The nature of arousal in sleep

The nature of arousal in sleep

P E TER HAL A S Z 1 , MAR IO TERZANO 2 , L I BOR IO PARR INO 2

and R O BERT B OD I Z S 3

1Neurological Department, National Institute of Psychiatry and Neurology, Budapest, Hungary, 2Department of Neurology, Sleep Disorders

Center, University of Parma, Parma, Italy and 3Institute of Behavioural Sciences Budapest, Semmelweis University, Budapest, Hungary

Accepted in revised form 12 December 2003; received 24 September 2003

SUMMARY The role of arousals in sleep is gaining interest among both basic researchers and

clinicians. In the last 20 years increasing evidence shows that arousals are deeply

involved in the pathophysiology of sleep disorders. The nature of arousals in sleep is

still a matter of debate. According to the conceptual framework of the American Sleep

Disorders Association criteria, arousals are a marker of sleep disruption representing a

detrimental and harmful feature for sleep. In contrast, our view indicates arousals as

elements weaved into the texture of sleep taking part in the regulation of the sleep

process. In addition, the concept of micro-arousal (MA) has been extended,

incorporating, besides the classical low-voltage fast-rhythm electroencephalographic

(EEG) arousals, high-amplitude EEG bursts, be they like delta-like or K-complexes,

which reflects a special kind of arousal process, mobilizing parallely antiarousal swings.

In physiologic conditions, the slow and fast MA are not randomly scattered but appear

structurally distributed within sleep representing state-specific arousal responses. MA

preceded by slow waves occurs more frequently across the descending part of sleep

cycles and in the first cycles, while the traditional fast type of arousals across the

ascending slope of cycles prevails during the last third of sleep. The uniform arousal

characteristics of these two types of MAs is supported by the finding that different MAs

are associated with an increasing magnitude of vegetative activation ranging hierar-

chically from the weaker slow EEG types (coupled with mild autonomic activation) to

the stronger rapid EEG types (coupled with a vigorous autonomic activation). Finally,

it has been ascertained that MA are not isolated events but are basically endowed with a

periodic nature expressed in non-rapid eye movement (NREM) sleep by the cyclic

alternating pattern (CAP). Understanding the role of arousals and CAP and the

relationship between physiologic and pathologic MA can shed light on the adaptive

properties of the sleeping brain and provide insight into the pathomechanisms of sleep

disturbances. Functional significance of arousal in sleep, and particularly in NREM

sleep, is to ensure the reversibility of sleep, without which it would be identical to coma.

Arousals may connect the sleeper with the surrounding world maintaining the selection

of relevant incoming information and adapting the organism to the dangers and

demands of the outer world. In this dynamic perspective, ongoing phasic events carry

on the one hand arousal influences and on the other elements of information

processing. The other function of arousals is tailoring the more or less stereotyped

endogenously determined sleep process driven by chemical influences according to

internal and external demands. In this perspective, arousals shape the individual course

of night sleep as a variation of the sleep program.

k e y w o r d s micro-arousal, NREM sleep, K-complex, cyclic alternating pattern

(CAP)

Correspondence: P. Halasz, Neurological Department, National Institute of Psychiatry and Neurology, Huvosvolgyi ut 116, 1021 Budapest,

Hungary. Tel.: +36 1 391 54 36; fax: +36 1 391 54 38; e-mail: [email protected]

J. Sleep Res. (2004) 13, 1–23

� 2004 European Sleep Research Society 1

SLEEP AND AROUSAL SYSTEM

The major contributions to understanding the nature of sleep

were achieved at the beginning of the last century with the rise

of experimental physiology, promoted by the Russian physi-

ologist Pavlov (1928) and later with the development of

neurophysiology in the western countries (Berger 1930; Bremer

1935; Dempsey et al. 1941; Moruzzi 1972). What emerged

from these pioneering studies was the sequence of events that

rules the cyclic alternation between sleep and wakefulness. The

sleep-promoting systems are concentrated in the medial part of

the brainstem, dorsal reticular substance of the medulla,

anterior hypothalamus and basal forebrain. The wake-promo-

ting areas are mainly concentrated in the pontine and midbrain

tegment, the posterior hypothalamus, and the basal forebrain

cholinergic neurons. These structures are included in the

arousal and activating systems during sleep. Compared with

wakefulness, sleep is subjectively perceived as a reduced

responsiveness to environmental stimuli induced by a selective

closure to the inputs arriving from the external world (Steriade

2000a). The filter that gates the flux of information from the

peripheral receptors to the cortex is situated in the thalamo-

cortical connections where the incoming signals are blocked or

attenuated via synaptic inhibition. This mechanism modulates

the susceptibility of the cerebral cortex to all the activating

stimuli. In particular, the generators of cortical electrical

activity are modified during sleep and shift from the produc-

tion of low-amplitude high-frequency electroencephalographic

(EEG) activity (LAHF mode) typical expression of the massive

activation of the cortical cells, to the production of high-

amplitude low-frequency EEG activity (HALF mode) indica-

ting a widespread synchronization of the cortical cells (Steriade

and Llinas 1988; Steriade and McCarley 1990; Steriade et al.

1990). Rapid eye movement (REM) sleep, which appears later

in the night, is characterized by the simultaneous occurrence of

LAHF EEG activity, absence of muscle tone and recurrent

rapid eye movements. If EEG slowing is considered as the

expression of a reduced cortical activation typical of sleep, the

presence of REM sleep is undoubtedly a paradoxical condi-

tion, which indicates that sleep does not exclude states of

transient cerebral and cortical activation. The alternation

between non-REM and REM sleep is the outcome of a

balanced action based on the cyclic function of brainstem

structures (McCarley and Hobson 1975).

ACTIVATED STATES OF THE BRAIN

Attention to the functions and importance of activated brain

states was first raised by Moruzzi and Magoun (1949) who

demonstrated an �activation� process in the changes of EEG

waves and verified their brainstem origin. The discovery and

localization of brainstem reticular arousal system (RAS) was

made by lesion experiments and by electrical stimulation of the

brainstem reticular core (Hobson 1978). The EEG effect of

arousal was called as �desynchronization�, but the coincidenceof desynchronization with the concept of arousal has created

severe limitations to the future development of the field.

Although slow synchronization thalamic devices are really

decoupled and the EEG activity is flattened, a fast (30–40 Hz)

EEG pattern synchronization appears in the cortical and

thalamic networks (Steriade 1995). Accordingly, the term

�desynchronization� should be considered as a rapid shift from

HALF, typical of sleep, to LAHF, typical of wakefulness.

The pathways and the chemical codes for this function have

been explored in detail. Activation in the wake state and in

REM is prolonged in duration (expressed by an EEG tonic

pattern) and is associated with a sustained depolarization and

tonic firing in thalamocortical neurons, enhancing the prob-

ability of thalamic responses to incoming volleys. Excitation of

RAS neurons enhances cortical-evoked potentials (Bremer and

Stoupel (1959). The arousal effect can be evoked by stimula-

tion from the mesopontine cholinergic nuclei (Jones and

Webster 1988; Montplaisir 1975) and by stimulation of the

locus coeruleus (Steriade and McCarley 1990) setting into

action another noradrenergic activation pathway. However,

the vast majority of those reticular neurons, which take part in

the classical arousal effect, are glutamatergic (Steriade 1995).

Now it is clear that there are several arousal systems in the

brainstem working in a more differentiated way during the

wake state and REM sleep than it was imagined. The most

important neurochemical difference between the two activated

brain states is that during REM the monoaminergic (noradr-

energic and serotoninergic) neurons are silent (Hobson et al.

1975; McGinty and Harper 1976).

Functional neuroimaging studies proved several differences

between arousal in wakefulness and REM sleep, characterized

by a specific distribution of blood flow and glucose utilization

patterns, which delineates different sites of cerebral-activated

function. The brain areas where REM sleep neural activity is

higher than in wakefulness are the anterior cingulate cortex

(Braun et al. 1997; Buchsbaum et al. 1989; Nofzinger et al.

1997), the amygdala and the limbic–paralimbic regions (Braun

et al. 1997; Nofzinger et al. 1997), and the associative visual

areas (Braun et al. 1997, 1998; Madsen et al. 1991). In the

subcortical structures the pons is significantly more active

during REM sleep than during wakefulness (Braun et al.

1997). Conversely, neural activity in prefrontal association

areas (Braun et al. 1997; Madsen et al. 1991) and in the

inferior parietal association cortex (Braun et al. 1997) is lower

during REM sleep than during wakefulness. The co-activation

of limbic–paralimbic regions and higher order visual process-

ing areas together with the absence of frontal activation was

interpreted as a closed-loop operation between the limbic and

the visual system, which could be the neurobiologic basis of

dream mentation (Braun et al. 1998). An REM sleep-specific

activation of the amygdala was found, compared with the

unified data of wakefulness and NREM sleep (Maquet et al.

1996), as well as a positive correlation between amygdala

activity and temporal lobe activation during REM but not

during wakefulness (Maquet and Phillips 1998). The amygdala

is a significant modulator of brain activation during REM

sleep but not during wakefulness. In general, subcortical and

2 P. Halasz et al.

� 2004 European Sleep Research Society, J. Sleep Res., 13, 1–23

midline structures are more active during REM sleep than

during wakefulness. Once again functional neuroimaging

studies delineated significant differences between wakefulness

and REM sleep-related arousal.

Arousal from REM sleep deserves more studies. Cantero

and Atienza (2000) suggest that some burst of alpha activity

may indicate a state specific micro-arousal (MA) in REM

sleep. The same idea was incorporated in the extension of

CAP concept to REM sleep by Terzano et al. (1985) in their

first description of the pattern. The transitory occurrence of

alpha activity in REM sleep was in the same time used to

explain the phenomena of �lucid dreams� (Ogilvie et al. 1982).According to these results and interpretation alpha bursts in

REM sleep may represent a transitory gate toward wakeful-

ness.

INTERACTION BETWEEN THE SLEEP

SYSTEM AND THE AROUSAL SYSTEM

Sleep regarded as a state condition of brain-body rest conflicts

with the principle that life requires permanent activity of

essential functions. Because the brain is the organ that

warrants the continuity of these functions, the issue of brain

rest during sleep is misleading. The brain is permanently active

and is able to control the autonomic, metabolic and hormonal

changes that take place within the body and simultaneously

determine the behavioral responses to the external stimuli.

Although sleep is characterized by decreased conscious

perception, these tasks are accomplished nevertheless during

sleep through a gradual activation of the brain or through a

partial activation confined to some cerebral areas (Ujszaszi

and Halasz 1988). Such activation is stimulated by the arousal

system.

During NREM sleep the systems responsible for activated

states are actively inhibited (Szymusiak et al. 2001) and the

reciprocal antagonistic relationship between sleep and arousal

system preserves on the one hand life against danger and on

the other support the natural evolution of sleep (Saper et al.

2001).

The sleep promoting system and the arousal-promoting

system are the two pillars that bridge the internal process of

sleep to the external world. In this way, the sleeping brain not

only regulates the reactions but also assimilates in its

functions the incoming information. From a functional point

of view, sleep modulates and is modulated by this series of

interactions.

AROUSAL FROM SLEEP

The term �arousal� conventionally indicates a temporary

intrusion of wakefulness into sleep (Atlas Task Force 1992),

or at least a sudden transient elevation of the vigilance level

due to arousal stimuli or to spontaneous vigilance level

oscillations. When arousal interrupts sleep in a definitive, not

reversible way, we speak about awakening. Arousal is a

�relative concept�. It is not possible to understand arousal

without the related vigilance state. Aroused state and sleep are

two different sides of vigilance; we cannot define them without

each other. To speak about arousal in sleep may sound

controversial. There are however strong evidences that one of

the essential features of sleep is the arousability and presence

of abundant arousals.

The concept of arousal has a long history, which is closely

connected with the development of concepts about the

neurophysiology of sleep and wakefulness. The criteria and

measure of arousal are controversial issues; hence, arousal has

several definitions (Halasz et al. 1979; Lofaso et al. 1998;

Martin et al. 1997a; Rees et al. 1995; Schieber et al. 1971;

Terzano et al. 1985) and several EEG, behavioral and auto-

nomic aspects. The EEG resultant of arousal has massive

impact on the evolution of the sleep profile. Behavioral and

autonomic concomitants of arousal may or may not be present

at the same time. When they are present, they can be graduated

in intensity, while presence or absence of the single compo-

nents of the arousal constellation depends on the involvement

of the specific cerebral compartments. The questions are:

which constellations or single signs are sufficient to be accepted

as arousal markers? How should we consider specific EEG

phasic events characterized by slow waves but still endowed

with activating properties? How should we classify the somato-

vegetative phenomena not associated with any detectable EEG

modification?

To address these questions available data on the relation-

ship between different aspects of arousal and the underlying

neural mechanisms need to be reviewed. In the present paper,

we will focus our attention on the nature of arousal in sleep

in the broader context of dynamical changes during sleep.

We will provide evidence in favor of a hierarchical con-

tinuum of arousal phenomena showing multiple features and

multiple components. These varieties depend on the state of

the sleeper and the source and strength of the arousal

generator, but all sharing a homogeneous neurophysiologic

background.

The overview and reconsideration of this topic seems to be

appropriate for several reasons. In the last years a consider-

able pool of data has been accumulated from different sources

with heterogeneous approaches and views about the phenom-

enology of arousals in sleep both under physiologic and

pathologic circumstances. There is an endeavor to categorize

and standardize arousals from sleep; however there are

several contradictions and controversial views around this

issue. The American Sleep Disorders Association (ASDA)

produced a consensus report (Atlas Task Force 1992) on the

criteria of arousals in sleep in the early 1990s. Arousal is

defined as a rapid modification in EEG frequency, which can

include theta and alpha activity, and/or frequencies higher

than 16 Hz but not spindles. It can be accompanied by an

increase of electromyographic activity, of cardiac frequency

or by body movements. An arousal must be preceded by at

least 10 s of continuous sleep. According to these rules, slow

EEG features such as K-complexes and transient delta

activities, were not scored as arousals unless these patterns

The nature of arousal in sleep 3


were associated with an EEG frequency shift toward theta,

alpha or beta rhythms. For these reasons, the proposed

scoring system for arousals was strongly criticized by other

research groups who have been engaged in the last 30 years

with the study of the microstructure of sleep (Terzano et al.

1991a). The conceptual basis of the ASDA criteria is that

arousal is a marker of sleep disruption, a detrimental and

harmful thing, while our study indicates arousals as elements

weaved into the texture of sleep taking part in the regulation

of the sleep process (Terzano and Parrino 1993a). Beyond

different conceptual approaches the essence of the controversy

is to include or exclude into the concept of arousal those

evoked or spontaneous elements of the EEG which are

characterized by high-voltage slow rhythms and/or K-com-

plexes and spindles instead of the traditional shift toward

rapid rhythms and voltage decrement, associated with the

same kind of behavioral and autonomic changes typically

accepted as arousal signs. From a practical point of view it is

questionable why those elements which are not signs of

cortical activation, although they are proved to be reactive

EEG patterns, are disregarded as arousals or as a prearousal

activation although most times they precede the EEG arousal

signs (De Carli et al. in press; Halasz 1993; Halasz and

Ujszaszi 1991; Roth et al. 1956). In effect, the ASDA criteria

neglect to consider the abrupt appearance of slow sleep

elements (K-complexes, delta bursts) as arousals even when

they are associated with somato-vegetative modifications

identical to those observed during arousals (Ferini-Strambi

et al. 2000; Ferri et al. 2000; Sforza et al. 2000a). To

overcome the general assumption that only arousals are

markers of cortical activation the coding system of cyclic

alternating pattern (CAP) identified different EEG features

endowed with activating properties and coalesced into a

common �brain beat� (Terzano et al. 1985). In the CAP

framework, arousals are viewed as complex phenomena

involving not only cortical areas but also other brain centers

and peripheral neural components (Fig. 1). These components

are involved with different latencies and intensities but are

nevertheless transformed into a unitary phenomenon by the

reciprocal interneural connections (Moruzzi 1972). The acti-

vating phenomena occurring within the somato-vegetative

systems do not always correspond to a cortical activation, as

the arousal definition seems to suggest. The outcome of

stimulation can also be a mild cortical activation expressed as

a mixed slow-rapid EEG pattern (as for subtypes A2 of CAP)

or can evoke a protective reaction of the sleeping brain (as for

subtypes A1 of CAP). In the latter case, arousal is aborted

and the response characterized by slow EEG pattern typical

of NREM sleep is more an anti-arousal phenomenon that

protects the continuity of sleep instead of fragmenting it

(Hirshkowitz 2002). From these considerations, it derives that

if all arousals are signs of activation not all the sleep EEG

patterns related to activation correspond to the conventional

definition of arousals (Atlas Task Force 1992). Therefore, the

activation response during sleep is not limited to a single

pattern but is part of a continuous spectrum including EEG-

synchronized features, EEG-desynchronized features or a

combination of both (Fig. 2).

WHAT IS A MICRO-AROUSAL AND HOW

IS IT RELATED TO THE COURSE OF SLEEP?

The term MA was first systematically used to designate

those phasic EEG events which were not associated with

Figure 1. Example of a cyclic alternating

pattern (CAP) sequence (top) and non-CAP

(bottom) in stage 2 NREM sleep. Notice that

CAP occurs as a spontaneous phenomenon in

the absence of any respiratory or muscle

abnormality. EOG, eye movements; EMG,

chin muscle; EKG, heart rate; O-N PNG,

oro-nasal flow; THOR PNG, thoracic effort;

TIB ANT R, right anterior tibialis muscle;

TIB ANT L, left anterior tibialis muscle.

4 P. Halasz et al.


awakenings regardless of their desynchronizational or syn-

chronizational (sleep response-like) morphology and regard-

less of their connection with autonomic or some sort of

behavioral arousal (Halasz et al. 1979). Concerning the

traditional desynchronization type morphology the phenom-

enon was described entirely by the early work of Schieber

et al. (1971) named at that time as �phases d’activation

transitoire� (PAT). The criteria for MA in NREM sleep

given by Schieber et al. (1971) were the following: increase

in EEG frequencies in conjunction with decrease of ampli-

tudes, disappearance of delta waves and spindles, transitory

enhancement of muscle tone or phasic appearance of groups

of muscle potentials, movements of the limbs or changes in

body posture, transitory rise in heart rate. In REM sleep the

criteria for MAs were temporary disappearance of eye

movements and appearance of alpha activities. The duration

of these changes varied from some seconds to more than

10 s. Temporary �activation� is followed by �deactivation�leading to a bi-phasic character of the phenomenon. The

term was modified by several workers in the last years and

used in the context of physiologic and pathologic studies,

with more or less the same meaning and criteria (Quattroc-

chi et al. 2000; Sforza et al. 2002). It is however surprising

how in the following studies the phenomenon of postarousal

deactivation has been neglected, while it has been succes-

sively recovered and amplified in the description of the so-

called phase B of CAP (Terzano and Parrino 1993b;

Terzano et al. 1985).

The occurrence of PAT like MAs is inversely proportional

to the depth of sleep, occurring more frequently in superficial

than in deep sleep with the highest incidence during REM sleep

and stage 1, appearing the least frequently during stage 3 and

4. The distribution of MA is not homogeneous across the sleep

cycles. MA are more frequent during the ascending slopes of

the cycles compared with the descending slopes, and their

frequency increases from evening to morning (Ferrillo et al.

1997; Halasz 1982; Schieber et al. 1971; Terzano and Parrino

2000; Terzano et al. 2000).

THE CONCEPT OF CORTICAL, SUBCORTICAL

AND AUTONOMIC AROUSAL

Those clear-cut arousals, which have enough activating

strength to change the level of vigilance on a macro-scale,

are characterized by a threefold phenomenology involving

simultaneously EEG, behavioral and autonomic compart-

ments. The conventional definition of arousal includes a

cluster of physiologic manifestations expressed by an activa-

tion of electrocorticographic rhythms, an increase of blood

pressure and muscle tone and a variation of heart rate. Arousal

has been considered as an essential element for restoration of

homeostasis during respiratory and cardiovascular failure

during sleep providing an excitation drive to vital processes.

Arousal, by definition, means cortical activation. However,

somatosensory and auditory stimulation during sleep may

result in cardiac, respiratory and somatic modifications with-

out overt EEG activation (Carley et al. 1997; Winkelman

1999). This observation implies that there is a range of partial

arousal responses with EEG manifestations different from

classical arousals and even without any EEG response. The

Figure 2. (a) Synchronization type micro-arousal (MA). Electroencephalography (EEG) pattern is dominated by K-complexes and deltas; the

polygraphy shows phasic increase in muscle activity and transitory tachycardia (b) Desynchronization type of MA. The EEG pattern shows

decrease in amplitudes and increase in frequencies. Polygraphy indicates pregnant tachycardia and increase in muscle activity.



different arousal responses rely on the different combinations

of the central and peripheral components, on the intensity

scale of their manifestation, and on the morphologic variations

of the cortical reactions. The spectrum of combination of the

three compartments in which arousal can appear is a matter of

debate. Any behavioral expression, which occurs associated

with low-voltage fast-EEG activities, is classified as a �behavi-oral arousal� (Moruzzi and Magoun 1949). Similar features are

shown by �movement arousals� described as any increase in

electromyographic activity that is accompanied by a change in

any other EEG channel (Rechtschaffen and Kales 1968). When

the EEG compartment is involved by transient desynchroni-

zation patterns, regardless of the participation of the auto-

nomic system or behavioral components, it was held as

�cortical arousal� (Atlas Task Force 1992). When there is

evidence of vegetative or behavioral activation associated with

an EEG pattern different from conventional arousal the event

was defined as �subcortical arousal� (McNamara et al. 2002;

Rees et al. 1995). When an autonomic activation appears

isolated or in conjunction with a respiratory event, but without

any concomitant EEG sign, it is commonly defined as an

�autonomic arousal� (Martin et al. 1997b; Pitson and Stradling

1998). There is an autonomic �overarousal� compared with the

periods of arousal from continuous awake state during periods

of awakening from NREM sleep (Horner et al. 1997), that also

represents a certain kind of quantitative decoupling between

the autonomic and other components of arousal.

The dichotomy of EEG/autonomic arousal versus move-

ment/behavioral arousal does not need much explanation;

hence placed on a gradual scale the latter represents obviously

a stronger activation. This is supported by the fact that

movement and behavioral arousals without either EEG or

autonomic concomitants do not exist. In contrast, there is

evidence that an arousal from sleep is associated with heart

rate acceleration and blood pressure increase even in the

absence of any behavioral or somatomotor activity (Trinder

et al. 2001, 2003).

The hierarchical relationship between the compartments

becomes clearer by taking into consideration the time rela-

tionships between the components (Kato et al. 2003; Riva

et al. 2002). As the autonomic component may precede the

EEG component (Bonnet and Arand 1997a), the cortical

compartment could not be considered as the univocal source of

autonomic activation. As both the EEG and vegetative

reactions can appear decoupled, these two kinds of arousal

manifestations may have separated and independent physio-

logic substrates activated simultaneously by the same input.

The temporal overlap between cortical, somato-motor and

vegetative events within the same arousal episode does not

necessarily imply synchrony and the order of activation of the

single compartments can vary in the different physiologic or

pathologic circumstances (Karadeniz et al. 2000). In arousal

phenomena during sleep there is no mandatory chronologic

and etiologic subordination. The phenomenon takes place

within interactive loops in which the cerebral cortex can be the

starting or the ending point but anyway a source of control.

The origin of arousal should be defined by the subsystem

primarily activated or perturbed. Arousal can be generated

directly by the cortex under the impulse of the physiologic

evolution of sleep or in response to a sensorial perturbation,

such as respiratory interruption, noisy environment, alteration

of blood pressure or heart rate, or a movement disorder. In

any case, it is the involvement of the brain that makes arousal

a unitary phenomenon in which activation is modulated

through a hierarchy of responses ranging from the generalized

activation of all subsystems to the controlled attenuation of

arousal-inducing activation (Black et al. 2000).

ELECTRODERMOGRAPHIC ACTIVITY AS AN

INDICATOR OF AROUSAL LEVEL DURING

SLEEP

Electrodermographic (EDG) activity, measured by the spon-

taneous fluctuations of skin conductance, is a rarely investi-

gated aspect of autonomic activity during sleep; the association

of EDG discharges with arousal was proved by several studies

(Jung 1954). Therefore the consequent finding of several

authors about a �storming effect� in EDG activity during slow

wave sleep was astonishing. (Broughton et al. 1965; Freixa

et al. 1983; Halasz et al. 1979; Johnson and Lubin 1966; Jung

1954; Lester et al. 1967; Liguori et al. 2000; McDonald et al.

1976). Investigating EDG activity in different experimental

conditions, including psychostimulant drug administration,

sleep deprivation, and random sensory stimulation, we found

that the frequency of EDG discharges was under the influence

of sleep depth and cycle order. The highest activity occurred

during the second and third sleep cycle and during slow wave

sleep, while in REM sleep the occurrence rate was similar to

wakefulness (Halasz et al. 1980). The activity was highest

under the influence of a psychostimulant and lowest during the

night after sleep deprivation, while baseline and placebo nights

showed values in between. During the sleep cycles the EDG

activity increased parallel with the deepening of sleep across

the descending slope (DS), which is the first part of the NREM

component of the sleep cycle and is characterized by the

transition from light (stages 1 and 2) to deep (stages 3 and 4)

sleep, persisted at a high level during the cycle trough, which is

the period of persistent deep sleep, decreased abruptly after the

cycle turn, across the ascending slope (AS), which is the period

of transition from deep to light NREM sleep and became

lowest during REM sleep (Fig. 3). Some authors (Broughton

et al. 1965; Johnson and Lubin 1966; Jung 1954) have assumed

that the increase of EDG activity in NREM sleep is due to the

release of the RAS from cortical inhibition. But in our study

the amount of slow wave sleep and the EDG activity did not

run parallel, and even during deep sleep the EDG activity

preserved its dependence from the activation level. Lester et al.

(1967) showed that previous day stress effect increased the level

of EDG activity during the next night and anxiousness as a

personality dimension also enhanced the level of slow wave

sleep EDG storming. In contrast to the assumption of the

static reciprocal inhibition between sleep promoting and

6 P. Halasz et al.


arousal influences (Saper et al. 2001) we interpreted the

association between the deepening tendency of sleep across

cycles and the increasing occurrence of EDG discharges as the

sign of an arousal process promoting the cycle turning and the

ensue of the AS. This assumption is supported by the findings

of Curzi-Dascalova and Dreyfus-Brisac (1976) and Curzi-

Dascalova et al. (1970) who could not find EDG storming

during quiet sleep of neonates, until the development of sleep

spindles. That means the development of EDG storming is

parallel in infants with the development of thalamic slow wave

sleep circuitry.

AROUSALS PRECEDED BY

SYNCHRONIZATION (SLOW WAVES,

K-COMPLEXES) EEG CHANGES

Overall, arousal phenomena are characterized by an extensive

variability not only due to different degrees of behavioral or

autonomic participation but also by the wide variability of

EEG features. The recognition of this kind of variability has a

long story and has required a development of views. Evidences

come from two different sources. One of them is the research

on K-complexes, which are distinctive elements of NREM

sleep, especially of stages 2 and 3, endowed with controversial

properties. Some authors (Roth et al. 1956; Sassin and

Johnson 1968) consider these features as partial forms of

arousal, while others (Nicholas et al. 2002; Waquier et al.

1995) indicate these elements as sleep-protective events.

According to a combinatory viewpoint, these events are

endowed with both activating and preserving properties

(Halasz et al. 1985a). Recently Bastuji et al. (1995) developed

the �forced awakening� method. In this paradigm subjects were

questioned about quantitative and qualitative aspects of

stimulus recall evoked by �oddball� type stimuli in parallel

with recording of the evoked cortical responses, after being

aroused by the stimuli from naps. In subjects whose quality of

recall was excellent, P300 waves were indistinguishable from

those obtained before sleep. When P300 was found attenuated,

delayed and desynchronized, recall was quantitatively degra-

ded and P300 was concomitant to or replaced by sleep

negativities (varieties of late negative components being part of

the K-complex) in subjects in whom stimulus recall was

severely degraded or absent (Garcia-Larrea et al. 2002). They

concluded that K-complex analog sleep negativities have two

aspects being, on the one hand, arousal driven and, on the

other, �erasers� preventing accurate memory encoding and

retrieval of the stimulus, promoting consequently sleep. The

same �Janus faced� nature of K-complexes were stressed by us

previously (Halasz 1982) and the possible functional import-

ance of this aspect will be treated later. An increase in the

amplitude of the K-complex N350-550 and P900 components

after sleep deprivation has been described recently (Peszka and

Harsh 2002). This again shows clearly that K-complex

characteristics are very close to those of delta sleep (Nicholas

et al. 2002).

The first studies of K-complexes showed that these grapho-

elements, which are held to be the building stones of slow wave

sleep (De Gennaro et al. 2000), are elicitable by all modalities

of sensory stimuli (Bastien and Campbell 1992; Niiyama et al.

1995; Roth et al. 1956; Sallinen et al. 1994) and are accom-

panied by autonomic discharges identical to those seen for

arousals (Ackner and Pampiglione 1957; Fruhstorfer et al.

1971; Guilleminault and Stoohs 1995; Hornyak et al. 1991;

Johnson and Karpan 1968; Sassin and Johnson 1968; Sforza

et al. 2000a, 2002; Takigawa et al. 1980). Later it was shown

that K-complexes rarely remain single events but are accom-

panied by other rhythms such as K-delta, K-alpha and

K-spindle according to the nature of the associated rhythm

(Halasz and Ujszaszi 1991; MacFarlane et al. 1996; Raynal

et al. 1974). These complex events beginning with

K-complexes are frequently followed by long-lasting changes

in the ongoing EEG, associated with distinct autonomic

modifications (Table 1).

Accordingly they could be considered as a �synchronizationtype� of MA (Halasz et al. 1985a). We report that arousals

proceeded by slow waves and K-complexes have a different

distribution across the sleep stages compared with the �desyn-chronization type� of MA. The former showed the greatest

occurrence rate during slow wave sleep, being most frequent in

stage 2 (Halasz et al. 1985b). Sforza et al. (2000a) scored 5820

events during the night sleep of 21 young adult volunteers.

Thirty-two percent of events were scored as arousals and in

Figure 3. Electrodermographic (EDG) discharges per minute count during the sleep cycles given in cycle parts (D, descending slope; Tr, trough of

the cycle; A, ascending slope; T, top of the cycle) as average of values in nights of eight young adult normal persons.



40% they were preceded by isolated K-complexes. PAT type

arousals represented 23% of the total arousals whereas delta

and K-complex bursts tended to occur mostly during the first

two sleep cycles. Other types of MA and clear-cut PAT

occurred during all sleep cycles with a greater density in light

and REM sleep. In an analysis carried out on 40 healthy

subjects, Boselli et al. (1998) ascertained that the number of

arousals during NREM sleep increase with age. In the same

sample, 87% of arousals were preceded by a K-complex or a

delta activity and showed a positive correlation with stages 1

and 2 (Terzano et al. 2002). Delta and K-bursts were concen-

trated in the first three sleep cycles and presented a divergent

behavior compared with ASDA arousals (Parrino et al. 2001).

Another line of evidence for different types of arousals came

from the discovery of CAP (Terzano et al. 1985). It was shown

that the CAP A-phase behaves like the synchronization

arousals, can be elicited by sensory stimuli and is associated

with clearly detectable autonomic discharges. Later the Parma

school differentiated within the CAP A-phase three subtypes

(Fig. 4). In subtype A1, EEG synchrony is the predominant

activity. If present, EEG desynchrony occupies <20% of the

entire phase A duration. Subtype A1 is generally associated

with mild autonomic and muscle activity. Subtype A2 contains

a mixture of slow and rapid rhythms with 20–50% of phase A

occupied by EEG desynchrony. Subtype A2 is linked with a

moderate increase of muscle tone and/or cardiorespiratory

rate. In subtype A3, the EEG activity is predominantly fast

low voltage rhythms with >50% of phase A occupied by EEG

desynchrony. Subtype A3 is coupled with a remarkable

Figure 4. Specimens of phase A subtypes: A1 (top), A2 (middle), and A3 (bottom). White boxes indicate electroencephalography (EEG) patterns in

synchronization, black dots indicate EEG patterns in desynchronization. Notice the progressive shift from dominant EEG synchrony to dominant

EEG desynchrony from subtypes A1 to subtypes A2 and A3. EOG, EMG, EKG: see Fig. 1. normal persons.

Table 1 Synchronization type of micro-arousals associated with

K-complex (es)

Name EEG morphology Description

Single

K-complex (es)

Single or serial

K-complexes

Roth et al. 1956

K-sigma K-complex followed

by a sleep spindle

Johnson and Karpan 1968

K-alpha K-complex followed

by alpha runs

Raynal et al. 1974

K-delta K-complex followed

by or mixed up with

delta group

Halasz and Ujszaszi 1991

8 P. Halasz et al.


activation of muscle tone and/or autonomic activities (Terzano

et al. 2001). The distribution of the different phase A subtypes

has been proved to be different across the sleep cycles.

Subtypes A1 occur most frequently in the first cycles of sleep

and during the DS of the cycles, while subtypes A2 and A3

subtypes are more frequent during the later part of sleep and in

the AS of the cycles (Terzano and Parrino 2000). Therefore we

can identify the A1 subtype with the �synchronization arousal�of Halasz et al. (1985a), and the A3 subtype with the original

PAT of the Strasbourg School (Schieber et al. 1971), while the

A2 subtype is a mixed one between the two (Parrino et al.

2001). Now it is clear that the most important factors that

determine the variable EEG morphology of arousals appearing

in NREM sleep are the linkage with stages and the position of

the given arousals within the course of sleep.

Other important factors are the nature and the intensity of

the stimulus originating the arousal.

THE INFLUENCE OF SENSORY STIMULATION

ON THE FORMATION OF BOTH TYPES OF

AROUSALS

Sensory stimuli can evoke EEG arousals with or without

behavioral and autonomic changes and their phenomenology

are exactly the same as experienced in the so-called sponta-

neous arousals. Ehrhart and Muzet (1974) showed that PAT

could be elicited by sensory stimuli. Stimulation decreased the

number of the spontaneous PATs; however, the total (spon-

taneous and evoked) number of PATs was similar to the

number of the spontaneous PATs without stimulation. Under

the influence of a psychostimulant drug the frequency of MA

slightly increased and the difference in the distribution between

the DS and AS of the cycles disappeared. Sensory stimulation

did not affect the average frequency of MA, but occurrence

during deep sleep increased and the difference between the AS

and DS decreased in a relevant way due to the increased

frequency during the DS. Elicitability by sensory stimulation

was best in superficial sleep stages and worst in deep sleep that

means it went parallel with rates of spontaneous occurrence

(Halasz et al. 1979).

Concentrating purely on K-complexes regardless of the

other associated rhythms Halasz (1982) found a significant

increase in the number of K-complexes under the influence of

continuous random sensory stimulation during stage 2 of

NREM. The elicitability of K-complexes was higher during the

AS of cycles (where the spontaneous occurrence rate was also

higher) compared with the DS. Under stimulation the number

of spontaneous K-complexes decreased, but the total number

(spontaneous and evoked) of K-complexes increased.

Using sound stimulation with 90-dB tones at 625 Hz, 1/1 to

1/5 min rate delivered by headphones, Levine et al. (1987)

found that the number of �natural arousals� decreased during

nights with frequent (1/1 min) stimulation resulting into

abundant evoked arousals. The polygraphic characteristics of

these arousals were not shown, but similar findings were

described (Nicholas et al. 2002).

STATE-SPECIFIC REACTIVITY IN SLEEP

Here we arrive at a more dynamic view in the understanding of

the nature of arousal in sleep. We must introduce an otherwise

well-known biologic concept, namely the �state-specific reac-

tivity�. In a certain biologic state the reactivity of the organism

to stimulation is determined by the given state in which the

input arrives. It is well known that sensory reactivity is

different in REM and NREM sleep. However, the change in

reactivity within NREM depending on whether the stimulus

arrives during the descending or ascending part of the sleep

cycle needs further elaboration. First of all we should know

more about the phenomenological and physiologic differences

of the two slopes. There are not many studies on this topic.

The first mention about the asymmetry of the DS and AS of

sleep cycles was made by Williams et al. (1964, 1966) and

confirmed by automatic analysis of sleep signals (Dijk et al.

1990; Merica and Fortune 1997). On the DS the deepening of

sleep occurs more slowly and gradually while the duration of

AS is shorter, the changes are more abrupt, and sometimes a

stage could be skipped. Sinha et al. (1972) claimed to forecast

the times of morning awakening by studying the tendency of

AS tangential across the hypnograms. Halasz (1982) measured

and compared the duration of DS and AS slopes and the

number and sequence of phase shifts in healthy volunteers.

The net result of this study was that sleep cycles – at least in the

first part of sleep where this phenomenon was possible to

investigate – are asymmetric: the DS is longer and sleep stages

shift gradually, the AS proved to be shorter, and changes less

gradual. In other words, the AS is steeper and 30–50% shorter

compared with the DS (Terzano et al. 2000).

The differences between the frequency and morphologic

features of arousals are in harmony with the asymmetric

dynamics of the two slopes of sleep cycles. Across the DS and

most prominently in the first cycles arousals are less frequent,

show slower EEG activities, are associated with only mild

autonomic perturbations, while across the AS arousals are

more frequent, and the EEG morphology and the concomitant

autonomic changes fulfill better the conventional arousal

expectations (Terzano et al. 2000). These polysomnographic

findings were confirmed by computerized analysis that showed

an increase of very fast rhythms in the final part of the sleep

cycle, when NREM sleep precedes the onset of REM sleep and

a sharp reduction of these rapid rhythms at the beginning of

NREM sleep in the following sleep cycle (Ferri et al. 2001).

On the basis of these findings we may speculate that the

differences in arousals might reflect an intimate relationship

between state responsivity and the tendencies of state shifts

according to the sleep profile (Table 2).

State determines sensory responsivity and the sensorial sti-

mulation – both in experimental and spontaneous situations –

may contribute to the state shifts. Sleep state shifts are

determined basically by chemical changes governed by brain-

stem influences. During the NREM–REM cyclicity there are

slowly moving tonic changes underlain by the cyclic alterna-

tion of brainstem aminergic and cholinergic influences. Besides



the involvement of chemical changes, the alternation of DS

and AS during the NREM component of the sleep cycle can be

influenced by the appearance of arousals, which also reflect the

influence of external factors on the sleep process. The

dynamics experienced in arousals suggest that sensory stimuli

may participate in the determination of the sleep profile and

co-operate in shaping the course of sleep cycles. We can

formulate this kind of double, �tonic� and �phasic� regulation, inwhich the effect of �phasic� arousals are tuned by the

background �tonic� chemical influences, and at the same time

�phasic� stimulation contributes to changes in �tonic� influences.It is clear that the DS and AS portions of the sleep cycles

represent two different substates. During the DS slope sleep-

promoting influences are overwhelming and the arousal system

is more inhibited compared with the AS (Evans 1993). During

this tonic sleep dominance the thalamo-cortical system works

in the bursting mode and the influence of brainstem arousal

systems are tonically repressed (Steriade and Llinas 1988).

Accordingly, in the DS phasic arousal events are rare and they

are often mixed with sleep-like responses. Here we do not

observe a complete breakdown of NREM bursting mode in

the thalamocortical network but it seems as if the distinct

subsystems are in conflict and influence each other reciprocally

throughout the arousal response (De Carli et al. in press;

Steriade and McCarley 1990). The slow EEG pattern elicited

by the arousing stimulus, which characterizes the first part of

the response, seems to prevent or attenuate the depolarizing

influence of cholinergic innervations of thalamic relay cells.

The outcome is a balance between anti-arousal and arousal

responses (Hirshkowitz 2002). There are two experimental

studies investigating the effect of arousal stimuli during the

bursting mode. Szymusiak et al. (1996) applied rostral mid-

brain monophasic electric stimulation with 0.2 ms duration

and 100–800 lA and registered a state-dependent effect on

thalamic single unit activity. While stimulation during wake

state and REM sleep evoked a short-latency action potential,

during NREM sleep stimulation commonly evoked a high

frequency burst of action potentials followed by a period of

suppressed discharge. In the majority of neurons a second

rebound burst of action potentials followed the period of

discharge suppression. The average interval between the initial

and rebound burst was similar to the interburst interval

recorded in the same cells during spontaneous EEG spindles.

The authors conclude that stimulation of the reticular forma-

tion evoked rhythmic discharges dependent upon the presence

of thalamo-cortical synchronization. Mariotti et al. (1989)

showed that in the nucleus VPL of the thalamus the response

to peripheral physiologic stimulation during NREM sleep

shows three main components: a very brief and scanty

excitatory response, followed by a long period of discharge

suppression and by excitatory rebound. The landmark of

arousal is a strong increase of the excitatory response and a

marked reduction of the inhibitory phase, eventually with

disappearance of the rebound. Another possibility to under-

stand the slow wave response to sensory stimulation would be

that the sensory input which arrives to the cortical level meets

the slow (<1 Hz) depolarizing oscillation, nowadays identified

as the K-complex generator (Amzica and Steriade 1997), in the

phase of fast (30–40 Hz) rhythm which allows MA in slow

wave sleep without long-lasting interruption of the inhibitory

rebound sequences in the thalamocortical network.

After the cycle turns to the AS the dominance of NREM sleep

decreases. The neurochemical background of this weakening

influence in the second part of the cycle could be the combined

result of a decreased amount of NREM sleep supporting

monoamines and an increasing antagonizing REM promoting

cholinergic influence, according to the �reciprocal-interaction�hypothesis of Hobson et al. (1975). This decrease in NREM

sleep-promoting influence results in an increase in the phasic

arousal activity which now has a better cortical arousal effect

reflected in the more arousal-like type EEG, behavioral and

autonomic activity. This increase in arousal activity also results

in more intensive arousals conjoined from time to time not only

with transitory EEG reactions but also with stage shifts. The

gradual weakening of NREM sleep and the increasing domin-

ance ofREMforces can explain the asymmetric conformationof

the sleep cycle with a smoother DS and a steeper AS.

THE HIERARCHY OF AROUSALS – THE

CONCEPT OF A CONTINUUM

As previously illustrated, arousals are variable according to the

different combinations of their EEG, behavioral and auto-

nomic activities. The phenomenology of arousals is influenced

not only by stages and sleep depth but also by the tendency of

the sleep process. If arousals really reflect the same physiologic

process of activation they should behave in a stereotyped way

regardless of the involvement of the different peripheral

compartments. Sforza et al. (2002) showed a stereotyped

rising and falling in the delta, theta, and alpha power

associated with periodic leg movements regardless of the

presence or absence of EEG arousals and regardless of the

absence or presence of slow EEG waves in arousals (Fig. 5).

Table 2 Sleep features and micro-arousal characteristics correspond-

ing to slopes of the sleep cycles

Descending slope Ascending slope

Duration Longer Shorter

Transition of stages Stepwise Skipped stages

Synchronization

type arousal

Overwhelming Rare

Desynchronization

type arousal

Rare Overwhelming

Conjoined autonomic

signs in arousal

Very rare Frequent

Conjoined behavioral

signs in arousal

Very rare Frequent

Association of arousals

and stage shifts

Only at the end

of cycle trough

Regular

Stimulus/answer relation Weak Close

Assumed function

of arousals

Promoting sleep Preparing REM sleep

REM, rapid eye movement.

10 P. Halasz et al.


Figure 5. Left: EEG spectrum percentage changes in uV2 divided to three bands before and after a PLM event (onset is indicated by the arrow)

with and without micro-arousal, and with slow wave activity (after Sforza et al. 2002). Right: poststimulus power spectra according to different

response types during NREM stage 2 and 3. Grand averages of four subject’s means, weighted with the individual response number. Poststimulus

power values are compared with the corresponding data for prestimulus 2 s. Cz-A1 derivation. Prestimulus power spectra on the top. KS,

K-complex followed by sleep spindle; KA, K-complex followed by alpha spindle; KD, K-complex followed by delta group (modified from Halasz

and Ujszaszi 1991, with permission).



Similar spectral changes were described by Halasz and

Ujszaszi (1991) in different K-complexes preceding arousals.

In this work we also showed the deactivation of sigma activity

followed by a long-lasting poststimulus inhibition. Because

spindles are the expression of the thalamic filter to the passage

of stimuli, their transient disappearance could provide a time

window for momentarily improved sensorial transmission

through the thalamic relay. In spite of the differences in the

intensity dimension and in the EEG, autonomic and behavi-

oral components, the variable forms of arousals are supported

by a uniform background along a hierarchic continuum

(Halasz 1998; Sforza et al. 2000b) concerning the degree of

activation they produce (Table 3).

ARE THERE ANY INNER SOURCES OF

AROUSALS OR ARE THEY ALL COMING FROM

OUTSIDE?

In the last 20–30 years of research on the microstructure of

sleep EEG and autonomic phenomena a large list of different

phasic events, their relationship with each other and with the

macrostructure of sleep have been revealed. It has become

clear that sleep is scattered by shorter or longer, milder or

stronger phasic events. The driving force of these phasic events

is obviously a recurring arousal triggered either by unknown

origin or by detectable sources outside the sleeper.

Schieber et al. (1971) and later the work of Ehrhart and

Muzet (1974) of the same school based especially on the

observed equilibrium between the evoked and spontaneous

MAs assumed an endogen pacemaker within the RAS,

working against sleep promoting influences and becoming

more and more active, promoting the awakening process

during the last third of night sleep. Regardless of their origin,

arousal stimuli exert a general arousal response through the

RAS, which is known to be activated by different sensory

modalities. McNamara et al. (2002) registered spontaneous

arousals in infants between 2 and 10 weeks of age and

observed frequent periodic arousals as a sequence involving

an augmented breath followed by startle and then cortical

arousal, but subcortical arousals were more common than

cortical ones. They concluded that there is an endogenous

rhythm of spontaneous activity in infants involving excitatory

processes from the brainstem, which may or may not be closely

followed by cortical excitation.

A well-known example for internal drives of brainstem

origin is the ponto-geniculo-occipital (PGO) spike activity

detectable in animals before and during REM sleep. PGO

waves spontaneously occur in the pons, lateral geniculate

body, and occipital cortex during REM sleep, and PGO-like

waves may be elicited during sleep and waking by sudden onset

stimuli. During REM sleep PGO activity correlates with eye

movement bursts. The auditory stimuli eliciting PGO waves

during wakefulness produce signs of increased EEG and

behavioral arousal, consisting of cortical desynchronization

and orienting movements (Kaufmann and Morrison 1981).

It is not definitely clear whether PGO waves exist in humans,

but parieto-occipital potentials similar to PGO waves were

obtained by averaging EEG segments before and after eye

movements during REM sleep (McCarley et al. 1983) and

recent functional neuroimaging data indicate a REM-specific

positive correlation between rapid eye movements and right

geniculate body as well as occipital activity (Peigneux et al.

2001).

The amplitudes of elicited PGO waves in wakefulness were

greatest when orienting responses were observed, and the

amplitudes of elicited PGO accompanying orienting responses

were not significantly different from elicited PGO amplitudes

in REM. Likewise, the amplitudes of elicited PGO during

REM were not significantly different from those of the highest

amplitude spontaneous PGO waves. These findings support

the hypothesis that the presence of high-amplitude PGO waves

in REM indicates that the brain is in a state of more-or-less

Table 3 EEG, autonomic and behavioral symptoms in different types of MA during NREM and REM sleep

EEG Autonomic Behavior

MA during NREM sleep

Synchronization type (K-delta,

phase A1 subtype of CAP)

Series of K-complexes,

deltas, spindles

Mild, short vegetative signs

(pulse rate increase) if at all

No signs

Mixed synchronization and

desynchronization type (K-alpha,


Slow waves, K-complexes

followed by spindles and

faster frequencies

Transitory pulse rate increase Short living increase of

muscle activity at the end

Desynchronization type (PAT,


Acceleration and amplitude

decrease of EEG

Transitory pulse rate increase,

PAT, blood pressure elevation

Transitory muscle activity

increase and/or movements

Stage shift Transition from a deeper to a

lighter NREM sleep stage

Maintaining or long-standing

tonic increase in pulse rate or

in other autonomic functions

Transitory or long-standing

increase of muscle tone

MA during REM sleep

PAT type Transitory disappearance of

any REM-specific graphoelement,

appearance of alpha rhythms

Transitory pulse rate increase

and/or any other signs of

elevated sympathic tone

Transitory reappearance

of muscle tone, disappearance

of eye movements

EEG, electroencephalography; MA, micro-arousal; NREM, non-rapid eye movement; REM, rapid eye movement; CAP, cyclic alternating pattern;

PAT, phases d’activation transitoire.

12 P. Halasz et al.


continual orienting (Sanford et al. 1993). Both waking and

REM sleep PGO waves are related to the pedunculopontine

tegmental nucleus that is involved in acoustic and somatosen-

sory stimuli processing (Reese et al. 1995). These data suggest

that during REM sleep there is an internal generation of

orienting responses similar to those occurring during arousing

stimulation in wakeful state (Johnson and Lubin 1967).

Orienting responses are also associated with physiologic

arousals of NREM sleep, i.e. K-complexes (Campbell et al.

1992) and can occur either spontaneously or be evoked by

external stimuli.

This PGO activity could be an internal source of brain

activation during REM sleep. This internal arousing system

seems to be an inherent part of REM sleep, because auditory

stimulation during REM sleep not only increases PGO

activity, but also enhances REM sleep duration in cats (Ball

et al. 1989; Drucker-Colin et al. 1983) and humans (Mouze-

Amady et al. 1986). The triggering neurons of the pontine

PGO wave generator are located within the caudolateral

peribrachial and the locus subcoeruleus areas, and the trans-

ferring neurons of the pontine PGO generator within the

cholinergic neurons of the laterodorsal tegmentum and the

pedunculopontine tegmentum. Thus PGO activity could be an

internal source of brain activation during REM sleep and

perhaps even beyond it.

So far, the inner source of arousals periodically appearing

during sleep were assumed to be, in the above-mentioned

works, in the brainstem, or at least as a result of the

interactions between brainstem systems. However, there is

another possibility, namely the cyclic variations in cortical

excitability providing periodically increased reactivity to any

incoming signal.

THE CYCLIC NATURE OF AROUSAL

The sleep process is the outcome of several mechanisms and

cyclic phenomena. The rising homeostatic pressure as a

function of diurnal waking is compensated by slow wave

activity during sleep which undergoes an exponential decline

according to the cyclic process S and interacts with the

oscillations of the circadian process C (Borbely 1982; Borbely

and Achermann 2000; Ferrillo et al. 1991). The ultradian

alternation between NREM and REM sleep is another cyclic

process that regulates the level of arousability and the degree

of EEG synchronization (McCarley and Hobson 1975).

Because spontaneous arousals are intimately related to the

sleep structure, they are involved in all the mentioned cyclic

processes and express an intrinsic rhythm as well. It has been

established that approximately 90% of MA are separated by

an interval <60 s. In particular, over 70% are separated by an

interval between 20 and 40 s (Terzano and Parrino 1991). This

means that MA are not randomly distributed but are organ-

ized in repetitive sequences based on an approximately

0.033 Hz periodicity (Achermann and Borbely 1997). The

CAP is the time domain in which arousal events are grouped in

conditions of reduced vigilance. First observed in comatose

patients as a cyclic simultaneous variation of EEG patterns

and monitored physiologic functions (Fischgold and Mathis

1959; Terzano et al. 1982), CAP was later recognized as a

physiologic component of normal NREM sleep (Bruni et al.

2002; Lofaso et al. 1998; Parrino et al. 1998; Terzano and

Parrino 2000).

In humans, the existence of a spontaneous ultra-slow

rhythm in the CAP range can be identified both in quiet

wakefulness and in the sleep condition (Fig. 1). EEG spectral

parameters analyzed during a resting period in healthy subjects

showed that both theta and alpha band powers oscillate at an

average frequency of 0.024 and 0.057 Hz (Novak et al. 1992).

A periodicity peaking at approximately 32 s in the domain of

slow waves (<4.5 Hz) has been described during NREM sleep

in humans (Achermann and Borbely 1997). Another human

study reported an ultra-slow rhythm of 0.05–0.025 Hz, which

was superimposed on the regular 0.6 Hz EEG rhythms during

deep NREM sleep (McKeown et al. 1998). It seems that 20–

40 s periodic changes modulate the background EEG activity

and regulate cortical excitability of human subjects.

Another line of evidence is given by animal studies, which

report multisecond oscillations corresponding to the CAP

range in different areas and conditions. Alternating amplitude

segments with a <1 Hz periodicity have been described during

NREM sleep in rats (Depootere et al. 1991), and periodic

oscillations in EEG and behavioral activity with a cycle length

of 15–30 s have been reported in chair-restrained squirrel

monkeys. These oscillations consist of alternating episodes of

vigilance and inattentiveness, the former characterized by

visual scanning and motor movement, the latter by behavioral

quiescence (Ehlers and Foote 1984). Oscillations with periods

in the 2–60 s range are present in the baseline activity of a

majority of basal ganglia neurons recorded in awake immo-

bilized rats (Ruskin et al. 1999). In urethane-anesthetized rats

many lateral geniculate neurons display a very slow oscillatory

behavior in the range of 0.025–0.01 Hz (Albrecht et al. 1998).

A mathematical model of hippocampal function predicted an

ultra-slow oscillation in the CA area (Klemm and Naugle

1980), and in fact a 0.025 Hz oscillation in the hippocampus

has been recorded from the CA1 and subicular regions in rats

of the Wistar and Sprague–Dawley strains, anesthetized with

urethane (Penttonen et al. 1999). The very slow oscillatory

activity (0.025–0.01 Hz), observed during urethane anesthesia

in the lateral geniculate nucleus can be blocked by continu-

ously illuminating the eyes. Light-induced suppression of very

slow oscillation could be re-induced by NMDA-antagonists,

by non-NMDA antagonists as well as by GABA agonists

(Albrecht et al. 1998). In other words, powerful stimulation

suppresses and pharmacologic inhibition re-induces the very

slow oscillatory activity. These results suggest that oscillatory

activity in the CAP range could be a general property of

central nervous system function during periods of reduced

arousal, and that this oscillatory activity, EEG expression of

unstable vigilance, can be manipulated by sensorial inputs.

During sleep, an acoustic stimulus delivered during stable

non-CAP (Fig. 1) can evoke a prolonged CAP sequence



(Terzano and Parrino 1991). Accordingly, the amount of CAP

increases when sleep is achieved under conditions of noise

stimulation (Terzano et al. 1990, 1993). CAP rate (the ratio of

CAP time to NREM sleep time) also surges in situations of

sleep disruption, such as psychophysiologic (Terzano and

Parrino 1992; Terzano et al. 1997a) and organic (Szucs et al.

2000) insomnia, while it is lowered by sleep-promoting

conditions and sedative pharmacologic treatment (Parrino

and Terzano 1996; Parrino et al. 1997). Accordingly, CAP rate

is decreased by nighttime recovery sleep after total sleep

deprivation (De Gennaro et al. 2002; Parrino et al. 1993) and

by hypnotic medication (Terzano et al. in press). During

NREM sleep, the phase A of CAP triggers and modulates the

distribution of epileptic events (Halasz et al. 2002; Parrino

et al. 2000a) and myoclonic jerks (El-Ad and Chervin 2000;

Haba-Rubio et al. 2002; Mahowald 2002; Parrino et al. 1996).

Similar observations were found for the ultra-slow oscillation

in the hippocampal CA1 region, which consists of an alterna-

tion of network excitability, triggering epileptic-like afterdis-

charges during phases of enhanced network excitability in

susceptible rat strains (Penttonen et al. 1999). In contrast,

phase B of CAP is closely related to the repetitive respiratory

events of sleep-disordered breathing (Parrino et al. 2000a;

Terzano et al. 1996; Thomas 2002), and only the powerful

autonomic activation during the following CAP-A phase can

restore postapnea breathing (Parrino et al. 2000b; Terzano

et al. 1996). These observations suggest that CAP-A is the

activation phase, which alternates with a reduced neural

excitability characterizing CAP-B phases.

All these results indicate that both spontaneous and elicited

phasic arousals, especially during NREM sleep, have a cyclic

nature following the multisecond oscillation. As a translation

of fluctuating arousal, CAP offers a favorable background for

sleep disorder manifestations (e.g. epileptic abnormalities,

PLM, nocturnal apneas, NREM parasomnias, insomnia)

which are related to a condition of unstable sleep (Terzano

and Parrino 1993a) during which CAP cycles play a promoting

(phase A) or a dysfacilitating (phase B) gating action on the

single EEG, behavioral and autonomic events.

Besides CAP, the other major EEG activity in the frequency

range below 1 Hz, characterizing states of reduced tonic

arousal, is the so-called slow oscillation (Steriade et al. 1993).

This 0.5–0.9 Hz EEG rhythm was outlined by deep EEG

recordings performed during anesthesia and NREM sleep of

cats and rats (Steriade 2000b) as well as by surface EEG and

magnetoencephalography during NREM sleep of human

subjects (Achermann and Borbely 1997; Amzica and Steriade

1997; Simon et al. 2000). Slow oscillation is generated in

cortical neurons, and consists of phases of depolarization,

characterized by intensive neural firing, followed by long-

lasting hyperpolarization (Steriade 2000a). Hence the two

phases of slow oscillation are characterized by opposite neural

phenomena: cortical excitation made up of synaptic potentials

and cortical inhibition mainly due to network dysfacilitation.

The excitatory component of slow oscillation is effective in

grouping the K-complexes and delta waves, which do not

occur in isolation but are grouped into complex wave

sequences. The coalescence of slow rhythms is especially

visible during NREM sleep (Steriade and Amzica 1998).

However, it is known that periodic K-complexes and delta

bursts, which coalesce within CAP, are the basic components

of phase A1 subtypes. The other phase A subtypes (A2 and

A3), instead, encompass not only slow rhythms but also fast

activities in different proportions. In experimental studies, fast

rhythms at 30–40 Hz, mainly described in the wake state and

in REM sleep, are present during NREM sleep as well

(Steriade 1995). The prerequisite of fast rhythms and cortical

activation is provided once again by the slow (<1 Hz) cortical

oscillation, which permits fast oscillation to occur periodically,

just timing with the occurrence of K-complexes (Amzica and

Steriade 1997). This can explain why K-complexes can be

associated often not only with slow activities, i.e. K-delta but

also with rapid activities, e.g. K-alpha and polyphasic bursts

(Halasz 1993). According to these data there is a periodic

window in NREM sleep, which allows, like an alternatively

opening and closing communication pore, the possibility for

the brain to be activated by sensory input. When the incoming

sensory bombardment coincides with the window opening the

conditions for activation are present. This explains why

periodic arousals are so closely associated with K-complexes,

appearing in the garment of sleep rhythms.

Another biologic hypothesis regarding arousal periodicity

during NREM sleep is to allow sleeping animals opportunities

to monitor their environment and thus avoid predation. The

periodic neuronal excitation serves as a sentinel function in a

state of disconnection from the external world and sets the

cerebral functions in a readiness state for a possible adaptive

behavior. CAP can be enhanced by any internal or external

factor of perturbation. When a disturbing factor is adminis-

tered to a sleeping brain, a poststimulus CAP sequence can

persist for some minutes. However, CAP appears even in the

absence of any environmental disturbance acting as a struc-

tural component of physiologic sleep intervening in close

temporal relation with stage shifts and body movements

(Terzano et al. 1988).

PATHOLOGIC AROUSALS

Spontaneous arousals are natural guests of the sleeping brain

(Boselli et al. 1998) and appear regularly embedded within the

CAP process (Parrino et al. 2001; Terzano et al. 2002).

However, arousal phenomena are also known to occur in

response to sleep-disturbing factors. Increased amounts of

arousals are a regular finding of obstructive sleep apnea

syndrome (OSAS), but typical manifestations of secondary

cortical events are also the respiratory effort-related arousals

(RERA) known as obstructed events that do not meet the

criteria for apnea or hypopnea but that nevertheless cause an

arousal. More specifically, RERA are defined as the absence of

apnea/hypopnea but with progressive negative Pes (esophageal

pressure) lasting ‡10 s culminating in an arousal. RERA are

increased both in OSAS and in the upper airway resistance

14 P. Halasz et al.


syndrome (UARS) as a reaction of the sleeping brain to a

repetitive breathing disturbance. RERA are secondary to

subtle obstructions of the upper airway during sleep and can

appear in the absence of apneas and hypopneas, causing

excessive daytime sleepiness. The common abundance of

RERA in sleep-disordered breathing (SDB) has supported

the idea that arousals are a sign of disturbed sleep and that

arousal responses reflect abnormal breathing (Douglas 2000).

The association between esophageal pressure alterations and

arousals even in the absence of apneas or hypnopneas justifies

this belief and has been one of the main reasons for

considering arousals as an epiphenomenon of SDB. However,

arousals can be elicited by non-respiratory disturbance.

Besides respiratory-driven, the so-called spontaneous arousals

could in effect be supported by some organic trigger such as

intestinal passage, excessive bladder loading or organ dysfunc-

tion. Accordingly, the occurrence and distribution of these

events should follow the randomness of internal phenomena

across the night. However, if we verify the position of non-

pathologic arousals during sleep we can ascertain that they are

not randomly distributed as they tend to vanish in the first part

of the DS (Evans 1993) and appear mainly concentrated in the

AS of the sleep cycle (Halasz et al. 1979; Terzano et al. 2000).

In particular, arousals commonly occur before and during

REM sleep but are rare during slow wave sleep (Bonnet and

Arand 1997b; Ehrhart and Muzet 1974). These findings

indicate that the occurrence of a certain amount of arousals

is related to the intrinsic organization of sleep regardless of any

superimposed source of disturbance. Accordingly, discrimin-

ation between spontaneous arousals and induced arousals can

be more reliably ascertained if we are able to identify which

and where are the arousals that belong to the physiologic

structure of sleep. This implies that when sleep is not severely

disrupted, pathologic arousals tend to appear in those portions

of sleep in which they have higher probabilities to occur

spontaneously. In SDB, a certain amount of respiratory-

induced arousals may simply replace the spontaneous ones as

expected from their natural distribution across the night. It has

been ascertained that a CAP sequence preceding the onset of

REMsleep is a structuralmarker of sleep organization (Terzano

et al. 1988). This means that this transitional portion of sleep

coexists with an underlying oscillation of vegetative functions.

The occurrence of unstable sleep in this particular position

within the sleep cycle can be an important factor for monitoring

respiratory oscillations and titrating ventilatory support (Tho-

mas 2002). Moreover, Poyares et al. (2002) hypothesize an

inability of theCNS tomanifest spontaneous arousalswhen they

are already occurring quite often due to a specific disturbance.

Acoustic stimulation during sleep increases the amount of noise-

induced arousals and reduces the amount of spontaneous

arousals (Halasz et al. 1979). These findings indicate a mutual

influence between physiologic and pathologic arousals.

Secondary arousals are not linked only to breathing

abnormalities but can also occur in association with motor

phenomena. Sleep bruxism is a typical form of oromotor

activity associated with sleep arousals (Kato et al. 2003;

Macaluso et al. 1998). Muscle jerks occurring in close

temporal relations with arousals are typical manifestations of

periodic limb movement. Painful syndromes are also com-

monly associated with increased arousals (Lavigne et al. 2000;

Parrino et al. 2003). However, increased arousals can occur in

clinical conditions lacking any detectable internal or external

factor of perturbation. Primary insomnia, a sleep disorder

without any evidence of mental, substance-induced or medical

disturbance, shows increased amounts of arousals and CAP

compared with sound sleepers (Terzano et al. in press).

WHEN TOO MANY AROUSALS DETERMINE

NON-RESTORATIVE SLEEP

There is a great body of evidence that sleep fragmentation –

punctuation of sleep with frequent, brief arousals – diminishes

its recuperative value (Bonnet 1985, 1986; Stepanski et al.

1987). This statement is valid even when these arousals do not

alter the standard 30-s epoch sleep stage scoring. In other

words too many arousals can impair sleep continuity even

when sleep efficiency is preserved. For a long time, in disorders

of sleep maintenance or those conditions in which sleep was

felt to be not enough satisfactory and recuperative, nothing

wrong was possible to detect when sleep was analyzed through

the traditional scoring system (Rechtschaffen and Kales 1968).

Only after the introduction of microstructural analysis of sleep

it became possible to find parameters changing parallel with

the subjective complaints of insomniac patients. Sleep of

insomniacs contains more sleep instability as measured by

CAP parameters (Paiva et al. 1993; Terzano and Parrino

1992). In primary insomnia, all phase A subtypes are increased

including subtypes A3 (which coincide with arousals). How-

ever, when these patients are treated with hypnotic agents and

report a significant improvement of sleep quality there is a

parallel reduction of CAP rate associated with an important

reduction of subtypes A1 and A2 (Terzano et al. in press).

In normal sleepers, noise-induced delta bursts, correspond-

ing to subtypes A1 and A2, reduce the restorative properties of

sleep and determine excessive daytime sleepiness even when

there is no evidence of sleep fragmentation (Martin et al.

1997b; Terzano and Parrino 1991; Terzano et al. 1990).

Accordingly, we can assume that a condition of disturbed

sleep can be associated with a paradoxical increase of delta

activity, which is considered as an expression of restorative

sleep (Borbely and Achermann 2000).

In general, arousal responses differ in the specific sleep

disorders. The association between sleep-related respiratory

events and EEG arousals is more frequently reported in OSAS

than in UARS. This is likely because OSAS subjects present

increase in effort accompanied by apneas and hypopneas, and

sometimes by short and limited oxygen saturation drops,

requiring a more intense stimulus to arouse. Correlation

between the number of arousals and daytime sleepiness in

OSAS patients has been reported (Sforza and Lugaresi 1995;

Zucconi et al. 1995a), but the activating role of phasic delta

activities during sleep (with diurnal consequences) should be



emphasized. However, Black et al. (2000) and Poyares et al.

(2002) have found that airway opening may occur in UARS

subjects with a predominant increase in delta power. In other

words, reopening of the airway at wakefulness and disappear-

ance of abnormal UARS are not necessarily associated with an

arousal. Reopening of the airway with an EEG pattern of delta

has been also observed in OSAS patients (Berry et al. 1998).

Involvement of either slow or fast EEG responses depends on

the regulation of upper airway pathway. Respiratory patterns

that need correction activate the CNS. This activation varies,

depending on the sensory recruitment and the adequacy of the

response. A respiratory challenge can be resolved by CNS

activation without involving a cortical arousal. The latter is

triggered only when thalamo-cortical structures fail to modu-

late breathing or when ascending reticular volleys are required

to restore respiration (Hirshkowitz 2002). Depending on the

amount of recruitment and numbers of neural structures

involved, the CNS activation will be variable. The autonomic

nervous system is enhanced when an arousal occurs, which

explains the greater increase in heart rate with EEG arousal

than without EEG arousal. Anyway, the problem is quantita-

tive not qualitative in the sense that delta bursts can also

determine heart rate acceleration and autonomic activation

(Sforza et al. 2000a). Generally, the slow and the fast compo-

nents of EEG activation have different latencies, with the delta

portion preceding the rapid activities (De Carli et al. in press).

This probably determines a graduated impact on the autonomic

system. The slow waves determine a softer vegetative reaction,

which in certain pathologic conditions may be strong enough to

overcome a disturbing factor, e.g. an obstructive event.

Otherwise, the slow rhythms are immediately replaced by faster

EEG activities, which guarantee a more powerful activation of

autonomic functions. Probably the effects on daytime function

is not linked to a single phase A subtype but to the reciprocal

amount and distribution of the single subtypes. In OSAS

patients treated effectively with nasal CPAP, ventilatory-

induced reduction of CAP rate, which correlates significantly

with daytime sleepiness, was associated with a robust curtail-

ment of subtypes A3 and an expansion of the A1 percentage

(Parrino et al. 2000b). Further studies will clarify the relation-

ship between sleep microstructure and diurnal wellness.

AROUSAL DISORDERS

Arousal disorders were first delineated by Broughton (1968).

He assumed that abnormality of the arousal process prevents

the normal arousal response from NREM that otherwise

would lead to full alertness and results in a pathologic arousal,

a dissociated state, amalgamating features of sleep and

wakefulness, in certain disorders. Disorders grouping together

by this assumed pathomechanism are known as sleepwalking

(SW) and sleep terror (ST) and a milder form of the continuum

of these disorders, named confusional arousal (CA). All three

of them has a beginning in childhood before puberty and

prevails in young adulthood. The common symptoms of the

dissociated state observed during these pathologic arousals

are: (a) mental confusion and disorientation, (b) automatic

behavior, (c) relative non-reactivity to external stimuli, (d)

poor response to efforts to provoke behavioral wakefulness, (e)

retrograde amnesia for many intercurrent events, (f) only

fragmentary or no recall of dream mentation (Thorpy 1990).

Macrostructure of sleep is preserved, but studying the

microstructure, several pathologic features were observed in

different works. NREM sleep in adults has shown increased

number of MA preceded and accompanied by EEG synchron-

ization (Halasz et al. 1985a; Zucconi et al. 1995b). Presence of

hypersynchronous delta (HSD) wave activity and increased

sleep instability and arousal oscillations, reflected in an

increased CAP rate (Zucconi et al. 1995a) were also reported.

An analysis of the pathologic behavioral events (SW and/or

ST) of 19 polysomnographic records in 12 adults showing 252

arousals from NREM sleep, compared with a control group,

showed delta wave clusters in 15.6% of pre-event periods and

in 37.9% immediately preceding the slow-wave sleep MA

(Schenck et al. 1998). The arousal period was characterized by

three kinds of EEG symptoms: (a) diffuse rhythmic delta

activity around 4 Hz, most prominent in bilateral anterior

regions, typically 20 s duration; (b) diffuse and irregular,

moderate to high voltage delta and theta activity with anterior

dominance intermixed with, or superimposed by, alpha and

beta frequencies; (c) prominent alpha and beta activity, at

times intermixed with moderate voltage thetas. Nearly half of

the patients showed one of the first two types of EEG pattern.

All the three types of EEG patterns were associated with

variable degrees of heart rate acceleration with a shortening of

R-R interval. It is clear from the report that a slow wave type

of MA characterizes pathologic arousal itself in half of the

patients. We do not know how much we should regard this

type of arousal from NREM sleep as pathologic in this age

group, compared, for example, with an abrupt arousal from

NREM sleep, due to a sudden pain. It is an everyday

experience for electroencephalographists dealing with sleep

records that this kind of delta synchronization occurs fre-

quently in slow wave arousals of children or adolescents, but it

is not known how much the maintenance of this type of

arousal to adulthood should be interpreted as pathologic.

Guilleminault et al. (2001) explored the spectral features of

EEG in SW patients across sleep cycles and immediately

preceding a CA. They confirmed an increased MA rate during

the first cycles of sleep and found an important increase in

relative power of low delta (0.75–2 Hz) just prior to the SW

episodes. They assumed that it is the �cortical reaction to brainactivation� which would serve to avoid the interruption of sleepand in the same time may be responsible for the confused state.

Gaudreau et al. (2000) reported similar findings suggesting

that arousal disorders reflect an exaggeration of the anti-

arousal defense mechanisms mainly restricted to the DS of first

sleep cycles. These findings again show that in NREM sleep

delta arousal is one of the possible forms of activation, and

it is questionable how much these slow wave arousals can be

held as pathologic arousals or are only the childhood form of

arousal preserved in adulthood, as proposed above.

16 P. Halasz et al.


AROUSALS GATING PATHOLOGIC EVENTS

Among pathologic arousals gating effect has the more exten-

ded literature. Several pathologic sleep events were found to be

associated with different forms of MA. The most explored

sleep perturbation in association with different sleep pathol-

ogies is the CAP pattern. Within the CAP it is mostly the

A-phase that is connected with these abrupt manifestations of

pathologic sleep events. Therefore CAP A-phase was inter-

preted as a kind of �gate� through which pathologic events

occur more easily. The gating effect has been demonstrated in

the last years among several sleep disturbances such as PLM

(El-Ad and Chervin 2000; Haba-Rubio et al. 2002; Parrino

et al. 1996), sleep bruxism (Kato et al. 2003), OSAS (Terzano

and Parrino; Thomas 2002) and epilepsy (Eisensehr et al.

2001; Halasz et al. 1985a, 2002; Terzano et al. 1989, 1991b,

1997b).

CONCLUSIVE REMARKS ON THE FUNCTIONS

OF AROUSAL DURING SLEEP

The data available on arousal activity during NREM sleep

clearly indicate that arousal is really woven into the texture of

sleep. What are the functions of the ongoing arousal activity

during NREM sleep, the essence of which is conventionally

held just the opposite to arousal? In general, arousals and

arousability ensure the reversibility of sleep, without which it

would be identical to coma. Arousals provide a connection of

the sleeper with the surrounding world maintaining the

selection of relevant incoming information and adapting the

organism to the dangers and demands of the outer world. In

this dynamic perspective, the ongoing phasic events carry on

the one hand arousal influences and on the other elements of

information processing. Therefore, arousal and information

processing are the two sides of the same coin in sleep. The

latter statement is supported by the increasing investigation of

different components of K-complexes and their relationship

with the presence/absence and different features of cognitive

workup during NREM sleep (Atienza et al. 2001; Bastuji and

Gracia-Larrea 1999; Niiyama et al. 1995; Perrin et al. 1999,

2000; Sallinen et al. 1994).

The other function of arousals is tailoring the more or less

stereotyped endogenously determined sleep process driven by

chemical influences according to the internal and external

demands. This is why the sleep process is variable from night

to night, lending flexibility to the process. Different forms of

Figure 6. A model of the parallel working mode of �tonic� and �phasic� modulation. S, sleep promoting system; A, arousal system exerts mutual

reciprocal antagonistic influences on each other (indicated by negative signs). Arrows indicate the influence of the inner and outer sensorial

surrounding (interrupted arrows) and of the endogenous chemical input (continuous arrows). Thickness of the arrows indicates the amount of the

influence. D, descending; A, ascending slope of the cycle. Interrupted bars and positive signs along the circuit between A and S indicate arousal

impulses in the form of phasic events and/or micro-arousals. For further explanation see text.



arousals provide the phasic regulation prevailing on top of the

slower waves of preprogrammed chemical codes, shaping in a

certain limited way the sleep process. This regulation is able to

modify mainly the AS of the sleep cycles and prevails in the

last third of the night sleep.

Speculations on how sleep and wakefulness are regulated

consider homeostatic and circadian factors as essential to

explain the timing of alternations of awake state and sleep

(Borbely 1982), while reciprocal interactions of brainstem

neuronal systems are thought to be involved in the alternations

of NREM and REM sleep (Hobson and McCarley 1977;

McCarley and Massaquoi 1992). In this perspective, arousals

shape the individual course of night sleep as a variation of the

sleep program (McCarley andMassaquoi 1992; Massaquoi and

McCarley 1992). Based on the data gathered from the study of

MA it seems plausible instead those arousals have a more

essential role in the reciprocal interactions between NREM

sleep and wake and between NREM sleep and REM sleep.

We can envisage control of sleep/wakefulness as a tonic

regulation under endogenously driven reciprocal antagonistic

chemical influences like the promoted �sleep switch� (flip-flop)model based on the hypothalamic control of sleep and

wakefulness (Saper et al. 2001). However, this interpretation

cannot explain the intermediate states and flexibility of the

system. This is assured by the parallel �phasic� regulation

provided by arousals in sleep, proposed to be incorporated in

the current models of sleep regulation. Fig. 6 shows schemat-

ically the parallel working mode of �tonic� modulation (mainly

intracerebral, slow, and chemical) and �phasic� changes (mainlyextracerebral, faster, and neuronal-synaptic). The sleep pro-

moting system (S) and arousal system (A) exert mutual

reciprocal antagonistic influences on each other. The detailed

description of this relationship and the role of the players

(both chemical and neural) of the two interacting subsystems

are brilliantly illustrated in Saper et al. (2001). In the DS of

sleep cycles the S system is dominating. When the S system

inhibits the A system to a certain extent (during DS) sensorial

input from the inner and outer surrounding (interrupted thick

arrows) result in rare and mild arousals. In contrast, during the

AS the tonic inhibition of the A system decreases and this

facilitates a greater frequency of arousals. The continuous

arrows represent the endogenous chemical and the interrupted

arrows the sensorial inflow. The thickness of the arrows

reflects the proportion of the relations. This model is able to

explain why sleep gets deeper during the DS even in the

presence of sensory stimulation (Hirshkowitz 2002), and how

arousals can promote, during the AS, the avalanche of the

awakening process. Here the dynamic changes across the sleep

cycle are fueled not only by chemical influences but also by the

parallel sensorial input which has state-specific different

functions during the two slopes of the cycle, being sleep-

promoting during DS and supporting the arousal process

during AS. The sleep-promoting effect of sensory stimuli

during the process of falling asleep has been reported by

several authors (Bohlin 1971; Oswald 1960; Webb and Agnew

1981), starting from Pavlov (1928).

Every biologic system tries to assure autonomy to achieve

independence from the surrounding, and at the same time

relies on the interrelationship between the organism and the

surrounding world, which is essential for adaptation and

survival of the system. Therefore an organism should avoid

external stimuli and try to regain the original prestimulus state,

but paradoxically, it will use the stimulus for building up its

autonomic state. The reciprocal interplay of the sleep/wake-

fulness system is a suitable example of how external stimuli are

used in a process modeling the internal structure and serving

the separation of the organism from the outer world (Atlan

1979).

Anyway, the sleeping brain can offer manifold types of MA

to internal or external inputs. Besides the classical low-voltage

fast-rhythm EEG arousals, high-amplitude EEG bursts, be

they like delta-like or K-complexes, reflect a possible arousal

process. Different MAs are associated with increasing magni-

tude of vegetative activation ranging hierarchically from the

weaker slow EEG types (coupled with mild autonomic

activation) to the stronger rapid EEG types (coupled with a

vigorous autonomic activation). In physiologic conditions,

slow and fast MAs are not randomly scattered but appear

structurally distributed within sleep where they are also

endowed with a cyclic nature expressed by the periodic

dimension of CAP. It is known that arousal responses differ

in various sleep disorders. Understanding the role of arousals

and CAP and the relationship between physiologic and

pathologic MA can shed light on the adaptive properties of

the sleeping brain and provide insight into the pathomecha-

nisms of sleep disturbances.

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