Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.

The gut-brain peptide neuromedin U (NMU) decreases food intake and body weight and improves glucose tolerance. Here, we characterized NMU as an enteropeptide and determined how it impacts glucose excursion. NMU was expressed predominantly in the proximal small intestine, and its secretion was triggered by ingestion of a mixed meal. Although a single peripheral injection of NMU in C57BL/6NRj mice prevented the rise of glycemia upon an oral but not an intraperitoneal load of glucose, it unexpectedly prevented insulin secretion, only slightly improved peripheral insulin sensitivity, and barely reduced intestinal glucose absorption. Interestingly, peripheral administration of NMU abrogated gastric emptying. NMU receptors 1 and 2 were detected in pyloric muscles and NMU was able to directly induce pyloric contraction in a dose-dependent manner ex vivo in isometric chambers. Using a modified glucose tolerance test, we demonstrate that improvement of oral glucose tolerance by NMU was essentially, if not exclusively, because of its impact on gastric emptying. Part of this effect was abolished in vagotomized (VagoX) mice, suggesting implication of the vagus tone. Accordingly, peripheral injection of NMU was associated with increased number of c-FOS-positive neurons in the nucleus of the solitary tract, which was partly prevented in VagoX mice. Finally, NMU kept its ability to improve oral glucose tolerance in obese and diabetic murine models. Together, these data demonstrate that NMU is an enteropeptide that prevents gastric emptying directly by triggering pylorus contraction and indirectly through vagal afferent neurons. This blockade consequently reduces intestinal nutrient absorption and thereby results in an apparent improved tolerance to oral glucose challenge.-Jarry, A.-C., Merah, N., Cisse, F., Cayetanot, F., Fiamma, M.-N., Willemetz, A., Gueddouri, D., Barka, B., Valet, P., Guilmeau, S., Bado, A., Le Beyec, J., Bodineau, L., Le Gall, M. Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.

Effect of Gender on Chronic Intermittent Hypoxic Fosb Expression in Cardiorespiratory-Related Brain Structures in Mice.

We aimed to delineate sex-based differences in neuroplasticity that may be associated with previously reported sex-based differences in physiological alterations caused by repetitive succession of hypoxemia-reoxygenation encountered during obstructive sleep apnea (OSA). We examined long-term changes in the activity of brainstem and diencephalic cardiorespiratory neuronal populations induced by chronic intermittent hypoxia (CIH) in male and female mice by analyzing Fosb expression. Whereas the overall baseline and CIH-induced Fosb expression in females was higher than in males, possibly reflecting different neuroplastic dynamics, in contrast, structures responded to CIH by Fosb upregulation in males only. There was a sex-based difference at the level of the rostral ventrolateral reticular nucleus of the medulla, with an increase in the number of FOSB/ΔFOSB-positive cells induced by CIH in males but not females. This structure contains neurons that generate the sympathetic tone and which are involved in CIH-induced sustained hypertension during waking hours. We suggest that the sex-based difference in neuroplasticity of this structure contributes to the reported sex-based difference in CIH-induced hypertension. Moreover, we highlighted a sex-based dimorphic phenomenon in serotoninergic systems induced by CIH, with increased serotoninergic immunoreactivity in the hypoglossal nucleus and a decreased number of serotoninergic cells in the dorsal raphe nucleus in male but not female mice. We suggest that this dimorphism in the neuroplasticity of serotoninergic systems predisposes males to a greater alteration of neuronal control of the upper respiratory tract associated with the greater collapsibility of upper airways described in male OSA subjects.

Current Perspectives for the use of Gonane Progesteronergic Drugs in the Treatment of Central Hypoventilation Syndromes.

BACKGROUND: Central alveolar hypoventilation syndromes (CHS) encompass neurorespiratory diseases resulting from congenital or acquired neurological disorders. Hypercapnia, acidosis, and hypoxemia resulting from CHS negatively affect physiological functions and can be lifethreatening. To date, the absence of pharmacological treatment implies that the patients must receive assisted ventilation throughout their lives. OBJECTIVE: To highlight the relevance of determining conditions in which using gonane synthetic progestins could be of potential clinical interest for the treatment of CHS. METHODS: The mechanisms by which gonanes modulate the respiratory drive were put into the context of those established for natural progesterone and other synthetic progestins. RESULTS: The clinical benefits of synthetic progestins to treat respiratory diseases are mixed with either positive outcomes or no improvement. A benefit for CHS patients has only recently been proposed. We incidentally observed restoration of CO2 chemosensitivity, the functional deficit of this disease, in two adult CHS women by desogestrel, a gonane progestin, used for contraception. This effect was not observed by another group, studying a single patient. These contradictory findings are probably due to the complex nature of the action of desogestrel on breathing and led us to carry out mechanistic studies in rodents. Our results show that desogestrel influences the respiratory command by modulating the GABAA and NMDA signaling in the respiratory network, medullary serotoninergic systems, and supramedullary areas. CONCLUSION: Gonanes show promise for improving ventilation of CHS patients, although the conditions of their use need to be better understood.

Desogestrel enhances ventilation in ondine patients: Animal data involving serotoninergic systems.

Congenital central hypoventilation syndrome (CCHS) is a neurorespiratory disease characterized by life-threatening sleep-related hypoventilation involving an alteration of CO2/H(+) chemosensitivity. Incidental findings have suggested that desogestrel may allow recovery of the ventilatory response to CO2. The effects of desogestrel on resting ventilation have not been reported. This study was designed to test the hypothesis that desogestrel strengthens baseline ventilation by analyzing the ventilation of CCHS patients. Rodent models were used in order to determine the mechanisms involved. Ventilation in CCHS patients was measured with a pneumotachometer. In mice, ventilatory neural activity was recorded from ex vivo medullary-spinal cord preparations, ventilation was measured by plethysmography and c-fos expression was studied in medullary respiratory nuclei. Desogestrel increased baseline respiratory frequency of CCHS patients leading to a decrease in their PETCO2. In medullary spinal-cord preparations or in vivo mice, the metabolite of desogestrel, etonogestrel, induced an increase in respiratory frequency that necessitated the functioning of serotoninergic systems, and modulated GABAA and NMDA ventilatory regulations. c-FOS analysis showed the involvement of medullary respiratory groups of cell including serotoninergic neurons of the raphe pallidus and raphe obscurus nuclei that seem to play a key role. Thus, desogestrel may improve resting ventilation in CCHS patients by a stimulant effect on baseline respiratory frequency. Our data open up clinical perspectives based on the combination of this progestin with serotoninergic drugs to enhance ventilation in CCHS patients.

Increased ventilatory variability and complexity in patients with hyperventilation disorder.

It has been hypothesized that hyperventilation disorders could be characterized by an abnormal ventilatory control leading to enhanced variability of resting ventilation. The variability of tidal volume (VT) often depicts a nonnormal distribution that can be described by the negative slope characterizing augmented breaths formed by the relationship between the probability density distribution of VT and VT on a log-log scale. The objectives of this study were to describe the variability of resting ventilation [coefficient of variation (CV) of VT and slope], the stability in respiratory control (loop, controller and plant gains characterizing ventilatory-chemoresponsiveness interactions) and the chaotic-like dynamics (embedding dimension, Kappa values characterizing complexity) of resting ventilation in patients with a well-defined dysfunctional breathing pattern characterized by air hunger and constantly decreased PaCO2 during a cardiopulmonary exercise test. Compared with 14 healthy subjects with similar anthropometrics, 23 patients with hyperventilation were characterized by increased variability of resting tidal ventilation (CV of VT median [interquartile]: 26% [19-35] vs. 36% [28-48], P = 0.020; slope: -6.63 [-7.65; -5.36] vs. -3.88 [-5.91; -2.66], P = 0.004) that was not related to increased chemical drive (loop gain: 0.051 [0.039-0.221] vs. 0.044 [0.012-0.087], P = 0.149) but that was related to an increased ventilatory complexity (Kappa values, P < 0.05). Plant gain was decreased in patients and correlated with complexity (with Kappa 5 - degree 5: Rho = -0.48, P = 0.006). In conclusion, well-defined patients suffering from hyperventilation disorder are characterized by increased variability of their resting ventilation due to increased ventilatory complexity with stable ventilatory-chemoresponsiveness interactions.

Source of ventilatory complexity in the postmetamorphic tadpole brainstem, Pelophylax ridibundus: A pharmacological study.

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.

New insights in gill/buccal rhythm spiking activity and CO(2) sensitivity in pre- and postmetamorphic tadpoles (Pelophylax ridibundus).

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.

Intravenous adenosine activates diffuse nociceptive inhibitory controls in humans.

Experimentally induced pain can be attenuated by concomitant heterotopic nociceptive stimuli (counterirritation). Animal data indicate that this stems from supraspinal "diffuse noxious inhibitory controls" (DNICs) triggered by C and Aδ fibers. In humans, only noxious stimuli induce counterirritation. This points at C fibers, but the effects of pharmacologically stimulating C fibers have not been studied. Intravenous adenosine activates pulmonary C fibers and induces dyspnea. This study tests the hypothesis that putative activation of pulmonary C fibers by adenosine would trigger DNICs in humans and induce counterirritation. Twelve healthy volunteers were included (with valid results available in 9) and studied according to a double-blind, randomized, cross-over design (intravenous adenosine, 140 µg·kg(-1)·min(-1), during 5 min vs. placebo). We measured ventilatory variables and end-tidal CO2 tension, dyspnea intensity by visual analog scale, and the intensity of putative chest pain. The primary outcome was the amplitude of the RIII component of the nociceptive flexor reflex recorded by biceps femoris electromyogram in response to painful electrical sural nerve stimulation (RIII), taken as a substitute for pain perception. Placebo did not induce any significant effect. Adenosine induced dyspnea, hyperpnea, tachycardia, and significant RIII inhibition (24 ± 8% at the 4th min, P < 0.0001). The temporal dynamics of adenosine-induced dyspnea and RIII inhibition differed (immediate onset followed by a slow decrease for dyspnea, slower onset for RIII inhibition). Intravenous adenosine in normal humans induces counterirritation, fueling the notion that C-fiber stimulation trigger DNICs in humans. The temporal dissociation between adenosine-induced dyspnea and RIII inhibition suggests that C fibers other than pulmonary ones might be involved.

The essential role of peripheral respiratory chemoreceptor inputs in maintaining breathing revealed when CO2 stimulation of central chemoreceptors is diminished.

Central sleep apnoea is a condition characterized by oscillations between apnoea and hyperpnoea during sleep. Studies in sleeping dogs suggest that withdrawal of peripheral chemoreceptor (carotid body) activation following transient ventilatory overshoots plays an essential role in causing apnoea, raising the possibility that sustaining carotid body activity during ventilatory overshoots may prevent apnoea. To test whether sustained peripheral chemoreceptor activation is sufficient to drive breathing, even in the absence of central chemoreceptor stimulation and vagal feedback, we used a vagotomized, decerebrate dual-perfused in situ rat preparation in which the central and peripheral chemoreceptors are independently and artificially perfused with gas-equilibrated medium. At varying levels of carotid body stimulation (CB PO2/PCO2: 40/60, 100/40, 200/15, 500/15 Torr), we decreased the brainstem perfusate PCO2 in 5 Torr steps while recording phrenic nerve activity to determine the central apnoeic thresholds. The central apnoeic thresholds decreased with increased carotid body stimulation. When the carotid bodies were strongly stimulated (CB 40/60), the apnoeic threshold was 3.6 ± 1.4 Torr PCO2 (mean ± SEM, n = 7). Stimulating carotid body afferent activity with either hypercapnia (60 Torr PCO2) or the neuropeptide pituitary adenylate cyclase-activating peptide restored phrenic activity during central apnoea. We conclude that peripheral stimulation shifts the central apnoeic threshold to very hypocapnic levels that would likely increase the CO2 reserve and have a protective effect on breathing. These data demonstrate that peripheral respiratory chemoreceptors are sufficient to stave off central apnoeas when the brainstem is perfused with low to no CO2.

Acute bronchodilation increases ventilatory complexity during resting breathing in stable COPD: toward mathematical biomarkers of ventilatory function?

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.

Persistent lung oscillator response to CO2 after buccal oscillator inhibition in the adult frog.

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.

Anandamide modulates carotid sinus nerve afferent activity via TRPV1 receptors increasing responses to heat.

Abnormal respiratory chemosensitivity is implicated in recurrent apnea syndromes, with the peripheral chemoreceptors, the carotid bodies, playing a particularly important role. Previous work suggests that supraphysiological concentrations of the endocannabinoid endovanilloid and TASK channel blocker anandamide (ANA) excite carotid bodies, but the mechanism(s) and physiological significance are unknown. Given that carotid body output is temperature-sensitive, we hypothesized that ANA stimulates carotid body chemosensory afferents via temperature-sensitive vanilloid (TRPV1) receptors. To test this hypothesis, we used the dual-perfused in situ rat preparation to confirm that independent perfusion of carotid arteries with supraphysiological concentrations of ANA strongly excites carotid sinus nerve afferents and that this activity is sufficient to increase phrenic activity. Next, using ex vivo carotid body preparations, we demonstrate that these effects are mediated by TRPV1 receptors, not CB1 receptors or TASK channels: in CB1-null mouse preparations, ANA increased afferent activity across all levels of Po(2), whereas in TRPV1-null mouse preparations, the stimulatory effect of ANA was absent. In rat ex vivo preparations, ANA's stimulatory effects were mimicked by olvanil, a nonpungent TRPV1 agonist, and suppressed by the TRPV1 antagonist AMG-9810. The specific CB1 agonist oleamide had no effect. Physiological levels of ANA had no effect alone but increased sensitivity to mild hyperthermia. AMG-9810 blocked ANA's effect on the temperature response. Immunolabeling and RT-PCR demonstrated that TRPV1 receptors are not expressed in carotid body glomus cells but reside in petrosal sensory afferents. Together, these results suggest that ANA plays a physiological role in augmenting afferent responses to mild hyperthermia by activating TRPV1 receptors on petrosal afferents.

Effects of maturation and acidosis on the chaos-like complexity of the neural respiratory output in the isolated brainstem of the tadpole, Rana esculenta.

Human ventilation at rest exhibits mathematical chaos-like complexity that can be described as long-term unpredictability mediated (in whole or in part) by some low-dimensional nonlinear deterministic process. Although various physiological and pathological situations can affect respiratory complexity, the underlying mechanisms remain incompletely elucidated. If such chaos-like complexity is an intrinsic property of central respiratory generators, it should appear or increase when these structures mature or are stimulated. To test this hypothesis, we employed the isolated tadpole brainstem model [Rana (Pelophylax) esculenta] and recorded the neural respiratory output (buccal and lung rhythms) of pre- (n = 8) and postmetamorphic tadpoles (n = 8), at physiologic (7.8) and acidic pH (7.4). We analyzed the root mean square of the cranial nerve V or VII neurograms. Development and acidosis had no effect on buccal period. Lung frequency increased with development (P < 0.0001). It also increased with acidosis, but in postmetamorphic tadpoles only (P < 0.05). The noise-titration technique evidenced low-dimensional nonlinearities in all the postmetamorphic brainstems, at both pH. Chaos-like complexity, assessed through the noise limit, increased from pH 7.8 to pH 7.4 (P < 0.01). In contrast, linear models best fitted the ventilatory rhythm in all but one of the premetamorphic preparations at pH 7.8 (P < 0.005 vs. postmetamorphic) and in four at pH 7.4 (not significant vs. postmetamorphic). Therefore, in a lower vertebrate model, the brainstem respiratory central rhythm generator accounts for ventilatory chaos-like complexity, especially in the postmetamorphic stage and at low pH. According to the ventilatory generators homology theory, this may also be the case in mammals.

Neurally adjusted ventilatory assist increases respiratory variability and complexity in acute respiratory failure.

BACKGROUND: Neurally adjusted ventilatory assist (NAVA) is a partial ventilatory support mode where positive pressure is provided in relation to diaphragmatic electrical activity (EAdi). Central inspiratory activity is normally not monotonous, but it demonstrates short-term variability and complexity. The authors reasoned that NAVA should produce a more "natural" or variable breathing pattern than other modes. This study compared respiratory variability and complexity during pressure support ventilation (PSV) and NAVA. METHODS: Flow and EAdi were recorded during routine PSV (tidal volume approximately 6-8 ml/kg) and four NAVA levels (1-4 cm H2O/microVEAdi) in 12 intubated patients. Breath-by-breath variability of flow and EAdi-related variables was quantified by the coefficient of variation (CV) and autocorrelation analysis. Complexity of flow and EAdi was described using noise titration, largest Lyapunov exponent, Kolmogorov-Sinai entropy, and three-dimensional phase portraits. RESULTS: Switching from PSV to NAVA increased the CV and decreased the autocorrelation for most flow-related variables in a dose-dependent manner (P < 0.05, partial eta for the CV of mean inspiratory flow 0.642). The changes were less marked for EAdi. A positive noise limit was consistently found for flow and EAdi. Largest Lyapunov exponent and Kolmogorov-Sinai entropy for flow were greater during NAVA than PSV and increased with NAVA level (P < 0.05, partial eta 0.334 and 0.312, respectively). Largest Lyapunov exponent and Kolmogorov-Sinai entropy for EAdi were not influenced by ventilator mode. CONCLUSIONS: Compared with PSV, NAVA increases the breathing pattern variability and complexity of flow, whereas the complexity of EAdi is unchanged. Whether this improves clinical outcomes remains to be determined.

Effects of inspiratory loading on the chaotic dynamics of ventilatory flow in humans.

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.

Source of human ventilatory chaos: lessons from switching controlled mechanical ventilation to inspiratory pressure support in critically ill patients.

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.

Effects of hypercapnia and hypocapnia on ventilatory variability and the chaotic dynamics of ventilatory flow in humans.

In humans, lung ventilation exhibits breath-to-breath variability and dynamics that are nonlinear, complex, sensitive to initial conditions, unpredictable in the long-term, and chaotic. Hypercapnia, as produced by the inhalation of a CO(2)-enriched gas mixture, stimulates ventilation. Hypocapnia, as produced by mechanical hyperventilation, depresses ventilation in animals and in humans during sleep, but it does not induce apnea in awake humans. This emphasizes the suprapontine influences on ventilatory control. How cortical and subcortical commands interfere thus depend on the prevailing CO(2) levels. However, CO(2) also influences the variability and complexity of ventilation. This study was designed to describe how this occurs and to test the hypothesis that CO(2) chemoreceptors are important determinants of ventilatory dynamics. Spontaneous ventilatory flow was recorded in eight healthy subjects. Breath-by-breath variability was studied through the coefficient of variation of several ventilatory variables. Chaos was assessed with the noise titration method (noise limit) and characterized with numerical indexes [largest Lyapunov exponent (LLE), sensitivity to initial conditions; Kolmogorov-Sinai entropy (KSE), unpredictability; and correlation dimension (CD), irregularity]. In all subjects, under all conditions, a positive noise limit confirmed chaos. Hypercapnia reduced breathing variability, increased LLE (P = 0.0338 vs. normocapnia; P = 0.0018 vs. hypocapnia), increased KSE, and slightly reduced CD. Hypocapnia increased variability, decreased LLE and KSE, and reduced CD. These results suggest that chemoreceptors exert a strong influence on ventilatory variability and complexity. However, complexity persists in the quasi-absence of automatic drive. Ventilatory variability and complexity could be determined by the interaction between the respiratory central pattern generator and suprapontine structures.

Respiratory inductive plethysmography to assess respiratory variability and complexity in humans.

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.