The Clinical Relevance of Autonomic Dysfunction, Cerebral Hemodynamics, and Sleep Interactions in Individuals Living With SCI.

A myriad of physiological impairments is seen in individuals after a spinal cord injury (SCI). These include altered autonomic function, cerebral hemodynamics, and sleep. These physiological systems are interconnected and likely insidiously interact leading to secondary complications. These impairments negatively influence quality of life. A comprehensive review of these systems, and their interplay, may improve clinical treatment and the rehabilitation plan of individuals living with SCI. Thus, these physiological measures should receive more clinical consideration. This special communication introduces the under investigated autonomic dysfunction, cerebral hemodynamics, and sleep disorders in people with SCI to stakeholders involved in SCI rehabilitation. We also discuss the linkage between autonomic dysfunction, cerebral hemodynamics, and sleep disorders and some secondary outcomes are discussed. Recent evidence is synthesized to make clinical recommendations on the assessment and potential management of important autonomic, cerebral hemodynamics, and sleep-related dysfunction in people with SCI. Finally, a few recommendations for clinicians and researchers are provided.

The hypoxic ventilatory response and hypoxic burden are predictors of the magnitude of ventilatory long-term facilitation in humans.

Mild intermittent hypoxia initiates progressive augmentation (PA) and ventilatory long-term facilitation (vLTF) in humans. The magnitude of these forms of plasticity might be influenced by anthropometric and physiological variables, as well as protocol elements. However, the impact of many of these variables on the magnitude of respiratory plasticity has not been established in humans. A meta-analysis was completed using anthropometric and physiological variables obtained from 124 participants that completed one of three intermittent hypoxia protocols. Simple correlations between the aggregate variables and the magnitude of PA and vLTF standardized to baseline was completed. Thereafter, the variables correlated to PA or vLTF were input into a multilinear regression equation. Baseline measures of the hypoxic ventilatory response was the sole predictor of PA (R = 0.370, P = 0.012). Similarly, this variable along with the hypoxic burden predicted the magnitude of vLTF (R = 0.546, P < 0.006 for both variables). In addition, the magnitude of PA was strongly correlated to vLTF (R = 0.617, P < 0.001). Anthropometric measures do not predict the magnitude of PA and vLTF in humans. Alternatively, the hypoxic ventilatory response was the sole predictor of PA, and in combination with the hypoxic burden, predicted the magnitude of vLTF. These influences should be considered in the design of mild intermittent hypoxia protocol studies in humans. Moreover, the strong correlation between PA and vLTF suggests that a common mechanistic pathway may have a role in the initiation of these forms of plasticity. KEY POINTS: Mild intermittent hypoxia initiates progressive augmentation (PA) and ventilatory long-term facilitation (vLTF) in humans. Many of the anthropometric and physiological variables that could impact the magnitude of these forms of plasticity are unknown. Anthropometric and physiological variables were measured from a total of 124 participants that completed one of three distinct intermittent hypoxia protocols. The variables correlated to PA or vLTF were input into a multilinear regression analysis. The hypoxic ventilatory response was the sole predictor of PA, while this variable in addition to the average hypoxic burden predicted the magnitude of vLTF. A strong correlation between PA and vLTF was also revealed. These influences should be considered in the design of mild intermittent hypoxia protocol studies in humans. Moreover, the strong correlation between PA and vLTF suggests that a common mechanistic pathway may have a role in the initiation of these forms of plasticity.

Daily Exposure to Mild Intermittent Hypoxia Reduces Blood Pressure in Male Patients with Obstructive Sleep Apnea and Hypertension.

Rationale: Daily exposure to mild intermittent hypoxia (MIH) may elicit beneficial cardiovascular outcomes. Objectives: To determine the effect of 15 days of MIH and in-home continuous positive airway pressure treatment on blood pressure in participants with obstructive sleep apnea and hypertension. Methods: We administered MIH during wakefulness 5 days/week for 3 weeks. The protocol consisted of twelve 2-minute bouts of hypoxia interspersed with 2 minutes of normoxia. End-tidal carbon dioxide was maintained 2 mm Hg above baseline values throughout the protocol. Control participants were exposed to a sham protocol (i.e., compressed air). All participants were treated with continuous positive airway pressure over the 3-week period. Results are mean ± SD. Measurements and Main Results: Sixteen male participants completed the study (experimental n = 10; control n = 6). Systolic blood pressure at rest during wakefulness over 24 hours was reduced after 15 days of MIH (142.9 ± 8.6 vs. 132.0 ± 10.7 mm Hg; P < 0.001), but not following the sham protocol (149.9 ± 8.6 vs. 149.7 ± 10.8 mm Hg; P = 0.915). Thus, the reduction in blood pressure from baseline was greater in the experimental group compared with control (-10.91 ± 4.1 vs. -0.17 ± 3.6 mm Hg; P = 0.003). Modifications in blood pressure were accompanied by increased parasympathetic and reduced sympathetic activity in the experimental group, as estimated by blood pressure and heart rate variability analysis. No detrimental neurocognitive and metabolic outcomes were evident following MIH. Conclusions: MIH elicits beneficial cardiovascular and autonomic outcomes in males with OSA and concurrent hypertension. Clinical trial registered with www.clinicaltrials.gov (NCT03736382).

Exposure to mild intermittent hypoxia increases loop gain and the arousal threshold in participants with obstructive sleep apnoea.

KEY POINTS: Repeated daily mild intermittent hypoxia has been endorsed as a therapy to promote the recovery of respiratory and limb motor dysfunction. One possible side-effect of this therapy is an increase in apnoeic event number and duration, which is particularly relevant to participants with motor disorders coupled with an increased incidence of sleep apnoea. In this study, we report that increases in apnoeic event number and duration, following exposure to daily intermittent hypoxia, are the result of an increase in respiratory loop gain and the arousal threshold, in participants with obstructive sleep apnoea. Daily exposure to mild intermittent hypoxia also led to an increase in the ventilatory response to arousal. Accordingly, individuals with motor disorders receiving mild intermittent hypoxia as a therapy should be screened for the presence of sleep apnoea, and if present, administration of intermittent hypoxia during hours of wakefulness should be combined with continuous positive airway pressure treatment during sleep. ABSTRACT: We determined if exposure to mild intermittent hypoxia (MIH) causes an increase in loop gain (LG) and the arousal threshold (AT) during non-rapid eye movement (NREM) sleep. Male participants with obstructive sleep apnoea (apnoea-hypopnoea index > 5 events/h), matched for age, body mass index and race were divided into two groups (n = 13 in each group). Following a baseline sleep study, one group was exposed to twelve 4-min episodes of hypoxia each day for 10 days and the other group to a sham protocol (SP). On Days 1 and 10, a sleep study was completed following exposure to MIH or the SP. For each sleep study, LG and the AT were measured during NREM sleep, using a model-based approach, and expressed as a fraction of baseline measures. LG increased after exposure to MIH (Day 1: 1.11 ± 0.03, P = 0.002, Day 10: 1.17 ± 0.05, P = 0.001), but not after the SP (Day 1: 1.03 ± 0.04, P = 1.0, Day 10: 1.0 ± 0.02, P = 1.0). AT also increased after exposure to MIH (Day 1: 1.13 ± 0.05, P = 0.01, Day 10: 1.19 ± 0.08, P = 0.05) but not after the SP (Day 1: 1.04 ± 0.05, P = 0.6, Day 10: 0.96 ± 0.04, P = 1.0). Our results might account for increases in apnoea frequency and duration previously observed during NREM sleep following exposure to MIH. Our results also have implications for the use of MIH as a therapeutic modality.

The sleep-wake cycle and motor activity, but not temperature, are disrupted over the light-dark cycle in mice genetically depleted of serotonin.

We examined the role that serotonin has in the modulation of sleep and wakefulness across a 12-h:12-h light-dark cycle and determined whether temperature and motor activity are directly responsible for potential disruptions to arousal state. Telemetry transmitters were implanted in 24 wild-type mice (Tph2(+/+)) and 24 mice with a null mutation for tryptophan hydroxylase 2 (Tph2(-/-)). After surgery, electroencephalography, core body temperature, and motor activity were recorded for 24 h. Temperature for a given arousal state (quiet and active wake, non-rapid eye movement, and paradoxical sleep) was similar in the Tph2(+/+) and Tph2(-/-) mice across the light-dark cycle. The percentage of time spent in active wakefulness, along with motor activity, was decreased in the Tph2(+/+) compared with the Tph2(-/-) mice at the start and end of the dark cycle. This difference persisted into the light cycle. In contrast, the time spent in a given arousal state was similar at the remaining time points. Despite this similarity, periods of non-rapid-eye-movement sleep and wakefulness were less consolidated in the Tph2(+/+) compared with the Tph2(-/-) mice throughout the light-dark cycle. We conclude that the depletion of serotonin does not disrupt the diurnal variation in the sleep-wake cycle, motor activity, and temperature. However, serotonin may suppress photic and nonphotic inputs that manifest at light-dark transitions and serve to shorten the ultraradian duration of wakefulness and non-rapid-eye-movement sleep. Finally, alterations in the sleep-wake cycle following depletion of serotonin are unrelated to disruptions in the modulation of temperature.

Long-term facilitation of ventilation in humans with chronic spinal cord injury.

RATIONALE: Intermittent stimulation of the respiratory system with hypoxia causes persistent increases in respiratory motor output (i.e., long-term facilitation) in animals with spinal cord injury. This paradigm, therefore, has been touted as a potential respiratory rehabilitation strategy. OBJECTIVES: To determine whether acute (daily) exposure to intermittent hypoxia can also evoke long-term facilitation of ventilation after chronic spinal cord injury in humans, and whether repeated daily exposure to intermittent hypoxia enhances the magnitude of this response. METHODS: Eight individuals with incomplete spinal cord injury (>1 yr; cervical [n = 6], thoracic [n = 2]) were exposed to intermittent hypoxia (eight 2-min intervals of 8% oxygen) for 10 days. During all exposures, end-tidal carbon dioxide levels were maintained, on average, 2 mm Hg above resting values. Minute ventilation, tidal volume, and breathing frequency were measured before (baseline), during, and 30 minutes after intermittent hypoxia. Sham protocols consisted of exposure to room air and were administered to a subset of the participants (n = 4). MEASUREMENTS AND MAIN RESULTS: Minute ventilation increased significantly for 30 minutes after acute exposure to intermittent hypoxia (P < 0.001), but not after sham exposure. However, the magnitude of ventilatory long-term facilitation was not enhanced over 10 days of intermittent hypoxia exposures. CONCLUSIONS: Ventilatory long-term facilitation can be evoked by brief periods of hypoxia in humans with chronic spinal cord injury. Thus, intermittent hypoxia may represent a strategy for inducing respiratory neuroplasticity after declines in respiratory function that are related to neurological impairment. Clinical trial registered with www.clinicaltrials.gov (NCT01272011).

Racial differences in upper airway collapsibility and loop gain in young adult males.

STUDY OBJECTIVES: Previous studies reported that the apnea-hypopnea index was similar in young adult Black and White participants. However, whether this similarity reflects an analogous combination of apneas and hypopneas is unknown. Likewise, the physiological mechanisms underlying this similarity has not been explored. METHODS: 60 Black and 48 White males completed the study. After matching for age and body mass index, 41 participants remained in each group. All participants completed a sleep study. Subsequently, standard sleep indices along with loop gain and the arousal threshold were determined. In addition, airway collapsibility (24 of 60 and 14 of 48 participants) and the hypoxic ventilatory response during wakefulness (30 of 60 and 25 of 48 participants) was measured. RESULTS: The apnea-hypopnea index was similar in Blacks and Whites (p = .140). However, the index was comprised of more apneas (p = .014) and fewer hypopneas (p = .025) in Black males. These modifications were coupled to a reduced loop gain (p = .0002) and a more collapsible airway (p = .030). These differences were independent of whether or not the groups were matched. For a given hypoxic response, loop gain was reduced in Black compared to White males (p = .023). CONCLUSIONS: Despite a similar apnea-hypopnea index, more apneas and fewer hypopneas were evident in young adult Black compared to White males. The physiological mechanisms that contribute to these events were also different between groups. Addressing these differences may be important when considering novel therapeutic approaches to eliminate apnea in Black and White participants.

Divergent Ventilatory and Blood Pressure Responses are Evident Following Repeated Daily Exposure to Mild Intermittent Hypoxia in Males with OSA and Hypertension.

Introduction: Resting minute ventilation and ventilation during and following hypoxia may be enhanced following daily exposure to mild intermittent hypoxia (MIH). In contrast, resting systolic blood pressure (SBP) is reduced following daily exposure to MIH. However, it is presently unknown if the reduction in resting SBP following daily exposure, is coupled with reduced SBP responses during and after acute exposure to MIH. Methods: Participants with obstructive sleep apnea (OSA) and hypertension (n = 10) were exposed to twelve 2-min bouts of MIH (oxygen saturation-87%)/day for 15 days. A control group (n = 6) was exposed to a sham protocol during which compressed air (i.e., FIO2 = 0.21) was inspired in place of MIH. Results: The hypoxic ventilatory response (HVR) and hypoxic systolic blood pressure response (HSBP) increased from the first to the last hypoxic episode on the initial (HVR: 0.08 ± 0.02 vs. 0.13 ± 0.02 L/min/mmHg, p = 0.03; HSBP: 0.13 ± 0.04 vs. 0.37 ± 0.06 mmHg/mmHg, p < 0.001) and final (HVR: 0.10 ± 0.01 vs. 0.15 ± 0.03 L/min/mmHg, p = 0.03; HSBP: 0.16 ± 0.03 vs. 0.41 ± 0.34 mmHg/mmHg, p < 0.001) day. The magnitude of the increase was not different between days (p ≥ 0.83). Following exposure to MIH, minute ventilation and SBP was elevated compared to baseline on the initial (MV: 16.70 ± 1.10 vs. 14.20 ± 0.28 L/min, p = 0.01; SBP: 167.26 ± 4.43 vs. 151.13 ± 4.56 mmHg, p < 0.001) and final (MV: 17.90 ± 1.25 vs. 15.40 ± 0.77 L/min, p = 0.01; SBP: 156.24 ± 3.42 vs. 137.18 ± 4.17 mmHg, p < 0.001) day. The magnitude of the increases was similar on both days (MV: 3.68 ± 1.69 vs. 3.22 ± 1.27 L/min, SBP: 14.83 ± 2.64 vs. 14.28 ± 1.66 mmHg, p ≥ 0.414). Despite these similarities, blood pressure at baseline and at other time points during the MIH protocol was reduced on the final compared to the initial day (p ≤ 0.005). Conclusion: The ventilatory and blood pressure responses during and following acute MIH were similar on the initial and final day of exposure. Alternatively, blood pressure was down regulated, while ventilation was similar at all time points (i.e., baseline, during and following MIH) after daily exposure to MIH.

The effect of brain serotonin deficiency on breathing is magnified by age.

Serotonin is an important mediator modulating behavior, metabolism, sleep, control of breathing, and upper airway function, but the role of aging in serotonin-mediated effects has not been previously defined. Our study aimed to examine the effect of brain serotonin deficiency on breathing during sleep and metabolism in younger and older mice. We measured breathing during sleep, hypercapnic ventilatory response (HCVR), CO2 production (VCO2 ), and O2 consumption (VO2 ) in 16-18-week old and 40-44-week old mice with deficiency of tryptophan hydroxylase 2 (Tph2), which regulates serotonin synthesis specifically in neurons, compared to Tph2+/+ mice. As expected, aging decreased VCO2 and VO2 . Tph2 knockout resulted in an increase in both metabolic indexes and no interaction between age and the genotype was observed. During wakefulness, neither age nor genotype had an effect on minute ventilation. The genotype did not affect hypercapnic sensitivity in younger mice. During sleep, Tph2-/- mice showed significant decreases in maximal inspiratory flow in NREM sleep, respiratory rate, and oxyhemoglobin saturation in REM sleep, compared to wildtype, regardless of age. Neither serotonin deficiency nor aging affected the frequency of flow limited breaths (a marker of upper airway closure) or apneas. Serotonin deficiency increased the amount and efficiency of sleep only in older animals. In conclusion, younger Tph2-/- mice were able to defend their ventilation and phenotypically did not differ from wildtype during wakefulness. In contrast, both young and old Tph2-/- mice showed sleep-related hypoventilation, which was manifested by hypoxemia during REM sleep.

Increased propensity for central apnea in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure.

RATIONALE: There is increasing evidence of increased ventilatory instability in patients with obstructive sleep apnea (OSA), but previous investigations have not studied whether the hypocapnic apneic threshold is altered in this group. OBJECTIVES: To compare the apneic threshold, CO2 reserve, and controller gain between subjects with and without OSA matched for age, sex, and body mass index. METHODS: Hypocapnia was induced via nasal mechanical ventilation for 3 minutes. Cessation of mechanical ventilation resulted in hypocapnic central hypopnea or apnea depending upon the magnitude of the hypocapnia. The apnea threshold (Pet(CO2)-AT) was defined as the measured Pet(CO2) at which the apnea closest to the last hypopnea occurred. The CO2 reserve was defined as the change in Pet(CO2) between eupneic Pet(CO2) and Pet(CO2)-AT. Controller gain was defined as the ratio of change in Ve between control and hypopnea or apnea to the DeltaPet(CO2). MEASUREMENTS AND MAIN RESULTS: Eleven pairs of subjects were studied. There was no difference in the Pet(CO2)-AT between the two groups. However, the CO2 reserve was smaller in the subjects with OSA (2.2 +/- 0.6 mm Hg) compared with the control subjects (4.5 +/- 1.4 mm Hg; P < 0.001). The controller gain was increased in the subjects with OSA (3.7 +/- 1.3 L/min/mm Hg) compared with the control subjects (1.6 +/- 0.5 L/min/mm Hg; P < 0.001). Controller gain decreased and CO2 reserve increased in seven subjects restudied after using continuous positive airway pressure for 1 month. CONCLUSIONS: Ventilatory instability is increased in subjects with OSA and is reversible with the use of continuous positive airway pressure.

Pathophysiology of Obstructive Sleep Apnea in Aging Women.

The following review is designed to explore the pathophysiology of sleep apnea in aging women. The review initially introduces four endotypes (i.e., a more collapsible airway, upper airway muscle responsiveness, arousal threshold, and loop gain) that may have a role in the initiation of obstructive sleep apnea. Thereafter, sex differences in the prevalence of sleep apnea are considered along with differences in the prevalence that exist between younger and older women. Following this discussion, we consider how each endotype might contribute to the increase in prevalence of sleep apnea in aging women. Lastly, we address how modifications in one form of respiratory plasticity, long-term facilitation, that might serve to mitigate apneic events in younger women may be modified in aging women with obstructive sleep apnea. Overall, the published literature indicates that the prevalence of sleep apnea is increased in aging women. This increase is linked primarily to a more collapsible airway and possibly to reduced responsiveness of upper airway muscle activity. In contrast, modifications in loop gain or the arousal threshold do not appear to have a role in the increased prevalence of sleep apnea in aging women. Moreover, we suggest that mitigation of long-term facilitation could contribute to the increased prevalence of sleep apnea in aging women.

A comprehensive review of respiratory, autonomic and cardiovascular responses to intermittent hypoxia in humans.

This review explores forms of respiratory and autonomic plasticity, and associated outcome measures, that are initiated by exposure to intermittent hypoxia. The review focuses primarily on studies that have been completed in humans and primarily explores the impact of mild intermittent hypoxia on outcome measures. Studies that have explored two forms of respiratory plasticity, progressive augmentation of the hypoxic ventilatory response and long-term facilitation of ventilation and upper airway muscle activity, are initially reviewed. The role these forms of plasticity might have in sleep disordered breathing are also explored. Thereafter, the role of intermittent hypoxia in the initiation of autonomic plasticity is reviewed and the role this form of plasticity has in cardiovascular and hemodynamic responses during and following intermittent hypoxia is addressed. The role of these responses in individuals with sleep disordered breathing and spinal cord injury are subsequently addressed. Ultimately an integrated picture of the respiratory, autonomic and cardiovascular responses to intermittent hypoxia is presented. The goal of the integrated picture is to address the types of responses that one might expect in humans exposed to one-time and repeated daily exposure to mild intermittent hypoxia. This form of intermittent hypoxia is highlighted because of its potential therapeutic impact in promoting functional improvement and recovery in several physiological systems.

Variations in loop gain and arousal threshold during NREM sleep are affected by time of day over a 24-hour period in participants with obstructive sleep apnea.

We investigated whether time of day affects loop gain (LG) and the arousal threshold (AT) during non-rapid eye movement (NREM) sleep. Eleven men with obstructive sleep apnea (apnea-hypopnea index > 5 events/h) completed a constant-routine protocol that comprised 3-h sleep sessions in the evening [10 PM (1) to 1 AM], morning (6 AM to 9 AM), afternoon (2 PM to 5 PM), and subsequent evening [10 PM (2) to 1 AM]. During each sleep session LG and the AT were measured during NREM sleep with a model-based approach. Our results showed the presence of a rhythmicity in both LG (P < 0.0001) and the AT (P < 0.001) over a 24-h period. In addition, LG and the AT were greater in the morning compared with both evening sessions [6 AM vs. 10 PM (1) vs. 10 PM (2): LG (1 cycle/min): 0.71 ± 0.23 vs. 0.60 ± 0.22 (P = 0.01) vs. 0.56 ± 0.10 (P < 0.001), AT (fraction of eupneic breathing): 1.45 ± 0.47 vs. 1.28 ± 0.36 (P = 0.02) vs. 1.20 ± 0.18 (P = 0.001)]. No difference in LG and the AT existed between the evening sessions (LG: P = 0.27; AT: P = 0.24). LG was correlated to measures of the hypocapnic ventilatory response (i.e., a measure of chemoreflex sensitivity) (r = 0.72 and P = 0.045) and the critical closing pressure (i.e., a measure of airway collapsibility) (r = 0.77 and P = 0.02) that we previously published. We conclude that time of day, independent of hallmarks of sleep apnea, affects LG and the AT during NREM sleep. These modifications may contribute to increases in breathing instability in the morning compared with other periods throughout the day/night cycle in individuals with obstructive sleep apnea. In addition, efficaciousness of treatments for obstructive sleep apnea that target LG and the AT may be modified by a rhythmicity in these variables.NEW & NOTEWORTHY Loop gain and the arousal threshold during non-rapid eye movement (NREM) sleep are greater in the morning compared with the afternoon and evening. Loop gain measures are correlated to chemoreflex sensitivity and the critical closing pressure measured during NREM sleep in the evening, morning, and afternoon. Breathing (in)stability and efficaciousness of treatments for obstructive sleep apnea may be modulated by a circadian rhythmicity in loop gain and the arousal threshold.

Effect of virtual reality-simulated exercise on sympathovagal balance.

Discovery of therapeutic avenues to provide the benefits of exercise to patients with enforced sedentary behavior patterns would be of transformative importance to health care. Work in model organisms has demonstrated that benefits of exercise can be provided to stationary animals by daily intermittent stimulation of adrenergic signaling. Here, we examine as a proof of principle whether exposure of human participants to virtual reality (VR) simulation of exercise can alter sympathovagal balance in stationary humans. In this study, 24 participants performed 15 minutes of cycling exercise at standardized resistance, then repeated the exercise with a virtual reality helmet that provided an immersive environment. On a separate day, they each controlled a virtual environment for 15 minutes to simulate exercise without actual cycling exercise. Response to each treatment was assessed by measuring heart rate (HR), norepinephrine, and heart rate variability, and each participant's response to virtual exercise was compared internally to his/her response to the actual cycling. We found that neither post-exercise norepinephrine nor post-exercise HR was significantly increased by VR simulation. However, heart rate variability measured during virtual exercise was comparable to actual cycling in participants that engaged in moderate exercise, but not in those that engaged in high-intensity exercise. These findings suggest that virtual exercise has the potential to mimic some effects of moderate exercise. Further work will be needed to examine the longitudinal effects of chronic exposure to VR-simulated exercise.

Progressive augmentation and ventilatory long-term facilitation are enhanced in sleep apnoea patients and are mitigated by antioxidant administration.

Progressive augmentation (PA) and ventilatory long-term facilitation (vLTF) of respiratory motor output are forms of respiratory plasticity that are initiated during exposure to intermittent hypoxia. The present study was designed to determine whether PA and vLTF are enhanced in obstructive sleep apnoea (OSA) participants compared to matched healthy controls. The study was also designed to determine whether administration of an antioxidant cocktail mitigates PA and vLTF. Thirteen participants with sleep apnoea and 13 controls completed two trials. During both trials participants were exposed to intermittent hypoxia which included twelve 4-min episodes of hypoxia (P(ETCO(2)), 50 mmHg; P(ETCO(2)), 4 mmHg above baseline) followed by 30 min of recovery. Prior to exposure to intermittent hypoxia, participants were administered, in a randomized fashion, either an antioxidant or a placebo cocktail. Baseline measures of minute ventilation during the placebo and antioxidant trials were not different between or within groups. During the placebo trial, PA was evident in both groups; however it was enhanced in the OSA group compared to control (last hypoxic episode 36.9 +/- 2.8 vs. 27.7 +/- 2.2 l min(-1); P

Intermittent hypoxia and respiratory plasticity in humans and other animals: does exposure to intermittent hypoxia promote or mitigate sleep apnoea?

This review focuses on two phenomena that are initiated during and after exposure to intermittent hypoxia. The two phenomena are referred to as long-term facilitation and progressive augmentation of respiratory motor output. Both phenomena are forms of respiratory plasticity. Long-term facilitation is characterized by a sustained elevation in respiratory activity after exposure to intermittent hypoxia. Progressive augmentation is characterized by a gradual increase in respiratory activity from the initial to the final hypoxic exposure. There is much speculation that long-term facilitation may have a significant role in individuals with sleep apnoea because this disorder is characterized by periods of upper airway collapse accompanied by intermittent hypoxia, one stimulus known to induce long-term facilitation. It has been suggested that activation of long-term facilitation may serve to mitigate apnoea by facilitating ventilation and, more importantly, upper airway muscle activity. We examine the less discussed but equally plausible situation that exposure to intermittent hypoxia might ultimately lead to the promotion of apnoea. There are at least two scenarios in which apnoea might be promoted following exposure to intermittent hypoxia. In both scenarios, long-term facilitation of upper airway muscle activity is initiated but ultimately rendered ineffective because of other physiological conditions. Thus, one of the primary goals of this review is to discuss, with support from basic and clinical studies, whether various forms of respiratory motor neuronal plasticity have a beneficial and/or a detrimental impact on breathing stability in individuals with sleep apnoea.