Relieving dyspnoea by non-invasive ventilation decreases pain thresholds in amyotrophic lateral sclerosis.

BACKGROUND: Dyspnoea is a threatening sensation of respiratory discomfort that presents many similarities with pain. Experimental dyspnoea in healthy subjects induces analgesia. This 'dyspnoea-pain counter-irritation' could, in reverse, imply that relieving dyspnoea in patients with chronic respiratory diseases would lower their pain thresholds. METHODS: We first determined pressure pain thresholds in 25 healthy volunteers (22-31 years; 13 men; handheld algometer), during unloaded breathing (BASELINE) and during inspiratory threshold loading (ITL). Two levels of loading were used, adjusted to induce dyspnoea self-rated at 60% or 80% of a 10 cm visual analogue scale (ITL6 and ITL8). 18 patients with chronic respiratory failure due to amyotrophic lateral sclerosis (ALS) were then studied during unassisted breathing and after 30 and 60 min of non-invasive ventilation-NIV30 and NIV60-(same dyspnoea evaluation). RESULTS: In healthy volunteers, pressure pain thresholds increased significantly in the deltoid during ITL6 (p<0.05) and ITL8 (p<0.05) and in the trapezius during ITL8 (p<0.05), validating the use of pressure pain thresholds to study dyspnoea-pain counter-irritation. In patients with ALS, the pressure pain thresholds measured in the deltoid during unassisted breathing decreased by a median of 24.5%-33.0% of baseline during NIV30 and NIV60 (p<0.05). CONCLUSION: Relieving dyspnoea by NIV in patients with ALS having respiratory failure is associated with decreased pressure pain thresholds. Clinical implications have yet to be determined, but this observation suggests that patients with ALS could become more susceptible to pain after the institution of NIV, hence the need for reinforced attention towards potentially painful diagnostic and therapeutic interventions.

Nefopam, a non-opioid analgesic, does not alleviate experimental work/effort dyspnoea in healthy humans: A randomised controlled trial.

BACKGROUND: Dyspnoea is a distressing and debilitating symptom with a major impact on quality of life. Alleviation of dyspnoea therefore constitutes a major clinical challenge. When causative physiological disorders cannot be corrected ("persistent dyspnoea"), nonspecific treatment must be considered. Morphine alleviates dyspnoea but has numerous side-effects including ventilatory depression, which justifies looking for alternatives. Certain forms of dyspnoea involve C-fibres, and can be attenuated by C-fibres blockade. We hypothesised that nefopam, a non-sedative benzoxazocine analgesic known to block the transient receptor potential vanilloid subtype 1 abundantly present on C-fibres, would attenuate dyspnoea. METHODS: We conducted a randomised, double-blind, placebo-controlled crossover study of nefopam in healthy subjects submitted to experimental work/effort dyspnoea by inspiratory threshold loading (15 healthy male volunteers; age 23-41). We studied a perceptual outcome (dyspnoea visual analogue scale -D-VAS-) and a neurophysiological outcome (effect of nefopam on dyspnoea-pain counter-irritation as assessed by laser-evoked potentials; an effect of nefopam on dyspnoea was hypothetised to reduce the ability of dyspnoea to inhibit pain). Somaesthetic evoked potentials (SEPs) were studied as a control. RESULTS: A statistically significant decrease in LEP amplitude was observed in response to loading with nefopam (F = 19.1; p < 0.001) and placebo (F = 5.73 and p < 0.001), with no significant difference between nefopam and placebo and no change in SEP characteristics. CONCLUSIONS: In this study, nefopam did not exhibit any effects on dyspnoea.

Dyspnoea: a multidimensional and multidisciplinary approach.

Dyspnoea is a debilitating symptom that affects quality of life, exercise tolerance and mortality in various disease conditions/states. In patients with chronic obstructive pulmonary disease (COPD), it has been shown to be a better predictor of mortality than forced expiratory volume in 1 s. In patients with heart disease it is a better predictor of mortality than angina. Dyspnoea is also associated with decreased functional status and worse psychological health in older individuals living at home. It also contributes to the low adherence to exercise training programmes in sedentary adults and in COPD patients. The mechanisms of dyspnoea are still unclear. Recent studies have emphasised the multidimensional nature of dyspnoea in the sensory-perceptual (intensity and quality), affective distress and impact domains. The perception of dyspnoea involves a complex chain of events that depend on varying cortical integration of several afferent/efferent signals and coloured by affective processing. This review, which stems from the European Respiratory Society research symposium held in Paris, France in November 2012, aims to provide state-of-the-art advances on the multidimensional and multidisciplinary aspects of dyspnoea, by addressing three different themes: 1) the neurophysiology of dyspnoea, 2) exercise and dyspnoea, and 3) the clinical impact and management of dyspnoea.

Dynamic respiratory mechanics and exertional dyspnoea in pulmonary arterial hypertension.

Patients with pulmonary arterial hypertension (PAH) may exhibit reduced expiratory flows at low lung volumes, which could promote exercise-induced dynamic hyperinflation (DH). This study aimed to examine the impact of a potential exercise-related DH on the intensity of dyspnoea in patients with PAH undergoing symptom-limited incremental cardiopulmonary cycle exercise testing (CPET). 25 young (aged mean±sd 38±12 yrs) nonsmoking PAH patients with no evidence of spirometric obstruction and 10 age-matched nonsmoking healthy subjects performed CPET to the limit of tolerance. Ventilatory pattern, operating lung volumes (derived from inspiratory capacity (IC) measurements) and dyspnoea intensity (Borg scale) were assessed throughout CPET. IC decreased (i.e. DH) progressively throughout CPET in PAH patients (average 0.15 L), whereas it increased in all the healthy subjects (0.45 L). Among PAH patients, 15 (60%) exhibited a decrease in IC throughout exercise (average 0.50 L), whereas in the remaining 10 (40%) patients IC increased (average 0.36 L). Dyspnoea intensity and ventilation were greater in PAH patients than in controls at any stage of CPET, whereas inspiratory reserve volume was lower. We conclude that DH-induced mechanical constraints and excessive ventilatory demand occurred in these young nonsmoking PAH patients with no spirometric obstruction and was associated with exertional dyspnoea.

Significance of changes in endurance shuttle walking performance.

BACKGROUND: The endurance shuttle walking test (ESWT) has shown good responsiveness to interventions in patients with chronic obstructive pulmonary disease (COPD). However, the minimal important difference (MID) for this test remains unknown, therefore limiting its interpretability. METHODS: Patients with COPD who completed two or more ESWTs following pulmonary rehabilitation (n=132; forced expiratory volume in 1 s (FEV1) 48 ± 22%) or bronchodilation (n=69; FEV1 50 ± 12%) rated their performance of the day in comparison with their previous performance on a 7-point scale ranging from -3 (large deterioration) to +3 (large improvement). The relationship between subjective perception of changes and objective changes in performance during the shuttle walk was evaluated. RESULTS: Following pulmonary rehabilitation, the anchor-based approach did not allow a valid estimation of the MID in the ESWT performance to be obtained. After bronchodilation, patient ratings of change correlated significantly with the difference in walking distance (r=0.53, p<0.001) and endurance time (r=0.55, p<0.001). For the pharmacotherapy data, regression analysis indicated that a 65 s (95% CI 45 to 85) change in endurance time and a 95 m (95% CI 60 to 115) change in walking distance were associated with a 1-point change in the rating of change scale. These changes represented 13-15% of the baseline values. CONCLUSIONS: A change in endurance shuttle walking performance of 45-85 s (or 60-115 m) after bronchodilation is likely to be perceived by patients. This MID value may be specific to the intervention from which it was derived.

The impact of obesity on walking and cycling performance and response to pulmonary rehabilitation in COPD.

BACKGROUND: We examined the influence of overweight and obesity on pulmonary function, exercise tolerance, quality of life and response to pulmonary rehabilitation in COPD. METHODS: 261 patients with COPD were divided into three groups: normal body mass index (BMI), overweight and obese. Baseline and post rehabilitation pulmonary function, 6-min walking test (6MWT), endurance time during a constant workrate exercise test (CET) and St. George's Respiratory Questionnaire (SGRQ) scores were compared between all three classes of BMI. RESULTS: At baseline, obese and overweight patients had less severe airflow obstruction compared to normal BMI patients. There was no baseline difference in CET performance or SGRQ scores across BMI classes and 6MWT was reduced in the presence of obesity (p < 0.01). Compared to baseline, post-rehabilitation 6MWT, CET performance and SGRQ scores improved significantly in each group (p < 0.01), but 6MWT was still significantly lower in the presence of obesity. CONCLUSIONS: Walking, but not cycling performance was worse in obese patients. This difference was maintained post rehabilitation despite significant improvements. Weight excess may counterbalance the effect of a better preserved respiratory function in the performance of daily activities such as walking. However, obesity and overweight did not influence the magnitude of improvement after pulmonary rehabilitation.

Effect of obesity on constant workrate exercise in hyperinflated men with COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and a high body mass index (BMI) can both affect pulmonary volumes as well as exercise tolerance, but their combined effect on these outcomes is not well known. The aim of this study was to investigate the effects of increased BMI during constant workrate cycle ergometry in patients with COPD. METHODS: Men with COPD and hyperinflation were divided according to World Health Organization BMI classification: 84 normal BMI (NBMI), 130 overweight (OW) and 64 obese (OB). Patients underwent spirometric and lung volumes assessment and an incremental cycling exercise test. This was followed by a constant workrate exercise test (CET) at 75% of peak capacity. Inspiratory capacity and Borg dyspnea scores were measured at baseline, during and at the end of CET. RESULTS AND DISCUSSION: FEV1 % predicted was not different across BMI classes. Total lung capacity and functional residual capacity were significantly lower in OB and OW compared to NBMI patients. Peak VO2 in L x min(-1) was significantly higher in OB and OW patients than in NBMI patients. CET time was not different across BMI classes (p = 0.11). Changes in lung volumes and dyspnea during CET were not different between BMI categories. CONCLUSIONS: OB and OW patients with COPD had a higher peak VO2 than their lean counterparts. Endurance time, dyspnea and changes in lung volumes during CET were similar between BMI categories.

Impact of preinduced quadriceps fatigue on exercise response in chronic obstructive pulmonary disease and healthy subjects.

Exercise intolerance in chronic obstructive pulmonary disease (COPD) results from a complex interaction between central (ventilatory) and peripheral (limb muscles) components of exercise limitation. The purpose of this study was to evaluate the influence of quadriceps muscle fatigue on exercise tolerance and ventilatory response during constant-workrate cycling exercise testing (CWT) in patients with COPD and healthy subjects. Fifteen patients with COPD and nine age-matched healthy subjects performed, 7 days apart, two CWTs up to exhaustion at 80% of their predetermined maximal work capacity. In a randomized order, one test was performed with preinduced quadriceps fatigue and the other in a fresh state. Quadriceps fatigue was produced by electrostimulation-induced contractions and quantified by maximal voluntary contraction and potentiated twitch force (TwQ(pot)). Endurance time and ventilatory response during CWT were compared between fatigued and fresh state. Endurance time significantly decreased in the fatigued state compared with the fresh condition in COPD (356 +/- 69 s vs. 294 +/- 45 s, P < 0.05) and controls (450 +/- 74 s vs. 340 +/- 45 s, P < 0.05). Controls showed significantly higher ventilation and end-exercise dyspnea scores in the fatigued condition, whereas, in COPD, fatigue did not influence ventilation or dyspnea during exercise. The degree of ventilatory limitation, as expressed by the Ve/maximum voluntary ventilation ratio, was similar in both conditions in patients with COPD. We conclude that it is possible to induce quadriceps fatigue by local electrostimulation-induced contractions. Our findings demonstrate that peripheral muscle fatigue is an additional important factor, besides intense dyspnea, that limits exercise tolerance in COPD.

Performance during constant workrate cycling exercise in women with COPD and hyperinflation.

We aimed to characterize gender differences in exercise endurance, operating lung volumes and symptoms limitation during exercise in patients with COPD. Ninety-three women and 93 men with COPD matched for age and disease severity were evaluated during symptom-limited constant-work rate cycle exercise at 75% of peak capacity. Breathing pattern, inspiratory capacity, dyspnoea and leg discomfort Borg scores were recorded during exercise. Endurance time was shorter in women compared to men. Inspiratory capacity decreased at a similar rate during exercise in women and men (0.71 vs. 0.81 ml x s(- 1) for women and men respectively, p = 0.47) despite lower ventilation at end-exercise in women. At end-exercise, women showed lower inspiratory reserve volume (p < 0.005). Dyspnoea responses during exercise occurred with a steep rise near end-exercise, when inspiratory reserve volume approached a critical value, at 10% of total lung capacity, this onset of dyspnoea acceleration occurred earlier in women (p < 0.0001). At the same relative exercise intensity, women with COPD had lower endurance time than men. Compared to men, women with COPD were disadvantaged during exercise as they reached a critical inspiratory reserve volume earlier, leading to a steep increase in dyspnoea and to exercise termination.

Early-onset emphysema in a large French-Canadian family: a genetic investigation.

BACKGROUND: Inherited mutations in SERPINA1 coding for the alpha-1 antitrypsin (A1AT) protein is the only well established cause of hereditary emphysema. We aimed to identify the genetic ecause of early-onset emphysema in a five-generation French-Canadian family free of A1AT deficiency. METHODS: Between Dec 1, 2014, and April 1, 2017, we investigated 63 individuals from a single pedigree, including 55 with DNA available. Whole-exome sequencing was done in a convenience sample of 14 individuals (nine with unambiguous expression of the typical form of emphysema observed in this family). We filtered rare non-synonymous variants that were predicted to be damaging to identify a single mutation in a biologically relevant gene shared among all affected individuals. We assessed segregation with the disease in additional family members who were not evaluated by whole-exome sequencing. The effect of the candidate variant on protein function was evaluated in vitro. mRNA and protein expression of the candidate gene was assessed in lung samples from unrelated individuals (n=80) with and without emphysema who underwent surgery for lung cancer at our institution. FINDINGS: A rare in-silico-predicted damaging variant (Ala455Thr) was identified in the protein tyrosine phosphatase non-receptor type 6 (PTPN6) gene, also known as SHP-1, an important negative regulator of immune processes. 20 (95%) of 21 family members with computed tomography-confirmed emphysema were heterozygotes for the Ala455Thr mutation. No Thr455 homozygotes were identified. Emphysema or reduced diffusion capacity was observed in all heterozygotes with a history of smoking. Incomplete penetrance of the mutation and variable degrees of emphysema were observed in never smokers. The Ala455Thr mutation in SHP-1 caused a reduction in phosphatase activity in vitro, confirming the loss-of-function effect of the mutation. mRNA and protein expression of PTPN6 were upregulated in smokers, but were not associated with emphysema or severity of airflow limitation. INTERPRETATION: An inherited variant in the gene PTPN6 is responsible for early-onset emphysema in this family. To our knowledge, this is the second form of hereditary emphysema since the discovery of A1AT deficiency in the 1960s, representing a breakthrough in understanding the genetics and pathogenesis of emphysema. FUNDING: Fonds sur les maladies respiratoires J.-D. Bégin-P.-H. Lavoie de l'Université Laval, Fondation de l'Institut universitaire de cardiologie et de pneumologie de Québec, CIHR/GSK research Chair on COPD at Université Laval, and the Canadian Institutes of Health Research.

Chronic obstructive pulmonary disease in women.

BACKGROUND: Little is known about the comparative impact of chronic obstructive pulmonary disease (COPD) between women and men and about women's response to pulmonary rehabilitation. OBJECTIVES: To compare lung function, disability, mortality and response to pulmonary rehabilitation between women and men with COPD. METHODS: In the present retrospective study, 68 women (mean age 62.5+/-8.9 years) and 168 men (mean age 66.3+/-8.4 years) were evaluated by means of pulmonary function testing and an incremental symptom-limited cycle exercise test. Forty women and 84 men also participated in a 12-week pulmonary rehabilitation program. A 6 min walking test and the chronic respiratory questionnaire were used to assess the effects of pulmonary rehabilitation. Survival status was also evaluated. RESULTS: Compared with men, women had a smaller tobacco exposure (31+/-24 versus 48+/-27 pack-years, P<0.05), displayed better forced expiratory volume in 1 s (44+/-13 versus 39+/-14 % predicted, P<0.05), a higher functional residual capacity (161+/-37 versus 149+/-36 % predicted, P<0.05) and total lung capacity (125+/-20 versus 115+/-19 % predicted, P<0.001). Peak oxygen consumption was not different between women and men when expressed in predicted values but lower in women when expressed in absolute values. Pulmonary rehabilitation resulted in significant improvements in 6 min walking test and quality of life in both sexes, but women had a greater improvement in chronic respiratory questionnaire dyspnea. Survival status was similar between sexes, but predictors of mortality were different between sexes. CONCLUSIONS: Women may be more susceptible to COPD than men. The clinical expression of COPD may differ between sexes with greater degree of hyperinflation in women, who also benefit from pulmonary rehabilitation.

Experimental dyspnea as a stressor: differential cardiovegetative responses to inspiratory threshold loading in healthy men and women.

Dyspnea is associated with an emotional reaction that involves limbic activation. The inspiratory threshold load (ITL) is known to elicit a dyspneic response in healthy subjects. Laboratory-induced stress conditions have been shown to elicit sex-related differences in cardiovascular responses. The aim of this study was to evaluate how healthy men (n = 8) and women (n = 9) react and adapt to 5-min periods of ITL at three levels (low, medium, and high) in terms of heart rate (HR), temporal (RMSSD) and spectral (LF, HF, LF/HF ratio) HRV indexes, and rating of breathing discomfort. HR increased with low, medium, and high ITL in men, whereas it increased only with high ITL in women. LF/HF ratio increased at low ITL in both men and women. Modifications appear to depend essentially on increased LF in men and on reduced HF in women. In addition, HRV modifications differ between men and women, following the order of presentation of ITLs. Our results show a continuous and sustained stress in men (increased HR, LF, and LF/HF ratio across ITL presentation) and a stress adaptation in women. Subjective responses of breathing discomfort were not correlated with sympatho-vagal balance modifications for a subgroup of subjects (n = 10). Breathing against the ITL induced autonomic modifications that are different between men and women, i.e., driven by sympathetic mediated responses in men, whereas women showed a greater parasympathetic modulation of cardiovascular activity. These results highlight the role of the mechanical inspiratory load in the heart rate variability seen in chronic obstructive pulmonary disease.NEW & NOTEWORTHY Breathing against the ITL induced autonomic modifications driven by sympathetic mediated responses in men, whereas women showed a greater parasympathetic modulation of cardiovascular activity, even for low load. A stress circuit could be at the origin of autonomic modifications induced by ITL. Our results would underline the role of the mechanic inspiratory load in the abnormalities in heart rate variability seen in COPD patients.

Use of facemask and mouthpiece to assess constant-workrate exercise capacity in COPD.

PURPOSE: To compare the response to constant-workrate cycling exercise between the mouthpiece and the facemask in patients with chronic obstructive pulmonary disease (COPD). METHODS: Ten patients with COPD (FEV1: 48 +/- 14% pred, mean +/- SD) performed two symptom-limited constant-workrate cycling exercise tests at 80% of their predetermined peak exercise capacity. One test was performed using a mouthpiece and the other with a facemask, in a random order. The endurance time to constant-workrate exercise was compared between the two interfaces. VO2, VCO2, ventilation (VE), inspiratory capacity, dyspnea Borg score, and heart rate responses during exercise were also compared. RESULTS: Endurance time was similar between the two interfaces (mean difference +/- SD, 30 +/- 74 s, P = 0.23). Except for the end-exercise values, which were lower with the facemask, the VO2, VCO2, and VE responses to submaximal exercise were similar between the two interfaces. Perception of dyspnea, inspiratory capacity, and heart rate kinetics were similar during the two exercise tests. No clear preference about either interface was expressed by the patients. CONCLUSION: The mouthpiece and the facemask can be used with comparable results to determine the endurance time to constant-workrate cycling exercise in patients with COPD. Compared with the mouthpiece, the end-exercise values for VO2, VCO2, and VE were underestimated when a facemask was used. The similar responses in heart rate and symptom perception suggest that this could be due to an air leak at end-exercise with the facemask.

Interactions Between Dyspnea and the Brain Processing of Nociceptive Stimuli: Experimental Air Hunger Attenuates Laser-Evoked Brain Potentials in Humans.

Dyspnea and pain share several characteristics and certain neural networks and interact with each other. Dyspnea-pain counter-irritation consists of attenuation of preexisting pain by intercurrent dyspnea and has been shown to have neurophysiological correlates in the form of inhibition of the nociceptive spinal reflex RIII and laser-evoked potentials (LEPs). Experimentally induced exertional dyspnea inhibits RIII and LEPs, while "air hunger" dyspnea does not inhibit RIII despite its documented analgesic effects. We hypothesized that air hunger may act centrally and inhibit LEPs. LEPs were obtained in 12 healthy volunteers (age: 21-29) during spontaneous breathing (FB), ventilator-controlled breathing (VC) tailored to FB, after inducing air hunger by increasing the inspired fraction of carbon dioxide -FiCO2- (VCCO2), and during ventilator-controlled breathing recovery (VCR). VCCO2 induced intense dyspnea (visual analog scale = 63% ± 6% of full scale, p < 0.001 vs. VC), predominantly of the air hunger type. VC alone reduced the amplitude of the N2-P2 component of LEPs (Δ = 24.0% ± 21.1%, p < 0.05, effect-size = 0.74) predominantly through a reduction in P2, and the amplitude of this inhibition was further reduced by inducting air hunger (Δ = 22.6% ± 17.9%, p < 0.05, effect-size = 0.53), predominantly through a reduction in N2. Somatosensory-evoked potentials (SEPs) were not affected by VC or VCCO2, suggesting that the observed effects are specific to pain transmission. We conclude that air hunger interferes with the cortical mechanisms responsible for the cortical response to painful laser skin stimulation, which provides a neurophysiological substrate to the central nature of its otherwise documented analgesic effects.

Expiratory load compensation is associated with electroencephalographic premotor potentials in humans.

In normal humans during quiet breathing, expiration is mostly driven by elastic recoil of the lungs. Expiration becomes active when ventilation must be increased to meet augmented metabolic demands, or in response to expiratory loading, be it experimental or disease-related. The response to expiratory loading is considered to be mediated by both reflex and cortical mechanisms, but the latter phenomenon have not been neurophysiologically characterized. We recorded the EEG in 20 healthy volunteers (9 men, 11 women, age: 22 to 50 yr) during unloaded breathing, voluntary expirations, and in response to 50 cmH2O·l(-1)·s expiratory resistive load (ERL), 20 cmH2O expiratory threshold load (high ETL), and 10 cmH2O expiratory threshold load (low ETL). EEGs were processed by ensemble averaging expiratory time-locked segments and examined for pre-expiratory potentials, defined as a slow negative shift from the baseline signal preceding expiration, and suggestive of cortical preparation of expiration involving the supplementary motor area. Four subjects were excluded because of technical EEG problems. Pre-expiratory potentials were present in one subject at baseline and in all subjects during voluntary expirations. They were present in eight subjects during low ETL, in 15 subjects during high ETL, and in 13 subjets during ERL (control vs. low ETL, P = 0.008; control vs. high ETL, P < 0.001; and control vs. ERL, P < 0.001). Respiratory discomfort was more intense in the presence of pre-expiratory potentials (P < 0.001). These results provide a neurophysiological substrate to a cortical component of the physiological response to experimental expiratory loads in humans.

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

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

Postural disturbances resulting from unilateral and bilateral diaphragm contractions: a phrenic nerve stimulation study.

Thoracoabdominal breathing movements are a complex source of postural disturbance, but there are contradictory reports in the literature with inspiration described as having either a backward or a forward disturbing effect. To elucidate the mechanisms underlying this phenomenon, the present study studied the postural disturbance caused by isolated contractions of the diaphragm. Eight male and four female healthy subjects followed an original paradigm of phrenic nerve stimulation (bilateral and unilateral) and "diaphragmatic" voluntary sniff maneuvers in the seated and standing postures. Center of gravity (CG) acceleration was calculated from force plate recordings, and respiratory kinematics were assessed with thoracic and abdominal sensor belts. CG and respiratory signals revealed that, while seated, bilateral phrenic stimulation and sniff maneuvers consistently produced expansion of the abdomen associated with a forward peak of CG acceleration. In the standing posture, the direction of the CG peak was reversed and always directed backward. Unilateral phrenic stimulation induced an additional medial-lateral acceleration of the CG, directed toward the nonactive side while seated, but in the opposite direction while standing. These results suggest that isolated diaphragmatic contractions produce a constant disturbing pattern for a given posture, but with opposite effects between standing and seated postures. This could be related to the different biomechanical configuration of the body in each posture, corresponding to distinct kinematic patterns of the osteoarticular chain. In addition, the lateral component of the CG acceleration induced by unilateral diaphragm contractions could be clinically relevant in patients with hemidiaphragm paralysis.