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Sleep Research Laboratory, Medical Service, John D. Dingell Veterans Affairs Medical Center, and Division of Pulmonary/Critical Care and Sleep Medicine, Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Long-term facilitation (LTF) is a
prolonged increase in ventilatory motor output after episodic
peripheral chemoreceptor stimulation. We have previously shown that LTF
is activated during sleep following repetitive hypoxia in snorers
(Babcock MA and Badr MS. Sleep 21: 709-716,
1998). The purpose of this study was 1) to ascertain the relative contribution of inspiratory flow limitation to the development of LTF and 2) to determine the effect of
eliminating inspiratory flow limitation by nasal CPAP on LTF. We
studied 25 normal subjects during stable non-rapid eye movement sleep.
We induced 10 episodes of brief repetitive isocapnic hypoxia (inspired O2 fraction = 8%; 3 min) followed by 5 min of room
air. Measurements were obtained during control and at 20 min of
recovery (R20). During the episodic hypoxia study,
inspiratory minute ventilation (
I) increased from
6.7 ± 1.9 l/min during the control period to 8.2 ± 2.7 l/min at R20 (122% of control; P < 0.05). Linear regression analysis confirmed that inspiratory
flow limitation during control was the only independent determinant of
the presence of LTF (P = 0.005). Six subjects
were restudied by using nasal continuous positive airway pressure to
ascertain the effect of eliminating inspiratory flow limitation on LTF.
I during the recovery period was 97 ± 10%
(P > 0.05). In conclusion, 1) repetitive hypoxia in sleeping humans is followed by increased
I in the recovery period, indicative of development
of LTF; 2) inspiratory flow limitation is the only
independent determinant of posthypoxic LTF in sleeping human;
3) elimination of inspiratory flow limitation abolished the
ventilatory manifestations of LTF; and 4) we propose that
increased I in the recovery period was a result of
preferential recruitment of upper airway dilators by repetitive hypoxia.
episodic hypoxia; ventilatory control; plasticity; non-rapid eye movement sleep
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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APNEAS AND HYPOPNEAS DURING sleep do not occur in isolation but in cycles of apnea/hypopnea, resulting in episodic hypoxia and followed by hyperpnea. Interestingly, episodic hypoxia has been shown to elicit a prolonged increase in ventilatory motor output subsequent to the removal of the stimulus, referred to as long-term facilitation (LTF). This phenomenon has been observed in some animal models (6, 8, 11, 13, 15, 18, 19, 26) but not others (10). Similarly, studies investigating the occurrence of LTF in humans have shown variable results. For example, the only study in humans during wakefulness found no evidence of LTF (14). In contrast, we have shown that ventilatory LTF for 40-60 min can be evoked by repetitive hypoxia in a subset of sleeping humans, specifically in subjects who snored and who demonstrated inspiratory flow limitation (IFL) while breathing room air (2). In addition, we have shown that ventilatory LTF occurs in association with decreased upper airway resistance in the recovery period (22). Thus ventilatory LTF may be a result of decreased upper airway resistance and unloading of the upper airway.
Despite the consistency of the LTF development in individuals with IFL, it is not clear whether IFL represents a true independent variable or whether it reflects another primary variable. Specifically, upper airway narrowing during inspiration is more common in men, and it correlates with body mass index (BMI) (17). Similarly, upper airway narrowing during sleep may dampen hypoxic ventilatory response. Thus the purpose of this study was twofold: first, to ascertain the relative contribution of IFL vs. other potential determinants of LTF and, second, to determine the effect of eliminating IFL on LTF. To this end, we unloaded the upper airway with nasal continuous positive airway pressure (CPAP) sufficient to eliminate snoring and IFL.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
The Human Investigation Committee of the Wayne State University School of Medicine and the John D. Dingell Veterans Affairs Medical Center approved the experimental protocol. Informed consent was obtained from each participant. We studied 25 healthy subjects free of any cardiopulmonary or sleep disorder. The group consisted of 14 men and 11 women with a mean age of 29.7 ± 3.5 yr and BMI of 25.9 ± 2.2 kg/m2.Breathing Circuit
The subject was connected to the circuit with an airtight silicone rubber mask strapped and glued to the face to prevent leaks. The mask was connected to a plateau exhalation valve (Respironics, Pittsburgh, PA) via a heated pneumotachometer. The valve, which provides a continuous leak path in the breathing circuit and serves as an exhaust vent, was connected on the inspiratory line. Three cylinders, containing 100% N2, 8% O2, or 100% O2, were connected to the inspiratory line. To maintain isocapnia, supplemental CO2 was added to the inspiratory line from an external source to maintain end-tidal PCO2 (PETCO2) at or near control levels.Measurements
Electroencephalograms, electrooculograms, and chin electromyograms were recorded by using standard methods. Inspiratory airflow was measured by a heated pneumotachometer (model 3700A, Hans Rudolph, Kansas City, MO) attached to a pressure transducer (Validyne, Northridge, CA), and tidal volume (VT) was computed by electronic integration of the flow signal (model FV156 Integrator, Validyne). Supraglottic airway pressure was measured by using a pressure transducer-tipped catheter (model TC-500XG, Millar Instruments, Houston, TX) in 12 subjects. The hypopharyngeal position was confirmed by advancing the catheter tip for 2 cm after it disappeared behind the tongue. To ascertain the presence of IFL in each subject who had a pressure catheter placed, a pressure-flow loop of each breath was used (n = 12). The effect of episodic hypoxia on upper airway resistance in this subgroup has been published separately (22). Flow limitation was defined as plateau in flow despite a decrease in supraglottic (downstream) pressure
1
cmH2O. In the remainder of the subjects, we used the flow
profile criteria of Teschler et al. (25) to ascertain the
presence of IFL. Flow limitation was determined as a dichotomous variable.
PETCO2 was measured by using air sampled continuously from the nasal mask by an infrared analyzer (model CD-3A, AEI Technologies, Pittsburgh, PA). Arterial O2 saturation (SaO2) was measured by using pulse oximetry (Biox 3700, Ohmeda). All signals were displayed on a polygraph recorder (model 7-D, Grass, West Warwick, RI) and recorded by using Power Lab digital acquisition software (Power Lab SP Series, version 4.0, AD Instruments, Mountain View, CA).
Protocol
Subjects lay in the supine position for the entire study, which was conducted during stable non-rapid eye movement (NREM) sleep (stable stage 2 or stage 3 sleep). Two protocols on separate nights were conducted as part of this investigation.Protocol 1: episodic hypoxia. Twenty-five subjects participated in this protocol, which has been previously described in detail (1, 2, 22). Ten cycles of episodic hypoxia were induced in each subject. Hypoxia was rapidly induced by having the subject breathe one or two breaths of 100% N2 followed by continuous 8% O2 for 3 min to maintain hypoxia (SaO2 80-84%). Supplemental CO2 was titrated to maintain isocapnia during hypoxia guided by PETCO2 on a breath-by-breath basis. Hypoxia was abruptly terminated with one breath of 100% O2. This was followed by 5 min of room air breathing. The breathing pattern was monitored for 40 min of recovery after the tenth exposure to hypoxia.
A sham study was also conducted to ascertain the presence of time-dependent changes in ventilation, independent of the experimental protocol. Eleven subjects were studied on a different night. This subgroup consisted of six men and five women with a mean age of 28.8 ± 6.5 yr and BMI of 26.8 ± 4.6 kg/m2. The participants were connected to the same breathing circuit with identical instrumentation. However, the subject breathed ambient air for the entire study time (120 min of sleep).Protocol 2: unloading. To test the effects of inspiratory unloading, a subgroup of subjects who demonstrated ventilatory LTF (n = 6) and IFL on the baseline study (protocol 1) agreed to undergo a repeat episodic hypoxia study with nasal CPAP unloading for the entire study period (120 min). This subgroup consisted of four men and two women with a mean age of 26 ± 4 yr and BMI of 27.1 ± 3.7 kg/m2. The level of CPAP was set so that all visual signs of IFL were eliminated. When the subjects reached stable stage 2 or 3 NREM, the episodic hypoxia protocol was performed as outlined above.
Data Analysis
We selected for analysis segments with stable sleep only. Sleep stage was scored according to Rechtschaffen and Kales criteria (20), and transient arousals were scored by using the American Sleep Disorders Association criteria (24). The number and duration of each arousal during hypoxia were calculated for each subject. To ensure that changes in ventilation were not a result of subtle changes in sleep state, an independent observer confirmed the stability of sleep state. The control period consisted of 3 min immediately preceding the first hypoxic exposure. Three minutes of recovery were selected at 20 min of recovery (R20). All breaths in the selected control and R20 segments were used for determination of IFL; the last 20 breaths were used for measurement of ventilation. A mean value for each variable was computed from 20 consecutive breaths. Data are presented as means ± SD. No hypoxia was induced during the sham study; breaths for measurement were selected at 100 min from the beginning of the control period to represent R20. All the data were normalized to the control period data for comparison.Statistical analysis.
A computer statistical package was used to analyze the data
(Sigma Stat 2.0, SPSS). The inspiratory minute ventilation
(I; as percentage of control) at R20 was
chosen as the dependent variable for the presence of LTF. Several
independent variables were considered for inclusion in a multiple
linear regression model, on the basis of an a priori reasoning that
they may contribute to I at R20. The
level of significance was set at P < 0.05. The
following potential variables were tested with univariate regression
analyses: 1) percentage of breaths that were flow limited
during the control period, 2) gender, 3) BMI,
4) number of arousals during hypoxia, and 5)
hypoxic ventilatory response. The latter was defined as the slope of
I against SaO2 from the
onset of hypoxia until steady state is reached (7) (see
Table 2).
I at
R20 from the regular LTF night and the night when nasal
CPAP was used to eliminate IFL. The Student's t-test was
used for the comparison.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Twenty-five subjects participated in the episodic hypoxia
protocol, and eleven subjects participated in the sham protocol. Figure
1 is a representative polygraph record
from one subject who snored habitually and demonstrated IFL during the
study. The segment depicts ventilation during room air control
conditions (A), hypoxia (B), and at
R20 (C). Note increased flow and diminished magnitude of supraglottic pressure during hypoxia and R20
relative to control.
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During the hypoxic trials, SaO2 decreased to
87 ± 4%. Although sleep state was stable in most of the trials,
a few brief episodes of arousal were inevitable. The number of arousals
per subject during the entire duration of hypoxia was 3.2 ± 3.0 arousals with sum duration of 4.2 ± 5.2 min. Hypoxia resulted in
increased I to 9.3 ± 2.1 vs. 6.7 ± 1.9 l/min during room air control (P < 0.05). No
significant change in PETCO2 was
noted during hypoxia (43.5 ± 5.8 vs. 44.8 ± 5.6 Torr during
room air control; P > 0.05).
Table 1 shows the changes in ventilation
and timing for episodic hypoxia studies during the recovery period
relative to control. I at R20 increased
to 122% of control (P < 0.05). The increase in
I was due to increased VT to 120% of
control (P < 0.05) as a result of increased
VT-to-inspiratory time (TI) ratio to 123% of
control (P = 0.01). The aftereffects of repetitive
hypoxia on timing parameters were not remarkable, because there was no significant change in TI, expiratory time
(TE), or TI-to-total breath
duration ratio. The findings of the sham study differed from the
repetitive hypoxia study; I and VT
during the recovery period were 98 and 100% of control, respectively
(P > 0.05; Fig. 2).
Table 2 compares findings between
repetitive hypoxia and sham nights in the 11 subjects who underwent
both studies. I increased at R20 during
the repetitive hypoxia but not the sham study. The only change from the
control period to R20 during the sham study was the
prolongation of TE from 1.91 ± 0.29 to 2.07 ± 0.24 s (P < 0.05; Table 2)
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Increased I at R20 did not occur in all
subjects. To explain the variability in I at
R20, several possible variables were tested with
univariate-regression analysis to determine which variable should be
included in a multiple-regression analysis with I at
R20 as the dependent variable (Table
3). The only independent variable
predicting the presence of LTF for I was the
percentage of breaths with IFL during the room air control period
(P = 0.003), as shown in Fig.
3. There was no correlation between any
of the other variables and I at R20.
Similarly, univariate-regression analysis for VT as the
independent variable identified the percentage of breaths with IFL
(P < 0.005) and the average
SaO2 during the hypoxic trials
(P < 0.05) as two potential predictors of LTF for
VT. However, multiple-regression analysis identified the
percentage of breaths of IFL as the only independent determinant of LTF
(P = 0.01).
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In protocol 2, subjects who had shown evidence of LTF during
protocol 1 (n = 6) were restudied by using
nasal CPAP to eliminate IFL. All were snorers with evidence of IFL
during eupneic breathing. The level of pressure assist that was used to
eliminate IFL was 2.9 ± 0.9 cmH2O. The nadir level of
hypoxia was 84.1 ± 2.8%, which was not different from the
baseline LTF study night (81.6 ± 3.2%). I at
R20 for the unloaded study was not different from
prehypoxia control (96.9 ± 10.2%; Table
4). Comparison of the
I at R20 between the loaded and unloaded
studies for each subject revealed a significant difference between the
two studies (P < 0.02; Fig. 4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Summary of Findings
Our study revealed three important findings: 1) posthypoxic hyperpnea occurred after repetitive hypoxia during sleep, 2) the only independent determinant of increasedI during the recovery period was the magnitude of
IFL in the control period, and 3) alleviation of IFL
eliminated posthypoxic hyperpnea.
Methodological Considerations
The validity of our results is dependent on stability of sleep state, which was confirmed by an independent observer. Similarly, passive mechanical changes such as changes in head or neck position may cause an increase in VT orI. This is
unlikely because no changes were noted in the head or neck position.
Furthermore, the consistent difference between ventilation during the
hypoxia and the sham studies is unlikely to be due to passive
mechanical changes.
Nasal CPAP may have other effects on lung volumes or respiratory muscle activity in addition to "unloading" the upper airway and elimination of IFL. However, we used the lowest possible level to eliminate flow limitation. We believe that the effects noted on the CPAP night are a result of unloading per se and not of effects on respiratory or upper airway muscle activity.
We selected several variables for inclusion in a linear regression model on the basis of our previous finding (2) that LTF was seen only in individuals who snored and demonstrated evidence of IFL. However, the magnitude of hypoxia and the hypoxic responsiveness were also included as potential independent variables, reflecting the intensity of the "signal" from the peripheral chemoreceptors and potentially the magnitude of LTF.
We collected the recovery data after 20 min of the termination of the last hypoxic exposure. This duration was used in many previous LTF studies. Furthermore, longer recovery periods may not be attainable in all subjects because we were not certain that sleep would remain stable for longer periods.
LTF in Sleeping Humans
The occurrence of posthypoxic hyperpnea indicates that hypoxia elicits LTF of ventilatory motor output (LTF). This corroborates previous studies demonstrating evidence of LTF in the aftermath of repetitive hypoxia. Similarly, our study has demonstrated increasedI manifested mainly as increased VT
without significant change in respiratory frequency.
The strong association between the presence of IFL and the development of LTF intrigued us. We considered that subjects who manifest LTF might be intrinsically different from non-LTF subjects. This interpretation was suggested by the fact that the activation of LTF is a serotonin-dependent central nervous system phenomenon (3). Theoretically, phenotypic differences in the density of serotonergic neurons or ability to increase serotonin level in the raphe nuclei may contribute to LTF variability among subjects. Accordingly, peripheral chemoreceptor stimulation sends excitatory signals to the brain stem integrative centers and to the raphe nuclei; the density of serotonergic neurons and hence the intensity of LTF might be different among different subjects. However, the elimination of LTF with acute unloading with nasal CPAP argues against phenotypic differences as an explanation for the variability of LTF.
Another possible explanation is that the development of LTF in some subjects only may reflect an augmentation of the magnitude of LTF after prior conditioning with a stimulus; this is referred to as metaplasticity (16). Examples of metaplasticity include cervical dorsal rhizotomy, which enhances LTF in rats (12), or chronic intermittent hypoxia, resulting in induction of hypoglossal LTF in a rat substrain that does not express LTF (27). Thus chronic snoring with ensuing repetitive arousals or transient hypoxia may condition the ventilatory control system to elicit LTF after repetitive hypoxia. The elimination of LTF with unloading also argues against metaplasticity and suggests that the manifestation of ventilatory LTF is influenced by upper airway mechanics (see below).
Mechanisms of Ventilatory LTF
The development of ventilatory LTF may be due to increased thoracic pump or upper airway-dilating muscle activity. There is evidence in several animal models that repetitive hypoxia elicits phrenic LTF diaphragmatic or intercostal inspiratory activity (3, 5, 15, 16). However, we have recently found that ventilatory LTF was noted without a corresponding increase in diaphragmatic activity as measured by surface electrodes (22). Although this observation suggests that thoracic inspiratory activity is not necessary for the development of LTF, it does not specifically exclude either muscle group given the low sensitivity of surface recordings.The development of ventilatory LTF may also be explained by active upper airway dilatation due to LTF of upper airway-dilating muscle activity. This interpretation is supported by animal studies demonstrating that repetitive hypoxia elicits LTF of ventilatory motor output to upper airway dilators. Mateika and Fregosi (13) have shown, in vagotomized cats, that repetitive hypoxia is followed by increased activity of the genioglossus and the alae nasae but not the diaphragm. Similarly, we have shown that repetitive hypoxia in sleeping humans is followed by decreased upper airway resistance in the recovery period, indicative of upper airway dilatation (22). Accordingly, increased VT during the recovery period would be due to decreased upper airway resistance or unloading of the pharyngeal airway.
The aforementioned observations combined with the association between
baseline IFL and the development of LTF suggest that ventilatory LTF is
due to preferential recruitment of upper airway dilators with ensuing
unloading of the upper airway. The magnitude of increased
I in the recovery period is consistent with the magnitude of hyperpnea after upper airway unloading with nasal CPAP in
our study (Table 3) or previous unloading studies with CPAP
(9) or He-O2 mixture (23). Thus
the present study suggests that LTF unloaded the upper airway almost to
the same level as nasal CPAP. The notion that upper airway dilators are
more amenable to the development of LTF compared with the diaphragm is
also supported by empirical evidence from animal studies as well
(13).
The preferential recruitment of upper airway dilators cannot solely explain the absence of ventilatory LTF in subjects without IFL, nor can it explain the elimination of LTF with nasal CPAP unloading. Instead, ventilatory LTF may reflect a mechanical consequence of upper airway dilator recruitment. Specifically, mechanical and ventilatory changes are more pronounced in snorers (subjects with IFL) relative to nonsnorers (no IFL) for a given magnitude of neuromuscular activation. For example, electrical stimulation of the genioglossus results in reduced upper airway resistance only in the presence of upper airway narrowing (21). Conversely, reduced ventilatory motor output causes worsening of flow limitation in subjects with high upper airway resistance and IFL only and not in normal subjects (4). Thus a narrow upper airway may be required for ventilatory manifestations of LTF.
In summary, we have shown that episodic hypoxia during sleep in normal
subjects elicits ventilatory LTF manifested by increased VT
and I in subjects with evidence of IFL during
eupneic breathing.
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ACKNOWLEDGEMENTS |
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This work was supported by the Department of Veterans Affairs and the National Heart, Lung, and Blood Institute (NHLBI). M. S. Badr is a recipient of midcareer award in patient-oriented research from the NHLBI (K24 HL-04174).
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. S. Badr, Harper Hospital, 3990 John R. 3-Hudson, R-3923, Detroit, MI 48201 (E-mail: sbadr{at}intmed.wayne.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.
September 6, 2002;10.1152/japplphysiol.00476.2002
Received 31 May 2002; accepted in final form 3 September 2002.
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REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Aboubakr, SE,
Taylor A,
Ford R,
Siddiqi S,
and
Badr MS.
Long-term facilitation in obstructive sleep apnea patients during NREM sleep.
J Appl Physiol
91:
2751-2757,
2001
2.
Babcock, MA,
and
Badr MS.
Long-term facilitation of ventilation in humans during NREM sleep.
Sleep
21:
709-716,
1998[ISI][Medline].
3.
Bach, KB,
and
Mitchell GS.
Hypoxia-induced long-term facilitation of respiratory activity is serotonin dependent.
Respir Physiol
104:
251-260,
1996[ISI][Medline].
4.
Badr, MS,
Kawak A,
Skatrud JB,
Morrell MJ,
Zahn BR,
and
Babcock MA.
Effect of induced hypocapnic hypopnea on upper airway patency in humans during NREM sleep.
Respir Physiol
110:
33-45,
1997[ISI][Medline].
5.
Baker, TL,
and
Mitchell GS.
Episodic but not continuous hypoxia elicits long-term facilitation of phrenic motor output in rats.
J Physiol
529:
215-219,
2000
6.
Cao, KY,
Berthon-Jones M,
Sullivan CE,
and
Zwillich CW.
Ventilatory response to oxygen after eucapnic hypoxia in conscious dogs.
J Appl Physiol
74:
1916-1920,
1993
7.
Douglas, NJ,
White DP,
Weil JV,
Pickett CK,
Martin RJ,
Hudgel DW,
and
Zwillich CW.
Hypoxic ventilatory response decreases during sleep in normal men.
Am Rev Respir Dis
125:
286-289,
1982[ISI][Medline].
8.
Fregosi, RF,
and
Mitchell GS.
Long-term facilitation of inspiratory intercostal nerve activity following carotid sinus nerve stimulation in cats.
J Physiol
477:
469-479,
1994[ISI][Medline].
9.
Henke, KG,
Dempsey JA,
Badr MS,
Kowitz JM,
and
Skatrud JB.
Effect of sleep-induced increases in upper airway resistance on respiratory muscle activity.
J Appl Physiol
70:
158-168,
1991
10.
Janssen, PL,
and
Fregosi RF.
No evidence for long-term facilitation after episodic hypoxia in spontaneously breathing, anesthetized rats.
J Appl Physiol
89:
1345-1351,
2000
11.
Kinkead, R,
Bach KB,
Johnson SM,
Hodgeman BA,
and
Mitchell GS.
Plasticity in respiratory motor control: intermittent hypoxia and hypercapnia activate opposing serotonergic and noradrenergic systems.
Comp Biochem Physiol
130:
207-218,
2002.
12.
Kinkead, R,
Zhan WZ,
Prakash YS,
Bach KB,
Sieck GC,
and
Mitchell GS.
Cervical dorsal rhizotomy enhances serotonergic innervation of phrenic motoneurons and serotonin-dependent long-term facilitation of respiratory motor output in rats.
J Neurosci
18:
8436-8443,
1998
13.
Mateika, JH,
and
Fregosi RF.
Long-term facilitation of upper airway muscle activities in vagotomized and vagally intact cats.
J Appl Physiol
82:
419-425,
1997
14.
McEvoy, RD,
Popovic RM,
Saunders NA,
and
White DP.
Effects of sustained and repetitive eucapnic hypoxia on ventilation and genioglossal and diaphragmatic EMGs.
J Appl Physiol
81:
866-875,
1996
15.
Millhorn, DE,
Eldridge FL,
and
Waldrop TG.
Prolonged stimulation of respiration by a new central neural mechanism.
Respir Physiol
41:
87-103,
1980[ISI][Medline].
16.
Mitchell, GS,
Baker TL,
Nanda SA,
Fuller DD,
Zabka AG,
Hodgeman BA,
Bavis RW,
Mack KJ,
and
Olson EB, Jr.
Intermittent hypoxia and respiratory plasticity.
J Appl Physiol
90:
2466-2475,
2001
17.
Morrell, MJ,
and
Badr MS.
Effects of NREM sleep on dynamic within-breath changes in upper airway patency in humans.
J Appl Physiol
84:
190-199,
1998
18.
Olson, EB, Jr,
Bohne CJ,
Dwinell MR,
Podolsky A,
Vidruk EH,
Fuller DD,
Powell FL,
and
Mitchel GS.
Ventilatory long-term facilitation in unanesthetized rats.
J Appl Physiol
91:
709-716,
2001
19.
Önal, E,
Burrows DL,
Hart RH,
and
Lopata M.
Induction of periodic breathing during sleep causes upper airway obstruction in humans.
J Appl Physiol
61:
1438-1443,
1986
20.
Rechtschaffen, A,
and
Kales A.
Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Bethesda, MD: National Institute of Neurological Disease and Blindness, 1998.
21.
Schnall, RP,
Pillar G,
Kelsen SG,
and
Oliven A.
Dilatory effects of upper airway muscle contraction induced by electrical stimulation in awake humans.
J Appl Physiol
78:
1950-1956,
1995
22.
Shkoukani, M,
Babcock MA,
and
Badr MS.
Effect of episodic hypoxia on upper airway mechanics in humans during NREM sleep.
J Appl Physiol
92:
2565-2570,
2002
23.
Skatrud, JB,
Dempsey JA,
Badr S,
and
Begle RL.
Effect of airway impedance on CO2 retention and respiratory muscle activity during NREM sleep.
J Appl Physiol
65:
1676-1685,
1988
24.
Task Force of the American Sleep Disorders Association.
EEG arousals: scoring and examples. A preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association.
Sleep
15:
174-184,
1992[ISI].
25.
Teschler, H,
Berthon-Jones M,
Thompson AB,
Henkel A,
Henry J,
and
Konietzko N.
Automated continuous positive airway pressure titration for obstructive sleep apnea syndrome.
Am J Respir Crit Care Med
154:
734-740,
1996[Abstract].
26.
Van de Graff, W.
Thoracic influence on upper airway patency.
J Appl Physiol
65:
2124-2133,
1988
27.
Zabka, AG,
Behan M,
and
Mitchell GS.
Selected Contribution: Time-dependent hypoxic respiratory responses in female rats are influenced by age and by the estrus cycle.
J Appl Physiol
91:
2831-2838,
2001
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M. McGuire, Y. Zhang, D. P. White, and L. Ling Phrenic long-term facilitation requires NMDA receptors in the phrenic motonucleus in rats J. Physiol., September 1, 2005; 567(2): 599 - 611. [Abstract] [Full Text] [PDF]
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M. McGuire and L. Ling Ventilatory long-term facilitation is greater in 1- vs. 2-mo-old awake rats J Appl Physiol, April 1, 2005; 98(4): 1195 - 1201. [Abstract] [Full Text] [PDF]
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 C. M. Bocchiaro and J. L. Feldman From The Cover: Synaptic activity-independent persistent plasticity in endogenously active mammalian motoneurons PNAS, March 23, 2004; 101(12): 4292 - 4295. [Abstract] [Full Text] [PDF]
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D. M. O'Driscoll, G. E. Meadows, D. R. Corfield, A. K. Simonds, and M. J. Morrell Cardiovascular response to arousal from sleep under controlled conditions of central and peripheral chemoreceptor stimulation in humans J Appl Physiol, March 1, 2004; 96(3): 865 - 870. [Abstract] [Full Text] [PDF]
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J. H. Mateika, C. Mendello, D. Obeid, and M. S. Badr Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans J Appl Physiol, March 1, 2004; 96(3): 1197 - 1205. [Abstract] [Full Text] [PDF]
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