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Breathing mild bouts of low oxygen air (i.e. acute intermittent hypoxia, AIH) has been shown to improve locomotor function in humans after a spinal cord injury. How AIH‐induced gains in motor performance are achieved remains unclear. We examined the hypothesis that AIH augments motor learning and motor retention during a locomotor adaptation task. We further hypothesized that gains in motor learning and retention will be associated with reductions in net metabolic power, consistent with the acquisition of energetically favourable mechanics. Thirty healthy individuals were randomly allocated into either a control group or an AIH group. We utilized a split‐belt treadmill to characterize adaptations to an unexpected belt speed perturbation of equal magnitude during an initial exposure and a second exposure. Adaptation was characterized by changes in spatiotemporal step asymmetry, anterior–posterior force asymmetry, and net metabolic power. While both groups adapted by reducing spatial asymmetry, only the AIH group achieved significant reductions in double support time asymmetry and propulsive force asymmetry during both the initial and the second exposures to the belt speed perturbation. Net metabolic power was also significantly lower in the AIH group, with significant reductions from the initial perturbation exposure to the second. These results provide the first evidence that AIH mediates improvements in both motor learning and retention. Further, our results suggest that reductions in net metabolic power continue to be optimized upon subsequent learning and are driven by more energetically favourable temporal coordination strategies. Our observation that AIH facilitates motor learning and retention can be leveraged to design rehabilitation interventions that promote functional recovery. Key points: Brief exposures to low oxygen air, known as acute intermittent hypoxia (AIH), improves locomotor function in humans after a spinal cord injury, but it remains unclear how gains in motor performance are achieved.In this study, we tested the hypothesis that AIH induces enhancements in motor learning and retention by quantifying changes in interlimb coordination, anterior–posterior force symmetry and metabolic cost during a locomotor adaptation task.We show the first evidence that AIH improves both motor learning and savings of newly learned temporal interlimb coordination strategies and force asymmetry compared to untreated individuals.We further demonstrate that AIH elicits greater reductions in metabolic cost during motor learning that continues to be optimized upon subsequent learning.Our findings suggest that AIH‐induced gains in locomotor performance are facilitated by enhancements in motor learning and retention of more energetically favourable coordination strategies. [ABSTRACT FROM AUTHOR]

To evaluate if acute intermittent hypoxia (AIH) coupled with transcutaneous spinal cord stimulation (tSCS) enhances task-specific training and leads to superior and more sustained gait improvements as compared with each of these strategies used in isolation in persons with chronic, incomplete spinal cord injury. Proof of concept, randomized crossover trial. Outpatient, rehabilitation hospital. Ten participants completed 3 intervention arms: (1) AIH, tSCS, and gait training (AIH + tSCS); (2) tSCS plus gait training (SHAM AIH + tSCS); and (3) gait training alone (SHAM + SHAM). Each arm consisted of 5 consecutive days of intervention with a minimum of a 4-week washout between arms. The order of arms was randomized. The study took place from December 3, 2020, to January 4, 2023. 10-meter walk test at self-selected velocity (SSV) and fast velocity, 6-minute walk test, timed Up and Go (TUG) and secondary outcome measures included isometric ankle plantarflexion and dorsiflexion torque TUG improvements were 3.44 seconds (95% CI: 1.24-5.65) significantly greater in the AIH + tSCS arm than the SHAM AIH + tSCS arm at post-intervention (POST), and 3.31 seconds (95% CI: 1.03-5.58) greater than the SHAM + SHAM arm at 1-week follow up (1WK). SSV was 0.08 m/s (95% CI: 0.02-0.14) significantly greater following the AIH + tSCS arm than the SHAM AIH + tSCS at POST. Although not significant, the AIH + tSCS arm also demonstrated the greatest average improvements compared with the other 2 arms at POST and 1WK for the 6-minute walk test, fast velocity, and ankle plantarflexion torque. This pilot study is the first to demonstrate that combining these 3 neuromodulation strategies leads to superior improvements in the TUG and SSV for individuals with chronic incomplete spinal cord injury and warrants further investigation. [ABSTRACT FROM AUTHOR]

Abstract Spasticity attributable to exaggerated stretch reflex pathways, particularly affecting the ankle plantar flexors, often impairs overground walking in persons with incomplete spinal cord injury. Compelling evidence from rodent models underscores how exposure to acute intermittent hypoxia (AIH) can provide a unique medium to induce spinal plasticity in key inhibitory pathways mediating stretch reflex excitability and potentially affect spasticity. In this study, we quantify the effects of a single exposure to AIH on the stretch reflex in able‐bodied individuals. We hypothesized that a single sequence of AIH will increase the stretch reflex excitability of the soleus muscle during ramp‐and‐hold angular perturbations applied to the ankle joint while participants perform passive and volitionally matched contractions. Our results revealed that a single AIH exposure did not significantly change the stretch reflex excitability during both passive and active matching conditions. Furthermore, we found that able‐bodied individuals increased their stretch reflex response from passive to active matching conditions after both sham and AIH exposures. Together, these findings suggest that a single AIH exposure might not engage inhibitory pathways sufficiently to alter stretch reflex responses in able‐bodied persons. However, the generalizability of our present findings requires further examination during repetitive exposures to AIH along with potential reflex modulation during functional movements, such as overground walking.

This article discusses the concept of acute intermittent hypoxia (AIH) and its potential effects on motoneuronal output. AIH involves alternating periods of hypoxia and normoxia, and animal studies have shown that it can enhance the output of respiratory motoneurones. However, the effects of AIH on human motoneurones are still unclear. The article presents the findings of several studies that have investigated the impact of AIH on motoneuronal output in humans, with mixed results. While some studies have shown potential benefits, others have found no significant changes. The article concludes that more research is needed to fully understand the effects of AIH on motoneuronal function in humans. [Extracted from the article]

Coordinated activation of sympathetic and respiratory nervous systems is crucial in responses to noxious stimuli such as intermittent hypoxia. Acute intermittent hypoxia (AIH) is a valuable model for studying obstructive sleep apnea (OSA) pathophysiology, and stimulation of breathing during AIH is known to elicit long-term changes in respiratory and sympathetic functions. The aim of this study was to record the renal sympathetic nerve activity (RSNA) and phrenic nerve activity (PNA) during the AIH protocol in rats exposed to monoanesthesia with sevoflurane or isoflurane. Adult male Sprague-Dawley rats (n = 24; weight: 280–360 g) were selected and randomly divided into three groups: two experimental groups (sevoflurane group, n = 6; isoflurane group, n = 6) and a control group (urethane group, n = 12). The AIH protocol was identical in all studied groups and consisted in delivering five 3 min-long hypoxic episodes (fraction of inspired oxygen, FiO2 = 0.09), separated by 3 min recovery intervals at FiO2 = 0.5. Volatile anesthetics, isoflurane and sevoflurane, blunted the RSNA response to AIH in comparison to urethane anesthesia. Additionally, the PNA response to acute intermittent hypoxia was preserved, indicating that the respiratory system might be more robust than the sympathetic system response during exposure to acute intermittent hypoxia. [ABSTRACT FROM AUTHOR]

Spasticity attributable to exaggerated stretch reflex pathways, particularly affecting the ankle plantar flexors, often impairs overground walking in persons with incomplete spinal cord injury. Compelling evidence from rodent models underscores how exposure to acute intermittent hypoxia (AIH) can provide a unique medium to induce spinal plasticity in key inhibitory pathways mediating stretch reflex excitability and potentially affect spasticity. In this study, we quantify the effects of a single exposure to AIH on the stretch reflex in able‐bodied individuals. We hypothesized that a single sequence of AIH will increase the stretch reflex excitability of the soleus muscle during ramp‐and‐hold angular perturbations applied to the ankle joint while participants perform passive and volitionally matched contractions. Our results revealed that a single AIH exposure did not significantly change the stretch reflex excitability during both passive and active matching conditions. Furthermore, we found that able‐bodied individuals increased their stretch reflex response from passive to active matching conditions after both sham and AIH exposures. Together, these findings suggest that a single AIH exposure might not engage inhibitory pathways sufficiently to alter stretch reflex responses in able‐bodied persons. However, the generalizability of our present findings requires further examination during repetitive exposures to AIH along with potential reflex modulation during functional movements, such as overground walking. What is the central question of this study?Acute intermittent hypoxia (AIH) has been shown to enhance walking performance in persons with spinal cord injury but might also trigger changes affecting dysregulated stretch reflex pathways, leading to spasticity. We examined the effect of AIH on stretch reflex excitability in able‐bodied individuals.What is the main finding and its importance?We did not find significant changes in reflex responses after AIH nor changes in reflex scaling from passive to active conditions. This study provides a crucial insight that enhances our understanding of AIH engagement of key inhibitory pathways that affect reflex excitability. [ABSTRACT FROM AUTHOR]

Coordinated activation of sympathetic and respiratory nervous systems is crucial in responses to noxious stimuli such as intermittent hypoxia. Acute intermittent hypoxia (AIH) is a valuable model for studying obstructive sleep apnea (OSA) pathophysiology, and stimulation of breathing during AIH is known to elicit long-term changes in respiratory and sympathetic functions. The aim of this study was to record the renal sympathetic nerve activity (RSNA) and phrenic nerve activity (PNA) during the AIH protocol in rats exposed to monoanesthesia with sevoflurane or isoflurane. Adult male Sprague-Dawley rats (n = 24; weight: 280–360 g) were selected and randomly divided into three groups: two experimental groups (sevoflurane group, n = 6; isoflurane group, n = 6) and a control group (urethane group, n = 12). The AIH protocol was identical in all studied groups and consisted in delivering five 3 min-long hypoxic episodes (fraction of inspired oxygen, FiO2 = 0.09), separated by 3 min recovery intervals at FiO2 = 0.5. Volatile anesthetics, isoflurane and sevoflurane, blunted the RSNA response to AIH in comparison to urethane anesthesia. Additionally, the PNA response to acute intermittent hypoxia was preserved, indicating that the respiratory system might be more robust than the sympathetic system response during exposure to acute intermittent hypoxia.

Purpose: Acute intermittent hypoxia (AIH) is a safe and non-invasive treatment approach that uses brief, repetitive periods of breathing reduced oxygen air alternated with normoxia. While AIH is known to affect spinal circuit excitability, the effects of AIH on cortical excitability remain largely unknown. We investigated the effects of AIH on cortical excitability within the primary motor cortex. Methods: Eleven healthy, right-handed participants completed two testing sessions: (1) AIH (comprising 3 min in hypoxia [fraction of inspired oxygen ~ 10%] and 2 min in normoxia repeated over five cycles) and (2) normoxia (NOR) (equivalent duration to AIH). Single- and paired-pulse transcranial magnetic stimulations were delivered to the primary motor cortex, before and 0, 25, and 50 min after AIH and normoxia. Results: The mean nadir in arterial oxygen saturation was lower (p < 0.001) during the cycles of AIH (82.5 ± 4.9%) than NOR (97.8 ± 0.6%). There was no significant difference in corticospinal excitability, intracortical facilitation, or intracortical inhibition between AIH and normoxia conditions at any time point (all p > 0.05). There was no association between arterial oxygen saturation and changes in corticospinal excitability after AIH (r = 0.05, p = 0.87). Conclusion: Overall, AIH did not modify either corticospinal excitability or excitability of intracortical facilitatory and inhibitory circuits within the primary motor cortex. Future research should explore whether a more severe or individualised AIH dose would induce consistent, measurable changes in corticospinal excitability. [ABSTRACT FROM AUTHOR]

People with cervical spinal cord injury (SCI) are likely to experience chronic intermittent hypoxia while sleeping. The physiological effects of intermittent hypoxia on the respiratory system during spontaneous sleep in individuals with chronic cervical SCI are unknown. We hypothesized that individuals with cervical SCI would demonstrate higher short‐ and long‐term ventilatory responses to acute intermittent hypoxia (AIH) exposure than individuals with thoracic SCI during sleep. Twenty participants (10 with cervical SCI [9 male] and 10 with thoracic SCI [6 male]) underwent an AIH and sham protocol during sleep. During the AIH protocol, each participant experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2) and 40% carbon dioxide (CO2) to achieve an oxygen saturation of less than 90%. This was followed by two breaths of 100% oxygen (O2). Measurements were collected before, during, and 40 min after the AIH protocol to obtain ventilatory data. During the sham protocol, participants breathed room air for the same amount of time that elapsed during the AIH protocol and at approximately the same time of night. Hypoxic ventilatory response (HVR) during the AIH protocol was significantly higher in participants with cervical SCI than those with thoracic SCI. There was no significant difference in minute ventilation (V.E.), tidal volume (V.T.), or respiratory frequency (f) during the recovery period after AIH in cervical SCI compared to thoracic SCI groups. Individuals with cervical SCI demonstrated a significant short‐term increase in HVR compared to thoracic SCI. However, there was no evidence of ventilatory long‐term facilitation following AIH in either group. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Does a single session of repeated bouts of acute intermittent hypoxic breathing enhance the motoneuronal output of the limb muscles of healthy able‐bodied participants?What is the main finding and its importance?Compared to breathing room air, there were some increases in motoneuronal output following acute intermittent hypoxia, but the increases were variable across participants and in time after the intervention and depended on which neurophysiological measure was checked. Acute intermittent hypoxia (AIH) induces persistent increases in output from rat phrenic motoneurones. Studies in people with spinal cord injury (SCI) suggest that AIH improves limb performance, perhaps via postsynaptic changes at cortico‐motoneuronal synapses. We assessed whether limb motoneurone output in response to reflex and descending synaptic activation is facilitated after one session of AIH in healthy able‐bodied volunteers. Fourteen participants completed two experimental days, with either AIH or a sham intervention (randomised crossover design). We measured H‐reflex recruitment curves and homosynaptic post‐activation depression (HPAD) of the H‐reflex in soleus, and motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS) and their recruitment curves in first dorsal interosseous. All measurements were performed at rest and occurred at baseline, 0, 20, 40 and 60 min post‐intervention. The intervention was 30 min of either normoxia (sham, FiO2${F_{{\rm{i}}{{\rm{O}}_{\rm{2}}}}}$ ≈ 0.21) or AIH (alternate 1‐min hypoxia [FiO2${F_{{\rm{i}}{{\rm{O}}_{\rm{2}}}}}$ ≈ 0.09], 1‐min normoxia). After AIH, the H‐reflex recruitment curve shifted leftward. Lower stimulation intensities were needed to evoke 5%, 50% and 99% of the maximal H‐reflex at 40 and 60 min after AIH (P < 0.04). The maximal H‐reflex, recruitment slope and HPAD were unchanged after AIH. MEPs evoked by constant intensity TMS were larger 40 min after AIH (P = 0.027). There was no change in MEP recruitment or the maximal MEP. In conclusion, some measures of the evoked responses from limb motoneurones increased after a single AIH session, but only at discrete time points. It is unclear to what extent these changes alter functional performance. [ABSTRACT FROM AUTHOR]

Acute intermittent hypoxia (AIH) elicits long‐term facilitation (LTF) of respiration. Although LTF is observed when CO2 is elevated during AIH in awake humans, the influence of CO2 on corticospinal respiratory motor plasticity is unknown. Thus, we tested the hypotheses that acute intermittent hypercapnic‐hypoxia (AIHH): (1) enhances cortico‐phrenic neurotransmission (reflecting volitional respiratory control); and (2) elicits ventilatory LTF (reflecting automatic respiratory control). Eighteen healthy adults completed four study visits. Day 1 consisted of anthropometry and pulmonary function testing. On Days 2, 3 and 4, in a balanced alternating sequence, participants received: AIHH, poikilocapnic AIH, and normocapnic‐normoxia (Sham). Protocols consisted of 15, 60 s exposures with 90 s normoxic intervals. Transcranial (TMS) and cervical (CMS) magnetic stimulation were used to induce diaphragmatic motor‐evoked potentials and compound muscle action potentials, respectively. Respiratory drive was assessed via mouth occlusion pressure (P0.1), and minute ventilation measured at rest. Dependent variables were assessed at baseline and 30–60 min after exposures. Increases in TMS‐evoked diaphragm potential amplitudes were observed following AIHH vs. Sham (+28 ± 41%, P = 0.003), but not after AIH. No changes were observed in CMS‐evoked diaphragm potential amplitudes. Mouth occlusion pressure also increased after AIHH (+21 ± 34%, P = 0.033), but not after AIH. Ventilatory LTF was not observed after any treatment. We demonstrate that AIHH elicits central neural mechanisms of respiratory motor plasticity and increases resting respiratory drive in awake humans. These findings may have important implications for neurorehabilitation after spinal cord injury and other neuromuscular disorders compromising breathing. Key points: The occurrence of respiratory long‐term facilitation following acute exposure to intermittent hypoxia is believed to be dependent upon CO2 regulation – mechanisms governing the critical role of CO2 have seldom been explored.We tested the hypothesis that acute intermittent hypercapnic‐hypoxia (AIHH) enhances cortico‐phrenic neurotransmission in awake healthy humans.The amplitude of diaphragmatic motor‐evoked potentials induced by transcranial magnetic stimulation was increased after AIHH, but not the amplitude of compound muscle action potentials evoked by cervical magnetic stimulation.Mouth occlusion pressure (P0.1, an indicator of neural respiratory drive) was also increased after AIHH, but not tidal volume or minute ventilation.Thus, moderate AIHH elicits central neural mechanisms of respiratory motor plasticity, without measurable ventilatory long‐term facilitation in awake humans. [ABSTRACT FROM AUTHOR]

Plasticity is a hallmark of the respiratory neural control system. Phrenic long-term facilitation (pLTF) is one form of respiratory plasticity characterized by persistent increases in phrenic nerve activity following acute intermittent hypoxia (AIH). Although there is evidence that key steps in the cellular pathway giving rise to pLTF are localized within phrenic motor neurons (PMNs), the impact of AIH on the strength of breathing-related synaptic inputs to PMNs remains unclear. Furthermore, the functional impact of AIH is enhanced by repeated/daily exposure to AIH (dAIH). Here, we explored the effects of AIH versus 2 wk of dAIH preconditioning on spontaneous and evoked phrenic responses in anesthetized, paralyzed, and mechanically ventilated rats. Evoked phrenic potentials were elicited by respiratory cycle-triggered lateral funiculus stimulation at the C2 spinal level delivered before and 60 min post-AIH (or the equivalent in time controls). Charge-balanced biphasic pulses (100 μs/phase) of progressively increasing intensity (100–700 μA) were delivered during the inspiratory and expiratory phases of the respiratory cycle. Although robust pLTF (∼60% from baseline) was observed after a single exposure to moderate AIH (3 × 5 min; 5-min intervals), there was no effect on evoked phrenic responses, contrary to our initial hypothesis. However, in rats preconditioned with dAIH, baseline phrenic nerve activity and evoked responses were increased, suggesting that repeated exposure to AIH enhances functional synaptic strength when assessed using this technique. The impact of daily AIH preconditioning on synaptic inputs to PMNs raises interesting questions that require further exploration. NEW & NOTEWORTHY Two weeks of daily acute intermittent hypoxia (dAIH) preconditioning enhanced stimulus-evoked phrenic responses to lateral funiculus stimulation (targeting respiratory bulbospinal projection to phrenic motor neurons). Furthermore, dAIH preconditioning enhanced baseline phrenic motor output responses to maximal chemoreflex activation in intact rats. [ABSTRACT FROM AUTHOR]

"Low-dose" acute intermittent hypoxia (AIH; 3-15 episodes/day) is emerging as a promising therapeutic strategy to improve motor function after incomplete cervical spinal cord injury (cSCI). Conversely, chronic "high-dose" intermittent hypoxia (CIH; > 80–100 episodes/day) elicits multi-system pathology and is a hallmark of sleep apnea, a condition highly prevalent in individuals with cSCI. Whereas daily AIH (dAIH) enhances phrenic motor plasticity in intact rats, it is abolished by CIH. However, there have been no direct comparisons of prolonged dAIH versus CIH on phrenic motor outcomes after chronic cSCI. Thus, phrenic nerve activity and AIH-induced phrenic long-term facilitation (pLTF) were assessed in anesthetized rats. Experimental groups included: 1) intact rats exposed to 28 days of normoxia (Nx28; 21% O2; 8 h/day), and three groups with chronic C2 hemisection (C2Hx) exposed to either: 2) Nx28; 3) dAIH (dAIH28; 10, 5-min episodes of 10.5% O2/day; 5-min intervals); or 4) CIH (IH28-2/2; 2-min episodes; 2-min intervals; 8 h/day). Baseline ipsilateral phrenic nerve activity was reduced in injured versus intact rats but unaffected by dAIH28 or IH28-2/2. There were no group differences in contralateral phrenic activity. pLTF was enhanced bilaterally by dAIH28 versus Nx28 but unaffected by IH28-2/2. Whereas dAIH28 enhanced pLTF after cSCI, it did not improve baseline phrenic output. In contrast, unlike shorter protocols in intact rats, CIH28-2/2 did not abolish pLTF in chronic C2Hx. Mechanisms of differential responses to dAIH versus CIH are not yet known, particularly in the context of cSCI. Further, it remains unclear whether enhanced phrenic motor plasticity can improve breathing after cSCI. [ABSTRACT FROM AUTHOR]

A key feature of sleep disordered breathing syndromes, such as obstructive sleep apnea is intermittent hypoxia. Intermittent hypoxia is well accepted to drive the sympathoexcitation that is frequently associated with hypertension and diabetes, with measurable effects after just 1 h. The aim of this study was to directly measure the glucose response to 1 h of acute intermittent hypoxia in pentobarbital anesthetized rats, compared to conscious rats. However, we found that while a glucose response is measurable in conscious rats exposed to intermittent hypoxia, it is suppressed in anesthetized rats. Intermittent hypoxia for 1, 2, or 8 h increased blood glucose by 0.7 ± 0.1 mmol/L in conscious rats but had no effect in anesthetized rats (−0.1 ± 0.2 mmol/L). These results were independent of the frequency of the hypoxia challenges, fasting state, vagotomy, or paralytic agents. A supraphysiological challenge of 3 min of hypoxia was able to induce a glycemic response indicating that the reflex response is not abolished under pentobarbital anesthesia. We conclude that pentobarbital anesthesia is unsuitable for investigations into glycemic response pathways in response to intermittent hypoxia in rats.

Moderate acute intermittent hypoxia (mAIH) elicits a progressive increase in phrenic motor output lasting hours post-mAIH, a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). mAIH-induced pLTF is initiated by activation of spinally-projecting raphe serotonergic neurons during hypoxia and subsequent serotonin release near phrenic motor neurons. Since raphe serotonergic neurons are also sensitive to pH and CO2, the prevailing arterial CO2 pressure (PaCO2) may modulate their activity (and serotonin release) during hypoxic episodes. Thus, we hypothesized that changes in background PaCO2 directly influence the magnitude of mAIH-induced pLTF. mAIH-induced pLTF was evaluated in anesthetized, vagotomized, paralyzed and ventilated rats, with end-tidal CO2 (i.e., a PaCO2 surrogate) maintained at: (1) ≤39 mmHg (hypocapnia); (2) ∼41 mmHg (normocapnia); or (3) ≥48 mmHg (hypercapnia) throughout experimental protocols. Although baseline phrenic nerve activity tended to be lower in hypocapnia, short-term hypoxic phrenic response, i.e., burst amplitude (Δ = 5.1 ± 1.1 μV) and frequency responses (Δ = 21 ± 4 bpm), was greater than in normocapnic (Δ = 3.6 ± 0.6 μV and 8 ± 4, respectively) or hypercapnic rats (Δ = 2.0 ± 0.6 μV and −2 ± 2, respectively), followed by a progressive increase in phrenic burst amplitude (i.e., pLTF) for at least 60 min post mAIH. pLTF in the hypocapnic group (Δ = 4.9 ± 0.6 μV) was significantly greater than in normocapnic (Δ = 2.8 ± 0.7 μV) or hypercapnic rats (Δ = 1.7 ± 0.4 μV). In contrast, although hypercapnic rats also exhibited significant pLTF, it was attenuated versus hypocapnic rats. When pLTF was expressed as percent change from maximal chemoreflex stimulation, all pairwise comparisons were found to be statistically significant (p < 0.05). We conclude that elevated PaCO2 undermines mAIH-induced pLTF in anesthetized rats. These findings contrast with well-documented effects of PaCO2 on ventilatory LTF in awake humans.

Acute intermittent hypoxia, carotid body, diaphragm, long-term facilitation, motoneuron, motor-evoked potential, phrenic, transcranial magnetic stimulation Initially observed with episodic electrical stimulation of the carotid sinus nerve, this phenomenon was then extensively demonstrated in rodent experiments via protocols of brief, episodic exposures to periods of hypoxia (i.e. acute intermittent hypoxia; AIH). Keywords: acute intermittent hypoxia; carotid body; diaphragm; long-term facilitation; motoneuron; motor-evoked potential; phrenic; transcranial magnetic stimulation EN acute intermittent hypoxia carotid body diaphragm long-term facilitation motoneuron motor-evoked potential phrenic transcranial magnetic stimulation 3017 3019 3 07/04/22 20220701 NES 220701 Pioneering experiments revealed that intermittent stimulation of afferent neurons from the carotid bodies elicits long-lasting increased activity of respiratory nerves, a phenomenon known as respiratory long-term facilitation (LTF). [Extracted from the article]

A key feature of sleep disordered breathing syndromes, such as obstructive sleep apnea is intermittent hypoxia. Intermittent hypoxia is well accepted to drive the sympathoexcitation that is frequently associated with hypertension and diabetes, with measurable effects after just 1 h. The aim of this study was to directly measure the glucose response to 1 h of acute intermittent hypoxia in pentobarbital anesthetized rats, compared to conscious rats. However, we found that while a glucose response is measurable in conscious rats exposed to intermittent hypoxia, it is suppressed in anesthetized rats. Intermittent hypoxia for 1, 2, or 8 h increased blood glucose by 0.7 ± 0.1 mmol/L in conscious rats but had no effect in anesthetized rats (−0.1 ± 0.2 mmol/L). These results were independent of the frequency of the hypoxia challenges, fasting state, vagotomy, or paralytic agents. A supraphysiological challenge of 3 min of hypoxia was able to induce a glycemic response indicating that the reflex response is not abolished under pentobarbital anesthesia. We conclude that pentobarbital anesthesia is unsuitable for investigations into glycemic response pathways in response to intermittent hypoxia in rats. [ABSTRACT FROM AUTHOR]

Moderate acute intermittent hypoxia (mAIH) elicits a progressive increase in phrenic motor output lasting hours post-mAIH, a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). mAIH-induced pLTF is initiated by activation of spinally-projecting raphe serotonergic neurons during hypoxia and subsequent serotonin release near phrenic motor neurons. Since raphe serotonergic neurons are also sensitive to pH and CO2, the prevailing arterial CO2 pressure (PaCO2) may modulate their activity (and serotonin release) during hypoxic episodes. Thus, we hypothesized that changes in background PaCO2 directly influence the magnitude of mAIH-induced pLTF. mAIH-induced pLTF was evaluated in anesthetized, vagotomized, paralyzed and ventilated rats, with end-tidal CO2 (i.e., a PaCO2 surrogate) maintained at: (1) ≤39 mmHg (hypocapnia); (2) ∼41 mmHg (normocapnia); or (3) ≥48 mmHg (hypercapnia) throughout experimental protocols. Although baseline phrenic nerve activity tended to be lower in hypocapnia, short-term hypoxic phrenic response, i.e., burst amplitude (Δ = 5.1 ± 1.1 μV) and frequency responses (Δ = 21 ± 4 bpm), was greater than in normocapnic (Δ = 3.6 ± 0.6 μV and 8 ± 4, respectively) or hypercapnic rats (Δ = 2.0 ± 0.6 μV and −2 ± 2, respectively), followed by a progressive increase in phrenic burst amplitude (i.e., pLTF) for at least 60 min post mAIH. pLTF in the hypocapnic group (Δ = 4.9 ± 0.6 μV) was significantly greater than in normocapnic (Δ = 2.8 ± 0.7 μV) or hypercapnic rats (Δ = 1.7 ± 0.4 μV). In contrast, although hypercapnic rats also exhibited significant pLTF, it was attenuated versus hypocapnic rats. When pLTF was expressed as percent change from maximal chemoreflex stimulation, all pairwise comparisons were found to be statistically significant (p < 0.05). We conclude that elevated PaCO2 undermines mAIH-induced pLTF in anesthetized rats. These findings contrast with well-documented effects of PaCO2 on ventilatory LTF in awake humans. [ABSTRACT FROM AUTHOR]

Acute intermittent hypoxia (AIH) and task-specific training (TST) synergistically improve motor function after spinal cord injury; however, mechanisms underlying this synergistic relation are unknown. We propose a hypothetical working model of neural network and cellular elements to explain AIH-TST synergy. Our goal is to forecast experiments necessary to advance our understanding and optimize the neurotherapeutic potential of AIH-TST. [ABSTRACT FROM AUTHOR]

• Cardiovascular changes that compromise oxygen availability in spinal cord tissue might impact expression of respiratory motor plasticity. • Impaired circulatory control and local tissue oxygen availability lead to extracellular adenosine accumulation. • Increased adenosine can trigger cross-talk inhibition or shift the balance from serotonergic towards adenosinergic mechanisms to pLTF. Acute intermittent hypoxia (AIH) elicits distinct mechanisms of phrenic motor plasticity initiated by brainstem neural network activation versus local (spinal) tissue hypoxia. With moderate AIH (mAIH), hypoxemia activates the carotid body chemoreceptors and (subsequently) brainstem neural networks associated with the peripheral chemoreflex, including medullary raphe serotonergic neurons. Serotonin release and receptor activation in the phrenic motor nucleus then elicits phrenic long-term facilitation (pLTF). This mechanism is independent of tissue hypoxia, since electrical carotid sinus nerve stimulation elicits similar serotonin-dependent pLTF. In striking contrast, severe AIH (sAIH) evokes a spinal adenosine-dependent, serotonin-independent mechanism of pLTF. Spinal tissue hypoxia per se is the likely cause of sAIH-induced pLTF, since local tissue hypoxia elicits extracellular adenosine accumulation. Thus, any physiological condition exacerbating spinal tissue hypoxia is expected to shift the balance towards adenosinergic pLTF. However, since these mechanisms compete for dominance due to mutual cross-talk inhibition, the transition from serotonin to adenosine dominant pLTF is rather abrupt. Any factor that compromises spinal cord circulation will limit oxygen availability in spinal cord tissue, favoring a shift in the balance towards adenosinergic mechanisms. Such shifts may arise experimentally from treatments such as carotid denervation, or spontaneous hypotension or anemia. Many neurological disorders, such as spinal cord injury or stroke compromise local circulatory control, potentially modulating tissue oxygen, adenosine levels and, thus, phrenic motor plasticity. In this brief review, we discuss the concept that local (spinal) circulatory control and/or oxygen delivery regulates the relative contributions of distinct pathways to phrenic motor plasticity. [ABSTRACT FROM AUTHOR]

Moderate acute intermittent hypoxia (mAIH) elicits plasticity in both respiratory (phrenic long-term facilitation; pLTF) and sympathetic nerve activity (sympLTF) in rats. Although mAIH produces pLTF in normal rats, inconsistent results are reported after cervical spinal cord injury (cSCI), possibly due to greater spinal tissue hypoxia below the injury site. There are no reports concerning cSCI effects on sympLTF. Since mAIH is being explored as a therapeutic modality to restore respiratory and non-respiratory movements in humans with chronic SCI, both effects are important. To understand cSCI effects on mAIH-induced pLTF and sympLTF, partial or complete C2 spinal hemisections (C2Hx) were performed and, 2 weeks later, we assessed: 1) ipsilateral cervical spinal tissue oxygen tension; 2) ipsilateral & contralateral pLTF; and 3) ipsilateral sympLTF in splanchnic and renal sympathetic nerves. Male Sprague-Dawley rats were studied intact, or after partial (single slice) or complete C2Hx (slice with ∼1 mm aspiration). Two weeks post-C2Hx, rats were anesthetized and prepared for recordings of bilateral phrenic nerve activity and spinal tissue oxygen pressure (PtO 2). Splanchnic and renal sympathetic nerve activity was recorded in intact and complete C2Hx rats. Spinal PtO 2 near phrenic motor neurons was decreased after C2Hx, an effect most prominent with complete vs. partial injuries; baseline PtO 2 was positively correlated with mean arterial pressure. Complete C2Hx impaired ipsilateral but not contralateral pLTF; with partial C2Hx, ipsilateral pLTF was unaffected. In intact rats, mAIH elicited splanchnic and renal sympLTF. Complete C2Hx had minimal impact on baseline ipsilateral splanchnic or renal sympathetic nerve activity and renal, but not splanchnic, sympLTF remained intact. Greater tissue hypoxia likely impairs pLTF and splanchnic sympLTF post-C2Hx, although renal sympLTF remains intact. Increased sympathetic nerve activity post-mAIH may have therapeutic benefits in individuals living with chronic SCI since anticipated elevations in systemic blood pressure may mitigate hypotension characteristic of people living with SCI. • Spinal tissue oxygenation is reduced in rats with cervical spinal hemisection. • Spinal oxygen pressure is lower in rats with lower mean arterial pressures. • AIH elicits phrenic LTF contralateral, but not ipsilateral to injury. • Ipsilateral sympathetic LTF can be elicited by AIH in injured rats. [ABSTRACT FROM AUTHOR]

Acute intermittent hypoxia (AIH) is an emerging technique for facilitating neural plasticity in individuals with chronic incomplete spinal cord injury (iSCI). A single sequence of AIH enhances hand grip strength and ankle plantarflexion torque, but underlying mechanisms are not yet clear. We sought to examine how AIH-induced changes in magnitude and spatial distribution of the electromyogram (EMG) of the biceps and triceps brachii contributes to improved strength. Seven individuals with iSCI visited the laboratory on two occasions, and received either AIH or Sham AIH intervention in a randomized order. AIH consisted of 15 brief (∼60s) periods of low oxygen (fraction of inspired O 2 = 0.09) alternating with 60s of normoxia, whereas Sham AIH consisted of repeated exposures to normoxic air. High-density surface EMG of biceps and triceps brachii was recorded during maximal elbow flexion and extension. We then generated spatial maps which distinguished active muscle regions prior to and 60 min after AIH or Sham AIH. After an AIH sequence, elbow flexion and extension forces increased by 91.7 ± 88.4% and 51.7 ± 57.8% from baseline, respectively, whereas there was no difference after Sham AIH. Changes in strength were associated with an altered spatial distribution of EMG and increased root mean squared EMG amplitude in both biceps and triceps brachii muscles. These data suggest that altered motor unit activation profiles may underlie improved volitional strength after a single dose of AIH and warrant further investigation using single motor unit analysis techniques to further elucidate mechanisms of AIH-induced plasticity. • Acute intermittent hypoxia (AIH) is an emerging therapeutic intervention for people with incomplete spinal cord injury (SCI). • Effects of AIH on respiratory motor function are well-studied, but the effects on limb function are not. • Here we show that AIH enhances elbow flexion and extension strength in persons with SCI at the cervical level. • AIH-induced improvements in strength were accompanied by an increase in the magnitude and area of muscle activity. [ABSTRACT FROM AUTHOR]

Objective: Acute intermittent hypoxia (AIH) causes long-term facilitation (LTF), known as a persistent increase in the amplitude of the ventilatory motor output response. LTF, requires motor neuron activation. furthermore, pro-inflammatory signal-induced glial cell activation has a role in LTF. In this study, it was hypothesized that COX-2 inhibition plays a role in ventilatory plasticity. Methods: In our study, divided into 2 groups as control (CON) and ibuprofen (IBU), 6 adult male, 3-month-old Spraque Dawley rats were used in each group were exposed to AIH. During the protocol, subjects were exposed to AIH and ventilation(V) measured. After that, tissue perfusion was performed and 20μ thick transverse medulla oblongata sections were taken. cFOS was used to show neuron activation, and GFAP, Iba-1/CD11b primary antibodies were used to show glial cell activation by immunofluorescence staining. The nucleus tractus solitarius (NTS) region on the medulla oblongata was visualized with a confocal microscope and density analyzes were performed. 2-way ANOVA tests were used for group comparison. p<0.05 was determined as a statistical significance level. Results: Baseline ventilation at 60th (666±35, p=0.0150) and 90th (658±35, p=0.0217) minutes after intermittent hypoxia increased significantly in CON group compared to baseline ventilation (549±16). There was no significant increase in IBU group. Expression of cFOS in NTS was significantly decreased in IBU group compared to CON group (p<0.05). There was no significant difference in expression of GFAP/Iba-1 and GFAP/CD11b in IBU group compared to CON group. Conclusion: Although LTF requires neuron activation, proinflammatory signaling pathway-dependent glial cell activation may also be required. Our data showed that ventilation was increased due to increased neuron activation in NTS. In addition, the absence of a significant increase in glial cell activation, but COX-2 inhibition causing depression in ventilation may result from this depression without and/or the initiation of glial cell activation. In conclusion, we think that COX-2 inhibition may block the LTF mechanism without glial cell activation after short-term intermittent hypoxia. [ABSTRACT FROM AUTHOR]

Phrenic motor facilitation (pMF), a form of respiratory plasticity, can be elicited by acute intermittent hypoxia (i.e., phrenic long-term facilitation, pLTF) or direct application of drugs to the cervical spinal cord. Moderate acute intermittent hypoxia (mAIH; 3 × 5-min episodes of 35–50 mmHg arterial Po2, 5-min normoxic intervals) induces pLTF by a serotonin-dependent mechanism; mAIH-induced pLTF is abolished by mild systemic inflammation induced by a low dose of lipopolysaccharide (LPS; 100 μg/kg ip). In contrast, severe acute intermittent hypoxia (sAIH; 3 × 5-min episodes of 25–30 mmHg arterial Po2, 5-min normoxic intervals) elicits pLTF by a distinct, adenosine-dependent mechanism. Since it is not known if systemic LPS blocks the mechanism giving rise to sAIH-induced pLTF, we tested the hypothesis that sAIH-induced pLTF and adenosine 2A (A2A) receptor-induced pMF are insensitive to mild systemic inflammation elicited by the same low dose of LPS. In agreement with our hypothesis, neither sAIH-induced pLTF nor cervical intrathecal A2A receptor agonist (CGS-21680; 200 μM, 10 μl × 3)-induced pMF were affected 24 h post-LPS. Pretreatment with intrathecal A2A receptor antagonist injections (MSX-3; 10 μM, 12 μl) blocked sAIH-induced pLTF 24 h post LPS, confirming that pLTF was adenosine dependent. Our results give insights concerning the differential impact of systemic inflammation and the functional significance of multiple cascades capable of giving rise to phrenic motor plasticity. The relative resistance of adenosine-dependent pMF to inflammation suggests that it provides a “backup” system in animals lacking serotonin-dependent pMF due to ongoing inflammation associated with systemic infections and/or neural injury. [ABSTRACT FROM AUTHOR]

To investigate the safety and efficacy of breathing low oxygen (acute intermittent hypoxia, AIH) as a pretreatment to enhance the functional benefits of transcutaneous spinal neuromodulation (TSN) on walking training (WALK+TSN) in people with chronic, motor-incomplete spinal cord injury (iSCI). Double-blind, placebo-controlled multisite randomized clinical trial. Spaulding Rehabilitation Hospital; Boston, MA and Shirley Ryan AbilityLab; Chicago, IL. We plan to enroll 60 adults (18-70 yrs.) with chronic (>1 yr. post injury) iSCI who are ambulatory. All participants will receive two weeks of high intensity (8, 60min sessions) walking practice (WALK) before randomly receiving either two weeks (8 sessions) of AIH (15 episodes; 90s at 10% O2, 60s intervals of room air) pretreatment to WALK+TSN, SHAM (15 episodes; 90s at 21% O2, with 60s intervals of room air) pretreatment to WALK+TSN, or AIH pretreatment to WALK+NoTSN. The primary outcome of this study is walking speed which we will quantify using the change in 10-meter walk test time relative to baseline as the primary endpoint. The timed up-and-go test, six-minute walk test, as well as measures of pain, spasticity, autonomic dysreflexia, cognition, and bladder and bowel function will be secondary outcomes. We will record these measures at baseline, after WALK, and after the combinatorial treatments, and at 1-week, 4-weeks, and 8-weeks follow-up. We hypothesize that AIH pretreatment to WALK+TSN safely increases potency and efficacy of training-related walking improvements in people with chronic iSCI more than either alone. We also predict dose-dependent associations between a single day of AIH pretreatment and the long-term effects of daily AIH pretreatment. Functional walking remains a significant goal for many persons with iSCI. Prior studies show daily AIH promotes rapid spinal plasticity and augments the benefits of other therapies that enhance walking ability in individuals with chronic iSCI. The outcomes from this study will offer new insight into the potential enduring benefits of AIH pretreatment for TSN training to boost walking recovery in people with chronic iSCI. Gad & Edgerton: SpineX. [ABSTRACT FROM AUTHOR]

The rostral ventrolateral medulla (RVLM) contains cardiovascular-related catecholaminergic neurons and respiratory-related pre-Bötzinger complex (pre-BötC) neurons, which are intermingled and functionally connected for coordinating cardiorespiratory activities. Daily acute intermittent hypoxia (dAIH) is known to elicit respiratory plasticity. However, it is unclear if the catecholaminergic neurons directly synapse onto pre-BötC neurons, and if the local circuitry exhibits plasticity when exposed to dAIH. The present study was aimed to determine the synaptic phenotypes between dopamine-β-hydroxylase (DβH)-immunoreactive (ir) catecholaminergic neurons and neurokinin 1 receptor (NK1R)-ir pre-BötC neurons, and the effect of dAIH on the neuronal network. Immunofluorescence histochemistry was used to reveal immunoreactivities of DβH and NK1R in the RVLM of normoxic and dAIH rats. Synaptic phenotypes were examined with double-labeling immunoelectron microscopy. We found that DβH immunoreactivity was expressed in somata and processes, some of which were in close apposition to NK1R-ir pre-BötC neurons. DβH-ir gold particles were localized to somata, dendrites, and axonal terminals. DβH-ir terminals formed asymmetric synapses, and occasionally, symmetric synapses in the pre-BötC, featuring the local circuitry. Of the synapses, 28% in normoxic and 29.6% in dAIH groups were apposed to NK1R-ir dendrites. Significant increases in DβH expression and NK1R-ir processes were found in the dAIH group. Moreover, the area and number of processes in close appositions were significantly elevated, strongly suggesting that dAIH induced plasticity with increased connections and interactions between the cardiovascular- and respiratory-related neurons in the local circuitry. In conclusion, asymmetric synapses are predominant in the crosstalk between catecholaminergic and pre-BötC neurons in the RVLM, elaborating excitatory transmission driving the coupling of cardiorespiratory activities. The neural network manifests plasticity in response to dAIH challenge. [ABSTRACT FROM AUTHOR]

Aim Acute intermittent hypoxia ( AIH) promotes persistent increases in ventilation and sympathetic activity, referred as long-term facilitation ( LTF). Augmented inspiratory activity is suggested as a major component of respiratory LTF. In this study, we hypothesized that AIH also elicits a sustained increase in expiratory motor activity. We also investigated whether the expiratory LTF contributes to the development of sympathetic LTF after AIH. Methods Rats were exposed to AIH (10 × 6-7% O2 for 45 s, every 5 min), and the cardiorespiratory parameters were evaluated during 60 min using in vivo and in situ approaches. Results In unanesthetized conditions ( n = 9), AIH elicited a modest but sustained increase in baseline mean arterial pressure ( MAP, 104 ± 2 vs. 111 ± 3 mmHg, P < 0.05) associated with enhanced sympathetic and respiratory-related variabilities. In the in situ preparations ( n = 9), AIH evoked LTF in phrenic (33 ± 12%), thoracic sympathetic (75 ± 25%) and abdominal nerve activities (69 ± 14%). The sympathetic overactivity after AIH was phase-locked with the emergence of bursts in abdominal activity during the late-expiratory phase. In anesthetized vagus-intact animals, AIH increased baseline MAP (113 ± 3 vs. 122 ± 2 mmHg, P < 0.05) and abdominal muscle activity (535 ± 94%), which were eliminated after pharmacological inhibition of the retrotrapezoid nucleus/parafacial respiratory group ( RTN/ pFRG). Conclusion These findings indicate that increased expiratory activity is also an important component of AIH-elicited respiratory LTF. Moreover, the development of sympathetic LTF after AIH is linked to the emergence of active expiratory pattern and depends on the integrity of the neurones of the RTN/ pFRG. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia induces plasticity in neural networks controlling breathing and cardiovascular function. Studies demonstrate that mechanisms causing cardiorespiratory plasticity rely on intracellular signalling pathways that are activated by specific neurotransmitters. Peptides such as serotonin, PACAP and orexin are well-known for their physiological significance in regulating the cardiorespiratory system. Their receptor counterparts are present in cardiorespiratory centres of the brainstem medulla and spinal cord. Microglial cells are also important players in inducing plasticity. The phenotype and function of microglial cells can change based on the physiological state of the central nervous system. Here, we propose that in the autonomic nuclei of the ventral brainstem the relationship between neurotransmitters and neurokines, neurons and microglia determines the overall neural function of the central cardiorespiratory system. [ABSTRACT FROM AUTHOR]

Cardiorespiratory plasticity induced by acute intermittent hypoxia (AIH) may contribute to recovery following spinal cord injury (SCI). We hypothesized that patients with cervical SCI would demonstrate higher minute ventilation (V¯E) following AIH compared with subjects with thoracic SCI and able-bodied subjects who served as controls. Twenty-four volunteers (8 with cervical SCI, 8 with thoracic SCI, and 8 able-bodied) underwent an AIH protocol during wakefulness. Each subject experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2), 8% O2, and 40% CO2 to achieve oxygen saturation ≤90% followed by room air (RA). Measurements were obtained before, during, and 40 min after AIH to obtain ventilation and heart rate variability data [R-R interval (RRI) and low-frequency/ high-frequency power (LF/HF)]. AIH results were compared with those of sham studies conducted in RA during the same time period. Individuals with cervical SCI had higherV¯E after AIH compared with able-bodied controls (117.9 ± 23.2% vs. 97.9 ± 11.2%, P < 0.05). RRI decreased during hypoxia in all individuals (those with cervical SCI, from 1,009.3 ± 65.0 ms to 750.2 ± 65.0 ms; those with thoracic SCI, from 945.2 ± 65.0 ms to 674.9 ± 65.0 ms; and those who were able-bodied, from 949 ± 75.0 to 682.2 ± 69.5 ms; P < 0.05). LH/HF increased during recovery in individuals with thoracic SCI and those who were able-bodied (0.54 ± 0.22 vs. 1.34 ± 0.22 and 0.67 ± 0.23 vs. 1.82 ± 0.23, respectively; P < 0.05) but remained unchanged in the group with cervical SCI. Our conclusion is that patients with cervical SCI demonstrate ventilatory long-term facilitation following AIH compared with able-bodied controls. Heart rate responses to hypoxia are acutely present in patients with cervical SCI but are absent during posthypoxic recovery. [ABSTRACT FROM AUTHOR]

Patients living with Amyotrophic Lateral Sclerosis (ALS) experience respiratory weakness and, eventually, failure due to inspiratory motor neuron degeneration. Routine pulmonary function tests (e.g., maximum inspiratory pressure (MIP)) are used to assess disease progression and ventilatory compromise. However, these tests are poor discriminators between respiratory drive and voluntary respiratory function at rest. To better understand ALS disease progression, we can look into compensatory strategies and how patients consciously react to the occlusion and the effort produced to meet the ventilatory challenge of the occlusion. This ventilatory challenge, especially beyond the P 0.1 (200 ms and 300 ms), provides information regarding the patient's ability to recruit additional respiratory muscles as a compensatory strategy. Utilizing a standard P 0.1 protocol to assess respiratory drive, we extend the occlusion time analysis to 200 ms and 300 ms (Detected Occlusion Response (DOR)) in order to capture compensatory respiratory mechanics. Furthermore, we followed an Acute Intermittent Hypoxia (AIH) protocol known to increase phrenic nerve discharge to evaluate the compensatory strategies. Inspiratory pressure, the rate of change in pressure, and pressure generation normalized to MIP were measured at 100 ms, 200 ms, and 300 ms after an occlusion. Airway occlusions were performed three times during the experiment (i.e., baseline, 30 and 60 minutes post-AIH). Results indicated that while AIH did not elicit change in the P 0.1 or MIP, the DOR increased for ALS patients. These results support the expected therapeutic role of AIH and indicate the potential of the DOR as a metric to detect compensatory changes. • ALS cohort generates more pressure at 0.3 s as a response to occlusion than controls. • MIP and P0.1 are unable to detect AIH impact on ALS patients. • AIH increases later inspiratory pressure generation in ALS without affecting P0.1. [ABSTRACT FROM AUTHOR]

This study examined whether time of day and repeated exposure to intermittent hypoxia have an impact on the hypoxic ventilatory response (HVR) and ventilatory long-term facilitation (vLTF). Thirteen participants with sleep apnea were exposed to twelve 4-min episodes of isocapnic hypoxia followed by a 30-min recovery period each day for 10 days. On days 1 (initial day) and 10 (final day) participants completed the protocol in the evening (PM); on the remaining days the protocol was completed in the morning (AM). The HVR was increased in the morning compared with evening on the initial (AM 0.83 ± 0.08 vs. PM 0.64 ± 0.11 1⋅min-1⋅%SaO2-1 P ≤ 0.01) and final days (AM 1.0 ± 0.08 vs. PM 0.81 ± 0.09 1⋅min- 1⋅%SaO2-1 P ≤ 0.01, where %SaO2 refers to percent arterial oxygen saturation). Moreover, the magnitude of the HVR was enhanced following daily exposure to intermittent hypoxia in the morning (initial day 0.83 ± 0.08 vs. final day 1.0 ± 0.08 1⋅min-1⋅%SaO2-1; P ≤ 0.03) and evening (initial day 0.64 ± 0.11 vs. final day 0.81 ± 0.09 1⋅min-1⋅%SaO2-1; P≤ 0.03). vLTF was reduced in the morning compared with the evening on the initial (AM 19.03 ± 0.35 vs. PM 22.30 ± 0.49 1/min; P ≤ 0.001) and final (AM 20.54 ± 0.32 vs. PM 23.11 ± 0.54 1/min; P ≤ 0.01) days. Following daily exposure to intermittent hypoxia, vLTF was enhanced in the morning (initial day 19.03 ± 0.35 vs. final day 20.54 ± 0.32 1/min; P ≤ 0.01). We conclude that the HVR is increased while vLTF is decreased in the morning compared with the evening in individuals with sleep apnea and that the magnitudes of these phenomena are enhanced following daily exposure to intermittent hypoxia [ABSTRACT FROM AUTHOR]

Abstract: We tested the hypotheses that: (1) long-term facilitation (LTF) following acute intermittent hypoxia (AIH) varies among three inbred rat strains: Fischer 344 (F344), Brown Norway (BN) and Lewis rats and (2) ventral cervical spinal levels of genes important for phrenic LTF (pLTF) vary in association with pLTF magnitude. Lewis and F344, but not BN rats exhibited significant increases in phrenic and hypoglossal burst amplitude 60min post-AIH that were significantly greater than control experiments without AIH, indicating strain differences in phrenic (98%, 56% and 20%, respectively) and hypoglossal LTF (66%, 77% and 5%, respectively). Ventral spinal 5-HT2A receptor mRNA and protein levels were higher in F344 and Lewis versus BN, suggesting that higher 5-HT2A receptor levels are associated with greater pLTF. More complex relationships were found for 5-HT7, BDNF and TrkB mRNA. BN had higher 5-HT7 and TrkB mRNA versus F344; BN and Lewis had higher BDNF mRNA levels versus F344. Genetic variations in serotonergic function may underlie strain differences in AIH-induced pLTF. [Copyright &y& Elsevier]

The role of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in mediating hypoxic preconditioning under the acute intermittent hypoxic condition (AIH) was investigated in this study. Male Wistar rats were randomly assigned and kept in normoxic conditions, (Nx) or in AIH conditions and subjected to brief cycles hypoxia/reoxygenation. Hearts were isolated, perfused, and subjected to in vitro global ischemia followed by reperfusion. During and at the end of reperfusion, left ventricular developed pressure (LVDP); LV end diastolic pressure (LVEDP); rate pressure product (RPP); peak left ventricular pressure rise (ΔP/Δtmax) and heart rate (HR) were measured. Hearts subjected to AIH displayed a significant higher LVDP (P < .001), RPP (P < .001), and ΔP/Δtmaxc (P < .001) Expression of VEGF and EPO were significantly increased at 3, 8, and 24 hours after AIH. Hypoxic training could provide a new approach to enhance endogenous cardioprotective mechanisms. [ABSTRACT FROM AUTHOR]

Acute intermittent hypoxia (AIH) and transcutaneous spinal cord stimulation (tSCS) are two non-invasive neuromodulation treatments that have been shown to individually induce spinal plasticity in persons with chronic incomplete spinal cord injury (iSCI). However, these two interventions have never been tested in combination to see if their combined effect is greater than each intervention alone. This proof of concept case study investigated how AIH combined with tSCS during ambulation training may facilitate improvements in walking function in individuals with iSCI. Single-blind, randomized, crossover trial. Outpatient, Rehabilitation Hospital. 1 participant (male, 70 years) with chronic iSCI. The participant completed 3 arms, in random order: 1. AIH+tSCS 2. Sham-AIH+Sham-tSCS 3. Sham-AIH+tSCS Each arm consisted of 5 treatment sessions on consecutive days. Assessments were performed at Baseline, Post-intervention (Post), and 1-week follow-up (1WFU), with a 4-week wash out between arms. Changes in gait performance were measured using the 10-meter walk test (10MWT) for fast and comfortable speeds, and the 6-minute walk test (6MWT). Overall, the participant showed potential improvements in his walking performance with AIH+tSCS at Post, relative to Baseline (10MWT-Fast: 5.6%; 10MWT-Comfortable: 7.0%; 6MWT: 15.6%), with further improvements at 1WFU (10MWT-Fast: 6.9%; 10MWT-Comfortable: 19.2%; 6MWT: 19.3%). The participant also showed potential improvements at Post, relative to Baseline with Sham-AIH+Sham-tSCS (10MWT-Fast: 12.2%; 10MWT-Comfortable: 6.6%; 6MWT: 15.1%) and with Sham-AIH+tSCS (10MWT-Fast: -2.5%; 10MWT-Comfortable: 15.3%; 6MWT: 6.0%). However, sustained improvements were not present at 1WFU with the Sham-AIH+Sham-tSCS (10MWT-Fast: 3.8%; 10MWT-Comfortable: -2.5%; 6MWT: 8.3%) or Sham-AIH+tSCS (10MWT-Fast: -3.9%; 10MWT-Comfortable: -5.5%; 6MWT: -2.1%), suggesting the combined intervention yielded retention effects. AIH +tSCS with gait training may promote persistent improvements in walking function compared to tSCS with gait training or gait training alone in persons with iSCI. Further studies are warranted to investigate this novel, combinational neuromodulation strategy. The authors have no conflicts of interest to disclose. [ABSTRACT FROM AUTHOR]

Respiratory failure is the main cause of death in amyotrophic lateral sclerosis (ALS). Since no effective treatments to preserve independent breathing are available, there is a critical need for new therapies to preserve or restore breathing ability. Since acute intermittent hypoxia (AIH) elicits spinal respiratory motor plasticity in rodent ALS models, and may restore breathing ability in people with ALS, we performed a proof-of-principle study to investigate this possibility in ALS patients. Quiet breathing, sniff nasal inspiratory pressure (SNIP) and maximal inspiratory pressure (MIP) were tested in 13 persons with ALS and 10 age-matched controls, before and 60 min post-AIH (15, 1 min episodes of 10% O 2 , 2 min normoxic intervals) or sham AIH (continuous normoxia). The root mean square (RMS) of the right and left diaphragm, 2nd parasternal, scalene and sternocleidomastoid muscles were monitored. A vector analysis was used to calculate summated vector magnitude (Mag) and similarity index (SI) of collective EMG activity during quiet breathing, SNIP and MIP maneuvers. AIH facilitated tidal volume and minute ventilation (treatment main effects: p < 0.05), and Mag (ie. collective respiratory muscle activity; p < 0.001) during quiet breathing in ALS and control subjects, but there was no effect on SI during quiet breathing. SNIP SI decreased in both groups post-AIH (p < 0.005), whereas Mag was unchanged (p = 0.09). No differences were observed in SNIP or MIP post AIH in either group. Discomfort was not reported during AIH by any subject, nor were adverse events observed. Thus, AIH may be a safe way to increase collective inspiratory muscle activity during quiet breathing in ALS patients, although a single AIH presentation was not sufficient to significantly increase peak inspiratory pressure generation. These preliminary results provide evidence that AIH may improve breathing function in people with ALS, and that future studies of prolonged, repetitive AIH protocols are warranted. • A single AIH session was well tolerated by ALS patients; • AIH enhanced tidal volume and collective respiratory muscle activity in ALS and control subjects during quiet breathing; • AIH altered respiratory muscle activation pattern during maximal inspiratory nasal sniff maneuvers in ALS and controls; • AIH had no effect on maximal inspiratory pressure generation; • The preliminary findings support the potential of repetitive AIH as a therapeutic modality to help preserve breathing in ALS. [ABSTRACT FROM AUTHOR]

• Lots of studies show that electrical stimulation has beneficial effects on neuromuscular. People also found an interesting phenomenon in the study of electrical stimulation of the genioglossus to treat OSA, that is, after the electrical stimulation, genioglossus can still maintain high muscle tension. We would like to further confirm the existence of this phenomenon and discuss its possible mechanisms. • Acute intermittent hypoxia is a stimulus method that induces a benign adaptive response in the body and has been proven to improve many diseases. However, the effect of acute intermittent hypoxia on nocturnal hypoxia in OSA patients has not been clearly studied, and we would like to further discuss its mechanism. • To our knowledge, this is the first research to investigate the interaction between acute intermittent hypoxia exposure and electrical stimulation on the genioglossus long-term facilitation. Exploring whether the genioglossus discharge in chronic intermittent hypoxia(CIH) – pretreated rats could be enhanced by intermittent electrical stimulation combined with acute intermittent hypoxia(AIH). Rats were pretreated with CIH for 4 weeks and then were randomly divided into 6 groups: time control, intermittent electric stimulation, AIH, intermittent electric stimulation + AIH, continuous electric stimulation and continuous hypoxia exposure. The genioglossus discharges were recorded and compared before and after stimulation. Normoxic-treated rats were grouped and treated with the same stimulation protocols. Intermittent electrical stimulation or AIH temporarily increased the activity of the genioglossus discharge, in which the degree of the increase was significantly higher in CIH-pretreated rats than in normoxic rats.After intermittent electrical stimulation, AIH evoked a sustained elevation of genioglossus discharge activities in CIH-pretreated rats, in which the degree of the increase was significantly higher than in rats induced by a single intermittent electric stimulation. Intermittent electrical stimulation combined with AIH strengthens the genioglossus plasticity in CIH-pretreated rats. [ABSTRACT FROM AUTHOR]

Spinal cord injuries (SCI) disrupt neural pathways between the brain and spinal cord, causing impairment of motor function and loss of independent mobility. Spontaneous plasticity in spared neural pathways improves function but is often insufficient to restore normal function. One unique approach to augment plasticity in spinal synaptic pathways is acute intermittent hypoxia (AIH), meaning brief exposure to mild bouts of low oxygen, interspersed with normoxia. While the administration of AIH elicits rapid plasticity and enhances volitional somatic motor output in the lower-limbs of people with incomplete SCI, it is not known if AIH-induced neuroplasticity is equally prevalent in spinal motor pathways regulating upper-extremity motor-function. In addition, how long the motor effects are retained following AIH has not yet been established. The goal of this research was to investigate changes in hand strength and upper-limb function elicited by episodic hypoxia, and to establish how long these effects were sustained in persons with incomplete cervical SCI. We conducted a randomized, blinded, placebo-controlled and cross-over design study consisting of a single AIH or sham AIH session in 14 individuals with chronic, incomplete cervical SCI. In a subset of six participants, we also performed a second protocol to determine the cumulative effects of repetitive AIH (i.e., two consecutive days). In both protocols, hand dynamometry and clinical performance tests were performed pre- and post-exposure. We found that a single AIH session enhanced bilateral grip and pinch strength, and that this effect peaked ~3 h post-intervention. The strength change was substantially higher after AIH versus sham AIH. These findings demonstrate the potential of AIH to improve upper-extremity function in persons with chronic SCI, although follow-up studies are needed to investigate optimal dosage and duration of effect. • Acute intermittent hypoxia (AIH) enhances grip and pinch strength in persons with incomplete spinal cord injury. • The effect of AIH peaks around 3 h post-intervention. • AIH significantly improves upper limb function as assessed by clinical measures (i.e., Box and Block Test). [ABSTRACT FROM AUTHOR]

After spinal cord injury (SCI) respiratory complications are a leading cause of morbidity and mortality. Acute intermittent hypoxia (AIH) triggers spinal respiratory motor plasticity in rodent models, and repetitive AIH may have the potential to restore breathing capacity in those with SCI. As an initial approach to provide proof of principle for such effects, we tested single-session AIH effects on breathing function in adults with chronic SCI. 17 adults (13 males; 34.1 ± 14.5 years old; 13 motor complete SCI; >6 months post injury) completed two randomly ordered sessions, AIH versus sham. AIH consisted of 15, 1-min episodes (hypoxia: 10.3% O2; sham: 21% O2) interspersed with room air breathing (1.5 min, 21% oxygen); no attempt was made to regulate arterial CO2 levels. Blood oxygen saturation (SpO2), maximal inspiratory and expiratory pressures (MIP; MEP), forced vital capacity (FVC), and mouth occlusion pressure within 0.1 s (P0.1) were assessed. Outcomes were compared using nonparametric Wilcoxon's tests, or a 2 × 2 ANOVA. Baseline SpO2 was 97.2 ± 1.3% and was unchanged during sham experiments. During hypoxic episodes, SpO2 decreased to 84.7 ± 0.9%, and returned to baseline levels during normoxic intervals. Outcomes were unchanged from baseline post-sham. Greater increases in MIP were evident post AIH vs. sham (median values; +10.8 cmH 2 O vs. -2.6 cmH 2 O respectively, 95% confidence interval (−18.7) – (−4.3), p =.006) with a moderate Cohen's effect size (0.68). P 0.1 , MEP and FVC did not change post-AIH. A single AIH session increased maximal inspiratory pressure generation, but not other breathing functions in adults with SCI. Reasons may include greater spared innervation to inspiratory versus expiratory muscles or differences in the capacity for AIH-induced plasticity in inspiratory motor neuron pools. Based on our findings, the therapeutic potential of AIH on breathing capacity in people with SCI warrants further investigation. [ABSTRACT FROM AUTHOR]

An important model of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a persistent increase in phrenic burst amplitude following acute intermittent hypoxia (AIH). Moderate AIH elicits pLTF by a serotonin-dependent mechanism known as the Q pathway to phrenic motor facilitation. In contrast, severe AIH (greater hypoxemia) increases spinal adenosine accumulation and activates phrenic motor neuron adenosine 2A receptors, thereby initiating a distinct mechanism of plasticity known as the S pathway. Since the Q and S pathways interact via mutual cross-talk inhibition, the balance between spinal serotonin release and adenosine accumulation is an important pLTF regulator. Spinal injury decreases spinal tissue oxygen pressure (PtO 2) caudal to injury. Since AIH is being explored as a neurotherapeutic to restore breathing ability after cervical spinal injury, we tested the hypothesis that decreased PtO 2 in the phrenic motor nucleus after C2 spinal hemisection (C2Hx) undermines moderate AIH-induced pLTF, likely due to shifts in the adenosine/serotonin balance. We recorded C3/4 ventral cervical PtO 2 with an optode, and bilateral phrenic nerve activity in anesthetized, paralyzed and ventilated rats, with and without C2Hx. In intact rats, PtO 2 was lower during severe versus moderate AIH as expected. In chronic C2Hx rats (> 8 weeks post-injury), PtO 2 was lower during baseline and moderate hypoxic episodes, approaching severe AIH levels in intact rats. After C2Hx, pLTF was blunted ipsilateral, but observed contralateral to injury. We conclude that C2Hx compromises PtO 2 near the phrenic motor nucleus and undermines pLTF, presumably due to a shift in the serotonin versus adenosine balance during hypoxic episodes. These findings have important implications for optimizing AIH protocols in our efforts to restore breathing ability with therapeutic AIH in people with chronic cervical spinal injury. [ABSTRACT FROM AUTHOR]

The intrinsic repair response of injured peripheral neurons is enhanced by brief electrical stimulation (ES) at time of surgical repair, resulting in improved regeneration in rodents and humans. However, ES is invasive. Acute intermittent hypoxia (AIH) - breathing alternate cycles of regular air and air with ~50% normal oxygen levels (11% O 2), considered mild hypoxia, is an emerging, promising non-invasive therapy that promotes motor function in spinal cord injured rats and humans. AIH can increase neural activity and under moderately severe hypoxic conditions improves repair of peripherally crushed nerves in mice. Thus, we posited an AIH paradigm similar to that used clinically for spinal cord injury, will improve surgically repaired peripheral nerves akin to ES, including an impact on regeneration-associated gene (RAG) expression–a predictor of growth states. Alterations in early RAG expression were examined in adult male Lewis rats that underwent tibial nerve coaptation repair with either 2 days AIH or normoxia control treatment begun on day 2 post-repair, or 1 h ES treatment (20 Hz) at time of repair. Three days post-repair, AIH or ES treatments effected significant and parallel elevated RAG expression relative to normoxia control at the level of injured sensory and motor neuron cell bodies and proximal axon front. These parallel impacts on RAG expression were coupled with significant improvements in later indices of regeneration, namely enhanced myelination and increased numbers of newly myelinated fibers detected 20 mm distal to the tibial nerve repair site or sensory and motor neurons retrogradely labeled 28 mm distal to the repair site, both at 25 days post nerve repair; and improved return of toe spread function 5–10 weeks post-repair. Collectively, AIH mirrors many beneficial effects of ES on peripheral nerve repair outcomes. This highlights its potential for clinical translation as a non-invasive means to effect improved regeneration of injured peripheral nerves. [ABSTRACT FROM AUTHOR]

Persons living with incomplete spinal cord injuries (SCI) often struggle to regain independent walking due to deficits in walking mechanics. They often dedicate many weeks of gait training before benefits to emerge, with additional training needed for benefits to persist. Recent studies in humans with SCI found that daily bouts of breathing low oxygen (acute intermittent hypoxia, AIH) prior to locomotor training elicited persistent (weeks) improvement in overground walking speed and endurance. AIH-induced improvements in overground walking may result from changes in control strategies that also enhance intralimb coordination; however, this possibility remains untested. Here, we examined the extent to which daily AIH combined with walking practice (AIH + WALK) improved overground walking performance and intralimb motor coordination in persons with chronic, incomplete SCI. We recruited 11 persons with chronic (> 1 year), incomplete SCI to participate in a randomized, double-blind, balanced, crossover study. Participants first received either daily (5 consecutive days) AIH (15, 90-s episodes of 10.0% O 2 with 60s intervals at 20.9% O 2) or SHAM (15, 90s episodes at 20.9% O 2 with 60s intervals at 20.9% O 2) followed by 30-min of overground walking practice. They received the second treatment after a minimum 2-week washout period. We quantified overground walking performance, in terms of speed and endurance, using the 10-Meter Walk Test (10MWT) and 6-Minute Walk Test (6MWT), respectively. We quantified intralimb motor coordination using kinematic variability measures of foot trajectory (i.e., endpoint variability, EV) and of inter-joint coupling between the hip and knee, as well as between the knee and ankle joints (i.e., angular coefficient of correspondence, ACC). We compared the changes in walking performance relative to baseline (BL) between daily AIH + WALK and daily SHAM+WALK on treatment day 5 (T 5), 1-week follow-up (F 1), and 2-weeks follow-up (F 2). We also compared these changes between participants who used bilateral walking aids (N = 5) and those who did not. To assess the effects of daily AIH + WALK on intralimb coordination, we compared potential treatment-induced changes in EV and ACC relative to BL at F 1 and F 2. Participants improved overground walking performance (speed and endurance) after daily AIH + WALK, but not SHAM+WALK. Following daily AIH + WALK, participants decreased their 10MWT time at T 5 by 28% (95% CI 0.2–10.1 s, p = 0.04), F 1 by 28% (95% CI 1.1–13.5 s, p = 0.01), and F 2 by 27% (95% CI 1.4–13.9 s, p = 0.01) relative to BL. The greatest decreases in the 10MWT occurred in participants who used bilateral walking aids (p < 0.05). We also found daily AIH + WALK resulted in an increase in 6MWT distance at T 5 by 22% (95% CI 13.3–72.6 m, p = 0.001), F 1 by 21% (95% CI 13.1–72.5 m, p = 0.001), and F 2 by 16% (95% CI 2.9–62.2 m, p = 0.02). However, measures of EV and ACC during self-selected walking conditions did not change following daily AIH + WALK (all p -values >0.50). Consistent with prior studies, daily AIH + WALK triggered improvements in walking speed and endurance that persisted for weeks after treatment. Greatest improvements in speed occurred in participants who used bilateral walking aids. No change in EV and ACC may suggest that intralimb motor coordination was not a significant gait training priority during daily AIH + WALK. • Five days of AIH and walking practice (AIH+WALK) improved walking speed and endurance in persons with chronic, incomplete SCI. • Participants who used bilateral arm-driven walking aids demonstrated greater improvement in walking speed following AIH+WALK. • Intralimb motor coordination remained impaired following AIH+WALK in persons with chronic, incomplete SCI. [ABSTRACT FROM AUTHOR]

Acute intermittent hypoxia (AIH) is a strategy to improve motor output in humans with neuromotor impairment. A single AIH session increases the amplitude of motor evoked potentials (MEP) in a finger muscle (first dorsal interosseous), demonstrating enhanced corticospinal neurotransmission. Since AIH elicits phrenic/diaphragm long-term facilitation (LTF) in rodent models, we tested the hypothesis that AIH augments diaphragm MEPs in humans. Eleven healthy adults (7 males, age = 29 ± 6 years) were tested. Transcranial and cervical magnetic stimulation were used to induce diaphragm MEPs and compound muscle action potentials (CMAP) recorded by surface EMG, respectively. Stimulus-response curves were generated prior to and 30–60 min after AIH. Diaphragm LTF was assessed by measurement of integrated EMG burst amplitude and frequency during eupnoeic breathing before and after AIH. Following baseline measurements, AIH was delivered from an oxygen generator connected to a facemask under poikilocapnic conditions (15 one minute episodes of 9% inspired oxygen with one minute room air intervals). There were no detectable changes in MEP (−1.5 ± 12.1%, p = 0.96) or CMAP (+0.1 ± 7.8%, p = 0.97) amplitudes across the stimulus-response curve. At stimulation intensities approximating 50% of the difference between minimum and maximum baseline amplitudes, MEP and CMAP amplitudes were also unchanged (p > 0.05). Further, no AIH effect was observed on diaphragm EMG activity during eupnoea post-AIH (p > 0.05). We conclude that unlike hand muscles, poikilocapnic AIH does not enhance diaphragm MEPs or produce diaphragm LTF in healthy humans. • Acute intermittent hypoxia (AIH) increases motor evoked potential (MEP) amplitude in a finger muscle, demonstrating enhanced corticospinal neurotransmission. • We examined AIH effects on diaphragm MEPs induced by transcranial magnetic stimulation in healthy young adults. • After a single AIH session, no detectable changes in MEP amplitudes were observed. • Differences between AIH effects on respiratory and non-respiratory motor systems are discussed. [ABSTRACT FROM AUTHOR]