Normal Sleep

 Has your competent? doctor ever figured out a sleep protocol for you?

Back in 2006 , when I had my stroke, nurses were handing out sleeping pills like candy at 10pm. Is that part of your protocol?

Usually at 7am the vampires came into my quad to drain blood from one of the patients, waking everyone up. Is preventing that part of your protocol?

Normal Sleep 

Karl Doghramji, MD, FAASM, DFAPA; Paul P Doghramji, MD, FAAFP 

Reviewed on December 15, 2023

Introduction

Sleep comprises one third of our adult life. It is essential for normal functioning; without it, we experience memory lapses, have difficulty with concentration, experience mood alterations, become more prone to accidents, perform poorly at work, experience breaches in interpersonal relationships and develop more medical and psychiatric problems. Animals deprived of sleep will experience metabolic abnormalities and eventually die. Despite all of this information, however, we do not fully understand the whys of sleep.

Scientists have yet to determine how physical and psychological restorative processes are coordinated during sleep and why such a behaviorally disconnected state is necessary to accomplish these tasks. The clearance of beta-amyloid, a neurotoxic waste product that accumulates in the brain during wakefulness, is enhanced during sleep. This and similar information suggests that the restorative function of sleep is a result of its importance in maintaining metabolic homeostasis through the removal of toxins that accumulate during wakefulness.

From a behavioral standpoint, sleep is characterized by diminished responsiveness to, and perceptual disengagement from, the environment. In these ways, it is similar to coma, with the exception that it is readily reversible. However, from a neurophysiologic standpoint, it bears no resemblance to comatose state at all. During sleep, the brain is highly active and undergoes characteristic changes that translate into parallel changes, not just in the central nervous system (CNS), but throughout the body. The apparent quiescence of the sleeper is a product of active processes that diminish responsiveness to environmental stimuli. Sleep seems to be an important aspect of the 4 Rs: rest, restore, rejuvenate and repair.

At the same time, there is a perceptual disengagement from the environment. However, this disengagement is not complete when important environmental sensory information is monitored, again emphasizing the active nature of the brain during sleep. An example is the mother who responds to the infant’s whimper yet sleeps through other loud noises of lesser significance.

Decades of sleep research have confirmed Aserinsky and Kleitman’s original discovery of rapid eye movement (REM) sleep in 1953 and have conclusively demonstrated that sleep is comprised of two fundamentally distinct states, REM and non-REM (NREM) sleep, which repeat in cyclical (ultradian) fashion throughout the night, forming a pattern widely known as sleep architecture (Figure 2-1). Proper characterization of sleep stages necessitates the simultaneous monitoring of the numerous physiologic parameters, a process known as polysomnography. Minimally required are the electroencephalogram (EEG), electro-oculogram (EOG) and electromyogram (EMG) of skeletal muscle, usually the submentalis.

The Rechtschaffen and Kales (R & K) sleep scoring manual was published in 1968, 15 years after REM sleep was discovered. For several decades, the manual has provided the methodology for human sleep research, dictating the scoring of sleep stages. Advances in the field have warranted a re-appraisal of these evaluation systems for sleep. In 2007, the American Academy of Sleep Medicine (AASM) standards manual provided revised criteria for scoring sleep stages, including standardizing epoch length, redefining sleep terminology and criteria, and simplifying certain scoring rules. Table 2-1 shows a comparison of the R&K and AASM sleep stage scoring systems.

In the American Academy of Sleep Medicine (AASM) Visual Scoring system, sleep is classified into four stages: stages N1-N3 (NREM), and stage R (REM). Patterns for each of these parameters during the sleep of a young adult are depicted in Figures 2-2 through 2-4. In addition to sleep scoring, the AASM criteria also include scoring of arousals, respiratory events, sleep-related movement disorders and cardiac abnormalities.

The relative distribution of sleep stages changes with age (Figure 2-5). N3 sleep is maximal in children and diminishes markedly with age, especially during adolescence. Seniors may have little or no N3 sleep. The loss of N3 sleep with age may be a consequence of the diminution in cortical synaptic activity. In contrast, N1 sleep increases with age. With aging, there is a general tendency toward sleep fragmentation, characterized by an increase in the frequency of awakenings and brief arousals. Older adults with specific EEG sleep characteristics (sleep latency >30 minutes, sleep efficiency <80%, REM sleep percentage in the lowest or highest 15% of the total sample distribution) have an excess risk of dying beyond that associated with age, gender, or medical burden.

Cognitive mental processes seem to be at a low level during N1 sleep since sleepers who are awakened from it usually report experiencing thought fragments or vague images. Most individuals awakened from delta (N3) sleep report no mental activity at all. In contrast, most sleepers report dreams when awakened from REM sleep.

Sleep needs are quite variable from individual to individual. Although the average nightly sleep duration is approximately 8 hours, children obtain about 10 hours, and the elderly <7 hours. Sleep lengths vary even within similar age groups, with some individuals reportedly requiring as little as 3 hours of nightly sleep. The most prudent answer to the question of “How much sleep do I need?” is that amount of sleep that results in optimal daytime alertness, no need to “catch up” on sleep on non-work days, and no tendency to fall asleep unintentionally during the course of normal daytime hours. Achieving sleep needs should lead to a sense of mental efficiency and well-being.

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Figure 2-1: Sleep Architecture of a Normal Adult. The horizontal axis portrays hours of sleep. Source: Kryger MH, et al, eds. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia, PA: Elsevier Saunders; 2022.

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Figure 2-2: Polysomnography of Wake to Sleep Transition. Notes: The most marked change is visible on the two electroencephalographic (EEG) channels (C3/A2 and O2/A1), where a clear pattern of rhythmic α activity (8 cps) changes to a relatively low-voltage, mixed-frequency pattern at about the middle of the figure. The level of electromyographic (EMG) activity does not change markedly. Slow eye movements (right outer canthus [ROC]/left outer canthus [LOC]) are present throughout this episode, preceding the EEG change by at least 20 seconds. In general, the change in EEG patterns to stage N1 as illustrated here is accepted as the onset of sleep. Source: Kryger MH, et al, eds. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia, PA: Elsevier Saunders; 2022.

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Figure 2-3: FIGURE 2.3 — Polysomnography of Non-REM Sleep. Notes: The four electroencephalogram tracings depicted here are from a 19-year-old female volunteer. Each tracing was recorded from a referential lead (C3/A2) on a Grass Instruments (West Warwick, RI) Model 7D polygraph with a paper speed of 10 mm/sec, time constant of 0.3 sec, and 12-amplitude high-frequency setting of 30 Hz. On the second tracing, the arrow indicates a K-complex and the underlining shows two sleep spindles. Stages 1 and 2 correspond to stages N1 and N2 in the current AASM scoring system, while stages 3 and 4 correspond to stage N3. Source: Kryger MH, et al, eds. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia, PA: Elsevier Saunders; 2022.

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Figure 2-4: Polysomnography of Patient in REM Sleep. Notes: On the left side is a burst of several rapid eye movements (out-of-phase deflections in right outer canthus [ROC]/A1 and left outer canthus [LOC]/A2). On the right side, there are additional rapid eye movements as well as twitches on the electromyographic (EMG) lead. The interval between eye movement bursts and twitches illustrates tonic REM sleep. Source: Kryger MH, et al, eds. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia, PA: Elsevier Saunders; 2022.

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Figure 2-5: Sleep and Age. Notes: Age-related percentile curves for sleep macrostructure and arousals in 100 healthy Caucasian volunteers. (A) N1%. (B) N2%. (C) N3%. (D) REM%. Circles represent women, squares represent men; figures show 10th, 25th, 50th, 75th and 90th percentile. Key: REM, rapid eye movement. Source: Adapted from Mitterling T, et al. Sleep. 2015;38(6):867-875.

Polysomnography

Polysomnography is typically performed in specialized facilities called sleep disorders centers and laboratories. In preparation for polysomnography, patients are introduced to their sleeping quarters during their initial office-based evaluation and provisions are made for special needs. On the night of the test, they arrive at the laboratory well in advance of the study time to acclimate to the new environment. Studies are conducted in noise-free and private rooms and comfort is maximized by making rooms aesthetically pleasing.

As noted earlier, characterization of sleep stages requires, at the minimum, an EEG, EOG and EMG of the submentalis. However, a typical clinical polysomnogram also includes monitors for airflow at the nose and mouth, respiratory-effort strain gauges placed around the chest and abdomen, and noninvasive oxygen-saturation monitors that function by introducing a beam of light through the skin. Other parameters include the electrocardiogram and EMG of the anterior tibialis muscles, which are intended to detect periodic leg movements (PLMs). Finally, a patient’s gross body movements are continuously monitored by audiovisual means (Figure 2-6).

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Figure 2-6: Patient Undergoing Polysomnography. Public domain image. Source: National Heart Lung and Blood Institute (NIH).

Mechanisms Underlying Sleep and Wakefulness

Sleep and wakefulness are believed to be the net effect of the interaction of two opposing, mutually inhibitory, interdependent processes (Figure 2-7).

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Figure 2-7: Brain Regions Involved in Regulation of Sleep and Wakefulness. Source: Adapted from Atkin T, et al. Pharmacol Rev. 2018;70(2):197-245.

Arousal Neurophysiology

The wake-promoting system is consists of noradrenergic, cholinergic (ACh), serotoninergic (5-HT), dopaminergic and histaminergic (His) neurons, which produce cortical arousal via two pathways: a dorsal route through the thalamus and a ventral route through the hypothalamus and basal forebrain (Table 2-2). The dorsal branch of ascending neurons receives input from cholinergic cell groups in the upper pons, the pedunculopontine and laterodorsal tegmental nuclei, which facilitate transmission of signals from the thalamus to the cerebral cortex.

The second branch of ascending neurons receives input from the monoaminergic neurons in the upper brainstem and caudal hypothalamus. This pathway also receives contributions from peptidergic neurons in the lateral hypothalamus (LH) containing orexin and from basal forebrain neurons containing acetylcholine and γ-aminobutyric acid (GABA). All of these ascending arousal pathways traverse the region at the midbrain-diencephalic junction, where it was observed that lesions caused hypersomnolence.

The neuropeptide hypocretin/orexin plays an important role as a stabilizer and maintainer of wakefulness, minimizing unplanned transitions to the sleep state through the reinforcement of wake-promoting signaling in the brain (Figure 2-8). Orexin deficiency results in narcolepsy in many species, suggesting that this system is particularly important for maintenance of wakefulness, although not necessarily its initiation. Orexin neurons receive abundant input from the limbic system and activate waking active monoaminergic and cholinergic neurons in the hypothalamus and brainstem regions to maintain a long, consolidated waking period. These neurons also interact with systems that regulate emotion, reward and energy homeostasis to maintain appropriate vigilance states.

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Figure 2-8: Hypocretin/Orexin Neurons. Source: Silber MH, Rye DB. Neurology. 2001;56(12):1616-1618.

Sleep Neurophysiology

After the identification of arousal centers more than 3 decades ago, it remained unclear how the arousal system was turned “off” so that sleep could be initiated and maintained. It was not until the mid-1990s that the identity of this sleep-promoting circuitry was revealed. It was demonstrated that wake-promoting neurons are inhibited during sleep by a system of ventrolateral preoptic nucleus (VLPO) neurons, which contain sleep-active cells that contain the inhibitory neurotransmitters GABA and galanin.

Primarily active during sleep, VLPO neurons project to all of the main cellular components in the hypothalamus and brainstem that participate in arousal. Inhibition of the arousal system by the VLPO during sleep is critical for the maintenance and consolidation of sleep. Work by Batini and colleagues has provided support for the concept that an active sleep-promoting area is located near the nucleus of the solitary tract in the medulla, but this remains largely unconfirmed. Because the VLPO neurons do not have orexin receptors, actions of the orexin neurons are primarily to reinforce the wake-promoting systems rather than to directly inhibit the VLPO (Figure 2-8).

Transitioning Between Wakefulness and Sleep

Transitions between the discrete states of wakefulness and sleep are rapid and complete and can be described as a “flip-flop” switch. As signaling from one side increases, so does its inhibitory influence on the signaling of the opposing process (Figure 2-9). As long as signaling from one side exceeds the other, that state is maintained. While the flip-flop switch avoids prolonged intermediate states between sleep and wakefulness, transitions can also occur with little warning and may have negative consequences. To minimize unplanned transitions from wake to sleep, wake signaling consists of redundant pathways that are stabilized via orexin neuropeptides, collectively making wake asymmetrically favored.

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Figure 2-9: The “Flip-Flop” Switch Model of Arousal and Sleep. The mutual inhibition between VLPO neurons and the monoaminergic cell groups forms a flip-flop switch, which produces sharp transitions in state but is relatively unstable. Source: Modified from Saper CB, et al. Nature. 2005;437(7063):1257-1263.

Factors Modulating Arousal and Sleep

There are many influences that affect the activity of the wake-sleep circuit, which can be categorized within three major factors — circadian rhythms, homeostatic drive and allostatic signaling.

The homeostatic influence is believed to be based on the accumulation of the drive for sleep during prolonged wakefulness and relief of this need during sleep. The mechanism for this homeostatic regulation may be linked to the accumulation of a sleep-promoting substance (believed to be adenosine) that enhances the activity of sleep-promoting cells and reduces the activity of wake-promoting neurons.

Circadian rhythms are governed mainly by the suprachiasmatic nucleus (SCN) area in the brain, which serves as a biological clock of roughly 24 hours. Signals from various areas in the body connect to the dorsal and ventral subparaventricular zones, as well as the dorsomedial nucleus of the hypothalamus (DMH). Neurons in these regions relay information necessary for organizing daily cycles of wake–sleep and rhythms of body temperature (Table 2-3). DMH neurons drive circadian cycles of sleep, activity, feeding and corticosteroid secretion. These integrative connections allow circadian rhythms to mold the daily cycles of sleep-wakefulness in accordance with internal and external cues.

Rather than maintaining a rigid sleep/wake schedule, the physiologic systems within the body are able to fluctuate to meet demands from external forces via allostatic signaling. Allostatic signaling adapts sleep and wakefulness to external behavioral events, such as environmental, sensory, cognitive and emotional inputs. These are thought to be mediated in part by cues from visceral sensory systems and feeding regulatory systems to the arousal systems, involving inputs to the SCN, VLPO and orexin neurons from corticolimbic sites.

The process of sleep is important for physical and mental restoration and normal functioning, although the mechanism by which sleep produces these effects is a matter of ongoing research. Nevertheless, the complex array of changes that is seen both in the brain and the peripheral organs during sleep is proof that sleep represents an active state that is highly regulated. The states of sleep and wakefulness are governed by different, but interconnected neural circuits in the brain, which are mutually interdependent and inhibitory. The transition between the distinct sleep/wake states is fast and complete, governed by many factors, such as circadian rhythms, homeostatic drive and allostatic signaling.

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References

• Doghramji K, Doghramji PP. Clinical Management of Insomnia, 3rd ed. Professional Communications Inc. 2023.
• Dew MA, Hoch CC, Buysse DJ, et al. Healthy older adults’ sleep predicts all-cause mortality at 4 to 19 years of follow-up. Psychosom Med. 2003;65(1):63-73.=