Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea? Exp Physiol

Department of Comparative Biosciences, University of Wisconsin Madison, 2015 Linden Drive, Madison, WI 53706, USA.
Experimental Physiology (Impact Factor: 2.67). 02/2007; 92(1):27-37. DOI: 10.1113/expphysiol.2006.033720
Source: PubMed


Although neuroplasticity is an important property of the respiratory motor control system, its existence has been appreciated only in recent years and, as a result, its functional significance is not completely understood. The most frequently studied models of respiratory plasticity is respiratory long-term facilitation (LTF) following acute intermittent hypoxia and enhanced LTF following chronic intermittent hypoxia. Since intermittent hypoxia is a prominent feature of sleep-disordered breathing, LTF and/or enhanced LTF may compensate for factors that predispose to sleep-disordered breathing, particularly during obstructive sleep apnoea (OSA). Long-term facilitation has been studied most frequently in rats, and exhibits interesting properties consistent with a role in stabilizing breathing during sleep. Specifically, LTF: (1) is prominent in upper airway respiratory motor activity, suggesting that it stabilizes upper airways and maintains airway patency; (2) is most prominent during sleep in unanaesthetized rats; and (3) exhibits sexual dimorphism (greatest in young male and middle-aged female rats; smallest in middle-aged male and young female rats). Although these features are consistent with the hypothesis that upper airway LTF minimizes the prevalence of OSA in humans, there is little direct evidence for such an effect. Here we review advances in our understanding of LTF and its underlying mechanisms and present evidence concerning a potential role for LTF in maintaining upper airway patency, stabilizing breathing and preventing OSA in humans. Regardless of the relationship between LTF and OSA, a detailed understanding of cellular and synaptic mechanisms that underlie LTF may guide the development of new drugs to regulate upper airway tone, thereby offsetting the tendency for upper airway collapse characteristic of heavy snoring and OSA.

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Available from: Gordon Mitchell, Oct 13, 2014
    • "One approach to enhance respiratory function in SCI patients is to induce plasticity in spared synaptic pathways to respiratory motor neurons (Dale et al., 2014; Mitchell, 2007; Ramer et al., 2000). Moderate acute intermittent hypoxia (AIH) induces respiratory motor plasticity (Devinney et al., 2013; Feldman et al., 2003; Mahamed and Mitchell, 2007; Mitchell et al., 2001), strengthening synaptic inputs to phrenic motor neurons (Fuller et al., 2003; Golder and Mitchell, 2005; Lovett-Barr et al., 2012). The functional consequences of this plasticity are: 1) persistent increases in phrenic nerve activity in anesthetized rats (phrenic long-term facilitation, pLTF) (Bach and Mitchell, 1996); 2) diaphragm (diaLTF) and second thoracic external intercostal (T2 EIC LTF) muscle long-term facilitation in unanesthetized rats (Navarrete-Opazo and Mitchell, 2014); and 3) ventilatory LTF (largely tidal volume; vLTF) in unanesthetized rats (Nakamura et al., 2010; Olson et al., 2001) and humans (Pierchala et al., 2008; Tester et al., 2014). "
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    ABSTRACT: Unlabelled: A major cause of mortality after spinal cord injury is respiratory failure. In normal rats, acute intermittent hypoxia (AIH) induces respiratory motor plasticity, expressed as diaphragm (Dia) and second external intercostal (T2 EIC) long-term facilitation (LTF). Dia (not T2 EIC) LTF is enhanced by systemic adenosine 2A (A2A) receptor inhibition in normal rats. We investigated the respective contributions of Dia and T2 EIC to daily AIH-induced functional recovery of breathing capacity with/without A2A receptor antagonist (KW6002, i.p.) following C2 hemisection (C2HS). Rats received daily AIH (dAIH: 10, 5-min episodes, 10.5% O2; 5-min normoxic intervals; 7 successive days beginning 7days post-C2HS) or daily normoxia (dNx) with/without KW6002, followed by weekly (reminder) presentations for 8weeks. Ventilation and EMGs from bilateral diaphragm and T2 EIC muscles were measured with room air breathing (21% O2) and maximum chemoreceptor stimulation ( Mcs: 7% CO2, 10.5% O2). dAIH increased tidal volume (VT) in C2HS rats breathing room air (dAIH+vehicle: 0.47±0.02, dNx+vehicle: 0.40±0.01ml/100g; p<0.05) and MCS (dAIH+vehicle: 0.83±0.01, dNx+vehicle: 0.73±0.01ml/100g; p<0.001); KW6002 had no significant effect. dAIH enhanced contralateral (uninjured) diaphragm EMG activity, an effect attenuated by KW6002, during room air breathing and MCS (p<0.05). Although dAIH enhanced contralateral T2 EIC EMG activity during room air breathing, KW6002 had no effect. dAIH had no statistically significant effects on diaphragm or T2 EIC EMG activity ipsilateral to injury. Thus, two weeks post-C2HS: 1) dAIH enhances breathing capacity by effects on contralateral diaphragm and T2 EIC activity; and 2) dAIH-induced recovery is A2A dependent in diaphragm, but not T2 EIC. Daily AIH may be a useful in promoting functional recovery of breathing capacity after cervical spinal injury, but A2A receptor antagonists (e.g. caffeine) may undermine its effectiveness shortly after injury.
    No preview · Article · Feb 2015 · Experimental Neurology
    • "Hence, LG is both an inherent and induced trait, and both a cause and a consequence of OSA [45] [71] [72]. Although it has been suggested that IH induced V LTF and hLTF could potentially help protect against OSA [27] [141], several human studies do not support this, and have instead shown an increase in AHI and thus an exacerbation of OSA [109] [116] [127]. Due to ventilatory feedback in a poikilocapnic environment, V LTF reduces eupnoeic P ET CO 2 [119] and CO 2 reserve [21] [29], thereby increasing controller gain below eupnoea. "
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    ABSTRACT: Intermittent hypoxia and unstable breathing are key features of obstructive sleep apnoea (OSA), the most common pathological problem of breathing in sleep. Unstable ventilatory control is characterised by high loop gain (LG), and likely contributes to cyclical airway obstruction by promoting airway collapse during periods of low ventilatory drive. Potential new strategies to treat OSA include manipulations designed to lower LG. However, the contribution of inherent versus induced LG abnormalities in OSA remains unclear. Hence, a better understanding of the mechanisms causing high LG in OSA is needed to guide the design of LG based treatments. OSA patients exhibit abnormal chemoreflex control which contributes to increased LG. These abnormalities have been shown to normalise after continuous positive airway pressure treatment, suggesting induced rather than inherent trait abnormalities. Experimental intermittent hypoxia, mimicking OSA, increases hypoxic chemosensitivity and induces long term facilitation; a sustained increase in ventilatory neural output which outlasts the original stimulus. These neuroplastic changes induce the same abnormalities in chemoreflex control as seen in OSA patients. This review outlines the evidence to support that a key component of high LG in OSA is induced by intermittent hypoxia, and is reversed by simply preventing this inducing stimulus. Copyright © 2014 Elsevier Ltd. All rights reserved.
    No preview · Article · Oct 2014 · Sleep Medicine Reviews
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    • "On one hand, a high loop gain would be expected to increase robustly the output from the central pattern generator to the upper airway dilator muscles, which will in turn act to stiffen the airway, thereby preserving pharyngeal patency. Indeed, intermittent hypoxia can induce long-term facilitation, which may be one mechanism leading to increased upper airway motor tone in OSA patients during wakefulness (Mahamed & Mitchell, 2007; Mateika & Narwani, 2009). On the other hand, a high loop gain will also cause disproportionately large fluctuations in response to small disturbances in ventilation, which can contribute to upper airway compromise when output to these muscles is at its nadir. "

    Full-text · Article · Jul 2014 · The Journal of Physiology
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