J. Sleep Res.

(1992) 1, 63-19

Concepts and models of sleep regulation: an overview

A L E X A N D E R A . B O R B E L Y and P E T E R A C H E R M A N N
Institute of Pharmacology. University of Zurich, CH-8006 Zurich, Switzerland

Accepted in revised form 25 February 1992; received 20 January 1992

SUMMARY Various mathematical models have been proposed to account for circadian,
ultradian and homeostatic aspects of sleep regulation. Most circadian models assume
that multiple oscillators underlie the differences in period and entrainment pro-
perties of the sleep/wake cycle and other rhythms (e.g. body temperature).
Interactions of the oscillators have been postulated to account for multimodal
sleep/wake patterns. The ultradim models simulate the cyclic alternation of
nonREM sleep and REM sleep by assuming a reciprocal interaction of two cell
groups. The homeostatic models propose that a sleep/wake dependent process
(Process S ) underlies the rise in sleep pressure during waking and its decay during
sleep. The time course of this process has been derived from EEG slow-wave
activity, an indicator of nonREM sleep intensity. The predictions of homeostatic
models have been most extensively tested in experiments. The interaction of Process
S with a single circadian process can account for multimodal sleep/wake patterns,
internal desynchronization and the time course of daytime sleepiness. Close links
have emerged between the processes postulated by the various models and specific
brain mechanisms. Due to its recent quantitative elaboration and experimental
validation, the modelling approach has become one of the potent research strategies
in sleep science.
KEYWORDS circadian, homeostatic, mathematical model, nap, ultradian

rhythms such as changing phase-relations between the

1 OVERVIEW OF T H E M O D E L S
Three basic processes underlie sleep regulation: (1) A
homeostatic process mediating the rise in ‘sleep pressure’
during waking and the dissipation of ‘sleep pressure’ during
sleep; (2) a circadian process, a clock-like mechanism
defining the alternation of periods with high and low sleep
propensity and being basically independent of prior sleep
and waking; and (3) an ultradian process occurring within
sleep and represented by the alternation of the two basic
sleep states nonREM sleep and R E M sleep. The three
processes are illustrated schematically in Fig. 1.
The tables provide a synopsis of models that have been
proposed to account for circadian, ultradian and homeos-
tatic aspects of sleep regulation. The mathematical
equations of the major models are compiled in the
appendix.
1.1 Models of circadian rhythms (Table 1)
The main objectives of these models are (1) to simulate
spontaneously occurring phenomena in free-running
Correspondence: Professor A. Borbkly, Institute of Pharmacology,
University of Zurich, Gloriastrasse 32, CH-8006 Zurich,
Switzerland
sleep/wake cycle and the temperature rhythm, and the
splitting of the rest-activity rhythm into two components;
and (2) to account mainly for the effects of light, the major
zeitgeber, on the phase, amplitude and period of circadian
rhythms. The database of the models consists in general of
records of rest and activity rather than of polygraphically
recorded sleep and waking. Moreover, the models attempt
to describe general features of the circadian system rather
than focus specifically on the sleep/wake rhythm. Neverthe-
less, a distinction can be made between models that address
more specifically issues that are relevant for sleep
regulation, and which are being continuously elaborated
(Table l), and older ones which cover more selective or
marginal aspects of sleep (some entries of Table 4). The
monographs by Enright (1980) and Strogatz (1986) on
models of the sleep/wake cycle should be particularly
mentioned not only because they cover the area in
considerable detail but also in view of the many innovative
propositions and analyses they contain.
A common feature of models of circadian rhythms is that
they consist of more than one oscillator. The influence of
these multiple oscillators is little apparent under entrained
conditions but may become manifest during free-run. They
account for splitting and other features of the rest-activity

63
64 A . A . Borbkly and P . Achermann
Oi00 23:OO 37.00
I Circadian
07.00 23:OO 07:OO
Ulrradian
I I
2300
Time of day
Figure 1. Schematic representation of the three major processes
underlying sleep regulation. W, waking; S, sleep; N, NonREM
sleep; R, REM sleep. The progressive decline of nonREM sleep
intensity i s represented both in the top and bottom diagram (decline limit cycle oscillation.
of ultradian amplitude). The increase in the duration of successive
REM sleep episodes i s indicated.
pattern in animals, and for the phase-dependence of sleep
duration and the biphasic sleep patterns in humans.
However, the assumption of multiple self-sustaining
oscillators is not mandatory for accounting for various
features of free-running rhythms. As pointed out by
Eastman (1984), the pattern of internal desynchronization
between the sleep/wake cycle and the temperature rhythm
can be simulated by periodic or occasional phase-shifts of
the former rhythm. Daan, Beersma and associates (Daan
and Beersma 1984; Daan et a / . 1984; Beersma et al. 1987)
then demonstrated that the interaction of a relaxation
oscillator (Process S) with a single circadian process can
account for various features of free-running rhythms such as
the pattern of internal desynchronization, ‘phase-trapping’,
and circabidian cycles as well as polyphasic sleep. However,
the assumption of subharmonics of components of a single
circadian oscillator or of multiple oscillators seems to be
necessary to account for the splitting phenomenon in
animals.
The circadian models summarized in Table 1 face two
major problems: (1) There is no compelling evidence for the
existence of more than one circadian pacemaker in
mammals*. (2) The homeostatic aspect of sleep regulation is
not addressed by circadian models (Nakao et a / . 1990a and
1991, make some provisions for such a process), thus
requiring additional assumptions.
1.2 Models of the nonREM-REM Sleep cycle (Table 2)
A distinctive feature of this class of models is that they
evolved from neurophysiological data obtained in animals
(McCarley and Hobson 1975). Although the original
anatomical and physiological assumptions have been
somewhat modified (McCarley and Massaquoi 1992), the
postulate that the nonREM-REM sleep cycle is generated
by the reciprocal interaction of two neuronal systems, has
been maintained. The original proposition o f a Lotka-
Volterra type of interaction was later transposed to humans,
and further elaborated into the limit cycle reciprocal
interaction model (McCarley and Massaquoi 1986; Massa-
quoi and McCarley 1990, 1992).
Qualitative simulations of the changes in the duration and
latency of R E M sleep under various experimental conditions
were performed. Moreover, the model was applied to
predict the ultradian phase-response to a cholinergic agent
07.00 and to forced awakenings. In its most recent extension
(Massaquoi and McCarley 1992), homeostatic processes
have been incorporated similar to those proposed by
Achermann et af. (1990). Moreover, an arousal process has
been included which affects both slow-wave activity and the
1.3 Models of sleep homeostasis and its interaction with
circadian and ultradian processes (Table 3)
It has been recognized as early as 1937 that sleep intensity is
reflected by the predominance of slow waves in the sleep
EEG (Blake and Gerard 1937). The relationship between
slow-wave sleep and the duration of prior waking has been
documented by Webb and Agnew (1971) and placed into a
theoretical framework by Feinberg (1974). The term ‘sleep
homeostasis’ (Borbely 1980) was proposed to characterize
the sleep/wake dependent aspect of sleep regulation. The
two-process model, originally proposed to account for sleep
regulation in the rat (BorbCly 1980; 1982a), postulates that
Process S rises during waking and declines during sleep, and
interacts with a circadian Process C. The time course of the
* This statement requires qualification, since there i s strong
evidence for an independent circadian oscillator in the eye ( R e m i el
al. 1991). However. this is unlikely t o be rclcvant in the prcscnt
context. For a discussion of the possibility that separatc paccmakcrs
reside in the left and right suprachiasmatic nucleus, see Beersma
and D a m (1992).
 Concepts and models of sleep regulation 65

Table 1 Two-oscillator and three-oscillator models of circadian rhythms. Asterisk indicates that model equations are provided in the
appendix

Assumption Des cription Cornm en t

~~~~ ~ ~~~ ~ ~ ~~ ~ ~~~~~

E-M model* (Pittendrigh and Daan 1976; Daan and Berde 197X)
Two coupled oscillators constitute the cir-
cadian pacemaker. Only phase information is
represented in the model equations.
D u d circudiun pucemukrr model (Beersma and Daan 1992)
Two coupled oscillators constitute the cir-
cadian pacemaker. Elaboration of the E-M
model.
Originul x - y model*. Predominant effect o//ight on v (Kronauer et ul., 19x2).
Two Van der Pol oscillators x and y affecting
each other by 'velocity' type coupling. Lar-
ger effect of x on y than y on x .
Revised x-y mode/*. Predominant effect of light oti x (Kronaucr. 1990)
Van der Pol oscillator for x ; cumulative
effect of light. Circadian modulation of sciv
sitivity to light.
Three-oscillutor model * (Kronauer , I9X7aj
Subdivision of y oscillator into identical y ,
and yz oscillators. Derived from x-y model.
Only phase information represented in thc
model equation.
Model of circadian rest-activity rhythm of Neurobiological basis: Existence of two sepa-
rodents. E-oscillator controlling initial ac- rate oscillators unconfirmed, but some evid-
tivity bout in nocturnal rodent; M- ence for bilateral oscillators (see Beersma
oscillator controlling terminal activity bout. and D a m 1992). Assumption of different
Oscillators exert mutual phase control. E phase-response curves not upheld by Tupaija
synchronized by dusk, M by dawn. experiments (Meijer et ul. 1990). Application
Differential effect of light. Accounts for of the model to pineal N A T rhythm (Illne-
(I)intcrdepcndcncc of free-running rova et ul. 19x9).
rhythm and activity time with changing
light intensity; (2) after-effects of prior
conditions on period and activity time; ( 3 )
splitting.
Two identical oscillators that arc usually in Neurobiological basis: see previous comment.
phase. Response to light pulses is identical. Adaptation to photoperiod not accounted
Splitting due to change in phase relation. for.
Multiplicative interaction t o account for
activity pattern during splitting. The output
o f the oscillators determines the probability
o f activity.
Phase and amplitude information reprc- Neurobiological basis: Existence of two sepa-
sented in the model equations but only rate oscillators unconfirmed. In original mo-
phase information interpreted. 'Strong' (x) del, sleep coincides with central two-thirds of
circadian oscillator controlling R E M sleep. y's trough. Later sleep assumed to occur
core body temperature. cortisol; 'weak' (y) symmetrically about mid-low y with a phase-
circadian oscillator controlling the delay o f 30" (Gander ('1 d.1984a).
sleep/wakc cycle. Simulation of data
(Gander et ul. 1984b;Gander et a / . 198s):
(I)Phcnonicna occurring at transition from
internal synchronization to desynchroniza-
tion (e.g. changes in period; 'phase-
trapping'); (2) phase-dependence of sleep
duration; ( 3 ) types of synchronization by
zeitgcbcrs; (4) resynchronization after
jet lag.
Simulation of the effect o f light pulses on The model addresses the difficulty of driving
phase and amplitude of circadian rhythms the human circadian system to the point of
in humans. singularity (i.e. zero amplitude. undefined
phase).
Simulation of 'split-desynchrony' patterns Neurobiological basis of y , and y2
o f human bimodal sleep pattern (main unspeci lied.
sleep. napping), and of splitting of rodent
rest-activity rhythm.

Two-o.scil1utorthermoregulutory model oJ.sleep conrrol* (Nakao et ul. l99Oa; 1991)

Two circadian oscillators, one influencing Simulation o f biphasic sleepiness pattcrn, Existence o f two separate circadian oscillators
temperature, the other sleepiness. Sleep h o - relation of sleep timing t o temperature not confirmed. Mechanism for the accumula-
meostasis assumed to be related to longterm rhythm. tion of ii heat load and its delayed effect on
temperature regulation (heat load during sleep n o t specified. Available data still
waking; heat dissipation during sleep). Adj- ambiguous.
ustable thresholds determining onset and
termination of sleep.
66 A . A . Borbdy and P. Achermann

Table 2 Models of the nonREM-REM sleep cycle. Asterisk indicates that model equations are provided in the appendix.
Assumption Description Comment

Reciprocal interaction model* (McCarley and

Hobson 1975; revised interpretation: Hobson
el al. 1986).
NonREM-REM sleep cycle generated by
two coupled cell populations in the brain-
stem with self-excitatory and self-inhibitory
connections according to the Lotka-Volterra
model.
Limit cycle reciprocal interaction model:
Original iiersion * (McCarley and Massaquoi
1986; Massaquoi and McCarley 1990)
NonREM-REM sleep cycle generated by
the reciprocal interaction of two coupled cell
populations.
Limit cycle reciprocal interaction model:
Extended uersions (Massaquoi and McCarley
1992)
NonREM-REM sleep cycle generated by
the reciprocal interaction o f two coupled cell
populations. Incorporation of sleep home-
ostasis and arousal events.
Simulation o f data: Dischargc ratc of chol- Neurobiological basis: The role o f postulated
inergic FTG ( o r LDI/PPT)cells in cat. cell populations in the control of R E M sleep.
Application o f the model with a modified and their interactions have undergone revi-
definition of REM sleep t o simulate sions (Hobson ef al. 1986: McCarley and
changes in REM sleep in depressive pati- M.‘lssdquoi
., 1992).
ents (Beersma et 01. 1984)
Main fcaturcs o f previous model main- Neurobiological basis: see previous comment.
tained. but assumption of a stahlc limit
cycle oscillation that is independent o f
initial conditions. Introduction o f a cir-
cadian term which determines modc of
approach to limit cycle. Simulation of data:
(1) REMS latency and REMS episode
durations in normal humans under various
experimental conditions and in dcpressivcs;
(2) prediction of an ultradian phase-
response curve to a cholinergic agent; (3)
effect of forced waking on the dynamics of
nonREM/REM sleep cyclc hy an cx-
ogenous excitatory input.
Assumption of first-order decay dynamics Neurobiological basis: See McCarley and
for the i i r ~ u s a lsystem. Oualitativc simula- Massaquoi (1992).
tion of ultradian slow-wave activity
pattern.

homeostatic variable S was derived from E E G slow-wave
activity. Various aspects of human sleep regulation were
addressed in a qualitative version of the two-process model
(Borbdy 1982b). Independently, an elaborated, quantitative
version of the model was established (Daan and Beersma
1984; Daan et al. 1984) which predicted the timing of human
sleep for a variety of different schedules. A further
elaboration of the model was accomplished by Achermann
and colleagues (Achermann 1988; Achermann and BorbCly
1990; Achermann et ul. 1990) by including the ultradian
variations of slow-wave activity. Recently, Folkard and
Akerstedt (1987, 1989, 1992: Akerstedt and Folkard 1990)
simulated the changes of daytime alertness by the combined
action of a homeostatic process, a circadian process and ;I
sleep inertia process. It is interesting that the time constants
of their homeostatic process that have been derived from
sleepiness ratings, and the time constants of Process S
derived from the sleep E E G , are in a similar range.
1.4 Miscellaneous models (Table 4)
The models summarized under this heading address either
general aspects of rhythms that are not directly related t o
sleep regulation or very specific points of sleep regulation.
Enright (1980) showed that a circadian pacemaker with a
high precision can be constituted from an ensemble of
‘sloppy’ relaxation oscillators. Wever (1984, 1985, 1987)
assumed the existence of several distinct yet interacting
oscillators. The rest-activity pattern was obtained by
applying a threshold. Three separate oscillators were
proposed by Kawato et af. (1982), two of which were
assumed to determine sleep onset and sleep termination. In
addition, Winfree (1983) simulated the distribution o f sleep
onset and sleep termination by analysing the interaction of a
recovery process and an oscillator, an approach that uses
similar basic assumptions as in the two-process model.
Strogatz (1986) accounted for the internal desynchronization
of the sleep/wake rhythm and body temperature by simple
two-oscillator models. The gated pacemaker model (Car-
penter and Grossberg 1984, 1987) assumes an interaction of
two cell populations in the suprachiasmatic nucleus (SCN)
as well as some other specific physiological processes to
simulate various properties of circadian rhythms. The
current views on the physiological processes in the SCN are
not all consistent with the assumptions of this complex
model. Lawder (1984) proposed that the interaction o f a
linearly declining process and a periodic REM sleep process
could account for the sleep stage distribution as well as for
other features of sleep. His qualitative model does not
 Concepts and models of sleep regulation 67

Table 3 Models of sleep homeostasis and its interaction with circadian and ultradian proccsses. Asterisk indicates that model equations are
provided in the appendix.

Assumption Description Comrneni

Two-process model* (BorbCly, 1982b; Daan

and Beersma, 1984; Daan ei a/. 1984;
BorbCly et al. 1989)
Sleep propensity in humans is determined by
a homeostatic Process S and circadian Proc-
ess C. The interaction of S and C determines
the timing of sleep and waking.
Model of ultradian variaiion of slow-wave
activity* (Achermann, 1988; Achermann and
Borbtly, 1990; Achermann el al. 1990)
Derived from the two-process model. The
level of S determines the buildup rate and
the saturation level of slow-wave activity
within nonREM sleep episodes.
Three-processmodel of the regulaiion of
sleepiness/alertness* (Folkard and Akerstcdt
1987, 1989, 1992; Akerstedt and Folkard
1990)
Sleepiness/alertness are simulated by the
combined action of a homeostatic process. a
circadian Process, and sleep inertia (Process
W).
Time course of S derived from E E G slow- Ncurobiological basis of ’slecp homeostat’
wave activity; phase position and shape unknown. Possible basis of E E G slow-wave
(skewed sine wave) of‘ C derived from activity: Burst discharge pattern in the delta
sleep duration data obtained at various rangc of hyperpolarized thalamic neurons
times of the 24-h cycle. Simulation of data: (Steriade et ul. 1991).
( I ) Timing o f sleep after slecp deprivation.
during prolongcd bcdrcst. internal dc-
synchronization during frcc run; variations
of sleep onset and sleep termination; (2)
level and time course of slow-wave activity
in sleep after total o r repeated partial sleep
deprivation, after daytime naps; ( 3 ) varia-
tions of slcep latency.
In contrast to the original two-process Possible ncurobiological basis of intraepisodic
model, the change of S. n o t the IevcI of S, changcs of slow-wave activity: Progressive
corresponds to slow-wavc activity. A KEM hyperpolarization of thalamic neurons (see
sleep oscillator triggers the decline of slow- previous comment). Evidence f o r a REM
wave activity prior t o REM sleep. Simula- sleep oscillator in the pons (see McCarley and
tion of data: ( 1 ) Time course o f slow-wave Massaquoi 1992).
activity during normal sleep. after slecp
deprivation, after daytime nap. aftcr selcc-
tive slow wave deprivation. during ex-
tended slecp; (2) increasing duration of
R E M sleep episodcs, slcep onset REM
sleep episode. skipped lirst REM slecp
episode; ( 3 ) parameter estimation and si-
mulation of indcpendcnt datasets.
Parameters dcrived from rated slcepincss Time constant of the homeostatic process
during sleep/wake manipuhtions. Simula- similar t o Process S in the two-process model
tion of data: Changes o f (Daan ei ul. 1984). However. the homeostatic
sleepiness/alcrtness during shift-work process and S change in oppositc directions.
schedules.

establish clear relations to physiological processes. Stoch-
astic models were formulated to account for sleep
architecture in humans (Kemp and Kamphuisen 19x6) and
for circadian rest-activity rhythms (Dirlich 1984). A model
of EEG slow wave generation has been recently published
(Caekebeke et a/. 1991). Finally, Nakao et a / . (1990b)
attempted to account for the dynamics of neuronal activity
in specific sleep states in the cat by a neural network model.
2 EXPERIMENTAL VALIDATION OF
M O D E L S IN H U M A N S
2.1 r-y model
In the first reports typical sleep/wake and body temperature
patterns under conditions of temporal isolation were
simulated (Kronauer et a/. 1982, fig. 1 ; Kronauer 1984). I n
the simulations, the x and y rhythms are initially
synchronized. Then as the period of y lengthens an internal
phase drift sets in. Finally, there is phase trapping that
signals the transition from synchrony to desynchrony.
Predictions were generated on the effects of zeitgebers of
different strengths and periods (Gander ef a/. 1Y84a).
Wever’s data were used to simulate various patterns of
partial and full entrainment which had been observed in
subjects exposed to artificial zeitgebers (Gander el a / .
l984b).
In a further study, features of resynchronization after time
zone shifts were simulated and compared to the data of four
subjects (Gander et a/. 1985). The rate of adjustment was
shown to depend o n the rhythm being measured. the extent
of the time zone shift, the flight direction, and the strength
of the zcitgebers in the new time zone. Interindividual
68 A . A . Borbkly and P. Achermann
Table 4 Miscellaneous models.
Designation
~ ~
~~
Multiple relaxation oscillator model (Enright 1980)
Multioscillator model of circadian rhythms (Wever 1984. 1985, 1987)
Three-oscillator model (Kawato et al. 1982)
Interaction of recovery process with an oscillator (Win free 1983)
Beats model and phase model of circadian rhythms (Strogatz 1986)
Gated pacemaker model (Carpenter and Grossberg 1984. 1987)
Model of sleep patterning (Lawder 1984)
Stochastic model of sleep architecture (Kemp and Kamphuisen 1986)
Stochastic models of circadian rest-activity cycle (Dirlich 1984)
Model of EEG slow wave generation (Caekebeke et a / . 1991; Da
Rosa et a / . 1991)
Neural network model of neuronal transition dynamics during d e e p
(Nakao et al. 1990b)
differences in pacemaker periods were reported to be an
important factor for explaining the observed variability in
the response to time zone shifts.
Originally it had been assumed that bright light acts on
the circadian system via the y oscillator. Experiments with
scheduled light exposure led to a modified model in which
light has its main effect directly on x . In a first version, it
was assumed that the change of brightness (dB/dt) and not
brightness itself affected x (Kronauer 1987b; Kronauer and
Frangioni 1987). Experiments showing that it is difficult to
completely suppress the amplitude of the core body
temperature rhythm by scheduled light exposures (Jewett et
al. 1991), led to a modified version of the model in which a
cumulative effect of light on x and its complementary
variable ( x c . ) is assumed, and a circadian variation of
sensitivity to light is incorporated (Kronauer 1990).
2.2 Reciprocal interaction model
Beersma el al. (1984) used the concepts of the model to
account for the altered distribution of R E M sleep latency in
Description /comment
~
~~~ ~~ ~~ ~~~ ~ ~~
Circadian pacemaker assumed to consist o f an ensemble of relaxa-
tion oscillators whose output feeds into an integrating element.
Simulation of effect of light pulses on phase, and light intensity on
period of circadian rest-activity rhythm. After-effects accounted for
by the model, but not splitting.
Coupled oscillators; dichotomy of rest and activity by applying a
threshold; simulation of an ultradian slow-wave activity pattern by
assuming an ultradian oscillator.
Separate oscillators controlling sleep onset, sleep termination and
body temperature; simulation o f internal desynchronization.
Analysis of 'forbidden zones' of awakening.
Superposition (beats) o r coupling (phase) of two oscillators; simula-
tion of internal desynchronization.
Assumption of interaction of on-cell and off-cell population in SCN
whose feedback signals are gated by slowly accumulating transmit-
ters; on-cells supposed to promote motor activity; fatigue factor
acting on off-cells; simulation of phase-response curves, light effects
in diurnal and nocturnal animals, AschoFf's rule. splitting, etc.
Linearly declining variable interacts with periodic REM sleep
process. Simulation of sleep stage distribution in normal nights and
after sleep deprivation; sleep onset R E M sleep episodes.
Model based o n sleep stage transition probabilities.
Models based on state transition probabilities o r a network of
random processes.
Frequency selective feedback circuit with variable coupling strength.
Simulation of phasic (K-complexes) and tonic slow waves, and sigma
activity.
Simulation of neuronal activity of the white noise type in nonREM
sleep and l / f type in REM sleep.
depression (bimodal distribution). They showed that sleep
abnormalities in depressive patients can be accounted for by
the decrease in the initial value of a single variable which
can be taken to represent the extent of REM sleep
inhibition. McCarley and Massaquoi (1986) showed with the
limit cycle reciprocal interaction model that by varying one
of the initial values, a bimodal distribution of REM sleep
latency could be obtained.
Forced awakenings in 4 subjects at various phases of their
nonREM-REM sleep cycle had phase-dependent effects on
cycle duration (Foret et al. 1990). These data were used to
assess the effect of the excitatory input E o n the cycle length
in the model (Massaquoi and McCarley 1990). The results
are interpreted in terms of 'weak' and 'strong' resettings,
and i t is concluded that a mixed type of resetting mode
prevails.
2.3 Two-process model
The basic assumptions of the model, and in particular of its
homeostatic facet, has been subjected to extensive
experimental verification.

2.3.1 Experiments testing the original version of the
model
Independence of S and C. One of the basic assumptions of
the model is the independence of the homeostatic process S
and the circadian process C. It is supported by results from
animal experiments showing that the homeostatic response
to sleep deprivation persists even after the circadian rhyth-
micity has been disrupted or abolished by lesioning the
suprachiasmatic nucleus (SCN) (Mistlberger et ul. 1983;
Tobler et al. 1983). Evidence that one of the two processes
can be independently manipulated, has been obtained in a
study in which the circadian phase of Process C (as indexed
by body temperature and plasma melatonin) was shifted by
bright light in the morning, while the time course o f
slow-wave activity remained unaffected (Dijk et al. 1987c,
1989).
Rise of Process S during waking. In the first, qualitative
version of the model. it was inferred from the initial and
terminal level of S in normal sleep and in recovery sleep
after sleep deprivation, that S rises monotonically during
waking according to a saturating exponential function
(BorbCly 1982b). The time constant of this fuiiction was
then estimated to be 18.2 h (Daan et ul. 1984). By determin-
ing slow-wave activity in daytime naps which were preceded
by different durations of waking, direct evidence for a
monotonic rise of S according to a saturating exponential
function was obtained (Beersma et al. 1087; Dijk et (11.
1987a). The time constant of the function fitted through the
extrapolated initial points of S in the naps was 18.7 h
(Beersma et ul. 1987). In another study, slow-wave sleep
and slow-wave activity was shown to be higher in afternoon
naps than in morning naps, which is in accordance with the
predictions of the model (Knowles et al. 1990a,b). Further
confirmation for the monotonic rise of S during waking was
obtained in an analysis of sleep studies in which the duration
of prior waking differed (Dijk et al. 1990b). Again a close
correspondence between the data points and a saturating
exponential function with a time constant of 18.2 h was
obtained.
Effect of a nap on subsequent sleep. The two-process model
predicts that due to the decline of S during daytime naps,
the level of slow-wave activity in the subsequent slecp
episode will be reduced. This prediction was confirmed
(Feinberg et al. 1985; Daan et al. 1988; Knowles et ul.
1990b).
Effect of shortened nighttime sleep on a subsequent duytitne
nap. When the duration of nighttime sleep was shortened,
slow-wave activity in a subsequent morning nap was en-
hanced (Akerstedt and Gillberg 1986; Gillberg and
Akerstedt 1991).
Effect of repeated partial sleep depriuation. Slow-wave ac-
tivity was measured during two or four nights o f shortened
Concepts und models of sleep regulution 69
sleep (sleep duration 4 h) and two or three recovery nights,
respectively (Brunner et al. 1990b, in preparation). The
repeated curtailment o f sleep duration induced only a minor
rise in slow-wave activity whose magnitude did not differ
significantly from the prediction of the model.
2.3.2 Experiments testing un elaborated version of the
model allowing f o r disturbed sleep
These experiments test the modified version of the model
(proposed by Beersma et al. 1987 and Dijk et al. 1987b. and
formalized by Achermann and BorbCly 1990) in which the
change of S, and not its level, is proportional to the
momentary slow-wave activity. The latter model addresses
not only the global changes of slow-wave activity as
represented by Process S, but also the changes within
nonREM sleep episodes.
Intranight rebound of slow-wave activity. When slow-wave
sleep was prevented by acoustic stimulation during the first
3 h of sleep, the magnitude and time course of the sub-
sequent rebound of slow-wave activity was in accordance
with the modified concept of the two-process model (Dijk et
al. 1987b). Recently, a rebound of slow-wave activity was
documented after a 5-h interval of selective slow-wave sleep
deprivation in the same nighttime sleep episode, and after a
3-h interval of selective slow-wave sleep deprivation during
daytime recovery sleep (Dijk and Beersma 1989). In
another study daytime sleep episodes with and without
slow-wave sleep deprivation were compared (Gillberg et al.
1991). The experimental suppression of slow-wave sleep
during an interval corresponding to 90% of the undisturbed
episode resulted in an increased accumulation of slow-wave
sleep and an extension of sleep duration.
Extended sleep ut different circadian phuses. To test the time
course of Process S during extended sleep, long sleep
episodes starting at the regular bedtime (00.00 hours; 17 h
prior waking; Dijk et ul. 1991b), at a phase-advanced
bedtime (19.00 hours, 12 h prior waking: Trachsel et al.
1900; 3 6 h prior waking: Dijk et al. 1990a) and at 21 8-h
phase-delayed bedtime (07.00 hours, 24 h prior waking:
Dijk et al. 1991a) were studied. O n average, slow-wave
activity showed a decline over the first 3-4 nonREM-REM
sleep cycles and then remained on a constant level. Occasi-
onal minor late peaks of slow-wave activity were observed
which can be accounted for by the model (Achermann el al.
in prep.).
2.3.3 Parameter estimation of the model crnd tests on
independent experimentul dutusets
A further elaborated version of thr model was subjected to
an optimization procedure based on the weighted
least-square error method. and using the mean time course
of empirical slow-wave activity from a large dataset (16
subjects, 26 nights) as a template (Achermann er d . in
prep.). A sensitivity analysis showed the system to be
70 A . A . Borbdy and P. Achermann
rather robust to moderate variations ( f 5 % ) of the
parameter values. To further test the performance of the
model, the estimated parameter values were used to
simulate data from three different experimental protocols
(prolonged waking followed either by sleep in the evening
or by sleep in the morning; and extended sleep initiated at
the habitual time). Empirical R E M sleep data were used to
activate the REM trigger parameter in the model. In
general, a close fit was obtained between the simulated and
empirical slow-wave activity data and their time course. In
particular, the occurrence of late slow-wave activity peaks
during extended sleep could be simulated. Minor dis-
crepancies in later cycles of sleep initiated in the evening or
in the morning could be due t o indirect or direct circadian
influences on slow-wave activity. The simulations dem-
onstrate that the model can account in quantitative terms for
empirical data and predict the changes induced by the
prolongation of waking or sleep.
2.3.4 Emerging discrepuncies and shortcomings ;
suggestions for eluborution of the model
Independence of S and C. One of the basic assumptions of
the model is the independence of its two constituent
processes. However, a possible feedback of S on C has been
noted (Daan et al. 1984) as the scheduling of sleep and
waking may alter the timing of light exposure and thereby
affect the phase of C. This effect has been assumed to
account for the phenomenon of phase-trapping (Beersma et
al. 1987). A further interaction of S and C may arise from
the phase-shift of the circadian pacemaker by daytime motor
activity. Such an effect has been demonstrated for animals
(Mrosovsky and Salmon 1987) but not yet for humans.
The incorporation of disturbing factors has allowed also
for an indirect effect of C on S. Thus when sleep is initiated
in the early morning, the circadian R E M sleep propensity is
high. This may impede the full manifestation of slow-wave
activity in the first nonREM-REM sleep cycle and thus alter
its time course (Dijk et al. 1991a; Lance1 and Kerkhof 1991).
Upper and lower threshold of the ‘somnostat’. In the model
the level of the upper threshold was assumed to be
influenced during waking by external stimuli that promote
or reduce arousal (Daan et al. 1984). No analogous provi-
sions were made for sleep. This is a shortcoming, since
prolonged sleep can be simulated only if sleep itself lowers
the level of the lower threshold. Moreover, the brevity of
brief waking bouts at night suggests that also the upper
threshold is lowered during sleep. An experiment was
designed to test the predicted prolongation of sleep duration
when slow-wave sleep was suppressed in the first part of the
night (Dijk and Beersma 1989). The manipulation did not
prolong sleep. However, in another study in which slow-
wave sleep was suppressed selectively during 90% of a
daytime sleep episode, a prolongation of sleep ensued
(Gillberg er al. 1991). The divergent results of these studies
indicate that a more detailed analysis of the interference
with sleep is necessary (e.g. by recording brief arousals)
before a satisfactory interpretation can be offered.
Sleep inertia and wake inertia. Sleep inertia following
awakening is reflected by the short sleep latency when
subjects are allowed to return to sleep. A n attempt was
made (BorbCly et al. 1989) to incorporate a decaying sleep
inertia process which had been proposed by Folkard and
Akerstedt (1987, 1989).
The possibility that a wake-inertia process may influence
the initial part of sleep, was suggested by the declining trend
of the tonic EMG level throughout the first nonREM sleep
episode (Brunner er al. 1990a). A gradual dissipation of
wake-inertia may impede the initial buildup of slow-wave
activity and thereby shift its maximum from the first t o the
second cycle. Such a slow-wave activity pattern occurs
occasionally in normal subjects (Feinberg et al. 1985) and
has been reported for depressed patients (Mendelson et al.
1987).
In the two-process model, wake-inertia could be
simulated by raising the level of the lower threshold. This
would allow to account for the brief duration of daytime
naps.
Multiple sleep latency. The multiple sleep latency test is a
method for quantifying the propensity of sleep initiation.
Usually, the test is applied to subjects who are fully aware
of the time of day and who adhere at least partially to their
habitual daytime activities (e.g. the timing of meals). Under
these circumstances, sleep latency is not a monotonic
function of the duration of prior waking as is the case for S.
Apart from the frequently occurring midday dip (Carskadon
1989) the values remain at a fairly uniform level throughout
the habitual waking period. If waking is prolonged, sleep
latency declines rapidly. Qualitative simulations have been
performed with the two-process model by assuming that
sleep latency is represented by the difference between the
upper threshold modulated by C , and Process S (BorbCly et
al. 1989). By an appropriate skewing of the sinusoidal
function representing the threshold, the typical features of
sleep latency including the midday dip could be qualitatively
simulated. However, these simulations are based on ar-
bitrary adjustments of the model parameters and various
features are rather sensitive to minor changes. Although the
basic assumption that the propensity of sleep initiation
depends on homeostatic and circadian processes is reason-
able, a stringent comparison with a larger database is
necessary.
Whereas some authors emphasize the importance of the
midday dip (e.g. Broughton and Mullington 1992), it should
be noted that the phenomenon has not been invariably
recorded, that its timing varies considerably, and that the
extent of the change is much smaller than the circadian
variation. In particular, it has not yet been demonstrated
unambiguously that the midday dip is due to an endogenous
process (see below). Only if its endogenous nature is
confirmed will it be necessary to investigate whether it is a
result of the interaction of S and C as postulated in the
model, or of a bimodal variation in the upper threshold.

Change of Process S during REM sleep. The direction of the
change of S during REM sleep episodes is still an open
question. It could be argued that S declines since REM
sleep is a part of the sleep process. However, this argument
is not compatible with the recent version of the model in
which the change of S is determined by slow-wave activity.
Since there are practically no slow waves in R E M sleep, S
should remain unchanged. However, if the absence of slow
waves is considered to be equivalent to waking, an increase
of S would be expected. The latter assumption was in-
corporated in the most recent version of the model in which
the rising component of S is permanently active and
interacts additively with the declining component of S which
is a function of slow-wave activity (Achermann er al. 1990 in
preparation). Due to the limited duration of R E M sleep
episodes, it is difficult to devise experiments for testing the
different hypotheses.
REM sleep homeostasis. In the first version of the model,
REM sleep propensity was assumed to be predominantly
determined by Process C (Borbely, 1982b). In addition, a
reciprocally inhibitory interaction of the R E M sleep con-
trolling factor and Process S was postulated. The homeos-
tatic regulation of REM sleep was recognized but not
incorporated in the model. In the subsequent quantitative
version, REM sleep was disregarded (Daan et al. 1984).
One of the difficulties in modelling REM sleep regulation is
the absence of an intensity measure in humans. A rise in
‘REM sleep pressure’ manifests itself only in the increased
duration of REM sleep.
During recovery from total sleep deprivation, slow-wave
sleep and E E G slow-wave activity exhibit an immediate
rebound whereas the increase in REM sleep is delayed to
subsequent nights or is not present at all (references in
BorbCly 1982b). These results suggested that the intensity of
nonREM sleep is much more finely regulated than R E M
sleep. Recent findings contradict this notion. A REM sleep
deprivation in the first 5 h of sleep induced a REM sleep
rebound in the subsequent 2.25 h (Beersma et al. 1990). A
curtailment of sleep duration in 2 nights which induced a
substantial REM sleep deficit, was followed by a REM sleep
rebound in the two recovery nights (Brunner et al. 1990b).
In both experiments, the REM sleep rebound occurred at a
time when slow-wave pressure was either low at the end of
sleep (Beersma et al. 1990) or was much less increased than
‘REM sleep pressure’ (Brunner et a / . 1990b). These results
suggest also that REM sleep is finely regulated but that the
manifestation of REM sleep homeostasis is hampered by an
elevated slow-wave pressure.
In accordance with the notion of a mutual inhibitory
interaction of the factors controlling slow-wave activity and
REM sleep (BorbCly 1982b), not only R E M sleep is
inhibited by ‘slow-wave pressure’, but also slow-wave
activity by ‘REM sleep pressure’. Thus there was a
significant reduction in the low-frequency activity of the
nonREM sleep E E G during selective REM sleep depriva-
tion (Beersma et al. 1990). Also the rise in ‘REM sleep
Concepts and models of sleep regulation 71
pressure’ induced by partial sleep deprivation seemed to
suppress the typical low-delta peak in the nonREM sleep
spectrum (Brunner et al. 1990b).
Before R E M sleep homeostasis and its interaction with
nonREM sleep homeostasis can be incorporated into a
model, it will be important to determine whether the
inhibitory influence of R E M sleep on the nonREM sleep
spectrum represents merely a suppression of the E E G
manifestation of Process S, or if S itself is affected.
Generation of the nonREM-REM sleep cycle. In the original
version of the model, the generation of the nonREM-REM
sleep cycle was not incorporated. In a recent version, an
oscillating variable interacts with a R E M sleep trigger
threshold (Achermann et al. 1990). R E M sleep occurs
whenever slow-wave activity falls below a threshold. Quant-
itative simulations have not yet been performed. There is a
convergence between the elaborated version of the two-
process model and the limit cycle reciprocal interaction
model: the ultradian oscillating variable of the former model
can be substituted by the limit cycle variable of the latter
model (Achermann and BorbCly 1992), and homeostatic
processes can be incorporated in the limit cycle interaction
model (Massaquoi and McCarley 1992).
Is Process S affected by the intensity of waking? Whereas
nonREM sleep intensity as indexed by slow-wave activity
determines the time course of Process S during sleep, its rise
during waking is assumed to occur invariably according to a
saturating exponential function. This means that S depends
exclusively on the duration of waking, and that the intensity
of waking is irrelevant.
There is some evidence to the contrary. Thus an increase
in slow-wave sleep was observed after a hyperthermic
episode several hours prior t o sleep as well as after a day of
exposure to intense and varied environmental stimuli (see
Horne 1988, 1991, 1992 for references). Horne (1992)
argues that the common effect of these procedures is the
increase in brain metabolism. The notion that sleep is
promoted by a cumulative effect of heat load has been
incorporated in the model of Nakao et al. (1990a, 1991).
Further experiments are needed to test this proposition.
3 C O N T R O V E R S I A L ISSUES A N D O P E N
PROBLEMS
3.1 Two-per-day rhythm of sleep propensity: endogenous
or exogenous?
Broughton ( 1975) proposed an endogenous two-per-day
rhythm to account for the biphasic time course of vigilance,
showing reductions in the afternoon and evening. He
proposed that this circasemidian sleep propensity rhythm
might be an integral harmonic component of the circadian
rhythm, and may constitute a fundamental rhythm of
wakefulness rather than of sleep (Broughton 1989). The
72 A . A . Borbkly and P. Achermanri
proposition was related by the author to the two circadian
activity peaks in animals.
Whereas there is ample evidence for a bimodal
distribution of sleep propensity in subjects living in the usual
24-h world, it is less clear that this pattern is generated by an
endogenous rhythm. A polymodal distribution of sleep is
typical in early childhood. As development proceeds and
both waking and sleep episodes increasingly consolidate, the
polymodal pattern becomes bimodal and eventually
monomodal. A rise in sleep propensity near the middle of
the waking episode may represent a remnant of the early
polyphasic sleep pattern. Midday sleep propensity may be
enhanced by the relaxation following lunch (the post-lunch
dip), social habits (siesta), and high environmental
temperature. These factors may be responsible for the
considerable variability in the occurrence and timing of this
phenomenon. The bimodal sleep propensity observed in
free-running schedules (Strogatz 1986, p. 92) could be
equally attributed to the subjects’ tendency of structuring
their days and maintaining a 3-meal-per-day pattern even
under these conditions. Recent results cast doubt on the
generality of the bimodal pattern. Thus the analysis of
alertness and performance under a forced desynchronization
schedule did not reveal the presence of a midday dip when
the influence of prior wakefulness and sleep was assessed by
folding the data at the 2X-h period of the subjects’
sleep/wake schedule (Dijk e t a / . 1992).
The constant routine protocol constitutes a stringent test
for the endogenous origin of the midday rise of sleepiness.
In this schedule, the body posture is kept constant, food and
liquid intake occur at short regular intervals, lighting is
uniform and information on the time of day is withheld.
There was no clear evidence for a biphasic pattern of
alertness and performance in young male subjects recorded
under constant routine conditions (Dijk et al. 1992).
Carskadon and Dement (19x5) reported in an abstract a
midday reduction in multiple sleep latency from a test which
was performed at 2-h intervals from morning to evening. It
is unclear from the report whether factors such as the
knowledge of the time of day or the anticipation of the end
of the experiment in the evening may have influenced the
results. Since the negative findings of the other groups were
based on subjective sleepiness measures, it will be important
to use objective measures of sleep propensity to resolve this
important issue.
With the two-process model a polymodal sleep/wake
pattern can be simulated by narrowing the interval between
the two thresholds (Daan et ul. 1984). Since the level of the
upper threshold is assumed to be influenced by the arousal
level, its reduction in sleep-promoting situations (e.g. heat,
monotony under continuous bedrest; in some subjects with
free-running rhythms, see Strogatz 1986, p. 82) is to be
expected. Also the bimodal ‘siesta pattern’ can be obtained
without assuming an additional rhythmic process. The
three-oscillator model (phase only) accounted in a different
way for the bimodal sleep-nap pattern (Kronauer 1987a): it
was proposed that the x oscillator must have an important
second harmonic influence on the y oscillators. Recently
Kronauer and Jewett (1992) described both a circadian and
a hemicircadian* body temperature rhythm, and suggested
that the latter may underlie the bimodal pattern of sleep
propensity. Evidence is presented for independent changes
of the two components under various experimental
schedules. It is important to realize, however, that the
conclusions are derived from a mathematical analysis in
which harmonic sine waves are fitted to the temperature
data. It has yet to be shown that the hemicircadian
component identified by this procedure corresponds to a
biological oscillation.
3.2 Multiple napping
Campbell and Zulley (1985, 1989) pointed out that under
prolonged bedrest conditions multiple naps per day can be
observed. A four-per-day rhythm of sleep propensity has
been described (Zulley 1988; Broughton et ul. 1990). A
multiphasic sleep pattern is typical for the human infant
(Kleitman and Engelmann 1953). A prominent ultradian
sleep/wake pattern has been reported also for the rat during
early development (Alfoldi et ul. 1990). In terms of sleep
structure (i.e. slow-wave activity), each ultradian
sleep/wake episode showed the characteristics of a
‘mini-day’.
A straightforward explanation of the multiple napping
pattern is the inability to sustain either sleep or waking for
prolonged time periods under conditions of extreme
monotony (e.g. prolonged bedrest) or in early development.
An episodic rather than a rhythmic occurrence of sleep
seems to be typical under such conditions. Lowering the
upper threshold in the two-process model could simulate a
multimodal sleep/wake pattern (Daan et al. 1984;
Achermann 1988).
3.3 Wake maintenance zones
The term ‘wake maintenance zones’ was coined by Strogatz
and Kronauer (1985) and designates the zones in the
circadian cycle (defined by body temperature) in which sleep
tends not to begin. Strogatz (1986, Fig. 4.11) described the
position of these zones in internally desynchronized subjects
at about 8 h before, and about 6 h after the temperature
minimum. The two zones thus precede the midday nap
phase and the major sleep phase. The presence of the two
zones of low sleep propensity or of the evening zone alone
has been inferred by Strogatz from the reanalysis of
ultradian sleep studies, the occurrence of unintended
microsleep during a constant routine schedule, the record of
a subject entrained to a 23.5-h schedule, and of another
subject free running in society (Wollmann and Lavie 1985).
Lavie has referred to the wake maintenance zones as
* Hemicircadian is equivalent to circasemidian

'forbidden zones' for sleep, and supported this notion by
data from ultrashort sleep/wake cycles (for recent reviews
see Lavie, 1989; 1991). He refers to the phases of high sleep
propensity as primary (i.e. night sleep) and secondary (i.e.
midday sleep) sleep gates. In his studies, the evening zone
preceding night sleep is characterized by the lowest sleep
propensity.
It should be realized that the terms 'wake maintenance
zone' and 'forbidden zone' suggest an absolute inability to
sleep during specific intervals, which is not born out by the
data. There are at best intervals of reduced sleep
propensity. However, even this proposition needs to be
further examined for different schedules. In particular, the
constant routine protocols are needed to demonstrate that
factors such as structuring the day by three meals,
knowledge of time of day, and sleep itself are not major
determinants of the bimodal patterns observed.
3.4 Recurrence of slow-wave sleep
Gagnon arid Dekoninck (1984) reported a recurrence of
slow-wave sleep (SWS) during extended sleep, results that
were interpreted in terms of a sleep-dependent 12.5-h
rhythm (Broughton et al. 1990). Studies of extended sleep in
which sleep was initiated at three different circadian phases.
did not confirm a consistent recurrence of SWS (Dijk et al.
1990a, 1991b). E E G slow-wave activity was determined
quantitatively in these studies to assess its extent in later
parts of extended sleep. The occasional peaks in one of the
studies (Dijk et a/. 1991a,b) may represent random
variations or could be attributed to prior intermittent
waking or to the variable episode durations of nonREM
sleep and REM sleep (Achermann et u l . , in prep.).
The data d o not appear to contradict the basic
assumptions of the two-process model and d o not constitute
compelling evidence for the existence of a circasemidian
rhythm.
3.5 Multiple circadian oscillators?
Presently there is no strong evidence for the existence of
multiple circadian pacemakers in the mammalian central
nervous system (see 1.1). Daan and Beersma (1992)
demonstrated that certain phenomena that have been
attributed to multiple osci?lators, may be explained by a
single oscillator. Nevertheless, there are observations that
seem to defy an explanation on the basis of a single
pacemaker. Thus under certain experimental conditions the
circadian rest-activity cycle of rodents may split into two
separate components that drift apart and may assume a new
stable phase relation. In their dual pacemaker model,
Beersma and Daan (1992) propose that two identical
oscillators that are usually in phase, exhibit a change in their
phase-relationship which gives rise to splitting. They suggest
that the output of these oscillators interacts in a
multiplicative way to determine the probability of activity.
Concepts and models of sleep regulation 73
In humans, there is no clear evidence for a splitting of the
sleep/wake cycle. Strogatz (1986, p. 120) presents records of
subjects showing an alternation between split and
consolidated modes of sleep, the former being defined as
two naps bracketing the interval of the habitual consolidated
sleep. According to Strogatz, the relative duration of a
nap-sleep pair is more dissimilar than for split sleep. A
biphasic sleep pattern has been recently described in
humans who were exposed for several weeks to a short
photoperiod (Wehr 1991, 1992). Strogatz (1986, p. 186)
succeeded with the two-process model (Daan et a/. 1984) to
simulate certain features of the alternations of the split and
consolidated mode of sleep. Thus a model with a single
circadian oscillator is able to generate a realistic bimodal
sleep/wake pattern. Nevertheless, other possibilities must
be considered. One alternative is the dual pacemaker model
described in the preceding paragraph in which the duality of
the oscillator manifests itself only under certain conditions.
Another possibility is the hemicircadian component
proposed by Kronauer and Jewett (1992) whose influence on
the body temperature rhythm becomes manifest only under
particular circumstances whereas its effect on sleep
propensity is assumed to be permanently present. The study
of Zulley and Carr (1992) indicates that a biphasic
distribution of sleep can be generated in free-running
subjects by restricting the main sleep episode below a
critical duration. Further experiments, data analyses and
simulations are needed to clarify this basic issue.
4 CONCLUDING REMARKS
The present overview reflects the increasing importance of
the modelling approach in sleep science. Models help
delineate the regulating processes underlying such a
complex and little understood phenomenon as sleep. and
thereby offer a conceptual framework for the analysis of
existing and new data. The major models have already
inspired a considerable number of experiments. This
approach has become particularly attractive by the
possibility of using quantitative physiological measures in
humans for testing the predictions of a model. Thus E E G
slow-wave activity represents the key parameter in the
investigation of nonREM sleep homeostasis, while the
'unmasked' core body temperature is being used as the
indicator of the circadian process. The interactions between
these two processes can be studied by 'conflict experiments'
in which their usual phase relationship is experimentally
altered. This has been achieved in animal studies (recovery
from sleep deprivation during the activity period: Borbely
and Neuhaus 1979; Trachsel et ul. 1986) as well as in hurnan
experiments (e.g. forced desynchrony: Dijk et nl. 1992;
sleep curtailment: Zulley and Carr 1992).
Another positive feature of the modelling approach is the
fact that the regulatory processes postulated are not
restricted to a single species but probably represent basic
mechanisms in mammalian sleep. The basic features of sleep
74 A . A . Borbdy and P . Achermann
homeostasis and its interaction with the circadian process
has been shown to be similar in many mammalian species
including humans, and quantitative simulations in an animal
species have been successfully performed (for a review see
Tobler et a/. 1992). Human circadian research and the
corresponding models have been continuously related t o
animal experiments, and in one case the same model was
used for simulating human and rodent data (Kronauer
1987a). Again there is little doubt that a considerable part of
circadian physiology is invariant across mammalian species.
Finally, the first model of the ultradian process underlying
the nonREM-REM sleep cycle has been derived from data
obtained in the cat. Subsequently, the basic concepts of the
model were applied to human sleep (see Table 2). The
pervasiveness of the basic sleep regulating mechanisms in
mammals raises the problem whether they may be present
also in other classes of animals. The homeostatic regulation
of the sleep or rest state has already been explored in a bird
(Tobler and BorbCly 1988), a fish (Tobler and BorbCly
1985), and even in invertebrates (Tobler 1983; Tobler and
Stalder 1988).
One of the problems of the modelling approach is the
abstract nature of the postulated processes. It is important
to explore the structures in the brain in which these
processes are generated as well as the underlying
neurobiological mechanisms. There is conclusive evidence
that the suprachiasmatic nuclei represent the site of the
circadian pacemaker. However, it is still unknown how the
information originating in this structure modulates the
sleep/wake and rest-activity cycles. There is also strong
evidence that nuclei in the pons are centrally involved in the
periodic generation of R E M sleep, although the precise
mechanisms remain to be elucidated. T h e most recent
evidence in favour of the reciprocal interaction hypothesis
has been summarized by McCarley and Massaquoi (1992). It
is still unclear, however, how the processes in the brain stem
interact with the forebrain mechanisms of sleep and
wakefulness. Also the structures involved in R E M sleep
homeostasis remain elusive. A final comment relates to the
mechanisms underlying nonREM sleep homeostasis. It has
been one of the shortcomings of the two-process model that
Process S is based on an E E G parameter whose
neurobiological origin is obscure. However, recent experi-
ments revealed that hyperpolarized thalamic neurons exhibit
fluctuations of membrane potential in the slow-wave
frequency range (Steriade et a/. 1991; see also McCarley and
Massaquoi 1992). If, as Steriade and his colleagues propose,
these fluctuations are at the origin of E E G slow waves, the
mechanisms underlying sleep homeostasis would be open for
investigations at the cellular level.
This overview focused on the role of modelling for
investigating basic sleep regulating mechanisms. However,
this work also has implications for applied and clinical sleep
research. Models can be used to simulate the duration and
intensity of sleep as well as the time course of daytime
sleepiness during shift work (e.g. Daan et a/. 1984;
Akerstedt and Folkard 1990) and to predict optimal
schedules. Models describing the effect of light on circadian
parameters (e.g. Kronauer 1990) need to be combined with
models accounting for sleep homeostasis. There are
preliminary attempts at such combinations (Achermann and
BorbCly 1992; Massaquoi and McCarley 1992). These
considerations are also relevant for the treatment of sleep
disturbances in older people in whom both the homeostatic
and circadian facet of sleep regulation may be impaired. The
relevance of the modelling approach to sleep in depression
has been recognized early. Thus the circadian coincidence
hypothesis (Wehr and Wirz-Justice 1980) and the Process
S-deficiency hypothesis (BorbCly and Wirz-Justice 1982;
BorbCly 1987) have attempted to account in different ways
for the altered sleep structure in depression as well as for
the antidepressant effect of sleep deprivation. The two
hypotheses gave rise to numerous studies which were
designed to test their basic tenets. Recently, a related
hypothesis has been advanced by Wu and Bunney (1990).
One of the gratifying aspects of modelling sleep regulation
is the fact that the postulated basic processes seem to be of a
very general nature. This has been clear for a long time for
the circadian process which, in addition to sleep propensity,
determines to a large extent such diverse parameters as core
body temperature, the secretion of certain hormones (e.g.
cortisol and melatonin), retinal disk shedding, performance
and memory. Ultradian changes are not restricted to the
alternation of the two sleep states, but involve many other
functions controlled by the autonomic nervous system (e.g.
thermoregulation, cardiovascular parameters, penile erec-
tion). Plasma renin levels have been recently shown to be
closely associated with the nonREM-REM sleep cycle
(Brandenberger et al. 1988). The homeostatic facet of sleep
regulation does not have many associated parameters as yet.
The plasma level of T S H is affected by sleep deprivation
(Sack et al. 1988), and GH secretion seems to be related to
sleep onset (Born ef a / . 1988). Nevertheless, the basic
concept of interacting circadian and homeostatic processes
has been adopted to account for the regulation of hormones
(Van Cauter 1990), body temperature (Nakao et a/. 1990a,
1991), and retinal sensitivity (two-process model of retinal
rhythmicity: RemC et al. 1991). To define the relationship
between these processes and sleep regulation will be one of
the challenging future tasks.
ACKNOWLEDGEMENTS
We thank Drs Domien Beersma, Serge Daan and Irene
Tobler for their comments on the manuscript. The
comments of the workshop participants o n a draft version of
this overview are gratefully appreciated. We thank Ms
Annette Kaltbrunner for her help in preparing the
manuscript. The authors’ work was supported by the Swiss
National Science Foundation, grant 31.25634.88.

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APPENDIX
The mathematical equations of the major models are
compiled in this appendix. For a detailed description of the
models the original papers should be consulted.
E-M model (Daan and Berde 1978)
e, = tt - m, + A , sin
1
78 A . A . Borbkly and P . Achermann

m, = r,,,,- el-

e, = E, - M,
, + A,,,,sin [ :
- (e,- I - $,, ,)I Two-oscillator thennoregulatory model of sleep control
(Nakao et al. 1990a [in Japanese, with English abstract];
Nakao et ul. 1991; Nakao, pers. comm.)
m,= M, - El- , TBODY + 2cwnTBOVY + wf,TBOVY = TSEI.+ TM

E , M: time of onset of 5 h of activity triggered by the E - and TsET= x ( t ) - ch heat-load(t)

M-oscillator, respectively; t E , t,,,,:period of the E - and (0 t
M-oscillator; A,, A,,,,: coupling strength; sine function: x ( t ) = a, sin(+ + 0),
phase response curve (PRC); Gt-,$,,,,: phase of the P R C
relative to the E and M events. See original paper for
(A ,+ A,s)(1 e-'h'T) A s (waking)
- -

zeitgeber terms. ( A , + A,s)e-'s'r- A,s (sleep)

Original x-y model. Predominant effect of light on y

(Kronauer et ul. 1982)
k2x+kpL,(-1+x2)X+w~++F,,y=0
heat-load(t) =
I,+ - TyFT(t')}
{ TBODY(t') dt'

@ [ y ( t ) c , heatLload(t); h,]
Sleepiness = 1 + e-[%)l>Y(f)- ~\lT(f)l/cz

x: strong circadian oscillator controlling core body

temperature; y : weak circadian oscillator controlling the
sleep/wake cycle; z : zeitgeber; k : scale factor ( k = 24/2n); TBODY:observable body temperature; TSE.,.:temperature
p , , p,,; stiffness; w,, io,,: intrinsic angular frequency; Fvx: set point; TM:masking effect due to sleep and waking; 5:
strength of velocity coupling of y to x ; F z v : strength of damping factor; w,: intrinsic frequency; x ( t ) : circadian
velocity coupling of x to y; Fzy: Coupling strength of the oscillator with amplitude a,, frequency w, and phase 0,;k :
zeitgeber . scaling factor (k = 2n/24); t: time constant; t,: beginning
of wake; t,y, tso: beginning of sleep; @[. . . ;h,]: linear
increasing function above threshold h,, 0 otherwise; y ( t ) :
Revised x-y model. Predominant effect of light on x
circadian oscillator with amplitude uy, frequency w , and
(Kronauer 1990)
phase 8."; ch, A,, A,,, E , ~ ,c S , c,, c,: positive constants.
X):( = x,. + 0.13(x 43+
-- B
Sleep onset occurs when sleepiness crosses a threshold h,s
upward and wake onset is defined by a downward crossing
of a threshold h , > h,).

B = ( I -mx)C/'/3 Reciprocal interaction model (McCarley and Hobson

1975)
x , x c . : deep circadian pacemaker; I : light intensity; B :
perceived brightness; r , : intrinsic period; m : modulation X = ux - bxy
index; C: scaling factor. I; = -CY + dxy
x : activity of FT'G cells (REM-on); y : activity of LC cells
(REM-off); a , b, c, d: positive constants representing
connection strength. R E M sleep occurs if x is above a
certain threshold.

Limit cycle reciprocal interaction (LCR) model: original

version (Massaquoi and McCarley 1990; McCarley and
Massaquoi 1986; Massaquoi, pers. comm.)

x : strong circadian oscillator with intrinsic frequency 1

controlling body temperature; y , , y2: weak circadian
oscillators with intrinsic frequency 1 + w controlling the
sleep/wake or rest-activity cycles; Or: phase of x ; 0 , : phase
of y , ; HZ: phase of y z ; F,,, F,,, FvA:coupling functions.
Note: Simulations were carried out with a simplified
version of the model.
 Concepts and models of sleep regulation 79

Model of ultradian variation of slow-wave activity

(Achermann et al. 1990)

SWA = rcSWA 1 -
( s3
~ - fc(SWA - SWA,)

dci,, = 0.975
c;
+ 0.125 sin -t + p,,
0.39 + 0.3 sin(p,,) - 0.05t,
1
if E > 0
X REMT(t)
S = -~CSWA + rs(1-
u= V
+ n(t)SWA
S)

else
V = aV(6 - U 2 )- w2U

x: REM-on activity, REM sleep occurs if x > 1.4; y : 1, if U > R T

REMT(t) = {0
REM-off activity; E: declining excitatory input depending , else
on circadian phase of sleep onset; po: circadian phase at
sleep onset; a @ ) , 6(x), S,(x), S , ( y ) : constraining functions; REM(t) = { 1,, ifSWA<R
else
d,,,,: circadian variation of parameter d.
Note: Time step is 10.7 min. SWA: slow-wave activity; S: homeostatic Process S; U , V :
ultradian oscillator (Van der Pol oscillator), generates the
REM trigger (REMT) event; rc: rise constant; fc: fall
constant; SWA,: lower asymptote of SWA; n ( t ) : noise
Two-process model (Daan et al. 1984) component, normal distribution; gc: gain constant ('decay
rate'); rs: 'rise rate' of S ; a : stiffness; 6 : 'amplitude'; w :
intrinsic frequency; RT, R : thresholds determining R E M T
and R E M sleep, respectively.
(wake)
A(0.97 sin[w(t - f , , ) ] + 0.22 sin[2w(t - t,,)] Three-process model of the regulation of
+ 0.07 sin[3w(t - t , J ] sleepiness/alertness (Akerstedt and Folkard 1990; Folkard
+ 0.03 sin[4w(t t,J]
- and Akerstedt 1987, 1989, 1992)
+ 0.001 sin[5w(t - t , J ] ) n
H=H+C [
C=2.5cos ( t - 16.8)-]
12
L=L+C
S={
+
- 2, 4)e --o 0353t 2.4 (waking)

14.3 - (14.3 - S,)e-" "Ir (sleep)

S: homeostatic process, increasing during waking, decreas-
ing during sleep; C: circadian process, modulates an upper
threshold ( H ) and a lower threshold ( L ) ;d : decay factor of
S ; r : rise factor of S; t,,,t,: time constants; At: time step;
A: circadian amplitude; w : angular frequency of the
circadian oscillator; t,l: circadian phase at the beginning of
the simulation; H : mean value of upper threshold; L: mean
value of lower threshold. A gaussian noise component is
superimposed on the thresholds. The timing of sleep and
waking is determined by the interaction of S and C; S
oscillates between H and L. Note: S is described by a
recursive equation (iteration).
W = 5.72e-I '"
A=C+S-W
A: alertness; C: changes in alertness due to circadian
factors; S: changes in alertness due to homeostatic factors;
W: sleep inertia, wake u p process; S; level of S at
awakening; S,; level of S at retiring. Time t has different
reference values: wake up for W a n d S during waking; sleep
onset for S during sleep; midnight for C.
Note: The time course of the homeostatic process is the
inverse of the time course of Process S of the two-process
model; it builds up during sleep and declines during waking.