OBJECTIVE: 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.
METHODS: Proof of concept, randomized crossover trial.
METHODS: Outpatient, rehabilitation hospital.
METHODS: 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.
METHODS: 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 RESULTS: 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.
CONCLUSIONS: 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.

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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.

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.

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.

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 (PtO2). Splanchnic and renal sympathetic nerve activity was recorded in intact and complete C2Hx rats.
Spinal PtO2 near phrenic motor neurons was decreased after C2Hx, an effect most prominent with complete vs. partial injuries; baseline PtO2 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.

Exposure to acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). Interest has grown in developing AIH interventions to treat ventilatory insufficiency, with promising results in spinal cord injury and amyotrophic lateral sclerosis. Therapeutic AIH may have application in neuromuscular disorders including muscular dystrophies. We sought to establish hypoxic ventilatory responsiveness and the expression of ventilatory LTF in X-linked muscular dystrophy (mdx) mice.Experiments were performed in 15 male wild-type (BL10) and 15 male mdx mice at 4 months of age. Ventilation was assessed using whole-body plethysmography. Baseline measures of ventilation and metabolism were established. Mice were exposed to 10 successive bouts of hypoxia, each lasting 5 min, interspersed with 5-min bouts of normoxia. Measurements were taken for 60 min following termination of AIH.In mdx mice, ventilation was significantly increased 60 min post-AIH compared to baseline. However, metabolic CO2 production was also increased. Therefore, ventilatory equivalent was unaffected by AIH exposure, i.e., no ventilatory LTF manifestation. In wild-type mice, ventilation and metabolism were not affected by AIH.Eliciting ventilatory LTF is dependent on many factors and may require concomitant isocapnia or hypercapnia during AIH exposures and/or repeated daily AIH exposures, which is worthy of further pursuit.

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 O2 = 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.

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.

OBJECTIVE: 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).
CONCLUSIONS: 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.