Electromyographic recordings in animal models indicate that tongue protrudor (genioglossus, GG) and retractor muscles (styloglossus, SG; hyoglossus, HG) are co-activated during inspiration (Yasui et al. 1993, Fregosi & Fuller, 1997. Moreover, recent experiments indicate that respiratory-related co-activation of protrudor and retractor muscles results in retraction of the tongue (Fregosi & Fuller, 1997;Fuller et al. 1998). The observation that tongue muscle co-activation causes retraction of the tongue implies that respiratory-related tongue-motor activity narrows, rather than dilates, the oropharynx. However, two groups of investigators have shown that co-activation of the protrudor and retractor muscles evoked by XIIth nerve stimulation results in increased inspiratory flow rates in obstructive sleep apnoea (OSA) patients, in spite of clear tongue retraction (Eisele et al. 1997;De Backer et al. 1998). Protrusion of the tongue, evoked by either medial XIIth nerve branch stimulation (Eisele et al. 1997) or direct GG muscle stimulation (Schwartz et al. 1996) is also associated with increased inspiratory flow rates in human subjects. These observations suggest that either co-activation of tongue protrudor and retractor muscles, or independent protrudor muscle activation will improve pharyngeal flow mechanics. This is in spite of the fact that the tongue retracts 1. The purpose of these experiments was to examine the mechanisms by which either coactivation or independent activation of tongue protrudor and retractor muscles influence upper airway flow mechanics. We studied the influence of selective hypoglossal (XIIth) nerve stimulation on tongue movements and flow mechanics in anaesthetized rats that were prepared with an isolated upper airway. In this preparation, both nasal and oral flow pathways are available. 2. Inspiratory flow limitation was achieved by rapidly lowering hypopharyngeal pressure (Php) with a vacuum pump, and the maximal rate of flow (ýI,max) and the nasopharyngeal pressure associated with flow limitation (Pcrit) were measured. These experimental trials were repeated while nerve branches innervating tongue protrudor (genioglossus; medial XIIth nerve branch) and retractor (hyoglossus and styloglossus; lateral XIIth nerve branch) muscles were stimulated either simultaneously or independently at frequencies ranging from 20-100 Hz. Co-activating the protrudor and retractor muscles produced tongue retraction, whereas independently activating the genioglossus resulted in tongue protrusion. 3. Co-activation of tongue protrudor and retractor muscles increased ýI,max (peak increase 44%, P < 0·05), made Pcrit more negative (peak decrease of 44%, P < 0·05), and did not change upstream nasopharyngeal resistance (Rn). Independent protrudor muscle stimulation increased ýI,max (peak increase 61%, P < 0·05), did not change Pcrit, and decreased Rn (peak decrease of 41%, P < 0·05). Independent retractor muscle stimulation did not significantly alter flow mechanics. Changes in Pcrit and ýI,max at all stimulation fr...

. A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol. J Appl Physiol 93: 1448-1456, 2002. First published June 14, 2002 10.1152/japplphysiol.00225.2002The A5 noradrenergic neurons are considered important for cardiorespiratory regulation. We hypothesized that A5 cells are silenced during rapid eye movement (REM) sleep, thereby contributing to cardiorespiratory changes and suppression of hypoglossal (XII) motoneuronal activity. We used an anesthetized, paralyzed, and artificially ventilated rat in which pontine microinjections of carbachol trigger signs of REM sleep, including hippocampal theta rhythm, motor suppression, and silencing of locus coeruleus neurons. All 16 putative noradrenergic A5 cells recorded were strongly suppressed when the REM sleep-like episodes were elicited and also after intravenous clonidine. Antidromic mapping showed that none of six neurons tested projected to the XII nucleus, whereas three of five projected to the nucleus of the solitary tract and two of four to the rostral ventrolateral medulla. Bilateral microinjections of clonidine into the A5 regions did not alter XII nerve activity. These data suggest that A5 neurons are silenced during natural REM sleep. This will lead to decreased norepinephrine release and may alter synaptic transmission in the nucleus of the solitary tract and rostral ventrolateral medulla without, however, a detectable impact on XII motoneurons. hypoglossal motoneurons; norepinephrine; nucleus of the solitary tract; pons; rapid eye movement sleep THE NOREPINEPHRINE-CONTAINING neurons of the A5 group, located in the ventrolateral pons between the root of the facial nerve and the superior olive, are considered important regulators of cardiorespiratory function (reviewed in Refs. 11,24,25,45,46). They have extensive axonal projections that include cardiorespiratory and motor regions of the brain stem and spinal cord (1,8,9,23,36). Through these projections, they may control, among others, sympathetic and respiratory outputs and, via projection to the hypoglossal (XII) motor nucleus, may mediate noradrenergic excitation of XII motoneurons (5,22,27,40,49). XII motoneurons are of particular interest because they innervate the genioglossus muscle of the tongue, an important airway dilator. Its decreased activity during sleep contributes, in predisposed individuals, to the pathophysiology of the obstructive sleep apnea syndrome (34).The noradrenergic neurons of the locus coeruleus (LC) and the sub-LC region show a robust relationship of their firing frequency with the sleep-wake cycle: the highest activity occurs during wakefulness, and the lowest during the rapid eye movement (REM) stage of sleep (6,43). Consistent with these findings, the extracellular level of norepinephrine is reduced in the XII nucleus during the motor atonia produced by electrical stimulation of the pontine reticular formation region implicated in the triggering of REM sleep (35). The noradrenergic cells of the A5 group may be similarly modulated with the sleep-wa...

Repeated electrical or hypoxic stimulation of peripheral chemoreceptors has been shown to cause a persistent poststimulus increase in respiratory motoneuron activity, termed long-term facilitation (LTF). LTF after episodic hypoxia has been demonstrated most consistently in anesthetized, vagotomized, paralyzed, artificially ventilated rats. Evidence for LTF in spontaneously breathing animals and humans after episodic hypoxia is equivocal and may have been influenced by the awake state of the subjects in these studies. The present study was designed to test the hypothesis that LTF is evoked in respiratory-related tongue muscle and inspiratory pump muscle activities after episodic hypoxia in 10 spontaneously breathing, anesthetized, vagotomized rats. The animals were exposed to three (5-min) episodes of isocapnic hypoxia, separated by 5 min of hyperoxia (50% inspired oxygen). Genioglossus, hyoglossus, and inspiratory intercostal EMG activities, along with respiratory-related tongue movements and esophageal pressure, were recorded before, during, and for 60 min after the end of episodic isocapnic hypoxia. We found no evidence for LTF in tongue muscle (genioglossus, hyoglossus) or inspiratory pump muscle (inspiratory intercostal) activities after episodic hypoxia. Rather, the primary poststimulus effect of episodic hypoxia was diminished respiratory frequency, which contributed to a reduction in ventilatory drive.

Rationale: Historically, respiratory-related research in sleep apnea has focused exclusively on the extrinsic tongue muscles (i.e., genioglossus, hyoglossus, and styloglossus). Until recently, the respiratory control and function of intrinsic tongue muscles (i.e., inferior and superior longitudinalis, transverses, and verticalis), which comprise the bulk of the tongue, were unknown. Objectives: The current study sought to determine if extrinsic and intrinsic tongue muscles are coactivated in conditions of hypoxemia comparable to that experienced by adults with obstructive sleep apnea. Measurements: Esophageal pressure and EMG activity of an extrinsic (hyoglossus) and an intrinsic (superior longitudinal) tongue muscle were studied in anesthetized, tracheotomized, spontaneously breathing rats. Average EMG activity was compared in a control gas condition (Pa O 2 , 160 Ϯ 12 mm Hg) and in mild isocapnic hypoxia (Pa O 2 , 69 Ϯ 7.2 mm Hg), with and without brief (3-breath) airway occlusions, pre-and postbilateral vagotomy. Main Results: (1 ) intrinsic and extrinsic tongue muscles are coactivated in mild hypoxia, (2 ) airway occlusion increased the activities of intrinsic retractor muscles in mild hypoxia, and (3 ) extrinsic retractor muscles have a steeper rate of rise of activity and an earlier burst onset relative to intrinsic retractor activities in mild hypoxia. Conclusions: These findings support our working hypothesis that airway patency is maintained not simply by activation of extrinsic tongue muscles but by the coactivation of intrinsic and extrinsic protrudor and retractor muscles. Keywords: EMG; hypoxia; sleep apneaThe tongue participates in a range of complex oromotor behaviors, including mastication, swallowing, and respiration. Functional deficits in tongue movement contribute to a host of disorders, including obstructive sleep apnea (1), dysarthria, and dysphagia (2-4). To date, studies that have examined the respiratoryrelated control of the tongue have focused primarily on the extrinsic tongue protrudor muscle, the genioglossus. As a result of this work, we know that the genioglossus is phasically active during the respiratory cycle and that its discharge onset precedes the onset of inspiratory airflow, stabilizing the airway for the negative pressure generated by the diaphragm (5-7). Although the genioglossus muscle is an important tongue muscle, it is only one of eight paired muscles that comprise the bulk of the tongue (8). Recent work in mammals has shown that the genioglossus and tongue retractor muscles are coactive in eupnea and hypercapnia (9-12), and that this coactivation improves pharyngeal airway patency (13,14). These findings confirm that numerous tongue muscles are involved in the maintenance of airway pat-(Received in original form November 19, 2004; accepted in final form March 12, 2005) Supported by the National Institutes of Health grants DC-05728 and HL-56876. Evidence of intrinsic tongue muscle activities in hypercapnia indicates that these muscles also have the potential to con...

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Our purpose was to determine the influence of posture and breathing route on electromyographic (EMG) activities of nasal dilator (NDM) and genioglossus (GG) muscles during exercise. Nasal and oral airflow rates and EMG activities of the NDM and GG were recorded in 10 subjects at rest and during upright and supine incremental cycling exercise to exhaustion. EMG activities immediately before and after the switch from nasal to oronasal breathing were also determined for those subjects who demonstrated a clear switch point (n = 7). NDM and GG EMG activities were significantly correlated with increases in nasal, oral, and total ventilatory rates during exercise, and these relationships were not altered by posture. In both upright and supine exercise, NDM activity rose more sharply as a function of nasal inspired ventilation compared with total or oral inspired ventilation (P< 0.01), but GG activity showed no significant breathing-route dependence. Peak NDM integrated EMG activity decreased (P = 0.008), and peak GG integrated EMG activity increased (P = 0.032) coincident with the switch from nasal to oronasal breathing. In conclusion, 1) neural drive to NDM and GG increases as a function of exercise intensity, but the increase is unaltered by posture; 2) NDM activity is breathing-route dependent in steady-state exercise, but GG activity is not; and 3) drive to both muscles changes significantly at the switch point, but the change in GG activity is more variable and is often transient. This suggests that factors other than the breathing route dominate drive to the GG soon after the initial changes in the configuration of the oronasal airway are made.

Tumor necrosis factor-alpha (TNF-alpha) causes pulmonary hypertension and arterial hypoxemia, but the mechanisms are unknown. We conducted two experiments to test the hypothesis that TNF-alpha alters pulmonary vascular reactivity, which in turn could cause either pulmonary hypertension or arterial hypoxemia. In experiment 1, rats were given acute or long-term injections of TNF-alpha (recombinant human) in vivo. Rats treated acutely received either saline or TNF-alpha (40 micrograms/kg iv in saline) 3 min (TNF-3 min; n = 8), 20 min (TNF-20 min; n = 8), or 24 h (TNF-24 h; n = 5) before the lungs were isolated. Rats treated chronically received injections of either saline or TNF-alpha (250 micrograms/kg ip in saline) two times per day for 7 days (TNF-7 days; n = 9). Lungs were isolated and perfused with Earle's salt solution (+2 g/l NaHCO3 + 4 g/100 ml Ficoll), and vascular reactivity was tested with acute hypoxia (3 min; 3% O2) and angiotensin II (ANG II; 0.025-0.40 micrograms). Pulmonary pressor responses to hypoxia were greater (P less than 0.05) in TNF-20 min and TNF-7 day groups. ANG II responses were increased (P less than 0.05) in TNF-7 day rats. In experiment 2, lungs were isolated and perfused and received direct pulmonary arterial injections of TNF-alpha (0.2, 2.0, and 20 micrograms) or saline, after stable responses to hypoxia and ANG II (0.10 microgram) were attained. Reactivity was not different between control and TNF-alpha rats before the injections, but TNF-alpha increased (P less than 0.05) responses to hypoxia and ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)

The velopharynx is the most collapsible segment of the upper airway in patients with obstructive sleep apnea. However, we do not know if velopharyngeal compliance is uniform throughout its length, or if compliance is modified by contraction of upper airway muscles. We tested the hypothesis that rostral and caudal velopharyngeal (VP) compliance differs, and that tongue muscle contraction reduces compliance. High-resolution MR images of the VP were made at nasopharyngeal pressures ranging from -9 to 9 cmH(2)O in anesthetized rats. Images were obtained twice at each pressure, once with and once without bilateral hypoglossal nerve stimulation. The volume of the caudal and rostral VP was computed at each pressure. The caudal VP was significantly (P = 0.0058) more compliant than the rostral VP, but electrical stimulation of the tongue muscles did not change compliance. VP critical pressure (Pcrit; pressure at zero airway volume) averaged -25.2 and -12.1 cmH(2)O in the rostral and caudal VP, respectively (P < 0.0001). Coactivation of tongue protrudor and retractor muscles or contraction of protrudor muscles alone dilated the VP and made Pcrit more negative (P < 0.0001), but only in the caudal VP. In the rat, the caudal VP is more collapsible than the rostral VP, and either coactivation of tongue protrudor and retractor muscles or contraction of protrudor muscles alone makes this region more difficult to close. Thus, tongue muscle contraction protects the caudal VP, which appears to be a particularly vulnerable segment of the nasopharyngeal airway. With suitable modification, the methods described here, including tongue muscle stimulation at different pharyngeal pressures, may be appropriate for experiments in human subjects.