light cycle. The lateral geniculate nucleus (LGN) activates the suprachiasmatic nucleus (SCN) in the case of the non-light-based stimuli such as motor activity. The raphe nuclei also impact on the SCN. Thus several pathways appear to be involved in the entraining process (see Figure 10.1).
In general, the sleep cycle is synchronized via the SCN. All sensory stimuli activate the ascending reticular activating system, thereby causing cortical arousal and preventing the cortex reverting to its basic slow-wave oscillating rhythm. The excitatory, arousing mechanisms are complemented by inhibitory inputs from the hypothalamus. At least four different types of neurotransmitters are involved in regulating the EEG pattern in the sleep-wake cycle. Thus acetylcholine causes a desynchronization of the cortical EEG while REM sleep is induced by cholinomimetic drugs (such as arecoline and physostigmine) but blocked by atropine.
The central histamine 1 receptors are active in the posterior hypothalamus during the waking phase but inactive during the slow-wave sleep and REM stages of the sleep-wake cycle. Antagonists of the H1 histamine receptors cause sedation.
There is evidence that the histaminergic tract that passes from the posterior hypothalamus to the cortex via the thalamus is inhibited by a GABAergic pathway. It is now known that H3 receptors act as autoreceptors on histaminergic neurons and that agonists of H3 receptors augment slow-wave sleep. In addition, histamine can increase cortical arousal by enhancing excitatory cholinergic neurons from the basal forebrain and also inhibits the hypothalamic pre-optic area which normally promotes sleep. With respect to the control of the circadian rhythm, histamine has both excitatory (Hj) and inhibitory (H2) effects on the SCN. Thus in addition to acetylcholine, noradrenaline and 5-HT, histamine would also appear to play a crucial role in regulating the sleep pattern.
Noradrenaline - the EEG is aroused by stimulants such as the amphetamines and methylphenidate whereas drugs such as reserpine which deplete brain noradrenaline have the opposite effect. Similar effects to the stimulants may be obtained by the electrical stimulation of the locus coeruleus which has been shown to decrease in activity during the REM sleep phase of the sleep cycle. The precise role that noradrenaline plays in sleep is uncertain. While it may be involved in sleep induction, noradrena-line also has many other physiological functions including control of the heart rate, blood pressure, autonomic activity, etc. which play a role in the entraining process.
Dopamine - low doses of the dopamine agonist apomorphine increase slow-wave sleep and, like other dopaminometics, cause somnolence in patients with Parkinson's disease. Conversely, dopamine autoreceptor antagonists, which enhance dopamine release, reduce both REM and non-REM sleep. Stimulants such as cocaine cause arousal by activating D2 postsynaptic receptors, effects which are blocked by most neuroleptics.
Serotonin - the reduction in the release of 5-HT in the brain (for example, by blocking 5-HT synthesis with parachlorophenyl alanine) induces sleep while the electrical stimulation of the raphe nuclei causes excitation. It would appear that the activity of the raphe nuclei is decreased in slow-wave sleep. However, the role of specific 5-HT receptors in mediating the effects of 5-HT is unclear. This is due to the relative lack of specificity of the drugs available but also due to the fact that 5-HT modulates the activity of other neurotransmitter systems involved in the regulation of sleep. For example, 5-HT1A receptor agonists increase the frequency of slow-wave sleep which may be due to its inhibitory effect on the release of acetylcholine from the nucleus basalis. It would appear however that the serotonergic system is active during the waking phase but reduced during the sleep phase of the sleep-wake cycle.
In animals, two main types of sleep pattern may be identified termed nonrapid eye movement sleep (non-REM or slow-wave sleep) and rapid eye movement sleep (REM sleep). Normal sleep is composed of several REM and non-REM cycles. Non-REM sleep is divided into light sleep (stages j and 2) and slow-wave or delta sleep (stages 3 and 4). Stage 1 sleep is characterized by alpha rhythm on the EEG and forms the transition between wakefulness and sleep; it occupies approximately 5% of the time. Muscle tone is relatively weak and while a certain amount of mental activity persists, concentration and imagination fluctuate. As the sleep deepens, hypnagogic hallucinations may occur. Stage 2 sleep represents over 50% of the total sleeping time and is marked by characteristic sleep spindles and K
complexes in the EEG; delta waves are also present occasionally. Muscle tone is weak and there are no eye movements. Stages 3 and 4, slow-wave sleep, occupy approximately 20% of the sleep time. The EEG is characterized by more than 50% of the sleep pattern being in the form of delta waves. This stage of sleep is the recuperative phase which is associated with growth hormone secretion and tissue repair; the secretion of prolactin is not associated with any specific phase of sleep. Dreaming may occur but tends to be of brief duration and of a rational nature. Nocturnal terrors and sleep walking are associated with stage 4 sleep.
REM sleep occupies approximately 20% of the sleep time in the normal adult, up to 30% in the young child and less than 20% in the aged or mentally handicapped. The cortical EEG activity resembles that of wakefulness, but is accompanied by muscular weakness; 4 Hz "sawtooth" waves herald the onset of REM sleep. The precise physiological function of REM sleep is unknown but it is associated with dreaming sleep, the dreams being long, emotional and animated. The physiological changes accompanying REM sleep include hypertension, tachycardia alternating with bradycardia, pelvic congestion in the female and penile tumescence in the male. Cortisol secretion appears to peak during the latter part of the sleep cycle when REM sleep is most pronounced. This type of sleep is also characterized by bursts of eye movement and small sporadic muscular twitches of the face and extremities.
The typical sleep pattern of the young adult is composed of four to six cycles of non-REM sleep alternating with REM sleep at approximately 90 minute intervals. The subject first goes into non-REM sleep and then gradually descends from stage 1 through to stage 4 sleep, the frequency of the waves becoming slower and their amplitude greater. The depth of sleep then briefly (for a few minutes) returns to stage 2, after which the first episode of REM sleep appears. Bodily movements often occur at this stage. This may be illustrated by means of a hypnogram, as shown in Figure 10.2.
It should be noted that stages 3 and 4 are more pronounced during the early part of the sleep period, whereas REM sleep tends to increase during the sleep cycle. The actual period of sleep is to some extent genetically determined, some individuals requiring at least 8 hours while others need only 4 hours to function normally. The sleep pattern becomes more fragile with advancing age, so that in the elderly the number of nocturnal awakenings increases and REM sleep becomes more evenly distributed throughout the night.
The sleep architecture may be modified by disease and by certain drugs. In the healthy individual, the duration of the first phase of REM sleep is usually 3 minutes. In patients with depression or narcoplexy, the time of onset of the first REM phase is shorter than usual, while those with anxiety
12 3 4 Clock time (hi
Figure 10.2. Typical hypnogram of a normal young adult.
disorders have a delayed time of onset of the first REM phase. The duration of the first REM phase is also increased in depressed patients.
All hypnotics in current clinical use alter the sleep architecture by reducing the quantity and quality of the REM sleep phase in particular. Thus a single dose of a hypnotic benzodiazepine suppresses REM during the period in which it is present, but for up to the two following nights the amount of REM sleep is generally increased (so-called REM rebound). When the hypnotic is given for a prolonged period, the REM sleep gradually returns to normal, but abrupt withdrawal can lead to prolonged rebound in REM sleep, which is often associated with intense and unpleasant dreams and anxiety on wakening. Most hypnotics also affect the quality of the non-REM sleep, particularly the slow-wave sleep pattern. Thus stage 3 and stage 4 sleep are suppressed and remain so during the period of drug administration. Following drug withdrawal, the slow-wave sleep gradually returns to normal, but this may take up to 15 days. However, no rebound effect appears to occur in slow-wave sleep. All hypnotics in current use also decrease stage 1 of non-REM sleep and prolong stage 2 sleep; this may be the reason why the nocturnal awakenings decrease, so that the individual feels that the quality of sleep under the influence of the hypnotic has improved! The effect of a hypnotic on the quality of the REM and slow-wave sleep is shown diagrammatically in Figure 10.3.
Disturbance in the sleep pattern commonly occurs in the alcoholic. The sleep pattern in this type of patient is characterized by frequent awakenings and decreased REM and slow-wave sleep. Concomitantly, stages 1 and 2 are increased but shallower than usual. After withdrawal from alcohol, the
Benzodiazepine Benzodiazepine administered withdrawn
Benzodiazepine Benzodiazepine administered withdrawn
Days after withdrawal
Figure 10.3. Illustration of the rebound effect following 15 days' continuous treatment with a benzodiazepine.
patient experiences insomnia and REM rebound occurs. The sleep profile of the alcoholic often remains abnormal for 1-2 years following withdrawal.
Most antidepressants decrease the quantity of REM sleep in the depressed patient, although it is difficult to say whether this is a reflection of the action of the drugs or due to the underlying pathology. Abrupt withdrawal of antidepressants, particularly the monoamine oxidase inhibitors, is often associated with REM rebound.
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