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Brain Function and Psychotropic Drugs$

Heather Ashton

Print publication date: 1992

Print ISBN-13: 9780192622426

Published to Oxford Scholarship Online: March 2012

DOI: 10.1093/acprof:oso/9780192622426.001.0001

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Arousal and sleep systems

Arousal and sleep systems

Chapter:
(p.10) (p.11) 2. Arousal and sleep systems
Source:
Brain Function and Psychotropic Drugs
Author(s):

Heather Ashton

Publisher:
Oxford University Press
DOI:10.1093/acprof:oso/9780192622426.003.0002

Abstract and Keywords

The arousal and sleep systems interact with other functional systems and generate patterns of neural activity which may at times have an asymmetric hemispherical distribution. They utilize many transmitters and employ multiple redundant back-up systems. They are subject to malfunction, as manifested in anxiety states and sleep disorders, and they are very sensitive to centrally-acting drugs. This chapter describes the neurological organization of these systems.

Keywords:   arousal, sleep, functional system, neural activity, sleep disorders, neurological organization, anxiety states

All the general principles described in Chapter 1 apply to arousal and sleep systems. They interact with other functional systems and generate patterns of neural activity which may at times have an asymmetric hemispherical distribution. They utilize many transmitters and employ multiple redundant back-up systems. They are subject to malfunction, as manifested in anxiety states and sleep disorders, and they are exquisitely sensitive to centrally-acting drugs. The neurological organization of these systems is described in this chapter; functional disorders and the effects of psychotropic drugs are discussed in Chapters 3 and 4.

Arousal systems

The ability to support consciousness is a fundamental attribute of the human brain. However, the degree of consciousness can vary from full alertness and vigilance, through a series of different levels and types of awareness, to deep sleep. These variable states of arousal, reactivity, or responsiveness, along with their somatic accompaniments, are largely controlled by the arousal systems of the brain.

There has been much discussion concerning the definition and measurement of arousal. Is it a behaviour or a psychological state? Can it be measured by its somatic accompaniments, such as motor activity or heart rate, or by its electrical correlates, such as the frequency and degree of synchronization of electroencephalographic activity? There are many instances in which these variables do not match (Vanderwolf and Robinson 1981). For example, low voltage fast activity on the electroencephalogram (EEG) is usually associated with behavioural arousal, but such EEG activity can also occur during behavioural sleep, as in paradoxical sleep, after some drugs, and in human subjects in coma.

Even when behavioural and EEG arousal apparently match, the quality of arousal may vary widely: it may consist of generalized vigilance, concentrated selective attention, motor readiness or activity, and each of these conditions may be accompanied by variable emotional states. Arousal occurs during laughing, but also during crying, and in fear or anger. Arousal, though a convenient term, is clearly not a unitary phenomenon operating along a single dimension. It is a complex of different states of neural activity produced through a variety of combinations (p.12) of several anatomical and functional subsystems, resulting in changeable patterns of brain and behavioural response to internal or external stimuli. Thus, it is not surprising that arousal cannot be measured in terms of any one variable, any more than ‘emotionality’ could be defined in terms of any one emotion. In referring to different states of arousal, it is necessary to specify which manifestations and which types of response are involved.

Arousal systems in the brain appear to include at least two closely integrated components (Routtenberg 1968): a general arousal system (Arousal System I), which exerts a tonic background control over central nervous system excitability, and a goal-directed or emotional arousal system (Arousal System II), which contributes phasic and affective components of arousal and is also concerned in selective attention. Both subsystems influence the somatic responses to external and internal stimuli. These systems allow for both very rapid (phasic) and for sustained (tonic) responses of the whole organism to the environment. The selection of the appropriate response to a stimulus is greatly influenced by activity in reward and punishment systems (Chapter 5), and by learning and memory (Chapter 8), but the state of readiness to respond, and the speed and degree of the response, is mainly determined by activity in arousal systems.

General arousal

The general arousal system is a non-specific system which exerts a tonic control on the degree of responsiveness of the cerebral cortex and many subcortical structures (Mountcastle 1974; Webster 1978). A major neurological substrate is the brainstem reticular formation, a system of nerve cells and fibre tracts which links sensory information from the internal and external environment with the cortex and with effector-motor systems (Fig. 2.1). The reticular formation receives an input, in afferent collaterals from the sensory pathways and via the spinothalamic tracts, from virtually all the sensory systems of the body. Its connections include fibres from pathways subserving pain, temperature, touch, pressure, from visceral sensory endings, from vestibular, auditory, olfactory and retinal pathways, and from brain areas concerned with thoughts and emotions. These connections are not specific for sensory modality since impulses from different sense organs impinge on the same reticular neurones. The output from the reticular formation is transmitted by long ascending fibres which are diffusely distributed to all cortical areas and also to other parts of the brain, and by descending motor fibres in the reticulospinal tracts.

The anterior part of the reticular formation, and also a central core of ascending fibres, carry mainly facilitatory influences to the cortex. This (p.13) portion comprises the reticular activating system, which has long been thought to be of primary importance in maintaining consciousness. Electrical stimulation of this area in animals evokes immediate and marked cortical EEG activation, and will cause a sleeping animal to awake instantaneously (Moruzzi and Magoun 1949). Furthermore, the neuronal activity provoked by reticular activating system stimulation is very widespread, including the whole cortex, thalamic nuclei, basal ganglia, hypothalamus, other portions of the brainstem, and the spinal cord. This diffuse activation continues for up to a minute after the initial stimulation.

                      Arousal and sleep systems

Fig. 2.1 Diagram of brainstem reticular formation and some connections involved in the general arousal system. Specific afferent pathways, ascending to localized cortical areas, also send inputs via afferent collaterals to the reticular formation. The output from the reticular formation is diffusely distributed to all cortical areas. Other outputs (not shown) are distributed to other parts of the brain and to the spinal cord. By this mechanism, a specific sensory stimulus not only excites a localized area of cortex but also, through the reticular formation, causes diffuse cortical excitation, allowing evaluation of the stimulus. Feedback systems, which may be either excitatory or inhibitory, also pass from cortex to reticular system. The appropriate behavioural response is then transmitted via descending pathways from the cortex.

The reticular activating system appears to provide a background level of stimulation which lowers the cortical threshold to excitation from (p.14) other pathways, including the specific sensory tracts. Thus, for example, a visual stimulus excites not only the visual cortex through its specific afferent pathways, but also the whole cortex through non-specific pathways from the reticular activating system. The discrete, specific projections allow the cortex to discriminate the origin and type of stimulus, while the diffuse non-specific projections, along with intracortical connections, presumably allow other parts of the cortex to evaluate the significance of each specific sensory stimulus in relation to the present situation, memories of past events, associated sensory input, and other relevant factors. The effect of sensory information entering the cortex via the specific sensory pathways, and therefore the behavioural response to it, is in this way modulated by the non-specific input from the reticular activating system.

                      Arousal and sleep systems

Fig. 2.2 Diagram of section through cat brain indicating location and effects of cerveau isolé, encéphàle isolé, and midpontine pre-trigeminal preparations. cer, nucleus coeruleus; RPC, nucleus reticularis pontis caudalis; RPO, nucleus reticularis pontis oralis; sol, nucleus parasolitarius; Ic, inferior colliculus; Sc, superior colliculus; III, oculomotor nucleus; IV, trochlear nucleus; V, trigeminal nucleus. (From Salamy 1976, by kind permission of John Wiley & Sons Inc., New York.)

However, reticular cells possess an intrinsic tone maintained by neuronal oscillators which confer an inherent rhythmicity independent of sensory input (Changeux 1985; Llinas 1987). In surgical preparations in which afferent input to the reticular activating system is sectioned (encéphàle isolé; Bremer 1935; Fig. 2.2), some cortical activity is maintained, as shown by the fact that such preparations show alternating patterns of sleep and wakefulness on the EEG. On the other hand, if the brain is sectioned rostral to the reticular activating system (Bremer’s cerveau isolé preparation) consciousness is lost and a state of perpetual sleep supervenes. Similar data is sometimes provided by disease. Thus, when the reticular activating system is damaged by haemorrhage, tumour, or infection, the patient loses consciousness even if the cortex is still intact. Pharmacological evidence also attests to the importance of the reticular activating system in maintaining consciousness. Drugs (p.15) which directly depress neuronal activity in the reticular activating system (low doses of barbiturates) decrease the level of consciousness, while drugs which directly stimulate activity at this site (amphetamines) have an alerting effect (Fig. 2.3).

The effect of reticular activating system activity on the cortex is modified by interacting feedback systems from cortex to reticular formation (Fig. 2.1). Descending cortico-reticular fibres may be either (p.16) excitatory or inhibitory. Activity in excitatory pathways further stimulates the reticular activating system so that the arousing effect of the original stimulus is magnified. Conversely, when descending inhibitory pathways are activated, the effect of the original stimulus is damped down and limited. Thus, the brain exerts a selective control over its own sensory input so that the arousing effect of relevant stimuli is greater than that of irrelevant stimuli.

                      Arousal and sleep systems

Fig. 2.3 Diagram showing sites of action of drugs affecting activity in the reticular activating system and its afferent collaterals. Drugs which directly affect activity in the reticular activating system (barbiturates, depressant; amphetamine, stimulant) alter the level of consciousness by effects on the diffuse cortical projection system. Drugs which depress activity in the afferent collaterals (chlorpromazine) do not impair consciousness because they do not affect the intrinsic tone of the reticular activating system. LSD-25 appears to facilitate transmission through the afferent collaterals, enhancing the diffuse cortical effects of sensory stimulation. (From Bradley 1961, by kind permission of Oxford University Press.)

Goal-directed and emotional arousal

Closely connected with the general arousal system is a second arousal system which appears to supply cortical responses with emotional qualities such as fear and anxiety, anger, pleasure, and aversion. To a large extent, this system determines the quality and strength of the response to any stimulus, and its activity adds a selective, goal-directed aspect to arousal behaviour.

                      Arousal and sleep systems

Fig. 2.4 Some structures and connections of the limbic system. Schematic diagram of the classic limbic system proposed by Papez (1937) and MacLean (1949). (From Stinus et al. 1984)

The main anatomical basis for this aspect of arousal is the limbic system, a heterogeneous group of functionally-related structures surrounding the midbrain (Papez 1937; MacLean 1949,1969; Isaacson 1974,1982; Fig. 2.4). It includes tissues derived from the limbic lobe of the paleocortex (cingulate, parahippocampal, hippocampal and dentate gyri, induseum griseum, olfactory lobe and bulb), related subcortical nuclei (amygdaloid nucleus, anterior thalamic, septal and hippocampal nuclei), (p.17) and fibre tracts (fornix, mammillothalamic tract, stria terminalis, and olfactory tract). These structures are closely interconnected with each other and also with the thalamus, hypothalamus, striatum, reticular activating system and median forebrain bundle.

Certain of the limbic nuclei appear to be directly involved in controlling emotional tone. For example, electrical stimulation of some parts of the amygdala in many animal species produces rage, aggression, and attacking behaviour, while stimulation of other parts of the amygdala inhibits this behaviour. There also seems to be a separation between fear and flight behaviour on the one hand and aggressive attacking behaviour on the other, depending upon which part of the amygdala is stimulated or sectioned. Stimulation of the septal region has a taming effect on various animals, and decreases most emotional responses, while destruction increases emotional and social responses. Interconnected with these limbic nuclei are nuclei in the lateral, ventromedial, and posterior hypothalamus, which appear to generate basic drives such as hunger, thirst, and sex.

All these nuclei also form part of the reward systems, described in Chapter 5. Electrical stimulation in many limbic areas appears to be highly rewarding in all animals species studied and it is thought that their activity contributes an element of incentive or motivation that leads to reward-seeking behaviour in arousal. Also of importance are ‘punishment’ areas where electrical stimulation is aversive. These appear to be involved in avoidance behaviour. At present, it is not possible to define exactly the neurophysiological substrates for separate emotions: presumably each emotion involves activation of a unique pattern of limbic and neocortical structures. The question is discussed further in relation to anxiety in Chapter 3 and to other emotions related to reward and punishment in Chapter 5. There is evidence of some right hemispherical specialization for the experience of emotions (Ross 1984; Geschwind 1983).

These emotional components of arousal mediated by the limbic system are integrated with the mechanisms for learning and memory, in which the hippocampus plays a vital role (Chapter 8). Through learning and memory, the arousing effects of repeated stimuli can be either enhanced or extinguished.

The reticular and limbic arousal systems interact closely with each other. In many ways, they can be thought of as complementary, the general arousal system providing a tonic background of cortical responsiveness while the goal-directed system focuses attention onto factors relevant at the moment. However, Routtenberg (1968) proposes that in certain respects the systems are mutually inhibitory, activity in one tending to suppress activity in the other. He suggests that there is a dynamic equilibrium between the two systems, and it seems likely that maximally efficient behaviour under different circumstances requires a shifting (p.18) optimal balance of activity between general and limbic arousal and their interactions with other cortical and subcortical systems.

Selective attention

As already mentioned, the brain exerts a selective control over its own sensory input. It is not a passive recipient of the multitude of environmental stimuli which impinge on it, but contains mechanisms which allow it to avoid distraction by irrelevant stimuli and to direct attention towards behaviourally relevant stimuli. Such selective attention is a complex process which includes several components such as vigilance, concentration, focusing, scanning, and exploration. The process involves co-operative activity within the reticular and limbic arousal systems, and in connected cortical and subcortical sensory and motor structures.

Observations, reviewed by Mesulam (1983), on patients with the syndrome of unilateral neglect and related experiments with laboratory primates have shed some light on the brain structures involved in selective attention. The posterior parietal cortex appears to be of particular importance. Patients with lesions in this area tend to ignore sensory events occurring within the contralateral half of the sensory field. Effects are most pronounced if the damage is on the right side of the brain: such patients may neglect to dress the left side of the body, ignore objects on the left, and fail to read or write on the left half of a page. They may deny that the left side of the body belongs to them: ‘Even when a hand, for example, is pinched so hard that the patient winces or cries out, they still deny that the hand is theirs’ (Melzack 1990, p. 90).

In the monkey, electrophysiological recordings have shown that individual neurones in the inferior parietal cortex increase their firing rate when the animal looks at or approaches motivationally relevant objects, such as food when the animal is hungry or water when it is thirsty. Detection of similar stimuli which have no motivational relevance does not increase the firing rate of the cells. It appears that these neurones are able to associate sensory information with internal drives and that increased firing corresponds to a state of heightened selective attention. In man, recordings from electrodes implanted deep in various brain areas show that cortical evoked responses associated with attention are also generated from the inferior parietal cortex with associated inputs from the hippocampus and frontal cortex (Smith et al. 1990). Mesulam (1983) suggests that these connections enable the brain to make a series of overlapping representations (sensory, motor, motivational) of the outside world and to take the appropriate action. These processes are relatively specialized in the right hemisphere which, unlike the left hemisphere, has a good understanding of bilateral corporal and extracorporal space (Cook 1986). In man, selective attention related to semantic information probably (p.19) involves Wernicke’s area (Chapter 8), and the dorsolateral prefrontal cortex appears to control higher levels of visuospatial and linguistic attention (Posner and Presti 1987).

Somatic arousal

Both arousal systems give off efferent connections which activate body responses to arousal (Fig. 2.5). Descending fibres from the reticular formation in the reticulospinal tracts play a major role in regulating muscle tone and are also involved in posture and movement. Thus, part of the response to excitation of the general arousal system is increased muscle tone, increased reflexes, an alert posture and readiness for movement, while inhibition of this system produces muscular relaxation. Centres for autonomic control of cardiovascular, respiratory, and other responses are also situated in the reticular formation. The limbic system, through its hypothalamic connections, is a major determinant of both autonomic and endocrine responses to arousal. Increased activity in the limbic arousal system results in increased sympathetic activity and increased output of anterior and posterior pituitary hormones, while decreased activity leads to a predominance of vegetative parasympathetic activity. There are also close interconnections between limbic and striatal (p.20) structures (Mogenson 1984) and alterations in muscle tone normally accompany emotional responses. Different emotions may trigger different somatic responses: the pallor of fear, the purple of rage, the blush of shame. Different patterns of cardiovascular and electrodermal activity are evoked by rewarding, as compared with frustrating, conditions (Tranel 1983). However, reports from subjects with spinal cord injuries show that such peripheral responses are not essential for the subjective experience of emotion (Lang et al. 1972). Somatic changes occurring in states of arousal are described in Chapter 3.

                      Arousal and sleep systems

Fig. 2.5 Diagram of some central connections involved in peripheral arousal responses.

Neurotransmitters and arousal

In view of the multiplicity of synaptic connections required for the integrated control of arousal, it is not surprising that several neurotransmitters are utilized. Cell bodies containing noradrenaline, dopamine, and serotonin are all present in the reticular formation, and cell groups containing cholinesterase, indicating cholinergic transmission, have also been demonstrated. Many of these neurones have overlapping projections to cortical and limbic areas, and it has therefore proved difficult to assign particular functions to individual cell groups.

Cholinergic systems

The distribution of cholinergic pathways in the brain is described by Cuello and Sofroniew (1984; Fig. 2.6) and Reavill (1990). One pathway from the reticular activating system to the cortex appears to be cholinergic. (p.21) Thus, stimulation of the reticular activating system produces both EEG and behavioural arousal, accompanied by increased release of acetylcholine from the cerebral cortex. There is an increase in acetylcholine turnover in the cortex during arousal and a decrease in slow wave sleep. Mason and Fibiger (1979) demonstrated a functional interaction between cholinergic and noradrenergic systems in the brain, and suggest that cholinergic activity modulates activity in noradrenergic systems to influence the degree of behavioural arousal.

                      Arousal and sleep systems

Fig. 2.6 Diagram of cholinergic cell groups and major cholinergic pathways in the rat brain. OB, olfactory bulb; AON, anterior olfactory nucleus; DB, nucleus of the diagonal band; S, septum; CP, caudate putamen; H, hippocampus; BN, nucleus basalis; A, amygdala; TH, thalamus; Ar, arcuate nucleus; TR, tegmental reticular system; LDT, lateral dorsal tegmental nucleus; RF, hindbrain reticular formation; C, cortex; IP, nucleus interpeduncularis; SM, stria medullaris; MH, medial habenula; OT, olfactory tubercle; FR, fasiculus retroflexus. Classical motor and autonomic preganglionic neurones are not represented. (From Cuello and Sofroniew 1984.)

A system of cholinergic neurons with their cell bodies in various fore-brain nuclei (nucleus of diagonal band, medial and lateral preoptic nuclei, nucleus basalis, and the extrapeduncular nucleus) project to all parts of the cerebral cortex. One of the functions of this system may be in learning and memory (Chapter 8). Cholinergic neurones in the periventricular system are involved in reward and punishment systems (Chapter 5). Both nicotinic and muscarinic cholinergic receptors are present in the brain but their functions are not clear. Nicotinic receptors control ion channels and mediate rapid excitatory responses; muscarinic receptors affect intracellular events and exert slower modulatory actions (Strange 1988).

Noradrenergic systems

Monoamine-containing cell groups in the reticular formation have been localized by histofluorescence techniques (Table 2.1). Cell groups containing noradrenaline are designated A1–7. Groups A1–5 project to the spinal cord and hypothalamus, and may be involved in autonomic (p.22) function. Groups A6,7 constitute the locus coeruleus, a collection of only a few thousand neurones with extremely diffuse projections to many areas including the cerebral cortex, limbic system and spinal cord (Fig. 2.7a). Individual neurones in the locus coeruleus innervate huge territories; for example a single cell may project both to the cortex and to the cerebellum (Saper 1987). Such connections suggest widely distributed functions and the locus coeruleus is thought to be involved in general and limbic arousal (Jouvet 1972, 1977; Webster 1978; Jacobs 1984), selective attention (Mason 1979; Clark et al. 1984), vigilance (Saper 1987), anxiety and fear reactions (Gray 1982; Chapter 3), affective and pain responses (Redmond 1987; Chapter 5), and cortical plasticity (Pettigrew 1978; Chapter 8). The extensive afferent and efferent connections of the locus coeruleus suggest that it may function (among other things) as an alarm relay or ‘enabling’ system associated with attention and anticipation (Redmond 1987; Karli 1984), and that it provides an important link between the general and limbic arousal systems.

Table 2.1 Monoamine-containing cell groups in the reticular formation

Cell group

Transmitter

Nuclei

Projections

A1,2

noradrenaline

various

spinal cord

A3,4,5

noradrenaline

various

hypothalamus, preoptic area

A6,7

noradrenaline

locus coeruleus and subcoeruleus

thalamus, neocortex, limbic system, cerebellum, spinal cord

A8,9

dopamine

substantia nigra

corpus striatum

A10

dopamine

ventral tegmentum

limbic system, frontal cortex

A11,12,13

dopamine

various

hypothalamus, thalamus, median eminence

B1–9

serotonin

raphe nuclei and several other nuclei

wide distribution in diencephalon and spinal cord

Electrical stimulation of the locus coeruleus produces increased EEG arousal with behavioural signs of fear and anxiety, while bilateral destruction in animals produces loss of forebrain noradrenaline and continuous slow wave sleep. Direct recording from single noradrenergic neurones in the locus coeruleus in freely-moving cats, rats, and monkeys (Jacobs 1984) show that the firing of these cells is strongly state-dependent, the highest firing rates occurring during behavioural arousal and attention, and the lowest during sleep.

Adrenergic pathways in the median forebrain bundle are also involved in reward and reinforcement (Chapter 5) which contributes part of the goal-directed limbic arousal system. Noradrenergic pathways in general are thought to play a role in the mechanism of drive and aggression.

A role of catecholamines in arousal is further indicated by the observations that behavioural and EEG arousal is produced both in animals and humans by the injection of noradrenaline into the cerebral ventricles or directly into the substance of the brain and that L-dopa and sympathomimetic drugs produce increased arousal, while depletion of brain monoamines with reserpine causes EEG and behavioural de-arousal (Candy and Key 1977; Vanderwolf and Robinson 1981).

The effects of noradrenaline released by noradrenergic neurones in the reticular formation depend on the type of noradrenergic receptor activated. Adrenergic receptor subtypes are described in more detail in Chapter 11. They include post-synaptic α1-receptors, which in general mediate excitatory effects, and post-synaptic β-receptors, which generally mediate depressant effects in the central nervous system (Bevan et al. 1977; Aghajanian and Rogawski 1983). Adrenergic α2autoreceptors exert an inhibitory modulatory control over noradrenaline release. The distribution of these receptors differs in different parts of the brain. The neocortex contains both α1and β-receptors, and may show either excitatory or depressant responses to noradrenaline. The locus coeruleus contains mainly α2-receptors and the iontophoretic application of noradrenaline depresses the firing of neurones in this nucleus. The dorsal raphe nuclei contain mainly α1-receptors and are almost universally activated by the iontophoretic application of noradrenaline (Aghajanian and Rogawski 1983).

(p.23)

                      Arousal and sleep systems

Fig. 2.7 Monoaminergic pathways in the brain, (a) Noradrenergic pathways. (b) Dopaminergic pathways. (c) Serotonergic pathways. Note wide distribution of noradrenergic and serotonergic pathways and more discrete dopaminergic projections. Diagrams are based on animal data. (From Kruk and Pycock 1979.)

(p.24) Dopaminergic systems

Cells of groups A8–3 in the reticular formation contain dopamine (Table 2.1 Fig. 2.7b). Groups A8,9 constitute the substantia nigra, project to the corpus striatum, and affect muscle tone. Group A10, situated in the ventral tegmental area, consists of the cell bodies of the dopaminergic mesolimbic pathway. These cells project along the median forebrain bundle to limbic areas and to the frontal cortex. This pathway is involved in limbic-mediated arousal; its stimulation by application of dopamine to the nucleus accumbens produces intense arousal, hypervigilance, hyperactivity and exploratory behaviour in several animal species (Stevens 1979). Furthermore, the cell bodies of Group A10 lie within the reward area found from self-stimulation experiments (Chapter 5). Single unit recording of the activity of dopaminergic cells in the substantia nigra and ventral tegmental area (Jacobs 1984) show a stable rate of discharge with little variation between quiet waking and sleep. However, the discharge rate increases during movement and appears to be particularly related to purposive movements. Groups A11–13 project to parts of the hypothalamus, thalamus, and median eminence; their functions are not clear, but they are involved in the release of hypothalamic and pituitary hormones. Dopaminergic systems involved in schizophrenia and in Parkinsonism, and dopamine receptor subtypes are described in Chapter 13.

Serotonergic systems

Cell groups B1–9 in the reticular formation all contain serotonin (Table 2.1, Fig. 2.7c). Groups B1–3 project to the spinal cord; the others have diffuse connections, passing along the median forebrain bundle, the whole cerebral cortex and also limbic and hypothalamic structures. The functions of these systems are not clear, but the upper and lower raphe nuclei which contain the cells of B7,8 and B1–3 are involved in arousal and sleep in animals. Single unit recordings from the dorsal raphe nuclei in freely moving cats (Jacobs 1984) shows that the discharge rate of these serotonergic cells is closely related to the level of behavioural arousal: the highest rates of discharge occur during arousal, lower rates during slow wave sleep, and the cells become completely quiescent during paradoxical sleep. Their activity appears to be modulated, but not controlled, by (p.25) noradrenergic activity. It is thought that serotonergic pathways from the raphe nuclei play a part in general perception (Andorn et al. 1989) and, by controlling ascending traffic through afferent collaterals into the reticular formation, may normally protect the brain from being overwhelmed by sensory information. Serotonergic pathways in the median forebrain bundle may interact with adrenergic and dopaminergic pathways in reward functions (Chapter 5). Serotonin receptor subtypes are described in Chapter 3.

Jacobs (1984) suggests that the various monoaminergic systems subserve different but related functions in arousal: noradrenergic and serotonergic systems, with their widespread projections, may transmit information to the rest of the central nervous system concerning the animal’s general behavioural state, while the more discretely projecting dopaminergic systems may be related to purposive movements and changes of muscle tone related to focused attention. The cell bodies of noradrenergic, serotonergic, and dopaminergic neurones in the reticular formation all appear to be autoactive, showing regular spontaneous activity during quiet waking; this property may largely account for the intrinsic tone of the reticular activating system.

Histaminergic systems

Histaminergic neurones have been identified in several magnocellular nuclei of the hypothalamic mammillary region in the rat. They project diffusely to large areas of the cortex with a distribution resembling that of monoaminergic pathways (Pollard and Schwartz 1987; Nicholson 1987). It seems likely that histamine is a central neurotransmitter, and three types of histamine receptors have been demonstrated in the brain (Schwartz et al. 1986). These include H1 and H2 receptors, similar to those in peripheral tissues, and H3 receptors which are probably auto-receptors modulating histamine release and synthesis. Stimulation of H1 and H2 receptors profoundly potentiates a variety of excitatory signals including depolarization induced by excitatory amino acids and synaptically-evoked spikes, and Schwartz et al. (1986) suggest that histamine acts as a ‘waking amine’, an action probably involving both H1 and H2 receptors. Pollard and Schwartz (1987) quote evidence that some histaminergic neurones in the caudal hypothalamus of cats discharge tonically during waking and paradoxical sleep, while others are selectively activated during waking. In addition, histamine antagonists (especially H1-receptor antagonists) which enter the brain have sedative actions in man.

Present knowledge thus suggests that several transmitter systems, cholinergic, noradrenergic, dopaminergic, serotonergic and histaminergic, are involved in various aspects of arousal. This list is unlikely to be exhaustive; for example, the dopaminergic pathway from the ventral (p.26) tegmental area to the nucleus accumbens is subject to feed-back control in which the neurotransmitter is GABA (Stevens 1979), and there is growing evidence that various polypeptides are involved in arousal and sleep and that these may be co-secreted with monoamines. Neurotransmitter systems involved in sleep are described later in this chapter. The locus coeruleus contains dopamine and opioids as well as noradrenaline and has receptors for GABA (Redmond 1987) and acetylcholine (Mason and Fibiger 1979). In addition, excitatory amino acids, such as glutamate (Chapter 8) are almost certainly involved in most excitatory processes in the brain.

Performance and arousal

The relationship between the level of arousal and performance is complex. If, for example, performance is measured as reaction time and this is plotted against an index of arousal such as subjective alertness, heart rate, or electrodermal activity, it is found that the speed of response becomes faster as the subject becomes more alert, but at a certain point, when the subject becomes over-aroused, the speed of response begins to decline. Such considerations led to the formation of the ‘Yerkes-Dodson (p.27) law’ (Corcoran 1965), which holds that the quality of performance is related in an inverted U-shaped function to arousal level. Thus, performance is poor when subjects are under-aroused, and also when they are over-aroused, with the optimal level of arousal lying somewhere in the middle (Fig. 2.8). The situation is further complicated by the fact that the particular level of arousal which is optimal for performance depends on the nature of the task. In general, complex tasks, especially those requiring fine motor co-ordination, are performed better at relatively low levels of arousal, while less demanding tasks are performed better at higher levels of arousal. Peak performance on a particular task presumably reflects an optimal balance of activity between the general and limbic arousal systems.

                      Arousal and sleep systems

Fig. 2.8 Relationships between level of arousal and performance. Performance is maximal when the level of arousal is optimal for a given task, but declines when the level of arousal is below (arousal 1) or above (arousal 2) the optimal level. Central stimulant drugs may improve performance in relatively under-aroused subjects, but impair it in highly aroused subjects; central depressant drugs may have the opposite effects. (From Ashton and Stepney 1982.)

These relationships are important in determining the effects of drugs on performance. Central nervous system stimulant drugs may improve performance in relatively under-aroused subjects. However, in moderately or highly aroused subjects, such drugs may impair performance by making them over-aroused. A similar dual effect on performance may occur with central nervous system depressants; the performance of highly aroused subjects may be enhanced when the arousal level is reduced, while that of relaxed subjects may be reduced in efficiency. Arousal levels of different subjects vary according to personality (Eysenck 1967, 1981), circumstances and pathological states such as anxiety neuroses, and the effects of drugs on performance vary with individuals and cannot always be predicted.

Electroencephalographic measures of arousal

Some aspects of arousal can be measured by behavioural testing, subjective report, and recording of peripheral autonomic activity (Chapter 3). However, the most direct and sensitive non-invasive method of measuring cortical activity is by means of the EEG. Surface recorded brain potentials are thought to reflect local currents flowing in the dendrites of the superficial cortex and may be paced from the thalamus. Characteristic patterns are generated in different states and both the amplitude and the frequency of surface waves are determined to a great extent by activity in the reticular activating system.

Eeg wave bands and power-frequency spectrum

EEG wave bands are conventionally divided into four frequency bands (Table 2.2). Although the exact designation of each frequency band is arbitrary, the different frequencies (although they may overlap) do not occur as a continuum from 1 to 40 Hz, but seem to reflect different types of brain activity. These activities may be localized in different cortical (p.28) areas during different mental activities and psychological states (Lorig and Schwartz 1989).

Table 2.2 Electroencephalographies wave bands

Wave band

Frequency (Hz)

Approximate amplitude (μV)

Characteristic associated activity

delta

1–3

100

deep sleep depressant drugs

theta

4–7

100

some pathological states

alpha

8–13

50

awake relaxation

beta

14–40 +

20

increased arousal,

    beta1

14–26

mental activity

    beta2

27–40

stimulant and

   beta3

over 40

depressant drugs

References: Cooper et al 1980; Stein (1982); Saletu (1980).

The amplitude of waves at each frequency can be measured as the power-frequency spectrum which allows analysis of shifts of frequency and/or amplitude under different conditions and electrode positions (Fink 1978). Hemispheric differences in frequency are associated with various mental tasks in normal subjects: linguistic tasks tend to induce greater fast activity in the left hemisphere, while visuospatial tasks induce greater fast activity in the right hemisphere. EEG frequency is also extremely sensitive to the effects of centrally acting drugs and a wide range of psychotropic drugs give distinctive profiles on spectral analysis (Itil and Soldatos 1980; Saletu 1989).

Cortical evoked potentials

Signal averaging techniques have made it possible to record cortical evoked responses to stimuli such as light, sound, and somatic sensory stimuli. The early, small amplitude, components of these potentials (up to 50 ms after the stimulus) reflect the passage of impulses through the brainstem to the primary and secondary cortical sensory areas. The later components reflect more generalized cortical activation, and are thought to be associated with cognitive events. Various well-defined positive and negative waves occurring up to about 500 ms post-stimulus have been identified and changes in amplitude and latency have been associated with different states of arousal, attention, decision making, linguistic processing, and with centrally acting drug effects (Shagass and Straumenis 1978; Shagass 1977; Dongier et al. 1977; Fenton 1984; Neville 1985; Hillyard 1985; Kutas and Hillyard 1984; Roth 1987). Slow eventrelated (p.29) cortical potentials such as the contingent negative variation (Walter et al. 1964) also show changes in different emotional and cognitive states and are altered by psychoactive drugs (Tecce et al. 1978; Ashton et al. 1974, 1976, 1980, 1981).

Brain mapping tehniques

Recent developments in computer technology have allowed spatial and temporal mapping and multivariate analysis of EEG data including both power spectra and evoked potentials. Such techniques are helping to provide a picture of abnormalities in local and hemispheric cortical activity in neurological and psychiatric disorders (Roth 1987; Maurier et al. 1989) and to show topographical differences in the actions of various psychotropic drugs (Itil et al. 1985; Saletu 1989). Complementary techniques for measuring brain electrical activity, such as magnetoencephalography (Hoke et al. 1989; Lancet 1990b) are under development.

Sleep systems

Towards the lower extreme of the arousal spectrum lies the phenomenon of sleep, itself an expression of two distinct levels of arousal. The two types of sleep, orthodox and paradoxical, are conventionally described in terms of their EEG accompaniments (Oswald 1980; Hartmann 1976; Salamy 1976; Koella 1981).

Orthodox sleep

Orthodox sleep is somewhat arbitrarily divided into four stages which merge into one another, and represent a continuum of decreasing cortical and behavioural arousal (Fig. 2.9). Stage 1 is a transient phase, occurring at the onset of sleep, in which the EEG shows a tendency towards synchronization, predominant alpha activity (8–13 Hz) and a general flattening of the trace. Stage 2 consists of low amplitude waves, punctuated by sleep spindles which are bursts of synchronized electrical activity at 12–15 Hz. Stages 3 and 4 are associated with increasing amounts of high voltage synchronized delta waves at 1–3 Hz. These latter stages represent the deepest level of sleep and are also termed slow wave sleep (SWS). Neuronal firing rates are decreased in the majority of brain cells, and delta activity is most intense in frontal and cortical regions (Buchsbaum et al. 1982).

Somatic accompaniments of orthodox sleep include decreased peripheral sympathetic activity, and a reduction in brain blood flow with a shift from frontal to temporal regions (Ingvar 1979). The eyes show slow rolling movements and the pupils are constricted. Some degree of tone (p.30) is preserved in the skeletal muscles and the tendon reflexes are usually present although they may be depressed in Stage 4. However, co-ordinated movements such as turning over in bed, occur in Stage 2. Considerable endocrine activity occurs during SWS and in man there is a surge in output of growth hormone which peaks early in the night during the first SWS episode (Adam and Oswald 1977; Horne 1988). Prolactin and, in early puberty, luteinizing hormone and testosterone also show sleep dependent secretion (Oswald 1976).

                      Arousal and sleep systems

Fig. 2.9 EEG characteristics of orthodox sleep stages in two subjects. Locations of leads: F, frontal; P, parietal; O, occipital. (From Dement and Kleitman 1957.)

Paradoxical sleep

Paradoxical sleep or rapid eye movement sleep (REMS) has quite different characteristics. The EEG shows low voltage, unsynchronized fast activity similar to that found in the alert conscious state. The eyes show rapid jerky movements which can be recorded on the electro-oculogram. The jaw muscles relax at the onset of REMS and the tone of the skeletal muscles is completely lost, with absence of tendon reflexes. However, this state is periodically interrupted by spasmodic jerky movements of the limbs with hypertonus and momentarily increased tendon reflexes. Peripheral autonomic activity is increased: the heart rate becomes (p.31) irregular with bursts of tachycardia, the blood pressure fluctuates, respiration becomes irregular, sweating and penile erection occurs, and there is an increased output of adrenaline and free fatty acids. There is an increase in blood flow to the brain which may reach levels above those of wakefulness (Oswald 1976); maximal rates of flow occur in the frontal and parietal regions (Ingvar 1979; Heiss et al. 1985), and the firing rate of most neurons is increased.

                      Arousal and sleep systems

Fig. 2.10. Distribution of sleep stages during a night in normal young adults. (From Horne 1976.)

Dreaming has been closely associated with REMS (Aserinsky and Kleitman 1953), but also occurs in orthodox sleep (Freemon 1972). The mental experiences during REMS are often more vivid, but dramatic and often frightening dreams are not uncommon at the onset of orthodox sleep (Vogel 1975, 1978). Such hypnagogic hallucinations (Ashworth 1989; Pearce 1988) occur in normal subjects but may also be associated with anxiety, alcohol, benzodiazepines and narcolepsy. It seems clear that some form of mentation and therefore cortical activity occurs in all sleep stages.

The distribution of orthodox and REMS during a night’s sleep in normal young adult subjects is shown in Fig. 2.10. Orthodox sleep makes up about 75 per cent of total sleeping time. Early in the night there is a predominance of SWS (Stages 3 and 4) while Stage 2 sleep predominates later. The first REM episode occurs about 90 min after the onset of sleep, lasting only a few minutes. REM episodes recur approximately every 90 min and last longer as the night progresses. There are normally between four and six episodes of REMS per night. One or two brief awakenings also commonly occur during the night. The sleep pattern is influenced by age, the amount and proportion of both SWS and REMS being greater in infants and smaller in the aged. Changes in sleep patterns produced by disease and drugs are mentioned in later sections.

(p.32) Neural mechanisms of sleep

Both types of sleep are largely the result of active processes promoted and maintained by neural mechanisms in the lower brainstem, basal fore-brain, pons, and vestibular nuclei and parts of the limbic system. Electrical stimulation of the lower brainstem and areas in the basal forebrain produces EEG synchronization and behavioural sleep in intact animals, and records from single neurones in these areas show that they begin to discharge 1–2 min before the onset of natural sleep (Bloch and Bonvallet 1960; Bremer 1970). Conversely, complete transection of the brain-stem rostral to the bulbar portion, isolating the brain from the lower portion of the reticular formation, causes marked insomnia in cats with desynchronization of the EEG and ocular signs of increased wakefulness (Batini et al. 1959; Fig. 2.2). Thus, the lower portion of the reticular formation contains mechanisms for activating orthodox sleep by means of inhibitory fibres to the reticular activiting system and, probably, via relays in the thalamic nuclei, to the cortex.

The neural mechanisms for REMS appear to originate in the pons, brain-stem, and vestibular nuclei. Stimulation and section experiments have demonstrated separate centres in these areas which control EEG desynchronization and flaccid paralysis on the one hand and the superimposed phasic events of clonic limb and eye movements on the other (Jouvet 1967,1973; Chase and Morales 1984). REMS appears to be a subcortical phenomenon since it can occur after decortication; SWS on the other hand depends on the integrity of the cortex (Jouvet 1973).

The mechanisms which promote both orthodox and REMS are thought also to have reciprocal inhibitory connections with the active waking systems, so that activation of the sleep mechanisms at the same time inhibits awakening, and vice versa. Thus, both awakening and sleep result from the combination of active waking or sleeping mechanisms and passive de-waking or de-sleeping mechanisms (Koella 1981).

Neurotransmitters and sleep

Several neurotransmitters, neuromodulators, and hormones appear to interact in a highly complex manner in the sleep-wakefulness cycle. These include serotonin (and possibly melatonin), noradrenaline, dopamine, acetylcholine, GABA, and probably various polypeptides and hormones.

Serotonergic systems

There is considerable evidence that serotonergic mechanisms are of prime importance in sleep in animals. Depletion of brain serotonin by chloro-phenylalanine (p-CPA), which inhibits serotonin synthesis, is followed in cats by marked insomnia, the degree of which is proportional to the (p.33) decrease in cerebral serotonin. This insomnia is reversed by small doses of the serotonin precursor 5-hydroxytryptophan (5-HTP). Similarly, surgical destruction of the mesencephalic and pontine raphe system produces severe insomnia proportional to the decrease in serotonin in the nerve terminals. In intact animals, parenteral injection of 5-HTP or the injection of small doses of serotonin into the carotid artery or fourth ventricle induce behavioural sleep with EEG synchronization, while the administration of serotonin antagonists decreases sleep.

While it seems clear that serotonin promotes SWS in animals, its role in REMS is less clear. Monnier and Gaillard (1981) suggest that there is some specialization in the raphe system, the anterior part being concerned with SWS and the posterior part with the priming of REMS. In addition, different subtypes of serotonin receptors (Chapter 3) may mediate different aspects of sleep and wakefulness. Antagonists at 5-HT2 receptors increase SWS and wakefulness (Dugovic et al. 1989). However, the raphe nuclei also contain 5-HT1A receptors in high density and Idzikowski et al. (1986) suggest that these may mediate SWS.

Serotonin also seems to be involved in sleep in man, although the role of the various 5-HT receptor sub-types is not clear. As in rats, SWS is increased by the 5-HT2 antagonist ritanserin, both in normal subjects (Adam and Oswald 1987; Idzikowski et al. 1986) and in patients with dysthymic disorders (Paiva et al. 1988) but there is no effect on REMS. L-tryptophan has been found to increase SWS in several studies reviewed by Hartmann (1979), although the effects on REMS are variable.

Melatonin

Melatonin is synthesized from serotonin in the pineal gland but may also occur in other parts of the brain, notably the hypothalamus (Koslow 1974). The output of pineal melatonin increases during darkness and is suppressed by daylight. A role for this substance in sleep is suggested by observations that it induces sleep in chicks, cats, rats (Holmes and Sugden 1982), and man (Waldhauser et al. 1990). Its physiological role is not known but it has been suggested that it acts as a synchronizer for various diurnal rhythms (Krause and Dubovich 1990). Subhypnotic doses administered at appropriate local times are reported to hasten sleep readjustment and alleviate jet-lag in travellers across time zones (Petrie et al. 1989).

Noradrenergic and dopaminergic systems

Serotonergic neurones in the raphe nuclei are connected anatomically with noradrenergic cells in the locus coeruleus and dopaminergic cells in the ventral tegmentum. The functional relationship between these systems is probably important in the sleep-waking cycle through mutually inhibitory feedback loops (Kostowski 1975). While serotonergic activity (p.34) promotes SWS, catecholamine systems inhibit SWS and promote waking (Koella 1981). Enhancement of central catecholaminergic activity produces behavioural and EEG arousal, while reduction of such activity induces behavioural and/or EEG sedation.

The role of catecholamines in REMS is not clear. In man, REMS is decreased by the α2 adrenergic agonist clonidine (which reduces noradrenaline release) and increased by the α2 antagonist yohimbine (Kanno and Clarenbach 1985). However chronic administration of drugs which deplete central monoamine systems or block adrenergic receptors (reserpine, methyldopa) increase REMS, while drugs which increase central monoamine activity (L-dopa, amphetamine, monoamine reuptake blockers, monoamine oxidase inhibitors) decrease REMS (Hartmann 1976; Kay et al. 1976; Wyatt and Gillin 1976). In manic depressive and schizophrenic psychoses there are profound abnormalities in REMS which may be related to abnormal central monoamine function (Chapters 11 and 13).

Cholinergic systems

Present evidence suggests that cholinergic mechanisms, as well as producing arousal, induce or facilitate paradoxical sleep. The rate of liberation of acetylcholine from the cerebral cortex (Jasper and Tessier 1971) and corpus striatum (Gadea-Ciria et al. 1973) of the cat is increased during REMS compared with slow wave sleep. Injection of acetylcholine or carbachol in the region of the locus coeruleus induces REMS in animals (George et al. 1964), and atropine reduces REMS in cats (Jouvet 1969). In man, anticholinergic drugs such as atropine and scopolamine suppress REMS, while anticholinesterases appear to increase REMS. Thus, nightmares and excessive dreaming are common symptoms of anticholinesterase poisoning and industrial workers exposed to organophosphates have been found to have longer REM periods than normal or reduced latency of REMS (Wyatt and Gillin 1976).

GABA-ergic systems

The general inhibitory actions of GABA are likely to be involved in sleep. Jasper et al. (1965) showed that the release of GABA from the cat’s cerebral cortex is increased during EEG synchrony, and infusion of GABA induces cortical synchronization and behavioural sleep (Godschalk et al. 1977). In man, benzodiazepines and barbiturates, which enhance GABA activity in the central nervous system (Chapter 3) promote Stage 2 orthodox sleep and inhibit REMS and SWS (Kay et al. 1976); (Chapter 4). In addition, GABA-ergic systems in several parts of the brain exert an inhibitory control over the release of neurotransmitters associated with arousal, including noradrenaline, dopamine and acetylcholine.

(p.35) Polypeptides

The possibility that various polypeptides are involved in sleep has been investigated for many years. These studies are reviewed by Drucker-Colin (1981), Inque et al. (1982), and Koella (1983). For example, cross-circulation experiments in dogs showed that a blood-borne substance from a sleeping donor induced EEG synchrony in the recipient and a dialysate from the venous blood draining the brain in sleeping rabbits which would induce SWS in recipient rabbits. The sleep-inducing agent was subsequently isolated and identified as a polypeptide containing eleven amino acids, with a molecular weight of approximately 800; it was named delta sleep inducing peptide (DSIP). This substance was later found also to increase REMS in cats and to be present in the human brain. Pappenheimer et al. (1967) collected the cerebrospinal fluid of sleep-deprived goats and isolated a tetrapeptide that induced SWS on intraventricular injection in several animal species. This substance has since been isolated from human urine and found to be a muramyl peptide (Garcia-Arraras 1981; Krueger et al. 1985). Difficulties in the interpretation of such studies were discussed by Drucker-Colin (1981) who concluded that the existence of a specific sleep-inducing peptide in animals was not yet proved conclusively.

In man, circulating polypeptides do not appear to be critical for sleep since conjoined twins with shared circulations have independent cycles of sleep, waking, REMS and orthodox sleep (Lenard and Schulte 1972). However, peptide sleep-promoting factors produced in the brain may be part of a multitude of hypnogenic or de-awaking substances signalling sleepiness in states of sleep deprivation, and they may also be involved in the circadian rhythmicity so characteristic of sleep.

Certain polypeptide hormones may also play a part in the modulation of sleep. For example, it has been suggested that the release of growth hormone during SWS early in the night triggers the subsequent appearance of REMS (Stern and Morgane 1977). Growth hormone induces a dose-dependent increase of REMS in cats, rats, and humans (Drucker-Colin 1981). Other pituitary hormones and brain polypeptides including substance P, cholecystokinin, somatostatin, neurotensin, endogenous opioids, arginine vasopressin, vasoactive intestinal polypeptide, hypothalamic releasing factors, as well as steroid hormones including oestrogens have all been implicated as possible neuromodulators of sleep processes (Drucker-Colin 1981; Koella 1983).

Sleep deprivation

Although most adults normally sleep for 6–8 h each night, insomnia is a common complaint and is associated with feelings of ill-health. (p.36) However, major deleterious effects resulting from sleep deprivation have been difficult to demonstrate experimentally. The literature is reviewed by Horne (1988). Total sleep deprivation leads to impairment of performance in tasks requiring vigilance, since there is an increasing tendency for subjects to snatch ‘microsleeps’. In continuous prolonged tasks, a marked deterioration in performance begins after about 18 h (Mullaney et al. 1983). However, performance in short tasks remains remarkably normal. After 60 h total sleep deprivation, performance in games of darts and table tennis remained at 97 per cent and 100 per cent of pre-deprivation values in one study reported by Wilkinson (1965). Neurological and psychological changes occur including visual disturbances, tremor, slowness of speech, nystagmus, misperceptions, visual hallucinations, and depersonalization, increased suggestibility, subjective lassitude, anxiety, and decreased pain tolerance. Total sleep deprivation combined with isolation has been used in ‘brain washing’ techniques.

Recovery from total sleep deprivation is characterized by a rebound of SWS and later of REMS, usually at the expense of Stages 1 and 2 sleep which appear to be more ‘expendable’. Kales et al. (1970), in a study of 205 h of total sleep deprivation, found that in the first three recovery nights SWS increased 350, 250, and 200 per cent, respectively, from pre-deprivation levels. REMS showed a smaller and delayed rebound, increasing 30, 60, and 20 per cent over the same nights. Total sleeping time was increased during recovery nights, with an increase is 50 per cent on the first night, smaller increases on succeeding nights, and a return to normal on the fourth night.

Healthy young adults appear to adjust remarkably well to moderate total sleep limitation (e.g., from 8 to 6 h for 6 weeks). A greater percentage of time is devoted to SWS, at the expense of Stages 1 and 2 and REMS, and few adverse effects have been demonstrated (Horne and Wilkinson 1985). However, more severe partial sleep deprivation, combined with work stress, has been found to impair cognitive performance and vigilance and to have deleterious effects on mood in medical house officers (Orton and Gruzelier 1989; Deary and Tait 1987). Naturally occurring short sleepers have comparatively large amounts of SWS and small amounts of Stages 1 and 2 and REMS (Jones and Oswald 1968).

Early reports of severe psychological effects after selective deprivation of REMS have not been supported by later work and numerous studies have reported only mild disturbances after REMS deprivation for up to 14 consecutive nights. These include irritability, anxiety, increased appetite, difficulty in concentration, possibly some disturbance of memory function, but normally little impairment in psychometric tests (Vogel 1975; Home 1988). On recovery nights, there is a rebound with an increase in REMS time and intensity, increased vividness of dreams and sometimes nightmares (Oswald 1980; Beersma et al. 1990). (p.37) More marked and longer-lasting changes occur after drugs which reduce both REMS and SWS (Oswald 1980; Chapter 4).

Selective deprivation of SWS has been less studied. However, Agnew et al. (1967) reported that deprived subjects became depressed and lethargic, physically inactive and less responsive to the environment. Johnson et al. (1974) found impairment in vigilance tasks similar to that after total sleep deprivation. Rebound in SWS occurs on recovery nights. Comparisons of selective sleep state deprivation in animals and man suggest that REMS deprivation leads to increased cortical excitability while SWS deprivation leads to decreased cortical excitability (Vogel 1975).

Function of sleep

Despite growing information on the mechanisms which generate and regulate sleep, its function remains enigmatic. The overwhelming desire to sleep when deprived, and the rapid restoration of SWS and REMS after deprivation suggest that both types of sleep are necessary in man. Horne (1988) proposed that only a proportion of sleep, ‘core sleep’ (Stages 3 and 4 SWS and the first three cycles of REMS), is essential for normal function in man: the remainder of sleep, ‘optional sleep’ (mainly Stage 2 sleep) is dispensable. This claim is based on the findings that only SWS and a portion of REMS are reclaimed after sleep deprivation and that normal subjects can adapt with little difficulty to reduced sleep periods composed of ‘core sleep’. Horne suggests that optional sleep in mammals is a behavioural drive which conserves energy and occupies unproductive hours. Core sleep, however, includes both orthodox SWS and paradoxical sleep and, since these states are so different physiologically, most authors have assumed that their functions also differ.

Orthodox sleep

It is generally accepted that sleep is necessary for growth in the young and that it performs restorative functions in the adult, although the precise nature of these functions is not clear. Much evidence (quoted by Adam and Oswald 1977; Oswald 1976) supports the idea that SWS is connected with anabolic activity throughout the body. Anabolic hormones, including growth hormone, prolactin, luteinizing hormone, and testosterone are released during SWS. Growing animals and humans sleep more than adults, and sleep deprivation in the young stunts growth. SWS and growth hormone secretion appear to increase in adults after physical exercise and other factors which increase cerebral metabolic rate, including body heating and sustained, demanding attention (Home 1988). SWS is correlated with changes in body weight: acute starvation (p.38) and hyperthyroidism, in which there is increased protein catabolism during the day, are associated with increased SWS and growth hormone output during the night, while in hypothyroidism SWS is decreased. In addition, a wide range of body tissues in animals and man show increased rates of protein synthesis or mitoses during sleep. However, somatic restorative processes can be achieved during relaxed wakefulness and do not require sleep (Horne 1979, 1988).

SWS, in which the majority of cortical neurons have reduced firing rates and cortical responsiveness is at its lowest, may be of particular importance for anabolic processes in the brain. Increased concentrations of ATP and RNA and increased rates of protein synthesis have been found in the brains of rats, cats, and golden hamsters during sleep, and lower concentrations during sleep deprivation. Other workers have related SWS to memory consolidation (Broughton and Gestaut 1973; Stern and Morgane 1977; Ekstrand et al. 1977) and to cognitive processes related to daytime visual load (Horne 1988), both of which may require protein synthesis in the brain.

Paradoxical sleep

The function of REMS is even less clear than that of SWS; nor is it known whether the separate hypo- and hypertonic phases of REMS subserve different functions. It seems possible that one of the functions of REMS in some mammals is to conserve heat and energy (Horne 1988). During REMS, peripheral vasoconstriction occurs in the heat dissipating vascular organs of rabbits, cats, and other mammals, suggesting a thermoregulatory function. Furthermore, the amount of REMS is greater in small mammals, who can conserve relatively more energy during sleep than in larger mammals, and is more abundant in rodents that hibernate than in non-hibernating rodents of similar size. Sleep in general, including hibernation, appears to have originated as an adaptive process in response to environmental factors such as difficulty in finding food and low temperatures. It may also serve to protect some animals from predators.

However, these considerations do not appear to apply to primates, and it is quite possible that REMS, like other subcortical processes, has further evolved to perform different or more complex functions. Among apes, the amount of REMS is no longer negatively correlated with size, but is more abundant in larger species. These differences may be related to the length of time the infant remains immature. Horne (1988) suggests that in primates REMS, which is greatest in the human fetus, is basically a fetal state retained into adulthood which serves to keep the cortex stimulated. Such stimulation might conceivably enhance neuronal growth and the formation of synaptic contacts in the absence of external stimulation.

Many investigations have sought to establish a link between REMS and (p.39) memory. Sleep in general seems to improve memory and learning in animals and man, while sleep deprivation, especially REMS deprivation, impairs these processes. Thus, it has been suggested that sleep, especially REMS, is necessary for some memory processes. Circumstantial evidence often adduced in support of a connection between REMS and memory includes the observations that memory defects in old age, Korsakoff’s and Alzheimer’s dementias, other brainstem lesions, and mental retardation are associated with decreased amounts of REMS, while infants and children have increased amounts of REMS. However, interpretation of the many conflicting results is difficult, and in critical reviews Vogel (1975) and Horne (1988) conclude that an effect of REMS deprivation on memory is not established.

REMS has also been closely connected with dreaming, although it now appears that dreams can occur in both sleep stages. The observations of increased cerebral blood flow and a rapid rate of firing of most cerebral neurons during REMS give evidence of a particularly high level of brain activity. Current thinking suggests that dreams may be a by-product of this activity, which is related as much to forgetting as to remembering. Thus, Moiseeva (1979) suggested that during REMS the brain is ‘editing’ information received during the day and maintaining or establishing some synaptic connections by rehearsal while inhibiting others. Crick and Mitchison (1983) made the similar suggestion that ‘unlearning’ occurs during REMS, in which unwanted memory traces are removed and strong ones reinforced. Dreams presumably appear as fragments of these processes which happen to each consciousness.

Further investigations of the tantalizing connections between REMS, dreaming, memory, and temporal lobe epilepsy are discussed in Chapter 9. Alterations of sleep in psychotic states are described in Chapters 11 and 13, and drug effects on SWS and REMS are mentioned in Chapters 4, 12 and 14.