Genioglossal Activation in Patients with Obstructive
Sleep Apnea versus Control Subjects
Mechanisms of Muscle Control
ROBERT B. FOGEL, ATUL MALHOTRA, GIORA PILLAR, JILL K. EDWARDS, JOSÉE BEAUREGARD, STEVEN A. SHEA,
and DAVID P. WHITE
Divisions of Sleep Medicine and Pulmonary and Critical Care, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School,
Boston, Massachusetts
Pharyngeal dilator muscle activation (GGEMG) during wakefulness is greater in patients with obstructive sleep apnea (OSA) than
in healthy control subjects, representing a neuromuscular compensatory mechanism for a more collapsible airway. As previous
work from our laboratory has demonstrated a close relationship
between GGEMG and epiglottic pressure, we examined the relationship between genioglossal activity and epiglottic pressure in
patients with apnea and in control subjects across a wide range of
epiglottic pressures during basal breathing, negative-pressure (ironlung) ventilation, heliox breathing, and inspiratory resistive loading. GGEMG was greater in the patients with apnea under all conditions (p 0.05 for all comparisons), including tonic, phasic, and
peak phasic GGEMG. In addition, patients with apnea generated a
greater peak epiglottic pressure on a breath-by-breath basis. Although the relationship between GGEMG and epiglottic negative
pressure was tight across all conditions in both groups (all R values
0.69), there were no significant differences in the slope of this
relationship between the two groups (all p values 0.30) under
any condition. Thus, the increased GGEMG seen in the patient
with apnea during wakefulness appears to be a product of an increased tonic activation of the muscle, combined with increased
negative-pressure generation during inspiration.
Keywords: genioglossus; sleep apnea; pharyngeal muscles
Obstructive sleep apnea (OSA) is a common disorder affecting 2 to 4% of the middle-aged population (1). This disorder is
characterized by repetitive collapse of the pharyngeal airway
during sleep (2, 3) and is associated with important adverse
consequences for afflicted individuals (4–8). Numerous studies have demonstrated that the pharyngeal airway of the patients with apnea is anatomically small when compared with
that of control subjects, and is thus potentially more vulnerable to collapse (9–12).
There is substantial evidence in both animals and humans
that upper airway dilator muscles play an important role in
maintaining airway patency (13). Many of the pharyngeal dila(Received in original form February 13, 2001; accepted in final form August 20, 2001)
Supported by grants NCRR GCRC MO1 RR02635, 1 P50 HL60292, RO1
HL48531, and K23 HL04400 from the National Institutes of Health.
Dr. Fogel is the recipient of a Pickwick Fellowship from the National Sleep Foundation.
Dr. Malhotra is the recipient of grants from the Medical Research Council of Canada and the American Heart Association.
Dr. Pillar is the recipient of a Fulbright scholarship.
Correspondence and requests for reprints should be addressed to Robert B. Fogel, Division of Sleep Medicine and Pulmonary and Critical Care, Brigham and
Women’s Hospital, Harvard Medical School, 221 Longwood Ave., Boston, MA
02115. E-mail: rfogel@partners.org
This article has an online data supplement, which is accessible from this issue’s
table of contents online at www.atsjournals.org
Am J Respir Crit Care Med Vol 164. pp 2025–2030, 2001
DOI: 10.1164/rccm2102048
Internet address: www.atsjournals.org
tor muscles are known to demonstrate inspiratory phasic activity, the onset of which precedes diaphragmatic activity, thus
“preparing” the pharyngeal airway for the development of negative pressure during inspiration. We have previously shown
in patients with OSA during wakefulness that there is augmented activity of the genioglossus (GG) muscle as well as other
pharyngeal dilator muscles when compared with healthy control subjects (14). This activity is thought to represent a neuromuscular compensatory mechanism for an anatomically small
and more collapsible pharyngeal airway. This augmented upper
airway dilator muscle activity is lost at sleep onset and is associated with pharyngeal collapse (15). Thus the mechanisms
controlling pharyngeal muscle activation are important in understanding disease pathogenesis.
The activity of the pharyngeal dilator muscles is influenced
by numerous variables, including blood gases (PaO2 and PaCO2),
sleep-wake state, gender-specific hormones, blood pressure,
temperature, lung inflation, pharyngeal airflow, and intrapharyngeal negative pressure (16–20). However, most data suggest that intrapharyngeal pressure is the primary stimulus to
phasic pharyngeal dilator muscle activation. First, it is well
known that the application of negative pressure to the pharyngeal airway in animals and in humans leads to a substantial increase in the activity of the genioglossus as well as other upper
airway muscles (21, 22). The time course of this response
(maximal response within 200 ms) suggests that it is a neural
reflex. Second, we have recently shown that peak phasic GG
activity correlates closely with the peak negative epiglottic
pressure generated during inspiratory resistive loading in healthy
control subjects (23). Finally, using an iron-lung model of passive ventilation, data from our laboratory have demonstrated
that during inspiration, there is an extremely tight correlation
between epiglottic negative pressure (Pepi) and GG electromyogram (GGEMG) (24). The responsiveness of the GGEMG
(slope of GGEMG/Pepi) was found to be remarkably constant in a given individual over a range of epiglottic pressures
and was not independently influenced by changes in PO2, PCO2,
or airflow (Malhotra, unpublished observation).
The mechanisms driving the increased genioglossal muscle
activation seen in patients with OSA during wakefulness has
not been carefully investigated. We hypothesized that the relationship between GG activation and pharyngeal negative
pressure would be augmented in the patient with apnea, representing a neural plasticity evolved over years of reflex muscle activation. In order to test this hypothesis we measured the
sensitivity of inspiratory GG activation to pharyngeal pressure
changes under a wide range of breathing conditions, including
basal breathing, increased negative epiglottic pressure generation (iron-lung ventilation and inspiratory resistive loading),
and reduced negative epiglottic pressure generation (heliox
breathing). The advantages of using the iron-lung was twofold. First, as we have previously shown, it allows us to substantially attenuate spontaneous ventilation. Thus, during rel-
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
atively “passive” ventilation we can evaluate the relation
between genioglossal muscle activation and epiglottic pressure changes across inspiration with a minimum of premotor
input. Second, the iron-lung allows us to substantially increase
the range of negative epiglottic pressures over which we can
evaluate this relationship. Thus, we could compare the slope
of this relationship (Pepi versus GGEMG) in patients with
OSA versus control subjects.
METHODS
Subjects
Ten men with moderate to severe Obstructive Sleep Apnea Syndrome (AHI 25/h of sleep) were studied. These participants were
recruited from the sleep laboratory of the Brigham and Women’s
Hospital. Control subjects were 12 healthy male volunteers who had
no sleep complaints. All control subjects had a body mass index 25
kg/m2 and had no history of snoring. Informed consent was obtained
from each participant, with the protocol having the prior approval of the
Human Subjects Committee of the Brigham and Women’s Hospital.
Equipment and Techniques
All studies were performed during wakefulness in the supine posture.
Subjects lay within a negative pressure ventilator (Series J; Iron Lung,
Emerson, MA). Inspiratory flow was determined with a calibrated
pneumotachometer (Fleish, Inc., Lausanne, Switzerland) and differential pressure transducer (Validyne Corp., Northridge, CA). For flow
measurements during Heliox (80% helium/20% oxygen) conditions a
correction quotient of 1.09 was used. This value is based on published
gas viscosity correction factors making the assumption that flow
through the pneumotachometer is largely laminar (25). The standard
techniques of our laboratory were used to measure end-tidal CO2
(PETco2), mask leak, mask pressure (Pmask), choanal pressure (Pcho),
epiglottic pressure (Pepi), and intramuscular genioglossus electromyography (GGEMG, as a percent of maximum activity) (14, 23).
Passive ventilation (“Iron lung”). Subjects were studied while supine with the head outside and the body within a negative pressure
ventilator. The ventilator was switched on only for specific parts of
the experiment. The iron lung could be adjusted to achieve the desired upper airway pressure and breathing frequency, so that passivity
(or completely synchronous ventilation) was achieved. The iron lung
excursions required to achieve passivity varied between subjects. All
subjects required some initial coaching to enable passive mechanical
ventilation. This involved asking the subjects to remain completely relaxed while the investigators provided feedback on a breath-by-breath
basis to achieve consistent timing and shape of the pressure and flow
traces. Recordings were stopped when there was departure from this
passive pattern until adequate passivity could be achieved, or the experiment was terminated. Measurements were recorded only during
steady-state conditions (24).
Heliox administration. Heliox was used as a condition in which
pressure and flow would change in opposite directions (pressure decreases and flow increases). A 50-liter meteorological balloon was attached to the inspiratory line of the breathing apparatus connected by
a three-way stopcock. When breathing room air, the device was open
to atmosphere. While breathing Heliox, the valve was open to the 50liter balloon, which had been previously filled with a mixture of helium (80%) and oxygen (20%). After each change in inspired gases, 3
to 5 min passed before data collection to allow full equilibration.
Inspiratory resistive loading (IRL). IRL leads to an increase in
pharyngeal negative pressure, which was generated by the subject/
patient (rather than passively in the iron lung). Resistance was added
to inspiration using a specially designed variable resistance device. Inspiration could be loaded to any desired level by varying the effective
caliber of the inspiratory pathway (26). In this experiment, two levels
of load were used (10 and 25 cm H2O/L/s). Each was applied for three
consecutive breaths and was repeated at least three times (nine
breaths per load).
Protocol
After obtaining informed consent, the equipment was attached and
calibrations were performed. In random order, each subject was re-
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2001
corded under a variety of conditions: (1) during spontaneous basal
breathing (air and heliox), (2) during passive (iron lung) ventilation,
and (3) during inspiratory resistive loading. Carbon dioxide was
added to the inspiratory line during iron-lung ventilation to maintain
eucapnia.
Data Recording and Analyses
All signals were recorded on a 16-channel Grass model 78 polygraph
(Grass Instruments, Astro-Med, Inc., West Warwick, RI). Certain signals (GGEMG MTA, airway pressures, inspiratory flow, ETCO2) were
also recorded onto a computer using signal-averaging software (Spike
2; Cambridge Electronic Design, Ltd, Cambridge, UK).
For each condition (except IRL), one buffered breath was generated by signal averaging all breaths in that particular condition. During IRL, each of the three loaded breaths was signal-averaged. For
each buffered breath the following variables were determined: peak
negative pressure (at the levels of choanae and epiglottis), peak flow,
tonic GGEMG, and peak phasic GGEMG (peak activation during inspiration). Phasic EMG was defined as the difference between peak
phasic and tonic EMG. Pharyngeal resistance (Rpha) and supraglottic
resistance (Rsg) were calculated at peak inspiratory flow. Data were
analyzed both within breaths to generate regression relationships between epiglottic pressure and GGEMG in a given condition, as well as
between breaths by comparing the mean nadir epiglottic pressure in
each condition with mean peak GGEMG.
Statistical Analyses
All statistical analyses were performed with commercially available
software (SigmaStat Sigmaplot, SPSS, Chicago, IL). Two-tailed independent t tests were performed to compare values between apneic
patients and control subjects (or nonparametric methods when appropriate). Alpha was set at 0.05. ANOVA for repeated measures (or
ANOVA on ranks when appropriate) was used to compare slopes and
correlations between conditions within each group. Results are presented as mean SEM.
RESULTS
Complete data sets were obtained in 20 of 22 subjects. In two
subjects (one control, 1 OSA), IRL could not be performed
because of repeated swallowing when the load was applied.
Otherwise their data sets were complete as well. The mean
age and BMI of the patients with OSA were significantly
higher than that of the control group (Age: 46.7 3.2 versus
29.9 3.7 yr, p 0.05; and BMI: 32.00 1.26 versus 22.43
0.54 kg/m2, p 0.05). The patients with OSA had moderatesevere apnea as demonstrated by a mean RDI of 71.53
11.73. Five of the 10 subjects were using nasal CPAP as therapy for OSA, the rest were not currently receiving therapy.
GG Activation and Pharyngeal Mechanics
Across all breathing conditions, GG muscle activity was greater
in patients with OSA than in control subjects (Table 1). This
was true for tonic, peak phasic, and phasic GGEMG (p values
0.05). During spontaneous breathing with heliox, these differences approached, but did not reach, statistical significance
(p 0.10). Peak phasic GGEMG was greater in both groups
during iron lung ventilation than during spontaneous breathing. Pharyngeal pressures were also more negative during ironlung ventilation than when encountered during spontaneous
breathing (p 0.05 for both control subjects and patients with
OSA, spontaneous breathing versus iron-lung, Table 1). There
was no significant change in tonic GGEMG between these
conditions (p 0.5 for all comparisons).
During all conditions, peak epiglottic negative pressure
and both pharyngeal plus supraglottic resistance were greater
in the apneic patients than in the control subjects (Table 1).
These differences were most marked during the high flow conditions seen during iron-lung ventilation. There were no significant differences in peak airflow rates between the patients
Fogel, Malhotra, Pillar, et al.: Genioglossal Activation: Obstructive Sleep Apnea vs Controls
TABLE 1. GENIOGLOSSAL MUSCLE ACTIVATION AND
PHARYNGEAL MECHANICS
Condition
Spontaneous breathing: Air
Tonic GGEMG
Peak GGEMG, % max
Phasic GGEMG, % max
Epiglottic pressure, cm H2O
Rph, peak flow cm H2O/L/s
Rsg, peak flow cm H2O/L/s
Slope, %max/cm H2O
Correlation
Spontaneous breathing: Heliox
Tonic GGEMG
Peak GGEMG, % max
Phasic GGEMG, % max
Epiglottic pressure, cm H2O
Rph, peak flow cm H2O/L/s
Rsg, peak flow cm H2O/L/s
Slope, %max/cm H2O
Correlation
Iron-lung ventilation
Tonic GGEMG
Peak GGEMG, % max
Phasic GGEMG, % max
Epiglottic pressure, cm H2O
Rph, peak flow cm H2O/L/s
Rsg, peak flow cm H2O/L/s
Slope, %max/cm H2O
Correlation
Control
Subjects
Patients with
OSA
p Value
3.06 0.46
6.43 1.35
2.32 0.59
1.80 0.14
0.85 0.20
1.72 0.25
0.63 0.15
0.73 0.09
6.02 1.15
10.96 1.41
4.85 0.69
3.57 0.46
3.02 0.60
4.00 0.88
0.69 0.11
0.69 0.07
0.016
0.034
0.023
0.001
0.003
0.009
0.767
0.665
2.89 0.42
5.62 1.33
2.12 0.59
1.35 0.11
0.56 0.11
1.09 0.24
0.86 0.21
0.76 0.07
5.68 1.46
9.67 1.89
3.94 0.66
3.06 0.27
2.34 0.35
3.35 0.43
0.67 0.11
0.75 0.04
0.050
0.087
0.060
0.001
0.001
0.001
0.370
0.872
3.02 0.52
7.10 1.14
4.08 1.08
6.31 0.68
1.64 0.41
4.11 0.55
0.72 0.14
0.81 0.10
6.11 0.92
17.47 2.52
11.35 2.16
9.58 1.63
4.45 0.73
9.34 2.21
0.82 0.05
0.91 0.13
0.006
0.001
0.005
0.057
0.002
0.017
0.571
0.215
Definition of abbreviations: GGEMG genioglossal electromyogram; OSA obstructive sleep apnea; Rph pharyngeal resistance; Rsg supraglottic resistance.
with sleep apnea and the control subjects (all p 0.10, data
not shown).
GGEMG/Epiglottic Pressure Relationship
Across all conditions, the genioglossal/inspiratory negative
pressure (GG/Pepi) relationship within breaths remained robust with statistically significant r values across all conditions
(r 0.69, p 0.05). An example of the consistency of this relationship is shown in Figure 1 for one patient with OSA and
Figure 1. The relationship between inspiratory epiglottic pressure and
genioglossal muscle activation in one patient with sleep apnea (top
panels) and one control subject (bottom panels). The conditions are (1)
spontaneous breathing, and (2) iron-lung breathing. The consistent
relationship between epiglottic pressure and genioglossal activation
across these conditions can be seen.
2027
one control subject during basal breathing and in the iron
lung. Furthermore, in both patients with OSA and control
subjects, the slope of the within-breath GG/Pepi relationship
was not statistically different between conditions, regardless
of the epiglottic pressure generated, resistance, airflow, or gas
density (ANOVA: control subjects, p 0.80; patients with
OSA: p 0.71; Table 1). Thus there was a constant relationship (slope) between GGEMG and epiglottic negative pressure across all conditions in both groups.
Contrary to our initial hypothesis, there was no significant
difference in the mean GGEMG/Pepi relationship between
patients with OSA and healthy control subjects (Figure 2 and
Table 1). In fact, the slope of this relationship in these two
groups was nearly identical under all conditions. Thus, the
higher peak phasic GGEMG seen in the apneic patients was
not due to an increased responsiveness to pharyngeal negative
pressure, but rather to the combination of a higher tonic
GGEMG and a greater phasic EMG as well with the increased phasic muscle activity being a product of greater intrapharyngeal negative pressure (higher resistance airway)
with a similar GGEMG/Pepi slope.
In both groups, mean peak epiglottic pressure across all
conditions (basal-breathing, heliox, iron lung ventilation, and
both levels of IRL) was strongly correlated (between-breath
analysis) with both phasic GGEMG and peak phasic
GGEMG in both patients with OSA and control subjects (Figure 3, between-breath relationships).
Air versus Heliox Breathing
During spontaneous breathing, there was a significant decrement in peak negative epiglottic pressure during heliox breathing in the group as a whole when compared with air breathing
(2.56 0.28 cm H2O versus 2.08 0.23 cm H2O, p 0.008)
(see online data supplement). This decreased epiglottic negative pressure was associated with an increase in peak inspiratory flow and a decrease in supraglottic resistance as expected.
In addition, a significant decrement in peak phasic and phasic
GGEMG were seen during heliox breathing (see online data
supplement). The greatest effect on upper airway resistance
during heliox was seen in supraglottic resistance, a finding that
is likely caused by a decrease in turbulent airflow in the nose
while breathing heliox.
Figure 2. The individual slopes of the GGEMG/Pepi within breath relationship as well as the mean slope ( SEM) during spontaneous
breathing is shown for patients with OSA and control subjects. There
were no statistically significant differences between patients with OSA
and control subjects, with considerable overlap between these two
groups.
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VOL 164
2001
Age-matched Data
Figure 3. The between-breath relationship between mean peak epiglottic pressure and mean peak phasic GGEMG for all conditions is
shown for patients with OSA (A) and control subjects (B). Each point
represents the mean ( SEM) GGEMG and epiglottic pressure for a
given condition. In both groups there is a tight correlation between
these variables.
Inspiratory Resistive Loading
During IRL, between-breath analysis revealed that in 14 of 18
subjects in whom data sets were available, there was a significant correlation between peak epiglottic pressure and peak
GGEMG (mean r values control subjects, 0.76 0.06; patients with OSA, 0.74 0.07; p NS between groups). Representative examples of the relationship between epiglottic pressure and peak GGEMG are shown in Figure 4. At an externally
applied load of 25 cm H2O/L/s, tonic, peak phasic, and phasic
GGEMG were all greater in the patients with sleep apnea
(Table 2). Induced pharyngeal pressure was also greater during loading in the apneic patients, as was pharyngeal and supraglottic resistance, although there was no difference in peak
inspiratory flow during loading (Table 2). There was no significant difference in the slope of the relationship between peak
epiglottic pressure and peak GGEMG between the two groups
(control subjects: slope, 0.72 0.19% max/cm H2O; patients
with OSA: slope, 0.90 0.21% max/cm H2O; p 0.54).
As the patients with sleep apnea were significantly older than
our control subjects, we performed a subgroup analysis in five
patients with OSA and five age-matched control subjects
(within 3 yr). The results were identical in this subgroup, and
they are shown for the basal breathing and the iron-lung conditions in Table 3. As for the group as a whole, tonic, phasic,
and peak phasic GGEMG were greater in the apneic patients
than in the aged-matched control subjects, as was peak epiglottic pressure and pharyngeal resistance. Although the magnitude
of the difference was the same in this subgroup, the findings
were occasionally no longer statistically significant, likely because of the small sample size (Table 3). Again, there was no
difference in the GGEMG/Pepi relationship between the two
groups (Table 3).
DISCUSSION
The findings of this study improve our understanding of pharyngeal motor control in normal persons and in patients with
OSA. First, we confirmed the finding that genioglossal muscle
activation is greater in the apneic patient during spontaneous
breathing than in the healthy control subject, and this increased activation is seen across a wide range of epiglottic
pressures and gas densities. This finding is consistent with the
observation that the pharyngeal airway of the apneic patient is
smaller and more collapsible, thus requiring higher dilator
muscle activation to maintain patency during wakefulness.
Contrary to our initial hypothesis, this increased dilator muscle activity in the patient with sleep apnea is not due to an increased responsiveness of the genioglossus to changes in pharyngeal pressure during inspiration. In fact, under all conditions, the
slope of the within-breath GGEMG/Pepi relationship was not
different in patients with OSA from that in control subjects. This
was true over a substantial range of pharyngeal negative pressures, both when this relationship was analyzed within breaths
and between breaths. It thus appears that the higher peak phasic
GGEMG seen in the apneic patient is due to a combination of
two factors. First, under all conditions, tonic GGEMG was
higher in the apneic patients. Second, as intrinsic upper airway
resistance was higher in the apneic patients, they generated
more negative intrapharyngeal pressures under all conditions,
which, in the face of an identical GGEMG/Pepi slope, yielded
increased phasic GGEMG. In both groups, we found that across
all conditions, phasic GGEMG was best correlated with peak
epiglottic pressure. Phasic genioglossal activity thus appears to
be regulated during inspiration largely by intrapharyngeal pressure on a moment-to-moment basis in both patients with sleep
apnea and control subjects, and this control mechanism is not intrinsically different in the apneic patient. All of these findings
TABLE 2. GENIOGLOSSAL ACTIVATION AND AIRWAY
MECHANICS (IRL)
Condition
(Load 25 cm H2O/L/s
Figure 4. The between-breath correlation between peak epiglottic
pressure and peak phasic GGEMG during inspiratory resistive loading in
two representative patients with sleep apnea (top panels) and two control subjects (bottom panels) is shown. Each point represents the averaged epiglottic pressure and GGEMG of the three trials of each load, as
well the three breaths immediately preceding the load (the baseline).
GG activation
Tonic GGEMG, % max
Peak GGEMG, % max
Phasic GGEMG, % max
Pharyngeal mechanics
Epiglottic pressure, cm H2O
Rph, peak flow cm H2O/L/s
Rsg, peak flow cm H2O/L/s
Peak inspiratory flow, L/s
Control
Subjects
Patients with
OSA
p Value
3.20 0.70
9.43 0.91
6.39 0.77
5.70 1.33
17.96 3.32
11.89 2.27
0.103
0.015
0.019
7.63 0.79
1.80 0.87
2.54 0.79
0.29 0.03
12.18 1.21
7.29 1.26
9.50 2.54
0.36 0.03
0.005
0.002
0.001
0.15
For definition of abbreviations, see Table 1.
Fogel, Malhotra, Pillar, et al.: Genioglossal Activation: Obstructive Sleep Apnea vs Controls
TABLE 3. AGED-MATCHED SUBGROUP ANALYSIS
Condition
Spontaneous breathing
Tonic GGEMG
Peak GGEMG, % max
Phasic GGEMG, % max
Epiglottic pressure, cm H2O
Rph, peak flow cm H2O/L/s
Rsg, peak flow cm H2O/L/s
Slope, %max/cm H2O
Correlation
Iron lung
Tonic GGEMG
Peak GGEMG, % max
Phasic GGEMG, % max
Epiglottic pressure, cm H2O
Rph, peak flow cm H2O/L/s
Rsg, peak flow cm H2O/L/s
Slope, %max/cm H2O
Correlation
Control
Subjects
Patients with
OSA
p Value
3.55 0.47
6.22 0.89
2.67 0.90
1.89 0.33
1.05 0.39
1.53 0.33
0.68 0.26
0.73 0.11
6.98 1.60
11.18 2.09
4.16 1.98
3.18 0.38
2.94 0.83
3.87 0.69
0.55 0.12
0.62 0.08
0.09
0.075
0.251
0.032
0.086
0.020
0.619
0.385
4.34 0.78
8.24 1.98
3.90 1.90
6.50 0.86
1.78 0.36
4.02 1.14
0.54 0.20
0.76 0.08
8.68 2.27
19.72 4.04
11.04 2.02
8.93 0.94
4.79 0.61
7.47 0.64
0.72 0.06
0.77 0.09
0.130
0.04
0.03
0.094
0.003
0.022
0.366
0.981
For definition of abbreviations, see Table 1.
would be consistent with the hypothesis that an anatomic abnormality (tissue characteristics, obesity, etc.) is the primary determinant of apnea pathogenesis, rather than altered pharyngeal
motor control.
Although inspiratory genioglossal activation was higher in
the patients with sleep apnea under all conditions, pharyngeal
and supraglottic resistance were higher as well. This finding
suggests that neuromuscular compensation is not complete.
However, this is not surprising and would be expected in any
physiologic control system. To compensate completely would
likely produce an unstable situation.
The increased tonic GGEMG seen in the apneic patients is
also of interest, although the mechanisms controlling tonic
GGEMG have not been well studied. In this study, tonic
GGEMG was constant across all conditions in both groups,
suggesting that it does not respond quickly to changes in pharyngeal pressure or airflow. However, it is possible that the increased tonic GGEMG seen in the apneic patient is a response
to chronically elevated upper airway pressures or resistance,
thus representing neural plasticity, which prevents complete
pharyngeal collapse during expiration. Other examples of neural plasticity clearly exist within the respiratory control system.
For example, chronic intermittent hypoxia leads to an upregulation of the hypoxic ventilatory response, a phenomenon
termed long-term facilitation (27). Neural plasticity thus represents permanent functional transformations that occur in
systems of neurons as a result of a chronic stimulus. In the setting of obstructive apnea, repetitive airway collapse or increased resistance could represent the stimulus for long-term
augmentation of tonic EMG. We have demonstrated previously that the EMG activity of a purely tonic pharyngeal muscle, the tensor palatini (TP), is increased in patients with sleep
apnea as well (28). If this increased tonic activity is the primary manifestation of neuromuscular compensation, it may
have important implications in the pathophysiology of OSA.
We have previously demonstrated a large decrement in the activity of a tonic upper airway dilator muscle (the tensor palatini) during sleep in normal subjects and a consistent, even
greater, rapid loss of activity in this muscle in apneic patients
(15). This is consistent with the observations of Orem and colleagues (29) who observed larger sleep-induced decrements in
the activity of respiratory neurons with less phasic activation
patterns when compared with those with more phasic ones.
2029
Thus, loss of basal tonic muscle activation plus the tonic neuromuscular compensation may importantly affect muscle performance during sleep.
Our study has several potential limitations that should be
recognized. First, all subjects may not have been completely
passive during iron-lung ventilation. However, we have previously shown that iron-lung ventilation leads to a loss of dilator
muscle preactivation prior to the onset of airflow in most subjects, and a decrement in surface diaphragmatic EMG, both of
which are consistent with the idea that brainstem premotor
output is decreased (24). However, even if subjects were not
passive in the iron lung, but rather were breathing synchronously with the ventilator, it would not substantially alter the
conclusions of this investigation, as the primary goal of ironlung ventilation was to increase the range of negative pressures that could be generated in the upper airway, rather than
decrease central drive. Second, in order to measure airflow
with variable gas densities, we have used the assumption that
flow through the pneumotachometer is purely laminar. Although some turbulence may exist in the Fleisch pneumotachometer within the range of flows measured in the present
study, we believe that any errors introduced by this assumption are small and unlikely to influence the conclusions of the
present study. Third, the methods we used to accomplish intersubject comparisons of EMG (% of maximum) could certainly be challenged. However, we have used this methodology for many years now, and have found the technique to be
reproducible within a given subject (14).
Finally we did not match our apneic patients and control
subjects for either BMI or age. To attempt a match for BMI
would have been difficult. Almost all middle-aged to older
men with a BMI 30 kg/m2 will snore or have some degree of
sleep apnea. Thus this was not attempted. To match for age
would have been desirable. For several reasons, we doubt that
the difference in age between patients and control subjects influenced our observations. First, in several previous studies we
have not observed an independent effect of age on either waking pharyngeal resistance or genioglossal activation/responsivity (30, 31). Second, in the subgroup of age-matched control
subjects and apneic patients in this study, the results were essentially identical to that for the groups as a whole. As a result, we doubt that age differences influenced our observations, although this possibility cannot be completely excluded.
In conclusion, we observed the relationship between pharyngeal negative pressure and inspiratory phasic genioglossal
muscle activation to be a tight one in both apneic patients and
normal control subjects across a wide range of breathing conditions both within and between breaths. In addition, the slope
of this relationship was identical between patients and control
subjects. The increased genioglossal activity seen in the apneic
patient therefore is a product of increased tonic genioglossal
activity and an increase in pharyngeal negative pressure during
inspiration. We hypothesize that the increased tonic GGEMG
represents long-term neuromuscular compensation, although
further investigation will be required to elucidate the mechanisms controlling this tonic genioglossal activity. Finally, loss
of the tonic EMG during sleep combined with reduced reflex
responsivity of the muscles may explain the decrement in
pharyngeal dilator muscle activation seen in patients with
sleep apnea at sleep onset, leading to airway collapse.
Acknowledgment: The writers thank Yvonne J. Gilreath for administrative
assistance.
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