Vol. 280, Issue 6, H2674-H2688, June 2001
Respiratory modulation of human autonomic rhythms
Leslie J.
Badra1,
William H.
Cooke2,
Jeffrey
B.
Hoag1,
Alexandra A.
Crossman1,
Tom A.
Kuusela3,
Kari U. O.
Tahvanainen4, and
Dwain L.
Eckberg1
1 Departments of Medicine and Physiology, Hunter Holmes
McGuire Department of Veterans Affairs Medical Center and Medical
College of Virginia at Virginia Commonwealth University, Richmond,
Virginia 23249; 2 Center for Biomedical Engineering, Michigan
Technological University, Houghton, Michigan 49931;
3 Physics, University of Turku, FIN-70211 Turku, Finland;
and 4 Clinical Physiology, Kuopio University Hospital, FIN-20014
Kuopio, Finland
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ABSTRACT |
We studied
the influence of three types of breathing [spontaneous, frequency
controlled (0.25 Hz), and hyperventilation with 100% oxygen] and
apnea on R-R interval, photoplethysmographic arterial pressure, and
muscle sympathetic rhythms in nine healthy young adults. We integrated
fast Fourier transform power spectra over low (0.05-0.15 Hz) and
respiratory (0.15-0.3 Hz) frequencies; estimated vagal
baroreceptor-cardiac reflex gain at low frequencies with cross-spectral
techniques; and used partial coherence analysis to remove the influence
of breathing from the R-R interval, systolic pressure, and muscle
sympathetic nerve spectra. Coherence among signals varied as functions
of both frequency and time. Partialization abolished the coherence
among these signals at respiratory but not at low frequencies. The mode
of breathing did not influence low-frequency oscillations, and they
persisted during apnea. Our study documents the independence of
low-frequency rhythms from respiratory activity and suggests that the
close correlations that may exist among arterial pressures, R-R
intervals, and muscle sympathetic nerve activity at respiratory
frequencies result from the influence of respiration on these measures
rather than from arterial baroreflex physiology. Most importantly, our
results indicate that correlations among autonomic and hemodynamic
rhythms vary over time and frequency, and, thus, are facultative rather than fixed.
hyperventilation; apnea; muscle sympathetic nerve activity; vagal; baroreflex
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INTRODUCTION |
BREATHING IS A READILY
OBSERVED human rhythm that exerts profound influences on
autonomic neural outflow. Not surprisingly, humans figure importantly
as experimental subjects for research into respiratory-autonomic
interactions. Alone among research subjects, they can cooperate and
they can breathe more slowly or rapidly, more shallowly or deeply, or
they can hold their breath and not breathe at all. Numerous authors
(17, 18, 45) have used controlled respiration as a means
to perturb and study important human autonomic mechanisms.
Notwithstanding the advantages humans bring as experimental subjects,
they also bring a major disadvantage: they are, perforce, closed-loop
preparations in whom fluctuations of recorded signals do not
necessarily betray their mechanisms. For example, because arterial
pressures and R-R intervals fluctuate in parallel at low and
respiratory frequencies, these fluctuations have been considered to be
causally related and to reflect baroreflex physiology; arterial
pressure changes provoke R-R interval changes (11). However, human time series contain no intrinsic information regarding whether the fluctuations result from actions of independent oscillators or reflexes, and cross-spectral analyses do not even indicate which
fluctuation precedes the other. In this study, we asked healthy young
subjects to breathe in different ways (or to not breathe at all) as a
means to study and better understand how respiration influences human
autonomic and hemodynamic rhythms.
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METHODS |
Subjects.
Eight men and one woman, ages 24 
35 yr, participated in this
study. All subjects were healthy and nonsmokers. Subjects refrained from imbibing alcohol or caffeine-containing drinks, and they did not
perform strenuous exercise 24 h before each study. This study was
approved by the human research committees of the Medical College of
Virginia at Virginia Commonwealth University and the Hunter Holmes
McGuire Department of Veterans Affairs Medical Center. Subjects gave
their informed, written consent before they participated.
Measurements.
We recorded data on digital tape (TEAC RD-145T;
Montebello, CA), and subsequently redigitized them at 500 Hz with
commercial hardware and software (WINDAQ, Dataq Instruments; Akron,
OH). We continuously measured electrocardiographic R-R intervals,
respiration (abdominal bellows connected to an uncalibrated
strain-gauge pressure transducer), and finger
photoplethysmographic arterial pressure (model 2300, Finapres,
Ohmeda; Englewood, CO). (In some subjects, we also recorded tidal
volume with a Fleisch pneumotachograph.) Subjects' left arms rested in
a sling with their hands placed at the level of the right atrium. An
infrared analyzer (Gambro; Engström, Sweden) measured
CO2 concentrations in samples withdrawn continuously from a
face mask. We did not attempt to control subjects' tidal volumes.
We recorded muscle sympathetic nerve activity directly (model 662C-1,
Nerve Traffic Analyzer, University of Iowa Bioengineering; Iowa City,
IA), as described previously (71). Briefly, we made our
recordings with a tungsten microelectrode (FHC; Bowdoinham, MA) with a
~2- to 5-µm uninsulated tip, inserted into the right peroneal
nerve, posterior to the fibular head. The microelectrode was used first
to deliver electrical stimuli to provoke muscle twitches and then to
record nerve signals. An uninsulated reference electrode was inserted
2-3 cm from the recording electrode. Both electrodes were
connected to a differential preamplifier and to an amplifier (total
gain of 70,000) where the nerve signal was band-pass filtered
(700-2,000 Hz) and then integrated (time constant 0.1 s) to
obtain mean voltage neurograms.
Recording electrodes situated in mixed peripheral nerves register all
traffic, afferent as well as efferent; however, only muscle and skin
sympathetic nerve traffic occurs as pulsatile bursts. These bursts of
nerve activity are efferent, not afferent, because they are abolished
by proximal, but not distal, anesthetic injections; they arrive at the
recording site after ganglionic transmission because they are
reversibly abolished by ganglionic blocking agents; and they are
succeeded by changes of sympathetic effector function, including
increases of arterial pressure or skin resistance (12,
29). The challenge is to determine whether such sympathetic
bursts travel to muscle or skin vascular beds. We used the following
criteria to differentiate muscle from skin sympathetic nerve activity:
1) bursts were pulse synchronous with the electrocardiogram;
2) Valsalva maneuvers increased burst frequency and size;
3) muscle stretch increased afferent nerve traffic; 4) light skin stroking did not increase afferent nerve
activity; and 5) loud noises did not affect activity. Nerve
signals were monitored throughout each experiment on a computer terminal.
Experiment protocol.
Subjects remained supine throughout the research protocol and breathed
in the following fixed sequence: 1) spontaneous,
uncontrolled breathing for 5 min; 2) controlled
fixed-frequency breathing at 0.25 Hz for 5 min; 3)
hyperventilation with 100% oxygen for 2 min; followed by 4)
inspiratory breath holding for as long as possible; and 5)
spontaneous, uncontrolled breathing for 30 s after apnea. The cue
for fixed-frequency breathing was a waveform displayed in real time on
the screen of a laptop computer (ThinkPad, IBM; Armonk, NY) positioned
on a stand for comfortable viewing. During 0.25 Hz controlled-frequency
breathing, the durations of inspiration and expiration were equal.
Data analysis.
We analyzed our results with custom software, WinCPRS, developed by one
of us (T. A. Kuusela, Turku, Finland).
Sympathetic nerve activity.
The WinCPRS program automatically detects sympathetic bursts with
signal-to-noise ratios >3:1 and the time from the preceding (one
removed) R wave to each sympathetic burst peaks occurring at 1.3 ± 0.50 s (21). Two observers manually over-read
results of automated analyses, removed erroneously detected
bursts, and added bursts that were missed by the computer program. The
integrals of all sympathetic burst areas and amplitudes occurring
during the initial 5-min period of uncontrolled breathing were divided by the number of bursts to derive an average control burst area and
amplitude. The area and amplitude of each sympathetic burst detected
subsequently were divided by these numbers to derive normalized burst
areas and amplitudes. (For example, if the area of a burst were twice
as large as the area of the average control burst, its normalized area
would be 2.0.) We expressed sympathetic nerve activity as bursts per
minute and total activity (bursts/min multiplied by average normalized
burst areas). For spectral analysis of the discontinuous sympathetic
nerve signal, we averaged sympathetic nerve activity over each second.
We measured average values and transients during each data segment. For
each breathing protocol, we averaged responses over 1) the
total duration; 2) the first and last 2 min; 3)
the first and last minute; and 4) every 15 s. We also
averaged 30-s epochs every 5 s at the beginning and end of apnea
and at the beginning of hyperventilation. (We could not average
responses of our subjects throughout apnea, because the durations of
apnea varied widely. However, because the shortest duration of apnea
was 3 min, we were able to average the first 3 min and back-average the
last 3 min of apnea for all subjects.)
Power spectra.
We used fast Fourier transformation to calculate spectral power of the
R-R interval, systolic and diastolic pressures, and muscle sympathetic
nerve activity time series, as described previously (8).
Briefly, the waveforms were linearly interpolated and resampled at 5 Hz. They were then passed through a low-pass impulse response filter
with a cut-off frequency of 0.50 Hz. Sixty-second (300 samples) data
sets, sliding every 10 s, were detrended, Hanning-filtered, and
fast Fourier transformed to their respective frequency representations. We used a periodogram method to estimate power distribution
(49). The areas under the low (0.05-0.15 Hz) and
respiratory frequency (0.15-0.30 Hz) peaks were integrated and
averaged for all subjects. Muscle sympathetic nerve spectral power was
characterized both in terms of frequency and normalized burst areas and amplitudes.
Baroreflex.
We estimated vagal baroreflex gain at low frequencies from the squared
coherence between pairs of measurements by dividing the squared
cross-spectral densities of systolic pressures and R-R intervals by the
product of the individual power spectral densities and the phase angle
as the arc tangent of the quotient of the quadrature and coincident
spectral density functions. The transfer function was calculated as the
quotient of the cross-spectral density and the power spectral density
of the systolic pressure. The modulus of the transfer function was used
to estimate baroreflex gain (58).
Partial coherence.
Partial coherence analysis is a technique that mathematically removes
the influence of one signal (in our case, respiration) from two other
signals (systolic pressure and R-R intervals), and then determines
coherence between the residual components of the other two signals. The
partial coherence function (the input signals have the index 1 and 2, and the output signal has the index y) was calculated as
where
and
Bendat and Piersol (4) give further in-depth
details about these calulations.
The smoothed cross-spectra were determined by
X(f) and
Y(f) are Fourier transforms
of the time signals x(t) and
y(t).
and w(f) is the triangular
weighting function
or
where M is the parameter determining the width of the
triangular smoothing window.
We averaged significant (
0.50) squared
coherences1 and partial
coherences from time series cross-spectra within the ranges 0.05-0.15 and 0.15-0.30 Hz. In subjects with multiple
significant coherence peaks, we arbitrarily chose coherences and
partial coherences that fell entirely within the boundaries set. In
subjects with continuous low-frequency coherences and partial
coherences that ended within the 0.05- to 0.15-Hz window but began at
frequencies below 0.05 Hz, we averaged coherence and partial coherence
over the entire range. We averaged phase angles over coherent segments and assumed that negative phase relations indicate that arterial pressure changes precede R-R interval changes (we discuss this assumption in RESULTS). We calculated latencies
from the average phase angle and center frequency over coherent
segments. Finally, we subtracted each subject's measured P-R interval
from arterial pressure-R-R interval latencies to derive true estimates
of the latencies between arterial pressure changes and sinoatrial node responses.
Statistical analysis.
Data are given as means ± SE. When data were distributed
normally, statistical comparisons among variables were made with one-way ANOVA. When data were not distributed normally, comparisons were made with a one-way repeated-measures ANOVA on ranks. The Tukey's
honestly significant difference procedure was used to determine the
significance of all pairwise multiple comparisons. Differences
were considered significant when P < 0.05.
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RESULTS |
Time domain analyses.
Average measurements from the group of subjects were comparable during
uncontrolled and fixed-frequency breathing, with one exception:
end-tidal CO2 concentration was significantly lower during
fixed frequency than spontaneous breathing (5.4 ± 0.1 vs. 4.7 ± 0.2%; P < 0.05).
Figure 1 depicts measurements obtained
from one subject during hyperventilation (which began at time
0). By about 30 s after the onset of hyperventilation, R-R
intervals, R-R interval fluctuations, systolic and diastolic pressures,
and (as expected) end-tidal CO2 concentrations had declined
substantially, and muscle sympathetic nerve activity had increased (in
this subject, total nerve activity increased 40% during
hyperventilation). Figure 2 shows 15-s
average measurements during hyperventilation from all subjects. The
changes of the group of subjects were similar to those shown for the
individual subject (Fig. 1): R-R intervals declined and remained at a
low level; systolic and diastolic pressures fell transiently and then recovered; and muscle sympathetic nerve activity increased during the
fall of arterial pressure and then drifted downward toward baseline
levels.
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Fig. 2.
Fifteen-second average responses (means + SE) of all subjects
to hyperventilation with 100% oxygen. Vertical dashed line indicates
the beginning of hyperventilation. Values to the left of this line are
average measurements made before hyperventilation, during the last
30 s of fixed-frequency breathing.
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Subjects were able to maintain apnea for an average of 290 s
(range: 181-407 s). Figure 3 is a
recording from one subject. In this and other subjects, R-R intervals
increased dramatically at the onset of breath holding (from the low
levels recorded at the end of hyperventilation) and then drifted
downward toward baseline levels. R-R interval fluctuations were
prominent during apnea. Arterial pressure (Fig. 3) fell initially and
then rose as apnea continued. There was a major volley of muscle
sympathetic nerve bursts at the onset of apnea (Fig. 3, left,
bottom panel), concurrent with the abrupt reduction of arterial
pressure, and a gradual increase of sympathetic activity as apnea
continued. Sympathetic nerve activity was absent after the resumption
of breathing (Fig. 3 left, bottom panel, extreme
right).
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Fig. 3.
Experimental record from one subject during 210 s of apnea.
Left shows measurements made from 25 s before, until
25 s after apnea. Vertical dotted lines bracket one "gasp,"
and right shows measurements made within this period, on an
expanded scale. Respiratory excursions were registered by an abdominal
bellows connected to a pressure transducer at high gain. Aortic
pulsations are apparent in the top right. A Fleisch
pneumotachograph did not indicate any air flow during apnea in this
subject. Insp, inspiration.
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During apnea, this and most other subjects had involuntary and
unrecognized changes of abdominal girth. (We regard these as aborted
breaths. However, in subjects in whom we recorded pneumotachograms, there was no air flow; therefore, we cannot exclude other
possibilities, such as minor coughs or throat clearings.) One of these
events (delimited by the vertical dashed lines in Fig. 3) is shown on an expanded scale on the right of Fig. 3. This change of abdominal girth was extremely small; the pressure gauge connected to the abdominal bellows was so sensitive that it registered pulsations of the
abdominal aorta (Fig. 3, top right), and the Fleisch
pneumotachograph recording (not shown) did not register any air flow.
Nonetheless, the sequential hemodynamic changes set in motion by this
small event were huge. R-R intervals fell from 1.19 to 0.94 s, and
then rose to 1.40 s. Systolic pressures fell from 139 mmHg at the
time of maximum R-R interval prolongation to 110 mmHg. During this pressure reduction, there was a major volley of eight large muscle sympathetic bursts in consecutive R-R intervals. During apnea in this
and most other subjects, these changes occurred erratically. The
autonomic and hemodynamic responses that followed (best seen in the R-R
interval tracing, Fig. 3, second left panel), tracked the
gasps, with identical periodicities.
Frequency domain analyses.
Figure 4 depicts a fast Fourier
transformation of muscle sympathetic burst amplitude spectral power
from one subject during apnea. (For this analysis, spectra were
calculated during 60-s windows moved by 1.5-s steps through the 180-s
time series.) The contour map on the right comprises horizontal
sections made from the three-dimensional representation on the left.
(The highest peaks of spectral power are shown in yellow.) This map
clearly documents persistence of major fluctuations of muscle
sympathetic nerve burst amplitude spectral power during apnea and
indicates further that such sympathetic oscillations come and go and at different low frequencies. Muscle sympathetic nerve activity during apnea was absent at respiratory frequencies.
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Fig. 4.
Power spectral density derived from a sliding fast Fourier
transformation of sympathetic nerve burst area from one subject during
apnea. Right depicts horizontal sections made through the
three-dimensional representation on left. The greatest
spectral power is in yellow areas. Muscle sympathetic nerve activity
fluctuated at different low frequencies during apnea. Muscle
sympathetic spectral power was absent at usual breathing frequencies
(0.2-0.3 Hz).
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Table 1 lists and Fig.
5 illustrates average measurements
made during all breathing protocols. The significant
differences among measurements are that R-R intervals were shorter
during hyperventilation than during all other breathing protocols, and systolic and diastolic pressures were higher during apnea than during
other breathing protocols. Muscle sympathetic nerve activity was
significantly higher during apnea than during fixed-frequency breathing. End-tidal CO2 levels, which had decreased
significantly during fixed-frequency breathing, from those measured
during spontaneous breathing, decreased further during
hyperventilation.
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Fig. 5.
Average responses of all subjects to all breathing modes. Letters a
and b denote statistical significance. Measurements with no or the same
letter are not significantly different, and measurements with different
letters are significantly different from each other (P < 0.05).
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Vagal baroreflex gain.
We calculated the modulus of the transfer function between systolic
pressure and R-R intervals (see METHODS) as 60-s windows moving by 1-s steps. Figure 6 illustrates
such estimates of vagal baroreflex gain measured in two subjects during
spontaneous breathing. We did not analyze these moving transfer
functions exhaustively. However, even cursory inspection of our data
indicated that transfer function moduli fluctuated quasiperiodically,
in all subjects during all protocols (including apnea).
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Fig. 6.
Moduli of low-frequency systolic pressure, R-R interval
transfer functions derived from cross-spectral analyses from two
subjects. Quasiperiodic fluctuations of these estimates of vagal
baroreflex gain were documented in all subjects during all
breathing modes and apnea.
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Other frequency domain analyses.
Figure 7 depicts average (heavy lines)
and individual (light lines) R-R intervals, systolic pressures, and
muscle sympathetic nerve burst amplitude spectral powers for all
breathing protocols. These results document substantial variability
among spectral power measurements obtained from individual subjects and
also among average measurements obtained during different protocols. R-R interval spectral power at respiratory frequencies (~0.25 Hz) was large during spontaneous and fixed-frequency breathing but
nearly absent during hyperventilation and apnea (Fig. 7, right portions
of top right two panels). Low-frequency R-R interval spectral power was present, but small, during spontaneous and fixed-frequency breathing and hyperventilation and was large during apnea.
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Fig. 7.
Power spectral densities from all subjects during all
breathing protocols. Light lines in each panel are values from
individual subjects; dark lines are group averages.
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Systolic pressure spectral power (Fig. 7, middle panels) was
minimal at respiratory frequencies during all breathing protocols. [However, there were major systolic pressure spectral peaks at breathing frequencies during hyperventilation (not shown: the breathing
rate during hyperventilation averaged 0.44 Hz, or 26 breaths/min)]
Muscle sympathetic nerve burst amplitude spectral power (Fig. 7,
bottom panels) was small at respiratory frequencies, but was
large over a wide range of low frequencies during all protocols.
Statistical analysis of the integrated low-frequency spectral powers
depicted in Fig. 7 failed to identify any significant differences among
measurements during the different breathing conditions and apnea.
Figure 8 depicts sliding squared
coherence and coherence after partialization (see METHODS)
of the relations between systolic pressures and R-R intervals made
during 5 min of spontaneous breathing in one subject. For these
analyses, the window for each spectrum was 90 s, and the steps
were 3 s. (Thus the first calculation was made 45 s into the
breathing epoch, and the last was made 45 s before its
conclusion.) The horizontal dashed lines in coherence and partial
coherence analyses (Fig. 8, left) indicate the level, 0.50 (10, 65), which as mentioned, is used almost universally to reflect significant coherence in studies of human autonomic oscillations.
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Fig. 8.
Sliding coherence and partial coherence and phase derived from
cross-spectral analyses of systolic pressures and R-R intervals for one
subject during spontaneous breathing. The window for these sliding
cross-spectra was 90 s, and each step was 3 s. Before
partialization (top panels), there were strong coherences
and relatively fixed phase angles over both low and respiratory
frequency ranges. Partialization (bottom panels) abolished
coherence and the relatively fixed phase angle at the respiratory
frequency, but did not alter these measurements at low frequencies.
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The top left of Fig. 8 indicates that in this subject,
systolic pressures and R-R intervals were broadly coherent over low (0.052-0.092) and respiratory frequency (0.19-0.33 Hz)
ranges. The top right of Fig. 8 indicates that the average
phase angles over coherent frequencies were 50° at the low
frequency, and 32° at the respiratory frequency. If systolic
pressures lead R-R intervals in such cross-spectral analyses (see
discussion below), these phase angles translate into latencies (to the
P wave) of 1.73 and 0.15 s at low and respiratory frequencies.
The results of partialization (with respiration as the first input
signal, the one whose influence was removed, and systolic pressure as
the second input signal) are shown in Fig. 8, bottom. Significant coherence persisted after partialization at low frequencies (0.048-0.084 Hz), with an average phase angle of 52° (latency: 2.00 s). Removal of respiratory influences by partialization
abolished the coherence and systematic phase angle between systolic
pressure and R-R interval cross spectra at respiratory frequencies
(Fig. 8, right portions of bottom panels).
Figure 9 shows average coherence and
coherence after removal of respiratory influences by partialization and
corresponding phase angles for all subjects. These results document for
the group what was apparent for the individual subject (Fig. 8). For the group, average coherence between systolic pressure and R-R interval
time series at respiratory frequencies was strikingly high (peak: 0.93, Fig. 9, top right, light line). Average coherence at respiratory frequencies fell to below 0.50 after partialization (Fig. 9, top right, heavy line).
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Fig. 9.
Average cross-spectral coherence and phase angles between
systolic pressure and R-R intervals from all subjects (light lines). As
with the individual subject whose responses were shown in Fig. 8,
partialization abolished significant coherence at the respiratory
frequency (top, right, heavy line).
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For the group of subjects, latencies between systolic pressure and P
wave fluctuations averaged 1.62 ± 0.20 at low frequencies and
0.03 ± 0.12 s at respiratory frequencies. All latencies at low frequencies were negative; five of nine latencies at respiratory frequencies were positive. If, as we assume, negative latencies indicate that systolic pressure changes precede P-P interval changes (the mathematical computation does not indicate which signal precedes the other), then positive latencies at respiratory frequencies indicate
that systolic pressure changes follow P-P interval changes. Latencies
at low frequencies were significantly (P < 0.001)
longer than latencies at respiratory frequencies. There was no
significant difference between low-frequency latencies calculated
before and after partialization (1.62 ± 0.20 vs. 1.46 ± 0.28, P = 0.33, Mann-Whitney rank sum test).
Figure 10, top two panels,
shows average (heavy lines) and individual (light lines) coherence
between respiration and diastolic pressure and muscle sympathetic nerve
burst amplitude cross spectra during fixed-frequency breathing. These
analyses support conclusions that were not expected and that might even
be counterintuitive. First, over a wide range of frequencies, from the
low to the respiratory frequency, the average coherences between
respiration and diastolic pressure and muscle sympathetic burst
amplitude spectra did not exceed the accepted threshold level for
significance, 0.50 (horizontal line). Even at the breathing frequency
(set at 0.25 Hz), average coherence barely exceeded 0.50. Second,
across subjects there is great variability of coherent frequencies
below the respiratory frequency. Third, partialization (Fig. 10,
bottom panel) reduced average coherences between diastolic
pressure and R-R interval and muscle sympathetic nerve burst amplitude
spectra at the breathing frequency to below 0.50.
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Fig. 10.
Cross-spectral analyses of the relations between
respiration and diastolic pressure and muscle sympathetic nerve
activity during fixed-frequency breathing. Light lines show responses
of individual subjects; heavy lines depict group averages. Average
coherence between respiration and diastolic pressure and muscle
sympathetic nerve activity for the group (top two panels)
was slightly above 0.5 (horizontal line) at the breathing frequency
(and was very high in some individual subjects). Partialization
(removal of the influence of respiration from diastolic pressure and
muscle sympathetic nerve signals, bottom) reduced average
coherence at respiratory frequencies to below 0.50.
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DISCUSSION |
We performed a simple study: we asked nine healthy young adult
volunteers to breathe in different ways (or to not breathe at all)
while we measured their R-R intervals, arterial pressures, and muscle
sympathetic nerve activity. We analyzed their responses mathematically
and drew inferences that may have important implications regarding how
human autonomic neural organization should be viewed.
First, breathing at usual frequencies does not merely entrain autonomic
rhythms; respiratory activity is a necessary condition for such
oscillations to occur. Second, the very strong coherence that may exist
among arterial pressure, R-R interval, and muscle sympathetic nerve
oscillations at breathing frequencies results from respiratory
influences on these variables; in healthy supine human subjects, this
temporal association does not reflect arterial baroreflex physiology.
Third, respiration at usual frequencies exerts no influence on
low-frequency autonomic rhythms; low-frequency rhythms are not altered
by differences of breathing frequency and persist undiminished in the
absence of breathing. Finally, and most importantly, the coherence and
coherent frequencies among autonomic and hemodynamic oscillations vary
continuously and profoundly. Therefore, the dimension (time) must be
considered in analyses of human autonomic interrelations; the
constructs of "stationarity," "steady-state," and even
"significant coherence" may have little relevance.
Autonomic and hemodynamic responses to different breathing modes
and apnea.
The low-frequency fluctuations we recorded were not influenced
significantly by hyperventilation. Barman and Gebber (2) reported that in most of the anesthetized cats they studied,
low-frequency carotid postganglionic sympathetic rhythms persisted
after phrenic nerve activity had been silenced by hyperventilation.
They took their observations (and we take ours) to mean that
low-frequency sympathetic rhythms are generated by mechanisms that are
independent of respiratory rhythm generators. Our results contradict
the observation of Hyndman et al. (34) that rapid
breathing abolishes low-frequency arterial pressure waves.
Apnea.
As ably reviewed by Koepchen (39), the arterial pressure
waves described by Traube (67) and E. Hering
(33) occurred at respiratory frequencies. However, both
Traube and Hering also reported persistence of slower arterial pressure
waves during apnea. We documented persistence of low-frequency arterial
pressure, R-R interval, and muscle sympathetic nerve fluctuations
during apnea (Figs. 4 and 7). The subjects we studied maintained apnea for long enough periods (181 to 407 s) to allow us to state with confidence that their low-frequency rhythms persisted. Our observation that low-frequency arterial pressure rhythms persist during apnea confirms results published earlier by Dornhorst et al.
(13), Joels and Samueloff (35), and Passino
et al. (52). Our finding that muscle sympathetic nerve
rhythms also persist at low frequencies during apnea confirms results
published preliminarily by Pawelczyk and Levine (53).
We did not observe persistence of respiratory-frequency R-R interval
fluctuations during apnea (Fig. 7), as reported by Trzebski (68) and Piepoli (56) and their co-workers.
However, we did observe that what we took to be aborted breaths,
triggered very large hemodynamic responses during apnea (one is shown
in Fig. 3, right). Our subjects' responses to those events
(whatever they were) were similar to those described by
Pe
áz and Buriánek (54), who recorded
responses to single breaths, introduced deliberately during apnea.
Katona et al. (36) reported that attempts of anesthetized but spontaneously breathing dogs to breathe after their respiratory drive had been suppressed by hyperventilation provoked abrupt reductions of vagal-cardiac nerve traffic. We speculate that the major
abrupt autonomic and hemodynamic changes that occurred with these
apparent aborted breaths during apnea were caused by respiratory motoneuron activity. If we are correct, these oscillations probably were not caused by afferent inputs from lung and thoracic stretch receptors, because no air movement (as gauged by a Fleisch
pneumotachograph) occurred. [This inference contradicts a conclusion
reached by St. Croix and colleagues (63) that respiratory
motoneuron activity makes a small or no contribution to respiratory
modulation of muscle sympathetic nerve activity.] It also is unlikely
that these oscillations represent responses to some intrinsic
pacemaker; they were time locked to the erratic, small pneumograph
signals that punctuated apnea.
Muscle sympathetic nerve activity increased during apnea compared with
levels measured during fixed-frequency breathing. An earlier study
documented significant, steady increases of muscle sympathetic nerve
activity during very brief periods of apnea (23). Because
arterial pressure also rose during apnea (Fig. 5), such parallel
changes indicate that apnea resets the usual relation that exists
between arterial pressure and muscle sympathetic nerve activity
(45). We did not study mechanisms responsible for apneic
increases of sympathetic activity and arterial pressure. However,
others (30, 47) have implicated small reductions of oxygen
saturation occurring within the normal range. We did not find that R-R
intervals are significantly higher during apnea than during spontaneous
breathing, as reported by Zwillich and co-workers (75).
Low-frequency rhythms.
As indicated, low-frequency autonomic and hemodynamic rhythms were
prominent during all breathing protocols and apnea (Figs. 4, 7, and 8).
An earlier study published by our group (7) and another
published by Ferretti et al. (22) also showed that
low-frequency arterial pressure oscillations are not influenced by
breathing rate. Similarly, phase angles between systolic pressures and
R-R intervals are not altered importantly by different breathing
algorithms (this study), positive pressure breathing or high-frequency
jet ventilation (40), or passive upright tilt
(8). The present study further dissociates respiration
from low-frequency rhythms, by partial coherence analysis. Whereas
partialization abolished coherence and the consistent phase relation
that exist between systolic pressure and R-R interval rhythms at the
respiratory frequency, it did not alter coherence or phase relations at
low frequencies (Figs. 8 and 9).
These figures document high coherence between systolic pressure and R-R
interval spectra at low frequencies. The average phase (1.62 s) is
compatible with a vagal arterial baroreflex mechanism. Latencies
between abrupt mechanical carotid baroreceptor (14, 60) or
electrical carotid sinus nerve (5) stimuli and sinoatrial responses are short (below 0.6 s) and peak responses occur at about 1.10 s (15). We cannot exclude the possibility
that low-frequency systolic pressure fluctuations follow and are
influenced by preceding R-R interval fluctuations. However, this seems
unlikely, because in supine subjects, fixed rate atrial pacing does not
alter systolic pressure spectral power (66).
Several authors (10, 28, 31, 46, 70) have speculated that
the occurrence of low-frequency arterial pressure waves reflects system
resonance such that arterial pressure waves 1) trigger
changes of arterial baroreceptor activity (57);
2) provoke reciprocal changes of efferent sympathetic and
vagal-cardiac nerve activity (41); and 3)
initiate a sequence of rising and then falling arterial pressures that
lasts about 10 s (72). However, published literature
indicates clearly that a reflex, resonant mechanism is not necessary to
explain low-frequency arterial pressure waves. Low-frequency arterial
pressure waves persist when pressure in arterial baroreceptive arteries
is held constant (26), and when baroreflex participation
is precluded by sinoaortic denervation (22, 42).
Thus some published studies suggest that low-frequency arterial
pressure waves are driven importantly by central oscillations. Accordingly, we had expected to find strong coherence between low-frequency muscle sympathetic nerve and arterial pressure rhythms. However, although coherence between diastolic pressure and muscle sympathetic burst amplitude spectra was highly significant in individual subjects, coherence over low frequencies [defined according to conventional usage (10, 65) as 0.50] was
insignificant for the group at large. We discuss this unexpected
negative observation below.
Respiratory frequency rhythms.
We documented strong coherence between systolic pressure and R-R
interval spectra at breathing frequencies (Figs. 8 and 9). Vagal
baroreflex gain, as estimated by moduli of transfer functions at
breathing frequencies, may be quantitatively similar to baroreflex gain
estimated at low frequencies and to baroreflex gain measured after
bolus phenylephrine injections (50, 73). This gain is diminished greatly by sinoaortic baroreceptor denervation. Therefore, it is not surprising that de Boer (11) and Pagani
(3, 50) and their associates suggested that consensual
changes of systolic pressure and R-R intervals at respiratory
frequencies reflect baroreflex physiology: breathing modulates arterial
pressure, which in turn, modulates R-R intervals. Several of our
results and results published by others provide what we consider
compelling evidence against this hypothesis.
As mentioned, despite the advantages human subjects bring to
physiological research, they also bring major disadvantages. Perhaps
none is more important than the fact that human subjects are studied
with their reflex loops "closed." Because of this, statistically
significant associations between time series do not necessarily prove
causality. Indeed, it is difficult to know from these associations what
is cause and what is effect, or even if there is a cause-and-effect
relation at all. We approached this challenge in a new way by analyzing
signals with partial coherence. Partial coherence analysis is a
technique (4, 43) that mathematically removes the
influences of one signal (in our case, respiration) on two other
signals (systolic pressure and R-R intervals) and then determines
coherence between the residual components of the other two signals. Our
results suggest strongly that correspondence between systolic pressures
and R-R intervals at respiratory frequencies is secondary to the
respiratory influence these signals share. This point is made
graphically by the analyses from one subject depicted in Fig. 8 and
from the analyses of group responses depicted in Fig. 9.
Our measurements of phase angle (the more apposite measure is latency)
provide additional evidence against a baroreflex explanation for the
strong coherence between systolic pressure and R-R interval signals at
breathing frequencies. As discussed, latencies at low frequencies were
always negative, were quite constant, and were such that they could be
explained simply by vagal baroreflex physiology. Latencies at breathing
frequencies, however, were positive more often than they were negative,
were quite variable among subjects, and were too short to be explained
by vagal baroreflex physiology.
Vagal baroreceptor-cardiac reflex latency is the pure time delay
between the beginning of a baroreceptor stimulus and the earliest P-P
interval prolongation it provokes (20). An earlier study
(14) broke out the individual components that are lumped together as "baroreflex latency." This analysis suggested that most
(about two-thirds) of the short vagal baroreceptor-cardiac reflex
latency in humans results from delays in the influence of acetylcholine
on sinoatrial node depolarization. The average latency between
respiratory frequency systolic pressure and P-P interval fluctuations
in our study was 0.03 s. This value is substantially shorter than the
shortest baroreflex latency published from human studies (0.24 s; see
Ref. 14). Moreover, if vagal baroreflex latencies reflect
primarily delays in the action of acetylcholine on sinoatrial pacemaker
cells, it is unclear why latencies at respiratory frequencies should be
so variable among subjects.
Another important question is, Why are systolic pressure-R-R interval
latencies much shorter at respiratory than low frequencies? One
explanation is that latencies at respiratory frequencies reflect rapid
vagal responses, whereas latencies at low frequencies reflect some
admixture of sluggish sympathetic and rapid vagal responses. This
explanation seems unlikely, because removal of potential sympathetic
contributions by 
-adrenergic blockade does not alter systolic
pressure-R-R interval latencies at low frequencies (27).
We suggest that the most parsimonious answer to the questions posed
above is that the close correlation between systolic pressures and R-R
intervals at breathing frequencies reflects the influence of
respiration on arterial pressure and R-R interval rhythm generators and
not baroreflex physiology. This interpretation can explain why when
subjects breathe at different rates, the latency between their breaths
and R-R intervals is constant, but the latency between their arterial
pressures and R-R intervals is highly variable (44).
In this connection, reductions of the respiratory frequency moduli of
transfer functions by baroreceptor denervation do not necessarily prove
that respiratory frequency R-R interval changes reflect baroreceptor
physiology. Vagal-cardiac motoneurons fire primarily because they are
stimulated by arterial baroreceptors (62). Schweitzer
(59) asserted that two influences are necessary for the
generation of respiratory sinus arrhythmia: 1) integrity of
brain stem respiratory centers, and 2) baroreceptor
stimulation of vagal-cardiac motoneurons. In this context, great
reductions of respiratory frequency R-R interval fluctuations can be
explained economically, on the basis that surgical denervation [or
pharmacological hypotension (19)] reduces the
baroreceptor stimulation that is necessary for vagal-cardiac motoneuron
firing to occur and then to be modulated by breathing
(24).
Our results also suggest that some respiratory frequency variations of
muscle sympathetic nerve activity reflect the influence of respiration
rather than baroreflex physiology. Partialization of diastolic pressure
and muscle sympathetic burst amplitude spectra substantially reduced
the squared coherence that was found with simple coherence analysis
(Fig. 10, bottom panel, right). These results confirm in a
new way results published by Adrian et al. (1), who showed
that respiratory grouping of sympathetic nerve activity persists in
anesthetized cats after sinoaortic denervation. Moreover, they can be
explained by an earlier study (18), which showed that
respiration "gates" responsiveness of muscle sympathetic motoneurons to baroreceptor influences, just as it does responsiveness of vagal-cardiac motoneurons (17, 24, 32).
Coordination among human autonomic and hemodynamic rhythms.
The foregoing discussion implicitly poses the question, Are the ongoing
autonomic and hemodynamic fluctuations observable in healthy resting
humans caused by intrinsic oscillators or by reflex mechanisms? We
propose that this question, which is fundamental to the physiology we
studied, is not one that admits of easy answers. Moreover, it may not
even be a good question.
If any feature of our measurements stands out, it is their lack of
stationarity. We documented major transients of autonomic function
during hyperventilation (Figs. 1 and 2), apnea (Fig. 4), and even
fixed-frequency breathing (Fig. 6), which we took to be the most
"steady-state" condition we studied. Several authors (25, 34,
74) have wrestled with the question, If human
pressure-regulating reflexes are intact, why does arterial pressure
vary?; and they have proposed that pressure varies because arterial
baroreflex gain varies. Earlier studies have documented augmentation of
vagal baroreflex gain during sleep (61) and unexplained
fluctuations of baroreflex gain during waking hours (51).
Our study identifies ongoing quasiperiodic fluctuations of baroreflex
gain in supine, resting, unperturbed human subjects (two examples are
shown in Fig. 6). Such fluctuations were present in varying degrees in all our subjects during all breathing protocols and apnea.
We were surprised by the general lack of coherence between respiration
and diastolic pressure and muscle sympathetic nerve activity (Fig. 10).
[However, some animal studies (6, 55) also failed to
identify significant coherence between sympathetic nerve activity and
arterial pressure.] A wealth of earlier research documents strong
correlations between sympathetic nerve activity and breathing (6,
55) and diastolic pressure (64). We considered that
if we could explain this apparently paradoxical result, we might be on
the way to explaining the poor coherence among the signals we recorded.
Figure 11 may have heuristic value in
explaining variabilities in human autonomic signals.
View larger version (141K):
[in this window]
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|
Fig. 11.
Respiration spectral power and coherence between diastolic
pressure and muscle sympathetic nerve spectral powers during
fixed-frequency breathing from two subjects. Both subjects controlled
their breathing frequencies very well (top). Average
coherence between diastolic pressure and muscle sympathetic nerve
activity (middle) was highly significant at low and
respiratory frequencies in one subject (left) and only
weakly significant at the respiratory frequency in the other
(right). The bottom panels represent contour maps made from
horizontal sections of three-dimensional, sliding (60 s window moved
over 2-s steps) cross-spectral coherence. Coherence <0.5 is shown as
white. Black lines begin at coherence of 0.5, and the highest coherence
is depicted in yellow. Both subjects had very high (approximately
>0.9) coherence. However, high coherence was more consistent over time
and frequency in the subject on the left, than in the
subject on the right. As a result, that subject's average
coherence (middle right panel) barely crossed the accepted
level for significance, 0.5.
|
|
For these analyses, we selected data from two subjects, one with
strong, and the other with weak coherence among respiration and
diastolic pressure and muscle sympathetic nerve activity. The top
panels of Fig. 11 are contour maps derived from sliding (60-s windows,
moved in 2-s steps through 180 s) fast Fourier transformations of
respiration. These analyses indicate that during these periods of
fixed-frequency breathing, variability of autonomic signals cannot be
ascribed to variability of respiration. The middle panels of Fig. 11
depict average diastolic pressure and muscle sympathetic burst
amplitude squared coherence measured during the same breathing epochs.
The subject on the left had strong coherence between diastolic pressure
and sympathetic nerve activity at low and respiratory frequencies, and
the subject on the right had only borderline coherence at respiratory frequencies.
The bottom panels of Fig. 11 are contour maps of sliding squared
coherence. The contour maps show only those times and frequencies with
coherences 0.50. [In this scheme, coherences 
0.50 are white, coherences 0.50 are colored, and the highest levels of coherence (~0.80 -1.0) are yellow.] These analyses indicate that coherence between diastolic pressure and muscle sympathetic nerve activity varies
not only over time but also over frequency. They also indicate, counterintuitively, that both subjects, including the one on the right
with marginally significant average coherence, had episodic, highly
significant levels of coherence.
The subject on the left panel of Fig. 11 had "significant" average
coherence (left middle panel), because his strong coherence persisted over low and respiratory frequency ranges during most of the
recording period. Conversely, the subject on the right panel had weak
coherence, not because his diastolic pressure and muscle sympathetic
nerve activity were uncoordinated, but because his strong coherence
came and went and shifted over a range of frequencies. One shift
extends from slightly below 0.15 at the beginning of the breathing
period (Fig. 11, bottom of the bottom right panel) to almost
0.30 Hz at the end of the breathing period. Thus, in resting humans,
autonomic coordination is not qualitative, present or absent,
significant or insignificant, or above or below squared
coherence values of 0.50, but is quantitative and is based on the
probability that strong coherence will persist over time at more or
less constant frequencies.
The notion that coordination between centrally generated neural
outflows is sliding, not fixed, was advanced first by von Holst
(69) on the basis of his studies of the fin movements of
fish and was championed over many years by Hans-Peter Koepchen (38) on the basis of his research in animals. Most studies
reporting transitions of autonomic rhythms deal with anesthetized
animals in which shifts of autonomic coordination occur after defined, sometimes major changes, including panting (41), voluntary
body movement (48), and cerebral ischemia
(37). Our study extends this literature by showing that
sliding coordination is an ongoing feature of autonomic physiology, and
that it can be observed in resting humans under very stable
circumstances with no discernible provocation whatever.
The principal limitation of our study is the brief duration of the
recording periods. Because of our limited periods of observation, we
were unable to determine whether the autonomic fluctuations we recorded
are stochastic or probabilistic, periodic or aperiodic, or even cause
and effect. Second, measurements we obtained during apnea must not be
considered to reflect usual human physiology; we used apnea following
hyperventilation with 100% oxygen as one more experimental tool to
remove respiration as a variable. The measurements we obtained during
apnea illustrate a third potential limitation: the occurrence of what
we regard as aborted breaths. These events occurred in almost all of
our subjects and were not recognized at the time by either the subjects
themselves or by the team making the recordings. A fourth (and major)
limitation is that human sympathetic bursts occur intermittently, not
continuously. We attempted to deal with this inherent limitation by
averaging muscle sympathetic nerve activity over 1-s intervals and
performing analyses on these equidistant measurements. Finally, all of
the results of our study are based on linear analyses; therefore, our
conclusions may not apply to situations in which relations vary
nonlinearly, as they surely must in resting humans.
In conclusion, our study treats relations among autonomic and
hemodynamic variables in a group of healthy young adults, as affected
by different breathing modes and apnea. Although we show that in supine
resting humans, breathing exerts no measurable influence on
low-frequency rhythms, we also show that that breathing is prepotent in
generating respiratory frequency rhythms. Arguably, the most important
contribution our study makes is to underscore the fluidity of human
autonomic transactions. Our conclusions are fully compatible with
Koepchen's summary (38) of autonomic periodicities:
"Their interactions are not unidirectional but bidirectional. Not
fixed but sliding, not obligatory but facultative and comprise not only
one but several rhythms."
| |
ACKNOWLEDGEMENTS |
This research was supported by grants from the Department of
Veterans Affairs, National Aeronautics and Space Administration contracts NAS9-19541 and NAG2-408, and National Heart Lung and Blood
Institute Grants HL-22296 and UO1HL-56417.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: D. L. Eckberg, Hunter Holmes McGuire Dept. of Veterans Affairs Medical Center, 1201 Broad Rock Blvd., 3C-126, Richmond, VA 23249 (E-mail: deckberg{at}aol.com).
1
Throughout this paper, we refer to
"significant" (squared) coherence as being 0.50. This value,
which indicates the strength of the linear association between two
spectra, was first proposed by de Boer, Karemaker, and Strackee
(9, 10) and was based on an appropriate mathematical
analysis of their data. After this group's seminal publications,
virtually all authors who use cross-spectral analysis have considered
that squared coherence values 0.50 indicate significant relations.
Although we have been critical of this nearly universal usage
(65), we use the value here, as a point of departure. The
results we report cast further doubt on determinations of significance
based on coherence, not on the basis of mathematics, but on the basis
of autonomic neurophysiology.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 6 November 2000; accepted in final form 26 January 2001.
| |
REFERENCES |
1.
Adrian, ED,
Bronk DW,
and
Phillips G.
Discharges in mammalian sympathetic nerves.
J Physiol (Lond)
74:
115-133,
1932.
2.
Barman, SM,
and
Gebber GL.
Basis for synchronization of sympathetic and phrenic nerve discharges.
Am J Physiol
231:
1601-1607,
1976[Abstract/Free Full Text].
3.
Baselli, G,
Cerutti S,
Badilini F,
Biancardi L,
Porta A,
Pagani M,
Lombardi F,
Rimoldi O,
Furlan R,
and
Malliani A.
Model for the assessment of heart period and arterial pressure variability interactions and respiration influences.
Med Biol Eng Comput
32:
143-152,
1994[ISI][Medline].
4.
Bendat, JS,
and
Piersol AG.
Random Data Analysis and Measurement Procedures (2nd ed.). New York: Wiley, 1986, chapt. 17, p. 201-251.
5.
Borst, C,
and
Karemaker JM.
Time delays in the human baroreceptor reflex.
J Auton Nerv Syst
9:
399-409,
1983[ISI][Medline].
6.
Burgess, DE,
Zimmerman TA,
Wise MT,
Li S-G,
Randall DC,
and
Brown DR.
Low-frequency renal sympathetic nerve activity, arterial BP, stationary "1/f noise," and the baroreflex.
Am J Physiol Regulatory Integrative Comp Physiol
277:
R894-R903,
1999[Abstract/Free Full Text].
7.
Cooke, WH,
Cox JF,
Diedrich AM,
Taylor JA,
Beightol LA,
Ames JA,
Hoag JB,
Seidel H,
and
Eckberg DL.
Controlled breathing protocols probe human autonomic cardiovascular rhythms.
Am J Physiol Heart Circ Physiol
274:
H709-H718,
1998[Abstract/Free Full Text].
8.
Cooke, WH,
Hoag JB,
Crossman AA,
Kuusela TA,
Tahvanainen KUO,
and
Eckberg DL.
Human responses to upright tilt: a window on central autonomic integration.
J Physiol (Lond)
517:
617-628,
1999[Abstract/Free Full Text].
9.
De Boer, RW,
Karemaker JM,
and
Strackee J.
Relationships between short-term blood-pressure fluctuations and heart-rate variability in resting subjects II: a simple model.
Med Biol Eng Comput
23:
359-364,
1985[ISI][Medline].
10.
De Boer, RW,
Karemaker JM,
and
Strackee J.
Relationships between short-term blood-pressure fluctuations and heart-rate variability in resting subjects 1: a spectral analysis approach.
Med Biol Eng Comput
23:
352-358,
1985[ISI][Medline].
11.
De Boer, RW,
Karemaker JM,
and
Strackee J.
Hemodynamic fluctuations and baroreflex sensitivity in humans: a beat-to-beat model.
Am J Physiol Heart Circ Physiol
253:
H680-H689,
1987[Abstract/Free Full Text].
12.
Delius, W,
Hagbarth KE,
Hongell A,
and
Wallin BG.
General characteristics of sympathetic activity in human muscle nerves.
Acta Physiol Scand
84:
65-81,
1972[ISI][Medline].
13.
Dornhorst, AC,
Howard P,
and
Leathart GL.
Respiratory variations in blood pressure.
Circulation
6:
553-558,
1952[ISI][Medline].
14.
Eckberg, DL.
Temporal response patterns of the human sinus node to brief carotid baroreceptor stimuli.
J Physiol (Lond)
258:
769-782,
1976[Abstract/Free Full Text].
15.
Eckberg, DL.
Adrenergic-cholinergic baroreflex interactions in man.
In: Neural Mechanisms in Cardiac Arrhythmias, edited by Schwartz PJ,
Brown AM,
Malliani A,
and Zanchetti A.. New York: Raven, 1978, p. 335-338.
16.
Eckberg, DL.
Nonlinearities of the human carotid baroreceptor-cardiac reflex.
Circ Res
47:
208-216,
1980[Abstract/Free Full Text].
17.
Eckberg, DL,
Kifle YT,
and
Roberts VL.
Phase relationship between normal human respiration and baroreflex responsiveness.
J Physiol (Lond)
304:
489-502,
1980[Abstract/Free Full Text].
18.
Eckberg, DL,
Nerhed C,
and
Wallin BG.
Respiratory modulation of muscle sympathetic and vagal cardiac outflow in man.
J Physiol (Lond)
365:
181-196,
1985[Abstract/Free Full Text].
19.
Eckberg, DL,
Rea RF,
Andersson OK,
Hedner T,
Pernow J,
Lundberg JM,
and
Wallin BG.
Baroreflex modulation of sympathetic activity and sympathetic neurotransmitters in humans.
Acta Physiol Scand
133:
221-231,
1988[ISI][Medline].
20.
Eckberg, DL,
and
Sleight P.
Human Baroreflexes in Health and Disease. Oxford: Clarendon, 1992, p. 256-259.
21.
Fagius, J,
Sundlöf G,
and
Wallin BG.
Variation of sympathetic reflex latency in man.
J Auton Nerv Syst
21:
157-165,
1987[ISI][Medline].
22.
Ferretti, R,
Cherniack NS,
Longobardo G,
Levine OR,
Morkin E,
Singer DH,
and
Fishman AP.
Systemic and pulmonary vasomotor waves.
Am J Physiol
209:
37-50,
1965[Abstract/Free Full Text].
23.
Fritsch, JM,
Smith ML,
Simmons DTF,
and
Eckberg DL.
Differential baroreflex modulation of human vagal and sympathetic activity.
Am J Physiol Regulatory Integrative Comp Physiol
260:
R635-R641,
1991[Abstract/Free Full Text].
24.
Gilbey, MP,
Jordan D,
Richter DW,
and
Spyer KM.
Synaptic mechanisms involved in the inspiratory modulation of vagal cardio-inhibitory neurones in the cat.
J Physiol (Lond)
356:
65-78,
1984[Abstract/Free Full Text].
25.
Golenhofen, K,
and
Hildebrandt G.
Die Beziehungen des Blutdruckrhythmus zu Atmung und peripherer Durchblutung.
Pflügers Arch
267:
27-45,
1958[ISI][Medline].
26.
Grasso, R,
Rizzi G,
Schena F,
and
Cevese A.
Arterial baroreceptors are not essential for low frequency oscillation of arterial pressure.
J Auton Nerv Syst
50:
323-331,
1995[ISI][Medline].
27.
Grasso, R,
Schena F,
Gulli G,
and
Cevese A.
Does low-frequency variability of heart period reflect a specific parasympathetic mechanism?
J Auton Nerv Syst
63:
30-38,
1997[ISI][Medline].
28.
Guyton, AC,
and
Harris JW.
Pressoreceptor-autonomic oscillation: a probable cause of vasomotor waves.
Am J Physiol
165:
158-166,
1951[Free Full Text].
29.
Hagbarth, K-E,
Hallin RG,
Hongell A,
Torebjörk HE,
and
Wallin BG.
General characteristics of sympathetic activity in human skin nerves.
Acta Physiol Scand
84:
164-176,
1972[ISI][Medline].
30.
Hardy, JC,
Gray K,
Whisler S,
and
Leuenberger U.
Sympathetic and blood pressure responses to voluntary apnea are augmented by hypoxemia.
J Appl Physiol
77:
2360-2365,
1994[Abstract/Free Full Text].
31.
Hatakeyama, I.
Analysis of baroreceptor control of the circulation.
In: Physical Bases of Circulatory Transport: Regulation and Exchange, edited by Reeve EB,
and Guyton AC.. Philadelphia, PA: Saunders, 1967, p. 91-112.
32.
Haymet, BT,
and
McCloskey DI.
Baroreceptor and chemoreceptor influences on heart rate during the respiratory cycle in the dog.
J Physiol (Lond)
245:
699-712,
1975[Abstract/Free Full Text].
33.
Hering, E.
Über den Einfluss der Athmung auf den Kreislauf I. über Athembewegungen des Gefässsystems.
Sitzungsberichte der Mathematisch-Naturwissenschaftlichen Classe der Kaiserlichen Akademie der Wissenschaften
60:
829-856,
1869.
34.
Hyndman, BW,
Kitney RI,
and
Sayers BM.
Spontaneous rhythms in physiological control systems.
Nature
233:
339-341,
1971[Medline].
35.
Joels, N,
and
Samueloff M.
The activity of the medullary centres in diffusion respiration.
J Physiol (Lond)
133:
360-372,
1956.
36.
Katona, PG,
Poitras JW,
Barnett GO,
and
Terry BS.
Cardiac vagal efferent activity and heart period in the carotid sinus reflex.
Am J Physiol
218:
1030-1037,
1970[Free Full Text].
37.
Kocsis, B,
Fedina L,
Gyimesi-Pelczer K,
Ladocsi T,
and
Pasztor E.
Differential sympathetic reactions during cerebral ischaemia in cats: the role of desynchronized nerve discharge.
J Physiol (Lond)
469:
37-50,
1993[Abstract/Free Full Text].
38.
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TOP
ABSTRACT
INTRODUCTION
