Long-term facilitation of genioglossus activity is present in normal humans during NREM sleep

Abstract

Episodic hypoxia (EH) is followed by increased ventilatory motor output in the recovery period indicative of long-term facilitation (LTF). We hypothesized that episodic hypoxia evokes LTF of genioglossus (GG) muscle activity in humans during non-rapid eye movement sleep (NREM) sleep. We studied 12 normal non-flow limited humans during stable NREM sleep. We induced 10 brief (3 minute) episodes of isocapnic hypoxia followed by 5 minutes of room air. Measurements were obtained during control, hypoxia, and at 5, 10, 20, 30 and 40 minutes of recovery, respectively, for minute ventilation (V̇I), supraglottic pressure (P SG ), upper airway resistance (R UA ) and phasic GG electromyogram (EMG GG ). In addition, sham studies were conducted on room air. During hypoxia there was a significant increase in phasic EMG GG (202.7±24.1% of control, p<0.01) and in V̇I (123.0 ±3.3% of control, p<0.05); however, only phasic EMG GG demonstrated a significant persistent increase throughout recovery (198.9±30.9%, 203.6±29.9% and 205.4±26.4% of control, at 5, 10, and 20 minutes of recovery, respectively, p<0.01). In multivariate regression analysis, age and phasic EMG GG activity during hypoxia were significant predictors of EMG GG at recovery 20 minutes. No significant changes in any of the measured parameters were noted during sham studies. Conclusion: 1) EH elicits LTF of GG in normal non-flow limited humans during NREM sleep, without ventilatory or mechanical LTF. 2) GG activity during the recovery period correlates with the magnitude of GG activation during hypoxia, and inversely with age.

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

“…Ventilatory LTF (mediated by LTF of the phrenic nerve) has been observed in anesthetized cats (103,251) and rabbits (370), conscious dogs (44), ducks (256), and goats (399), in awake or in anesthetized mice and rats (14, 144, 292, 312, 395), and in awake or sleeping humans (12, 269, 407). In addition to LTF of the phrenic nerve, LTF has been reported in the vagal nerve in rats (383), in the hypoglossal nerve in cats (231), rats (104, 106, 243), and humans (48,141), and in the upper airway muscles in rats (289). …”

Experimental protocols and preparations to study respiratory long term facilitation

“…The vast majority of this work has been completed by Badr and colleagues (Babcock & Badr, 1998;Aboubakr et al , 2001;Shkoukani et al , 2002;Babcock et al , 2003;Rowley et al , 2007;Pierchala et al , 2008;Chowdhuri et al , 2008;Chowdhuri et al , 2010) (Table 1). In their initial study participants were exposed to 10 episodes of hypoxia that were 3 minutes in duration (Babcock & Badr, 1998).…”

“…Whether or not maintenance of carbon dioxide levels as a consequence of the shortened episodes or another mechanism linked to the reduction in episode duration was primarily responsible for this finding remains to be established. Nevertheless, it has now been recognized that vLTF or genioglossus LTF can be induced during sleep in both flow limited and non-flow limited individuals (Babcock & Badr, 1998;Aboubakr et al , 2001;Pierchala et al , 2008;Chowdhuri et al , 2008;Chowdhuri et al , 2010). …”

Glossopharyngeal long-term facilitation requires serotonin 5-HT2 and NMDA receptors in rats

“…Although LTF was not elicited in normal humans during wakefulness (McEvoy et al, 1996; Jordan et al, 2002), it was evident in the presence of elevated CO 2 levels (Harris et al, 2006; Wadhwa et al, 2008) or during NREM sleep (Chowdhuri et al, 2008; Pierchala et al, 2008). LTF was also elicited during NREM sleep in individuals with inspiratory flow limitation (e.g., snorers and OSA patients), mainly as a persistent decrease in upper airway resistance, a probable indication of upper airway dilatation due to motor output LTF of dilator muscles (Babcock and Badr, 1998; Aboubakr et al, 2001).…”