Breathing Phases Research Articles

Comparison of two instructions for deep breathing exercise: non-specific and diaphragmatic breathing.

[Purpose] Breathing exercises are frequently prescribed to reduce pulmonary complications after abdominal and thoracic surgery. Appropriate instructions ensuring the integrity of the self-exercise are important. This study compared the effects of two instructions, focusing on non-specific breathing (NB) and diaphragmatic breathing (DB) patterns, respectively, on the ventilatory efficiency and work of breathing. [Subjects and Methods] The participants were healthy men (n=15) and women (n=15). Ventilatory parameters, heart rate, and autonomic nervous system activity were measured during natural and deep breathing phases performed under the two instructions (NB and DB), with the deep breathing phase following the natural breathing phase. [Results] For both men and women, ventilatory efficiency was increased during deep breathing relative to natural breathing, regardless of the instructions. In women, the increment in ventilatory efficiency during deep breathing was greater under NB compared to that under DB. The work of breathing decreased during deep breathing in women under both instructions, but did not change in men under DB. [Conclusion] Under NB instruction, deep breathing elicits similar or greater effects on ventilatory efficiency compared to that under DB instruction.

A method of respiratory phase optimization for better dose sparing of organs at risks: A validation study in patients with lung cancer.

BackgroundTo propose an effective and simple cost value function to determine an optimal respiratory phase for lung treatment using either respiratory gating or breath-hold technique.ResultsThe optimized phase was obtained at a phase close to end inhalation in 11 out of 15 patients. For the rest of patients, the optimized phase was obtained at a phase close to end exhalation indicating that optimal phase can be patient specific. The mean doses of the Organs-at-risk (OARs) significantly decreased at the optimized phase without compromising the planning target volume (PTV) coverage (about 8% for all 3 OARs considered).Materials and MethodsFifteen lung patients were included for the feasibility test of the cost function. For all patients and all phases, delineation of the target volume and selected OARs such as esophagus, heart, and spinal cord was performed, and then cost values were calculated for all phases. After the breathing phases were ranked according to the cost values obtained, the relationship between score and dose distribution was evaluated by comparing dose volume histogram (DVH).ConclusionsThe proposed cost value function can play an important role in choosing an optimal phase with minimal effort, that is, without actual plan optimization at all phases.

Estimation and validation of patient-specific high-resolution lung elasticity derived from 4DCT.

Lung diseases are commonly associated with changes in lung tissue's biomechanical properties. Functional imaging techniques, such as elastography, have shown great promise in measuring tissue's biomechanical properties, which could expand the utility and effectiveness of radiotherapy treatment planning. We present a novel methodology for characterizing a key biomechanical property, parenchymal elasticity, derived solely from 4DCT datasets. Specifically, end-inhalation and end-exhalation breathing phases of the 4DCT datasets were deformably registered and the resulting displacement maps were considered to be ground-truth. A mid-exhalation image was also prepared for verification purposes. A GPU-based biomechanical model was then generated from the patient end-exhalation dataset and used as a forward model to iteratively solve for the elasticity distribution. Displacements at the surface of the lungs were applied as boundary constraints for the model-guided tissue elastography, while the inner voxels were allowed to deform according to the linear elastic forces within the biomechanical model. A convergence criteria of 10% maximum deformation was employed for the iterative process. The lung tissue elasticity estimation was documented for a set of 15 4DCT patient datasets. Maximum lung deformations were observed to be between 6 and 31 mm. Our results showed that, on average, 89.91±4.85% convergence was observed. A validation study consisting of mid-exhalation breathing phases illustrated an accuracy of 87.13±10.62%. Structural similarity, normalized cross-correlation, and mutual information were used to quantify the degree of similarity between the following image pairs: (a) the model-generated end-exhalation and ground-truth end-exhalation, and (b) model-generated mid-exhalation images and ground-truth mid-exhalation. Overall, the results suggest that the lung elasticity can be measured with approximately 90% convergence using routinely acquired clinical 4DCT scans, indicating the potential for a lung elastography implementation within the radiotherapy clinical workflow. The regional lung elasticity found here can lead to improved tissue sparing radiotherapy treatment plans, and more precise monitoring of treatment response.

Acceleration sensors in abdominal wall position as a non-invasive approach to detect early breathing alterations induced by intolerance of increased airway resistance

BackgroundEarly detection of respiratory overload is crucial to mechanically ventilated patients, especially during phases of spontaneous breathing. Although a diversity of methods and indices has been established, there is no highly specific approach to predict respiratory failure. This study aimed to evaluate acceleration sensors in abdominal and thoracic wall positions to detect alterations in breathing excursions in a setting of gradual increasing airway resistance.MethodsTwenty-nine healthy volunteers were committed to a standardized protocol of a two-minutes step-down spontaneous breathing on a 5 mm, 4 mm and then 3 mm orally placed endotracheal tube. Accelerator sensors in thoracic and abdominal wall position monitored breathing excursions. 15 participants passed the breathing protocol (“completed” group), 14 individuals cancelled the protocol due to subjective intolerance to the increasing airway resistance (“abandoned” group).ResultsGradual increased respiratory workload led to a significant decrease of acceleration in abdominal wall position in the “abandoned” group compared to the “completed” group (p < 0.001), while these gradual accelerating changes were not observed in thoracic wall position (p = 0.484). Thoracic acceleration sensors did not detect any time- and group-specific changes (p = 0.746).ConclusionsThe abdominal wall position of the acceleration sensors may be a non-invasive, economical and practical approach to detect early breathing alterations prior to respiratory failure.Trial registrationEK 309–15; by the Ethics Committee of the Faculty of Medicine, RWTH Aachen, Aachen, Germany. Retrospectively registered 28th of December 2015.

Air sampling unit for breath analyzers.

The paper presents a portable breath sampling unit (BSU) for human breath analyzers. The developed unit can be used to probe air from the upper airway and alveolar for clinical and science studies. The BSU is able to operate as a patient interface device for most types of breath analyzers. Its main task is to separate and to collect the selected phases of the exhaled air. To monitor the so-called I, II, or III phase and to identify the airflow from the upper and lower parts of the human respiratory system, the unit performs measurements of the exhaled CO2 (ECO2) in the concentration range of 0%-20% (0-150 mm Hg). It can work in both on-line and off-line modes according to American Thoracic Society/European Respiratory Society standards. A Tedlar bag with a volume of 5 dm3 is mounted as a BSU sample container. This volume allows us to collect ca. 1-25 selected breath phases. At the user panel, each step of the unit operation is visualized by LED indicators. This helps us to regulate the natural breathing cycle of the patient. There is also an operator's panel to ensure monitoring and configuration setup of the unit parameters. The operation of the breath sampling unit was preliminarily verified using the gas chromatography/mass spectrometry (GC/MS) laboratory setup. At this setup, volatile organic compounds were extracted by solid phase microextraction. The tests were performed by the comparison of GC/MS signals from both exhaled nitric oxide and isoprene analyses for three breath phases. The functionality of the unit was proven because there was an observed increase in the signal level in the case of the III phase (approximately 40%). The described work made it possible to construct a prototype of a very efficient breath sampling unit dedicated to breath sample analyzers.

Unraveling the breathing puzzle: The generation of the three phases of breathing

Unraveling the breathing puzzle: The generation of the three phases of breathing

A NONINVASIVE METHOD TO EVALUATE THE DEGREE OF UPPER AIRWAY STENOSIS

Purpose: This paper presented a new approach to noninvasively evaluate the upper airway stenosis for obstructive sleep apnea syndrome (OSAS) patients. Methods: In the proposed method, thoracic and abdominal movements were selected to calculate the respiratory movement (RM) and to indicate the change of lung volume. Due to the cumulative effect of thermal sensor, the oronasal-thermistor signal (T_flow) is applied to estimate the air mass change in lung. Based on the mathematical relationship, the “RM–T_flow curves”, drawn by RM and T_flow, together with the correlation coefficients ([Formula: see text] were used to analyze the upper airway stenosis. Results: This method was verified through portable monitoring (PM) based experiments, and numerical analysis of the polysomnography (PSG) data from 20 OSAS patients and 15 non-OSAS controls. Our results indicate the [Formula: see text] values decrease with the narrowing of the upper airway. At each sleep stage, the [Formula: see text] mean values of OSAS subjects are significantly ([Formula: see text]) smaller than those of the controls. These facts demonstrate that the [Formula: see text] value can be used to quantify the upper airway stenosis and the analysis of “RM–T_flow curves” is an efficient way to assess upper airway condition associated with the breathing phase. Conclusions: As this method can be used in spontaneous sleep and home sleep testing, we believe it will benefit the popularity of the diagnosis and evaluation of OSAS.

Positioning Accuracy for Frameless Lung SBRT Using 4-Dimensional Cone Beam CT Guidance

To quantify the localization accuracy and intrafraction stability of lung cancer patients treated with frameless stereotactic body radiotherapy (SBRT) using 4-dimensional cone beam CT (4D-CBCT) guidance and to calculate the Internal Target Volume (ITV) margins to account for the setup errors. Nine patients with a single peripheral lung tumor, smaller than 30 cc, were included in this study. These patients were positioned in a flat and reproducible position: supine with both arms above their head. For each patient a 4D-CT was acquired in a Philips Brilliance CT. The ITV was delineated according to six breathing phases. In total, 35 fractions were delivered to these patients, who were treated with SBRT without a body frame. Two risk-adapted fractionation schemes were used: 3 fractions of 18 Gy and 5 fractions of 10 Gy. For each fraction, three 4D-CBCT scans were acquired: before treatment to measure and correct the mean tumor position (initial set-up), after correction to validate the correction applied, and after treatment to estimate the intrafraction stability. These scans were volume registered with the localization CT, using a soft-tissue match, in the Elekta XVI software. Corrections were performed by a robotic patient positioning platform (Elekta HexaPOD RT system). Treatment was delivered using 6 MV photons generated from Elekta Synergy Beam Modulator Linac. Patient positioning data from all scans were recorded to determine systematic (Ʃ) and random (σ) set- up errors for initial set-up, after correction and after treatment imaging, in the left-right (X), craniocaudal (Y) and anteroposterior (Z) directions. The ITV to PTV margin (M) was also calculated for after correction and after treatment imaging, using the Van Herk formula: M=2.5 Ʃ +0.7 σ A summary of patient set-up errors and ITV to PTV margins, in the three orthogonal directions, is shown in Table I.Abstract 3691; Table ISummary of set-up errors and ITV marginsDirectionsCBCT initial set-upCBCT aftercorrectionCBCT aftertreatmentƩ(mm)σ(mm)Ʃ(mm)σ(mm)M(mm)Ʃ(mm)σ(mm)M(mm)X2.12.20.71.02.51.11.53.8Y5.43.61.31.24.01.51.44.6Z2.62.70.30.81.41.01.23.3 Open table in a new tab Intrafraction stability was 1.1, 0.6 and 1.0 mm (systematic) and 1.2, 0.9 and 1.1 mm (random) for X, Y and Z directions, respectively. Calculated margins do not account for target delineation and organ motion uncertainties and are consistent with our current 7 mm margins in all directions. Frameless SBRT can be safely administrated using 4D-CBCT. This was demonstrated with small intrafraction movements after initial set-up correction using imaging guidance. Our data suggest that lung SBRT should not be delivered without image guidance to correct initial set-up uncertainties owing to the small size of the lesions treated and the large dose delivered each fraction. ITV margins can safely be kept small, allowing patients to benefit of advantages of SBRT.

Lung respiration motion modeling: a sparse motion field presentation method using biplane x-ray images

Respiration-introduced tumor location uncertainty is a challenge in the precise lung biopsy for lung lesions. Current statistical modeling approaches hardly capture the complex local respiratory motion information. In this study, we formulate a statistical respiratory motion model using biplane x-ray images to improve the accuracy of motion field estimation by efficiently preserving local motion details for specific patients. Given CT data sets of 18 healthy subjects at end-expiratory and end-inspiratory breathing phases, the respiratory motion field is constructed based on deformation vector fields which are extracted from these CT data sets, and a lung contour motion repository respiratory is generated dependent on displacements of boundary control points. By varying the sparse weight coefficients of the statistical sparse motion field presentation (SMFP) method, the newly-input motion field is approximately presented by a sparse linear combination of a subset of the motion repository. The SMFP method is employed twice in the coefficient optimization process. Finally, these non-zero coefficients are fine-tuned to maximize the similarity between the projection image of reconstructed volumetric images and the current x-ray image. We performed the proposed method for estimating respiratory motion field on ten subject datasets and compared the result with the PCA method. The maximum average target registration error of the PCA-based and the SMFP-based respiratory motion field estimation are 3.1(2.0) and 2.9(1.6) mm, respectively. The maximum average symmetric surface distance of two methods are 2.5(1.6) and 2.4(1.3) mm, respectively.

4DCT imaging to assess radiomics feature stability: An investigation for thoracic cancers

Background and purposeQuantitative tissue characteristics derived from medical images, also called radiomics, contain valuable prognostic information in several tumour-sites. The large number of features available increases the risk of overfitting. Typically test–retest CT-scans are used to reduce dimensionality and select robust features. However, these scans are not always available. We propose to use different phases of respiratory-correlated 4D CT-scans (4DCT) as alternative. Materials and methodsIn test–retest CT-scans of 26 non-small cell lung cancer (NSCLC) patients and 4DCT-scans (8 breathing phases) of 20 NSCLC and 20 oesophageal cancer patients, 1045 radiomics features of the primary tumours were calculated. A concordance correlation coefficient (CCC) >0.85 was used to identify robust features. Correlation with prognostic value was tested using univariate cox regression in 120 oesophageal cancer patients. ResultsFeatures based on unfiltered images demonstrated greater robustness than wavelet-filtered features. In total 63/74 (85%) unfiltered features and 268/299 (90%) wavelet features stable in the 4D-lung dataset were also stable in the test–retest dataset. In oesophageal cancer 397/1045 (38%) features were robust, of which 108 features were significantly associated with overall-survival. Conclusion4DCT-scans can be used as alternative to eliminate unstable radiomics features as first step in a feature selection procedure. Feature robustness is tumour-site specific and independent of prognostic value.

Activation-Dependent Breathing in a Flexible Metal-Organic Framework and the Effects of Repeated Sorption/Desorption Cycling.

A non-interpenetrated metal-organic framework with a paddle-wheel secondary building unit has been activated by direct thermal evacuation, guest exchange with a volatile solvent, and supercritical CO2 drying. Conventional thermal activation yields a mixture of crystalline phases and some amorphous content. Exchange with a volatile solvent prior to vacuum activation produces a pure breathing phase with high sorption capacity, selectivity for CO2 over N2 and CH4 , and substantial hysteresis. Supercritical drying can be used to access a guest-free open phase. Pressure-resolved differential scanning calorimetry was used to confirm and investigate a systematic loss of sorption capacity by the breathing phase as a function of successive cycles of sorption and desorption. A corresponding loss of sample integrity was not detectable by powder X-ray diffraction analysis. This may be an important factor to consider in cases where flexible MOFs are earmarked for industrial applications.

Activation‐Dependent Breathing in a Flexible Metal–Organic Framework and the Effects of Repeated Sorption/Desorption Cycling

AbstractA non‐interpenetrated metal–organic framework with a paddle‐wheel secondary building unit has been activated by direct thermal evacuation, guest exchange with a volatile solvent, and supercritical CO2 drying. Conventional thermal activation yields a mixture of crystalline phases and some amorphous content. Exchange with a volatile solvent prior to vacuum activation produces a pure breathing phase with high sorption capacity, selectivity for CO2 over N2 and CH4, and substantial hysteresis. Supercritical drying can be used to access a guest‐free open phase. Pressure‐resolved differential scanning calorimetry was used to confirm and investigate a systematic loss of sorption capacity by the breathing phase as a function of successive cycles of sorption and desorption. A corresponding loss of sample integrity was not detectable by powder X‐ray diffraction analysis. This may be an important factor to consider in cases where flexible MOFs are earmarked for industrial applications.

Impact of physiological breathing motion for breast cancer radiotherapy with proton beam scanning – An in silico study

This study investigates the impact of breathing motion on proton breast treatment plans. Twelve patients with CT datasets acquired during breath-hold-at-inhalation (BHI), breath-hold-at-exhalation (BHE) and in free-breathing (FB) were included in the study. Proton plans were designed for the left breast for BHI and subsequently recalculated for BHE or designed for FB and recalculated for the extreme breath-hold phases. The plans were compared from the point of view of their target coverage and doses to organs-at-risk. The median amplitude of breathing motion determined from the positions of the sternum was 4.7mm (range 0.5–14.6mm). Breathing motion led to a degradation of the dose coverage of the target (heterogeneity index increased from 4–7% to 8–11%), but the degraded values of the dosimetric parameters of interest fulfilled the clinical criteria for plan acceptance. Exhalation decreased the lung burden [average dose 3.1–4.5Gy (RBE)], while inhalation increased it [average dose 5.8–6.8Gy (RBE)]. The individual values depended on the field arrangement. Smaller differences were seen for the heart [average dose 0.1–0.2Gy (RBE)] and the LAD [1.9–4.6Gy (RBE)]. Weak correlations were generally found between changes in dosimetric parameters and respiratory motion. The differences between dosimetric parameters for various breathing phases were small and their expected clinical impact is consequently quite small. The results indicated that the dosimetric parameters of the plans corresponding to the extreme breathing phases are little affected by breathing motion, thus suggesting that this motion might have little impact for the chosen beam orientations with scanned proton beams.

Feasibility of using single photon counting X-ray for lung tumor position estimation based on 4D-CT

PurposeIn stereotactic body radiation therapy of lung tumors, reliable position estimation of the tumor is necessary in order to minimize normal tissue complication rate. While kV X-ray imaging is frequently used, continuous application during radiotherapy sessions is often not possible due to concerns about the additional dose. Thus, ultra low-dose (ULD) kV X-ray imaging based on a single photon counting detector is suggested. This paper addresses the lower limit of photons to locate the tumor reliably with an accuracy in the range of state-of-the-art methods, i.e. a few millimeters. Method18 patient cases with four dimensional CT (4D-CT), which serves as a-priori information, are included in the study. ULD cone beam projections are simulated from the 4D-CTs including Poisson noise. The projections from the breathing phases which correspond to different tumor positions are compared to the ULD projection by means of Poisson log-likelihood (PML) and correlation coefficient (CC), and template matching under these metrics. ResultsThe results indicate that in full thorax imaging five photons per pixel suffice for a standard deviation in tumor positions of less than half a breathing phase. Around 50 photons per pixel are needed to achieve this accuracy with the field of view restricted to the tumor region. Compared to CC, PML tends to perform better for low photon counts and shifts in patient setup. Template matching only improves the position estimation in high photon counts. The quality of the reconstruction is independent of the projection angle. ConclusionsThe accuracy of the proposed ULD single photon counting system is in the range of a few millimeters and therefore comparable to state-of-the-art tumor tracking methods. At the same time, a reduction in photons per pixel by three to four orders of magnitude relative to commercial systems with flatpanel detectors can be achieved. This enables continuous kV image-based position estimation during all fractions since the additional dose to the patient is negligible.

Reducing radiation dose and enhancing imaging quality of 4DCT for radiation therapy using iterative reconstruction algorithms

PurposeFour-dimensional computed tomography (CT) images are typically used to quantify the necessary internal target volumes for thoracic and abdominal tumors. However, 4-dimensional CT is typically associated with excessive imaging dose to patients and the situation is exacerbated when using repeat 4-dimensional CT imaging on a weekly or daily basis throughout fractionated therapy. The aim of this work is to evaluate an iterative reconstruction (IR) algorithm that helps reduce the imaging dose to the patient while maintaining imaging quality as quantified by point spread function and contrast-to-noise ratios (CNRs). Methods and materialsAn IR algorithm, SAFIRE, was applied to CT data of a phantom and patients with varying CT doses and reconstruction kernels. Phantom data enable measurements of spatial resolution, contrast, and noise. The impact of SAFIRE on 4-dimensional CT was assessed with patient data acquired at 2 different dose levels during image guided radiation therapy with an in-room CT. ResultsPhantom data demonstrate that IR reduces noise approximately in proportion to the number of iterations indicated by the strength (SAFIRE 1 to SAFIRE 5). Spatial resolution and contrast are conserved independent of dose and reconstruction parameters. The CNR increases with an increase of imaging dose or an increase in the number of iterations. The use of IR on CT sets confirms the results that were derived from phantom scans. The IR significantly enhances single breathing phase CTs in 4-dimensional CT sets as assessed by CT number discrimination. Furthermore, the IR of the low dose 4-dimensional CT features a 45% increase in the CNR in comparison with the standard dose 4-dimensional CT. ConclusionsThe use of IR algorithms reduces noise while preserving spatial resolution and contrast, as evaluated from both phantom and patient CT data sets. For 4-dimensional CT, the IR can significantly improve image quality and reduce imaging dose without compromising image quality.

Reslizumab in Eosinophilic Asthma: A Review.

Reslizumab (Cinqaero®; Cinqair®) is a humanized monoclonal antibody against interleukin-5 (IL-5), a cytokine mediator of eosinophilic airway inflammation. Reslizumab is indicated as an add-on treatment for severe eosinophilic asthma in adults, on the basis of data from the BREATH phase III clinical trial programme. In three double-blind BREATH studies of up to 52weeks' duration, adding intravenous reslizumab (3mg/kg, once every 4weeks) to the current asthma therapy of patients (aged 12-75years) with eosinophilic asthma inadequately controlled with inhaled corticosteroids resulted in significant reductions in clinical asthma exacerbation frequency and significant improvements in lung function, asthma control and health-related quality of life relative to adding placebo. Pooled data from the two trials of 52weeks' duration indicated similar benefits with reslizumab across various patient subgroups, including patients with severe eosinophilic asthma. Reslizumab was generally well tolerated, with very few recipients experiencing severe or serious treatment-related adverse events. Moreover, in an open-label extension study, continued use of reslizumab for up to 2years was associated with durable lung function benefit, without any new tolerability concerns. Thus, intravenous reslizumab extends the valuable add-on treatment options for adults with severe eosinophilic asthma inadequately controlled with standard therapies.

Adaptive neuro-fuzzy inference system for breath phase detection and breath cycle segmentation

BackgroundThe monitoring of the respiratory rate is vital in several medical conditions, including sleep apnea because patients with sleep apnea exhibit an irregular respiratory rate compared with controls. Therefore, monitoring the respiratory rate by detecting the different breath phases is crucial. ObjectivesThis study aimed to segment the breath cycles from pulmonary acoustic signals using the newly developed adaptive neuro-fuzzy inference system (ANFIS) based on breath phase detection and to subsequently evaluate the performance of the system. MethodsThe normalised averaged power spectral density for each segment was fuzzified, and a set of fuzzy rules was formulated. The ANFIS was developed to detect the breath phases and subsequently perform breath cycle segmentation. To evaluate the performance of the proposed method, the root mean square error (RMSE) and correlation coefficient values were calculated and analysed, and the proposed method was then validated using data collected at KIMS Hospital and the RALE standard dataset. ResultsThe analysis of the correlation coefficient of the neuro-fuzzy model, which was performed to evaluate its performance, revealed a correlation strength of r = 0.9925, and the RMSE for the neuro-fuzzy model was found to equal 0.0069. ConclusionThe proposed neuro-fuzzy model performs better than the fuzzy inference system (FIS) in detecting the breath phases and segmenting the breath cycles and requires less rules than FIS.

Triple Oscillator Hypothesis: Three Excitatory Rhythm Generating Networks Control the Three Phases of Breathing

Breathing is composed of three phases: inspiration, postinspiration, and active expiration. Excitatory rhythm generating networks have been identified for the generation of inspiration, the preBötzinger complex (preBötC), and for active expiration, the lateral parafacial (pFL). By utilizing a combination of a new in vitro horizontal slice preparation, optogenetics, and in vivo techniques, we have recently identified and characterized a novel population of neurons that we show to be necessary and sufficient for the generation of postinspiration (Anderson et al. 2016). This network, located dorsomedial to the nucleus ambiguus and caudal to the facial nucleus, is referred to as the postinspiratory complex, or PiCo. PiCo can function as an independent oscillator dependent on excitatory, non‐NMDA mechanisms. Here we show that a subpopulation of PiCo neurons are endowed with ICAN and INaP dependent pacemaker properties, suggesting that PiCo has similar rhythm generating properties to the preBötC. Additionally, we observed differential effects of inhibitory antagonists. When strychnine, a glycine receptor antagonist, was bath applied to the horizontal slice in vitro, the burst duration of fictive inspiratory preBötC bursts significantly decreased while PiCo burst duration was unchanged. Upon the additional application of gabazine, a GABAergic receptor antagonist, the two rhythms progressively synchronized. Furthermore, in the presence of gabazine, the average burst area and amplitude significantly increased for both preBötC and PiCo rhythms. Based on our discovery, we propose a triple‐oscillator hypothesis that states that the three phases of respiration are generated by three, anatomically distinct, excitatory, rhythmogenic and interactive networks: the preBötC, PiCo, and PFL. We further conclude that network inhibition serves to coordinate the timing, phasing and patterning of these rhythms.Support or Funding Information1F31NS087828‐01RO1 HL107084‐01

Phasic Inhibition Differentially Modulates Synaptic Dynamics Among Excitatory preBötzinger Complex Populations to Promote Rapid Breathing In Vivo

The preBötzinger Complex (preBötC), located in the medulla, generates the inspiratory phase of breathing. A specific lineage of excitatory neurons, derived from Dbx1 expressing precursors, seems to underlie rhythmogenesis in the preBötC. In vitro and modelling studies suggest excitatory synaptic dynamics (e.g. presynaptic facilitation and depression) among Dbx1 neurons result in neuronal synchrony, population burst termination, and a refractory period for neural synchrony following a preBötC population burst. However, Dbx1 neurons are estimated to comprise only ~50% of the total glutamatergic population within the preBötC, and an additional ~50% of all preBötC neurons are inhibitory. Moreover, in intact animals, preBötC activity is influenced by sensory feedback, including vagally‐mediated lung stretch afferents that activate preBötC inhibitory neurons in phase with inspiration and increase respiratory frequency (rf). The mechanism by which sensory feedback increases rf and the functional implications of preBötC heterogeneity remain unclear. To investigate how these populations of preBötC neurons influence rf in vivo, we employed an optogenetic approach using transgenic mice expressing channelrhodopsin‐2 specifically within Dbx1 (Dbx1ERT2‐Cre), glutamatergic (VgluT2‐Cre), and gabaergic (Gad2‐Cre) neurons. In spontaneously breathing anesthetized mice with intact or bilaterally transected vagal nerves, the ventral medulla was exposed and an optical fiber was placed over the preBötC. Rhythmic XII activity was recorded during continuous (10 sec) light stimulation, repeated light stimulation occurring specifically during the inspiratory or expiratory phase, and random 100–200 ms light pulses. In vagus‐intact Dbx1‐Cre and VgluT2‐Cre mice, rf slowed when light stimulation occurred during inspiration. When light stimulation occurred during expiration, rf was dramatically increased in VgluT2‐Cre mice, but only modestly increased in Dbx1‐Cre mice. During continuous light stimulation, the inspiratory and expiratory effects of Dbx1 stimulation offset such that rf was unchanged, whereas VgluT2 stimulation increased rf. Phase shift plots revealed a refractory period for Dbx1 stimulation that was substantially longer than that for VgluT2 stimulation. In contrast, in vagotomized mice, stimulation during inspiration did not slow rf, the ability of Dbx1 and VgluT2 stimulation to reset the rhythm was no longer different, and refractory periods were dramatically increased. In vagus‐intact or vagotomized Gad2‐Cre mice, continuous light stimulation or stimulation during expiration slowed rf. However, if isolated to the inspiratory phase, Gad2 stimulation dramatically increased rf. This was confirmed by phase shift plots revealing that Gad2 stimulation during inspiration advances the subsequent inspiration, has little effect during early expiration (refractory period), and delays the subsequent inspiration during late expiration. All changes in frequency were primarily a result of changes in expiratory time (Te). Given these results, we propose a network structure in which phasic inhibition modulates excitatory synaptic dynamics. Specifically, sensory feedback inhibition differentially influences Dbx1 and non‐Dbx1 glutamatergic preBötC populations and promotes rapid breathing frequencies observed in vivo by reducing presynaptic depression of excitatory synapses.Support or Funding InformationNIH NRSA: F32HL134207NIH RO1: R01HL126523NIH PPG: P01 HL090554

A Novel Method of Cone Beam CT Projection Binning Based on Image Registration.

Accurate sorting of beam projections is important in 4D cone beam computed tomography (4D CBCT) to improve the quality of the reconstructed 4D CBCT image by removing motion-induced artifacts. We propose image registration-based projection binning (IRPB), a novel marker-less binning method for 4D CBCT projections, which combines intensity-based feature point detection and trajectory tracking using random sample consensus. IRPB extracts breathing motion and phases by analyzing tissue feature point trajectories. We conducted experiments with two phantom and six patient datasets, including both regular and irregular respirations. In experiments, we compared the performance of the proposed IRPB, Amsterdam Shroud method (AS), Fourier transform-based method (FT), and local intensity feature tracking method (LIFT). The results showed that the average absolute phase shift of IRPB was 3.74 projections and 0.48 projections less than that of FT and LIFT, respectively. AS lost the most breathing cycles in the respiration extraction for the five patient datasets, so we could not compare the average absolute phase shift between IRPB and AS. Based on the peak signal-to-noise ratio (PSNR) of the reconstructed 4D CBCT images, IRPB had 5.08, 1.05, and 2.90 dB larger PSNR than AS, FT, and LIFT, respectively. The average Structure SIMilarity Index (SSIM) of the 4D CBCT image reconstructed by IRPB, AS, and LIFT were 0.87, 0.74, 0.84, and 0.70, respectively. These results demonstrated that IRPB has superior performance to the other standard methods.