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Vol. 83, Issue 6, 1923-1932, December 1997
The John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin 53705-2368
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Smith, C. A., K. S. Henderson, L. Xi, C.-M. Chow, P. R. Eastwood, and J. A. Dempsey. Neural-mechanical coupling of breathing in REM sleep. J. Appl.
Physiol. 83(6): 1923-1932, 1997.
During rapid-eye-movement (REM) sleep the
ventilatory response to airway occlusion is reduced. Possible
mechanisms are reduced chemosensitivity, mechanical impairment of the
chest wall secondary to the atonia of REM sleep, or phasic REM events
that interrupt or fractionate ongoing diaphragm electromyogram (EMG)
activity. To differentiate between these possibilities, we studied
three chronically instrumented dogs before, during, and after
15-20 s of airway occlusion during non-REM (NREM) and phasic REM
sleep. We found that 1) for a given inspiratory time the integrated diaphragm EMG
(
Di) was similar or reduced in REM sleep relative
to NREM sleep; 2) for a given
Di in response to airway occlusion and the
hyperpnea following occlusion, the mechanical output (flow or pressure)
was similar or reduced during REM sleep relative to NREM sleep;
3) for comparable durations of
airway occlusion the Di and integrated
inspiratory tracheal pressure tended to be smaller and more variable in
REM than in NREM sleep, and 4)
significant fractionations (caused visible changes in tracheal
pressure) of the diaphragm EMG during airway occlusion in
REM sleep occurred in ~40% of breathing efforts. Thus reduced
and/or erratic mechanical output during and after airway
occlusion in REM sleep in terms of flow rate, tidal volume, and/or pressure generation is attributable largely to reduced neural activity of the diaphragm, which in turn is likely attributable to REM effects, causing reduced chemosensitivity at the level of the
peripheral chemoreceptors or, more likely, at the central integrator.
Chest wall distortion secondary to the atonia of REM sleep may
contribute to the reduced mechanical output following airway occlusion
when ventilatory drive is highest.
dogs; rapid-eye-movement sleep; non-rapid-eye-movement sleep; obstructive apnea; sleep-disordered breathing
INTRODUCTION THE REGULATION OF BREATHING in rapid-eye-movement (REM)
sleep, especially "phasic" REM sleep, is substantially different
from that in non-REM (NREM) sleep (21, 26). During eupnea, frequency is
generally higher and more variable and tidal volume
(VT) is reduced in REM sleep;
during airway occlusion or with increased arterial
PCO2
(PaCO2), the more negative tracheal
pressure (Ptr) values and/or increases in flow rate tend to be
more erratic and blunted in contrast to the predictable, progressive
responses to increasing chemoreceptor stimuli observed in NREM sleep
(5, 27, 30). After release of airway occlusion in NREM sleep, marked
overshoots of flow rate and VT
occur and in turn often lead to central apnea. In contrast, in phasic
REM sleep the VT responses
following occlusion are generally much smaller and more variable, and
central apneas are very rare (2, 29).
The goal of the present study was to determine the cause(s) of the
decreased ventilatory responses during and after airway occlusion in
REM sleep. The three most likely causes of these effects of REM sleep
on the ventilatory responses are 1)
increased distortion of the chest wall during inspiratory efforts
secondary to the atonia of rib cage and accessory respiratory muscles,
thus compromising neural-to-mechanical coupling [i.e., a given
inspiratory neural/EMG input produces less mechanical (pressure and
flow) output] (20, 21); 2)
decreased responsiveness of chemoreceptors and/or of medullary
integration of chemoreceptor input to the asphyxic stimuli developed
during the occlusion (27); and 3) phasic REM events that cause fractionations of neural input to inspiratory muscles (16).
The present study analyzed the flow rates or Ptr and diaphragm
electromyogram (EMG) obtained in NREM and REM sleep in three dogs
during eupnea, during airway occlusion, and after occlusion. The
findings support a major role for a decreased and highly variable neural respiratory motor output, as reflected in the diaphragm EMG in
REM sleep, in accounting for the limited and erratic pressure and
ventilatory responses obtained during eupnea and especially during and
after airway occlusion. Chest wall distortion may also contribute to
the reduced ventilatory responses following airway occlusion where
ventilatory drive is highest.
METHODS
Ptr, i.e., area under the inspiratory pressure
waveform) was derived by computer. Raw EMGs were amplified, rectified,
and moving time averaged with a 100-ms time constant. Integrated
diaphragm activity (Di, i.e., area under
moving-time-average waveform) was derived by computer. The
Di is reported in arbitrary units, normalized to
the daily mean of all eupneic, NREM breaths recorded for a given dog.
Fractionations of the diaphragm EMG were determined manually from the
raw diaphragm EMG signal. Fractionations were defined as EMG silence
for >50 ms during inspiration.
Sleep state was determined by means of a five-lead montage of
percutaneous Basmajian-type wire electroencephalogram (EEG) electrodes
and standard criteria (see Ref. 29 for details). In the present study
we examined only NREM and phasic REM sleep. Phasic REM sleep was
defined as a desynchronization of EEG, eye movement density >0.25/s
(the average during REM sleep was ~0.35/s), and loss of EMG activity
in the nuchal muscles. Any trials that did not meet these criteria were
excluded from analysis.
Choice of electrical and mechanical variables.
There are at least three potential ways to express neural-mechanical
coupling of breathing in REM sleep. One method is to use the rate of
rise of the moving time average of diaphragm EMG and its mechanical
analogs, VT-to-inspiratory time
(TI) ratio or rate of fall of
Ptr. A second method is to compare peak EMG activity of the diaphragm
and its mechanical analogs, peak inspiratory flow and peak Ptr. A third
method is to compare Di with its mechanical
analogs, VT and
Ptr. We have chosen to use the latter method in this
study of phasic REM sleep in the dog because of problems associated
with determination of a meaningful rate of rise (or fall) in EMG,
pressure, or flow. These problems are present throughout REM sleep but
can be best illustrated by an example from an occlusion trial (Fig.
1). Breath
1 (the last eupneic, nonoccluded breath) shows a
reasonably ramplike increase in EMG activity and inspiratory flow;
however, the remaining breaths in this trial illustrate various
problems. Breaths 2-4 present almost rectangular waveforms (i.e., very steep initial rate of rise
followed by a slowly rising plateau). Breaths
5 and 6 have two
distinct slopes in each breath, and breath
6 has a clear decrease in activity in the middle of the
breath. These different shapes are reflected in Ptr during the
occlusion. Thus determining a true rate of rise is problematic for
electrical and mechanical variables. Clearly, a simple peak-over-time
approach could badly over- or underestimate the rate of rise.
Similarly, examining the rate of rise over the early portion of a
breath (e.g., 100 ms) could also be misleading, especially in breaths
with a rectangular waveform where the early rate of rise is very steep
but then reaches a plateau. Measurements of peak values can also be
misleading because of the brief, sharp transients present in REM sleep
that may not be representative of an entire breath. In the present study we have attempted to avoid these problems by using
VT (eupnea and postocclusion),
Ptr (occlusion), and Di,
which make no assumptions about the shape or duration of the waveform.
, airflow; au, arbitrary units.
Protocol. Our protocol is illustrated in Fig. 2. Once a stable sleep state had been achieved (NREM or REM), a 60-s eupneic control period was followed by tracheal occlusion, which averaged 16.3 ± 1.4 (range 11.8-21.1) s; the occlusion was released before EEG arousal. Ventilation, Ptr, diaphragm EMG, and EEG/electrooculogram were recorded continuously throughout each trial, such that 60 s of eupneic control, all occluded breathing efforts, and
60 s of postocclusive breathing were obtained. We report only on trials in
which sleep state (NREM or REM) was stable during and after the
occlusion.
Analysis and statistics. Regression slopes of
Ptr (during airway
occlusion) or VT (during eupnea
and after occlusion) as a function of Di, which
we have termed "input-output" plots, were compared across NREM
and REM sleep only between zero Di and the lowest
maximum Di for each of the three conditions
(eupnea, occlusion, and postocclusion) in a given dog for NREM or REM
sleep. We did this because we thought we could legitimately compare
slopes only over comparable ranges of data, where the data from both sleep states tended to show linear relationships.
Differences between regression slopes were determined by means of
analysis of covariance (SYSTAT). Differences in slopes were considered
significant if P 
0.05. Differences
between grouped data were determined by independent
t-tests (SYSTAT) and were considered
significant if P 0.05.
RESULTS
Di
was unchanged in two dogs and significantly decreased in the third.
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Ptr, and Di are shown in Fig.
3 and Table 1. During airway occlusion
in NREM sleep, Di and Ptr
typically increased progressively with each inspiratory effort
throughout the occlusion period. In contrast, during REM sleep,
Di and Ptr during the
occlusion period did not consistently increase in a progressive manner,
and their magnitudes tended to be smaller at the termination of
occlusion in REM than in NREM sleep.
Ptr) and
integrated diaphragm EMG activity 
Di) over time
of occlusion. Also note VT and
Di achieved after occlusion. REM sleep shows more
variable eupneic breaths, a reduced and disorganized response of
Ptr and Di during
occlusion, and generally smaller
VT and Di
after occlusion. Linear regression of Ptr and
Di as a function of time during occlusion was
positive and significant in all dogs in NREM and REM sleep.
After release of airway occlusion in NREM sleep, ventilatory overshoots occurred consistently, inasmuch as VT and
Di were greater than control in most trials. In REM sleep the ventilatory overshoots and increase in Di after release of
occlusion were much less consistent and smaller in magnitude.
Relationship of TI and
Di in NREM vs. REM sleep.
Figure 4 shows the magnitude of
Di as a function of
TI for eupnea, airway occlusion,
and postocclusion in NREM and REM sleep. There is considerable overlap
of TI values between NREM and
REM sleep. Di tended to decrease as a linear
function of decreasing TI during
eupnea. Occlusion and postocclusion relationships of
Di and TI
could not easily be described with simple functions, although here too
Di always tended to decrease as
TI shortened. During eupnea in
REM sleep all dogs had a number of breaths with
TI values <1 s, whereas in
NREM TI values <1 s were
unusual, and these few were in one dog. Even in this range, Di continued to decrease as
TI became shorter.
Di as a function of inspiratory time
(TI) during eupneic breathing
in REM (A) and NREM sleep
(B). All trials in all dogs are
shown. Note considerable overlap of TI values between NREM and REM
sleep and prevalence of breaths in REM sleep that have
TI values <1 s. Despite these
short TI values,
Di continued to falll as
TI decreased. Mean
Di for each dog for all breaths with
TI between 1 and 2 s (a range
common to all conditions) combined revealed no significant differences
between NREM and REM sleep for eupnea (108 ± 21 vs. 102 ± 18),
occlusion (161 ± 84 vs. 205 ± 73), or postocclusion (346 ± 165 vs. 300 ± 68) breathing.
Neural input-mechanical output relationships, NREM vs. REM sleep. The relationship of neural input (
Di) to
mechanical output (VT) during
eupnea is illustrated in Fig. 5, and mean
values are listed in Table 2. In all cases
the slopes of the relationship between
VT and Di were significantly different from zero. Also in two dogs there was a
small but significant increase in slope in REM vs. NREM sleep, and in
the third dog there was a small but significant decrease in slope. On
average, at a representative Di of 100 units,
there was an ~6% decrease in
VT during REM vs. NREM sleep.
Di and lowest maximum Di
value in NREM or REM sleep.
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Di vs.
Ptr (occlusion) or
VT (postocclusion) was
significantly greater than zero in all conditions in all dogs. During
airway occlusion the slopes of the neural input-mechanical output
relationships in REM were equal to or slightly less than those in NREM
sleep. On average, at a representative value for Di of 400 units, Ptr was
only ~2% less in REM than in NREM sleep. In contrast, after airway
occlusion the slopes of the neural input-mechanical output relationships in REM sleep were significantly less than those observed
in NREM sleep. Thus, on average, for an Di of 400 units the VT would be ~26%
smaller in REM than in NREM sleep.
Di, Ptr responses in REM
sleep are similar to or less than those during NREM sleep.
Di, responses in REM sleep are similar
to or less than those during NREM sleep.
Fractionations of EMG and mechanical outputs in REM sleep. Examples of diaphragm EMGs with and without fractionations are shown in Fig. 8. Fractionations longer than ~50 ms were detected in 41% of the occluded breaths. Some of the fractionated breaths had more than one fractionation; thus, on average, there were 1.6 fractionations per fractionated breath during airway occlusion. Sixty-three percent of the fractionations were associated with positive-going spikes in Ptr, i.e., an interruption in the ramp of negative-going Ptr. This mechanical effect of EMG fractionation was usually associated with the longer (more than ~100-ms) fractionations.
DISCUSSION
In summary, we have found that 1)
for a given TI the
Di was similar or reduced in REM sleep relative to NREM sleep; 2) for a given
activation of the diaphragm EMG in response to airway occlusion and the
hyperpnea following occlusion, the mechanical output (flow or pressure)
is similar or slightly reduced in REM vs. NREM sleep; in eupnea the
results are equivocal; 3) for
comparable durations of airway occlusion the Di and Ptr tended to be smaller and more erratic in
REM than in NREM sleep; and 4)
fractionations of the diaphragm EMG during airway occlusion in REM
sleep occurred in ~40% of breathing efforts and in some instances
may have contributed to the diminished and erratic ventilatory
responses observed. Thus reduced mechanical output during and after
airway occlusion in REM sleep in terms of flow rate,
VT, and/or pressure
generation appears to be attributable largely to reduced neural
activity of the diaphragm, which in turn is likely attributable to REM effects, causing reduced chemosensitivity at the chemoreceptor level
or, more likely, at the level of central integration.
Di would appear to
disagree with the findings of Orem et al. (19-21) in cats,
inasmuch as we found no change or a decrease in
Di during eupneic breathing in phasic REM vs.
NREM sleep in the dog (Table 1). Moreover, when these data were
normalized by plotting Di as a function of
TI, we found no difference in
the Di between eupneic breaths taken in REM and
NREM sleep. Very short TI values
(<1 s) were present only in REM sleep, but the
Di in REM sleep continued to decrease as
TI became shorter (Fig. 4). Thus our data in the sleeping dog do not support the idea of a compensatory increase in ventilatory drive during eupnea in REM sleep.
There are several possible explanations for this apparent disagreement
between studies. First, our observations were confined to
phasic REM sleep, i.e., periods with consistently high eye movement densities, whereas Orem and colleagues
(19-21) used data from tonic and phasic REM sleep. At
least one study in unanesthetized cats (16) showed that the rate of
rise of diaphragm EMG is more variable in phasic than in tonic REM
sleep, and the range of values not only overlaps but also extends above
and below values observed in tonic REM sleep. However, we believe that
the large number of observations obtained in the present study
precludes a systematic error due to variability. Second, we do not
believe that state-related changes in posture were a factor, because
our dogs remained in a constant posture throughout our observations in
REM and NREM sleep and our diaphragm EMGs did not appear to be
contaminated by nondiaphragm EMGs. Third, species differences (cats vs.
dogs) may be significant in neural control of respiratory muscles
and/or chest wall compliance. However, in contrast to Orem and
colleagues (19-21), at least two studies in unanesthetized cats
(16, 25) found no consistent effect of REM sleep on the rate of rise of diaphragm EMG activity during eupnea. Without a consensus in the cat,
it is clear that more work in the cat model is required before this
issue can be resolved.
REM effects on neural input-mechanical output relationships during
chemoreceptor-driven breathing.
The effects of phasic REM sleep on mechanical output and on diaphragm
EMG and their relationship were most striking in response to increasing
chemostimulation, as occurred during and immediately after airway
occlusion. Ptr (during occlusion) and
VT (after occlusion) were
markedly reduced and highly variable in REM vs. NREM sleep.
Furthermore, inasmuch as chemoreceptor stimuli increased with time
during the occlusion, peak Ptr often failed to decrease continuously
breath by breath in REM sleep, unlike the situation in NREM sleep,
where each succeeding breath is typically more negative than the
preceding breath. Most importantly, these effects of phasic REM sleep
on mechanical output were also present in the Di,
inasmuch as the relationships of mechanical output to EMG of the
diaphragm were significant and equal or slightly reduced in REM vs.
NREM sleep. Accordingly, we attribute these effects of REM sleep on the
reduced amplitude and increased variability of Ptr during airway
occlusion and of inspiratory flow rate and
VT after release of occlusion
largely to REM sleep effects on neural respiratory motor output via
decreased chemosensitivity.
REM effects on chest wall stability during chemostimulated breathing
appear to play little or no modulatory role in ventilatory responses
during airway occlusion in the absence of volume changes. However,
chest wall distortion secondary to the muscle atonia of REM sleep
appeared to reduce significantly the ventilatory responses in the
postocclusion period (Fig. 7, Table 2). It is not clear why this
reduction was observed only in the postocclusion period and not during
occlusion or in eupnea. We speculate that the contribution of REM
sleep-induced atonia and associated chest wall distortion is
sufficiently small in this species (see below) that mechanical effects
can be detected only where ventilatory drive, airflow, and
VT values are high, such as in
the postocclusion period.
Our data obtained during and after airway occlusion are consistent with
the blunted and erratic responses of ventilatory output to
experimentally induced hypoxia and hypercapnia previously reported in
REM sleep in humans, cats, and dogs (7, 25, 27). On the basis of our
present data in the dog, we would attribute these blunted ventilatory
responses to chemostimulation to a reduced respiratory neural output.
Contrary to the increased rate of rise of medullary inspiratory neurons
reported during eupnea in REM sleep in the cat (see above), would
medullary inspiratory neuronal activity reflect what we observed in the
dog's diaphragm EMG and show markedly blunted responses relative to
those in NREM sleep? We would predict that this would be the case, but
clearly direct measurement of medullary neuronal activity during
chemostimulation is needed in REM sleep.
Why is diaphragm EMG reduced and more variable in REM sleep?
We believe that there are four possible explanations for decreased
diaphragm EMG activity in response to chemostimulation in REM sleep.
First, brief interruptions or fractionations of the ramp of diaphragm
EMG accounted for at least some of the decreased responsiveness to
chemostimulation during airway occlusion (Fig. 8). In cats, Veasey et
al. (28) observed that fractionations were present in 13-27% of
eupneic breaths, and we observed EMG fractionations in 41% of occluded
breaths. We also observed that many of the longer diaphragm EMG
fractionations actually resulted in a measurable effect on Ptr, flow
rate, or VT developed during
inspiration. That not all the EMG fractionations had obvious mechanical
consequences may not be surprising, inasmuch as many EMG fractionations
were very brief; furthermore, Hendricks and Kline (11) showed
considerable regional within-breath heterogeneity of fractionations in
the costal diaphragm of cats. Thus many EMG fractionations may occur in
only a small region of the diaphragm and/or may be too brief to
have a significant mechanical effect.
Second, the generally faster and more variable frequency of inspiratory
efforts during chemostimulation in phasic REM sleep suggests that many
inspirations are probably terminated early. This interruption of the
diaphragmatic EMG activity during phasic REM events could account for
the reduced amplitude of EMG activity.
Third, REM sleep or phasic REM events may actually interfere with true
chemosensitivity at the level of the chemoreceptor(s) and/or at
the level of central integration of chemoreceptor sensory inputs. At
our level of measurement of stimulus response, we cannot distinguish
between these proposed effects. Indeed, even the effects of diaphragm
EMG fractionations or TI
truncation on diaphragm EMG (see above) may be interpreted as an
apparent blunting of the "chemoresponse." The only advance our
findings have made in understanding the nature of this REM-induced
blunted response of ventilatory output and pressure development to the
asphyxia of airway occlusion is to show that it occurs at the level of the neural activation of the diaphragm. Other respiratory
mechanoreceptor reflex responses from lung stretch and from airway
stimulation have also been shown to be blunted in phasic REM sleep (10, 15, 17, 27, 30). However, we think it unlikely that these reflexes are
involved in the reduced ventilatory responses in REM sleep, because
1) they tend to be inhibitory, and
blunting an inhibitory reflex should, if anything, enhance ventilation, and 2) the increase of ventilatory
efforts over the duration of occlusion strongly suggests to us a
buildup of chemical stimuli (5).
Fourth, the increase in cerebral blood flow during REM sleep
demonstrated by Parisi et al. (23) in the sleeping goat would probably
have reduced medullary PCO2. This in
turn would have reduced the stimulus at the level of the medullary
chemoreceptors and may have caused an apparent reduction in
chemosensitivity in REM sleep.
Implications of decreased chemoresponsiveness to breathing during
REM sleep.
The depressed chemoresponsiveness of REM sleep may have some bearing on
breathing stability in this state. Central apneas in NREM sleep are
commonly caused by ventilatory overshoots resulting from many types of
stimuli, including transient periods of airway obstruction (2, 5, 14).
In the human, these types of central apnea are thought to be primarily
determined by transient hypocapnia (2, 6, 14), whereas in the dog,
hypocapnia and vagally mediated lung stretch (prompted by
VT overshoots) cause ensuing central apneas (5, 29). The reduced chemoresponsiveness to the asphyxia
of airway occlusion means that the subsequent overshoot of ventilation
and especially VT are blunted in
phasic REM sleep, and this lessens the probability of ensuing central
apnea or hypopnea (29). The reduced diaphragmatic EMG and pressure
responses during occlusion in REM sleep may also mean that increasing
sensory input from the chest wall leading to cortical arousal (8) will
be reduced and less dependent on apnea duration, perhaps contributing to prolongation of occlusive apneas in REM.
ACKNOWLEDGEMENTS
The contributions of Dr. Gordon S. Mitchell are gratefully acknowledged.
FOOTNOTES
Address for reprint requests: C. A. Smith, Dept. of Preventive Medicine, 504 N. Walnut St., Madison, WI 53705-2368.
Received 3 January 1997; accepted in final form 29 July 1997.
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EMG, AU 
AU 
Di EMG, area of
integrated moving-time-averaged diaphragm EMG; AU, arbitrary units;
TE and TI, expiratory and inspiratory time; f,
breathing frequency; 
