Ventilatory Long-Term Facilitation at Rest Increases the Feedforward Contribution to Subsequent Exercise Ventilatory Responses.

The respiratory control system exhibits neural plasticity, adjusting future ventilatory responses based on experience. We tested the hypothesis that ventilatory long-term facilitation induced by hypercapnic acute intermittent hypoxia (AIH) at rest enhances subsequent ventilatory responses to steady-state exercise. Fourteen healthy adults (age = 27 ± 5 years; 7 males) participated in the study.

Inaugural Review Prize 2023: The exercise hyperpnoea dilemma: A 21st-century perspective.

During mild or moderate exercise, alveolar ventilation increases in direct proportion to metabolic rate, regulating arterial CO pressure near resting levels. Mechanisms giving rise to the hyperpnoea of exercise are unsettled despite over a century of investigation. In the past three decades, neuroscience has advanced tremendously, raising optimism that the 'exercise hyperpnoea dilemma' can finally be solved.

Cardiorespiratory Responses to Acute Intermittent Hypoxia in Humans With Chronic Spinal Cord Injury.

Brief exposure to repeated episodes of low inspired oxygen, or acute intermittent hypoxia (AIH), is a promising therapeutic modality to improve motor function after chronic, incomplete spinal cord injury (SCI). Although therapeutic AIH is under extensive investigation in persons with SCI, limited data are available concerning cardiorespiratory responses during and after AIH exposure despite implications for AIH safety and tolerability. Thus, we recorded immediate (during treatment) and enduring (up to 30 min post-treatment) cardiorespiratory responses to AIH in 19 participants with chronic SCI (>1 year post-injury; injury levels C1 to T6; American Spinal Injury Association Impairment Scale A to D; mean age = 33.

APOE4, Age, and Sex Regulate Respiratory Plasticity Elicited by Acute Intermittent Hypercapnic-Hypoxia.

Rationale: Acute intermittent hypoxia (AIH) shows promise for enhancing motor recovery in chronic spinal cord injuries and neurodegenerative diseases. However, human trials of AIH have reported significant variability in individual responses.

Objectives: Identify individual factors (eg, genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH).

Control of Breathing.

Substantial advances have been made recently into the discovery of fundamental mechanisms underlying the neural control of breathing and even some inroads into translating these findings to treating breathing disorders. Here, we review several of these advances, starting with an appreciation of the importance of V̇:V̇CO:PaCO relationships, then summarizing our current understanding of the mechanisms and neural pathways for central rhythm generation, chemoreception, exercise hyperpnea, plasticity, and sleep-state effects on ventilatory control. We apply these fundamental principles to consider the pathophysiology of ventilatory control attending hypersensitized chemoreception in select cardiorespiratory diseases, the pathogenesis of sleep-disordered breathing, and the exertional hyperventilation and dyspnea associated with aging and chronic diseases.

fNIRS analysis of rostral prefrontal cortex activity and perception of inspiratory loads.

It is well-established that the brainstem is responsible for the automatic control of breathing, however, cortical areas control perception and conscious breathing. This study investigated activity in the prefrontal cortex (PFC) during breathing difficulty using functional near-infrared spectroscopy (fNIRS). It was hypothesized that extrinsic inspiratory loads will elicit regional changes in PFC activity and increased perception ratings, as a function of load magnitude and type.

APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia.

Rationale: Acute intermittent hypoxia (AIH) is a promising strategy to induce functional motor recovery following chronic spinal cord injuries and neurodegenerative diseases. Although significant results are obtained, human AIH trials report considerable inter-individual response variability.

Objectives: Identify individual factors ( , genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH).

Effects of hypoxia on exercise-induced diaphragm fatigue in healthy males and females.

Following high-intensity, normoxic exercise there is evidence to show that healthy females, on average, exhibit less fatigue of the diaphragm relative to males. In the present study, we combined hypoxia with exercise to test the hypothesis that males and females would develop a similar degree of diaphragm fatigue following cycle exercise at the same relative exercise intensity. Healthy young participants (n = 10 male; n = 10 female) with a high aerobic capacity (120% predicted) performed two time-to-exhaustion (TTE; ~85% maximum) cycle tests on separate days breathing either a normoxic or hypoxic (FiO  = 0.

Predictors of Expiratory Flow Limitation during Exercise in Healthy Males and Females.

Rationale: It is unclear whether the frequency and mechanisms of expiratory flow limitation (EFL) during exercise differ between males and females.

Purpose: This study aimed to determine which factors predispose individuals to EFL during exercise and whether these factors differ based on sex. We hypothesized that i) EFL frequency would be similar in males and females and ii) in females, EFL would be associated with indices of low ventilatory capacity, whereas in males, EFL would be associated with indices of high ventilatory demand.

Acute intermittent hypercapnic-hypoxia elicits central neural respiratory motor plasticity in humans.

Acute intermittent hypoxia (AIH) elicits long-term facilitation (LTF) of respiration. Although LTF is observed when CO is elevated during AIH in awake humans, the influence of CO 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).

Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease.

We review progress towards greater mechanistic understanding and clinical translation of a strategy to improve respiratory and non-respiratory motor function in people with neuromuscular disorders, therapeutic acute intermittent hypoxia (tAIH). In 2016 and 2020, workshops to create and update a "road map to clinical translation" were held to help guide future research and development of tAIH to restore movement in people living with chronic, incomplete spinal cord injuries. After briefly discussing the pioneering, non-targeted basic research inspiring this novel therapeutic approach, we then summarize workshop recommendations, emphasizing critical knowledge gaps, priorities for future research effort, and steps needed to accelerate progress as we evaluate the potential of tAIH for routine clinical use.

Daily acute intermittent hypoxia enhances phrenic motor output and stimulus-evoked phrenic responses in rats.

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.

Single-session effects of acute intermittent hypoxia on breathing function after human spinal cord injury.

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.

Effect of acute intermittent hypoxia on cortico-diaphragmatic conduction in healthy humans.

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.

Ventilatory responses to constant load exercise following the inhalation of a short-acting ß-agonist in a laboratory-controlled diesel exhaust exposure study in individuals with exercise-induced bronchoconstriction.

Objective: Individuals with exercise-induced bronchoconstriction (EIB) use ß-agonists to reduce respiratory symptoms during acute exercise. The resultingbronchodilation could increase the dose of inhaled pollutants and impair respiratory function when exercise is performedin air pollution. We aimed to assess respiratory responses in individuals with EIB when completing a cycling bout while being exposed to diesel exhaust (DE) or filtered air (FA) with and without the inhalation of salbutamol (SAL), a short-acting ß-agonist.

Sex differences in diaphragmatic fatigue: Effects of hypoxia during inspiratory loading.

Key Points: Under normoxic conditions, both healthy female and male diaphragms fatigue at a similar degree when matched for absolute diaphragmatic work during inspiratory loading. We investigated whether similarities in diaphragm fatigability persist under acute hypoxic conditions. We found that, in acute hypoxia, fatigue of the diaphragm is greater in women compared to men, whereas the magnitude of fatigue in normoxia did not differ between sexes.

Reliability of diaphragmatic motor-evoked potentials induced by transcranial magnetic stimulation.

The diaphragmatic motor-evoked potential (MEP) induced by transcranial magnetic stimulation (TMS) permits electrophysiological assessment of the cortico-diaphragmatic pathway. Despite the value of TMS for investigating diaphragm motor integrity in health and disease, reliability of the technique has not been established. The study aim was to determine within- and between-session reproducibility of surface electromyogram recordings of TMS-evoked diaphragm potentials.

Synergy between Acute Intermittent Hypoxia and Task-Specific Training.

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.

Diaphragm fatigue and inspiratory muscle metaboreflex in men and women matched for absolute diaphragmatic work during pressure-threshold loading.

Key Points: The female diaphragm fatigues at a slower rate compared to that of males, with blunted cardiovascular consequences (i.e. inspiratory muscle metaboreflex).

Effect of diaphragm fatigue on subsequent exercise tolerance in healthy men and women.

Women are more resistant to diaphragmatic fatigue (DF) and experience an attenuated inspiratory muscle metaboreflex relative to men. The effects of such sex-based differences on whole body exercise tolerance are yet to be examined. It was hypothesized that DF induced prior to exercise would cause less of a reduction in subsequent exercise time in women compared to men.

Does competitive swimming affect lung growth?

Whether the large lungs of swimmers result from intensive training or genetic endowment has been widely debated. Given that peak lung growth velocities occur during puberty, this study examined if competitive swimming during puberty affected lung growth. Eleven- to fourteen-year-old healthy female competitive swimmers and controls were assessed before (PRE) and after (POST) one swimming season (7.

Sex differences in diaphragmatic fatigue: the cardiovascular response to inspiratory resistance.

Key Points: Diaphragmatic fatigue (DF) elicits a sympathetically mediated metaboreflex resulting in increased heart rate, blood pressure and limb vascular resistance. Women may be more resistant to DF compared to men, and therefore it was hypothesised that women would experience an attenuated inspiratory muscle metaboreflex during inspiratory pressure-threshold loading (PTL) performed to task failure. At the time of PTL task failure, the severity of DF was not different between sexes; however, inspiratory muscle endurance time was significantly longer in women than in men.

Temporal characteristics of exercise-induced diaphragmatic fatigue.

There is evidence suggesting diaphragmatic fatigue (DF) occurs relatively early during high-intensity exercise; however, studies investigating the temporal characteristics of exercise-induced DF are limited by incongruent methodology. Eight healthy adult males (25 ± 5 yr) performed a maximal incremental exercise test on a cycle ergometer on day 1. A constant-load time-to-exhaustion (TTE) exercise test was conducted on day 2 at 60% delta between the calculated gas exchange threshold and peak work rate.

Classical experiments in whole-body metabolism: closed-circuit respirometry.

As part of a series of reviews aimed at providing historical context to the study of whole-body metabolism, this article focuses on the technique of closed-circuit respirometry. Developed by nineteenth century physiologists Henri-Victor Regnault and Jules de Reiset, a constant-pressure closed-circuit calorimeter capable of measuring oxygen consumption and carbon dioxide production in small animals became the framework for future experiments on whole-body metabolism in humans. The volume-loss and volume-replenishment techniques can be used to indirectly assess energy expenditure using an oxygen reservoir; spirometers are simplistic in design but difficult to operate.