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The neural respiratory output of isolated brainstems of post-metamorphic tadpoles displays two motor patterns, the buccal and the lung rhythms. Their global dynamics are complex and chaos-like. This study aimed at determining the source of this complexity. The neural respiratory output was recorded during exposure to increasing concentration of DAMGO or to reduced chloride concentration. Complexity was quantified with the noise limit (NL) and the largest Lyapunov exponent (LLE) values. DAMGO decreased lung frequency (p<0.0001), NL (p<0.0001) and LLE (p=0.0001) without changing buccal frequency (p=0.2392). Reduced concentration of chloride decreased buccal frequency (p=0.011) without changing lung frequency (p=0.2393) whereas NL (p=0.011) and LLE (p=0.027) increased significantly. When taking all the recordings into account, NL and LLE were correlated to lung frequency (r=0.661, p<0.0001 and r=0.3948, p=0.0012, respectively) but not to buccal frequency (r=0.1191, p=0.3487 and r=0.2083, p=0.0985, respectively). Therefore, the lung neural oscillator is both necessary and sufficient to the ventilatory complexity in the isolated brainstem of the post-metamorphic tadpole., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Central CO(2) chemosensitivity is crucial for all air-breathing vertebrates and raises the question of its role in ventilatory rhythmogenesis. In this study, neurograms of ventilatory motor outputs recorded in facial nerve of premetamorphic and postmetamorphic tadpole isolated brainstems, under normo- and hypercapnia, are investigated using Continuous Wavelet Transform spectral analysis for buccal activity and computation of number and amplitude of spikes during buccal and lung activities. Buccal bursts exhibit fast oscillations (20-30Hz) that are prominent in premetamorphic tadpoles: they result from the presence in periodic time windows of high amplitude spikes. Hypercapnia systematically decreases the frequency of buccal rhythm in both pre- and postmetamorphic tadpoles, by a lengthening of the interburst duration. In postmetamorphic tadpoles, hypercapnia reduces buccal burst amplitude and unmasks small fast oscillations. Our results suggest a common effect of the hypercapnia on the buccal part of the Central Pattern Generator in all tadpoles and a possible effect at the level of the motoneuron recruitment in postmetamorphic tadpoles., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Human tidal breathing features mathematical complexity and breath-by-breath variability. Fluctuations in these descriptors from one state to another are related to the load imposed on the respiratory system. We hypothetized that bronchodilators would increase ventilatory complexity and variability in patients suffering from chronic obstructive pulmonary disease (COPD). Eleven patients with stable COPD (9 men; age 48-79; FEV1 42-80%; FRC above 120%) were studied before and after 400 μg salbutamol. Breath-by-breath variability (coefficient of variation of tidal volume and breathing frequency -f) and ventilatory complexity (noise limit - NL, a quantifier of nonlinearity and complexity; largest Lyapunov exponent - LLE, an indicator of the sensitivity of the system to initial conditions) were described. Acute bronchodilation revealed or increased nonlinearity (NL 31% [20-38] to 43% [35-58], P=0.0051). Little changes in variability were observed (increased coefficient of variation of f). These observations might open new avenues toward resting breathing pulmonary function testing and novel respiratory biomarkers suitable for home-based lung disease monitoring., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The automatic ventilatory drive in amphibians depends on two oscillators interacting with each other, the gill/buccal and lung oscillators. The lung oscillator would be homologous to the mammalian pre-Bötzinger complex and the gill/buccal oscillator homologous to the mammalian parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN). Dysfunction of the pFRG/RTN has been involved in the development of respiratory diseases associated to the loss of CO(2) chemosensitivity such as the congenital central hypoventilation syndrome. Here, on adult in vitro isolated frog brainstem, consequences of the buccal oscillator inhibition (by reducing Cl(-)) were evaluated on the respiratory rhythm developed by the lung oscillator under hypercapnic challenges. Our results show that under low Cl(-) concentration (i) the buccal oscillator is strongly inhibited and the lung burst frequency and amplitude decreased and (ii) it persists a powerful CO(2) chemosensitivity. In conclusion, in frog, the CO(2) chemosensitivity depends on cellular contingent(s) whose the functioning is independent of the concentration of Cl(-) and origin remains unknown., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Patients suffering from congenital central hypoventilation syndrome (CCHS) depend on mechanical ventilation during sleep, from birth and throughout life. They lack CO₂-chemosensitivity. Hope has recently been raised by serendipitous observations of chemosensitivity recovery under treatment by desogestrel, a very potent progestin (Straus et al., 2010). Caution is however needed, because this effect could depend on dose, idiosyncrasies, or be transient. Desogestrel should not be prescribed to CCHS patients with a respiratory purpose until the results of a pending clinical trial (clinicaltrials.gov. NCT01243697) are available., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Congenital central hypoventilation syndrome (CCHS), or Ondine's curse syndrome, is a rare genetic disorder associated with mutations of the PHOX2B gene. It is characterized by sleep-related life-threatening hypoventilation that requires mechanical ventilation. The ventilatory response to hypercapnia and hypoxia is absent or dramatically reduced. Spontaneous or pharmacologically induced recovery has never been reported. We have fortuitously observed a case of CO(2)-chemosensitivity recovery in a woman with CCHS who took a progestin contraceptive - desogestrel. We hypothesized that the desogestrel could be responsible for this effect. We tested this hypothesis in a second adult patient. Her lack of CO(2)-chemosensitivity was documented 5 months before she was prescribed desogestrel. Three weeks after initiation of the treatment she exhibited a ventilatory and sensory response to hypercapnia. This response persisted 3 weeks later. This is the first documented case of pharmacologically restored chemosensitivity in CCHS. It suggests that a very potent progestin such as desogestrel could unveil latent chemosensitive neural circuits., ((c) 2010 Elsevier B.V. All rights reserved.)

Human ventilation at rest exhibits complexity and chaos. The aim of this study was to determine whether suprapontine interferences with the automatic breathing control could contribute to ventilatory chaos. We conducted a post hoc analysis of a previous study performed in awake volunteers exhibiting cortical pre-motor potentials during inspiratory loading. In eight subjects, flow was recorded at rest, while breathing against inspiratory threshold loads (median 21.5 cm H(2)O) and resistive loads (50 cm H(2)Ol(-1)s(-1)) loads, and while inhaling 7% CO(2)-93% O(2). Chaos was identified through noise titration (noise limit, NL) and the sensitivity to initial conditions was assessed through the largest Lyapunov exponent (LLE). Breath-by-breath variability was evaluated using the coefficient of variation of several ventilatory variables. Chaos was consistently present in ventilatory flow recordings, but mechanical loading did not alter NL, LLE, or variability. In contrast, CO(2) altered chaos and reduced variability. In conclusion, inspiratory loading - and any resultant respiratory-related cortical activity - were not associated with changes in ventilatory chaos in this study, arguing against suprapontine contributions to ventilatory complexity.

Ventilatory flow measured at the airway opening in humans exhibits a complex dynamics that has the features of chaos. Currently available data point to a neural origin of this feature, but the role of respiratory mechanics has not been specifically assessed. In this aim, we studied 17 critically ill mechanically ventilated patients during a switch form an entirely machine-controlled assistance mode (assist-controlled ventilation ACV) to a patient-driven mode (inspiratory pressure support IPS). Breath-by-breath respiratory variability was assessed with the coefficient of variation of tidal volume, total cycle time, inspiratory time, expiratory time, mean inspiratory flow, duty cycle. The detection of chaos was performed with the noise titration technique. When present, chaos was characterized with numerical indexes (correlation dimension, irregularity; largest Lyapunov exponent, sensitivity to initial conditions). Expectedly, the coefficients of variations of the respiratory variables were higher during IPS than during ACV. During ACV, noise titration failed to detect nonlinearities in 12 patients who did not exhibit signs of spontaneous respiratory activity. This indicates that the mechanical properties of the respiratory system were not sufficient to produce ventilatory chaos in the presence of a nonlinear command (ventilator clock). A positive noise limit was found in the remaining 5 cases, but these patients exhibited signs of active expiratory control (highly variable expiratory time, respiratory frequency higher than the set frequency). A positive noise limit was also observed in 16/17 patients during IPS (p<0.001). These observations suggest that ventilatory chaos predominantly has a neural origin (intrinsic to the respiratory central pattern generators, resulting from their perturbation by respiratory afferents, or both), with little contribution of respiratory mechanics, if any.

Assessing diaphragm function is clinically and physiologically pertinent. It can rely on the measurement of pressure responses to phrenic stimulation. Combining mouth pressure (Pm) with cervical magnetic stimulation (CMS) is painless and easy to perform, but Pm-CMS poorly reflects esophageal pressure (Pes-CMS) because of poor pressure transmission across the airway. We reasoned that the mouth opening and neck flexion that are associated with the measurement of Pm-CMS would impair upper airway dynamics and further hinder pressure transmission. Therefore, we assessed the CMS-related pressure measured in a nasal mask (Pmask; mouth closed) without neck flexion as a possible surrogate of Pes-CMS, in 14 men and 3 women, age 24.5+/-2.2. Pes-CMS was 15.7+/-4.3 cmH2O, significantly higher than Pm-CMS (13.5+/-5.6 cmH2O, P<0.0001) but not different from Pmask-CMS (15.2+/-4.9 cmH2O). The concordance correlation coefficient was low (0.6808) between Pes-CMS and Pm-CMS. It was higher between Pes-CMS and Pmask-CMS (0.8730). Pm-CMS wrongly classified five subjects as abnormal (<10 cmH2O), versus 1 for Pmask and 5 for Pm (P=0.025). Passing and Bablok regressions found no difference between Pes-CMS and Pmask-CMS, but identified a systematic difference and a proportional error between Pes-CMS and Pm-CMS. We conclude that Pmask-CMS is a better surrogate of Pes-CMS than Pm-CMS.

Human ventilation is aperiodic, exhibiting a breath-by-breath variability and a complexity of which the characteristics may be interesting physiologically and clinically. In the present study, we tested the ability of respiratory inductive plethysmography (RIP) to describe these properties. Indeed, RIP does not have the effects on ventilation described with mouthpiece measurements. We compared the ventilatory flow recorded with a pneumotachograph (V'PNT) and the ventilatory flow derived from the mathematical treatment of the thoracoabdominal motion signals obtained from a particular type of RIP (V'RIP, Visuresp, Meylan, France) in 8 freely breathing normal subjects. Using the Z correlation coefficient, Passing-Bablock regressions and Bland and Altman graphical analyses, we compared the coefficients of variation of the main discrete respiratory variables determined with V'PNT and V'RIP and a set of nonlinear descriptors including the noise limit (chaotic nature of the signal), largest Lyapunov exponent (sensitivity to initial conditions), the Kolmogorov-Sinai entropy (unpredictability) and the correlation dimension (irregularity). When the recordings were obtained with the two techniques simultaneously, all the measurements were correlated and interchangeable. RIP can be safely used to quantify the breath-by-breath variability of ventilation and to study the complexity and the chaotic behavior of the ventilatory flow.

Unlabelled: The human ventilation depends on bulbospinal and corticospinal commands. This study assessed their interactions in five healthy volunteers (two men, age 25-35) through the description of diaphragm and abductor pollicis brevis (APB) motor potentials (DiMEPs, abpMEPs) evoked by transcranial magnetic stimulation (TMS) during relaxed expiration and tidal inspiration and during wake and sleep. NREM decreased corticospinal excitability and REM further did so, for both the diaphragm and the APB. During wake, inspiration shortened supine DiMEPs latencies (expiration 18.56+/-1.90ms; inspiration 17.37+/-1.48ms, P<0.001). This persisted during sleep in an augmented manner (expiration: 21.05+/-1.39ms; inspiration 18.69+/-1.17ms, P=0.002). Inspiration had no effect on apbMEPs during wake and sleep., In Conclusion: (1) the tidal bulbospinal input to phrenic motoneurones is sufficient to modulate the throughput of the corticospinal pathway to these neurones; (2) this modulation is best seen after the sleep related removal of corticospinal and/or afferent inputs.

The mammalian ventilatory behaviour exhibits nonlinear dynamics as reflected by certain nonlinearity or complexity indicators (e.g. correlation dimension, approximate entropy, Lyapunov exponents, etc.) but this is not sufficient to determine its possible chaotic nature. To address this, we applied the noise titration technique, previously shown to discern and quantify chaos in short and noisy time series, to ventilatory flow recordings obtained in quietly breathing normal humans. Nine subjects (8 men and 1 woman, 24-42 years) were studied during 15-min epochs of ventilatory steady-state (10.1+/-3.0 breaths/min, tidal volume 0.63+/-0.2 L). Noise titration applied to the unfiltered signals subsampled at 5 Hz detected nonlinearity in all cases (noise limit 20.2+/-12.5%). Noise limit values were weakly correlated to the correlation dimension and the largest Lyapunov exponent of the signals. This study shows that the noise titration approach evidences a chaotic dimension to the behavior of ventilatory flow over time in normal humans during tidal breathing.

Studying the inspiratory recruitment of the scalenes is clinically relevant, but the interpretation of surface electromyographic (EMG) recordings is difficult. The aim of this study was to optimize an averaging method to analyze the surface EMG activity of the scalenes. Ten healthy subjects were studied. Nasal flow and surface EMG of the right scalene were recorded during 15 min epochs of quiet breathing. In four subjects, needle scalene EMG was also recorded. The flow signal was used to trigger the ensemble averaging of the ventilatory wave forms from 80 consecutive breaths. In eight cases, this evidenced a phasic inspiratory activation of the scalenes and permitted the determination of the electromechanical inspiratory delay (134+/-55 ms) and post-inspiratory activity (811+/-233 ms). When simultaneously available, surface and intramuscular recordings provided identical results. An averaging method triggered from a respiratory flow signal can identify and characterize a low phasic inspiratory activity of the scalenes within a noisy surface signal.

Gas exchange at the acinar level involves several physico-chemical phenomena within a complex geometry. A gas transport model, which takes into account both the diffusion into the acinus and the diffusion across the alveolar membrane, is used to understand gas mixing in realistic systems. It is first shown that the behaviour of the system, computed on model geometries in 3D, only depends on the topological structure of the acinus. Taking advantage of this property, a new efficient method based on random walks on a lattice is used to compute gas diffusion in structures taken from real morphological data. This approach shows that, at rest, the human acinus efficiency is only 30-40%. These results provide a new evidence of the existence of diffusional screening at the acinar level. This implies permanent spatial inhomogeneity of oxygen and carbon dioxide partial pressure. The notion of an "alveolar gas" is reinterpreted as a spatial average of the gas distribution. This model casts new light on the respiratory properties of other gas mixtures, such as helium-oxygen.