Disparity in the effect of morphine on eupnea and gasping in anesthetized spontaneously breathing adult rats.

The goal of this study was to examine the effects of systemic morphine on the pattern and morphology of gasping breathing during respiratory autoresuscitation from transient anoxia. We hypothesized that systemic morphine levels sufficient to cause significant depression of eupnea would also cause depression of gasping breathing. Respiratory and cardiovascular variables were studied in 20 spontaneously breathing pentobarbital-anaesthetized adult male rats. Sham (saline) injections caused no significant change in resting respiratory or cardiovascular variables (n = 10 rats). Morphine, on the other hand, caused significant depression of eupneic breathing, with ventilation and peak inspiratory flow decreased by ∼30-60%, depending on the background condition (n = 10 rats). In contrast, morphine did not depress gasping breathing. Duration of primary apnea, time to restore eupnea, the number and amplitude of gasping breaths, average and maximum peak flows, and volume of gasping breaths were not significantly different postinjection in either condition. Blood pressures were all significantly lower following morphine injection at key time points in the process of autoresuscitation. Last, rate of successful recovery from anoxia was 80% in the morphine group (8/10 rats) compared with 100% (10/10 rats) in the sham group, postinjection. We conclude that the mechanisms and/or anatomic correlates underlying generation of gasping rhythm are distinct from those underlying eupnea, allowing gasping to remain robust to systemic morphine levels causing significant depression of eupnea. Morphine nevertheless decreases likelihood of recovery from transient anoxia, possibly as a result of decreased tissue perfusion pressures at critical time points during the process of respiratory autoresuscitation.

Augmented breaths ('sighs') are suppressed by morphine in a dose-dependent fashion via naloxone-sensitive pathways in adult rats.

Morphine treatment can eliminate augmented breaths (ABs; 'sighs') during spontaneous breathing. In the present study, unanesthetized rats were studied to: (1) determine the involvement of naloxone-sensitive receptor pathways, and (2) establish the dose-response relationship of this side effect. At a dosage of 5mg/kg (2-10mg/kg is recommended range for analgesia) morphine eliminated ABs from the breathing rhythm across nearly 100 min post-administration (vs. 6.2 ± 1.6 ABs in 15 min, control condition, p<0.001). This occurred despite no apparent effect on indices of ventilation. By contrast, when naloxone was co-administered with morphine, the occurrence of ABs was not different compared to control. The suppression of ABs by morphine followed a sigmoidal pattern across the low-mid dosage range (R(2)=0.83), whereas tidal volume and breathing frequency were unaffected. We conclude that the opioid-induced suppression of ABs is mediated by naloxone-sensitive opioid receptor pathways, and that this side effect is potent across the low-mid dosage range, and cannot be simply avoided by restricting dosage.

Control of breathing in invertebrate model systems.

The invertebrates have adopted a myriad of breathing strategies to facilitate the extraction of adequate quantities of oxygen from their surrounding environments. Their respiratory structures can take a wide variety of forms, including integumentary surfaces, lungs, gills, tracheal systems, and even parallel combinations of these same gas exchange structures. Like their vertebrate counterparts, the invertebrates have evolved elaborate control strategies to regulate their breathing activity. Our goal in this article is to present the reader with a description of what is known regarding the control of breathing in some of the specific invertebrate species that have been used as model systems to study different mechanistic aspects of the control of breathing. We will examine how several species have been used to study fundamental principles of respiratory rhythm generation, central and peripheral chemosensory modulation of breathing, and plasticity in the control of breathing. We will also present the reader with an overview of some of the behavioral and neuronal adaptability that has been extensively documented in these animals. By presenting explicit invertebrate species as model organisms, we will illustrate mechanistic principles that form the neuronal foundation of respiratory control, and moreover appear likely to be conserved across not only invertebrates, but vertebrate species as well.

The "other" respiratory effect of opioids: suppression of spontaneous augmented ("sigh") breaths.

The purpose of this study was to examine the effects of a clinically relevant opioid on the production of augmented breaths (ABs) in unanesthetized animals breathing normal room air, using a dosage which does not depress breathing. To do this we monitored breathing noninvasively, in unrestrained animals before and after subcutaneous injection of either morphine, or a saline control. The effect of ketamine/xylazine was also studied to determine the potential effect of an alternative sedative agent. Last, the effect of naloxone was studied to determine the potential influence of endogenous opioids in regulating the normal incidence of ABs. Morphine (5 mg/kg) had no depressive effect on breathing, but completely eliminated ABs in all animals in room air (P = 0.027). However, when animals breathed hypoxic air (10% O(2)), animals did express ABs, although their incidence was still reduced by morphine (P < 0.001). This was not a result of sedation per se, as ABs continued at their normal rate in room air during sedation with ketamine. Naloxone had no effect on breathing or AB production, and so endogenous opioids are not likely involved in regulating their rate of production under normal conditions. Our results show that in unanesthetized animals breathing normal room air, a clinically relevant opioid eliminates ABs, even at a dose that does not cause respiratory depression. Despite this, hypoxia-induced stimulation of breathing can facilitate the production of ABs even with the systemic opioid present, indicating that peripheral chemoreceptor stimulation provides a potential means of overcoming the opioid-induced suppression of these respiratory events.

Breathing patterns during cardiac arrest.

The absence of respiratory movements is a major criterion recommended for use by bystanders for recognizing an out-of-hospital cardiac arrest (CA), as the persistence of eupneic breathing is considered to be incompatible with CA. The basis for CA-related apnea is, however, uncertain, since brain stem Po(2) is not expected to drop immediately to the critical level where anoxic apnea occurs. It is therefore essential on both clinical and physiological grounds to determine whether and when breathing stops after the onset of CA. In eight patients, we measured the ventilatory response at the onset of ventricular fibrillation (VF) for 12-15 s during the placement of an implantable cardioverter-defibrillator device. We found that regular eupneic breathing was maintained unchanged despite the cessation of systemic and pulmonary blood flow generated by the heart. We extended these findings in adult sheep and found that, as in humans, the normal ventilatory pattern persists unchanged for the first 15 s despite the drop in blood pressure, followed by a progressive increase in minute ventilation, which was sustained for up to 164 s. The ensuing apnea was disrupted by typical gasps occurring at a very slow frequency. These observations suggest a complete "decoupling" between the return of CO(2) to the pulmonary circulation and continued effective respiratory activity, contrary to what we predicted. This delayed cessation of eupneic breathing during the absence of cardiac pump function is likely related to the time needed for brain stem anoxia to develop. These findings challenge the notions that 1) ventilation stops as pulmonary blood flow/cardiac output ceases and 2) the presence of eupneic breathing is a reliable sign of effective cardiac pumping activity.

Respiratory effects of changing the volume load imposed on the peripheral venous system.

This study was designed to determine if acute distension of the hindlimb venous circulation stimulates breathing, thereby contributing to the respiratory responses to rapid changes in total blood volume. In 10 spontaneously breathing anesthetized sheep, we withdrew 15 ml kg(-1) of blood from a femoral vein over approximately 1-2 min. We then compared the respiratory effects of infusing this venous blood back into the femoral veins across two conditions: the inferior vena cava (IVC) was either unobstructed or obstructed by a balloon-tipped catheter. We found that when blood was withdrawn and blood volume decreased, an absolute increase in breathing often occurred, but more importantly that a relative hyperventilation was always observed. When this blood was re-infused into the animal, effectively increasing blood volume, the respiratory response depended upon whether or not the IVC was open or obstructed. With the IVC unobstructed, a relative hypoventilation occurred, accompanied by an increase in alveolar PCO(2). In contrast, when the venous blood was re-infused and the IVC was obstructed, ventilation increased significantly, and the response was often hypocapnic. These results indicate that increasing the volume load in the venous circulation increases breathing, and that the transduction mechanism is contained within the peripheral venous system. Further, the respiratory drive from this sensory mechanism is subject to modulation via changes in the circulatory status, most likely within the arterial side.

The hypoxia-induced facilitation of augmented breaths is suppressed by the common effect of carbonic anhydrase inhibition.

The typical respiratory response to hypoxia includes a dramatic facilitation of augmented breaths (ABs) or 'sighs' in the breathing rhythm. We recently found that when acetazolamide treatment is used to promote CO(2) retention and counteract alkalosis during exposure to hypoxia, then the hypoxia-induced facilitation of ABs is effectively prevented. These results indicate that hyperventilation-induced hypocapnia/alkalosis is an essential factor involved in the hypoxia-induced facilitation of augmented breaths. However, acetazolamide is also known to decrease the sensitivity of the arterial chemoreceptors. Therefore, the question remains as to whether acetazolamide prevents the facilitation of ABs during hypoxia by offsetting the effects of respiratory alkalosis, or alternatively by suppressing carotid body afferent activity. In the present study, we addressed this question by studying the effects of treatment with an alternative carbonic anhydrase inhibitor, methazolamide, which has been reported to leave carotid body responsiveness to hypoxia intact. Respiratory variables were monitored before, during and after 2 days of methazolamide treatment (10 mg kg(-1) IP, bid) in unsedated and unrestrained adult male rats. Pre-treatment, the number of ABs observed in a 5 min observation window was 1.2 + or - 0.8 and 17.4 + or - 3.8 in room air and hypoxia, respectively. During methazolamide treatment, the facilitation of ABs in hypoxia was rapidly and reversibly suppressed such that ABs we no longer significantly more frequent than they were in room air. The present results demonstrate that the hypoxia-induced facilitation of ABs can be suppressed via the general effects of carbonic anhydrase inhibition, which are common to both acetazolamide and methazolamide. We discuss these results as they pertain to the mechanisms regulating augmented breath production, and the possible association between hypocapnia/alkalosis and sleep disordered breathing.

Control of breathing during acute change in cardiac preload in a patient with partial cardiopulmonary bypass.

We recently had the opportunity to investigate the ventilatory effects of changing the rate of venous return to the heart (and thus pulmonary gas exchange) in a patient equipped with a venous-arterial oxygenated shunt (extracorporeal membrane oxygenation (ECMO) support). The presence of the ECMO support provided a condition wherein venous return to the right heart could be increased or decreased while maintaining total aortic blood flow and arterial blood pressure (ABP) constant. The patient, who had received a heart transplant 12 years ago, was admitted for acute cardiac failure related to graft rejection. The clinical symptomatology was that of right heart failure. We studied the patient on the 4th day of ECMO support, while she was breathing spontaneously. The blood flow diverted through the ECMO system represented 2/3 of the total aortic flow (4 l min(-1)). With these ECMO settings, the baseline level of ventilation was low (3.89+/-0.99 l min(-1)), but PET(CO2) was not elevated (37+/-2 mmHg). When Pa(CO2) in the blood coming from the ECMO was increased, no stimulatory effect on ventilation was observed. However, when the diversion of the venous return to the ECMO was stopped then restored, minute ventilation respectively increased then decreased by more than twofold with opposite changes in PET(CO2). These maneuvers were associated with large changes in the size of the right atrium and ventricle and of the left atrium. This observation suggests that the change in venous return affects breathing by encoding some of the consequences of the changes in cardiac preload. The possible sites of mediation are discussed.

Acetazolamide suppresses the prevalence of augmented breaths during exposure to hypoxia.

Augmented breaths, or "sighs," commonly destabilize respiratory rhythm, precipitating apneas and variability in the depth and rate of breathing, which may then exacerbate sleep-disordered breathing in vulnerable individuals. We previously demonstrated that hypocapnia is a unique condition associated with a high prevalence of augmented breaths during exposure to hypoxia; the prevalence of augmented breaths during hypoxia can be returned to normal simply by the addition of CO(2) to the inspired air. We hypothesized that counteracting the effect of respiratory alkalosis during hypocapnic hypoxia by blocking carbonic anhydrase would yield a similar effect. We, therefore, investigated the effect of acetazolamide on the prevalence of augmented breaths in the resting breathing cycle in five awake, adult male rats. We found a 475% increase in the prevalence of augmented breaths in animals exposed to hypocapnic hypoxia compared with room air. Acetazolamide treatment (100 mg/kg i.p. bid) for 3 days resulted in a rapid and potent suppression of the generation of augmented breaths during hypoxia. Within 90 min of the first dose of acetazolamide, the prevalence of augmented breaths in hypoxia fell to levels that were no greater than those observed in room air. On cessation of treatment, exposure to hypocapnic hypoxia once again caused a large increase in the prevalence of augmented breaths. These results reveal a novel means by which acetazolamide acts to stabilize breathing and may help explain the beneficial effects of the drug on breathing stability at altitude and in patients with central forms of sleep-disordered breathing.

Comparison of the metabolic and ventilatory response to hypoxia and H2S in unsedated mice and rats.

Hypoxia alters the control of breathing and metabolism by increasing ventilation through the arterial chemoreflex, an effect which, in small-sized animals, is offset by a centrally mediated reduction in metabolism and respiration. We tested the hypothesis that hydrogen sulfide (H(2)S) is involved in transducing these effects in mammals. The rationale for this hypothesis is twofold. Firstly, inhalation of a 20-80 ppm H(2)S reduces metabolism in small mammals and this effect is analogous to that of hypoxia. Secondly, endogenous H(2)S appears to mediate some of the cardio-vascular effects of hypoxia in non-mammalian species. We, therefore, compared the ventilatory and metabolic effects of exposure to 60 ppm H(2)S and to 10% O(2) in small and large rodents (20g mice and 700g rats) wherein the metabolic response to hypoxia has been shown to differ according to body mass. H(2)S and hypoxia produced profound depression in metabolic rate in the mice, but not in the large rats. The depression was much faster with H(2)S than with hypoxia. The relative hyperventilation produced by hypoxia in the mice was replaced by a depression with H(2)S, which paralleled the drop in metabolic rate. In the larger rats, ventilation was stimulated in hypoxia, with no change in metabolism, while H(2)S affected neither breathing nor metabolism. When mice were simultaneously exposed to H(2)S and hypoxia, the stimulatory effects of hypoxia on breathing were abolished, and a much larger respiratory and metabolic depression was observed than with H(2)S alone. H(2)S had, therefore, no stimulatory effect on the arterial chemoreflex. The ventilatory depression during hypoxia and H(2)S in small mammals appears to be dependent upon the ability to decrease metabolism.

Hypoxia-induced modulation of the respiratory CPG.

Despite recent advances in our understanding of the neural control of breathing, the precise cellular, synaptic, and molecular mechanisms underlying the generation and modulation of respiratory rhythm remain largely unknown. This lack of fundamental knowledge in the field of neural control of respiration is likely due to the complexity of the mammalian brain where synaptic connectivity between central respiratory neurons, motor neurons and their peripheral counterparts cannot be mapped reliably. We have therefore developed an invertebrate model system wherein the essential elements of the central pattern generator (CPG), the motor neurons and the peripheral chemosensory cells involved in respiratory control have been worked out both in vivo and in vitro. We discuss our recent identification of peripheral, hypoxia sensitive chemoreceptor elements in a sensory organ of the pulmonate freshwater pond snail Lymnaea stagnalis, which provide an excitatory drive to the respiratory CPG neuron RPeD1 via direct chemical synaptic connections. Further studies using this unique invertebrate model system may reveal highly conserved principles of CPG neuromodulation that will remain relevant to more complex mammalian systems.

Hypocapnia increases the prevalence of hypoxia-induced augmented breaths.

Augmented breaths promote respiratory instability and have been implicated in triggering periods of sleep-disordered breathing. Since respiratory instability is well known to be exacerbated by hypocapnia, we asked whether one of the destabilizing effects of hypocapnia might be related to an increased prevalence of augmented breaths. With this question in mind, we first sought to determine whether hypoxia-induced augmented breaths are more prevalent when hypocapnia is also present. To do this, we studied the breath-by-breath ventilatory responses of a group of freely behaving adult rats in a variety of different respiratory background conditions. We found that the prevalence of augmented breaths was dramatically increased during hypocapnic-hypoxia compared with room air conditions. When hypocapnia was prevented during exposure to hypoxia by adding 5% CO2 to the inspired air, the rate of occurrence of augmented breaths was no greater than that observed in room air. The addition of CO2 alone to room air had no effect on the prevalence of augmented breaths. We conclude that in spontaneously breathing rats, hypoxia promotes the generation of augmented breaths, but only in poikilocapnic conditions, where hypocapnia develops. Our results, therefore, reveal a means by which CO2 exerts a stabilizing influence on breathing, which may be of particular relevance during sleep in conditions commonly associated with respiratory instability.

Control of breathing and volitional respiratory rhythm in humans.

When breathing frequency (f) is imperceptibly increased during a volitionally paced respiratory rhythm imposed by an auditory signal, tidal volume (Vt) decreases such that minute ventilation (Ve) rises according to f-induced dead-space ventilation changes (18). As a result, significant change in alveolar ventilation and Pco(2) are prevented as f varies. The present study was performed to determine what regulatory properties are retained by the respiratory control system, wherein the spontaneous automatic rhythmic activity is replaced by a volitionally paced rhythm. Six volunteers were asked to trigger each breath cycle on hearing a brief auditory signal. The time interval between subsequent auditory signals was imperceptibly changed for 10-15 min, during 1) air breathing (condition 1), 2) the addition of a 300 ml of instrumental dead space (condition 2), 3) an increase in the inspired level of CO(2) (condition 3), and 4) light exercise (condition 4). We found that as f was slowly increased the elaborated Vt decreased in accordance to the background level of CO(2) and metabolic rate. Indeed, for any given breath duration, Vt was shifted upward in condition 2 vs. 1, whereas the slope of Vt changes according to the volitionally rhythm was much steeper in conditions 3 and 4 vs. 1. The resulting changes in Ve offset any f-induced changes in dead-space ventilation in all conditions. We conclude that there is an inherent, fundamental mechanism that elaborates Vt based on f when imposed by the premotor cortex in humans. The chemoreflex and exercise drive to breath interacts with this cortically mediated rhythm maintaining alveolar rather than Ve constant as f changes. The implications of our findings are discussed in the context of our current understanding of the central generation of breathing rhythm.

A peripheral oxygen sensor provides direct activation of an identified respiratory CPG neuron in Lymnaea.

The mechanisms by which peripheral, hypoxia-sensitive chemosensory cells modulate the output from the respiratory central pattern generator (CPG) remain largely unknown. In order to study this topic at a fundamental level, we have developed a simple invertebrate model system, Lymnaea stagnalis wherein we have identified peripheral chemoreceptor cells (PCRCs) that relay hypoxia-sensitive chemosensory information to a known respiratory CPG neuron, right pedal dorsal 1 (RPeD1). Significance of this chemosensory drive was confirmed via denervation of the peripheral sensory organ containing the PCRCs, and subsequent behavioral observation. This study provides evidence for direct synaptic connectivity between oxygen sensing PCRCs and a CPG neuron, and describes a unique model system appropriate for studying mechanisms of hypoxia-induced, respiratory plasticity from the level of an identified synapse to whole animal behavior.

Peripheral oxygen-sensing cells directly modulate the output of an identified respiratory central pattern generating neuron.

Breathing is an essential homeostatic behavior regulated by central neuronal networks, often called central pattern generators (CPGs). Despite ongoing advances in our understanding of the neural control of breathing, the basic mechanisms by which peripheral input modulates the activities of the central respiratory CPG remain elusive. This lack of fundamental knowledge vis-à-vis the role of peripheral influences in the control of the respiratory CPG is due in large part to the complexity of mammalian respiratory control centres. We have therefore developed a simpler invertebrate model to study the basic cellular and synaptic mechanisms by which a peripheral chemosensory input affects the central respiratory CPG. Here we report on the identification and characterization of peripheral chemoreceptor cells (PCRCs) that relay hypoxia-sensitive chemosensory information to the known respiratory CPG neuron right pedal dorsal 1 in the mollusk Lymnaea stagnalis. Selective perfusion of these PCRCs with hypoxic saline triggered bursting activity in these neurons and when isolated in cell culture these cells also demonstrated hypoxic sensitivity that resulted in membrane depolarization and spiking activity. When cocultured with right pedal dorsal 1, the PCRCs developed synapses that exhibited a form of short-term synaptic plasticity in response to hypoxia. Finally, osphradial denervation in intact animals significantly perturbed respiratory activity compared with their sham counterparts. This study provides evidence for direct synaptic connectivity between a peripheral regulatory element and a central respiratory CPG neuron, revealing a potential locus for hypoxia-induced synaptic plasticity underlying breathing behavior.

Respiratory control at exercise onset: an integrated systems perspective.

The near-immediate increase in breathing that accompanies the onset of constant load, dynamic exercise has remained a topic of interest to respiratory physiologists for the better part of a century. During this time, several theories have been proposed and tested in an attempt to explain what has been called the phase I response of exercise hyperpnoea, or the fast neural drive to breathe, and much controversy still remains as to what mediates this response. 'Central motor command' and 'afferent feedback' mechanisms, as described in animal models, have been centre stage in the debate, with much supportive evidence for their involvement. This review presents three relatively recent and controversial mechanisms and examines the increasing evidence for their involvement in the initial phase of exercise hyperpnoea: (1) the vascular distension hypothesis, (2) the vestibular feedback hypothesis and (3) the behavioral state hypothesis. Some outstanding fundamental questions and directions for future research are presented throughout, always with a focus on mechanistic efficacy in the integrated system response.

Rapid increases in ventilation accompany the transition from passive to active movement.

We used a novel movement transition technique to look for evidence of a rapid onset drive to breathe related to the active component of exercise in humans. Ten volunteers performed the following transitions in a specially designed tandem exercise chair apparatus: rest to passive movement, passive to active movement, and rest to active movement. The transition from rest to active exercise was accompanied by an immediate increase in ventilation, as was the transition from rest to passive leg movement (Delta = 6.06 +/- 1.09 l min(-1), p < 0.001 and Delta = 3.30 +/- 0.57 l min(-1), p = 0.002, respectively). When subjects actively assumed the leg movements, ventilation again increased immediately and significantly (Delta = 2.55 +/- 0.52 l min(-1), p = 0.032). Ventilation at the first point of active exercise was the same when started either from rest or from a background of passive leg movement (p = 1.00). We conclude that the use of a transition from passive to active leg movements in humans recruits a ventilatory drive related to the active component of exercise, and this can be discerned as a rapid increase in breathing.

The initial phase of exercise hyperpnoea in humans is depressed during a cognitive task.

Increased wakefulness is known to suppress the initial ventilatory response to passive movement and the steady-state ventilatory response to exercise. However, the effect of increased wakefulness upon the integrated ventilatory response at the onset of exercise is not known. We hypothesized that increasing wakefulness via a cognitive task would attenuate the initial ventilatory response to exercise, and so we examined the response to active leg extensions under two conditions: with and without concurrently solving a puzzle. At rest before exercise, subjects demonstrated greater minute ventilation while solving a puzzle (mean +/- S.E.M., 12.38 +/- 0.55 versus 10.12 +/- 0.51 l min(-1), P < 0.001), due to a higher mean breathing frequency (mean +/- S.E.M., 17.1 +/- 0.93 versus 13.6 +/- 0.59 breaths min(-1), P < 0.001). At the start of exercise, subjects did not increase their ventilation significantly while solving the puzzle (P = 0.170), but did by a mean +/-s.e.m. of 6.16 +/- 1.12 l min(-1) (P < 0.001) when not puzzle solving. The ventilation achieved at the start of exercise in absolute terms was also lower while solving the puzzle (14.6 +/- 1.1 versus 16.3 +/- 1.3 l min(-1), P = 0.047). Despite differences in the rapid ventilatory response to exercise between conditions, the steady-state responses were not different. We conclude that the performance of a cognitive task decreases the initial phase of exercise hyperpnoea, and suggest that this might occur because of either a competitive interaction between drives to breathe or a behavioural distraction from the 'task' of exercise.

Respiratory response to passive limb movement is suppressed by a cognitive task.

Feedback from muscles stimulates ventilation at the onset of passive movement. We hypothesized that central neural activity via a cognitive task source would interact with afferent feedback, and we tested this hypothesis by examining the fast changes in ventilation at the transition from rest to passive leg movement, under two conditions: 1) no task and 2) solving a computer-based puzzle. Resting breathing was greater in condition 2 than in condition 1, evidenced by an increase in mean +/- SE breathing frequency (18.2 +/- 1.1 vs. 15.0 +/- 1.2 breaths/min, P = 0.004) and ventilation (10.93 +/- 1.16 vs. 9.11 +/- 1.17 l/min, P < 0.001). In condition 1, the onset of passive movement produced a fast increase in mean +/- SE breathing frequency (change of 2.9 +/- 0.4 breaths/min, P < 0.001), tidal volume (change of 233 +/- 95 ml, P < 0.001), and ventilation (change of 6.00 +/- 1.76 l/min, P < 0.001). However, in condition 2, the onset of passive movement only produced a fast increase in mean +/- SE breathing frequency (change of 1.3 +/- 0.4 breaths/min, P = 0.045), significantly smaller than in condition 1 (P = 0.007). These findings provide evidence for an interaction between central neural cognitive activity and the afferent feedback mechanism, and we conclude that the performance of a cognitive task suppresses the respiratory response to passive movement.