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. Participants were exposed to varying magnitudes of resistive (R) and pressure threshold (PT) inspiratory loads to increase breathing effort. Perception ratings of breathing effort and load magnitude were positively correlated (p < 0.05). PT loads were rated more effortful than R loads (p < 0.05). Differences in perceived effort were a function of inspiratory pressure-time-product (PTP) and inspiratory work of breathing (WoB). PFC activity increased with the largest PT load (p < 0.01), suggesting that the PFC is involved in processing respiratory stimuli. The results support the hypothesis that the PFC is an element of the neural network mediating effortful breathing perception.

Complex Network Model Reveals the Impact of Inspiratory Muscle Pre-Activation on Interactions among Physiological Responses and Muscle Oxygenation during Running and Passive Recovery.

Although several studies have focused on the adaptations provided by inspiratory muscle (IM) training on physical demands, the warm-up or pre-activation (PA) of these muscles alone appears to generate positive effects on physiological responses and performance. This study aimed to understand the effects of inspiratory muscle pre-activation (IMPA) on high-intensity running and passive recovery, as applied to active subjects. In an original and innovative investigation of the impacts of IMPA on high-intensity running, we proposed the identification of the interactions among physical characteristics, physiological responses and muscle oxygenation in more and less active muscle to a running exercise using a complex network model. For this, fifteen male subjects were submitted to all-out 30 s tethered running efforts preceded or not preceded by IMPA, composed of 2 × 15 repetitions (1 min interval between them) at 40% of the maximum individual inspiratory pressure using a respiratory exercise device. During running and recovery, we monitored the physiological responses (heart rate, blood lactate, oxygen saturation) and muscle oxygenation (in vastus lateralis and biceps brachii) by wearable near-infrared spectroscopy (NIRS). Thus, we investigated four scenarios: two in the tethered running exercise (with or without IMPA) and two built into the recovery process (after the all-out 30 s), under the same conditions. Undirected weighted graphs were constructed, and four centrality metrics were analyzed (Degree, Betweenness, Eigenvector, and Pagerank). The IMPA (40% of the maximum inspiratory pressure) was effective in increasing the peak and mean relative running power, and the analysis of the complex networks advanced the interpretation of the effects of physiological adjustments related to the IMPA on exercise and recovery. Centrality metrics highlighted the nodes related to muscle oxygenation responses (in more and less active muscles) as significant to all scenarios, and systemic physiological responses mediated this impact, especially after IMPA application. Our results suggest that this respiratory strategy enhances exercise, recovery and the multidimensional approach to understanding the effects of physiological adjustments on these conditions.

Impact of inspiratory threshold loading on brain activity and cognitive performances in healthy humans.

In healthy humans, inspiratory threshold loading deteriorates cognitive performances. This can result from motor-cognitive interference (activation of motor respiratory-related cortical networks vs. executive resources allocation), sensory-cognitive interference (dyspnea vs. shift in attentional focus), or both. We hypothesized that inspiratory loading would concomitantly induce dyspnea, activate motor respiratory-related cortical networks, and deteriorate cognitive performance. We reasoned that a concomitant activation of cortical networks and cognitive deterioration would be compatible with motor-cognitive interference, particularly in case of a predominant alteration of executive cognitive performances. Symmetrically, we reasoned that a predominant alteration of attention-depending performances would suggest sensory-cognitive interference. Twenty-five volunteers (12 men; 19.5-51.5 yr) performed the Paced Auditory Serial Addition Test (PASAT-A and B; calculation capacity, working memory, attention), the Trail Making Test (TMT-A, visuospatial exploration capacity; TMT-B, visuospatial exploration capacity, and attention), and the Corsi block-tapping test (visuospatial memory, short-term, and working memory) during unloaded breathing and inspiratory threshold loading in random order. Loading consistently induced dyspnea and respiratory-related brain activation. It was associated with deteriorations in PASAT-A [52 [45.5;55.5]; (median [interquartile range]) to 48 [41;54.5], P = 0.01], PASAT-B (55 [47.5;58] to 51 [44.5;57.5], P = 0.01), and TMT-B (44 s [36;54.5] to 53 s [42;64], P = 0.01), but did not affect TMT-A and Corsi. The concomitance of cortical activation and cognitive performance deterioration is compatible with competition for cortical resources (motor-cognitive interference), whereas the profile of cognitive impairment (PASAT and TMT-B but not TMT-A and Corsi) is compatible with a contribution of attentional distraction (sensory-cognitive interference). Both mechanisms are therefore likely at play.NEW & NOTEWORTHY To our knowledge, this is the first study exploring the interferences between inspiratory loading and cognition in healthy subjects with the concomitant use of neuropsychological tests and electroencephalographic recordings. Inspiratory loading was associated with dyspnea, respiratory-related changes in brain activation, and a pattern of deterioration of neuropsychological tests suggestive of attentional disruption. Inspiratory loading is therefore likely to impact cognitive performances through both motor-cognitive interference (engagement of cortical networks) and sensory-cognitive interference (dyspnea-related shift in attentional focus).

Sleep deprivation reduces vagal tone during an inspiratory endurance task in humans.

STUDY OBJECTIVES: Sleep deprivation alters inspiratory endurance by reducing inspiratory motor output. Vagal tone is involved in exercise endurance. This study aimed to investigate the effect of sleep deprivation on vagal tone adaptation in healthy subjects performing an inspiratory effort. METHODS: Vagal tone was assessed using Heart Rate Variability normalized units of frequency domain component HF (high frequency) before, at the start, and the end of an inspiratory loading trial performed until exhaustion by 16 volunteers after one night of sleep deprivation and one night of normal sleep, where sleep deprivation reduced the inspiratory endurance by half compared to the normal sleep condition (30 min vs 60 min). RESULTS: At rest, heart rate was similar in sleep deprivation and normal sleep conditions. In normal sleep condition, heart rate increased during inspiratory loading task; this increase was greater in sleep deprivation condition. In normal sleep condition, vagal tone increased at the beginning of the trial. This vagal tone increase was absent in sleep deprivation condition. CONCLUSIONS: Sleep deprivation abolished vagal tone response to inspiratory load, possibly contributing to a higher heart rate during the trial and to a reduced inspiratory endurance. CLINICAL TRIAL REGISTRATION: NCT02725190.

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. When matched for maximal diaphragm strength, women and men had a similar pressor response to work-matched inspiratory loading, independent of oxygen availability. ABSTRACT: In normoxia, women and men display a comparable magnitude of diaphragmatic fatigue (DF) after work-matched inspiratory loading. Whether these sex similarities are maintained under acute hypoxic conditions is unknown. We investigated the influence of acute hypoxia during work-matched inspiratory pressure-threshold loading (PTL) on DF in healthy women (n = 8) and men (n = 8). Two 5 min isocapnic PTL tasks targeting a transdiaphragmatic pressure (Pdi ) of 92 cmH2 O in normoxia and hypoxia (8% O2 ) were performed on separate days (≥48 h). DF was quantified by twitch Pdi (Pdi,tw ) via cervical magnetic stimulation post-PTL. Women and men had similar maximal Pdi (Pdi,max ; women: 171 ± 16, men: 178 ± 20 cmH2 O) and relative target workload (women: 54 ± 5%, men: 53 ± 6% Pdi,max ). The absolute cumulative diaphragmatic work did not differ between sexes in normoxia (women: 12,653 ± 1796 cmH2 O s-1 , men: 13,717 ± 1231 cmH2 O s-1 ; P = 0.202) or hypoxia (women: 11,624 ± 1860 cmH2 O s-1 , men: 12 722 ± 1502 cmH2 O s-1 ; P = 0.189). In normoxia, the magnitude of reduction in Pdi,tw post-PTL was similar between sexes (women: -21.1 ± 8.4%, men: -22.5 ± 4.9 %; P = 0.193); however, a higher degree of DF was observed in women compared to men following PTL in acute hypoxia (women: -27.6 ± 7.7%, men: -23.4 ± 9.6%, P = 0.019). We conclude that the female diaphragm is more susceptible to fatigue after inspiratory loading under acute hypoxic conditions. This finding may be related to sex differences in diaphragm muscle metabolism, such as fibre type composition, contractile properties, substrate utilisation and blood perfusion.

The reliability of inspiratory resistive load magnitude and detection testing.

OBJECTIVES: To assess the test-retest reliability of inspiratory load detection and load magnitude perception tests in healthy volunteers. DESIGN: Cohort of convenience. SETTING: Respiratory physiology laboratory. PARTICIPANTS: Twenty healthy adults. INTERVENTIONS: On two separate occasions participants performed tests of inspiratory loading. Participants breathed through custom made resistive tubing and were asked to indicate when they detected a different resistance during inspiration. In a second test participants rated the magnitude of presented inspiratory loads using the modified Borg score. MAIN OUTCOME MEASURES: Intra-class Correlation Coefficient (ICC2,1) values for repeated tests of inspiratory load detection threshold and load magnitude rating. RESULTS: ICC2,1 values ranged from 0.657-0.786 for load detection testing and 0.739 to 0.969 for rating of load magnitude. CONCLUSIONS: The tests are simple and reliable measures of inspiratory load detection and magnitude rating. They can be used in future research to determine the effectiveness of interventions to reduce the effort of breathing in health and disease.

Reduced Phrenic Motoneuron Recruitment during Sustained Inspiratory Threshold Loading Compared to Single-Breath Loading: A Twitch Interpolation Study.

In humans, inspiratory constraints engage cortical networks involving the supplementary motor area. Functional magnetic resonance imaging (fMRI) shows that the spread and intensity of the corresponding respiratory-related cortical activation dramatically decrease when a discrete load becomes sustained. This has been interpreted as reflecting motor cortical reorganization and automatisation, but could proceed from sensory and/or affective habituation. To corroborate the existence of motor reorganization between single-breath and sustained inspiratory loading (namely changes in motor neurones recruitment), we conducted a diaphragm twitch interpolation study based on the hypothesis that motor reorganization should result in changes in the twitch interpolation slope. Fourteen healthy subjects (age: 21-40 years) were studied. Bilateral phrenic stimulation was delivered at rest, upon prepared and targeted voluntary inspiratory efforts ("vol"), upon unprepared inspiratory efforts against a single-breath inspiratory threshold load ("single-breath"), and upon sustained inspiratory efforts against the same type of load ("continuous"). The slope of the relationship between diaphragm twitch transdiaphragmatic pressure and the underlying transdiaphragmatic pressure was -1.1 ± 0.2 during "vol," -1.5 ± 0.7 during "single-breath," and -0.6 ± 0.4 during "continuous" (all slopes expressed in percent of baseline.percent of baseline-1) all comparisons significant at the 5% level. The contribution of the diaphragm to inspiration, as assessed by the gastric pressure to transdiaphragmatic pressure ratio, was 31 ± 17% during "vol," 22 ± 16% during "single-breath" (p = 0.13), and 19 ± 9% during "continuous" (p = 0.0015 vs. "vol"). This study shows that the relationship between the amplitude of the transdiaphragmatic pressure produced by a diaphragm twitch and its counterpart produced by the underlying diaphragm contraction is not unequivocal. If twitch interpolation is interpreted as reflecting motoneuron recruitment, this study supports motor reorganization compatible with "diaphragm sparing" when an inspiratory threshold load becomes sustained.

Maximal inspiratory pressure is influenced by intensity of the warm-up protocol.

The aim of the study was to compare the effect of inspiratory muscle warm-up protocols with different intensities and breathing repetitions on maximal inspiratory pressure (MIP). Ten healthy and recreationally active men (183.3±5.5cm, 83.7±7.8kg, 26.4±4.1years) completed four different inspiratory muscle (IM) warm-up protocols (2×30 inspirations at 40% MIP, 2×12 inspirations at 60% MIP, 2×6 inspirations at 80% MIP, 2×30 inspirations at 15% MIP) on separate, randomly assigned visits. Pre-post values of MIP using MicroRPM (Micro Medical, Kent, UK) showed a significant increase in the mean values after the IM warm-up (POWERbreathe(®) K1, Warwickshire, UK) with 40% MIP and 60% MIP warm-up protocols, when MIP increased by 7cm H2O (95% CI: 0.10…13.89) (p=0.047) and by 6.4cm H2O (95% CI: 2.98…13.83) (p=0.027), respectively. In conclusion, a higher intensity inspiratory muscle warm-up protocol (2×12 breaths at 60% of MIP) can increase IM strength.

Repetitive transcranial magnetic stimulation over the supplementary motor area modifies breathing pattern in response to inspiratory loading in normal humans.

In awake humans, breathing depends on automatic brainstem pattern generators. It is also heavily influenced by cortical networks. For example, functional magnetic resonance imaging and electroencephalographic data show that the supplementary motor area becomes active when breathing is made difficult by inspiratory mechanical loads like resistances or threshold valves, which is associated with perceived respiratory discomfort. We hypothesized that manipulating the excitability of the supplementary motor area with repetitive transcranial magnetic stimulation would modify the breathing pattern response to an experimental inspiratory load and possibly respiratory discomfort. Seven subjects (three men, age 25 ± 4) were studied. Breathing pattern and respiratory discomfort during inspiratory loading were described before and after conditioning the supplementary motor area with repetitive stimulation, using an excitatory paradigm (5 Hz stimulation), an inhibitory paradigm, or sham stimulation. No significant change in breathing pattern during loading was observed after sham conditioning. Excitatory conditioning shortened inspiratory time (p = 0.001), decreased tidal volume (p = 0.016), and decreased ventilation (p = 0.003), as corroborated by an increased end-tidal expired carbon dioxide (p = 0.013). Inhibitory conditioning did not affect ventilation, but lengthened expiratory time (p = 0.031). Respiratory discomfort was mild under baseline conditions, and unchanged after conditioning of the supplementary motor area. This is the first study to show that repetitive transcranial magnetic stimulation conditioning of the cerebral cortex can alter breathing pattern. A 5 Hz conditioning protocol, known to enhance corticophrenic excitability, can reduce the amount of hyperventilation induced by inspiratory threshold loading. Further studies are needed to determine whether and under what circumstances rTMS can have an effect on dyspnoea.

Functional magnetic resonance imaging suggests automatization of the cortical response to inspiratory threshold loading in humans.

Inspiratory threshold loading (ITL) induces cortical activation. It is sustained over time and is resistant to distraction, suggesting automaticity. We hypothesized that ITL-induced changes in cerebral activation may differ between single-breath ITL and continuous ITL, with differences resembling those observed after cortical automatization of motor tasks. We analyzed the brain blood oxygen level dependent (BOLD) signal of 11 naive healthy volunteers during 5 min of random, single-breath ITL and 5 min of continuous ITL. Single-breath ITL increased BOLD in many areas (premotor cortices, bilateral insula, cerebellum, reticular formation of the lateral mesencephalon) and decreased BOLD in regions co-localizing with the default mode network. Continuous ITL induced signal changes in a limited number of areas (supplementary motor area). These differences are comparable to those observed before and after overlearning of motor tasks. We conclude that the respiratory-related cortical activation observed in response to ITL is likely due to automated, attention-independent mechanisms. Also, ITL activates cortical circuits right from the first breath.