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Departments of 1 Physiology, 2 Pediatrics, and 3 Medicine, Medical College of Wisconsin, Zablocki Veterans Affairs Medical Center, and 4 Department of Physical Therapy, Marquette University, Milwaukee, Wisconsin 53226
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The effects of spontaneous swallows on breathing before, during, and after solitary swallows were investigated in 13 awake goats. Inspiratory (TI) and expiratory (TE) time and respiratory output were determined from inspiratory airflow [tidal volume (VT)] and peak diaphragmatic activity (Diapeak). The onset time for 1,128 swallows was determined from pharyngeal muscle electrical activity. During inspiration, the later the swallowing onset, the greater increase in TI and VT, whereas there was no significant effect on TE and Diapeak. Swallows in early expiration increased the preceding TI and reduced TE, whereas later in expiration swallows increased TE. After expiratory swallows, TI and VT were reduced whereas minimal changes in Diapeak were observed. Phase response analysis revealed a within-breath, phase-dependent effect of swallowing on breathing, resulting in a resetting of the respiratory oscillator. However, the shift in timing in the breaths after a swallow was not parallel, further demonstrating a respiratory phase-dependent effect on breathing. We conclude that, in the awake state, within- and multiple-breath effects on respiratory timing and output are induced and/or required in the coordination of breathing and swallowing.
respiration; deglutition; pharyngeal muscles; diaphragm; electromyography
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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BOTH BREATHING AND SWALLOWING are continual ongoing events in mammals, although at different frequencies. As a result of the shared use of the upper airway, it is extremely important that the motor pattern generators associated with breathing and swallowing are tightly coupled to provide effective coordination for cleansing and removing secretions from the lower airways (3, 8, 16). A loss of coordination between these pattern generators is associated with dysphasia, weight loss, coughing, and pulmonary aspiration leading to pneumonia. However, the exact neural and physiological nature of the interconnections between the swallowing and breathing pattern generators is unknown. Nevertheless, the functional relationships between these generators have been investigated for decades.
Although the frequency of spontaneous swallows during the different phases of respiration varies among species, swallowing has been generally reported to inhibit breathing in human, dogs, rabbits, and cats (1, 2, 5, 7, 8, 22, 23, 25, 29). For example, swallows during inspiration or expiration are reported to increase the phase of respiration in which it occurred. In the few studies that measured respiratory output [e.g., tidal volume (VT) and electrical activity of the diaphragm and laryngeal abductors], swallowing reduced inspiratory output (11, 23, 24). In addition, the observations of swallows during the transition between inspiration-expiration or expiration-inspiration are infrequent (18, 22), but if observed they disrupt respiratory timing in humans (27).
The neural substrates that generate and coordinate the motor patterns for swallowing and breathing are located in the dorsomedial and ventrolateral brain stem (1, 4, 16, 14). To understand the interaction between these pattern generators, several interpretative models have been applied, mostly using anesthetized or decerebrate models with superior laryngeal nerve stimulation (7, 19, 27). Few studies have examined this interaction on the swallowing and respiratory pattern generators in unanesthetized animals and humans (20, 23-25).
The aim of this study was to investigate in unanesthetized, awake goats the effect of spontaneous swallows on respiratory output and timing. We hypothesized that a swallow in either phase of respiration would produce a within-breath effect to increase respiratory timing, enough to cause a phase delay but not a resetting of the respiratory rhythm. We also hypothesized that swallows would not have an effect on the timing or VT of the breath before the swallow but would reduce the VT if the swallow occurred during inspiration.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Thirteen adult goats of various breeds that were used in this study received humane care in compliance with the Guide for the Care and Use of Laboratory Animals formulated by the National Research Council, 1996. The study protocol was approved by the Institutional Animal Care Committee of the Medical College of Wisconsin.
Surgical procedures. Surgery was performed to implant chronic electromyographic (EMG) electrodes in the diaphragm (EMGDia), thyropharyngeus (EMGTP), posterior cricoarytenoid (EMGPCA), and thyroarytenoid (EMGTYA) muscles. In four goats, a tracheostoma was created at the level of the eighth tracheal ring to isolate the upper airway. The animals received an intravenous injection of ketamide (Ketaset) and xylazine (12:1 ratio, 15 mg/kg) for induction of anesthesia before intubation. After intubation for mechanical ventilation, general anesthesia was maintained with 1.5-2.5% halothane in oxygen (sufficient to eliminate the withdrawal reflex and any signs of pain.)
EMG electrode placement has been previously described (10). Briefly, Teflon-coated 32-gauge stainless steel bipolar microelectrodes were inserted into the muscles defined above. For implants into airway muscles, a midline incision was made on the ventral surface of the neck from the hyoid bone to 4 cm below the thyroid cartilage, exposing the lateral aspect of the pharynx. The EMGTP electrode was sewn into the thyropharyngeus midway between the posterior midline of the pharynx and the insertion on the thyroid cartilage 0.5 cm below the cranial laryngeal nerve. To implant the EMGPCA, a small window was made at the inferior edge of the thyroid cartilage, and the tissue was dissected between the anterior wall of the esophagus and the posterior wall of the cricoid cartilage to expose the posterior cricoarytenoid. For placement of the EMGTYA electrode, a U-shaped window was made in the lateral wall of the thyroid cartilage to expose the thyroarytenoid. The EMGSP electrode was sewn into the stylopharyngeus muscle close to its disappearance under the hypopharyngeus. The wires were looped in the subcutaneous layer of connective tissue and exited on the lateral ventral surface of the neck. For the EMGDia, a lateral thoracotomy was performed between the ninth and tenth ribs midway between the sternum and spine. The diaphragm electrodes were implanted in the costal portion of the diaphragm and exteriorized next to the incision. After the above instrumentation, the carotid arteries were elevated bilaterally so that they could be easily catheterized for monitoring of arterial blood pressure during the experimental studies. A 5-cm segment of each carotid artery was elevated subcutaneously and sutured in place. For at least 24 h after surgery, laboratory personnel frequently inspected the animals. The animals received daily intramuscular antibiotics (ceftiofur sodium, 2 mg/kg), and their rectal temperature, eating habits, and behavior were monitored daily. These measures indicated that the goats were in good health and fitness during recovery from surgery and the subsequent experimental period.Methods of measurement and experimental design. For measurements of airflow in the animals without a tracheostoma, a tight-fitting, custom facemask was connected to a one-way breathing circuit. In the animals with a tracheostoma, airflow measurements were made via an 8-Fr cuffed tracheostomy tube that was inserted into the trachea, cuff inflated, and connected to a one-way breathing circuit with a two-way nonrebreathing valve (model 2600, Hans Rudolph). A pneumotachograph was connected in-line on the inspiratory side of the nonrebreathing valve and connected to a differential pressure transducer to measure inspiratory airflow only. The proximal ends of the EMG wires were connected via microclips to a Grass recorder for signal processing and recording. The EMG signals were filtered at a band pass of 3-500 Hz. A carotid artery was catheterized at least 2 days before initiation of experimental studies. Arterial blood pressure was monitored during all studies by connecting the arterial catheter via a Statham blood pressure transducer to a Grass recorder. The airflow, raw EMG signals, and arterial blood pressure were sent to a CODAS computer data acquisition system at a sampling rate of 250 Hz for display, digital recording, and analysis.
Before initiation of data collection, the goats were acclimated for several hours a day for a week in a stanchion where they were connected to the recording system. On the days the goats were studied, respiration, upper airway EMG activity, and blood pressure were continuously monitored for a minimum of 2 h. Chewing and other movement artifacts were eliminated from the analysis. All goats were studied in the awake state in the prone recumbent position. Respiratory rate and arterial blood pressure were normal throughout the experimental period, indicating that the goats were in good health, relaxed, and free of pain.Data analysis. Respiratory airflow and EMG signals were processed and analyzed (WinDaq, DATAQ Instruments). Raw EMG data were full-wave rectified and passed through a moving time averager (time constant of 0.1 s) to obtain an integrated EMG signal. The integrated EMGTP, EMGPCA, and EMGTYA signals were analyzed to obtain the occurrence of swallowing. The absolute time of a swallow was determined at the peak of a 10-fold increase in the integrated EMGTP and EMGTYA activity with a 200-ms duration and without signs of movement artifacts. The start of a swallow was then set at 0.15 s before peak EMGTP activity. Even though the TP muscle is activated in the later part of the recruitment order of pharyngeal muscles, the onset of activation is within 0.2 s of the initiation of the oropharyngeal phase of swallowing (8, 9, 18). In this study, spontaneous swallows were considered as nonfeeding swallows that were initiated reflexively by the accumulation of oropharyngeal secretions. These secretions were presumably sensed by afferent receptors in the laryngeal mucosa innervated by the trigeminal, glossopharyngeal, and vagal nerves (1, 8, 15, 16). None of the swallows analyzed were related to mastication.
For the analysis of ventilation, a two-state computer algorithm (inspiration-expiration) was used for the automatic detection of the breath-by-breath calculations for VT, duration of inspiration (TI), and duration of expiration (TE) from the airflow signal. Peak EMGDia activity (Diapeak) was obtained for each breath. In this two-state computer algorithm, inspiration was determined when flow exceeded zero respiratory flow by 0.01 l/s for a minimum duration of 0.2 s. The start of expiration was determined when a pause in the EMGDia activity and in the inspiratory flow longer than 0.35 s was detected. Although this period was shorter than the reported deglutition apnea in animals and humans (5, 17, 22-24, 27, 30), we felt that it was a conservative estimate of the establishment of expiratory cycle. In addition, our observations in goats led us to the use of these criteria, because deglutition apneas, if present during inspiration, were very short. Therefore, we believe that the determination of the phase of breathing was accurately and reliably determined. The absolute time for the start of inspiration for each breath was recorded along with the time of each swallow. The total duration of a breath (Ttot) was calculated as the sum of TI and TE. The inspiratory duty cycle (TI/Ttot) and the ratio of VT to TI (VT/TI) were calculated for each breath. Three types of analysis of the effects of swallowing on breathing were made. First, to examine the general effects of swallowing on breathing, swallows were categorized into one of four phases of ventilation (Fig. 1): expiration (SwE), the transition from expiration to inspiration (SwEI), inspiration (SwI), and the transition from inspiration to expiration (SwIE). The effects of SwE, SwEI, SwI, and SwIE on TI, TE, Ttot, VT, TI/Ttot, VT/TI, and Diapeak (expressed as a percentage of control) on the breath before (n
1), during (n), and
after (n + 1) the swallows were evaluated. Second, the gamma
analysis (
) evaluated whether the time of occurrence of a
swallow, within either inspiration (I) or expiration
(E), had an effect on the breath before or during a
swallow (23, 24). For this analysis, five consecutive
breaths were evaluated, with a solitary swallow in the fourth breath
(Fig. 2, A and B). In this analysis, a breath was considered to start with expiration followed by inspiration. Swallows with movement or augmented breaths within the set of five consecutive breaths were eliminated from this
analysis. Averages for TI, TE, VT,
and Diapeak were calculated from the first, second, and
fifth breaths of the set of five breaths and used as control values.
The value for I was calculated as the time from the
beginning of inspiration to the onset of the solitary swallow,
expressed as percentage of the control TI. The value for
E was calculated as the time from the beginning of expiration to the onset of the solitary swallow, expressed as percentage of the control TE. Values for TI,
TE, VT, and Diapeak for the
previous breath (n 1) and the breath during
(n) the swallow were expressed as a percentage of its
control value and were plotted against I or
E.
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) was
defined as the time from the beginning of inspiratory flow of the
fourth breath to the onset of the swallow (Fig.
3A). The subsequent cophases
(
) were defined as the time from the onset of swallow to the
beginning of inspiratory flow of breaths 5 (n1) and 6 (n2) and to the end of expiration
of breath 6 (n3). The
cophase for the breath before the swallow (n
1) was calculated as the time from the beginning of the
swallow backward to the beginning of inspiratory flow of breath
3. Movement or augmented breaths in any of these breaths
eliminated the set from analysis. Ventilatory values from breaths
1, 2, and 6 of the set were averaged and
used as controls. All values of and were expressed as a
fraction of control values. Values of VT and
Diapeak in this analysis were calculated as a percent of
control values.
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and , the effect of
swallowing on the respiratory rhythm can be assessed, as previously presented by Paydarfar et al. (27). As defined in Fig.
3A, the normalized measures of and would equal 1 ( + = 1) if swallowing had no effect on rhythm at any
time during the respiratory cycle, and the slope of
n1 vs. would be 1.
Furthermore, as demonstrated in Fig. 3B, the effect on any subsequent breaths (n) would be anticipated by the equation,
n = + n with a similar
slope. A phase advance or delay in the onset of breathing would be
anticipated if swallowing has an effect on the respiratory rhythm
generator to shorten or lengthen inspiration or expiration. If
swallowing had more than a transient effect on the respiratory rhythm,
then a permanent shift or resetting of the subsequent start of
ventilation would occur. To evaluate the possible phase shift in the
phase response curves, the difference in the onset from the previous
breath (n1 n 1,
n2 n1,
n3 n2) for each swallow in all the animals was calculated and averaged every 0.05 interval of . Given
sequential breaths and the above equation for
n, a parallel shift in the
n curves would result in a difference of 1. A
phase delay would result in an increase in the difference between
n curves relative to the previous swallow,
whereas a phase advance would result in a decrease in the difference. To estimate the potential phase shift of the breath before the swallow,
the difference between n 1 and
a nonaffected old phase (ideal) with a slope
of 1 was calculated and averaged every 0.05 interval of . In this
later comparison (n 1 ideal), the expected difference
would be zero if there were no difference between the curves for any
value of .
The phase transition from inspiration to expiration (IE) for the
breaths with swallows was estimated by calculating the half-cycle period relative to a specific old phase that began at the start of
inspiration. The cophase (
IE) in this analysis was
calculated as the period of time from the start of the swallow to the
start of expiration. The average phase transition was then estimated for the breaths with swallows by solving for the relationship of vs. IE by using a third-order polynomial equation for an intercept of zero.
Statistical analysis. The average rate of swallowing and its standard deviation were calculated for each goat, and a Kolmogorov-Smirnov test was performed to test whether the rate of swallowing significantly deviated from Gaussian distribution (P < 0.05). For the categorization of swallows, a Student's t-test was performed on the means of the percent change of TI, TE, Ttot, VT, TI/Ttot, VT/TI, and Diapeak for the breaths before, during, and after the swallows, compared with no change (100%) within SwE, SwEI, SwI, and SwIE (P < 0.02). A comparison was also made using a one-way ANOVA between the means of the percent change for the breaths before, during, and after the swallows within SwE, SwEI, SwI, and SwIE (P < 0.02).
In the gamma analysis, a linear regression analysis was performed on TE, TI, VT, and Diapeak (expressed as a fraction of its control) on the previous breath, and the breath in which the swallow occurred was evaluated forI and E (P < 0.02). The
slopes and intercepts were compared to determine whether the time of
occurrence of the swallow (I or E) during
inspiration or expiration had an effect on respiratory parameters from
the breath before and during the swallow.
In the evaluation of the phase shift, the mean value of
n1 n 1, n2 n1, and
n3 n2 at every 0.05 interval of was tested to determine whether it differed significantly from a
hypothetical value of 1 using a Student's t-test
(P < 0.02). Similarly, the mean of
n 1 ideal was compared with a value of 0 by using a
Student's t-test (P < 0.02).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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During expiration, the normal phasic respiratory activity of EMGTP was inhibited just before its recruitment for a swallow (Fig. 1B, a). Commonly associated with the swallows during expiration was a small burst of activity in the EMGDia (Fig. 1B, b). During late expiration, swallows were associated with a burst of inspiratory airflow, usually termed a "swallow breath" or Schluckatmung. However, if a swallow occurred during the first third of expiration, inspiratory flow was not seen. During inspiration, phasic EMGSP activity was inhibited at the onset of EMGTP swallow activity (Fig. 1B, c). A short inhibition, or pause, in EMGDia activity occurred midway through EMGTP swallow activity (Fig. 1B, d). In all goats (with an intact upper airway or with a tracheostomy), a short pause (<0.1 s) and a significant decrease in inspiratory airflow were seen during swallows after increases in EMGTP activity and decreases in EMGDia.
The average rate of swallowing for all the goats was 2.88 ± 1.22 swallows/min (Table 1). Goats with
tracheotomies had an average rate of 1.86 ± 0.31 swallows/min,
whereas goats with intact airways presented with an average rate of
3.3 ± 1.9 swallows/min. On average, 12.4% of the swallows from
each goat were not used in the analysis because of movement artifacts
or the presence of more than one swallow within a breath. The average
duration of the moving time average of a swallow in the TP signal was
0.25 ± 0.03 s. No pharyngolaryngeal or swallowing
dysfunction was observed in any goat in this study.
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Effects of spontaneous SwE, SwEI,
SwI, and SwIE on breathing.
In this analysis, shown in Fig.
4, a total of 1,128 solitary swallows met the criteria for evaluation during the
observation of 7,573 breaths. In the SwE analysis (317 swallows, 28% of total), TE was significantly increased in
the breaths before, during, and after the swallow. In contrast,
TI decreased during the inspiration after the
SwE. As a result, Ttot was increased in the breaths before,
during, and after the swallows despite the decrease in TI
after the swallow. The inspiratory duty cycle, TI/Ttot, was decreased in the subsequent breath after SwE because of the
decrease in TI and increase in TE. The
VT just before and after SwE was significantly
reduced, as well as VT/TI. Similarly,
Diapeak activity was decreased in the inspirations before
and after the SwE. Therefore, swallows during early and mid
expiration had an immediate effect on timing during expiration
(increasing) and the subsequent inspiration (decreasing), while having
a wider effect over time by decreasing respiratory output, as indicated
by VT and Diapeak on the breaths before and
after the swallow.
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Within-breath effects of swallows: gamma inspiratory and expiratory
analysis.
In the gamma inspiratory analysis, the slope of the
TI-vs.-I relationship for the n
breaths was significantly different (P < 0.01) from
zero and from the n 1 breaths (Fig.
5B, Table
2). In addition, the estimated
y-intercept of the TI-vs.-I
relationship was significantly above control (P < 0.02). However, the observed TI did not show a linear
increase from the estimated intercept but, rather, an abrupt increase
around 0 to 15 I. In contrast, no differences were found
in the TE-vs.-I relationship either for the
breaths before (n 1) or during (n) the
swallow (Fig. 5A and Table 2). Swallows during early
inspiration tended to reduce VT as demonstrated by the
significantly reduced y-intercept of the
VT-vs.-I relationship for n
breaths (P < 0.02), whereas swallows in the later part
of inspiration increased VT, as indicated by the
significant positive slope of the VT-vs.-I
relationship (P < 0.01; Fig. 5C, Table 2).
In contrast, the slope of Diapeak vs. I was
not significantly different from zero for both the n and
n 1 relationships. However, a significant reduction
in the y-intercept of the Diapeak vs.
I was seen for the n breaths (Fig.
5D, Table 2). Primarily because of the lengthening of
TI above control in the n breaths (Fig.
5B), values greater than control (100%) were observed for
I.
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E), swallows during
expiration had a different effect on the respiratory pattern generator. In the n 1 breaths, the slope of the
TE-vs.-E relationship, although
significantly greater than zero, was small (Fig.
6A, Table
3). However, in the n
breaths, swallowing during expiration had a significant effect on
TE, although there was considerable variation in the data.
The slope of the TE-vs.-E relationship (0.42) was significantly greater than zero and significantly different from the slope of the n 1 breaths (P < 0.01), whereas the y-intercept was significantly less
than the control (71.42%; P < 0.01; Fig. 6A, Table 3). In contrast, the slope of
TI-vs.-E relationship for n 1 breaths was significantly less than zero (0.10,
P < 0.01), with a y-intercept that was
significantly greater than control (109.8, P < 0.02).
However, the y-intercept for the
TI-vs.-E relationship for the n
breaths was significantly less than control (93.8%; P < 0.01; Fig. 6B, Table 3), whereas the slope was not significantly different from zero. Therefore, although swallows during
expiration demonstrated a moderate effect on TE in the cycle before the swallow, these results demonstrate a strong
within-phase dependency of TE on the timing of the onset of
a swallow (not shown in the categorical analysis). For the effect of
expiratory swallows on TI, the data suggest the later the
swallow occurs in expiration, the less effect it has on the previous
TI, whereas, in contrast, the following inspiratory period
is attenuated irrespective of when the swallow occurred in the previous
expiration. Similar to what was observed in I analysis
above, the increases in TI and TE produced
E values >100%.
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E for both the
n 1 and n breaths were not significantly
different from zero. However, only the y-intercept for the
n breaths relationship was significantly less (88%) than control (P < 0.02; Table 3). In contrast, neither the
slopes nor the intercepts for either
Diapeak-vs.-E relationships were significant
(Fig. 6, Table 3). These results suggest that total respiratory output
was not altered, but the overall attenuation of VT was
similar to the decrease in inspiratory flow.
Effect of swallows on the respiratory phase response and output.
The occurrence of spontaneous swallows that meet the criteria for the
phase response analysis (427) demonstrated a bimodal distribution (Fig. 7A), with
~53% occurring during inspiration (average IE transition 0.47 ± 0.006; see arrow in Fig. 7A) and 47% during
expiration. The n 1 curve in
Fig. 7B illustrates the effect of swallowing on respiratory timing in the breath before the swallow. A linear regression analysis of the n 1 curve found a slope
of 1.01 ± 0.01, with a y-intercept of 0.004 ± 0.001 and a correlation coefficient (R2) of
0.97, indicating that swallowing had no effect on the timing of the
previous cycle regardless of the phase of onset in the respiratory
cycle. In contrast, the flattening of the
n1 curve between the values
of 0.1 and 0.3 reflects a phase delay in the respiratory timing
produced by increases in TI with swallows during
inspiration. The slope of the n1 curve after the IE transition (
0.4) to a value of 0.7 was
approximately 1.23. This slope was more negative than that found for
the n 1 curve over the same
period, indicating that swallows during this period may have produced a
phase advance in the respiratory rhythm. This latter finding is
supported by the tendency of TE to decrease early in the
TE-vs.-E relationship (Fig. 6A).
After values of 0.7, the n1
curve again flattens and runs parallel with its expected intersection
with zero. This flattening of the
n1 curve and its extension beyond
values of 1.0 is a result of both an increase in TE,
delay in the onset of the next cycle, and a comparable decrease in the
subsequent TI. These later observations are also seen in
the E analysis in the TE above 90% and in
the generally depressed TI-vs.-E
relationship in the breaths with swallows (Fig. 6 and Table 3). There
was a parallel shift between the n1 and
n2 and
n3 curves, except between of 0.9 and 1.2, where an upturn in
n2 and
n3 suggests a slight phase
delay. These results clearly support a type 1 or weak resetting
of the respiratory rhythm generator.
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0.4), the cause of the increased TI/Ttot is due to an
overall shortening of TE relative to TI, as
shown in the E analysis (Fig. 6). Thereafter, the
eventual return to control levels of the
TI/Ttot(n1)-TI/Ttot(c) curve is due
to the relative lengthening of TE compared with a
general shortening of TI (Fig. 6). The effect of swallows
on TI/Ttot is limited to the n1 breaths, as
n2 and n3 curves are observed at control levels.
In Fig. 8, the effect of swallows on
VT is seen during expiration ( ~0.8-1.5), where
the VT(n)/VT(c) curve is lowered
during the inspiration after the swallow (n2 curve).
Subsequent compensation due to a reduction in VT was not
seen in the n3 curve. A modest decrease in
Diapeak(n)/Diapeak(c) is observed at
different sections of the n1 and n2 curves. The
n1 curve is slightly depressed near the IE transition
( 0.35), whereas the n2 curve is depressed in
the later part of expiration ( 0.8; Fig. 8B). In
contrast to the categorical data (Fig. 4) and the within-breath data
(Figs. 5 and 6), these latter data show that swallowing has a limited, temporal perturbation effect on respiratory output.
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n 1 ideal, n1 n 1,
n2 n1, and
n3 n2 every 0.05 interval. No
significant difference was found for n 1 ideal at any value of (P < 0.02), thus supporting the observation that the
timing of the previous breath was unaltered. In contrast, n1 n 1 differed significantly
from the predicted difference of 1 at several points along the axis
(P < 0.02). The increase in
n1 n 1 from 0.15 to 0.40 of reflects a phase delay in the n1 curve due solely to increases in TI. Thereafter, from a value of 0.40 to 0.60, the
n1 n 1 curve progressively
decreased. Although fewer swallows were observed during this phase of
ventilation, this decrease was due to the mixed and varied effects of
swallows to 1) increase TI just before the
swallow (phase delay) and 2) decrease TE (phase
advance) in early expiration. From a value of 0.65 to 0.85, the
difference between n1 and
n 1 was not significantly
different either from 1 or from the expected difference if swallowing
had no effect on respiration. Thereafter, n1 n 1 significantly increased
because of the effect of swallows late in expiration to increase
TE or phase delay the onset of the next breath
(P < 0.02). A significant decrease (P < 0.2) in the n2 n1 curve between a of 0.9 and 1.1 is a result of the effect of swallows during the later part of
expiration to also decrease the subsequent TI and produce a phase advance of the next respiratory cycle.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our data suggest that spontaneous swallows have a phase-dependent effect on respiratory timing and output in the awake state. Changes in breathing before and after a swallow further suggest that the interaction between the respiratory and swallowing pattern generators exists beyond the apparent, immediate, all-or-nothing event of swallowing.
The interaction between swallowing and breathing. The distribution of swallows during the phases of ventilation differs among animals, infants, and adults. In unanesthetized (18, 20) and anesthetized (18, 19, 20) animals, 80-95% of the spontaneous swallows occur during inspiration. In human infants, spontaneous swallows are reported to be equally distributed during expiration and inspiration (30). In unanesthetized and anesthetized adults, spontaneous swallows are primarily produced during expiration (5, 23, 24, 27). These studies suggest that swallowing may be coupled to specific phases of ventilation. In goats, a biphasic occurrence of swallows during the phases of ventilation was observed, with the least number of swallows occurring during the IE transition and early expiration. That over half of the swallows occur during inspiration suggests a well-coordinated, anatomically efficient means to minimize aspirations during a phase of ventilation that is normally at high risk, at least in human adults. In goats, the epiglottis overlaps the soft palate (10), which has been shown to allow a bolus to circumvent the glottis during an inspiratory swallow and pass into the esophagus (22). On the basis of this anatomy, Negus (22) proposed that airflow would continue during a swallow. A similar anatomic mechanism has been proposed to occur in infants during inspiratory swallows that not only minimizes aspirations but also allows for an uninterrupted airflow (6, 28). However, in goats, we observed an interruption of airflow with inspiratory swallows similar to that found in infants by Wilson et al. (30). We attribute this interruption to a decrease in diaphragm activity (observed in this study) and upper airway closure due to constrictor activity (10). Therefore, we hypothesize that in goats the overlapping of the soft palate and epiglottis allows for inspiratory swallows with a low risk for aspirations but does not allow for separate air and liquid channels.
Although both the presence of swallows during EI transition and inspiration and the absence of pharyngolaryngeal problems suggest a benign interaction between the respiratory and swallowing functions, the lack of spontaneous swallows during the IE transition and early expiration is curious. In awake humans, Paydarfar et al. (27) observed the highest occurrence of spontaneous swallows during the IE transition and the lowest during EI transition, suggesting a very different relationship between the swallowing and respiratory pattern generators in humans, dogs, monkeys, and goats. Several studies (19, 27) have shown that stimulation of peripheral afferents during IE transition has a disruptive effect on respiratory timing, which may be the neurophysiological basis for the reduced occurrence of spontaneous swallows during transition in these animals. Less well investigated has been the effect of spontaneous swallows on respiratory timing and total output. Studies in decerebrate cats showed that swallows increased the duration of the current and subsequent respiratory cycle (21). In awake rabbits, swallows during expiration significantly increased TE and the preceding TI, whereas during inspiration swallows significantly increased TI and the subsequent TE (20). These swallows did not significantly affect TI or TE in the breaths that followed. In unanesthetized humans, both spontaneous and water-induced swallows during expiration increased TE and Ttot, as well as VT, immediately after the swallow (23). Spontaneous swallows during inspiration reduced TI, VT, and the following TE. In the subsequent breath, VT was increased. A similar response was found in stimulated swallows that occurred during inspiration, except that Ttot was decreased (23). In goats, swallows during expiration also had a similar effect on TE and Ttot. However, in contrast to data in humans (23), the ensuing TI, VT, and Diapeak were significantly reduced, suggesting that an inhibitory effect of swallowing persisted in the following inspiratory timing and output. The increase in TI with swallows during inspiration in goats was similar to that found in rabbits (20) but is in contrast to the findings in humans (23). Similarly, VT was slightly increased, which is opposite of that found in humans (23), and the findings of Diapeak in goats study further support the idea that total respiratory output is unaltered whereas respiratory timing increases with swallows during inspiration. Although the information in the literature on the effect of swallows on the present and subsequent breaths reveals general trends in the interaction between respiratory and swallowing centers, it does not investigate or eliminate a within-breath and/or multibreath interaction. Most studies (20, 23) utilized the breath(s) before the swallows as controls. This latter point assumes that stimulated and spontaneous swallows only have an effect on breathing during and after the swallows. Although our results support these findings, they also show that both timing and the output to the diaphragm are altered before a swallow. The neural substrate for this interaction is unknown. However, it is presumed that a build-up of secretions in the upper airway activates receptors that travel to the nucleus tractus solitarius via the superior laryngeal nerve (15). Jean (12-14) reported that some neurons in the nucleus tractus solitarius exhibit a "preswallowing activity" that may act as trigger neurons for swallowing whose activity is increased with stimulation of the superior laryngeal nerve. Dick et al. (7) also observed that stimulation of the superior laryngeal nerve below the threshold for eliciting a swallow resulted in a prolongation of TE. Together, these results suggest a peripheral feedback mechanism to the medullary neurons that may elicit changes before a swallow and function to prepare the animal for a swallow. The within-breath analysis of the effects of swallowing on the pattern of breathing provides an insight into the moment-to-moment relationship between the swallowing and respiratory centers. In infants, there is a linear relationship between the duration of inspiration and the TI at the onset of airway closure due to a swallow (30). The earlier the swallow occurred (within the first half of a breath), the shorter the TI. Thereafter, swallows produced a longer period of inspiration. Swallows during expiration also had the greatest effect in increasing Ttot. This relationship produced a negative correlation between Ttot and the occurrence of swallow during expiration. This finding is in contrast to the observation in anesthetized and unanesthetized adult humans, in whom spontaneous swallows occurred primarily during expiration, producing a positive relationship between TE and the occurrence of swallows during expiration, thereby increasing Ttot (23, 24). However, in anesthetized adult humans, swallows during inspiration abruptly interrupted inspiration and were followed by a short expiratory period, thereby producing a significant positive correlation between TI and the onset time of the swallows (24). Similarly, there is a positive correlation between VT and the onset of swallows during inspiration in anesthetized and unanesthetized adults (23, 24). In contrast, an abrupt cessation of inspiration followed by expiration was not observed in goats. Instead, swallows progressively lengthened TI the later they occurred in inspiration (Table 2, Fig. 5B). In addition, although swallows at the very beginning of inspiration were related to a reduced VT, thereafter a positive correlation (above control) was observed for VT and the onset of the swallow during inspiration. In contrast, no change in Diapeak was observed. These observations suggest that not only did swallowing insert a pause into the inspiratory period while not widening the swallow complex and increasing the interruption in flow, it also had a mild progressive inhibition on ventilation (decreasing) while not altering total activity of the diaphragm. During expiration in goats, the relationships between the onset of a swallow and the values of TE, TI, and VT are considerably different from previously reported data. In contrast to those for humans, our data show that the earlier the onset of a swallow during expiration, the shorter the TE observed, until ~75%E, at which point
swallowing increased TE above control. This temporal effect
of swallowing during expiration is also seen in the negative slope of
n 1 TI data, whereas a generalized
overall inhibitory effect of swallowing was found in the relationship
of the TI vs. E for the n
breaths. Also consistent with this latter finding was the significant
effect of expiratory swallows on the subsequent VT, whereas
Diapeak was not altered. These findings suggest that output
to the diaphragm is not reduced during inspiration after a swallow;
only the timing and the subsequent VT are reduced.
Phase response analysis in the interaction of breathing and
swallowing.
A major advantage of the phase response analysis is the capability to
characterize the relationship between pattern generators without
knowing a priori the specific neuroanatomic basis of the interaction
(29, 31). The phase response of stimulated and spontaneous
swallows has only been investigated in humans by Paydarfar et al.
(27), who found that the later a swallow occurred during inspiration, the later the onset of the subsequent breath. The peak of
this response was near IE transition, after which no effect on the
onset of the next cycle was seen until the swallow occurred at the very
end of the respiratory cycle. This nonlinear effect of swallowing on
breathing is very similar to the results of Nishino and colleagues
(23, 24). In addition, Paydarfar et al. (27) demonstrated that swallows produced a "true" resetting of the respiratory rhythm. In other words, instead of an immediate, short-term shift in the bulbospinal output produced by swallowing, a parallel shift in the subsequent breaths occurred. In goats, resetting of the
respiratory rhythm generator also occurs after swallows at different
onsets within the respiratory cycle, with a parallel shift in the
starting of subsequent breaths. The continuity of the calculated
cophases () further supports the concept of a continual oscillation
of the respiratory pattern generator and true phase resetting.
. Except for the phase delay
and advance observed in the n1
and n2 curves, the net slope of
the n1,
n2, and
n3 curves in our study
approximated a negative slope of 1, demonstrating a type 1 (weak)
resetting effect of swallowing on breathing in goats (29,
31). This is also in contrast to a type 0 resetting observed in
the breathing of anesthetized cats by different levels of superior
laryngeal nerve stimulation (26).
EI and IE transitions and swallows. The transition from EI or IE has been suggested as a critical period during the respiratory cycle (7, 23, 24, 26, 27). Dick et al. (7) observed in decerebrate, unanesthetized cats that superior laryngeal nerve stimulation during EI and IE transitions consistently produced more swallows during EI transition and the least during IE transition, which is consistent with our observations of spontaneous swallows. They interpreted the occurrence of the swallows during phase transitions as points of interactions between the respiratory and swallowing pattern generators in which medullary postinspiratory neurons provide a possible neural substrate for this interaction. The definition of the IE transition period in our study extended from the observed occurrence of the thyroarytenoid activity in goats (10), which begins immediately after peak inspiratory activity. During eupnea, classifying swallows within the IE period (Fig. 1A) coincides with the abrupt depolarization of the medullary postinspiratory neurons. Too few swallows were seen during the IE transitions to interpret their effect, except to infer that the natural probability of swallows during this period is greatly reduced. The lack of swallows during the early phase of expiration also coincides with the repolarization of these medullary neurons in phase I of expiration. The observed values for timing and output for swallows during the EI transition were halfway between the observed values for swallows during expiration and inspiration. Immediately after swallows during EI transition, TI and VT were reduced, whereas there was no effect on Diapeak. Similar to the findings with swallows during inspiration, VT in the subsequent breaths was increased whereas TI and Diapeak were not changed. Therefore, these results support the concept that EI and IE transitions are critical periods of interaction between the respiratory and swallowing centers for timing but not respiratory output in goats. These results also suggest that the underlying neural substrate integrating superior laryngeal stimulation and swallowing and the respiratory pattern generator in goats, compared with humans and cats, is functionally different. However, to address these findings more conclusively, we believe that a combination of within- and multibreath analyses of swallowing and breathing are essential to provide an in-depth view of the nature and type of relationship between the two generators under various physiological conditions and using a wide range of whole and reduced animal preparations.
In conclusion, our study shows that swallowing produces a phase-dependent resetting of the respiratory rhythm generator in goats. Furthermore, the data suggest that the interaction between swallowing and breathing occurs before and after a swallow. We suggest that the interrelationship between the pattern generators is functionally diverse in different species and may involve not just the pattern generators directly by also a diversity of peripheral feedback mechanisms and their integration centrally.| |
ACKNOWLEDGEMENTS |
|---|
The authors thank Nancy Schlick, Julie Wenninger, and Alex Serra for technical assistance and Donna Dale for help in preparation of the manuscript.
| |
FOOTNOTES |
|---|
This study was supported by National Heart, Lung, and Blood Institute Grant 25739 and by the Veterans Administration.
Address for reprint requests and other correspondence: H. V. Forster, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: bforster{at}mcw.edu).
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.
First published December 7, 2001;10.1152/japplphysiol.01079.2000
Received 13 November 2000; accepted in final form 4 December 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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, inspiratory flow. The percentages of control
respiratory values evaluated in this study were compared for
SwE, SwEI, SwI, and
SwIE on the breath before (n 
Means are significantly
different from n breath (P < 0.01).
