Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disorder, characterised by progressive decline in skeletal muscle function due to the secondary consequences of dystrophin deficiency. Weakness extends to the respiratory musculature, and cardiorespiratory failure is the leading cause of death in men with DMD. Intermittent hypoxia has emerged as a potential therapy to counteract ventilatory insufficiency by eliciting long-term facilitation of breathing. Mechanisms of sensory and motor facilitation of breathing have been well delineated in animal models. Various paradigms of intermittent hypoxia have been designed and implemented in human trials culminating in clinical trials in people with spinal cord injury and amyotrophic lateral sclerosis. Application of therapeutic intermittent hypoxia to DMD is considered together with discussion of the potential barriers to progression owing to the complexity of this devastating disease. Notwithstanding the considerable challenges and potential pitfalls of intermittent hypoxia-based therapies for DMD, we suggest it is incumbent on the research community to explore the potential benefits in pre-clinical models. Intermittent hypoxia paradigms should be implemented to explore the proclivity to express respiratory plasticity with the longer-term aim of preserving and potentiating ventilation in pre-clinical models and people with DMD.

Cervical spinal cord injury creates lasting respiratory deficits which can require mechanical ventilation long-term. We have shown that closed-loop epidural stimulation (CL-ES) elicits respiratory plasticity in the form of increased phrenic network excitability (Malone et. al., E Neuro, Vol 9, 0426-21.2021, 2022); however, the ability of this treatment to create functional benefits for breathing function per se after injury has not been demonstrated. Here, we demonstrate in C2 hemisected anesthetized rats, a 20-minute bout of CL-ES administered at current amplitudes below the motor threshold restores paralyzed hemidiaphragm activity in-phase with breathing while potentiating contralesional activity. While this acute bout of stimulation did not elicit the increased network excitability seen in our chronic model, a subset of stimulated animals continued spontaneous ipsilesional diaphragm activity for several seconds after stopping stimulation. These results support the use of CL-ES as a therapeutic to rescue breathing after high cervical spinal cord injury, with the potential to lead to lasting recovery and device independence.

Degenerative cervical myelopathy (DCM) is a debilitating neurological condition characterized by chronic compression of the cervical spinal cord leading to impaired upper and lower limb function. Despite damage to areas of the cervical spinal cord that house the respiratory network, respiratory dysfunction is not a common symptom of DCM. However, DCM may be associated with respiratory dysfunction, and this can affect the ventilatory response to respiratory challenges during emergence from anesthesia, exercise, or pulmonary disease. Surgical spinal cord decompression, which is the primary treatment for DCM, leads to improved sensorimotor function in DCM; yet its impact on respiratory function is unknown. Here, using a clinically relevant model of DCM, we evaluate respiratory function during disease progression and assess adaptive ventilation to hypercapnic challenge before and after surgical intervention. We show that despite significant and progressive forelimb and locomotor deficits, there was no significant decline in eupneic ventilation from the early to late phases of spinal cord compression. Additionally, for the first time, we demonstrate that despite normal ventilation under resting conditions, DCM impairs acute adaptive ventilatory ability in response to hypercapnia. Remarkably, akin to DCM patients, surgical decompression treatment improved sensorimotor function in a subset of mice. In contrast, none of the mice that underwent surgical decompression recovered their ability to respond to hypercapnic ventilatory challenge. These findings underscore the impact of chronic spinal cord compression on respiratory function, highlighting the challenges associated with ventilatory response to respiratory challenges in individuals with DCM. This research highlights the impact of cervical spinal cord compression on respiratory dysfunction in DCM, as well as the persistence of adaptive ventilatory dysfunction after surgical spinal cord decompression. These results indicate the need for additional interventions to enhance recovery of respiratory function after surgery for DCM.

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Chronic hypoxia (CH) from birth attenuates the acute hypoxic ventilatory response (HVR) in rats and other mammals, but CH is often reported to augment the HVR in adult mammals. To test the hypothesis that this transition - from blunting to augmenting the HVR - occurs in the third or fourth postnatal week in rats, juvenile and adult rats were exposed to normobaric CH (12% O2) for 7 days and the HVR was assessed by whole-body plethysmography. No transition was observed, however, and the acute HVR was reduced by 61 - 85% across all ages studied. The failure to observe an augmented HVR in adult rats could not be explained by the substrain of Sprague Dawley rats used, the duration of the CH exposure, the order in which test gases were presented, the level of hypoxia used for CH and to assess the HVR, or the effects of CH on the metabolic response to hypoxia and the hypercapnic ventilatory response. A literature survey revealed several distinct patterns of ventilatory acclimatization to hypoxia (VAH) in adult rats, with most studies (77%) revealing a decrease or no change in the acute HVR after CH. In conclusion, the effects of CH on respiratory control are qualitatively similar across age groups, at least within the populations of Sprague Dawley rats used in the present study, and there does not appear to be one \"typical\" pattern for VAH in adult rats.

Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) selectively eliminates respiratory (e.g., phrenic) motor neurons, and mimics motor neuron death and respiratory deficits observed in rat models of neuromuscular diseases. Additionally, microglial density increases in the phrenic motor nucleus following CTB-SAP. This CTB-SAP rodent model allows us to study the impact of motor neuron death on the output of surviving phrenic motor neurons, and the underlying mechanisms that contribute to enhancing or constraining their output at 7 days (d) or 28d post-CTB-SAP injection. 7d CTB-SAP rats elicit enhanced phrenic long-term facilitation (pLTF) through the Gs-pathway (inflammation-resistant in naïve rats), while pLTF is elicited though the Gq-pathway (inflammation-sensitive in naïve rats) in control and 28d CTB-SAP rats. In 7d and 28d male CTB-SAP rats and controls, we evaluated the effect of cyclooxygenase-1/2 enzymes on pLTF by delivery of the nonsteroidal anti-inflammatory drug, ketoprofen (IP), and we hypothesized that pLTF would be unaffected by ketoprofen in 7d CTB-SAP rats, but pLTF would be enhanced in 28d CTB-SAP rats. In anesthetized, paralyzed and ventilated rats, pLTF was surprisingly attenuated in 7d CTB-SAP rats and enhanced in 28d CTB-SAP rats (both p < 0.05) following ketoprofen delivery. Additionally in CTB-SAP rats: 1) microglia were more amoeboid in the phrenic motor nucleus; and 2) cervical spinal inflammatory-associated factor expression (TNF-α, BDNF, and IL-10) was increased vs. controls in the absence of ketoprofen (p < 0.05). Following ketoprofen delivery, TNF-α and IL-10 expression was decreased back to control levels, while BDNF expression was differentially affected over the course of motor neuron death in CTB-SAP rats. This study furthers our understanding of factors (e.g., cyclooxygenase-1/2-induced inflammation) that contribute to enhancing or constraining pLTF and its implications for breathing following respiratory motor neuron death.

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% O2, 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.

暂无摘要。

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.

UNASSIGNED: What is the central question of this study? Do cardiorespiratory experience-dependent effects (EDEs) differ between two different stimulus durations of acute isocapnic intermittent hypoxia (IHx; 5-min vs. 90-s cycles between hypoxia and normoxia)? What is the main finding and its importance? There was long-term facilitation in ventilation and blood pressure in both IHx protocols, but there was no evidence of progressive augmentation or post-hypoxia frequency decline. Not all EDEs described in animal models translate to acute isocapnic IHx responses in humans, and cardiorespiratory responses to 5-min versus 90-s on/off IHx protocols are largely similar.
UNASSIGNED: Peripheral respiratory chemoreceptors monitor breath-by-breath changes in arterial CO2 and O2 , and mediate ventilatory changes to maintain homeostasis. Intermittent hypoxia (IHx) elicits hypoxic ventilatory responses, with well-described experience-dependent effects (EDEs), derived mostly from animal work involving intermittent 5-min cycles of hypoxia and normoxia. These EDEs include post-hypoxia frequency decline (PHxFD), progressive augmentation (PA) and long-term facilitation (LTF). Comparisons of these EDEs between animal models and humans using similar IHx protocols are lacking. In addition, it is unknown whether shorter bouts of hypoxia, which may be more relevant to clinical conditions, elicit EDEs of similar magnitudes in humans. Respiratory (frequency, tidal volume and minute ventilation ( V ̇ I ) and cardiovascular (heart rate and mean arterial pressure (MAP)) variables were measured during and following two patterns of acute isocapnic IHx in 14 healthy human participants (four female): (1) 5 × 5 min and (2) 5 × 90 s on/off hypoxia. Participants\' end-tidal P O 2 was clamped at 45 Torr during hypoxia and 100 Torr during normoxia. We found that (1) PHxFD and PA were not present in either IHx pattern (P > 0.14), (2) LTF was present in V ̇ I following both 5-min (P < 0.001) and 90-s isocapnic IHx trials (P < 0.001), and (3) LTF was present in MAP following 5-min isocapnic IHx (P < 0.001), and trended towards significance following 90-s IHx (P = 0.058). We demonstrate that acute isocapnic IHx alone may not elicit all of the EDEs that have been described in animal models. Additionally, ventilatory LTF occurred regardless of the length of hypoxia-normoxia cycles.