Tracheal occlusion conditioning causes stress, anxiety and neural state changes in conscious rats.

Evidence from human and animal studies indicates that mechanical loads to breathing are stressful stimuli and evoke compensatory behaviours. Conditioning of stressful stimuli is known to cause changes in basal stress levels and behaviour. Individuals with respiratory obstructive diseases repeatedly experience bouts of airway obstruction, which may act as a form of conditioning, and often have affective disorders, such as anxiety and depression. It is unknown whether the development of affective disorders in these individuals results from the unexpected recurring respiratory perturbations. To investigate this possibility, we developed a model to elicit tracheal occlusion (TO) in conscious rats and exposed them to 10 days of TO conditioning. We hypothesized that healthy, conscious animals exposed to TO conditioning would develop stress and anxiety and would have modulated neural activity in respiratory, stress, discriminative and affective neural regions. Following TO conditioning, rats had increased basal corticosterone levels, greater adrenal weights and elevated anxiety levels compared with animals not receiving TO. Significant increases in cytochrome oxidase staining were found in brainstem respiratory nuclei, periaqueductal grey, dorsal raphe, thalamus and insular cortex. These results suggest that healthy animals develop stress and anxiety responses to respiratory load conditioning via inescapable tracheal occlusions, which may be mediated through state changes in specific brain nuclei.

Workshop: tuning the 'cough center'.

The Workshop considered the mechanisms whereby the 'cough center' could be tuned by various afferent inputs. There were particular presentations on the effects of inputs from the nose, mouth, respiratory tract and lungs, cerebral cortex, somatic tissues and the pharynx. From all these sites cough induced from the lungs could be increased or decreased in its strength or modified in its pattern. Thus 'tuning' of cough could be due to the interaction of afferent inputs, or to the sensitization or desensitization of brainstem neural pathways. The pattern of response depended on the 'type' of cough being studied and, in some instances, on the timing of the sensory input into the brainstem. Cough inputs could also affect various 'non-cough' motor outputs from the brain, although this was not the main theme of the Workshop. The main conclusion was that cough is not a stereotyped output from the medullary 'cough center', but that its pattern and strength depend on many afferent inputs acting on the 'cough center'.

Urge to cough with voluntary suppression following mechanical pharyngeal stimulation.

OBJECTIVE: The goal of this project was to determine if mechanical stimulation to the posterolateral oropharynx would elicit the urge-to-cough and/or cough. BACKGROUND: Inhaled agents, such as capsaicin and citric acid, readily produce coughing and the sensation of urge-to-cough. Areas below the glottis are thought to be the primary sensory mediators of these responses, however it is unknown if there are specific areas in the oropharynx or laryngopharynx that are important for the sensation and production of coughing. METHODS: Paired-pulse air puffs were delivered to the posterolateral oropharyngeal walls of 11 healthy adults (5 men, 6 women) between the ages of 18 and 30 years. Air puffs were delivered via custom mouthpiece in 4 trials, 50 sets per trial. Instances of cough were recorded, and a modified Borg scale was used to gauge urge-to-cough throughout each trial. RESULTS: Instances of cough were recorded in 12/37 trials, and the sensation of an urge-to-cough was present in 25/37 trials. No motor cough response was elicited with an urge-to-cough rating less than 2.4 on the modified Borg scale. A trend towards higher urge-to-cough was noted for later (3rd and 4th) trials. CONCLUSIONS: Oropharyngeal mechanical stimulation elicits urge-to-cough and cough in healthy young adults. Like other methods to elicit coughing, the motor and sensory thresholds are different using the oropharyngeal air-puff stimuli. Further, it appears there is a sensitization to the air puff stimuli with later trials associated with stronger urge-to-cough and higher likelihood of coughing versus the first and second trial (Tab. 1, Fig. 5, Ref. 21).

Clinical cough I: the urge-to-cough: a respiratory sensation.

Cough is generated by a brainstem neural network. Chemical and mechanical stimulation of the airway can elicit a reflex cough and can elicit a cognitive sensation, the urge-to-cough. The sensation of an urge-to-cough is a respiratory-related sensation. The role of the respiratory sensation of an urge-to-cough is to engage behavioral modulation of cough motor action. Respiratory sensations are elicited by a combination of modalities: central neural, chemical, and mechanical. Stimulation of respiratory afferents or changes in respiratory pattern resulting in a cognitive awareness of breathing are mediated by central neural processes that are the cognitive neural basis for respiratory sensations, including the urge-to-cough. It is proposed that the urge-to-cough is a component of the cough motivation-to-action system. The urge-to-cough is induced by stimuli that motivate subjects to protect their airway by coughing. Cough receptor stimulation is gated into suprapontine brain systems. In the proposed cough motivation system, the cough stimulus would produce an urge-to-cough which then matches with the cognitive desire for a response to the urge. If a cough is produced by the motor action system, the descending cognitive drive modulates the brainstem cough neural network. Receptors within the respiratory system provide sensory feedback indicating if the cough occurred, the motor pattern, and the magnitude. The limbic system uses that information to determine if the coughing behavior satisfied the urge. Cough is stopped if the urge-to-cough is satisfied; if the urge has not been satisfied then the urge-to-cough will continue to motivate the central nervous system. The central component within this cough motivation system is the intrinsic brain mechanism which can be activated to start the cycle for motivating a cough, the urge-to-cough. Eliciting a cognitive urge-to-cough is dependent on the integration of respiratory afferent activity, respiratory motor drive, affective state, attention, experience, and learning.

Disinhibition of the dorsomedial hypothalamus increases the frequency of augmented breaths in the anesthetized rat.

The present study was undertaken to identify if activation of the dorsomedial hypothalamus (DMH) elicits augmented breaths (ABs). DMH disinhibition in urethane anesthetized rats produced both an increase in baseline respiratory rate (RR) and an increase in the number of ABs. The increase in RR was associated with a decrease in both the time of inspiration (T(i)) and expiration (T(e)) and the peak change in RR was observed 5 min post DMH activation. In contrast, the increase in ABs was greatest during the first 1.25 min, and both T(i)s of the ABs did not change significantly from pre-injection values. The T(e) of the ABs did decrease but remained significantly greater than the T(e) of the normal breath during DMH disinhibition. Our results support the hypothesis that the central neural pathway involved in the maintenance of normal respiratory pattern may be distinct from pathways involved in the generation of ABs.

Effects of systemic administration of mirtazapine on respiratory muscle activity in sleeping rats.

Mirtazapine (MIRT) is an antidepressant with mixed noradrenergic and serotonergic effects in central nervous system. The present study was undertaken to assess whether MIRT can stimulate genioglossus muscle (GG) activity in the conscious, behaving rat. Nine male rats were chronically instrumented with GG and neck muscle EMG electrodes. EEG electrodes were implanted to acquire sleep stage. Results demonstrated a dose-dependent effect of MIRT on GG activity during sleep, although no changes reached statistical significance. Low dose MIRT (0.1 mg/kg) showed a slight increase in GG phasic activity. In contrast, higher doses of MIRT (0.5-1.0 mg/kg) tended to decrease GG activity relative to vehicle, in addition to decreasing total sleep time.

A pilot study of high-adsorption hemofiltration in human septic shock.

BACKGROUND: To compare the hemodynamic and biological effects of high-adsorption continuous veno-venous hemofiltration (CVVH) with standard CVVH in septic shock. METHODS: In a randomized cross-over clinical trial twelve patients with septic shock and multiple organ failure were enrolled at a tertiary intensive care unit. Patients were allocated to either 9 hours of high-adsorption hemofiltration (CVVH with 3 hourly filter change using AN69 hemofilters - 3FCVVH) or 9 hours of standard hemofiltration (CVVH without filter change - 1F-CVVH). RESULTS: Changes in hemodynamic variables, dose of noradrenaline required to maintain a mean arterial pressure greater than 75 mmHg and plasma concentrations of cytokines (IL-6, IL-8, IL-10 and IL-18) were measured. A 9-hour period of 3F-CVVH was associated with greater reduction in noradrenaline dose than a similar period of 1F-CVVH (median reduction: 16 vs. 3.5 microg/min, p=0.036; median percentage reduction: 48.1% vs. 17.5%, p=0.028). Unlike 1F-CVVH, 3F-CVVH was associated with a reduction in the plasma concentration of IL-6, IL-10 and IL-18 at 9 hours and a significant decrease 30 minutes after additional filter changes (IL-6: p<0.01, p<0.01; IL-10: p=0.03, p=0.016 and IL-18: p=0.016, p<0.01, respectively). Both, 3F-CVVH and 1F-CVVH were associated with decreased plasma concentrations of IL-8 at 9 hours (p<0.01, p<0.01, respectively). In a confirmatory ex-vivo experiment IL-6 concentrations substantially decreased during 3F-CVVH (at baseline 511 pg/mL and at end: 21 pg/mL) whereas IL-6 concentrations increased in control blood (at baseline 511 pg/mL and at end: 932 pg/mL). CONCLUSIONS: High-adsorption CVVH appears more effective than standard CVVH in decreasing noradrenaline requirements and plasma concentrations of cytokines in septic shock patients.

Impact of Azithromycin on the Quorum Sensing-Controlled Proteome of Pseudomonas aeruginosa.

The macrolide antibiotic, azithromycin (AZM), has been reported to improve the clinical outcome of cystic fibrosis patients, many of whom are chronically-infected with Pseudomonas aeruginosa. However, the highest clinically-achievable concentrations of this drug are well-below the minimum inhibitory concentration for P. aeruginosa, raising the question of why AZM exhibits therapeutic activity. One possibility that has been raised by earlier studies is that AZM inhibits quorum sensing (QS) by P. aeruginosa. To explicitly test this hypothesis the changes brought about by AZM treatment need to be compared with those associated with specific QS mutants grown alongside in the same growth medium, but this has not been done. In this work, we used quantitative 2D-difference gel electrophoresis and 1H-NMR spectroscopy footprint analysis to examine whether a range of clinically-relevant AZM concentrations elicited proteomic and metabolomic changes in wild-type cultures that were similar to those seen in cultures of defined QS mutants. Consistent with earlier reports, over half of the AZM-induced spot changes on the 2D gels were found to affect QS-regulated proteins. However, AZM modulated very few protein spots overall (compared with QS) and collectively, these modulated proteins comprised only a small fraction (12-13%) of the global QS regulon. We conclude that AZM perturbs a sub-regulon of the QS system but does not block QS per se. Reinforcing this notion, we further show that AZM is capable of attenuating virulence factor production in another Gram-negative species that secretes copious quantities of exoenzymes (Serratia marcescens), even in the absence of a functional QS system.

Central administration of nicotine suppresses tracheobronchial cough in anesthetized cats.

We tested the hypothesis that nicotine, which acts peripherally to promote coughing, might inhibit reflex cough at a central site. Nicotine was administered via the vertebral artery [intra-arterial (ia)] to the brain stem circulation and by microinjections into a restricted area of the caudal ventral respiratory column in 33 pentobarbital anesthetized, spontaneously breathing cats. The number of coughs induced by mechanical stimulation of the tracheobronchial airways; amplitudes of the diaphragm, abdominal muscle, and laryngeal muscles EMGs; and several temporal characteristics of cough were analyzed after administration of nicotine and compared with those during control and recovery period. (-)Nicotine (ia) reduced cough number, cough expiratory efforts, blood pressure, and heart rate in a dose-dependent manner. (-)Nicotine did not alter temporal characteristics of the cough motor pattern. Pretreatment with mecamylamine prevented the effect of (-)nicotine on blood pressure and heart rate, but did not block the antitussive action of this drug. (+)Nicotine was less potent than (-)nicotine for inhibition of cough. Microinjections of (-)nicotine into the caudal ventral respiratory column produced similar inhibitory effects on cough as administration of this isomer by the ia route. Mecamylamine microinjected in the region just before nicotine did not significantly reduce the cough suppressant effect of nicotine. Nicotinic acetylcholine receptors significantly modulate functions of brain stem and in particular caudal ventral respiratory column neurons involved in expression of the tracheobronchial cough reflex by a mecamylamine-insensitive mechanism.

Assessment of aspiration risk in stroke patients with quantification of voluntary cough.

BACKGROUND: Dysphagia and subsequent aspiration are serious complications of acute stroke that may be related to an impaired cough reflex. It was hypothesized that aspirating stroke patients would have impaired objective measures of voluntary cough as compared with both nonstroke control subjects and nonaspirating stroke patients. METHODS: Swallowing was evaluated by standard radiologic or endoscopic methods, and stroke patients were grouped by aspiration severity (severe, n = 11; mild, n = 17; no aspiration, n = 15). Airflow patterns and sound pressure level (SPL) of voluntary cough were measured in stroke patients and in a group of normal control subjects (n = 18). Initial stroke severity was determined retrospectively with the Canadian Neurological Scale. RESULTS: All cough measures were altered in stroke patients as a group relative to nonstroke control subjects. Univariate analysis showed that peak flow of the inspiration phase (770.6 +/- 80.6 versus 1,120.1 +/- 148.4 mL/s), SPL (90.0 +/- 3.1 versus 100.2 +/- 1.6 dB), peak flow of the expulsive phase (875.1 +/- 122.7 versus 1,884.1 +/- 221.6 mL/s), expulsive phase rise time (0.34 +/- 0.1 versus 0.09 +/- 0.01 s), and cough volume acceleration (5.5 +/- 1.3 versus 27.8 +/- 3.9 mL/s/s) were significantly impaired in severe aspirators as compared with nonaspirators. Aspirating patients had more severe strokes than nonaspirators (mean Canadian Neurological Scale score 7.7 +/- 0.7 versus 9.8 +/- 0.3). Multivariate logistic regression found only expulsive phase rise time values during cough correlated with aspiration status. CONCLUSION: Objective analysis of cough may provide a noninvasive way to identify the aspiration risk of stroke patients.

Interleukin-1 receptor antagonist: characterisation of its gene expression in rabbit tissues and large-scale expression in eucaryotic cells using a baculovirus expression system.

The gene expression of rabbit interleukin-1 receptor antagonist (RbIL-lra) was examined in rabbit tissues. RNA was isolated from heart, lung, kidney, muscle, liver, spleen, brain, and peripheral blood monocytes (PBMs), and RbIL-lra mRNA was identified as a single species by Northern analysis using a RbIL-lra probe. RbIL-lra was abundantly expressed in lung, brain, heart, and liver, expressed at low levels in spleen, and undetectable in kidney and unstimulated PBMs. Expression of large scale recombinant production of RbIL-lra was achieved by subcloning the cDNA into a baculovirus expression vector. Recombination of this vector was completed with the BacPAK6 baculovirus genome. The recombinant virus, containing the RbIL-lra cDNA, was used to infect Spodoptera frugiperda (Sf21) insect cells in a spinner flask system and in monolayers in cell culture flasks. Recombinant rabbit IL-lra (rRbIL-lra) was secreted into the culture medium in this system at very high levels (35 mg/l). The protein was identified by reducing SDS-PAGE electrophoresis, was variably glycosylated and had a molecular weight between 19-25 kDa. It was then purified by size exclusion HPLC on a Du Pont Gf-250 column. The rRbIL-lra was demonstrated to be functionally active by inhibiting recombinant human IL-1 alpha in a mouse thymocyte proliferation assay. 20 ng/ml (6.7 U/ml) of rRbIL-lra inhibited 95% of the activity of 2 ng/ml IL-1 alpha.

Chronic inflammatory meningoencephalitis should not be mistaken for Alzheimer's disease.

We describe two patients with a chronic encephalopathy that clinically resembled dementia but that resolved after oral administration of high-dose corticosteroid therapy. Both patients had serologically documented Sjögren's syndrome, a diagnosis that was further supported by biopsy of a salivary gland in one. Neither patient had radiologic evidence of vasculitis of the central nervous system. In one patient, meningeal and brain biopsy specimens showed perivascular inflammatory lymphocytic infiltrates. Chronic inflammatory meningoencephalitis is a treatable cause of chronic encephalopathy that should be clinically distinguished from dementia associated with Alzheimer's disease.

High-volume haemofiltration in human septic shock.

OBJECTIVE: To evaluate whether high volume haemofiltration improves haemodynamics and affects serum cytokine and complement concentrations in human septic shock. DESIGN AND SETTING: Randomized cross-over clinical trial in a tertiary intensive care unit. PATIENTS: Eleven patients with septic shock and multi-organ failure. INTERVENTIONS: Patients were assigned to either 8 h of high-volume haemofiltration (HVHF; 6 l/h) or 8 h of standard continuous veno-venous haemofiltration (CVVH; 1 l/h) in random order. MEASUREMENTS AND MAIN RESULTS: We measured changes in haemodynamic variables, dose of norepinephrine required to maintain a mean arterial pressure greater than 70 mmHg and plasma concentrations of complement anaphylatoxins and several cytokines. An 8-h period of HVHF was associated with a greater reduction in norepinephrine requirements than a similar period of CVVH (median reduction: 10.5 vs. 1.0 microg/min; p = 0.01; median percentage reduction: 68 vs. 7%; p = 0.02). Both therapies were associated with a temporary reduction (p < 0.01) in the plasma concentration of C3a, C5a, and interleukin 10 within 2 h of initiation. HVHF was associated with a greater reduction in the area under the curve for C3a and C5a (p < 0.01). The concentration of the measured soluble mediators in the ultrafiltrate was negligible. CONCLUSIONS: HVHF decreases vasopressor requirements in human septic shock and affects anaphylatoxin levels differently than standard CVVH.

Super high flux hemofiltration: a new technique for cytokine removal.

OBJECTIVE: To test whether hemofiltration using a hemofilter with large pores (super high flux hemofiltration) achieves effective cytokine removal. DESIGN: : Ex vivo study. SETTING: Laboratory of an intensive care unit in a tertiary hospital. PATIENTS AND PARTICIPANTS: Five healthy volunteers. INTERVENTIONS: Blood was spiked with 1 mg of endotoxin and then circulated through a closed hemofiltration circuit with a large pore polyamide super high flux hemofilter (nominal cut-off point: 100 kDa). Hemofiltration was conducted at 1 l/h or 6 l/h of ultrafiltrate flow. Samples were taken from the arterial, venous and ultrafiltration sampling ports. MEASUREMENTS AND RESULTS: Sieving coefficients (SC) above 0.6 were achieved for interleukin (IL)-1beta, IL-6 and IL-10 and SCs above 0.3 were achieved for IL-8 and TNF-alpha at 1 l/h. SCs of all cytokines (except IL-1) were reduced when the ultrafiltration rate was increased from 1 l/h to 6 l/h ( p<0.01), but cytokine clearances still increased ( p<0.01). The highest SC for albumin was 0.1 at 1 l/h and fell to 0.01 at 6 l/h. No adsorption of cytokines and albumin was observed. CONCLUSION: High volume ultrafiltration using a super high flux filter achieved cytokine clearances comparable to, or greater than, those currently achieved for urea during standard continuous renal replacement therapy.

Effects of timing of inspiratory occlusion on cerebral evoked potentials in humans.

Previous studies from these laboratories have shown that airway occlusion applied from the onset of inspiration or during midinspiration is associated with cerebral evoked potentials in human subjects. The hypothesis tested in the present study was that the more abrupt decrease in mouth pressure produced by midinspiratory occlusion will be associated with evoked potentials that have shorter peak latencies and greater peak amplitudes than those produced by occlusions from the onset of inspiration. The second objective of the present study was to determine whether there is bilateral projection of inputs from the respiratory system to the somatosensory cortex. Random presentation of 64 midinspiratory occlusions and 64 occlusions from the onset of inspiration was performed in eight subjects. The inspirations preceding the occlusions served as control. Evoked potentials were recorded from the scalp with electrode pairs Cz-C3 and Cz-C4. Reaction time to each type of occlusion was measured from the burst in electromyogram activity produced by contraction of the muscles encircling the eye. Each type of inspiratory occlusion was associated with evoked potentials that could be recorded bilaterally. The peak amplitudes of the evoked potentials recorded over the right cerebral hemisphere were significantly greater than those recorded from the left side. The peak amplitude was greater and the peak latency shorter for the evoked potentials produced by the midinspiratory occlusions. The results are consistent with the hypothesis that afferents mediating these potentials are stimulated by added loads to breathing and project bilaterally to the somatosensory cortex in humans.

Effect of expiratory loading on expiratory duration and pulmonary stretch receptor discharge.

Slowly adapting pulmonary stretch receptors have been hypothesized to be the afferents mediating the vagally dependent, volume-related prolongation of expiratory time (TE) during expiratory loading. It has been further suggested that the vagal component of this prolongation of TE is due to the temporal summation of pulmonary stretch receptor (PSR) activity during expiratory loading. This hypothesis was tested in rabbits exposed to resistive and elastic single-breath expiratory loading while PSR's were simultaneously recorded. Both types of loads resulted in a decreased expired volume (VE) and increased expiratory duration (TE). The TE for resistive loads were significantly greater than for elastic loads for equivalent VE. Thus two different VE-TE relationships were found for resistive and elastic loads. When TE was plotted against the area under the expired volume trajectory, a single linear relationship was observed. PSR activity recorded during expiratory loading increased as VE decreased and TE increased. A single linear relationship resulted when the number of PSR spikes during the expiration was plotted against the associated TE for all types of loads. These findings demonstrate that the volume-related prolongation of TE with single-breath expiratory loads is associated with an increase in PSR discharge. These results support the hypothesis that the vagal component of load-dependent prolongation of TE is a function of both the temporal and spatial summation of PSR activity during the expiratory phase.

c-Fos expression in the central nervous system elicited by phrenic nerve stimulation.

Phrenic nerve afferents (PNa) have been shown to activate neurons in the spinal cord, brain stem, and forebrain regions. The c-Fos technique has been widely used as a method to identify neuronal regions activated by afferent stimulation. This technique was used to identify central neural areas activated by PNa. The right phrenic nerve of urethane-anesthetized rats was stimulated in the thorax. The spinal cord and brain were sectioned and stained for c-Fos expression. Labeled neurons were found in the dorsal horn laminae I and II of the C3-C5 spinal cord ipsilateral to the site of PNa stimulation. c-Fos-labeled neurons were found bilaterally in the medial subnuclei of the nucleus of the solitary tract, rostral ventral respiratory group, and ventrolateral medullary reticular formation. c-Fos-labeled neurons were found bilaterally in the paraventricular and supraoptic hypothalamic nuclei, in the paraventricular thalamic nucleus, and in the central nucleus of the amygdala. The presence of c-Fos suggests that these neurons are involved in PNa information processing and a component of the central mechanisms regulating respiratory function.

High-frequency ventilation-induced apnea: interaction of frequency, volume, FRC, and CO2.

Apnea is often observed during high-frequency oscillatory ventilation (HFOV). This study on anesthetized dogs varied the oscillator frequency (f) and determined the stroke volume (SV) at which apnea occurred. Relaxation functional residual capacity (FRC) and the eupneic breathing end-tidal CO2 level were held constant. Airway pressure and CO2 were measured from a side port of the tracheostomy cannula. An arterial cannula was inserted for blood gas analysis. Diaphragm electromyogram (EMG) was recorded with bipolar electrodes. Apnea was defined as the absence of phasic diaphragm EMG activity for a minimum of 60 s. During HFOV, SV was increased at each f (5-40 Hz) until apnea occurred. The apnea inducing SV decreased as f increased. SV was minimal at 25-30 Hz. Frequencies greater than 30 Hz required increased SV to produce apnea. The f-SV curve was defined as the apneic threshold. Increased FRC resulted in a downward shift (less SV at the same f) in the apneic threshold. Elevated CO2 caused an upward shift (more SV at the same f) in the apneic threshold. These results demonstrate that the apnea elicited by HFOV is dependent on the interaction of oscillator f and SV, the FRC, and CO2.

Volume-timing relationships during cough and resistive loading in the cat.

The relationship between pulmonary volume-related feedback and inspiratory (CTI) and expiratory (CTE) phase durations during cough was determined. Cough was produced in anesthetized cats by mechanical stimulation of the intrathoracic tracheal lumen. During eupnea, the animals were exposed to single-breath inspiratory and expiratory resistive loads. Cough was associated with large increases in inspiratory volume (VI) and expiratory volume (VE) but no change in phase durations compared with eupnea. There was no relationship between VI and CTI during coughing. A linear relationship with a negative slope existed between VI and eupneic inspiratory time during control and inspiratory resistive loading trials. There was no relationship between VE and CTE during all coughs. However, when the first cough in a series or a single cough was analyzed, the VE/CTE relationship had a positive slope. A linear relationship with a negative slope existed between VE and eupneic expiratory time during control and expiratory resistive loading trials. These results support separate ventilatory pattern regulation during cough that does not include modulation of phase durations by pulmonary volume-related feedback.

Relationship between resistive loads and P1 peak of respiratory-related evoked potential.

This study investigated the relationship between resistive-load (DeltaR) magnitude, the first positive peak (P1) amplitude of the respiratory-related evoked potential (RREP), and load-magnitude estimation (ME). The first experiments determined the subject's (n = 9) ME of five DeltaR magnitudes randomly presented at the onset of an inspiration or by interrupting an inspiration. No significant differences were found in the slopes of the two different presentations, but the subjects estimated the interrupted inspiratory loads to be of lesser magnitude than loads presented at the onset of the breath. In the second series of experiments, the subject's (n = 6) RREPs were recorded in response to three DeltaR magnitudes. The amplitude of the short-latency P1 peak of the RREP significantly increased with increases in the DeltaR magnitude. A log-log plot of the group-averaged P1 amplitudes showed a linear relationship with DeltaR. These results were consistent with the hypothesis that the perceptual magnitude of the respiratory load was related to the P1 amplitude of the RREP, suggesting the physical magnitude of the load-related stimulus was correlated with the amplitude of the cortical neural activation.