Analysis of A Sleep-Dependent Neuronal Feedback Loop: The Slow-Wave Microcontinuity of The EEG
Analysis of A Sleep-Dependent Neuronal Feedback Loop: The Slow-Wave Microcontinuity of The EEG
Analysis of A Sleep-Dependent Neuronal Feedback Loop: The Slow-Wave Microcontinuity of The EEG
Abstract—Increasing depth of sleep corresponds to an in- anatomical characteristics of the head. Therefore, effects in the
creasing gain in the neuronal feedback loops that generate the power plots do not necessarily reflect effects on sleep. For in-
low-frequency (slow-wave) electroencephalogram (EEG). We stance, females have twice the SWP of males, but this does not
derived the maximum-likelihood estimator of the feedback gain
and applied it to quantify sleep depth. The estimator computes imply that they really sleep more deeply [5], [6]. This uncer-
the fraction (0%–100%) of the current slow wave which continues tainty also exists when within-subject effects on total duration
in the near-future (0.02 s later) EEG. Therefore, this percentage of NREM-sleep are studied. The amplitude (or power) thresh-
was dubbed slow-wave microcontinuity (SW%). It is not affected olds that are involved in the computation of durations depend
by anatomical parameters such as skull thickness, which can also on nonsleep-related processes: the power thresholds corre-
considerably bias the commonly used slow-wave power (SWP).
In our study, both of the estimators SW% and SWP were spond to different sleep depths in different subjects.
monitored throughout two nights in 22 subjects. Each subject These nonsleep-related effects can be partly avoided by ap-
took temazepam (a benzodiazepine) on one of the two nights. plying relative power measures, such as the percentage of the
Both estimators detected the effects of age, temazepam, and time total power that is in the slow-wave frequency band, or the ratio
of night on sleep. Females were found to have twice the SWP of of powers in the slow-wave and alpha band. However, it is not
males, but no gender effect on SW% was found. This confirms
earlier reports that gender affects SWP but not sleep depth. clear how such a ratio would be related to real, physiological,
Subjectively assessed differences in sleep quality between the sleep depth. Also, relative power measures are based on fre-
nights were correlated to differences in SW%, not in SWP. quency analysis, which implies a rather limited time resolution
These results demonstrate that slow-wave microcontinuity, when compared to the frequent and abrupt sleep depth varia-
being based on a physiological model of sleep, reflects sleep depth tions that can occur in, for instance, sleep apnea patients.
more closely than SWP does.
Some physiological models of NREM sleep [7]–[9], [4]
Index Terms—Aliasing, EEG, estimator, sleep, temazepam. suggest a different method that would not suffer from these
drawbacks. These models describe how NREM sleep depth is
I. INTRODUCTION related to the neuronal mechanism that generates slow waves.
This mechanism is essentially feedback through closed loops
with (1)
II. THE FEEDBACK MODEL: GENERATION OF SLOW WAVES IN
THE EEG where is the complex operator, and Hz and
Hz are the center frequency and bandwidth, respectively. The
The derivation of the feedback gain estimator is based on a resulting 3 dB frequencies of the resonance filter are 0.5 Hz
simple mathematical model of the slow-wave generating feed- and 2 Hz. The roll-off at both ends is only 6 dB/octave, which
back system. This model describes three essential characteris- implies that a considerable part of the signal below 0.5 Hz and
tics of the above-mentioned physiological models: 1) the exis- above 2 Hz is also passed. These settings roughly correspond to
tence of a low-frequency feedback loop in which the feedback the frequency content of slow waves. They also result in sim-
gain is proportional to sleep depth; 2) unpredictable activity ulated signals and power spectral densities that best resemble
from external sources drives the loop; 3) increased feedback those of actual EEG recordings [14]. Note that , and
gain corresponds to larger SWP. These characteristics can be all other frequencies are attenuated as well as changed in phase.
implemented in various practical mathematical models. Physi- The equivalent notation in the complex-frequency
ological knowledge does not provide clear criteria to select be- domain reads
tween these models. Therefore, we have implemented a variety
of models, based on the three above mentioned characteristics.
The models differed in types of low-frequency filters in the feed-
back loop, in random processes driving the filter, and in location with
of the feedback gain. We selected the model that most realisti- and
cally simulated EEG.
Fig. 1 shows a block diagram of that model. Standard white (2)
noise, , drives a feedback loop containing a resonance
filter, , and a feedback-gain, . This feedback gain In all our applications we have , which makes and
represents sleep depth. The feedback loop produces an output complex constants. In the time domain, the resonance filter
signal, . The resonance filter passes only the rhythmic (in is specified by its impulse response function:
this case, the slow-wave) component, , of this output signal.
The feedback gain determines which fraction of this component
actually continues in the near-future output signal. The output (3)
KEMP: ANALYSIS OF A SLEEP-DEPENDENT NEURONAL FEEDBACK LOOP 1187
In the open-loop situation, i.e., , the filter produces the In the general, closed-loop situation, the filter produces the
rhythmic component, , by convoluting the white-noise input rhythmic component, , by convoluting as
as follows: follows:
(7)
(4)
The closed-loop transfer function from to reads is produced by a causal feedback loop while
is defined as a forward increment with respect to .
We finally assume that the initial state, , of the feedback
filter, , is known so that its output, , can be updated
(11) on-line from the input, . The likelihood of
, which is of the observations
This transfer function is identical to the open-loop transfer func- over the full interval, given the value of , can be factorized
tion of (1), except that the bandwidth is instead of according to Bayes’ rule [18, Ch. 4.5] into a product of, in this
, and the gain at is instead of 1. Therefore, the case Gaussian, distributions
closed-loop power of can directly be deduced from (6). It
equals
(12)
(13) (15)
where Hz is the dB cutoff frequency. For the third equality, we have used (14) and the Gaussian dis-
tribution of . The value of that maximizes this likeli-
III. MODEL-BASED ESTIMATION OF THE NEURONAL-FEEDBACK hood, maximizes the sum in the last line of this equation. There-
GAIN: SLOW-WAVE MICROCONTINUITY fore, the maximum-likelihood estimator, , is the value of for
which the derivative of this sum with respect to equals 0. This
The model’s feedback gain, , represents sleep depth. We value is
will, therefore, quantify sleep depth by estimating the feedback
gain. The discrete-time maximum-likelihood estimator can be
derived as follows. Discrete-time intervals, , are 0.02 s in
the present application (EEG slow waves), corresponding to a (16)
sampling frequency of 50 Hz. This frequency is sufficiently
high for an accurate representation of the slow-wave compo-
nent. Selecting still higher sampling frequencies increases the
risk of bias by unknown technical of physiological high-fre- Substituting from (14) into (16) shows that indeed
quency filters that are not accounted for by the model. The con- converges to , because and are mutually in-
tinuous-time observations, over an interval , dependent. In Sections IV and V, is expressed as a percentage,
are sampled with sample counter, , resulting in discrete-time .
observations, over an interval Fig. 1 shows how to reconstruct that is required
, with . We assume for the mo- for the computation of (16). Applying the inverse of , that
ment (see Section IV) that this interval is short when compared is , to the EEG and subsequent integration would give
to the dynamics of , so that . We fur- . The discrete-time equivalent, , is obtained
ther note that the sampling interval, , is short when compared by applying the bilinear transformation [19], [20, chapters 4.0
to the slow-wave frequencies (being around 1 Hz), so that we and 5.1.3] to . Subtracting subsequent samples of
assume that in the interval, . then results in the following algorithm for obtaining
The discrete-time equivalent of the model is then obtained by from the EEG samples, :
integrating (8) and reads
with
(14) and
(17)
in which is the increment
of the standard continuous-time Wiener process, , over the in which is the prewarped [see (19)].
time increment, , and, therefore, has a Gaussian distribution Fig. 1 also shows how to reconstruct that is also re-
with mean 0 and variance . As in the continuous-time model, quired for the computation of (16). Applying the inverse of
the increments are independent of because , that is , to the EEG and subsequent filtering by
KEMP: ANALYSIS OF A SLEEP-DEPENDENT NEURONAL FEEDBACK LOOP 1189
discrete-time filtering, acts as a perfect anti-aliasing filter on the multiplied the result by 100 in order to express the estimated mi-
white noise component. crocontinuity as a percentage
(24)
and
(31)
Fig. 2. The seven-hour sleep period of a male, aged 20, under placebo
condition (sleep-wake recording 7141/94). From top to bottom six charts, each
one with solid bars indicating the REM sleep periods. Chart 1: EEG (PzOz),
SWP, in (V) . Chart 2: EEG slow-wave feedback gain, i.e., SW%, which is
the fraction of the present slow wave that is transferred to the near-future EEG.
Chart 3 (top trace): SW0 in (V) , the part of the SWP variations in chart 1 that
V. SLOW-WAVE MICROCONTINUITY COMPARED TO the model could not predict from SW%. Chart 3 (bottom trace) illustrates that
SLOW-WAVE POWER: EFFECTS OF TIME OF NIGHT, dynamic attenuation of the EEG amplitude by the square root of SWP (chart 1)
AGE, GENDER, AND TEMAZEPAM ~
removed all variations from the resulting SWP, SWP. Chart 4: EEG slow-wave
~
feedback, SW%, computed from the thus dynamically attenuated EEG. Note
that despite this attenuation, charts 2 and 4 are identical, which implies that
In a study [23] of the pharmacodynamics of temazepam (a SW% only depends on EEG shape, not amplitude. Chart 5: neuronal power
benzodiazepine which promotes NREM-sleep duration), EEG ~
variations as reconstructed by model equation (27) from SW% in chart 4. Note
(PzOz derivation) was recorded throughout two nights in 22 that charts 1 and 5 are almost identical, which implies that the original neuronal
power variations are almost fully coded in the shape of the EEG. Note also
subjects. The recorder was a digital telemetric system [24], from the scales of charts 1 and 5 that the absolute values of neuronal power
[25] with frequency response range (3-dB points) 0.03–1000 could not be reconstructed because of the unknown factor x (we assumed
Hz, 14-bit sampling at 100 Hz per signal, and a total noise =
SW0(n) 1 in the reconstruction). Chart 6: traditional manual classification
(R&K) into (from top to bottom) the six sleep stages: Wakefulness, REM sleep
level of 2- V p-p. The subjects were grouped by age and (bold), drowsiness, and the increasingly deep NREM sleep stages 2, 3, and 4.
gender (F: females, M: males) as follows: 18–34 years (6F, Note that removing all power variations from the EEG (chart 3) did not affect
4M), and 35–78 years (9F, 3M). Each subject took 20 mg the dynamics of microcontinuity (chart 4). Note also that the model can even
reconstruct the original power variations (chart 5).
of temazepam on one of the two nights (randomized, double
blind, cross-over). Sleep stages were scored manually, using
additionally recorded signals, and according to the standard Fig. 2 illustrates that the well-known night-time dynamics in
scoring rules of Rechtschaffen and Kales [17]. SWP are fully coded in SW%. Charts 2 and 4 illustrate that
The slow-wave analyzer automatically monitored at a 1 s time SW% depends only on the shape of the EEG, not on amplitude:
resolution the SWP (26) and its two components; the sleep- chart 2 shows the microcontinuity as computed directly from
dependent SW% (25) and the nonsleep-dependent factor (28), the EEG while chart 4 is computed in the same way but after
SW0. The result was a SWP, SW%, and SW0 plot for each attenuation of the EEG by the dynamic SWP plot. This attenua-
recorded night (Fig. 2). tion completely removed the power fluctuations from the EEG
1192 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 47, NO. 9, SEPTEMBER 2000
(see chart 3). Still, charts 2 and 4 are identical. This implies TABLE I
that SW% analysis is indeed independent of the EEG ampli- SIGNIFICANCE LEVELS OF THE EFFECTS OF AGE, GENDER AND TEMAZEPAM ON
WHOLE-NIGHT MAXIMA OF BOTH RSWPs AND RSWPw, SWP AND ITS TWO
tude and that the night-time dynamics in SWP are fully coded COMPONENTS, SLOW WAVE FEEDBACK (SW%) AND NONSLEEP-RELATED
in the microcontinuity (shape) of the EEG. The latter is also ATTENUATION (SW0). NOTE THAT TEMAZEPAM AND GENDER AFFECT SWP
EXCLUSIVELY THROUGH SW% AND SW0, RESPECTIVELY. AGE SEEMS TO
demonstrated by chart 5. This chart shows that the model can AFFECT SWP THROUGH BOTH SW% AND SW0
reconstruct the original neuronal-power fluctuations even after
removal of all EEG-power variations!
These illustrations are consistent with the model, which
predicts that sleep-related variations in SWP are caused by
variations in slow-wave feedback, SW%. Objective validation
of this prediction was based on computation of the whole-night
correlation between the SW% and SWP plots in each subject. TABLE II
The relationship (28) between SW% and SWP is nonlinear, QUESTIONS FOR ASSESSING SSQ. THE ORIGINAL QUESTIONNAIRE WAS IN
DUTCH. AFTER EACH POLYGRAPHIC SLEEP/WAKE RECORDING, THE SUBJECT
which would bias the correlation analysis (and also ANOVA ANSWERED EACH QUESTION BY MARKING THE “YES” OR THE “NO” BOX. IN
[6]). Therefore, the relationship was first linearized by loga- THE EXAMPLE BELOW, THE MARKINGS WERE MADE BY A “PERFECT”
(32)
effect on sleep quality was found to be significantly correlated method of rejecting these artifacts from the analysis. However,
with the effect on SW%-duration, not a considerable advantage of SW% in detecting effects on
with the effects on SWP, RSWPs-, RSWPw-, or R&K-duration sleep will remain that SW% is computed in the time domain
(the four values were 0.22, 0.36, 0.21, and 0.32 respecively. and, therefore, offers a much better time resolution. This is
The four values 0.1). important when neuronal feedback gain can change rapidly,
such as in sleep apnea patients or in other applications such as
alpha-blocking [10], the detection of K-complexes [29] and the
VI. CONCLUSION cycling alternating pattern (CAP) in sleep [30].
SW% is, by definition (16), the fraction of the currently The formal derivation of the analyzer precludes the use of
present slow wave that is continued in the near-future EEG. anti-aliasing filters. Therefore, not-modeled high-frequency
Continuation of current activity into the future essentially im- signal generators such as muscle artifacts may bias the results.
plies a temporal feedback mechanism. The fact that we found Although the model-based artifact rejection of paragraph
clear time-of-night variations in SW%, therefore, inevitably IV handles these artifacts very well, not all artifacts will
implies the existence of a slow-wave generating closed loop be rejected. Therefore, more practical experience must assert
in which the feedback gain varies in the course of the night. whether or when this is a serious problem. The results discussed
Reasoning based on physiology, neuronal feedback gain was above indicate that this was not the case in the present study.
also found [7]–[9] to be the dynamic physiological state rep- Recent physiological evidence [31] shows that different
resenting NREM-sleep depth. These two independent lines of frequencies within the slow-wave range may point to different
evidence strongly suggest that NREM-sleep depth corresponds mechanisms of sleep. Components, the slow component ( 1
to the feedback gain of neuronal slow-wave oscillating loops. Hz) and the delta component (1–4 Hz), are the result of different
A simple model of this principle suggests that variations in feedback mechanisms. But both mechanisms have a feedback
SWP are due to variations of sleep-related microcontinuity, ac- gain that increases with increasing sleep depth. This may partly
cording to the multiplicative relationship given in (28). Our data explain the success of methods, including the microcontinuity
support the model because we indeed found strong correlations estimator, that roughly cover both frequency bands. Still,
(0.89 to 0.99) between logarithmically transformed whole-night because physiological research suggests the existence of
power and microcontinuity plots (see also Fig. 2). functionally different frequency bands in the slow-wave range,
Our data confirm previously reported effects of age, a next step should be to apply the microcontinuity analysis
temazepam and gender on SWP. But only age and temazepam, separately to the two EEG components.
not gender, affected SW%. This suggests that age and In the same reference [31], it was argued that EEG analysis
temazepam affect real sleep depth but gender affects SWP “should take into consideration the actual aspect of waves and, if
through a nonsleep-related (possibly anatomical) process. possible, their relationship with the state of the cellular aggre-
These results support an independent study [5] suggesting gates of the corticothalamic network” underlying slow waves.
that the gender effect on SWP is not due to a gender effect on The microcontinuity estimator is the first method that does both.
physiological sleep depth. As a consequence, microcontinuity allows a physiological in-
These results also suggest that the microcontinuity analysis terpretation: it reflects the degree of activation of the low-fre-
can distinguish sleep-related from nonsleep-related effects on quency neuronal feedback loops that generate the slow waves
SWP. In that case, SW% is a more accurate estimator of sleep in the EEG.
depth than SWP is. This suggestion was confirmed by the fact
that the effects of temazepam on SSQ correlated to SW%-dura-
tion, not to SWP-duration. ACKNOWLEDGMENT
Similar to SW%, both RSWP plots should not be affected The authors would like to thank A. Janssen and M. Roessen
by anatomical parameters that do affect SWP. Indeed, gender who made the recording hardware and software and R. Biemond
had no effect on RSWP-maximum. Also, SSQ was more and E. Kemp who made most of the recordings.
strongly correlated to RSWPw-duration than to SWP-duration.
However, the correlation between SSQ and SW%-duration was
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format for exchange of digitized polygraphic recordings,” Electroen- Leiden, The Netherlands, in 1996.
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results,” Clin. Neurophysiol., vol. 110, pp. 585–592, 1999. general) and GnRH antagonists.