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Background: Due to respiratory motion, accurate radiotherapy delivery to thoracic and abdominal tumors is challenging. We aimed to quantify the ability of mechanical ventilation to reduce respiratory motion, by measuring diaphragm motion magnitudes in the same volunteers during free breathing (FB), mechanically regularized breathing (RB) at 22 breaths per minute (brpm), variation in mean diaphragm position across multiple deep inspiration breath-holds (DIBH) and diaphragm drift during single prolonged breath-holds (PBH) in two MRI sessions., Methods: In two sessions, MRIs were acquired from fifteen healthy volunteers who were trained to be mechanically ventilated non-invasively We measured diaphragm motion amplitudes during FB and RB, the inter-quartile range (IQR) of the variation in average diaphragm position from one measurement over five consecutive DIBHs, and diaphragm cranial drift velocities during single PBHs from inhalation (PIBH) and exhalation (PEBH) breath-holds., Results: RB significantly reduced the respiratory motion amplitude by 39%, from median (range) 20.9 (10.6-41.9) mm during FB to 12.8 (6.2-23.8) mm. The median IQR for variation in average diaphragm position over multiple DIBHs was 4.2 (1.0-23.6) mm. During single PIBHs with a median duration of 7.1 (2.0-11.1) minutes, the median diaphragm cranial drift velocity was 3.0 (0.4-6.5) mm/minute. For PEBH, the median duration was 5.8 (1.8-10.2) minutes with 4.4 (1.8-15.1) mm/minute diaphragm drift velocity., Conclusions: Regularized breathing at a frequency of 22 brpm resulted in significantly smaller diaphragm motion amplitudes compared to free breathing. This would enable smaller treatment volumes in radiotherapy. Furthermore, prolonged breath-holding from inhalation and exhalation with median durations of six to seven minutes are feasible., Trial Registration: Medical Ethics Committee protocol NL.64693.018.18., (© 2022. The Author(s).)

Purpose: Reducing respiratory motion during the delivery of radiation therapy reduces the volume of healthy tissues irradiated and may decrease radiation-induced toxicity. The purpose of this study was to assess the potential for rapid shallow non-invasive mechanical ventilation to reduce internal anatomy motion for radiation therapy purposes., Methods and Materials: Ten healthy volunteers (mean age, 38 years; range, 22-54 years; 6 female and 4 male) were scanned using magnetic resonance imaging during normal breathing and at 2 ventilator-induced frequencies: 20 and 25 breaths per minute for 3 minutes. Sagittal and coronal cinematic data sets, centered over the right diaphragm, were used to measure internal motions across the lung-diaphragm interface. Repeated scans assessed reproducibility. Physiologic parameters and participant experiences were recorded to quantify tolerability and comfort., Results: Physiologic observations and experience questionnaires demonstrated that rapid shallow non-invasive ventilation technique was tolerable and comfortable. Motion analysis of the lung-diaphragm interface demonstrated respiratory amplitudes and variations reduced in all subjects using rapid shallow non-invasive ventilation compared with spontaneous breathing: mean amplitude reductions of 56% and 62% for 20 and 25 breaths per minute, respectively. The largest mean amplitude reductions were found in the posterior of the right lung; 40.0 mm during normal breathing to 15.5 mm (P < .005) and 15.2 mm (P < .005) when ventilated with 20 and 25 breaths per minute, respectively. Motion variations also reduced with ventilation; standard deviations in the posterior lung reduced from 14.8 mm during normal respiration to 4.6 mm and 3.5 mm at 20 and 25 breaths per minute, respectively., Conclusions: To our knowledge, this study is the first to measure internal anatomic motion using rapid shallow mechanical ventilation to regularize and minimize respiratory motion over a period long enough to image and to deliver radiation therapy. Rapid frequency and shallow, non-invasive ventilation both generate large reductions in internal thoracic and abdominal motions, the clinical application of which could be profound-enabling dose escalation (increasing treatment efficacy) or high-dose ablative radiation therapy., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Only the carotid chemoreceptors stimulate breathing during hypoxia in Man. They are also ideally located to warn if the brain's oxygen supply falls, or if hypercapnia occurs. Since their discovery ~80 years ago stimulation, ablation, and recording experiments still leave 3 substantial difficulties in establishing how important the carotid chemoreceptors are in controlling breathing during exercise in Man: (i) they are in the wrong location to measure metabolic rate (but are ideally located to measure any mismatch), (ii) they receive no known signal during exercise linking them with metabolic rate and no overt mismatch signals occur and (iii) their denervation in Man fails to prevent breathing matching metabolic rate in exercise. New research is needed to enable recording from carotid chemoreceptors in Man to establish whether there is any factor that rises with metabolic rate and greatly increases carotid chemoreceptor activity during exercise. Available evidence so far in Man indicates that carotid chemoreceptors are either one of two mechanisms that explain breathing matching metabolic rate or have no importance. We still lack key experimental evidence to distinguish between these two possibilities.

Baroreflex sensitivity (BRS) is known to be attenuated by inspiration and all the original BRS methodologies took this into account by measuring only in expiration. Spontaneous sequence analysis (SSA) is a non-invasive clinical tool widely used to estimate BRS in Man but does not take breathing into account. We have therefore modified it to test whether it too can detect inspiratory attenuation. Traditional SSA is also entangled with issues of distinguishing causal from random relationships between blood pressure and heart period and of the optimum choice of data filter settings. We have also tested whether the sequences our modified SSA rejects do behave as random relationships and show the limitations of the absence of filter standardization. SSA was performed on eupneic data from 1 h periods in 20 healthy subjects. Applying SSA traditionally produced a mean BRS of 23 ± 3 ms mmHg(-1). After modification to measure breathing, SSA detected significant inspiratory attenuation (11 ± 1 ms mmHg(-1)), and the mean expiratory BRS was significantly higher (26 ± 5 ms mmHg(-1)). Traditional SSA therefore underestimates BRS by an amount (3 ms mmHg(-1)) as big as the major physiological and clinical factors known to alter BRS. We show that the sequences rejected by SSA do behave like random associations between pressure and period. We also show the minimal effect of the r(2) filter and the biases that some pressure and heart period filters can introduce. We discuss whether SSA might be improved by standardization of filter settings and by also measuring breathing.

This article reviews the basic properties of breath-holding in humans and the possible causes of the breath at breakpoint. The simplest objective measure of breath-holding is its duration, but even this is highly variable. Breath-holding is a voluntary act, but normal subjects appear unable to breath-hold to unconsciousness. A powerful involuntary mechanism normally overrides voluntary breath-holding and causes the breath that defines the breakpoint. The occurrence of the breakpoint breath does not appear to be caused solely by a mechanism involving lung or chest shrinkage, partial pressures of blood gases or the carotid arterial chemoreceptors. This is despite the well-known properties of breath-hold duration being prolonged by large lung inflations, hyperoxia and hypocapnia and being shortened by the converse manoeuvres and by increased metabolic rate. Breath-holding has, however, two much less well-known but important properties. First, the central respiratory rhythm appears to continue throughout breath-holding. Humans cannot therefore stop their central respiratory rhythm voluntarily. Instead, they merely suppress expression of their central respiratory rhythm and voluntarily 'hold' the chest at a chosen volume, possibly assisted by some tonic diaphragm activity. Second, breath-hold duration is prolonged by bilateral paralysis of the phrenic or vagus nerves. Possibly the contribution to the breakpoint from stimulation of diaphragm muscle chemoreceptors is greater than has previously been considered. At present there is no simple explanation for the breakpoint that encompasses all these properties.

In mammals that use the ventilatory system as the principal means of increasing heat loss, raising body temperature causes the adoption of a specialised breathing pattern known as panting and this is mediated by the thermoregulatory system in the preoptic area of the hypothalamus. In these species an additional respiratory drive is also present at raised body temperature, since breathing can reappear at low Pa,CO2 levels, when stimulation of chemoreceptors is minimal. It is not known whether the preoptic area is also the source of this additional drive. Rats do not pant but do possess this additional respiratory drive at raised body temperatures. We have therefore tested whether the preoptic area of the hypothalamus is the source of this additional respiratory drive in rats. Urethane anaesthesia and hyperoxia were used in eleven rats to minimise behavioural and chemical drives to breathe. The presence of the additional respiratory drive was indicated if rhythmic diaphragmatic EMG activity reappeared during hypocapnia (a mean Pa,CO2 level of 21+/-2 mm Hg, n = 11), induced by mechanical ventilation. The additional respiratory drive was absent at normal body temperature (37¿C). When the temperature of the whole body was raised using an external source of radiant heat, the additional respiratory drive appeared at 40.6+/-0.5 degrees C (n = 3). In two further rats this drive was induced at normal body temperature by localised warming in the preoptic area of the intact hypothalamus. The additional respiratory drive appeared at similar temperatures to those in control rats in three rats following isolation of the hypothalamus from more rostral areas of the brain. In contrast, the additional respiratory drive failed to appear at these temperatures in three rats after isolating the hypothalamus from the caudal brainstem, by sectioning pathways medial to the medial forebrain bundle. Since the preoptic area is known to contain thermoreceptors and to receive afferents from peripheral thermoreceptors, the results show that this area is also the source of the additional respiratory drive at raised body temperature in anaesthetised rats.

1. In order to assess the importance of the parabrachial nuclei in modulating cardiorespiratory activity, electric current or microinjections of glutamate were used to stimulate discrete regions of the parabrachial nuclei in anaesthetized rats. 2. Stimulation of cell bodies in the medial region of the parabrachial nuclei and in the Kölliker-Fuse nuclei, caused an expiratory facilitatory response. This consisted mainly of a decrease in respiratory rate as measured by observing phrenic nerve activity. 3. Stimulation of cell bodies in the lateral region of the parabrachial nuclei caused an inspiratory facilitatory response. This consisted mainly of an increase in respiratory rate. 4. At the majority of sites (16 out of 20) where changes in respiratory rate were elicited by glutamate injection or electrical stimulation an increase in blood pressure was observed. The coexistence of increases in blood pressure and heart rate indicates the presence of inhibition of the heart rate component of the baroreflex and/or an increase in cardiac sympathetic drive. 5. The expiratory facilitatory response was not evoked reflexly by the rise in blood pressure since it was still present after administration of guanethidine, which abolished the rise in blood pressure. 6. The interactions between the parabrachial nuclei and the medullary respiratory complex in eliciting these changes are discussed.

1. We examined the effects on fetal breathing movements (FBM) and electrocortical activity (ECoG) of the administration of pilocarpine to three groups of fetal sheep in utero: one group had peripheral chemodenervation; one group had peripheral chemodenervation and transection of the brain stem at the level of the colliculi; a third group of sham-operated animals acted as a control. 2. Pilocarpine induced a period of FBM characterized by their high amplitude (ca. 24 mmHg) and low frequency (ca. 0.65 Hz). It also produced low-voltage ECoG. These effects were seen both in normoxia and in hypoxia. They were independent of the ECoG state in which the drug was given. 3. In normoxia, pilocarpine-induced FBM were blocked by cholinergic antagonists which enter the central nervous system, atropine sulphate and scopolamine hydrobromide, but were either unaffected or were reduced in amplitude by antagonists with restricted access to the central nervous system, atropine methylnitrate and scopolamine methylbromide. In hypoxia, atropine sulphate and scopolamine hydrobromide again blocked FBM but now scopolamine methylbromide and atropine methylnitrate blocked the FBM in 42% of trials. In the remaining trials FBM remained virtually unchanged. 4. No differences were observed in the effects of pilocarpine on FBM or ECoG between chemodenervated fetuses and those which had been sham-operated. 5. In fetuses with transection of the brain stem, breathing was continuous irrespective of the ECoG. Pilocarpine increased the amplitude of FBM but did not alter the frequency of these FBM. These effects occurred both in normoxia and in hypoxia. 6. We conclude that pilocarpine produces effects on fetal behaviour via at least two sites in the central nervous system. One site lies in the pons or medulla and is responsible for the stimulation of FBM. The other site is above the level of the colliculi and is responsible for producing sustained low-voltage ECoG. These effects do not require the integrity of the peripheral chemoreceptors and we find no evidence to support the previous suggestion that the action of pilocarpine is via stimulation of these receptors.

Whilst hypoxia stimulates fetal peripheral chemoreceptors, fetal breathing movements do not increase as hypoxia also has central effects. We wondered whether specific stimulation of the arterial chemoreceptors by almitrine would produce a stimulation of fetal breathing movements. When almitrine was given to 5 intact and 3 peripherally-chemodenervated fetal sheep in utero, fetal breathing movements rapidly ceased for 1-12 h. There was also a decrease in the amount of time spent in low voltage electrocortical activity. The effects of almitrine are therefore similar to those of hypoxia, and are independent of the peripheral chemoreceptors. Thus it may be a valuable tool in the study of the control of fetal breathing.

1. In fetal lambs in late gestation, systemic infusion of L-5-hydroxytryptophan (L-5-HTP) during normoxia greatly increases the incidence of fetal breathing movements (FBM) and high-voltage electrocortical activity (HV ECoG). It also induces FBM during HV ECoG and increases blood pressure. To investigate its mechanism of action, L-5-HTP was administered in conjunction with the 5-hydroxy-tryptamine (5-HT) antagonists ketanserin or cyproheptadine. L-5-HTP was also infused with or without the antagonists during hypoxia, to test whether it would overcome the inhibition of FBM by hypoxia. 2. When L-5-HTP was given in normoxia, cyproheptadine blocked and ketanserin reduced the increase in blood pressure, both drugs blocked the stimulation of FBM, but neither drug prevented the induction of prolonged episodes of HV ECoG. 3. In hypoxia, L-5-HTP similarly stimulated FBM. This effect was also blocked by cyproheptadine and was delayed by ketanserin. 4. The antagonism of the effects of L-5-HTP on blood pressure and the incidence of FBM in normoxia and hypoxia is consistent with the action of L-5-HTP via 5-HT receptors. At present there is no clear explanation of the mechanism by which L-5-HTP induces HV ECoG.

The incidence of fetal breathing movements and low voltage electrocortical activity was measured in three groups of fetal sheep, at 123-137 days gestation. The first group (transected & denervated) had the brainstem transected at the level of the colliculi and also had peripheral arterial chemodenervation. The second group (denervated) had a sham brain-stem transection and peripheral arterial chemodenervation. The third group (sham-operated) had sham brain-stem transection and sham peripheral chemodenervation. No differences were observed in the incidence of fetal breathing movements or low voltage electrocortical activity between the sham-operated and the denervated groups in normoxia, or in hypoxia when all these fetuses became apnoeic. There were however differences between these 2 groups and the transected & denervated group, in which fetal breathing movements where dissociated from electrocortical activity and which in some fetuses were continuous. During isocapnic hypoxia 3 of 8 transected & denervated fetuses made fetal breathing movements. We discuss the problems of interpreting data from brain-stem transected fetuses, but conclude that the evidence reveals no tonic influence of the peripheral arterial chemoreceptors on fetal breathing movements.