Dr Shakeeb Moosavi

Research question: We previously reported that Deep Brain Stimulation (DBS) of motor thalamus (MT), in a patient with post-stroke tremor, relieved breathlessness associated with chronic obstructive pulmonary disease. This raised the question of whether MT DBS mitigates the ascending dyspnoea signal. We therefore sought to conduct a fully powered cohort study of experimentally induced air hunger (AH), an uncomfortable urge to breathe in patients with MT DBS ON and OFF. Methods: 16 patients (3 females) with DBS of the ventral intermediate nucleus (VIM) as treatment for tremor, underwent hypercapnic AH tests, with DBS ‘ON’ and ‘OFF’. Patients rated AH on a visual analogue scale (VAS) every 15s. Hypercapnia and ventilation were matched for ON and OFF states (mean±sd 43±4 and 43±4mmHg for end-tidal PCO2, 13.7 and 13.4 L/min for ventilation). Participants ventilation was constrained to baseline levels by breathing from a 3-litre inspiratory reservoir with fixed flow of fresh gas while targeting their resting breathing frequency to a metronome. Results: Overall steady state AH was 52±28%VAS for ‘ON’ and 67±20%VAS for ‘OFF’ (p=0.002; two-tailed paired t-test). The mean reduction in AH during VIM DBS was - 14.4%VAS. MT DBS relieved AH in thirteen patients, heightened AH in two and caused no change in one. Conclusion: MT DBS for tremor relief also mitigates the AH component of dyspnoea. We posit that DBS of the MT heightens the gating control of the thalamus modulating the ascending air hunger signal. Extent of relief suggests that thalamic DBS may prove to be a viable therapy for intractable dyspnoea

Better understanding of breathlessness perception addresses an unmet clinical need for more effective treatments for intractable dyspnoea, a prevalent symptom of multiple medical conditions. The insular-cortex is predominantly activated in brain-imaging studies of dyspnoea, but its precise role remains unclear. We measured experimentally-induced hypercapnic air-hunger in three insular-glioma patients before and after surgical resection. Tests involved one-minute increments in inspired CO2, raising end-tidal PCO2 to 7.5 mmHg above baseline (38.5 ± 5.7 mmHg), whilst ventilation was constrained (10.7 ± 2.3 L/min). Patients rated air-hunger on a visual analogue scale (VAS). Patients had lower stimulus–response (2.8 ± 2 vs. 11 ± 4 %VAS/mmHg; p = 0.004), but similar threshold (40.5 ± 3.9 vs. 43.2 ± 5.1 mmHg), compared to healthy individuals. Volunteered comments implicated diminished affective valence. After surgical resection; sensitivity increased in one patient, decreased in another, and other was unable to tolerate the ventilatory limit before any increase in inspired CO2.We suggest that functional insular-cortex is essential to register breathlessness unpleasantness and could be targeted with neuromodulation in chronically-breathless patients. Neurological patients with insula involvement should be monitored for blunted breathlessness to inform clinical management

Aim 

Blood pressure guidelines have undergone multiple revisions in accordance with updated science. Understanding patients’ hypertension symptoms can assist healthcare professionals’ awareness of individual, cultural, and behavioural responses and improve diagnostic accuracy to optimize treatment. Therefore, the purpose of this review was to evaluate and synthesize current literature exploring symptoms experienced by patients with hypertension. 

Methods 

Databases searched included MEDLINE® (PubMed®), CINAHL® (EBSCO), Scopus, and Web of Science™ from January 2010 to January 2022 for studies with reported hypertension symptoms.  The search followed the PRISMA guidelines.  The McMaster critical review forms were used to determine quality of both qualitative and quantitative articles. Synthesis of the data was guided by the Joanna Briggs Institute Convergent Integrated Approach to Mixed Study Systematic Reviews. 

Results 

Forty-one articles were included in the review, including nine qualitative studies and thirty-two quantitative.  Quality of the articles varied. Symptoms included commonly reported symptoms and some less prevalent, including some reporting absence of symptoms. Factors that affected symptoms included culture, beliefs, psychosocial factors and knowledge. We also found that there may be a bidirectional relationship with symptoms and behaviours that may lead to self-management. 

Conclusion 

Hypertension is common and symptoms are frequently reported. Hypertension management is related to multiple factors. Symptoms continue in a number of individuals after initial diagnosis. Evaluating symptoms after initial diagnosis may help to optimally manage and meet BP guidelines.  

Keywords: hypertension, symptoms, mixed methods review, systematic review 

Desaturation on exercise has been suggested as a predictive feature for deterioration in COVID-19. The objective of this paper was to determine the feasibility and validity for the 40-steps desaturation test.A prospective observational cohort study was undertaken in patients assessed in hospital prior to discharge. One-hundred and fifty-two participants were screened between November 2020 and February 2021, and 64 were recruited to perform a 40-steps desaturation test. Patients who were able to perform the test were younger and less frail. Four patients were readmitted to hospital and one patient deteriorated within 30 days but no patient died.The majority of patients showed little change in saturations during the test, even with pre-existing respiratory pathology. Change in saturations, respiratory rate, heart rate and breathlessness were not predictive of death or readmission to hospital within 30 days. Of 13 patients who had a desaturation of 3% or more during exercise, none was readmitted to hospital within 30 days.Not enough patients with COVID-19 could be recruited to the study to provide evidence for the safety of the test in this patient group.The 40-steps desaturation test requires further evaluation to assess clinical utility.

The role of subcortical structures and cerebral cortex in the maintenance of respiratory homeostasis in humans remains poorly understood. Emerging evidence suggests an important role of the anterior cingulate cortex (ACC) in respiratory control. In this study, local field potentials (LFPs) from dorsal ACC were recorded in humans through implanted deep brain electrodes during several breathing activities, including voluntary activities of breath-holding and deep breathing, and involuntary activities of inspiration of varying concentrations of carbon dioxide (1%, 3%, 5% and 7%). We found that the breath-holding task induced significant unilateral left-sided ACC changes in LFP power, including an increased activity in lower frequency bands (3-5 Hz) and decreased activity in higher frequency bands (12-26 Hz). The respiratory task involving reflex increase in ventilation due to hypercapnia (raised inspired CO2 ) was associated with bilateral changes in activity of the ACC (again with increased activity in lower frequency bands and reduced activity in higher frequency bands). The voluntary breathing task with associated hypocapnia (deep breathing) induced bilateral changes in activity within low frequency bands. Furthermore, probabilistic diffusion tractography analysis showed left-sided connection of the ACC with the insula and frontal operculum, and bilateral connections within subsections of the cingulate gyrus and the thalamus. This electrophysiological analysis provides direct evidence for a role of the ACC in respiratory control in humans.

Blood Oxygen Level Dependent (BOLD) fMRI is a common technique for measuring brain activation that could be affected by low-level carbon monoxide (CO) exposure from e.g. smoking. This study aimed to probe the vulnerability of BOLD fMRI to CO and determine whether it may constitute a significant neuroimaging confound. Low-level (6ppm exhaled) CO effects on BOLD response were assessed in 12 healthy never-smokers on two separate experimental days (CO and air control). fMRI tasks were breath-holds (hypercapnia), visual stimulation and fingertapping. BOLD fMRI response was lower during breath holds, visual stimulation and fingertapping in the CO protocol compared to the air control protocol. Behavioural and physiological measures remained unchanged. We conclude that BOLD fMRI might be vulnerable to changes in baseline CO, and suggest exercising caution when imaging populations exposed to elevated CO levels. Further work is required to fully elucidate the impact on CO on fMRI and its underlying mechanisms.

Objective. Respiratory abnormalities such as upper airway obstruction are common in Parkinson's disease (PD) and are an important cause of mortality and morbidity. We tested the effect of pedunculopontine region (PPNr) stimulation on respiratory maneuvers in human participants with PD, and separately recorded PPNr neural activity reflected in the local field potential (LFP) during these maneuvers. Methods. Nine patients with deep brain stimulation electrodes in PPNr, and seven in globus pallidus interna (GPi) were studied during trials of maximal inspiration followed by forced expiration with stimulation OFF and ON. Local field potentials (LFPs) were recorded in the unstimulated condition. Results. PEFR increased from 6.41 ± 0.63 L/sec in the OFF stimulation state to 7.5 L ± 0.65 L/sec in the ON stimulation state (z = −2.666, df = 8, P = 0.024). Percentage improvement in PEFR was strongly correlated with proximity of the stimulated electrode contact to the mesencephalic locomotor region in the rostral PPN (r = 0.814, n = 9, P = 0.008). Mean PPNr LFP power increased within the alpha band (7–11 Hz) during forced respiratory maneuvers (1.63 ± 0.16 μV2/Hz) compared to resting breathing (0.77 ± 0.16 μV2/Hz; z = −2.197, df = 6, P = 0.028). No changes in alpha activity or spirometric indices were seen with GPi recording or stimulation. Percentage improvement in PEFR was strongly positively correlated with increase in alpha power (r = 0.653, n = 14 (7 PPNr patients recorded bilaterally), P = 0.0096). Interpretation. PPNr stimulation in PD improves indices of upper airway function. Increased alpha‐band activity is seen within the PPNr during forced respiratory maneuvers. Our findings suggest a link between the PPNr and respiratory performance in PD.

The cerebral mechanisms of dyspnoea (breathlessness) are not well understood. Neuroimaging studies of experimentally induced dyspnoea in healthy individuals have identified several cortical areas that might form a neural network for perception of dyspnoea [1], much like those identified for pain perception [2]. However, functional imaging studies alone do not reveal neurophysiological pathways and may miss putative targets for dyspnoea relief. The objective of this study was to assess the effects of Deep Brain Stimulation (DBS) of four different brain nuclei on the sensation of dyspnoea in an individual with Chronic Obstructive Pulmonary Disease (COPD) using an established multidimensional dyspnoea tool [3].

Background. Inhaled furosemide offers a potentially novel treatment for dyspnoea, which may reflect modulation of pulmonary stretch receptor feedback to the brain. Specificity of relief is unclear because different neural pathways may account for different components of clinical dyspnoea. Our objective was to evaluate if inhaled furosemide relieves the air hunger component (uncomfortable urge to breathe) but not the sense of breathing work/effort of dyspnoea. Methods. A randomised, double blind, placebo-controlled crossover trial in 16 healthy volunteers studied in a university research laboratory. Each participant received 3 mist inhalations (either 40 mg furosemide or 4 ml saline) separated by 30–60 min on 2 test days. Each participant was randomised to mist order ‘furosemide-saline-furosemide’ (n- = 8) or ‘saline-furosemide-saline’ (n = 8) on both days. One day involved hypercapnic air hunger tests (mean ± SD PCO2 = 50 ± 3.7 mmHg; constrained ventilation = 9 ± 1.5 L/min), the other involved work/effort tests with targeted ventilation (17 ± 3.1 L/min) and external resistive load (20cmH2O/L/s). Primary outcome was ratings of air hunger or work/effort every 15 s on a visual analogue scale. During saline inhalations, 1.5 mg furosemide was infused intravenously to match the expected systemic absorption from the lungs when furosemide is inhaled. Corresponding infusions of saline during furosemide inhalations maintained procedural blinding. Average visual analogue scale ratings (%full scale) during the last minute of air hunger or work/effort stimuli were analysed using Linear Mixed Methods. Results. Data from all 16 participants were analysed. Inhaled furosemide relative to inhaled saline significantly improved visual analogues scale ratings of air hunger (Least Squares Mean ± SE − 9.7 ± 2%; p = 0.0015) but not work/effort (+ 1.6 ± 2%; p = 0.903). There were no significant adverse events. Conclusions. Inhaled furosemide was effective at relieving laboratory induced air hunger but not work/effort in healthy adults; this is consistent with the notion that modulation of pulmonary stretch receptor feedback by inhaled furosemide leads to dyspnoea relief that is specific to air hunger, the most unpleasant quality of dyspnoea.

Besides some non-linear measurements used in autonomic modulation (AM) analysis can be suitable using short term series, they usually depend on long time-series of data. To transpose this, chaotic global methods were formulated, putting together heart rate variability (HRV) linear methods. Chaos provides information about vegetative function control related to cardiovascular risks. Applying this method to investigate the complexity of the health condition after resistance training protocols, used as a therapeutic intervention, on AM in metabolic syndrome individuals (MetS) is important. This study aimed to compare the effects of two resistance training programs (conventional vs. functional) in MetS using nonlinear analysis of AM. MetS subjects (n=50), both sexes, aged 40 to 60 years were randomized between two programs. Also, there was a control group (n=12). Both groups performed 30 sessions of training. AM was accessed in chaos domain by chaotic global techniques. The main results showed that both resistance training, functional and conventional, increased chaos when compared to the control group, respectively observed by CFP1 (13.9±17.9 vs. 12.8±14.4 vs. -2.23±7.96; p≤0.05) and CFP3 (15.4±19.8 vs. 21.9±13.2 vs. -4.82±11.4; p≤0.05). In addition, 30 sessions of both resistance programs increase chaos, and nonlinear analysis enables discriminates AM after interventions when compared to control group.

Introduction: Fetal heart rate and its variability during the course of gestation have been extensively re-searched. The overall reduction in heart rate and increase in fetal HRV is associated with fetal growth and the increase in neural integration. The increased complexity of the demands on the cardiovascular system leads to more variation in the temporal course of the heart rate which has been shown to be refl ected in measures of complexity. The aim of this work was to investigate novel complexity measures with respect to  their  ability  to  quantify  changes  over  gestational  age  in  individual  fetuses  consistently  and  in  a  stable  manner.

Methods:  We  examined  215  fetal  magnetocardiograms  (FMCG),  each  of  5  min  duration,  in  11  fetuses  during the second and third trimesters (at least 10 data sets per fetus). From the FMCG we determined the fetal RR beat durations. For each 5 min time-series of RR intervals we then calculated Shannon entropy, high spectral entropy, high spectral Detrended Fluctuation Analysis, spectral Multi-Taper Method as well as the standard deviation and two commonly used complexity measures: Approximate Entropy and Sample Entropy. For each subject and HRV measure, we performed regression analysis with respect to ges tational age. The coeffi cient of determination R2 was used to es timate ‘goodness-of-fi t’, the slope of the regression indicated the strength of the individual dependency on gestational age.

Results: We found that the new complexity measures do not outperform ApEn.

Conclusion: This study has now rejected the hypothesis that the spectral complexity measures outperform those applied previously

OBJECTIVE: The effects of natural adjuvants on lung inflammation and tracheal responsiveness were examined in sensitized guinea pigs. METHODS: The responses of guinea pig tracheal chains and the serum levels of interleukin-4 and interferon-gamma were examined in control pigs and three other groups of guinea pigs: the sensitized group and two other sensitized groups treated with either adjuvant G2 or adjuvant G2F (n=7 for each group). Sensitization of the animals was achieved by injection and inhalation of ovalbumin. RESULTS: The results showed that sensitized animals had increased tracheal responsiveness and increased serum levels of interleukin-4 and interferon-gamma compared to controls (p

Objective: To determine the validity and reliability of the Dyspnoea-12 (D-12) for the assessment of breathlessness in patients with interstitial lung disease (ILD). Methods: 101 patients with ILD completed the D-12 (scaling range 0-36, high score indicates worse dyspnea), MRC dyspnea scale, St George" s Respiratory Questionnaire (SGRQ), and Hospital anxiety and depression scale (HADS) at baseline, and 84 patients completed the D- 12 and a global health transition score at follow-up 2-weeks later. D-12 psychometric properties, including floor and ceiling effects, internal consistency, test-retest reliability and construct validity of the D-12 were examined. Results: The D-12 showed good internal consistency (Cronbach" s a =0.93) and repeatability (Intra-class correlation coefficient = 0.94). Its scores were significantly associated with MRC grade (r = 0.56, p<0.001), SGRQ (symptoms r = 0.57; activities r = 0.78; impacts r = 0.75; total r = 0.79, p<0.001). Confirmatory factor analysis confirmed the previously determined structure of the D-12 in this patient group. Conclusion: In patients with ILD, the patient reported D-12 - a patient reported measure of dyspnoea severity that requires no reference to activity, is a reliable and valid instrument. It is short, simple to complete, and easy to score.

Rationale: Dyspnoea is a debilitating and distressing symptom that is reflected in different verbal descriptors. Evidence suggests that dyspnoea, like pain perception, consists of sensory quality and affective components. The objective of this study was to develop an instrument that measures overall dyspnoea severity using descriptors that reflect its different aspects. Methods: 81 dyspnoea descriptors were administered to 123 patients with chronic obstructive pulmonary disease (COPD), 129 with interstitial lung disease and 106 with chronic heart failure. These were reduced to 34 items using hierarchical methods. Rasch analysis informed decisions regarding further item removal and fit to the unidimensional model. Principal component analysis (PCA) explored the underlying structure of the final item set. Validity and reliability of the new instrument were further assessed in a separate group of 53 patients with COPD. Results: After removal of items with hierarchical methods (n=47) and items that failed to fit the Rasch model (n=22), 12 were retained. The"-˜Dyspnoea-12" " had good internal reliability (Cronbach" s alpha=0.9) and fit to the Rasch model (x2 p=0.08). Items patterned into two groups called"-˜physical" " (n=7) and"-˜affective" " ( n=5). In the separate validation study, Dyspnoea-12 correlated with the Hospital Anxiety and Depression Scale (anxiety r=0.51; depression r=0.44, p,0.001, respectively), 6-minute walk distance (r=20.38, p,0.01) and MRC (Medical Research Council) grade (r=0.48, p,0.01), and had good stability over time (intraclass correlation coefficient=0.9, p,0.001). Conclusion: Dyspnoea-12 fulfills modern psychometric requirements for measurement. It provides a global score of breathlessness severity that incorporates both"-˜physical" " and"-˜affective" " aspects, and can measure dyspnoea in a variety of diseases.

Refractory breathlessness is one of the most common and devastating symptoms of advanced cardiorespiratory disease, both malignant and nonmalignant. In spite of increased interest in research in the last 20 years, there have been few significant advances in the palliation of this distressing condition. The most successful palliative regimens for breathlessness always include pharmacological and nonpharmacological interventions used concurrently. When patients are active, nonpharmacological treatments (e.g., exercise) are the most effective. As the patient becomes more breathless, eventually becoming breathless at rest, pharmacological treatments become more important. Opioids have the most extensive evidence base to guide their use. Other pharmacological interventions may act partly by helping breathlessness (by mechanisms still uncertain) or by treating concomitant precipitating and exacerbating conditions, such as depression and anxiety. A specific treatment to palliate breathlessness remains elusive. The neurophysiological substrate of breathlessness perception is still relatively poorly understood and not well reproduced in animal models. Research using functional MRI and other imaging, with more precise clinical trial methods, may help to bring significant advances. In the next 5 years, novel approaches to delivering opioids may be developed, the effective use of inhaled furosemide may be elucidated and the place of antidepressants and anxiolytics will become clearer. A role for cannabinoids may emerge. New drugs may be developed as our understanding of neurophysiology grows.

Recent evidence suggests that inhaled furosemide relieves dyspnoea in patients and in normal subjects made dyspnoeic by external resistive loads combined with added dead-space. Furosemide sensitises lung inflation receptors in rats, and lung inflation reduces air hunger in humans. We therefore hypothesised that inhaled furosemide acts on the air hunger component of dyspnoea. Ten subjects inhaled aerosolized furosemide (40 mg) or placebo in randomised, double blind, crossover experiments. Air hunger was induced by hypercapnia (50 ± 2 mmHg) during constrained ventilation (8 ± 0.9 L/min) before and after treatment, and rated by subjects using a 100 mm visual analogue scale. Subjects described a sensation of air hunger with little or no work/effort of breathing. Hypercapnia generated less air hunger in the first trial at 23 ± 3 min after start of furosemide treatment (58 ± 11% to 39 ± 14% full scale); the effect varied substantially among subjects. The mean treatment effect, accounting for placebo, was 13% of full scale (P = 0.052). We conclude that 40 mg of inhaled furosemide partially relieves air hunger within 1 h and is accompanied by substantial diuresis.

Determining response dynamics of hypoxic air hunger may provide information of use in clinical practice and will improve understanding of basic dyspnea mechanisms. It is hypothesized that air hunger arises from projection of reflex brain stem ventilatory drive (“corollary discharge”) to forebrain centers. If perceptual response dynamics are unmodified by events between brain stem and cortical awareness, this hypothesis predicts that air hunger will exactly track ventilatory response. Thus, during sustained hypoxia, initial increase in air hunger would be followed by a progressive decline reflecting biphasic reflex ventilatory drive. To test this prediction, we applied a sharp-onset 20-min step of normocapnic hypoxia and compared dynamic response characteristics of air hunger with that of ventilation in 10 healthy subjects. Air hunger was measured during mechanical ventilation (minute ventilation = 9 ± 1.4 l/min; end-tidal Pco2 = 37 ± 2 Torr; end-tidal Po2 = 45 ± 7 Torr); ventilatory response was measured during separate free-breathing trials in the same subjects. Discomfort caused by “urge to breathe” was rated every 30 s on a visual analog scale. Both ventilatory and air hunger responses were modeled as delayed double exponentials corresponding to a simple linear first-order response but with a separate first-order adaptation. These models provided adequate fits to both ventilatory and air hunger data (r2 = 0.88 and 0.66). Mean time constant and time-to-peak response for the average perceptual response (0.36 min−1 and 3.3 min, respectively) closely matched corresponding values for the average ventilatory response (0.39 min−1 and 3.1 min). Air hunger response to sustained hypoxia tracked ventilatory drive with a delay of ∼30 s. Our data provide further support for the corollary discharge hypothesis for air hunger.

We previously used a verbal ordinal rating scale to measure dyspnea. That scale was easy for subjects to use and the words provided consistency in ratings. We have recently developed a word labeled visual analog scale (LVAS) with labels placed by the subjects, retaining the advantages of a verbal scale while offering a continuous scale that generates parametric data. In a retrospective meta-analysis of data from 43 subjects, individuals differed little in their placement of words on the 100 mm LVAS (mean±S.D. for slight=20±2.5 mm, moderate=50±5 mm and severe=80±6 mm) and ratings were distributed uniformly along the scale. A significant stimulus–response correlation was obtained for both the LVAS (r2=0.98) and for the verbal ordinal scale (Spearman r=0.94). The resolution of the two scales differed only slightly. With meaningful verbal anchors, well-defined end-points, and clear instructions about the specific sensation to be rated, both scales provide valid measures of dyspnea.

Anecdotal observations suggest that hypoxia does not elicit dyspnea. An opposing view is that any stimulus to medullary respiratory centers generates dyspnea via “corollary discharge” to higher centers; absence of dyspnea during low inspired Po 2 may result from increased ventilation and hypocapnia. We hypothesized that, with fixed ventilation, hypoxia and hypercapnia generate equal dyspnea when matched by ventilatory drive. Steady-state levels of hypoxic normocapnia (end-tidal Po 2 = 60–40 Torr) and hypercapnic hyperoxia (end-tidal Pco 2= 40–50 Torr) were induced in naive subjects when they were free breathing and during fixed mechanical ventilation. In a separate experiment, normocapnic hypoxia and normoxic hypercapnia, “matched” by ventilation in free-breathing trials, were presented to experienced subjects breathing with constrained rate and tidal volume. “Air hunger” was rated every 30 s on a visual analog scale. Air hunger-Pet O2 curves rose sharply at Pet O2 P > 0.05). Hypercapnia had unpleasant nonrespiratory effects but was otherwise perceptually indistinguishable from hypoxia. We conclude that hypoxia and hypercapnia have equal potency for air hunger when matched by ventilatory drive. Air hunger may, therefore, arise via brain stem respiratory drive.

We employed an associative learning paradigm to test the hypothesis that exercise hyperpnea in humans arises from learned responses forged by prior experience. Twelve subjects undertook a “conditioning” and a “nonconditioning” session on separate days, with order of performance counterbalanced among subjects. In both sessions, subjects performed repeated bouts of 6 min of treadmill exercise, each separated by 5 min of rest. The only difference between sessions was that all the second-to-penultimate runs of the conditioning session were performed with added dead space in the breathing circuit. Cardiorespiratory responses during the first and last runs (the “control” and “test” runs) were compared for each session. Steady-state exercise end-tidal Pco 2 was significantly lower (P= 0.003) during test than during control runs for both sessions (dropping by 1.8 ± 2 and 1.4 ± 3 Torr during conditioning and nonconditioning sessions, respectively). This and all other test-control run differences tended to be greater during the first session performed regardless of session type. Our data provide no support for the hypothesis implicating associative learning processes in the ventilatory response to exercise in humans.

Asthma evokes several uncomfortable sensations including increased “effort to breathe” and chest “tightness.” We have tested the hypotheses that “effort” and “tightness” are due to perception of increased work performed by the respiratory muscles. Bronchoconstriction was induced by inhaled methacholine in 15 subjects with mild asthma (FEV1/FVC baseline = 81.9% ± 5.8; bronchoconstriction = 64.0% ± 8.6). To relieve the work of breathing, and thereby minimize activation of respiratory muscle afferents and motor command, subjects were mechanically ventilated. Subjects separately rated effort to breathe and tightness during mechanical ventilation and during spontaneous breathing. Bronchoconstriction produced elevated end-expiratory lung volume (279 ± 62 ml); in a control study, end-expiratory lung volume was increased equally in the absence of bronchoconstriction by increasing end-expiratory pressure. During bronchoconstriction, ratings of effort were greater during spontaneous breathing than during mechanical ventilation (p

The rostro-ventrolateral medulla (RVLM) is a site of chemosensitivity in animals; such site(s) have not been defined in humans. We studied the effect of unilateral focal lesions in the rostrolateral medulla (RLM) of man, on the ventilatory CO2 sensitivity and during awake and sleep breathing. Nine patients with RLM lesions (RLM group), and six with lesions elsewhere (non-RLM group) were studied. The ventilatory CO2 sensitivity was lower in the RLM compared with the non-RLM group (mean (S.D.), RLM, 1.4 (0.9), non-RLM 3.0 (0.6) L min−1 mmHg−1). In both groups resting breathing was normal. During sleep all RLM patients had frequent arousals, four had significant sleep disordered breathing (SDB), only one non-RLM patient had SDB. Our findings in humans resemble those in animals with focal RVLM lesions. This review provides evidence that in humans there is an area of chemosensitivity in the RLM. We propose that in humans, dorsal displacement of the RVLM area of chemosensitivity in animals, arises from development of the olive plus the consequences of the evolution of the cerebellum/inferior peduncle.

Breathing sensations of AIR HUNGER, WORK and EFFORT may depend on projections of central motor discharge (corollary discharge) to the forebrain. Source of motor drive (brainstem or cortex) may determine what is perceived. To test the effect of changing motor discharge at constant ventilation, we induced partial neuromuscular blockade during hypercapnic hyperpnea (31±9 L min−1; PETCO2=49±2 Torr) and during matched volitional hyperpnea (34±5 L min−1; PETCO2=41±1 Torr). Decline of vital capacity was similar between conditions (39%). Ventilation was unchanged with paralysis, indicating increased respiratory motor drive to maintain hyperpnea. Sensations were rated on a seven point ordinal scale. Median EFFORT and WORK increased 3–3.5 points with paralysis during both forms of hyperpnea (PP

The device described in this study uses functionally variable dead space to keep effective alveolar ventilation constant. It is capable of maintaining end-tidalPCO2 andPO2 within ±1 Torr of the set value in the face of increases in breathing above the baseline level. The set level of end-tidal PCO2 or PO2 can be independently varied by altering the concentration in fresh gas flow. The device comprises a tee at the mouthpiece, with one inlet providing a limited supply of fresh gas flow and the other providing reinspired alveolar gas when ventilation exceeds fresh gas flow. Because the device does not depend on measurement and correction of end-tidal or arterial gas levels, the response of the device is essentially instantaneous, avoiding the instability of negative feedback systems having significant delay. This contrivance provides a simple means of holding arterial blood gases constant in the face of spontaneous changes in breathing (above a minimum alveolar ventilation), which is useful in respiratory experiments, as well as in functional brain imaging where blood gas changes can confound interpretation by influencing cerebral blood flow.

OBJECTIVES The rostrolateral medulla (RLM) has been identified in animals as an important site of chemosensitivity; in humans such site(s) have not been defined. The aim of this study was to investigate the physiological implications of unilateral lesions in the lower brainstem on the control of breathing.

METHODS In 15 patients breathing was measured awake at rest, asleep, during exercise, and during CO2 stimulation. The lesions were located clinically and by MRI; in nine patients they involved the RLM (RLM group), in six they were in the pons, cerebellum, or medial medulla (Non-RLM group). All RLM group patients, and three non-RLM group patients had ipsilateral Horner’s syndrome.

RESULTS Six of the RLM group had a ventilatory sensitivity to inhaled CO2(V˙/PET CO2) below normal (group A:V˙/PET CO2, mean, 0.87; range 0.3–1.4 l.min-1/mm Hg). It was normal in all of the non-RLM group (group B: V˙/PET CO2, mean, 3.0; range, 2.6–3.9 min-1/mmHg). There was no significant difference in breathing between groups during relaxed wakefulness (V˙, group A: 7.44 (SD 2.5) l.min-1; group B: 6.02 (SD 1.3) l.min-1; PET CO2, group A: 41.0 (SD 4.2) mm g; group B: 38.3 (SD2.0) mm Hg) or during exercise (V˙/V˙O2: group A: 21 (SD 6.0) l.min-1/l.min-1; group B: 24 (SD 7.3) l.min-1/l.min-1). During sleep, all group A had fragmented sleep compared with only one patient in group B (group A: arousals, range 13 to > 60 events/hour); moreover, in group A there was a high incidence of obstructive sleep apnoea associated with hypoxaemia.

CONCLUSION Patients with unilateral RLM lesions require monitoring during sleep to diagnose any sleep apnoea. The finding that unilateral RLM lesions reduce ventilatory sensitivity to inhaled CO2 is consistent with animal studies. The reduced chemosensitivity had a minimal effect on breathing awake at rest or during exercise.

We have assessed corticospinal function in 19 post-coma patients severely brain-injured by anoxia or physical trauma. Eleven patients were unresponsive (Category 1) and eight demonstrated minimal, non-verbal responses to simple commands (Category 2). Motor evoked potentials (MEPs) could be elicited in hand and leg muscles in nine Category 1 and all eight Category 2 patients in response to transcranial magnetic stimulation (TMS). In comparison with normal subjects, threshold to TMS was significantly elevated in Category 1 but not in Category 2. Central conduction times were within the normal range except for two patients (one in each category) in whom they were prolonged. The variability in MEP amplitude to constant TMS was not significantly different from normal in either category. The size of MEPs recorded simultaneously in different hand muscles were correlated in all three groups. The presence of H-reflexes in hand muscles was associated with an absence of MEPs or a high threshold to TMS. Variability of MEPs was substantially greater than that of H-reflexes. We conclude that brain injury of a severity that may preclude consciousness and voluntary movement does not invariably predicate a non-functional motor cortex and corticospinal system.

1. The cardiorespiratory response to imagination of previously performed treadmill exercise was measured in six competitive sportsmen and six non-athletic males. This was compared with the response to a control task (imaging letters) and a task not involving imagination (‘treadmill sound only’). 2. In athletes, imagined exercise produced increases in ventilation which varied within and between subjects. The mean maximal increase (11.71 min-1) was approximately 20% of the ventilatory response to actual exercise. This was primarily due to treadmill speed-related increases in respiratory frequency (mean maximal increase, 14.8 breaths min-1) and resulted in significant reductions in end-tidal PCO2 (mean maximal fall, 7 mmHg). These effects were greater (P 0.2). 4. In non-athletes, imagination of exercise produced no changes in cardiorespiratory variables. No significant differences were detected in subjective assessments of movement imagery ability between athletes and non-athletes (P = 0.17). 5. This study demonstrates that ventilatory effects, when observed, are specific to imagination of exercise. The greater likelihood of generating ventilatory responses in highly trained athletes, experienced in ‘rhythmic’ sports, may be related to awareness of breathing and its role in exercise imagination strategy. A volitional component of the response cannot be discounted.

The question of whether functional residual capacity (FRC) falls in infants during active sleep has been clouded by studies using different subject groups and techniques for measurements of lung volume and determination of sleep state. Twenty healthy full-term infants within the first week of life participated in the present study. Neurophysiological and behavioral criteria were used to define sleep state, and measurements of FRC were made using a specially constructed closed-circuit helium dilution system. Regularity of respiration was recorded using magnetometers on the chest and a modified respirator monitor. Results showed that no significant changes in FRC occurred, related either to sleep state or to regularity of respiration. In addition, we failed to detect any differences in FRC between the sexes.