Motor-evoked potentials in the human upper and lower limb do not increase after single 30-min sessions of acute intermittent hypoxia.

Acute intermittent hypoxia (AIH) can induce sustained facilitation of motor output in people with spinal cord injury (SCI). Most studies of corticospinal tract excitability in humans have used 9% fraction inspired oxygen ([Formula: see text]) AIH (AIH-9%), with inconsistent outcomes. We investigated the effect of single sessions of 9% [Formula: see text] and 12% [Formula: see text] AIH (AIH-12%) on corticospinal excitability of a hand and leg muscle in able-bodied adults. Ten naïve participants completed three sessions on separate days comprising 15 epochs of 1 min of AIH-9%, AIH-12%, or sham (SHAM-21%) followed by 1 min of room air (21% [Formula: see text]) in a randomized crossover design. Motor-evoked potentials (MEPs; n = 30, ∼1 mV) elicited at rest by transcranial magnetic stimulation and maximal M-waves (Mmax) evoked by peripheral nerve stimulation were measured from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles at baseline and at ∼0, 20, 40, and 60 min post intervention. AIH-9% induced the greatest reduction in peripheral oxygen saturation (to 85% vs. 93% and 100% in AIH-12% and SHAM-21%, respectively; P < 0.001) and the greatest increase in ventilation [by 22% vs. 12% and -3% in AIH-9%, AIH-12%, and SHAM-21%, respectively (P < 0.001)]. There was no difference in MEP amplitudes (%Mmax) after any of the three conditions (AIH-9%, AIH-12%, SHAM-21%) for both the FDI (P = 0.399) and TA (P = 0.582). Despite greater cardiorespiratory changes during AIH-9%, there was no evidence of corticospinal facilitation (tested with MEPs) in this study. Further studies could explore variability in response to AIH between individuals and other methods to measure motor facilitation in people with and without spinal cord injuries.NEW & NOTEWORTHY This is the first study that tests whether acute intermittent hypoxia (AIH) induces motor output facilitation in humans after two different doses of AIH (9% and 12% [Formula: see text]) and the reproducibility of participant responses after a repeat AIH intervention at 9% AIH. There was no motor output facilitation in response to either dose of AIH. The results question the effectiveness of a single 30-min session of AIH in inducing motor output facilitation, tested in this way.

Respiratory-related evoked potentials in chronic obstructive pulmonary disease and healthy aging.

Altered neural processing and increased respiratory sensations have been reported in chronic obstructive pulmonary disease (COPD) as larger respiratory-related evoked potentials (RREPs), but the effect of healthy-aging has not been considered adequately. We tested RREPs evoked by brief airway occlusions in 10 participants with moderate-to-severe COPD, 11 age-matched controls (AMC) and 14 young controls (YC), with similar airway occlusion pressure stimuli across groups. Mean age was 76 years for COPD and AMC groups, and 30 years for the YC group. Occlusion intensity and unpleasantness was rated using the modified Borg scale, and anxiety rated using the Hospital Anxiety and Depression Scale. There was no difference in RREP peak amplitudes across groups, except for the N1 peak, which was significantly greater in the YC group than the COPD and AMC groups (p = 0.011). The latencies of P1, P2 and P3 occurred later in COPD versus YC (p < 0.05). P3 latency occurred later in AMC than YC (p = 0.024). COPD and AMC groups had similar Borg ratings for occlusion intensity (3.0 (0.5, 3.5) [Median (IQR)] and 3.0 (3.0, 3.0), respectively; p = 0.476) and occlusion unpleasantness (1.3 (0.1, 3.4) and 1.0 (0.75, 2.0), respectively; p = 0.702). The COPD group had a higher anxiety score than AMC group (p = 0.013). A higher N1 amplitude suggests the YC group had higher cognitive processing of respiratory inputs than the COPD and AMC groups. Both COPD and AMC groups showed delayed neural responses to the airway occlusion, which may indicate impaired processing of respiratory sensory inputs in COPD and healthy aging.

Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial.

BACKGROUND AND OBJECTIVE: Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes). METHODS: Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. RESULTS: The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (-26.6 ± 14.5 vs. -33.8 ± 20.3 cm H2 O, p = 0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. CONCLUSION: Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness.

Effects of hypnotics on obstructive sleep apnea endotypes and severity: Novel insights into pathophysiology and treatment.

Impaired upper airway anatomy is the main cause of obstructive sleep apnea (OSA). However, there are other important non-anatomical contributors or "endotypes" including ventilatory control instability, poor pharyngeal dilator muscle responsiveness and waking up too easily to minor respiratory events (low arousal threshold). Recent studies have focused on the potential to target specific OSA causes with novel treatments to reduce OSA severity and improve efficacy with existing non-CPAP therapies which are often suboptimal (e.g., mandibular advancement splints). One novel target is pharmacotherapy with hypnotics to increase the threshold for arousal and reduce OSA severity in the approximately 30% of patients who have a low arousal threshold endotype. This increasing body of work has produced varied and at times unexpected findings which have challenged previous knowledge on the effects of hypnotics on upper airway physiology and breathing during sleep in people with OSA. This review provides a concise overview of the latest research that has investigated the effects of common hypnotics/sedative agents on upper airway physiology and OSA severity and potential implications for OSA pathophysiology, treatment and safety. This includes a summary of the latest knowledge on the effects of hypnotics on OSA endotypes. Priorities for future research are also highlighted.

Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity.

KEY POINTS: A decreased respiratory arousal threshold is one of the main contributors to obstructive sleep apnoea (OSA) pathogenesis. Several recent studies have sought to find a drug capable of increasing the respiratory arousal threshold without impairing pharyngeal muscle activity to reduce OSA severity, with variable success. Here we show that zolpidem increases the respiratory arousal threshold by ∼15%, an effect size which was insufficient to systematically decrease OSA severity as measured by the apnoea-hypopnoea index. Unlike recent physiological findings that showed paradoxical increases in pharyngeal muscle responsiveness during transient manipulations of airway pressure, zolpidem did not alter pharyngeal muscle responsiveness during natural sleep. It did, however, increase sleep efficiency without changing apnoea length, oxygen desaturation, next-day perceived sleepiness and alertness. These novel findings indicate that zolpidem was well tolerated and effective in promoting sleep in people with OSA, which may be therapeutically useful for people with OSA and comorbid insomnia. ABSTRACT: A recent physiology study performed using continuous positive airway pressure (CPAP) manipulations indicated that the hypnotic zolpidem increases the arousal threshold and genioglossus responsiveness in people with and without obstructive sleep apnoea (OSA). Thus, zolpidem may stabilise breathing and reduce OSA severity without CPAP. Accordingly, we sought to determine the effects of zolpidem on OSA severity, upper airway physiology and next-day sleepiness and alertness. Nineteen people with OSA with low-to-moderate arousal threshold received 10 mg zolpidem or placebo according to a double-blind, randomised, cross-over design. Participants completed two overnight in-laboratory polysomnographies (1-week washout), with an epiglottic catheter, intramuscular genioglossus electromyography, nasal mask and pneumotachograph to measure OSA severity, arousal threshold and upper airway muscle responsiveness. Next-morning sleepiness and alertness were also assessed. Zolpidem did not change the apnoea-hypopnoea index versus placebo (40.6 ± 12.3 vs. 40.3 ± 16.4 events/h (means ± SD), p = 0.938) or nadir oxyhaemoglobin saturation (79.6 ± 6.6 vs. 79.7 ± 7.4%, p = 0.932), but was well tolerated. Zolpidem increased sleep efficiency by 9 ± 14% (83 ± 11 vs. 73 ± 17%, p = 0.010). Arousal threshold increased by 15 ± 5% with zolpidem throughout all sleep stages (p = 0.010), whereas genioglossus muscle responsiveness did not change. Next-morning sleepiness and alertness were not different between nights. In summary, a single night of 10 mg zolpidem is well tolerated and does not cause next-day impairment in alertness or sleepiness, or overnight hypoxaemia in OSA. However, despite increases in arousal threshold without any change in pharyngeal muscle responsiveness, zolpidem does not alter OSA severity. It does, however, increase sleep efficiency by ∼10%, which may be beneficial in people with OSA and insomnia.

Randomized Trial on the Effects of High-Dose Zopiclone on OSA Severity, Upper Airway Physiology, and Alertness.

BACKGROUND: Studies indicate that standard doses of hypnotics reduce or do not change the apnea-hypopnea index (AHI) or pharyngeal muscle activity. A 1-month trial of nightly zopiclone (7.5 mg) modestly reduced the AHI vs baseline without changing other sleep parameters or next-day sleepiness. RESEARCH QUESTION: This study aimed to determine the effects of high-dose zopiclone (15 mg) on AHI, arousal threshold, genioglossus muscle responsiveness, and next-day alertness in selected people with OSA (low to moderate arousal thresholds without major overnight hypoxemia). We hypothesized that high-dose zopiclone would yield greater increases in arousal threshold and therefore larger reductions in AHI but may come at the expense of increased hypoxemia and next-day impairment. STUDY DESIGN AND METHODS: Twenty-eight participants (AHI = 29 ± 20 events/h) suspected to have low to moderate arousal thresholds were studied during two in-laboratory polysomnographies, separated by 1 week, with an epiglottic pressure catheter and genioglossus intramuscular electrodes. Participants received 15 mg of zopiclone or placebo at each visit according to a double-blind, randomized, crossover design. Each morning, subjective sleepiness and alertness via a driving simulator task were assessed. RESULTS: The AHI did not change from placebo to zopiclone (-1.5 events/h; 95% CI, -6.6 to 3.5 events/h; P = .54). Arousal threshold, genioglossus muscle responsiveness, and most other sleep parameters and measures of next-day sleepiness and alertness also did not change with zopiclone. INTERPRETATION: A single night of treatment with high-dose zopiclone does not systematically reduce the AHI or increase the arousal threshold in selected people with OSA. The mechanisms for these unexpected findings require further investigation. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry; No.: ACTRN12617000988358; URL: https://www.anzctr.org.au.

Polysomnography with an epiglottic pressure catheter does not alter obstructive sleep apnea severity or sleep efficiency.

Pharyngeal and oesophageal manometry is used clinically and in research to quantify respiratory effort, upper-airway mechanics and the pathophysiological contributors to obstructive sleep apnea. However, the effects of this equipment on respiratory events and sleep in obstructive sleep apnea are unclear. As part of a clinical trial (ANZCTRN12613001106729), data from 28 participants who successfully completed a physiology night with an epiglottic catheter and nasal mask followed by a standard in-laboratory polysomnography were compared. The apnea-hypopnea index was not different during the physiology night versus standard polysomnography (22 ±â€…14 versus 23 ±â€…13 events per hr, p = 0.71). Key sleep parameters were also not different compared between conditions, including sleep efficiency (79 ±â€…13 versus 81 ±â€…11%, p = 0.31) and the arousal index (26 ±â€…11 versus 27 ±â€…11 arousals per hr, p = 0.83). There were, however, sleep stage distribution changes between nights with less N3 and rapid eye movement sleep and more N1 on the physiology night, with no difference in N2 (53 ±â€…15 versus 48 ±â€…9, p = 0.08). However, these changes did not increase next-day sleepiness. These findings indicate that while minor sleep stage distribution changes do occur towards lighter sleep, epiglottic manometry does not alter obstructive sleep apnea severity or sleep efficiency. Thus, epiglottic manometry can be used clinically and to collect detailed physiological information for research without major sleep disruption.

Effect of 1†month of zopiclone on obstructive sleep apnoea severity and symptoms: a randomised controlled trial.

Hypnotic use in obstructive sleep apnoea (OSA) is contraindicated due to safety concerns. Recent studies indicate that single-night hypnotic use worsens hypoxaemia in some and reduces OSA severity in others depending on differences in pathophysiology. However, longer clinical trial data are lacking. This study aimed to determine the effects of 1 month of zopiclone on OSA severity, sleepiness and alertness in patients with low-moderate respiratory arousal thresholds without major overnight hypoxaemia.69 participants completed a physiology screening night with an epiglottic catheter to quantify arousal threshold. 30 eligible patients (apnoea-hypopnoea index (AHI) 22±11 events·h-1) then completed standard in-laboratory polysomnography (baseline) and returned for two additional overnight sleep studies (nights 1 and 30) after receiving either nightly zopiclone (7.5 mg) or placebo during a 1-month, double-blind, randomised, parallel trial (ANZCTR identifier ANZCTRN12613001106729).The change in AHI from baseline to night 30 was not different between zopiclone versus placebo groups (-5.9±10.2 versus -2.4±5.5 events·h-1; p=0.24). Similarly, hypoxaemia, next-day sleepiness and driving simulator performance were not different.1 month of zopiclone does not worsen OSA severity, sleepiness or alertness in selected patients without major overnight hypoxaemia. As the first study to assess the effect of a hypnotic on OSA severity and sleepiness beyond single-night studies, these findings provide important safety data and insight into OSA pathophysiology.

Obstructive sleep apnea: current perspectives.

The prevalence of obstructive sleep apnea (OSA) continues to rise. So too do the health, safety, and economic consequences. On an individual level, the causes and consequences of OSA can vary substantially between patients. In recent years, four key contributors to OSA pathogenesis or "phenotypes" have been characterized. These include a narrow, crowded, or collapsible upper airway "anatomical compromise" and "non-anatomical" contributors such as ineffective pharyngeal dilator muscle function during sleep, a low threshold for arousal to airway narrowing during sleep, and unstable control of breathing (high loop gain). Each of these phenotypes is a target for therapy. This review summarizes the latest knowledge on the different contributors to OSA with a focus on measurement techniques including emerging clinical tools designed to facilitate translation of new cause-driven targeted approaches to treat OSA. The potential for some of the specific pathophysiological causes of OSA to drive some of the key symptoms and consequences of OSA is also highlighted.

Zopiclone Increases the Arousal Threshold without Impairing Genioglossus Activity in Obstructive Sleep Apnea.

STUDY OBJECTIVES: To determine the effects of the nonbenzodiazepine sedative zopiclone on the threshold to arousal with increasing respiratory effort and genioglossus muscle activity and to examine potential physiological factors mediating disparate effects of zopiclone on obstructive sleep apnea (OSA) severity between patients. METHODS: Twelve patients with OSA (apnea-hypopnea index = 41 ± 8 events/h) were studied during 2 single night sleep studies conducted approximately 1 w apart after receiving 7.5 mg of zopiclone or placebo according to a double-blind, placebo-controlled, randomized, crossover design. The respiratory arousal threshold (epiglottic pressure immediately prior to arousal during naturally occurring respiratory events), genioglossus activity and its responsiveness to pharyngeal pressure during respiratory events, and markers of OSA severity were compared between conditions. Genioglossus movement patterns and upper airway anatomy were also assessed via magnetic resonance imaging in a subset of participants (n = 7) during wakefulness. RESULTS: Zopiclone increased the respiratory arousal threshold versus placebo (-31.8 ± 5.6 versus -26.4 ± 4.6 cmH2O, P = 0.02) without impairing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure during respiratory events (-0.56 ± 0.2 versus -0.44 ± 0.1 %max/-cmH2O, P = 0.48). There was substantial interindividual variability in the changes in OSA severity with zopiclone explained, at least in part, by differences in pathophysiological characteristics including body mass index, arousal threshold, and genioglossus movement patterns. CONCLUSIONS: In a group of patients with predominantly severe OSA, zopiclone increased the arousal threshold without reducing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure. These properties may be beneficial in some patients with OSA with certain pathophysiological characteristics but may worsen hypoxemia in others. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au, trial ID: ACTRN12614000364673.