Defining sleep is not at all straightforward but its general features comprise (see Hendricks, Sehgal and Pack 2000) (1) a sterotypical, species-specific posture; (2) an absence of voluntary movements; (3) elevated threshold for arousing stimuli; (4) reversibility on stimulation of the individual (or organism). The following sections outline what is known about how these changes come about and how they are regulated.
THE ELECTROENCEPHALOGRAM (EEG)
Probably the most important breakthrough in sleep research came in the mid-1930s when it was discovered that the profile of the electroencephalogram (EEG) changed markedly during the sleep-waking cycle (Fig. 22.4). To this day, the EEG is a major
Figure 22.4 Idealised EEG-like patterns in sleep and waking. When we are awake and aroused the EEG is desynchronised (a). As we become drowsy and pass into sleep the EEG waves become more synchronised with 8-12 Hz alpha waves (b), sleep spindles then appear (c) before the EEG becomes even more synchronised with slow (about 1-2 Hz) high-voltage waves characteristic of deep slow-wave sleep (SWS). About every 90 min this pattern is disrupted and the EEG becomes more like that in arousal (d) except that the subject remains asleep. This phase of sleep is also characterised by rolling, rapid eye movements, the so-called REM sleep. SWS is consequently also known as non-REM sleep. These tracings have been drawn to show the main features of the different EEG phases of sleep and as such are much simpler than those that are actually recorded
Figure 22.4 Idealised EEG-like patterns in sleep and waking. When we are awake and aroused the EEG is desynchronised (a). As we become drowsy and pass into sleep the EEG waves become more synchronised with 8-12 Hz alpha waves (b), sleep spindles then appear (c) before the EEG becomes even more synchronised with slow (about 1-2 Hz) high-voltage waves characteristic of deep slow-wave sleep (SWS). About every 90 min this pattern is disrupted and the EEG becomes more like that in arousal (d) except that the subject remains asleep. This phase of sleep is also characterised by rolling, rapid eye movements, the so-called REM sleep. SWS is consequently also known as non-REM sleep. These tracings have been drawn to show the main features of the different EEG phases of sleep and as such are much simpler than those that are actually recorded focus of sleep research but is usually complemented by measurements of muscle tone (the electromyogram, EMG) and eye movements (the electro-occulogram, EOG) which also show marked changes during the sleep cycle.
When we are aroused and awake, the EEG is random (desynchronised) with multiple high-frequency (of at least 15 Hz), low-amplitude y(gamma)-wave forms. As we become drowsy and close our eyes, the EEG becomes more synchronised and a clear rhythm emerges (stage 1 sleep): this is a(alpha)-rhythm which has a frequency of 8-12 Hz. At the onset of sleep (stage 2), 0(theta)-waves (4-7 Hz) are evident but these are disrupted to some extent by the intermittent appearance of waves, known as K-complexes and 'sleep spindles'. The former are single spikes whereas the latter are short trains of pulses (12-14 Hz). Progressing still further into the sleep state (as assessed by the EMG and EOG), the EEG becomes even more synchronised so that slower (about 1-2 Hz) and larger waves become more prominent. These are the ¿(delta)-waves which are associated with stage 4 (deep) sleep, often called 'slow-wave sleep' (SWS). At the same time as all these changes are developing, the threshold for arousal by sensory stimuli increases.
It was not until much later (1953) that another phase of the sleep cycle was discovered. At about 90 min after the onset of sleep, the EEG becomes desynchronised and, in fact, it bears a strong resemblance to that seen in stage 1, apart from the appearance of so-called 'PGO-waves' (see below). Also, rapid eye movements, resembling those while reading in the awake state, are evident on the EOG: this is REM (rapid eye movement) or 'paradoxical' sleep. However, in adults, other physiological changes that occur during REM sleep are quite different from those of stage 1. In particular, there is a flaccid paralysis of the limb muscles together with a loss of fine control of body temperature and other homeostatic mechanisms. It is often maintained that dreaming is restricted to these periods of REM sleep, which occur some three or four times during the night, each lasting about 30 min. However, it is now thought that dreams also occur during SWS but that these are more logical and more consistent with normal life events than are those occurring during REM sleep.
This sleep pattern, seen in adults, takes some time to develop and appears in infants only around 6 months to one year after birth. Instead, as new parents will testify, young babies have a sleep cycle that lasts only around 3-6 h. Further striking differences are that babies' REM sleep accounts for as much as half the sleep cycle (compared with only a quarter in the adult) and is accompanied by increased motor activity with spasmodic movements of the limbs and facial muscles, rather than the muscle atonia seen in adults. In fact, the adult sleep cycle can take up to 20 years to stabilise and its pattern changes again in the elderly who show a reduction in the duration of SWS, an increase in the proportion of REM sleep, and increased daytime 'napping'.
The functions of these different phases of sleep are not at all clear but chronic sleep deprivation does eventually lead to death. It seems to be the slow-wave component of sleep (SWS) that is vital and it is thought to serve a restorative purpose. This would be consistent with its greater occurrence during the early stages of the sleep cycle when hormone secretion supports anabolic metabolism. If subjects are wakened every time they enter a period of REM sleep (evidenced by the EEG) there appears to be no overt harmful effect on their behaviour. In fact, REM sleep deprivation has even been used, with some claims of success, as a treatment for minor depression. However, there is an unproven belief that REM sleep is important for memory consolidation.
It appears that the voltage waves recorded in the EEG represent the summation of synaptic potentials in the apical dendrites of pyramidal cells in the cortex. These cells generate sufficient extracellular current for it to reach, and be recorded from, the cranium and scalp. Although these waves originate from the cortex rather than the SCN, the distinctive REM and non-REM phases of sleep still remain after destruction of the SCN but they then occur randomly over the 24-h cycle. This is a further indication that the SCN is at least partly responsible for setting the overall circadian rhythm of the sleep cycle.
The more synchronised the activity of the cortical neurons, the greater the summation of currents and the larger and slower the EEG wave, as in the sleep pattern (Fig. 22.4). While there are some dissociations between EEG pattern and behavioural states, the EEG offers one way of determining experimentally the pathways (and neurotransmitters) that control arousal and sleep, and can be regarded as an important objective measurement of the cortical correlates of sleep and waking.
The slow (deep sleep) ¿-waves probably originate in the cortex because they survive separation from, or lesions of, the thalamus. However, the rhythm and appearance of spindles in earlier phases of the sleep cycle do depend on links with the thalamus (see Steriade 1999). Unlike stimulation of the specific sensory relay nuclei in the thalamus, which only affects neurons in the appropriate sensory areas of the cortex, the nonspecific nuclei can produce responses throughout the cortex and may not only control, but also generate, cortical activity. Certainly, in vitro studies show that neurons of the non-specific reticular thalamic nucleus (NspRTN) can fire spontaneously at about 812 Hz (equivalent to EEG a-rhythm) or lower, and that low-frequency stimulation of this area can induce sleep.
Maintenance of these frequencies relies on the degree of depolarisation of the thalamic neurons (Jahnsen and Llinas 1985) and this, in turn, depends on the nature and intensity of their afferent inputs. The NspRTN and other thalamic nuclei receive reciprocal inputs from the cortex and it is possible that it is the ensuing oscillations in neuronal activity in this circuit between the cortex and thalamus that give rise to the sleep spindle waves in stages 2-4. In fact, it has been suggested that the stronger and clearer these oscillations become, the more likely it is that there will be loss of consciousness.
Apart from neuronal inputs originating in the cortex, thalamic afferents (see Fig. 22.5) come from:
(1) Collaterals from neurons of neighbouring specific thalamocortical relay nuclei. Because these neurons are themselves activated by sensory inputs transmitted along the spinothalamic tract, this provides one way in which sensory stimuli can influence cortical activity generally, as well as specifically.
(2) Ascending inputs from the brainstem ascending reticular activating system (ARAS). As described below, these seem to be particularly important and probably disrupt the thalamo-cortical synchrony.
One of the first experiments to investigate the brain mechanisms that might be involved in regulation of sleep and waking showed that after transection of the brain of cats, so that the cerebrum was separated from the brainstem, the animal displayed continuous sleep. Conversely, transection that separated the entire brain, including the brainstem, from the spinal cord (at the level of Cl) caused continuous arousal. Jouvet (1974) extended this work by showing that a lesion at a specific site in the pons abolished REM sleep, together with the associated muscle atonia and EEG changes, but did not affect SWS. All this work suggested the existence, not only of 'sleep' and 'waking' centres in the brain, but also that a separate brain area was responsible for REM sleep. Later studies confirmed the existence of these brain centres in that stimulation of the anterior hypothalamus, at a frequency similar to that of the sleep spindles in the EEG, induced sleep whereas stimulation of a zone of the brainstem, that came to be known as the ascending reticular activating system (ARAS), induced arousal (Moruzzi and Mayoun 1949).
The generally accepted view is that the stimulatory drive for the ARAS comes from collaterals of the classical ascending sensory pathways. Indeed, this is another way in which sensory stimuli can affect our state of arousal (Fig. 22.5). The diffuse activating
Figure 22.5 Pathways involved in cortico-thalamic synchrony and EEG arousal. The ascending reticular activating system (ARAS) extends from the cephalic medulla through the pons and midbrain to the thalamus (see Moruzzi and Mayoun 1949). It is activated by impulses in collaterals of the spinothalamic sensory pathway running to specific thalamic nuclei (SpThNc) and in turn activates much of the cortex, partly through the non-specific thalamic nuclei (NspThNc), which also receive inputs from SpThNc and also via the nucleus basalis (NcB). Its stimulation is followed by EEG arousal. It is probable that reciprocal links between cortical areas and the thalamus, particularly NspThN, lead to slow-wave (8 Hz) cortical EEG synchrony and, in the absence of appropriate sensory input and ARAS activity, a sleep state
Figure 22.5 Pathways involved in cortico-thalamic synchrony and EEG arousal. The ascending reticular activating system (ARAS) extends from the cephalic medulla through the pons and midbrain to the thalamus (see Moruzzi and Mayoun 1949). It is activated by impulses in collaterals of the spinothalamic sensory pathway running to specific thalamic nuclei (SpThNc) and in turn activates much of the cortex, partly through the non-specific thalamic nuclei (NspThNc), which also receive inputs from SpThNc and also via the nucleus basalis (NcB). Its stimulation is followed by EEG arousal. It is probable that reciprocal links between cortical areas and the thalamus, particularly NspThN, lead to slow-wave (8 Hz) cortical EEG synchrony and, in the absence of appropriate sensory input and ARAS activity, a sleep state system ensures that all sensory stimuli, whatever their strength or modality, contribute collectively to cortical arousal. This is possible because part of any sensory input is diverted to the ARAS and so prevents the cortex from reverting to its basic slow-wave oscillating rhythm. Thus, not only will the sensory cortex be more responsive to any primary sensory input it receives, but its activation keeps us alert. In this respect, the ARAS can be considered to contribute to our circadian rhythm by helping to ensure that we have an active cortex and so stay awake when we have adequate stimulation. Nevertheless, humans deprived of diurnal cues (such as when they are confined in an insulated, 'time-free' chamber) still show a sleep-waking cycle, although it progressively adopts a longer time period.
In addition to the excitatory drive, there are also inhibitory neurons from the anterior hypothalamus which provide one route for suppressing activity in the ARAS. Another inhibitory influence comes from the spinal cord. Together, these links could help to ensure smooth progression from one state of arousal to another. Also, during REM sleep, pontine-geniculate-occipital (PGO) waves travel to the cerebral cortex and spinal cord and it is this wave of activity, passing through intermediate brain regions, that is thought to blunt sensory and motor function.
It is important to emphasise that a lesion of the reticular system disrupts a number of afferent inputs to the cortex. Particularly important in this respect are the mono-aminergic (especially noradrenaline, 5-HT and histamine) and cholinergic pathways. When the ascending inputs from these neurons are destroyed, sleep is passive and not at all like natural sleep which, as detailed above, has distinct phases and depends on brainstem influences on cortical function. How these different neurotransmitters might influence sleep and arousal will be considered next.
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