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.

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.

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).

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.

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.

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.

Increased Oxidative Stress, Loop Gain And The Arousal Threshold Are Clinical Predictors Of Increased Apnea Severity Following Exposure To Intermittent Hypoxia.

PURPOSE: We determined if oxidative stress prior to sleep onset is correlated to loop gain (LG) and the arousal threshold (AT) during non-rapid eye movement (NREM) sleep. We also explored if LG and AT are correlated with apnea severity and indices of upper airway collapsibility during NREM sleep. METHODS: Thirteen male participants with obstructive sleep apnea (apnea-hypopnea index > 5 events/hr) were administered an antioxidant or placebo cocktail while exposed to mild intermittent hypoxia in the awake state. Thereafter, loop gain and measures of arousal, apnea severity and upper airway collapsibility were ascertained during NREM sleep. RESULTS: Modification in oxidative stress (i.e., 8-hydroxy-2-deoxyguanosine) prior to sleep onset was correlated to LG (r = 0.8, P = 0.003), the number (r = 0.71, P = 0.01) and duration (r = 0.63, P = 0.04) of apneic events and the percentage of time breathing was stable (r = -0.66, P = 0.03) during sleep. Using a forward stepwise regression analysis, our results showed that LG, AT, the ventilatory response to arousal and nadir end-tidal carbon dioxide were determinants of the apnea-hypopnea index (P value range = 0.04-0.001). In addition, the AT was a predictor of measures of upper airway collapsibility, including the hypopnea/apnea + hypopnea ratio and the degree of flow reduction that accompanied hypopneic events (P < 0.001). CONCLUSION: Modifications in oxidative stress following exposure to intermittent hypoxia during wakefulness are positively associated with loop gain and apnea severity during NREM sleep. Moreover, an increase in the arousal threshold is a predictor of increased upper airway collapsibility.

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.

Genetic depletion of 5-HT increases central apnea frequency and duration and dampens arousal but does not impact the circadian modulation of these variables.

We examined the impact of serotonin (5-HT) on the frequency and duration of central apneic events and the frequency of accompanying arousals during nonrapid and rapid eye movement (NREM and REM, respectively) sleep across the light/dark cycle. Electroencephalography, electromyography, core body temperature, and activity were recorded for 24 h following implantation of telemeters in wild-type (Tph2+/+) and tryptophan hydroxylase 2 knockout (Tph2-/-) male mice. The frequency and duration of central apneic events were increased, the number of apneic events coupled to an arousal was decreased, and the ventilatory sensitivity to hypoxia and hypercapnia was decreased in the Tph2-/- compared with the Tph2+/+ mice during NREM sleep. Apnea frequency and duration were similar in the Tph2-/- and Tph2+/+ mice during REM sleep. The duration of apneic events during REM compared with NREM sleep was similar in the Tph2-/- mice. In contrast, the duration was greater during REM sleep in the Tph2+/+ mice. Our results also revealed that apnea frequency was greater during the light compared with the dark cycle. Circadian modulation of this variable was evident in both the Tph2-/- and Tph2+/+ mice during NREM and REM sleep. We conclude that depletion of 5-HT increases the frequency and duration of central apneic events, dampens arousal, and blunts the ventilatory response to hypoxia and hypercapnia during NREM sleep but is not essential for the circadian modulation of these variables. NEW & NOTEWORTHY The presence of serotonin (5-HT) in the central nervous system diminishes the frequency of central apneic events. This neuromodulator also moderates the duration of central apneic events and promotes arousal from central events if they occur during nonrapid eye movement (NREM) sleep. However, 5-HT is not responsible for the circadian modulation of apnea frequency, which we found was greater during NREM sleep in the light compared with the dark cycle.

The impact of intermittent or sustained carbon dioxide on intermittent hypoxia initiated respiratory plasticity. What is the effect of these combined stimuli on apnea severity?

The following review explores the effect that intermittent or sustained hypercapnia coupled to intermittent hypoxia has on respiratory plasticity. The review explores published work which suggests that intermittent hypercapnia leads to long-term depression of respiration when administered in isolation and prevents the initiation of long-term facilitation when administered in combination with intermittent hypoxia. The review also explores the impact that sustained hypercapnia alone and in combination with intermittent hypoxia has on the magnitude of long-term facilitation. After exploring the outcomes linked to intermittent hypoxia/hypercapnia and intermittent hypoxia/sustained hypercapnia the translational relevance of the outcomes as it relates to breathing stability during sleep is addressed. The likelihood that naturally induced cycles of intermittent hypoxia, coupled to oscillations in carbon dioxide that range between hypocapnia and hypercapnia, do not initiate long-term facilitation is addressed. Moreover, the conditions under which intermittent hypoxia/sustained hypercapnia could serve to improve breathing stability and mitigate co-morbidities associated with sleep apnea are considered.