Medical Physiology Pdf Notes

[Sebasten Lizarraga]

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Sleep architecture refers to the basic structural organization of normal sleep. There are two types of sleep, non-rapid eye-movement (NREM) sleep and rapid eye-movement (REM) sleep. NREM sleep is divided into stages 1, 2, 3, and 4, representing a continuum of relative depth. Each has unique characteristics including variations in brain wave patterns, eye movements, and muscle tone. Sleep cycles and stages were uncovered with the use of electroencephalographic (EEG) recordings that trace the electrical patterns of brain activity (Loomis et al., 1937; Dement and Kleitman, 1957a).

Over the course of a period of sleep, NREM and REM sleep alternate cyclically (Figure 2-1). The function of alternations between these two types of sleep is not yet understood, but irregular cycling and/or absent sleep stages are associated with sleep disorders (Zepelin et al., 2005). For example, instead of entering sleep through NREM, as is typical, individuals with narcolepsy enter sleep directly into REM sleep (Carskadon and Rechtschaffen, 2005).

The four stages of NREM sleep are each associated with distinct brain activity and physiology. Figure 2-2 shows the EEG patterns characteristic of the four NREM stages. Other instruments are used to track characteristic changes in eye movement and muscle tone.

Stage 2 sleep lasts approximately 10 to 25 minutes in the initial cycle and lengthens with each successive cycle, eventually constituting between 45 to 55 percent of the total sleep episode. An individual in stage 2 sleep requires more intense stimuli than in stage 1 to awaken. Brain activity on an EEG shows relatively low-voltage, mixed-frequency activity characterized by the presence of sleep spindles and K-complexes (Figure 2-2). It is hypothesized that sleep spindles are important for memory consolidation. Individuals who learn a new task have a significantly higher density of sleep spindles than those in a control group (Gais et al., 2002).

Sleep stages 3 and 4 are collectively referred to as slow-wave sleep (SWS), most of which occurs during the first third of the night. Each has distinguishing characteristics. Stage 3 lasts only a few minutes and constitutes about 3 to 8 percent of sleep. The EEG shows increased high-voltage, slow-wave activity (Figure 2-2).

The last NREM stage is stage 4, which lasts approximately 20 to 40 minutes in the first cycle and makes up about 10 to 15 percent of sleep. The arousal threshold is highest for all NREM stages in stage 4. This stage is characterized by increased amounts of high-voltage, slow-wave activity on the EEG (Carskadon and Dement, 2005).

In addition to the physiological changes listed in Table 2-1, there are other body system changes that occur during sleep. Generally, these changes are well tolerated in healthy individuals, but they may compromise the sometimes fragile balance of individuals with vulnerable systems, such as those with cardiovascular diseases (Parker and Dunbar, 2005). Physiological changes also occur in the following systems:

The sleep-wake system is thought to be regulated by the interplay of two major processes, one that promotes sleep (process S) and one that maintains wakefulness (process C) (Gillette and Abbott, 2005). Process S is the homeostatic drive for sleep. The need for sleep (process S) accumulates across the day, peaks just before bedtime at night and dissipates throughout the night.

Sleep process S is regulated by neurons that shut down the arousal systems, thus allowing the brain to fall asleep. Many of these neurons are found in the preoptic area of the hypothalamus (Figure 2-3A). These neurons, containing molecules that inhibit neuronal communication, turn off the arousal systems during sleep. Loss of these nerve cells causes profound insomnia (Saper et al., 2005a,c). Inputs from other regions of the brain also greatly influence the sleep system. These include inputs from the lower brainstem that relay information about the state of the body (e.g., a full stomach is conducive to falling asleep), as well as from emotional and cognitive areas of the forebrain. In addition, as described further in the next section, there are inputs from the circadian system that allow the wake-sleep system to synchronize with the external day-night cycle, but also to override this cycle when it is necessitated by environmental needs.

The sleep-generating system also includes neurons in the pons that intermittently switch from NREM to REM sleep over the course of the night. These neurons send outputs to the lower brainstem and spinal cord that cause muscle atonia, REMs, and chaotic autonomic activity that characterize REM sleep. Other outputs are sent to the forebrain, including activation of the cholinergic pathways to the thalamus to activate the EEG.

Wakefulness is generated by an ascending arousal system from the brainstem that activates forebrain structures to maintain wakefulness (Figure 2-3B). This idea, originally put forward by Morruzzi and Magoun (1949), has more recently been refined (Jones, 2005a; Saper et al., 2005c). The main source for the ascending arousal influence includes two major pathways that originate in the upper brainstem. The first pathway, which takes origin from cholinergic neurons in the upper pons, activates parts of the thalamus that are responsible for maintaining transmission of sensory information to the cerebral cortex. The second pathway, which originates in cell groups in the upper brainstem that contain the monoamine neurotransmitters (norepinephrine, serotonin, dopamine, and histamine), enters the hypothalamus, rather than the thalamus, where it picks up inputs from nerve cells that contain peptides (orexin or hypocretin and melanin-concentrating hormone). These inputs then traverse the basal forebrain, where they pick up additional inputs from cells containing acetylcholine and gamma-aminobutyric acid. Ultimately, all of these inputs enter the cerebral cortex, where they diffusely activate the nerve cells and prepare them for the interpretation and analysis of incoming sensory information.

In mammals, two proteins, Clock and Bmal1, bind together and move into the nucleus of the cell, where they bind to specific sites in the DNA that activate specific genes (Figure 2-4). Among the genes that they activate are Period and Cryptochrome. The products of these genes also move back into the nucleus, where they disrupt the binding of Clock and Bmal1 to the DNA, thus inhibiting their own synthesis. This results in a rising and falling pattern of expression of the Period and Cryptochrome gene products with a periodicity that is very close to 24 hours.

Many other genes are also regulated by Clock and Bmal1, and these genes cycle in this way in many tissues in the body, giving rise to daily patterns of activity. These rhythmically expressed genes contribute to many aspects of cellular function, including glucose and lipid metabolism, signal transduction, secretion, oxidative metabolism, and many others, suggesting the importance of the circadian system in many central aspects of life.

The suprachiasmatic nucleus (SCN) is responsible for regulating circadian rhythms in all organs. It receives direct inputs from a class of nerve cells in the retina that act as brightness detectors, which can reset the clock genes in the SCN on a daily basis. The SCN then transmits to the rest of the brain and body signals that bring all of the daily cycles in synchrony with the external day-night cycle.

The main influence of the SCN on sleep is due to a series of relays through the dorsomedial nucleus of the hypothalamus, which signals to the wake-sleep systems to coordinate their activity with the day-night cycles. The SCN also coordinates cycles of feeding, locomotor activity, and hormones, such as corticosteroids (Chou et al., 2003). Under some conditions (e.g., limited food availability) when there are changes in the external temperature, or even under conditions of behavioral stress (e.g., the need to avoid a predator), animals must shift their daily cycles to survive. In such circumstances, the dorsomedial nucleus may shift to a new daily cycle, which can be completely out of phase with the SCN and the light-dark cycle, and its signals also shift the daily cycles of sleep, activity, feeding, and corticosteroid hormone secretion (Saper et al., 2005b,c).

Another major output of the SCN is to a pathway that controls the secretion of melatonin, a hormone produced by the pineal gland. Melatonin, which is mainly secreted at night, acts to further consolidate the circadian rhythms but has only limited effects directly on sleep.

Sleep architecture changes continuously and considerably with age. From infancy to adulthood, there are marked changes in how sleep is initiated and maintained, the percentage of time spent in each stage of sleep, and overall sleep efficiency (i.e., how successfully sleep is initiated and maintained). A general trend is that sleep efficiency declines with age (Figure 2-6). Although the consequences of decreased sleep efficiency are relatively well documented, the reasons are complex and poorly understood. Exami nation of sleep characteristics by age, however, allows a closer understanding of the function of sleep for human development and successful aging.

At birth, sleep timing is distributed evenly across day and night for the first few weeks, with no regular rhythm or concentration of sleeping and waking. Newborns sleep about 16 to 18 hours per day; however, it is discontinuous with the longest continuous sleep episode lasting only 2.5 to 4 hours (Adair and Bauchner, 1993; Roffwarg et al., 1966). Newborns have three types of sleep: quiet sleep (similar to NREM), active sleep (analogous to REM), and indeterminate sleep (Davis et al., 2004). Sleep onset occurs through REM, not NREM, and each sleep episode consists of only one or two cycles (Jenni and Carskadon, 2000; Davis et al., 2004). This distinctive sleep architecture occurs mostly because circadian rhythms have not yet been fully entrained (Davis et al., 2004).

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