Physiological Basis of Sleep and Wakefulness

Introduction

Knowledge about the physiological basis of sleep has increased rapidly over the last few years. It is now recognized to be a highly complex and heterogeneous state, which is intimately connected with the state of wakefulness. There is a dynamic balance between the processes controlling both these states, which is complex and has important implications for many sleep disorders.

Functions of sleep

The functions of sleep are still uncertain, but NREM and REM sleep almost certainly have different functions. Sleep is in many ways a vulnerable state, because of the reduced awareness and responsiveness to the environment, but it has been highly conserved during evolution suggesting that it has a survival advantage. The proposed functions for sleep fall into the following categories.

Biochemical

Several anabolic hormones, such as growth hormone, are secreted primarily during sleep, whereas catabolic hormones, such as cortisol, are produced mainly during wakefulness. The metabolic rate slows during NREM sleep, in which energy is conserved, the body temperature falls, and protein synthesis and other anabolic processes are accentuated.

Wakefulness may also have important biochemical effects on neurones which are compensated for by sleep. During wakefulness neuronal glucose utilization is more rapid, and intracellular stores of glyco-gen within astrocytes are consumed. This process is reversed during sleep so that glucose can be available for neuronal activity and to enable normal metabolic functioning during the next episode of wakefulness. Replenishment of other metabolites or removal of oxygen free radicals during NREM sleep may also be important.

Physiological

Sleep has been considered to be a restorative or a recovery phase, or to prepare the organism physiologically for the next phase of wakefulness. Cell division is most rapid during NREM sleep, at which time protein synthesis is increased. Sleep also has important effects on the immune system and is itself influenced by, for instance, cytokines which are an integral component of immunity. Energy is conserved during sleep, but this is only between 100 and 200 calories per night and is probably of little significance.

Neurological

Synchronization of cortical activity during NREM sleep may in some way coordinate cortical networks. The prefrontal cortex is inactive during NREM sleep as well as REM sleep, and this may also have some benefit.

REM sleep may have a neurodevelopmental role. It is most prolonged in mammals whose offspring are least mature at birth, and in neonates and young children. The ability to form new neurones (neurogenesis) slows early in life and new behaviour patterns are mainly due to the development of neural networks. During REM sleep the cerebral cortex is open to sensory inputs and makes loose associations which are not possible during wakefulness. The basal ganglia are also active so that behavioural patterns that are essential for survival can be developed without them being manifested by motor activity. The REM sleep processing and integration of newly acquired information into existing neural templates enables future responses to also reflect the previous experience of the individual and the inherited potential [1]. These are given an emotional charge through the activity of the limbic system.

Psychological

Both NREM and REM sleep appear to be involved in consolidation of memory, but they almost certainly have different influences on this. Acquisition of new information during sleep is extremely limited, but consolidation or maintenance of memory from experiences during the previous day is considerable [2]. Learning of visually acquired information is improved during the first night of sleep, and sleep deprivation on this night impairs recall of information. Retention is best if stages 3 and 4 NREM sleep in the first 2 h of the night are followed by REM sleep in the last 25% of the night. The sequence of NREM and REM sleep appears to be important.

Learning of motor sequences improves during the first night of sleep and appears to be dependent particularly on stage 2 NREM sleep later in the night, during which individual components of the learnt sequence can be integrated, particularly the most complex parts.

Recall of cognitive procedures is better if there is a sequence of NREM and then REM sleep, but declarative memory appears not to require REM sleep [3]. Probabilistic learning, in which associations are made according to the likelihood of events being related, improves after sleep on the first night after the experience. Declarative memory during sleep may be related to spindle activity in stage 2 NREM sleep [4].

Dreams are a manifestation of the underlying cerebral activity and reflect the loose mental associations of REM sleep which enable new neuronal networks to be formed, probably promoting creative mental activity and improving problem-solving ability. At sleep onset explicit images of the day's events are often recalled if the subject is awoken during stage 1 NREM sleep, but as the REM sleep episodes progress during the night these become incorporated into associative networks and are less readily recognizable. This creative activity of REM sleep complements its function in memory consolidation.

Social

In non-developed societies it is usual for some members of a group to be awake while others are sleeping in order to afford protection for the group. The rapid reversibility of sleep to the waking state in response to significant stimuli also gives protection against adverse environmental events.

Non-rapid eye movement (NREM) sleep

Neurophysiology

The thalamocortical pathways synchronize cortical activity, particularly during the deeper stages of NREM sleep. The cortex is in effect removed from the influence of ascending sensory input by the thalamic 'gate' and also by reduction in the activity of the ascending reticular activating system. This disconnection contrasts with wakefulness and REM sleep (Table 2.1).

The synchronization of the cortical activity is not homogeneous. Early in NREM sleep it is most marked in the prefrontal area, suggesting that this region, which is particularly active during wakefulness, develops a greater homeostatic drive to enter NREM sleep. This regional difference is particularly marked after sleep deprivation.

Thalamic activity in NREM sleep stabilizes this state and inhibits arousals. Arousal stimuli may however lead to a reduction in delta activity and an increase in alpha and beta rhythms. The threshold for painful stimuli causing arousal increases from stage 1 through to stage 4 NREM sleep. Impulses ascending in the spinoreticular tract can be inhibited in the nucleus

Table 2.1 Comparison of NREM and REM sleep.

Characteristic

NREM sleep

REM sleep

Cerebral cortex

Prefrontal cortex inactive Limbic cortex inactive Deafferented

Prefrontal cortex inactive Limbic cortex active Active information processing Dreams

Somatic reflexes

Reduced

Intense inhibition

Movements

Constant for each stage (1-4) Reduced

Rapid eye movements

Autonomic function

Constant for each stage (1-4) Parasympathetic dominance

Fluctuates

Overall parasympathetic dominance

Metabolic

Reduced metabolic rate Anabolic

Slightly reduced metabolic rate

reticularis gigantocellularis so that afferent stimuli are prevented from causing arousals.

Functional neuro-imaging

Functional neuro-imaging has revealed global shifts in cerebral function between wakefulness and NREM sleep, particularly stages 3 and 4. In this state there is reduced activity in the brainstem, particularly the pons and cerebellum, in the basal forebrain and lim-bic cortex, such as the anterior cingulate gyrus, and especially in the dorsolateral prefrontal and inferior parietal cortex. There is little change in activity relative to wakefulness in the basal ganglia and primary sensory and motor cortex.

On waking from NREM sleep there is an increase in brainstem activity, followed by increasing activity in the cerebral cortex. The prefrontal cortex is the last to be activated after waking, and this sequence may explain the features of sleep inertia. Activity patterns midway between normal wakefulness and NREM sleep are seen during wakefulness following sleep deprivation. Wakefulness in the evening is associated with increasing brainstem and hypothalamic metabolic activity, possibly due to increased input from the cir-cadian rhythm generators to maintain wakefulness.

Electroencephalogram (EEG) activity

The depth of NREM sleep can be quantified by electroencephalogram (EEG) fluctuations. Four stages of NREM sleep are recognized on conventional EEG criteria (page 61). These are categorized by the frequency and amplitude of the EEG, the presence of sleep spindles and K-complexes, and electro-oculogram (EOG) and electromyogram (EMG) findings.

Mental activity

Subjects woken during NREM sleep frequently report awareness of fragmented, thought-like processes, particularly in the lighter stages and later in the night. These contain less action than the dreams that occur during REM sleep. The simpler dream mentation in NREM sleep is probably due to the functional disconnection of the cortex from sensory input by the thalamus. This may represent a process of reorganization of neural networks in an analogous, but different, manner to that which occurs in REM sleep.

Motor activity

The separation of the cerebral cortex from brainstem functioning during NREM sleep frees the somatic reflexes from higher control. Reflex activity is depressed, with the result, for instance, that tendon reflexes are reduced, and in 50% of subjects there is an upgoing plantar (Babinski) reflex during NREM sleep.

Autonomic function

There is a relative increase in parasympathetic to sympathetic activity. The parasympathetic activity is also increased due to circadian factors at night. In contrast, the sympathetic system is more influenced by the sleep-wake state than circadian rhythms. The parasympathetic activity increases from stage 1 through to stage 4 of NREM sleep, and, in contrast to REM sleep, within each stage the balance of parasympa-thetic to sympathetic activity remains stable.

Metabolic rate

The metabolic rate is reduced in NREM sleep by 5-10%.

Temperature control

The core body temperature normally falls as NREM sleep is entered at the start of the night, and the control of sleep is closely related to thermoregulation. The reduced metabolic rate and vasodilatation of NREM sleep tend to reduce body temperature.

Respiratory function

The minute ventilation falls (1.23) and the arterial Pco2 rises by 2-3 mmHg. The stage of NREM sleep oscillates frequently at sleep onset and the threshold for carbon dioxide to act as a respiratory stimulus fluctuates correspondingly. This may lead either to frequent central sleep apnoeas or to Cheyne-Stokes respiration. During the apnoeic phases the Pco2 rises progressively at a rate determined by the metabolic rate, and when it exceeds the apnoeic threshold, respiration restarts, often with a phase of hyperventilation until the Pco2 again falls below the threshold and the next apnoea begins.

The threshold for arousal from NREM sleep rises progressively from stage 1 to stage 4, but remains lower than in REM sleep [5] (Table 2.2).

The reduction in cerebral cortical influence on the respiratory centres and the reduction in somatic reflexes have important effects on respiration in NREM sleep. The respiratory drive is reduced, although it remains greater than in REM sleep. Within each NREM sleep stage the respiratory pattern is regular, but it varies between stages as the threshold for responding to Pco2 (apnoeic threshold) alters. The threshold for the ventilatory response to Pco2 increases from wakeful-ness to stage 1 NREM sleep and progressively into the deeper stages of NREM sleep with the effect that a

Table 2.2 Effects of REM and NREM sleep on respiration.
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