got deep and then became superficial, and that during this superficial stage rapid eye movements appeared and then sleep deepened once again. Through the same series of observations it was found that, during the first half of the night deep sleep was more frequent and that REM sleep constituted 20–25% of the total length of the sleep [2, 3]. Sleep has an important function in an individual and sleep deprivation for a couple of days can hinder an individual's cognitive and physical performance, general productivity and health. The vital role of sleep on homeostasis can be clearly demonstrated by the possible death of rats who suffer from sleep deprivation for 2–3 weeks. Despite the obvious importance of sleep, we still have limited information about why it is an obligatory part of life. Sleep has two main types of physiological effects: First, its effect on the nervous system itself and second its effects on other functional systems of the body. There is no doubt that the effects on the nervous system are important. Long lasting wakefulness generally leads to progressive impairments of thought processes and even to abnormal behavioral activities (thoughts are blurred, as the duration of wakefulness lengthens irritability and psychosis ensues). Therefore, sleep is considered to protect the normal order of brain activity by different means and to preserve the normal "balance" between the different functions of the central

In the regulation of wakefulness and sleep brain stem, hypothalamus, basal fore brain and their neurotransmitters all play a role. When we analyze *the neuroanatomy of wakefulness and sleep*, we mainly see that neurons activating wakefulness and sleep are located at pontis oralis, mesencephalic central tegmentum, posterior hypothalamus and midline brain stem, dorsolateral medulla reticular formation and anterior hypothalamic-preoptic fields at different concentrations and different localizations. *Brain stem and reticular formation* are important anatomic localizations. Wakefulness is managed by reticular activating system (RAS). RAS is localized in the pons and midbrain. RAS stimulates the cortex by ventral and dorsal tracts. Ventral tract stimulates the frontal parts of the brain through hypothalamus and subthalamus, dorsal tract stimulates the cortex through the nucleus groups in the thalamus. During wakefulness transmission of sensory information from thalamus is permitted through RAS control managed by thalamus. During sleep, the activity of RAS stops and the transmission of sensory information through thalamus is blocked and the stimulation of cortex is prevented. *Anatomic structures responsible for the hypothalamic control of sleep and wakefulness*: for wakefulness, stimuli originating from rostral pons and caudal midbrain regions reach paramedian midbrain in diencephalon and here the signals divide into two paths aiming to reach thalamus and hypothalamus. Main structures projecting to thalamus are PedunculoPontine Tegmental (PPT) and LateroDorsal Tegmental (LDT) nuclei

*DOI: http://dx.doi.org/10.5772/intechopen.82754*

nervous system [4, 14].

*2.1.1 Mechanisms of wakefulness and sleep*

#### *Sleep Physiology and Polysomnogram, Physiopathology and Symptomatology in Sleep Medicine DOI: http://dx.doi.org/10.5772/intechopen.82754*

weakening in the activation of the reticular activating system. Later, based on transection studies, brain stem was shown to be responsible for generating sleep especially studies in cats; where total sections performed on pontine tegmentum induce sleeplessness. Physiologist Nathaniel Kleitman was working at Chicago University and he discovered REM sleep together with his colleague Dement in 1959 leading to a revolution in the field of sleep medicine. Two colleagues demonstrated the nature of sleep and the relation of eye movements with sleep by recording spontaneous whole night sleep. During their observations, it was understood for the first time that sleep consisted of 90–120 minutes cycles, it first got deep and then became superficial, and that during this superficial stage rapid eye movements appeared and then sleep deepened once again. Through the same series of observations it was found that, during the first half of the night deep sleep was more frequent and that REM sleep constituted 20–25% of the total length of the sleep [2, 3]. Sleep has an important function in an individual and sleep deprivation for a couple of days can hinder an individual's cognitive and physical performance, general productivity and health. The vital role of sleep on homeostasis can be clearly demonstrated by the possible death of rats who suffer from sleep deprivation for 2–3 weeks. Despite the obvious importance of sleep, we still have limited information about why it is an obligatory part of life. Sleep has two main types of physiological effects: First, its effect on the nervous system itself and second its effects on other functional systems of the body. There is no doubt that the effects on the nervous system are important. Long lasting wakefulness generally leads to progressive impairments of thought processes and even to abnormal behavioral activities (thoughts are blurred, as the duration of wakefulness lengthens irritability and psychosis ensues). Therefore, sleep is considered to protect the normal order of brain activity by different means and to preserve the normal "balance" between the different functions of the central nervous system [4, 14].

## *2.1.1 Mechanisms of wakefulness and sleep*

In the regulation of wakefulness and sleep brain stem, hypothalamus, basal fore brain and their neurotransmitters all play a role. When we analyze *the neuroanatomy of wakefulness and sleep*, we mainly see that neurons activating wakefulness and sleep are located at pontis oralis, mesencephalic central tegmentum, posterior hypothalamus and midline brain stem, dorsolateral medulla reticular formation and anterior hypothalamic-preoptic fields at different concentrations and different localizations. *Brain stem and reticular formation* are important anatomic localizations. Wakefulness is managed by reticular activating system (RAS). RAS is localized in the pons and midbrain. RAS stimulates the cortex by ventral and dorsal tracts. Ventral tract stimulates the frontal parts of the brain through hypothalamus and subthalamus, dorsal tract stimulates the cortex through the nucleus groups in the thalamus. During wakefulness transmission of sensory information from thalamus is permitted through RAS control managed by thalamus. During sleep, the activity of RAS stops and the transmission of sensory information through thalamus is blocked and the stimulation of cortex is prevented. *Anatomic structures responsible for the hypothalamic control of sleep and wakefulness*: for wakefulness, stimuli originating from rostral pons and caudal midbrain regions reach paramedian midbrain in diencephalon and here the signals divide into two paths aiming to reach thalamus and hypothalamus. Main structures projecting to thalamus are PedunculoPontine Tegmental (PPT) and LateroDorsal Tegmental (LDT) nuclei

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

and as outpatient, it is the most basic electrophysiological signal recording in which five waves (P, Q, R, S, and T) are interpreted. When all monitorization activities performed at the bedside of the patient are taken into consideration, recording electrophysiological signals with well-calibrated equipment and correct interpretation of the obtained results by doctors and healthcare staff seems to be at the crossroads of correct diagnosis, follow-up and treatment. In sleep monitorization, electrophysiological signal recordings are performed by multiple electrodes and provide us with important clinical information. In fact, monitoring wakefulness as much as sleep is quite important in clinical practice; it helps to establish a correct diagnosis in clinical practice and sometimes provides the opportunity to have access to unsuspected information. If PSG could be used as frequently as ECG by well-trained medical doctors and healthcare personnel in sleep medicine, sleep health and sleep disorders of the individuals in the society could be understood much better. Therefore, health could be evaluated not only in wakefulness but also in sleep leading to a continuum. During its preliminary years, sleep related studies attracted the attention of physiologists and as time passed clinical information regarding sleep disorders increased significantly and the possibility to treat all these diseases brought the attention of clinicians into this field. For human physiology and especially for the central nervous system to continue its functioning; there needs to be a healthy interaction and an organism specific balance between wakefulness and sleep cycles. Sleep is a physiological need; a state where the response of the brain to environmental stimuli has stopped reversibly. The insufficiency or absence of this need negatively influences the interactions in the neuronal circuits and pathways that are responsible for the wakefulness of the brain. It is very well known that many functions of the organism change during sleep and different physiological mechanisms come into play during NREM and REM sleep. Diseases also show changes during sleep and during NREM and REM phases. Electrophysiological studies could assist in the understanding of basic mechanisms in neurological sciences. Electrophysiological methods and PSG that are geared to understand the nights as well as the days aim at not only establishing correct diagnosis and delineating pathophysiological mechanisms but also engaging in innovation and developing novel diagnostic and

**2. Sleep physiology and polysomnogram, physiopathology and** 

Sleep is a physiological and behavioral process that an individual requires to carry out his daily functions. This process is completed in a regular and continuous manner every night. As a part of biological rhythm, human brain has a healthy functioning by differentiating dark and day hours of the day. From controlling hormone levels to muscle tone, from regulating pace of breathing to contents of our thought; sleep influences all bodily and mental functions. It is not surprising that sleep can make these changes happen in the body because sleep causes significant changes in the electrical activity of the brain as a whole [1]. Sleep characterizes itself by not responding to one's surroundings and by drifting away from perception; yet it is a reversible behavior. During 1940–1950, physiologists believed that sleep was initiated as a result of tiredness that developed during the day and by a slowing down in the activation of the fore brain from

**2.1 Sleep physiology and polysomnogram in sleep medicine**

**4**

therapeutic methods.

**symptomatology in sleep medicine**

that are of cholinergic nature. The structure that initiates sleep is thought to be the ventrolateral preoptic nucleus (VLPO) located on the anterior part of the hypothalamus. VLPO nucleus suppresses the activities of brain stem, pons and locus coeruleus, dorsal raphe nucleus, laterodorsal tegmental pedunculopontine tegmental nucleus via GABA and galanin neurotransmitters. *Suprachiasmatic Nucleus (SCN)* is known as the light sensitive circadian pacemaker. Throughout daytime light stimulus is transmitted from retina to hypothalamus through neural pathways and results in secretion of melatonin from the pineal gland. It is an anatomical structure that has a central role in maintaining the day-night rhythm [3–5, 10]. Neurotransmitters controlling sleep and wakefulness can be listed as: "Glutamate, Acetylcholine, Histamine, Norepinephrine and GABA". Reticular activating system stimulates the cortex by using glutamate while ponto-mesencephalic tegmental neurons do the same job by using acetylcholine. Neurons at locus coeruleus use mostly norepinephrine, these extend from the brain stem to the cerebral cortex by including the fore brain, and they activate the stimulation of the cortex and contribute to maintaining sleep. Cholinergic neuronal network results in wakefulness in two types of cortexes: (1) It projects to laterodorsal tegmental and pedunculopontine tegmental nuclei, midline and intralaminar thalamic nuclei and to a lesser degree to lateral hypothalamus and basal for brain. (2) Cholinergic neuron group starts from the basal for brain and has a widespread projection to cortex. This pontomesencephalic neuron group is part of the ascending reticular activating system; they not only play a part in the activation during wakefulness but also are actively involved in paradoxical sleep. Glutamate is another excitatory neurotransmitter; it acts as the primary neurotransmitter of the ascending reticular activating system. Glutamate is found at a very high concentration at the brain stem reticular formation. This neurotransmitter plays an active role in the wakeful brain and is secreted from the cortical cells to a significant degree throughout wakefulness. During slow wave sleep "burst discharges" appear due to the activation of special glutamate receptors. Histamine also plays an important role in wakefulness. Neurons containing histamine are found in tuberomammillary nuclei and in posterior hypothalamus. Noradrenergic neurons (locus coeruleus), have diffuse projections in the brain that extend to the cortex. Histaminergic neurons are associated with cortical activation during wakefulness whereas they are shut down during REM sleep. To sleep there needs to be a shift from sympathetic regulation to parasympathetic regulation. Parasympathetic centers of significance are found in "solitary tract nucleus neurons, anterior hypothalamus and preoptic fields". Serotonergic raphe neurons facilitate the initiation of sleep while GABA-ergic neurons inhibit the activating system. These GABA-ergic neurons are selectively activated during slow wave sleep. As a result of this inhibition, brain stem, hypothalamus and nasal fore brain are suppressed and disfacilitation (inhibition) and hyperpolarization of thalamocortical system takes place. Thereby from the wakeful state where we see rapid, tonic discharges on EEG, the system shifts to sleep state we start recording sleep spindles and slow wave activity. Initiation and continuation of slow wave sleep is made possible by lengthening and strengthening the inhibition of the activating system with GABA-ergic system [1, 4–11].

#### *2.1.2 Normal sleep*

Sleep is a complex mix of physiological and behavioral processes. Typically, sleep takes place while the individual is in a horizontal position, immobile with closed eyes and when all other indicators point out to sleep. There are two

**7**

REM sleep [10, 11].

*2.1.3 Electrophysiological signal recordings of wakefulness and sleep*

During wakefulness electroencephalogram (EEG) reflects an active cerebral cortex engaged in perception and cognitive functions that shows relatively low voltage, high frequency and rapid activity. The discharge by a single neuron or a single nerve fiber can never be recorded from the scalp surface. Only when thousands even millions of neurons or fibers are simultaneously fired, electrical potentials pertaining to a single neuron or a single fiber can be recorded as this much of an electrical potential would suffice to make such a measurement from scalp surface [1]. When eyes are closed, several neurons show synchronous discharges at a frequency of 12 per second constituting alpha waves. When the eyes are opened afterwards, the activity of the brain increases to a greater degree; but the synchronicity of the signals decrease which leads to the canceling out of the brain waves. As a result of this, weak waves of higher but irregular frequency which are called beta waves appear. If the cortex does not have any connection with the thalamus, then alpha waves are not generated. Stimulation of non-specific reticular nuclei that surround thalamus and stimulation of diffuse nuclei that are located inside the thalamus result in the generation of waves in the thalamocortical system with a frequency of 8–13 per second which is the natural frequency for

*Sleep Physiology and Polysomnogram, Physiopathology and Symptomatology in Sleep Medicine*

distinct stages of sleep: The one with non-rapid eye movements (NREM) and the one with rapid eye movements (REM). These stages are differentiated from one another and from wakefulness with clear margins. NREM sleep is classically divided into three stages based on EEG. EEG patterns usually consist of a mixture of synchronous sleep spindles, regular waves like K-complexes and high voltage slow waves. Based on the depth of sleep, there are three NREM stages, during the first two stages, wake-up thresholds are generally low and during the third stage it is at its highest or a body that can move and for a brain that can regulate, NREM sleep is a relatively inactive state going together with minimal and fragmental activity. On the other hand, during REM stage, the body is immobile because of muscular atonia, in EEG shows activation and episodic rapid eye movements can be observed. Sleep cycle starts with NREM (calm, synchronized sleep, deep wave sleep); nearly every 90 minutes NREM and REM (mobile, desynchronized, paradoxical sleep) follow one another. Slow wave sleep dominates the first one third of the night and is related to the duration of wakefulness before sleep. REM sleep dominates the last one-third portion of the night and is related to the circadian rhythm. First stage of sleep, namely NREM-1 lasts only for a couple of minutes after the initiation of sleep and it goes together with low wake-up threshold and provides the transition from wakefulness to sleep. NREM-2 stage of sleep is identified by the presence of sleep spindles and K-complexes on EEG. To wake-up, there needs to be a more intense stimulus during NREM-2 compared to NREM-1. If stimuli given during NREM-1 are administered during NREM-2, there is no arousal; but K-complexes will appear. NREM-2 gradually progresses to high voltage slow activity and transforms into NREM-3 stage. In a young healthy individual, the percentage of slow waves in sleep pattern should be 20–50%. NREM-REM cycles of sleep follow throughout the night by repetitions. First NREM-REM cycle lasts about 70–100 minutes, the second and further cycles last around 90–120 minutes. In young adults, during the first one third of the night deep sleep is predominantly seen during NREM stage, whereas during the last one-third portion of the night REM sleep dominates. Short wake-up periods usually happen when shifting to

*DOI: http://dx.doi.org/10.5772/intechopen.82754*

*Sleep Physiology and Polysomnogram, Physiopathology and Symptomatology in Sleep Medicine DOI: http://dx.doi.org/10.5772/intechopen.82754*

distinct stages of sleep: The one with non-rapid eye movements (NREM) and the one with rapid eye movements (REM). These stages are differentiated from one another and from wakefulness with clear margins. NREM sleep is classically divided into three stages based on EEG. EEG patterns usually consist of a mixture of synchronous sleep spindles, regular waves like K-complexes and high voltage slow waves. Based on the depth of sleep, there are three NREM stages, during the first two stages, wake-up thresholds are generally low and during the third stage it is at its highest or a body that can move and for a brain that can regulate, NREM sleep is a relatively inactive state going together with minimal and fragmental activity. On the other hand, during REM stage, the body is immobile because of muscular atonia, in EEG shows activation and episodic rapid eye movements can be observed. Sleep cycle starts with NREM (calm, synchronized sleep, deep wave sleep); nearly every 90 minutes NREM and REM (mobile, desynchronized, paradoxical sleep) follow one another. Slow wave sleep dominates the first one third of the night and is related to the duration of wakefulness before sleep. REM sleep dominates the last one-third portion of the night and is related to the circadian rhythm. First stage of sleep, namely NREM-1 lasts only for a couple of minutes after the initiation of sleep and it goes together with low wake-up threshold and provides the transition from wakefulness to sleep. NREM-2 stage of sleep is identified by the presence of sleep spindles and K-complexes on EEG. To wake-up, there needs to be a more intense stimulus during NREM-2 compared to NREM-1. If stimuli given during NREM-1 are administered during NREM-2, there is no arousal; but K-complexes will appear. NREM-2 gradually progresses to high voltage slow activity and transforms into NREM-3 stage. In a young healthy individual, the percentage of slow waves in sleep pattern should be 20–50%. NREM-REM cycles of sleep follow throughout the night by repetitions. First NREM-REM cycle lasts about 70–100 minutes, the second and further cycles last around 90–120 minutes. In young adults, during the first one third of the night deep sleep is predominantly seen during NREM stage, whereas during the last one-third portion of the night REM sleep dominates. Short wake-up periods usually happen when shifting to REM sleep [10, 11].

#### *2.1.3 Electrophysiological signal recordings of wakefulness and sleep*

During wakefulness electroencephalogram (EEG) reflects an active cerebral cortex engaged in perception and cognitive functions that shows relatively low voltage, high frequency and rapid activity. The discharge by a single neuron or a single nerve fiber can never be recorded from the scalp surface. Only when thousands even millions of neurons or fibers are simultaneously fired, electrical potentials pertaining to a single neuron or a single fiber can be recorded as this much of an electrical potential would suffice to make such a measurement from scalp surface [1]. When eyes are closed, several neurons show synchronous discharges at a frequency of 12 per second constituting alpha waves. When the eyes are opened afterwards, the activity of the brain increases to a greater degree; but the synchronicity of the signals decrease which leads to the canceling out of the brain waves. As a result of this, weak waves of higher but irregular frequency which are called beta waves appear. If the cortex does not have any connection with the thalamus, then alpha waves are not generated. Stimulation of non-specific reticular nuclei that surround thalamus and stimulation of diffuse nuclei that are located inside the thalamus result in the generation of waves in the thalamocortical system with a frequency of 8–13 per second which is the natural frequency for

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

that are of cholinergic nature. The structure that initiates sleep is thought to be the ventrolateral preoptic nucleus (VLPO) located on the anterior part of the hypothalamus. VLPO nucleus suppresses the activities of brain stem, pons and locus coeruleus, dorsal raphe nucleus, laterodorsal tegmental pedunculopontine tegmental nucleus via GABA and galanin neurotransmitters. *Suprachiasmatic Nucleus (SCN)* is known as the light sensitive circadian pacemaker. Throughout daytime light stimulus is transmitted from retina to hypothalamus through neural pathways and results in secretion of melatonin from the pineal gland. It is an anatomical structure that has a central role in maintaining the day-night rhythm [3–5, 10]. Neurotransmitters controlling sleep and wakefulness can be listed as: "Glutamate, Acetylcholine, Histamine, Norepinephrine and GABA". Reticular activating system stimulates the cortex by using glutamate while ponto-mesencephalic tegmental neurons do the same job by using acetylcholine. Neurons at locus coeruleus use mostly norepinephrine, these extend from the brain stem to the cerebral cortex by including the fore brain, and they activate the stimulation of the cortex and contribute to maintaining sleep. Cholinergic neuronal network results in wakefulness in two types of cortexes: (1) It projects to laterodorsal tegmental and pedunculopontine tegmental nuclei, midline and intralaminar thalamic nuclei and to a lesser degree to lateral hypothalamus and basal for brain. (2) Cholinergic neuron group starts from the basal for brain and has a widespread projection to cortex. This pontomesencephalic neuron group is part of the ascending reticular activating system; they not only play a part in the activation during wakefulness but also are actively involved in paradoxical sleep. Glutamate is another excitatory neurotransmitter; it acts as the primary neurotransmitter of the ascending reticular activating system. Glutamate is found at a very high concentration at the brain stem reticular formation. This neurotransmitter plays an active role in the wakeful brain and is secreted from the cortical cells to a significant degree throughout wakefulness. During slow wave sleep "burst discharges" appear due to the activation of special glutamate receptors. Histamine also plays an important role in wakefulness. Neurons containing histamine are found in tuberomammillary nuclei and in posterior hypothalamus. Noradrenergic neurons (locus coeruleus), have diffuse projections in the brain that extend to the cortex. Histaminergic neurons are associated with cortical activation during wakefulness whereas they are shut down during REM sleep. To sleep there needs to be a shift from sympathetic regulation to parasympathetic regulation. Parasympathetic centers of significance are found in "solitary tract nucleus neurons, anterior hypothalamus and preoptic fields". Serotonergic raphe neurons facilitate the initiation of sleep while GABA-ergic neurons inhibit the activating system. These GABA-ergic neurons are selectively activated during slow wave sleep. As a result of this inhibition, brain stem, hypothalamus and nasal fore brain are suppressed and disfacilitation (inhibition) and hyperpolarization of thalamocortical system takes place. Thereby from the wakeful state where we see rapid, tonic discharges on EEG, the system shifts to sleep state we start recording sleep spindles and slow wave activity. Initiation and continuation of slow wave sleep is made possible by lengthening and strengthening the inhibition of the activating system with

Sleep is a complex mix of physiological and behavioral processes. Typically,

sleep takes place while the individual is in a horizontal position, immobile with closed eyes and when all other indicators point out to sleep. There are two

**6**

GABA-ergic system [1, 4–11].

*2.1.2 Normal sleep*

alpha waves. That is why it is possible that alpha waves appear from the spontaneous negative feedback impulses in the diffuse thalamocortical system that also includes brain stem activating system. Delta waves include all the waves in EEG that have a frequency of less than 3–5 per second. They appear during very deep sleep, they also appear in the experimental animal studies where cortex has been separated from the thalamus with a subcortical section. Therefore, delta waves can appear in the cortex independent of the activities in the lower parts of the brain. Sleep spindles are produced by the thalamus. They appear as 12–15 Hz oscillations in between slow waves during NREM sleep in human EEGs. The production mechanism of these oscillations is related to the degree of hyperpolarization in thalamocortical cells. While shifting from wakefulness to sleep, the membrane potentials of thalamocortical cells are exposed to a progressive hyperpolarization, thus synaptic responsiveness decreases and sensory information transfer is prevented. When a sufficient level of hyperpolarization is achieved, we start seeing rhythmic bursting in nucleus reticularis neurons belonging to thalamus at a frequency interval which is in correlation with sleep spindle. Furthermore, slow wave oscillations due to membrane hyperpolarization also take place. It is accepted that sleep homeostasis is significantly affected by the size and characteristics of the sleep spindles that are formed [11–14].
