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Purpose: The use of motion mitigation techniques such as breath-hold can reduce the dosimetric uncertainty of lung cancer proton therapy. We studied the feasibility of pencil beam scanning (PBS) proton therapy field delivery within a single breath-hold at PSI's Gantry 2. Methods: In PBS proton therapy, the delivery time for a field is determined by the beam-on time and the dead time between proton spots (the time required to change the energy and/or lateral position). We studied ways to reduce beam-on and lateral scanning time, without sacrificing dosimetric plan quality, aiming at a single field delivery time of 15 seconds at maximum. We tested this approach on 10 lung cases with varying target volumes. To reduce the beam-on time, we increased the beam current at the isocenter by developing new beam optics for PSI's PROSCAN beamline and Gantry 2. To reduce the dead time between the spots, we used spot-reduced plan optimization. Results: We found that it is possible to achieve conventional fractionated (2 Gy(RBE)/fraction) and hypofractionated (6 Gy(RBE)/fraction) field delivery times within a single breath-hold (, Radiotherapy & Oncology, 174, ISSN:0167-8140, ISSN:1879-0887

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is defined by pauses in breathing during sleep, but daytime breathing dysregulation may also be present. Sleep may unmask breathing instability in OSA that is usually masked by behavioral influences during wakefulness. A breath-hold (BH) challenge has been used to demonstrate breathing instability. One measure of breathing stability is breathing rate variability (BRV). We aimed to assess BRV during rest and in response to BH in OSA. METHODS: We studied 62 participants (31 with untreated OSA: respiratory event index [mean ± SD] 20 ± 15 events/h, 12 females, age 51 ± 14 years, body mass index [BMI] 32 ± 8 kg/m(2); 31 controls: 17 females, age 47 ± 13 years; BMI 26 ± 4 kg/m(2)). Breathing movements were collected using a chest belt for 5 minutes of rest and during a BH protocol (60 seconds baseline, 30 seconds BH, 90 seconds recovery, 3 repeats). From the breathing movements, we calculated median breathing rate (BR) and interquartile BRV at rest. We calculated change in BRV during BH recovery from baseline. Group comparisons of OSA vs control were conducted using analysis of covariance with age, sex, and BMI as covariates. RESULTS: We found 10% higher BRV in OSA vs controls (P < .05) during rest. In response to BH, BRV increased 7% in OSA vs 1% in controls (P < .001). Resting BR was not significantly different in OSA and controls, and sex and age did not have any significant interaction effects. BMI was associated with BR at rest (P < .05) and change in BRV with BH (P < .001), but no significant BMI-by-group interaction effect was observed. CONCLUSIONS: The findings suggest breathing instability as reflected by BRV is high in OSA during wakefulness, both at rest and in response to a stimulus. Breathing instability together with high blood pressure variability in OSA may reflect a compromised cardiorespiratory consequence in OSA during wakefulness. CITATION: Pal A, Martinez F, Akey MA, et al. Breathing rate variability in obstructive sleep apnea during wakefulness. J Clin Sleep Med. 2022;18(3):825–833.

Available online 22 March 2023 Cerebrovascular reactivity (CVR), defined as the cerebral blood flow response to a vasoactive stimulus, is an imag- ing biomarker with demonstrated utility in a range of diseases and in typical development and aging processes. A robust and widely implemented method to map CVR involves using a breath-hold task during a BOLD fMRI scan. Recording end-tidal CO 2 (P ET CO 2 ) changes during the breath-hold task is recommended to be used as a refer- ence signal for modeling CVR amplitude in standard units (%BOLD/mmHg) and CVR delay in seconds. However, obtaining reliable P ET CO 2 recordings requires equipment and task compliance that may not be achievable in all settings. To address this challenge, we investigated two alternative reference signals to map CVR amplitude and delay in a lagged general linear model (lagged-GLM) framework: respiration volume per time (RVT) and average gray matter BOLD response (GM-BOLD). In 8 healthy adults with multiple scan sessions, we compare spatial agreement of CVR maps from RVT and GM-BOLD to those generated with P ET CO 2 . We define a threshold to determine whether a P ET CO 2 recording has “sufficient ”quality for CVR mapping and perform these comparisons in 16 datasets with sufficient P ET CO 2 and 6 datasets with insufficient P ET CO 2 . When P ET CO 2 quality is sufficient, both RVT and GM-BOLD produce CVR amplitude maps that are nearly identical to those from P ET CO 2 (after accounting for differences in scale), with the caveat they are not in standard units to facilitate between-group comparisons. CVR delays are comparable to P ET CO 2 with an RVT regressor but may be underestimated with the average GM-BOLD regressor. Importantly, when P ET CO 2 quality is insufficient, RVT and GM-BOLD CVR recover reasonable CVR amplitude and delay maps, provided the participant attempted the breath-hold task. Therefore, our framework offers a solution for achieving high quality CVR maps in both retrospective and prospective stud- ies where sufficient P ET CO 2 recordings are not available and especially in populations where obtaining reliable measurements is a known challenge (e.g., children). Our results have the potential to improve the accessibility of CVR mapping and to increase the prevalence of this promising metric of vascular health. This research was supported by the European Union’s Horizon 2020 research and innovation program (Marie Sk ł odowska-Curie grant agreement No. 713673 ), a fellowship from La Caixa Foundation (ID 100010434 , fellowship code LCF/BQ/IN17/11620063 ), the Spanish Ministry of Economy and Competitiveness (Ramon y Cajal Fellowship, RYC-2017–21845 ), the Spanish State Research Agency (BCBL “Severo Ochoa ”excellence accreditation, SEV-2015–490 ), the Basque Govern- ment ( BERC 2018–2021 and PIBA_2019_104 ), the Spanish Ministry of Science, Innovation and Universities (MICINN; PID2019–105520GB- 100 and FJCI-2017–31814 ). K.M.Z. was supported by the National In- stitutes of Health under a training program ( T32EB025766 ) and by the National Heart, Lung, And Blood Institute under Award Number F31HL166079 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National In- stitutes of Health.

Background: The standard in Denmark for treating breast cancer patients receiving loco-regional irradiation is tangential 3D Conformal RadioTherapy (3DCRT), treated in deep inspiration breath-hold (DIBH). Treating with Volumetric Modulated Arc Therapy (VMAT) may reduce the treatment time, which is particularly important for DIBH treatments. The VMAT should be performed without increased dose to the heart, lung, and contralateral breast. This study compares VMAT and 3DCRT for left-sided breast cancer patients with intramammary lymph node involvement. Material and methods: Twenty left-sided breast cancer patients were included. VMAT and tangential plans were created for all patients, with a prescription dose of 50 Gy. The tangential plans used 6 MV and for larger breast combined with 18 MV. The VMAT plans utilised two 6 MV fields in a butterfly configuration. Dose planning was done in Pinnacle3 16.0 using the Auto-Planning module for the VMAT plans. Comparison of the plans was based on: mean doses, metrics provided by DBCG guidelines, dose-volume histograms and required number of breath-holds for treatment delivery in DIBH. Results: For most OAR, the doses were similar for VMAT and 3DCRT. The target coverage was comparable, with VMAT having a statistically significant improved dose homogeneity of the target volumes. Less than half the number of breath-hold was required for VMAT compared to 3DCRT. Mean gamma pass rates (3 mm and 3%) from ArcCHECK of the VMAT plans was 98.4% (range 96.6–99.8%). Conclusion: Automatic VMAT planning of left-sided breast cancer patients with lymph node involvement can produce dose distributions comparable to those of tangential 3DCRT, while reducing the number of breath-holds in DIBH by more than a factor of two. The reduction in breath-holds is beneficial for patient comfort and reduces the risk of intra-fraction patient motion.

Lars J Bjertnaes,1,2 Anton Hauge,3 Marianne Thoresen,3,4 Lars Walløe3 1Anesthesia and Critical Care Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, N-9037, Norway; 2Department of Intensive Care Medicine, University Hospital of North Norway, Tromsø, N- 9017, Norway; 3Division of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, 0317, Norway; 4Translational Health Sciences, University of Bristol, Bristol, UKCorrespondence: Lars J BjertnaesAnesthesia and Critical Care Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, N-9037, NorwayTel +47 77627001Fax +47 77626042Email lars.bjertnaes@uit.noBackground: Successful cardiopulmonary resuscitation after drowning or avalanche is often attributed to hypothermia-induced decrease in metabolism, which adapts the oxygen demand to the amount supplied under cardiac compression. Four decades ago, we speculated if oxygen-sparing mechanisms like those found in marine mammals, may improve cerebral oxygenation during acute airway blockade in humans. We investigated hemodynamic changes during steady state ergometer cycling with intermittent periods of apnea and face immersion (AFI) in ice-cold water. During AFI, heart rate (HR) dropped by 58% whereas average blood velocity (ABV) determined by means of a Doppler ultrasound velocity meter (UNIDOP University of Oslo, Oslo, Norway) fell by 85% in the radial artery and rose by 67% in the vertebral artery. Similar changes occured in radial artery ABV, albeit more slowly, when the test subject only held his breath while cycling. When he breathed via a snorkel during face immersion, HR remained unchanged while radial artery ABV fell transiently and subsequently returned to its pre-immersion level. These findings later were confirmed by other investigators. Moreover, a recent study revealed that the seal even has a system for selective brain cooling during the dive.Conclusion: Our research has confirmed prioritized cerebral circulation during AFI in cold water. We hypothesize that these changes may improve brain oxygenation due both to greater blood flow and possibly also to faster brain cooling, as demonstrated in diving seals.Keywords: apnea, breath-hold, cardiopulmonary resuscitation, diving response, hypothermia

Background Trained breath-hold divers have shown physiological adaptations that might improve athletes’ aerobic and anaerobic performance.Objective This study aimed to systematically review the scientific literature and perform a meta-analysis to assess the effects of voluntary apnoea training on markers of anaerobic and aerobic performance, such as blood lactate and VO2max.Methods A literature search on three databases (Web of Science, PubMed and SCOPUS) was conducted in March 2022. The inclusion criteria were 1) peer-reviewed journal publication; 2) clinical trials; 3) healthy humans; 4) effects of apnoea training; 5) variables included markers of aerobic or anaerobic performance, such as lactate and VO2max.Results 545 manuscripts were identified following database examination. Only seven studies met the inclusion criteria and were, therefore, included in the meta-analysis. 126 participants were allocated to either voluntary apnoea training (ApT; n = 64) or normal breathing (NB; n = 63). Meta-analysis on the included studies demonstrated that ApT increased the peak blood lactate concentration more than NB (MD = 1.89 mmol*L−1 [95% CI 1.05, 2.73], z = 4.40, p < 0.0001). In contrast, there were no statistically significant effects of ApT on VO2max (MD = 0.89 ml*kg−1*min−1 [95% CI −1.23, 3.01], z = 0.82, p = 0.41).Conclusion ApT might be an alternative strategy to enhace anaerobic performance associated with increased maximum blood lactate; however, we did not find evidence of ApT effects on physiological aerobic markers, such as VO2max.Systematic Review Registration: [PRISMA], identifier [registration number].

Dopamine (DA) mediated brain activity is intimately linked to reward‐driven cerebral responses, while aberrant reward processing has been implicated in several psychiatric disorders. fMRI has been a valuable tool in understanding the mechanism by which DA modulators alter reward‐driven responses and how they may exert their therapeutic effect. However, the potential effects of a pharmacological compound on aspects of neurovascular coupling may cloud the interpretability of the BOLD contrast. Here, we assess the effects of risperidone on reward driven BOLD signals produced by reward anticipation and outcome, while attempting to control for potential drug effects on regional cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). Healthy male volunteers (n = 21) each received a single oral dose of either 0.5 mg, 2 mg of risperidone or placebo in a double‐blind, placebo‐controlled, randomised, three‐period cross‐over study design. Participants underwent fMRI scanning while performing the widely used Monetary Incentive Delay (MID) task to assess drug impact on reward function. Measures of CBF (Arterial Spin Labelling) and breath‐hold challenge induced BOLD signal changes (as a proxy for CVR) were also acquired and included as covariates. Risperidone produced divergent, dose‐dependent effects on separate phases of reward processing, even after controlling for potential nonneuronal influences on the BOLD signal. These data suggest the D2 antagonist risperidone has a wide‐ranging influence on DA‐mediated reward function independent of nonneuronal factors. We also illustrate that assessment of potential vascular confounds on the BOLD signal may be advantageous when investigating CNS drug action and advocate for the inclusion of these additional measures into future study designs., Single dose risperidone produces dose‐response and divergent effects on different phases of reward‐related brain activity in healthy human volunteers in a placebo‐controlled fMRI study. These effects persist after accounting for potential nonneuronal effects of the drug on cerebral blood flow and cerebrovascular reactivity (as measured by a breath hold challenge).

In Proton therapy, the potential of using high dose rates in cancer treatment is being explored. High dose rates could improve efficiency and throughput in standard clinical practice, allow efficient utilization of motion mitigation techniques for moving targets, and potentially enhance normal tissue sparing due to the FLASH effect. However, high dose rates are difficult to reach when lower energy beams are applied in cyclotron-based proton therapy facilities, because they result in large beam sizes and divergences downstream of the degrader, incurring large losses from the cyclotron to the patient. In current facilities the emittance after the degrader is reduced using circular collimators (emittance selection collimators after the energy degrader); this however does not provide an optimal matching to the acceptance of the following beamline, causing a low transmission for these energies. We, therefore, propose to use a collimation system asymmetric in both beam size and divergence, which allows to maximize the transmission of low energy beams, while resulting in symmetric emittance in both planes as required for a gantry system. Using a specifically designed asymmetric collimation system, we found in simulations that low energy (70 MeV) beam transmission increases almost 6 times compared to the currently used circular collimator system [1]. Such a system could easily be implemented in facilities interested in increasing dose rates for efficient motion mitigation and FLASH experiments alike. [1] Maradia et. al., “A new emittance selection system to maximize beam transmission for low-energy beams in cyclotron-based proton therapy facilities with gantry,” doi: https://doi.org/10.1002/mp.15278.

The objective of the study was to determine the age-related peculiarities of functional and motor fitness of students of a special medical department of higher education institutions. Material and methods. The study participants were 1st year (n = 34); 2nd year (n = 14); 3rd year (n = 58); 4th year (n = 21); 5th year (n = 16) male students. One group was organized in each year of study, which added up to five experimental groups. All the students participated in physical education classes twice a week. To solve the tasks set, the following research methods were used: analysis of scientific literature, pedagogical observation, pedagogical testing, formative experiment, index method, biomedical methods, and methods of mathematical statistics. During classes, the study used the method of strictly regulated exercise (motor density of the class was 50-70%), for developing general endurance – the continuous method with covering a distance of 1,000-2,000 m (heart rate: 120-150 beats per minute), circuit and repetition methods. Results. The study results show positive changes in the functional state of the respiratory system and speed and strength abilities in the 1st-5th year students of the special medical department (p < 0.05). Conclusions. A successful development of the basic functional body systems and motor abilities in 1st-5th year students can be achieved under the influence of pedagogical conditions, namely: the method of strictly regulated exercise using exercise equipment (motor density of the class was 50-70%); the continuous method with covering a distance of 1,000-2,000 m at a slow pace (heart rate: 120-150 beats per minute); circuit and repetition methods. By the results of comparative analysis of the functional and motor fitness, the 1st-5th year male students of the special medical department show better results in tests for assessing the cardiovascular and respiratory systems, speed and strength abilities. In the 18-22 age range, according to the Ruffier index, there is an increase in the number of male students of the special medical department with a “good” and “satisfactory” cardiovascular system state and a decrease in the number of students with a “bad” result.

Purpose: For locally advanced-stage non-small cell lung cancer (NSCLC), inter-fraction target motion variations during the whole time span of a fractionated treatment course are assessed in a large and representative patient cohort. The primary objective is to develop a suitable motion monitoring strategy for pencil beam scanning proton therapy (PBS-PT) treatments of NSCLC patients during free breathing. Methods: Weekly 4D computed tomography (4DCT; 41 patients) and daily 4D cone beam computed tomography (4DCBCT; 10 of 41 patients) scans were analyzed for a fully fractionated treatment course. Gross tumor volumes (GTVs) were contoured and the 3D displacement vectors of the centroid positions were compared for all scans. Furthermore, motion amplitude variations in different lung segments were statistically analyzed. The dosimetric impact of target motion variations and target motion assessment was investigated in exemplary patient cases. Results: The median observed centroid motion was 3.4 mm (range: 0.2–12.4 mm) with an average variation of 2.2 mm (range: 0.1–8.8 mm). Ten of 32 patients (31.3%) with an initial motion 2 mm, 4DCBCT should be considered for motion monitoring due to substantial motion variations observed.

Background The aim of this work was to investigate the serum amino acid (AA) changes after a breath-hold diving (BH-diving) training session under several aspects including energy need, fatigue tolerance, nitric oxide (NO) production, antioxidant synthesis and hypoxia adaptation. Twelve trained BH-divers were investigated during an open sea training session and sampled for blood 30 min before the training session, 30 min and 4 h after the training session. Serum samples were assayed for AA changes related to energy request (alanine, histidine, isoleucine, leucine, lysine, methionine, proline threonine, valine), fatigue tolerance (ornithine, phenylalanine, tyrosine), nitric oxide production (citrulline), antioxidant synthesis (cystine, glutamate, glycine) and hypoxia adaptation (serine, taurine). Main results Concerning the AA used as an energy support during physical effort, we found statistically significant decreases for all the investigated AA at T1 and a gradual return to the basal value at T2 even if alanine, proline and theonine still showed a slight significant reduction at this time. Also, the changes related to the AA involved in tolerance to physical effort showed a statistically significant decrease only at T1 respect to pre-diving value and a returned to normal value at T2. Citrulline, involved in NO production, showed a clear significant reduction both at T1 and T2. Concerning AA involved in endogenous antioxidant synthesis, the behaviour of the three AA investigated is different: we found a statistically significant increase in cystine both at T1 and T2, while glycine showed a statistically significant reduction (T1 and T2). Glutamate did not show any statistical difference. Finally, we found a statistically significant decrease in the AA investigated in other hypoxia conditions serine and taurine (T1 and T2). Conclusions Our data seem to indicate that the energetic metabolic request is in large part supported by AA used as substrate for fuel metabolism and that also fatigue tolerance, NO production and antioxidant synthesis are supported by AA. Finally, there are interesting data related to the hypoxia stimulus that indirectly may confirm that the muscle apparatus works under strong exposure conditions notwithstanding the very short/low intensity of exercise, due to the intermittent hypoxia caused by repetitive diving.

Background Recently, we reported a novel neuroimaging technique, unbalanced T1 Relaxation-Enhanced Steady-State (uT1RESS), which uses a tailored 3D unbalanced steady-state free precession (3D uSSFP) acquisition to suppress the blood pool signal while minimizing bulk motion sensitivity. In the present work, we hypothesized that 3D uSSFP might also be useful for dark blood imaging of the chest. To test the feasibility of this approach, we performed a pilot study in healthy subjects and patients undergoing cardiovascular magnetic resonance (CMR). Main body The study was approved by the hospital institutional review board. Thirty-one adult subjects were imaged at 1.5 T, including 5 healthy adult subjects and 26 patients (44 to 86 years, 10 female) undergoing a clinically indicated CMR. Breath-holding was used in 29 subjects and navigator gating in 2 subjects. For breath-hold acquisitions, the 3D uSSFP pulse sequence used a high sampling bandwidth, asymmetric readout, and single-shot along the phase-encoding direction, while 3 shots were acquired for navigator-gated scans. To minimize signal dephasing from bulk motion, electrocardiographic (ECG) gating was used to synchronize the data acquisition to the diastolic phase of the cardiac cycle. To further reduce motion sensitivity, the moment of the dephasing gradient was set to one-fifth of the moment of the readout gradient. Image quality using 3D uSSFP was good-to-excellent in all subjects. The blood pool signal in the thoracic aorta was uniformly suppressed with sharp delineation of the aortic wall including two cases of ascending aortic aneurysm and two cases of aortic dissection. Compared with variable flip angle 3D turbo spin-echo, 3D uSSFP showed improved aortic wall sharpness. It was also more efficient, permitting the acquisition of 24 slices in each breath-hold versus 16 slices with 3D turbo spin-echo and a single slice with dual inversion 2D turbo spin-echo. In addition, lung and mediastinal lesions appeared highly conspicuous compared with the low blood pool signals within the heart and blood vessels. In two subjects, navigator-gated 3D uSSFP provided excellent delineation of cardiac morphology in double oblique multiplanar reformations. Conclusion In this pilot study, we have demonstrated the feasibility of using ECG-gated 3D uSSFP for dark blood imaging of the heart, great vessels, and lungs. Further study will be required to fully optimize the technique and to assess clinical utility.

The physiopathology consequences of hypoxia during breath-hold diving are a matter of debate. Adenosine (AD), an ATP derivative, is suspected to be implicated in the adaptive cardiovascular response to apnea, because of its vasodilating and bradycardic properties, two clinical manifestations observed during voluntary apnea. The aim of this study was to evaluate the adenosine response to apnea-induced hypoxia in trained spearfishermen (SFM) who are used to perform repetitive dives for 4–5 h. Twelve SFM (11 men and 1 woman, mean age 41 ± 3 years, apnea experience: 18 ± 9 years) and 10 control (CTL) subjects (age 44 ± 7 years) were enrolled in the study. Subjects were asked to main a dry static apnea and stopped it when they began the struggle phase (average duration: SFM 120 ± 78 s, CTL 78 ± 12 s). Capillary blood samples were collected at baseline and immediately after the apnea and analyzed for standard parameters and adenosine blood concentration ([AD]b). Heart rate (HR), systolic (SBP), and diastolic (DBP) blood pressures were also recorded continuously during the apnea. During the apnea, an increase in SBP and DBP and a decrease in HR were observed in both SFM and CTL. At baseline, [AD]b was higher in SFM compared with CTL (1.05 ± 0.2 vs. 0.73 ± 0.11 μM, p < 0.01). [AD]b increased significantly at the end of the apnea in both groups, but the increase was significantly greater in SFM than in controls (+90.4 vs. +12%, p < 0.01). Importantly, in SFM, we also observed significant correlations between [AD]b and HR (R = −0.8, p = 0.02), SpO2 (R = −0.69, p = 0.01), SBP (R = −0.89, p = 0.02), and DBP (R = −0.68, p = 0.03). Such associations were absent in CTL. The adenosine release during apnea was associated with blood O2 saturation and cardiovascular parameters in trained divers but not in controls. These data therefore suggest that adenosine may play a major role in the adaptive cardiovascular response to apnea and could reflect the level of training.

Purpose Serum erythropoietin (EPO) concentration is increased following static apnoea-induced hypoxia. However, the acute erythropoietic responses to a series of dynamic apnoeas in non-divers (ND) or elite breath-hold divers (EBHD) are unknown. Methods Participants were stratified into EBHD (n = 8), ND (n = 10) and control (n = 8) groups. On two separate occasions, EBHD and ND performed a series of five maximal dynamic apnoeas (DYN) or two sets of five maximal static apnoeas (STA). Control performed a static eupnoeic (STE) protocol to control against any effects of water immersion and diurnal variation on EPO. Peripheral oxygen saturation (SpO2) levels were monitored up to 30 s post each maximal effort. Blood samples were collected at 30, 90, and 180 min after each protocol for EPO, haemoglobin and haematocrit concentrations. Results No between group differences were observed at baseline (p > 0.05). For EBHD and ND, mean end-apnoea SpO2 was lower in DYN (EBHD, 62 ± 10%, p = 0.024; ND, 85 ± 6%; p = 0.020) than STA (EBHD, 76 ± 7%; ND, 96 ± 1%) and control (98 ± 1%) protocols. EBHD attained lower end-apnoeic SpO2 during DYN and STA than ND (p p p = 0.622). EBHD EPO increased from baseline (6.85 ± 0.9mlU/mL) by 60% at 30 min (10.82 ± 2.5mlU/mL, p = 0.017) and 63% at 180 min (10.87 ± 2.1mlU/mL, p = 0.024). Serum EPO did not change after the STA (EBHD, p = 0.534; ND, p = 0.850) and STE (p = 0.056) protocols. There was a significant negative correlation (r = − 0.49, p = 0.003) between end-apnoeic SpO2 and peak post-apnoeic serum EPO concentrations. Conclusions The novel findings demonstrate that circulating EPO is only increased after DYN in EBHD. This may relate to the greater hypoxemia achieved by EBHD during the DYN.

Purpose: Post-contrast liver magnetic resonance imaging is typically performed with breath-hold 3D gradient echo sequences. However, breath-holding for >10 s is difficult for some patients. In this study, we compared the quality of hepatobiliary phase (HBP) imaging without breath-holding using the prototype pulse sequences stack-of-stars liver acquisition with volume acceleration (LAVA) (LAVA Star) with or without navigator echoes (LAVA Starnavi+ and LAVA Starnavi−) and Cartesian LAVA with navigator echoes (Cartesian LAVAnavi+). Methods: Seventy-two patients were included in this single-center, retrospective, cross-sectional study. HBP imaging using the three LAVA sequences (Cartesian LAVAnavi+, LAVA Starnavi−, and LAVA Starnavi+) without breath-holding was performed for all patients using a 3T magnetic resonance system. Two independent radiologists qualitatively analyzed (overall image quality, liver edge sharpness, hepatic vein clarity, streak artifacts, and respiratory motion/pulsation artifacts) HBP images taken by the three sequences using a five-point scale. Quantitative evaluations were also performed by calculating the liver-to-spleen, -lesion, and -portal vein (PV) signal intensity ratios. The results were compared between the three sequences using the Friedman test. Results: LAVA Starnavi+ showed the best image quality and hepatic vein clarity (P < 0.0001). LAVA Starnavi− showed the lowest image quality (P < 0.0001–0.0106). LAVA Starnavi+ images showed fewer streak artifacts than LAVA Starnavi− images (P < 0.0001), while Cartesian LAVAnavi+ images showed no streak artifacts. Cartesian LAVAnavi+ images showed stronger respiratory motion/pulsation artifacts than the others (P < 0.0001). LAVA Starnavi− images showed the highest liver-to-spleen ratios (P < 0.0001–0.0005). Cartesian LAVAnavi+ images showed the lowest liver-to-lesion and -PV ratios (P < 0.0001–0.0108). Conclusion: In terms of image quality, the combination of stack-of-stars acquisition and navigator echoes is the best for HBP imaging without breath-holding.

Purpose A major burden of introducing an online daily adaptive proton therapy (DAPT) workflow is the time and resources needed to correct the daily propagated contours. In this study, we evaluated the dosimetric impact of neglecting the online correction of the propagated contours in a DAPT workflow. Material and methods For five NSCLC patients with nine repeated deep-inspiration breath-hold CTs, proton therapy plans were optimised on the planning CT to deliver 60 Gy-RBE in 30 fractions. All repeated CTs were registered with six different clinically used deformable image registration (DIR) algorithms to the corresponding planning CT. Structures were propagated rigidly and with each DIR algorithm and reference structures were contoured on each repeated CT. DAPT plans were optimised with the uncorrected, propagated structures (propagated DAPT doses) and on the reference structures (ideal DAPT doses), non-adapted doses were recalculated on all repeated CTs. Results Due to anatomical changes occurring during the therapy, the clinical target volume (CTV) coverage of the non-adapted doses reduces on average by 9.7% (V95) compared to an ideal DAPT doses. For the propagated DAPT doses, the CTV coverage was always restored (average differences in the CTV V95 < 1% compared to the ideal DAPT doses). Hotspots were always reduced with any DAPT approach. Conclusion For the patients presented here, a benefit of online DAPT was shown, even if the daily optimisation is based on propagated structures with some residual uncertainties. However, a careful (offline) structure review is necessary and corrections can be included in an offline adaption., Radiotherapy & Oncology, 159, ISSN:0167-8140, ISSN:1879-0887

While magnetic resonance cholangiopancreatography (MRCP) is routinely used, compressed sensing MRCP (CS-MRCP) and gradient and spin-echo MRCP (GRASE-MRCP) with breath-holding (BH) may allow sufficient image quality with shorter acquisition times. This study qualitatively and quantitatively compared BH-CS-MRCP and BH-GRASE-MRCP and evaluated their clinical effectiveness. Data from 59 consecutive patients who underwent both BH-CS-MRCP and BH-GRASE-MRCP were qualitatively analyzed using a five-point Likert-type scale. The signal-to-noise ratio (SNR) of the common bile duct (CBD), contrast-to-noise ratio (CNR) of the CBD and liver, and contrast ratio between periductal tissue and the CBD were measured. Paired t-test, Wilcoxon signed-rank test, and McNemar’s test were used for statistical analysis. No significant differences were found in overall image quality or duct visualization of the CBD, right and left 1st level intrahepatic duct (IHD), cystic duct, and proximal pancreatic duct (PD). BH-CS-MRCP demonstrated higher background suppression and better visualization of right (p = 0.004) and left 2nd level IHD (p < 0.001), mid PD (p = 0.003), and distal PD (p = 0.041). Image quality degradation was less with BH-GRASE-MRCP than BH-CS-MRCP (p = 0.025). Of 24 patients with communication between a cyst and the PD, 21 (87.5%) and 15 patients (62.5%) demonstrated such communication on BH-CS-MRCP and BH-GRASE-MRCP, respectively. SNR, contrast ratio, and CNR of BH-CS-MRCP were higher than BH-GRASE-MRCP (p < 0.001). Both BH-CS-MRCP and BH-GRASE-MRCP are useful imaging methods with sufficient image quality. Each method has advantages, such as better visualization of small ducts with BH-CS-MRCP and greater time saving with BH-GRASE-MRCP. These differences allow diverse choices for visualization of the pancreaticobiliary tree in clinical practice.

A pseudocontinuous arterial spin labeling (PCASL) sequence combined with background suppression and single-shot accelerated 3D RARE stack-of-spirals was used to evaluate cerebrovascular reactivity (CVR) induced by breath-holding (BH) in ten healthy volunteers. Four different models designed using the measured change in PETCO2 induced by BH were compared, for CVR quantification. The objective of this comparison was to understand which regressor offered a better physiological model to characterize the cerebral blood flow response under BH. The BH task started with free breathing of 42 s, followed by interleaved end-expiration BHs of 21 s, for ten cycles. The total scan time was 12 min and 20 s. The accelerated readout allowed the acquisition of PCASL data with better temporal resolution than previously used, without compromising the post-labeling delay. Elevated CBF was observed in most cerebral regions under hypercapnia, which was delayed with respect to the BH challenge. Significant statistical differences in CVR were obtained between the different models in GM (p < 0.0001), with ramp models yielding higher values than boxcar models and between the two tissues, GM and WM, with higher values in GM, in all the models (p < 0.0001). The adjustment of the ramp amplitude during each BH cycle did not improve the results compared with a ramp model with a constant amplitude equal to the mean PETCO2 change during the experiment.

Cerebrovascular reactivity (CVR) is defined as the ability of vessels to alter their caliber in response to vasoactive factors, by means of dilating or constricting, in order to increase or decrease regional cerebral blood flow (CBF). Importantly, CVR may provide a sensitive biomarker for pathologies where vasculature is compromised. Furthermore, the spatiotemporal dynamics of CVR observed in healthy subjects, reflecting regional differences in cerebral vascular tone and response, may also be important in functional MRI studies based on neurovascular coupling mechanisms. Assessment of CVR is usually based on the use of a vasoactive stimulus combined with a CBF measurement technique. Although transcranial Doppler ultrasound has been frequently used to obtain global flow velocity measurements, MRI techniques are being increasingly employed for obtaining CBF maps. For the vasoactive stimulus, vasodilatory hypercapnia is usually induced through the manipulation of respiratory gases, including the inhalation of increased concentrations of carbon dioxide. However, most of these methods require an additional apparatus and complex setups, which not only may not be well-tolerated by some populations but are also not widely available. For these reasons, strategies based on voluntary breathing fluctuations without the need for external gas challenges have been proposed. These include the task-based methodologies of breath holding and paced deep breathing, as well as a new generation of methods based on spontaneous breathing fluctuations during resting-state. Despite the multitude of alternatives to gas challenges, existing literature lacks definitive conclusions regarding the best practices for the vasoactive modulation and associated analysis protocols. In this work, we perform an extensive review of CVR mapping techniques based on MRI and CO2 variations without gas challenges, focusing on the methodological aspects of the breathing protocols and corresponding data analysis. Finally, we outline a set of practical guidelines based on generally accepted practices and available data, extending previous reports and encouraging the wider application of CVR mapping methodologies in both clinical and academic MRI settings.

Functional magnetic resonance imaging for presurgical brain mapping enables neurosurgeons to identify viable tissue near a site of operable pathology which might be at risk of surgery-induced damage. However, focal brain pathology (e.g., tumors) may selectively disrupt neurovascular coupling while leaving the underlying neurons functionally intact. Such neurovascular uncoupling can result in false negatives on brain activation maps thereby compromising their use for surgical planning. One way to detect potential neurovascular uncoupling is to map cerebrovascular reactivity using either an active breath-hold challenge or a passive resting-state scan. The equivalence of these two methods has yet to be fully established, especially at a voxel level of resolution. To quantitatively compare breath-hold and resting-state maps of cerebrovascular reactivity, we first identified threshold settings that optimized coverage of gray matter while minimizing false responses in white matter. When so optimized, the resting-state metric had moderately better gray matter coverage and specificity. We then assessed the spatial correspondence between the two metrics within cortical gray matter, again, across a wide range of thresholds. Optimal spatial correspondence was strongly dependent on threshold settings which if improperly set tended to produce statistically biased maps. When optimized, the two CVR maps did have moderately good correspondence with each other (mean accuracy of 73.6%). Our results show that while the breath-hold and resting-state maps may appear qualitatively similar they are not quantitatively identical at a voxel level of resolution.

Postmastectomy radiotherapy (PMRT) has been shown to improve the overall survival for invasive breast cancer patients. However, it represents a challenging treatment geometry and individualized planning strategies with complex field arrangements are usually adopted to decrease radiotoxicity to heart and lungs. Automated treatment planning has the potential to improve plan quality consistency and planning efficiency. Herein, we describe the application of the Pinnacle3 Autoplanning engine as a valuable technological resource able to allow the treatment of challenging patients theoretically unfit for radiotherapy for major cardiac and pulmonary comorbidities. Treatment was planned for three left-sided chest wall and regional lymph-nodes postmastectomy breast cancer patients. A deep inspiration breath-hold (DIBH) technique was used aiming to reduce the OARs irradiation. Three manually generated plans (hybrid-IMRT (HMRT), hybrid-VMAT (HVMAT) and full VMAT (MP-VMAT) and a fully automated plan created by the Autoplanning engine (AP-VMAT) were optimized in order to ensure a safe radiation therapy to the patients. The plans were evaluated based on planning target volumes (PTVs) coverage, dose homogeneity index (HI), conformity index (CN), dose to organs at risk (OARs) and normal tissue complication probabilities (NTCPs) of pericarditis, long term mortality and pneumonitis. Despite the use of deep moderated breath-hold, all human-driven plans failed to reach the stringent dose objectives for OARs. All plans provided an optimal coverage for chest wall and lymph-nodal area. AP-VMAT delivered the lowest mean dose to the heart (3.4 to 4.9 Gy) and ipsilateral lung (7.5 to 12.5 Gy) reporting the lowest NTCP for pneumonitis (

International audience; The physiopathology consequences of hypoxia during breath-hold diving are a matter of debate. Adenosine (AD), an ATP derivative, is suspected to be implicated in the adaptive cardiovascular response to apnea, because of its vasodilating and bradycardic properties, two clinical manifestations observed during voluntary apnea. The aim of this study was to evaluate the adenosine response to apnea-induced hypoxia in trained spearfishermen (SFM) who are used to perform repetitive dives for 4–5 h. Twelve SFM (11 men and 1 woman, mean age 41 ± 3 years, apnea experience: 18 ± 9 years) and 10 control (CTL) subjects (age 44 ± 7 years) were enrolled in the study. Subjects were asked to main a dry static apnea and stopped it when they began the struggle phase (average duration: SFM 120 ± 78 s, CTL 78 ± 12 s). Capillary blood samples were collected at baseline and immediately after the apnea and analyzed for standard parameters and adenosine blood concentration ([AD]b). Heart rate (HR), systolic (SBP), and diastolic (DBP) blood pressures were also recorded continuously during the apnea. During the apnea, an increase in SBP and DBP and a decrease in HR were observed in both SFM and CTL. At baseline, [AD]b was higher in SFM compared with CTL (1.05 ± 0.2 vs. 0.73 ± 0.11 μM, p < 0.01). [AD]b increased significantly at the end of the apnea in both groups, but the increase was significantly greater in SFM than in controls (+90.4 vs. +12%, p < 0.01). Importantly, in SFM, we also observed significant correlations between [AD]b and HR ( R = −0.8, p = 0.02), SpO 2 ( R = −0.69, p = 0.01), SBP ( R = −0.89, p = 0.02), and DBP ( R = −0.68, p = 0.03). Such associations were absent in CTL. The adenosine release during apnea was associated with blood O 2 saturation and cardiovascular parameters in trained divers but not in controls. These data therefore suggest that adenosine may play a major role in the adaptive cardiovascular response to apnea and could reflect the level of training.

Background: Successful cardiopulmonary resuscitation after drowning or avalanche is often attributed to hypothermia-induced decrease in metabolism, which adapts the oxygen demand to the amount supplied under cardiac compression. Four decades ago, we speculated if oxygen-sparing mechanisms like those found in marine mammals, may improve cerebral oxygenation during acute airway blockade in humans. We investigated hemodynamic changes during steady state ergometer cycling with intermittent periods of apnea and face immersion (AFI) in ice-cold water. During AFI, heart rate (HR) dropped by 58% whereas average blood velocity (ABV) determined by means of a Doppler ultrasound velocity meter (UNIDOP University of Oslo, Oslo, Norway) fell by 85% in the radial artery and rose by 67% in the vertebral artery. Similar changes occured in radial artery ABV, albeit more slowly, when the test subject only held his breath while cycling. When he breathed via a snorkel during face immersion, HR remained unchanged while radial artery ABV fell transiently and subsequently returned to its pre-immersion level. These findings later were confirmed by other investigators. Moreover, a recent study revealed that the seal even has a system for selective brain cooling during the dive. Conclusion: Our research has confirmed prioritized cerebral circulation during AFI in cold water. We hypothesize that these changes may improve brain oxygenation due both to greater blood flow and possibly also to faster brain cooling, as demonstrated in diving seals. Keywords: apnea, breath-hold, cardiopulmonary resuscitation, diving response, hypothermia

New Findings What is the central question of this study? How does deep breath-hold diving impact cardiopulmonary function, both acutely and over the subsequent 2.5 hours post-dive? What is the main finding and its importance? Breath-hold diving, to depths below residual volume, is associated with acute impairments in pulmonary gas exchange, which typically resolve within 2.5 hours. These data provide new insight into the behaviour of the lungs and pulmonary vasculature following deep diving. Breath-hold diving involves highly integrative and extreme physiological responses to both exercise and asphyxia during progressive elevations in hydrostatic pressure. Over two diving training camps (Study 1 and 2), 25 breath-hold divers (recreational to world- champion) performed 66 dives to 57 +/- 20 m (range: 18-117 m). Using the deepest dive from each diver, temporal changes in cardiopulmonary function were assessed using non-invasive pulmonary gas exchange (indexed via the O-2 deficit), ultrasound B-line scores, lung compliance and pulmonary haemodynamics at baseline and following the dive. Hydrostatically induced lung compression was quantified in Study 2, using spirometry and lung volume measurement, enabling each dive to be categorized by its residual volume (RV)-equivalent depth. From both studies, pulmonary gas exchange inefficiency - defined as an increase in O-2 deficit - was related to the depth of the dive (r(2 )= 0.345 ; P < 0.001), with dives associated with lung squeeze symptoms exhibiting the greatest deficits. In Study 1, although B-lines doubled from baseline (P = 0.027), cardiac output and pulmonary artery systolic pressure were unchanged post-dive. In Study 2, dives with lung compression to

Available online 6 March 2021. Performing a BOLD functional MRI (fMRI) acquisition during breath-hold (BH) tasks is a non-invasive, robust method to estimate cerebrovascular reactivity (CVR). However, movement and breathing-related artefacts caused by the BH can substantially hinder CVR estimates due to their high temporal collinearity with the effect of interest, and attention has to be paid when choosing which analysis model should be applied to the data. In this study, we evaluate the performance of multiple analysis strategies based on lagged general linear models applied on multi- echo BOLD fMRI data, acquired in ten subjects performing a BH task during ten sessions, to obtain subject-specific CVR and haemodynamic lag estimates. The evaluated approaches range from conventional regression models, i.e. including drifts and motion timecourses as nuisance regressors, applied on single-echo or optimally-combined data, to more complex models including regressors obtained from multi-echo independent component analysis with different grades of orthogonalization in order to preserve the effect of interest, i.e. the CVR. We compare these models in terms of their ability to make signal intensity changes independent from motion, as well as the reliability as measured by voxelwise intraclass correlation coefficients of both CVR and lag maps over time. Our results reveal that a conservative independent component analysis model applied on the optimally-combined multi-echo fMRI signal offers the largest reduction of motion-related effects in the signal, while yielding reliable CVR amplitude and lag estimates, although a conventional regression model applied on the optimally-combined data results in similar estimates. This work demonstrates the usefulness of multi-echo based fMRI acquisitions and independent component analysis denoising for precision mapping of CVR in single subjects based on BH paradigms, fostering its potential as a clinically-viable neuroimaging tool for individual patients. It also proves that the way in which data-driven regressors should be incorporated in the analysis model is not straight-forward due to their complex interaction with the BH-induced BOLD response. This research was supported by the European Union’s Horizon 2020 research and innovation program ( Marie Sk ł odowska-Curie grant agreement No. 713673 ), a fellowship from La Caixa Foundation (ID 100010434 , fellowship code LCF/BQ/IN17/11620063 ), the Spanish Ministry of Economy and Competitiveness ( Ramon y Cajal Fellowship, RYC-2017- 21845 ), the Spanish State Research Agency (BCBL “Severo Ochoa ”excellence accreditation, SEV- 2015-490 ), the Basque Govern- ment ( BERC 2018-2021 and PIBA_2019_104 ), the Spanish Ministry of Science, Innovation and Universities (MICINN; PID2019-105520GB-100 and FJCI-2017-31814 ), and the Eunice Kennedy Shriver National Insti- tute of Child Health and Human Development of the National Institutes of Health under award number K12HD073945 .

Highlights • A new protocol was developped to prolong deep inspiration breath-holds. • Multiple prolonged breath-holds are achievable with minimal side effects. • DIBH was prolonged to 3 min using HFNO and hyperventilation in breast cancer patients., Background and purpose Deep inspiration breath-hold is an established technique to reduce heart dose during breast cancer radiotherapy. However, modern breast cancer radiotherapy techniques with lymph node irradiation often require long beam-on times of up to 5 min. Therefore, the combination with deep inspiration breath-hold (DIBH) becomes challenging. A simple support technique for longer duration deep inspiration breath-hold (L-DIBH), feasible for daily use at the radiotherapy department, is required to maximize heart sparing. Materials and methods At our department, a new protocol for multiple L-DIBH of at least 2 min and 30 s was developed on 32 healthy volunteers and validated on 8 breast cancer patients during radiotherapy treatment, using a pragmatic process of iterative development, including all major stakeholders. Each participant performed 12 L-DIBHs, on 4 different days. Different methods of pre-oxygenation and voluntary hyperventilation were tested, and scored on L-DIBH duration, ease of use, and comfort. Results Based on 384 L-DIBHs from 32 healthy volunteers, voluntary hyperventilation for 3 min whilst receiving high-flow nasal oxygen at 40 L/min was the most promising technique. During validation, the median L-DIBH duration in prone position of 8 breast cancer patients improved from 59 s without support to 3 min and 9 s using the technique (p

Background: FMRI signal amplitude can change during stimulus presentation due to underlying neural function and hemodynamic responses limiting the accuracy of fMRI in pre-surgical planning. To account for these changes in fMRI activation signal, we used breath-hold tasks to mimic hemodynamic changes in brain tumor subjects and scaled the activation response. Methods: Motor and/or language fMRI was performed in 21 subjects with brain tumor. A breath-hold task was also performed in these subjects to obtain the hemodynamic response changes independent of neural changes. The task activation signals were calibrated on a voxel wise basis for all the subjects. Direct cortical stimulation was used to verify the scaled results of task-based fMRI. Results: After scaling for the hemodynamic response function (HRF) on a voxel wise basis, the spatial extent of the scaled activation was more clustered together and appeared to minimize false positives. Similarly, accounting for the underlying canonical HRF, the percentage increase of active voxels after scaling had lower standard non-deviation suggesting that the activation response across voxels were more similar. Conclusion: Although preliminary in nature, this study suggests that the variation in hemodynamic changes can be calibrated using breath-hold in brain tumor subjects and can also be used for other clinical cases where the underlying HRF has been altered.

This study investigated the impact of repeated-sprint (RS) training with voluntary hypoventilation at low lung volume (VHL) on RS ability (RSA) and on performance in a 30-15 intermittent fitness test (30-15IFT). Over 4 weeks, 17 basketball players included eight sessions of straight-line running RS and RS with changes of direction into their usual training, performed either with normal breathing (CTL, n = 8) or with VHL (n = 9). Before and after the training, athletes completed a RSA test (12 × 30-m, 25-s rest) and a 30-15IFT. During the RSA test, the fastest sprint (RSAbest), time-based percentage decrement score (RSASdec), total electromyographic intensity (RMS), and spectrum frequency (MPF) of the biceps femoris and gastrocnemius muscles, and biceps femoris NIRS-derived oxygenation were assessed for every sprint. A capillary blood sample was also taken after the last sprint to analyse metabolic and ionic markers. Cohen's effect sizes (ES) were used to compare group differences. Compared with CTL, VHL did not clearly modify RSAbest, but likely lowered RSASdec (VHL: −24.5% vs. CTL: −5.9%, group difference: −19.8%, ES −0.44). VHL also lowered the maximal deoxygenation induced by sprints ([HHb]max; group difference: −2.9%, ES −0.72) and enhanced the reoxygenation during recovery periods ([HHb]min; group difference: −3.6%, ES −1.00). VHL increased RMS (group difference: 18.2%, ES 1.28) and maintained MPF toward higher frequencies (group difference: 9.8 ± 5.0%, ES 1.40). These changes were concomitant with a lower potassium (K+) concentration (group difference: −17.5%, ES −0.67), and the lowering in [K+] was largely correlated with RSASdec post-training in VHL only (r = 0.66, p < 0.05). However, VHL did not clearly alter PO2, hemoglobin, lactate and bicarbonate concentration and base excess. There was no difference between group velocity gains for the 30-15IFT (CTL: 6.9% vs. VHL: 7.5%, ES 0.07). These results indicate that RS training combined with VHL may improve RSA, which could be relevant to basketball player success. This gain may be attributed to greater muscle reoxygenation, enhanced muscle recruitment strategies, and improved K+ regulation to attenuate the development of muscle fatigue, especially in type-II muscle fibers.

Background Imaging of the lung by MRI is challenging due to the intrinsic low proton density and rapid T2* relaxation. MRI methods providing lung parenchyma and function are in demand. Purpose To investigate the feasibility of two���dimensional ultrashort echo���time (2D UTE) imaging for lung function assessment. Study Type Prospective. Population Eleven healthy volunteers. Field Strength/Sequence 3T, 2D tiny golden angle UTE (2D���tyUTE). Assessment The applicability of breath���hold (BH) and self���gated (SG) 2D���tyUTE for quantification of the lung parenchyma signal���to���noise ratio (SNR), proton fraction (fP), fractional ventilation (FV), and perfusion (f) was investigated. Dependencies on repetition time (BHS/I1/I2) and respiratory phase (expiration [EX], inspiration [IN]) were investigated and compared between smokers and nonsmokers. Statistical Tests Analysis of variance (ANOVA), Kendell's W. Results Significant differences of SNR (EX: 10.98 �� 3.19(BHS), 14.58 �� 3.89(BHI1), 17.59 �� 4.92(BHI2), 11.00 �� 5.42(SG); IN: 7.17 �� 2.07(BHS), 9.51 �� 2.37(BHI1), 10.49 �� 2.33(BHI2), 10.00 �� 4.14(SG)) (P, publishedVersion

(SaO2)To facilitate recovery from hypoxia, many freedivers use a breathing method called "hook breathing" (HB) after diving, involving an interrupted exhale to build up intrapulmonary pressure. Some divers experience a delay in recovery of arterial oxygen saturation (SaO2) after diving, interpreted as symptoms of mild pulmonary edema, and facilitated recovery may be especially important in this group to avoid hypoxic "blackout." We examined the influence of HB on recovery of (SaO2) in freedivers with slow recovery (SR) and fast recovery (FR) of (SaO2) after deep "free immersion" (FIM) apnea dives to 30 m depth. Twenty-two male freedivers, with a mean (SD) personal best in the discipline FIM of 57(26) m, performed two 30 m deep dives, one followed by HB and one using normal breathing (NB) during recovery, at different days and weighted order. (SaO2) and heart rate (HR) were measured via pulse oximetry during recovery. The SR group (n = 5) had a faster (SaO2) recovery using HB, while the FR group (n = 17) showed no difference between breathing techniques. At 105 s, the SR group reached a mean (SD) SaO(2) of 95(5)% using HB, while using NB, their (SaO2) was 87(5)% (p < 0.05), and 105-120 s after surfacing(SaO2) was higher with HB (p < 0.05). In SR subjects, the average time needed to reach 95% (SaO2) with HB was 60 s, while it was 120 s at NB (p < 0.05). HR was similar in the SR group, while it was initially elevated at HB in the FR group (p < 0.05). We conclude that HB efficiently increases (SaO2) recovery in SR individuals, but not in the FR group. The proposed mechanism is that increased pulmonary pressure with HB will reverse any pulmonary edema and facilitate oxygen uptake in divers with delayed recovery., Funding Agencies:Centro Superior de Estudios Universitarios La Salle (Madrid) Swedish Centre for Research in Sports (CIF) Mid Sweden University

Technical freediving can be defined as freediving augmented by the use of oxygen-enriched gases or oxygen before, during, or after a freedive. As a result of these techniques, breath-hold divers can visit and enjoy underwater wrecks, reefs, and other diving locations previously located at depths unreachable to apnea divers. By pre-breathing oxygen-enriched gases in conjunction with hyperventilation—which decreases the partial pressure of carbon dioxide (PCO2)—the technical freediver now has additional oxygen to facilitate aerobic respiration during the dive. In addition, pre-breathing oxygen decreases tissue nitrogen tensions, which limits inert gas loading and decreases the risk of decompression sickness (DCS). Finally, this technique decreases PCO2, which diminishes the urge to breathe. Consequently, a diver may be able to dive longer before critical hypoxia or hypercarbia forces an ascent. Technical freediving can also be complemented by the use of a diver propulsion vehicle to increase the speed of descent and ascent and minimize exertion. The techniques of technical freediving may be associated with increased risks in central nervous system oxygen toxicity, DCS, and arterial gas embolism. As the boundaries of apnea diving continue to expand, there will be considerable opportunities to investigate the physiological limits of the human body and to determine the safest methodologies to practice this evolving discipline.

We developed a training protocol based on Intrapulmonary Percussive Ventilation in order to prolong breath-hold while nearly suppressing the thorax motion. This protocol allowed ten subjects to achieve a 20-minutes-breath-hold, while reducing the residual surface motion to 1 mm around its mean position for more than 95% of the breath-hold duration.

Breath-hold divers train to minimize their oxygen consumption to improve their apneic performance. Dietary nitrate has been shown to reduce the oxygen cost in a variety of situations, and our aim was to study its effect on arterial oxygen saturation (SaO2) after dynamic apnea (DYN) performance. Fourteen healthy male apnea divers (aged 33 ± 11 years) received either 70 mL of concentrated nitrate-rich beetroot juice (BR) or placebo (PL) on different days. At 2.5 h after ingesting the juice, they were asked to perform 2 × 75 m DYN dives in a pool with 4.5-min recovery between dives. Each dive started after 2-min countdown and without any warm-up apneas, hyperventilation, or lung packing. SaO2 and heart rate were measured via pulse oximetry for 90 s before and after each dive. Mean SaO2 nadir values after the dives were 83.4 ± 10.8% with BR and 78.3 ± 11.0% with PL (P < 0.05). At 20-s post-dive, mean SaO2 was 86.3 ± 10.6% with BR and 79.4 ± 10.2% with PL (P < 0.05). In conclusion, BR juice was found to elevate SaO2 after 75-m DYN. These results suggest an oxygen conserving effect of dietary nitrate supplementation, which likely has a positive effect on maximal apnea performance. First published: 31 March 2016

Age and apolipoprotein E (APOE) e4 genotype are two of the strongest known risk factors for sporadic Alzheimer's disease (AD). Neuroimaging has shown hemodynamic response changes with age, in asymptomatic carriers of the APOE e4 allele, and in AD. In this study, we aimed to characterize and differentiate age- and APOE gene-specific hemodynamic changes to breath-hold and visual stimulation. A further aim was to study whether these responses were modulated by 3-day intake of nitrate, a nitric oxide (NO) source. The study was designed as a randomized, double-blinded, placebo-controlled crossover study, and the study cohort comprised 41 APOE e4 carriers (e3/e4 or e4/e4 genotype) and 40 non-carriers (e3/e3 genotype) aged 30–70 years at enrollment. The participants underwent two scanning sessions, each preceded by ingestion of sodium nitrate or sodium chloride (control). During functional magnetic resonance imaging (fMRI) sessions, participants performed two concurrent tasks; a breath-hold task to probe cerebrovascular reactivity and a visual stimulation task to evoke functional hyperemia, respectively. We found that the blood oxygenation level dependent (BOLD) hemodynamic response to breath-hold was altered in APOE e4 carriers relative to non-carriers. Mid-aged (50–60 years of age) e4 carriers exhibited a significantly increased peak time relative to mid-aged e3 carriers, and peak time for younger (30–40 years of age) e4 carriers was significantly shorter than that of mid-aged e4 carriers. The response width was significantly increased for e4 carriers. The response peak magnitude significantly decreased with age. For the visual stimulation task, we found age-related changes, with reduced response magnitude with age but no significant effect of APOE allele type. We found no effect of nitrate ingestion on BOLD responses evoked by the breath-hold and visual stimulation tasks. The APOE gene-dependent response to breath-hold may reflect NO-independent differences in vascular function., Highlights • Age and APOE e4 genotype are two of the strongest known risk factors for sporadic Alzheimer’s disease. • We characterized and differentiated age- and APOE gene-specific hemodynamic changes to breath-hold and visual stimulation. • We found altered temporal dynamics of BOLD responses to breath-hold in APOE e4 carriers relative to non-carriers. • We found differential age-related changes in BOLD responses to breath-hold across APOE types. • We found age-related changes in BOLD responses to visual stimulation.

The relationship between cognitive function and breath-holding time is in need of further investigation. We aim to determine whether cognitive mobile games (CMG) are sensitive enough to assess the link between cognition and breath-holding time in non-trained subjects. Thirty-one healthy subjects participated in this study. A set of 3 short CMG: Must Sort (response control), Rush Back (attention, working memory) and True Color (mental flexibility, inhibition) was used. Apneic time was recorded in three different conditions: Total Lung Capacity (TLC): 88 ± 35 s, Functional Residual Capacity (FRC): 49 ± 17 s, and Residual Volume (RV): 32 ± 14 s. In males, breath-holding time at RV was correlated with True Color (r = 0.48) and Rush Back (r = 0.65) and at TLC with True Color (r = 0.45). In women, breath-holding time at TLC and FRC was inversely correlated with Must Sort (r = -0.59 and r = -0.49 respectively). Males and females appeared to differ in their use of cognitive resources during different breath-holding conditions., info:eu-repo/semantics/published

Purpose: The purpose of this study was to evaluate patient-related non-dosimetric predictors of cardiac sparing with the use of deep inspiration breath-hold (DIBH) in patients with left-sided breast cancer undergoing irradiation (RT).Materials and Methods: We retrospectively reviewed charts and treatment plans of one-hundred and three patients with left-sided breast cancer. All patients had both free-breathing (FB) and DIBH (with body surface tracking) plans available. (MHD) and V4 (heart volume receiving at least 4 Gy) were extracted from dose volume histograms. Fisher's exact and Chi-square tests were used to identify predictors of reductions in MHD and V4 after DIBH.Results: One-hundred and three patients were identified and most underwent mastectomy. MHD and V4 decreased significantly in DIBH plans (0.74 ± 0.25 Gy vs. 1.72 ± 0.98 Gy, p < 0.0001 for MHD; 4 ± 4.98 cc vs. 20.79 ± 18.2 cc, p < 0.0001 for V4). Body mass index (BMI), smoking and timing of CT simulation (spring/winter vs. summer/fall) were significant predictors of reduction in MHD whereas BMI, field size, chemotherapy, axillary dissection, and timing of CT simulation predicted reduction in V4. On multivariate analysis, BMI, and timing of CT simulation remained significant predictors of the heart-sparing effect of DIBH.Conclusions: In the setting of limited resources, identifying patients who will benefit the most from DIBH is extremely important. Prior studies have identified multiple dosimetric predictors of cardiac sparing and hereby we identified new non-dosimetric factors such as BMI and timing of treatments.

An advanced technique for multiple breath-hold volumetric modulated arc therapy (VMAT) has been proposed under fluoroscopic image guidance with a fiducial marker implanted close to a tumor. The marker coordinates on a digitally reconstructed radiography image at a gantry start angle, under a planned breath-hold condition, were transferred to the fluoroscopic image window. Then, a reference lateral line passing through the planned breath-hold marker position was drawn on the fluoroscopic image. Additional lateral lines were further added on both sides of the reference line with a distance of 3 mm as a tolerance limit for the breath-hold beam delivery. Subsequently, the patient was asked to breathe in slowly under fluoroscopy. Immediately after the marker position on the fluoroscopic image moved inside the tolerance range, the patient was asked to hold the breath and the VMAT beam was delivered. During the beam delivery, the breath-hold status was continuously monitored by checking if the deviation of the marker position exceeded the tolerance limit. As long as the marker stayed within the tolerance range, a segmented VMAT delivery continued for a preset period of 15 to 30 seconds depending on the breath-hold capability of each patient. As soon as each segmented delivery was completed, the beam interrupt button was pushed; subsequently, the patient was asked for free breathing. This procedure was repeated until all the segmented VMAT beams were delivered. A lung tumor case is reported here as an initial study. The proposed technique may be clinically advantageous for treating respiratory moving tumors including lung tumor, liver cancer, and other abdominal cancers.

Functional MRI (fMRI) is well-established for the study of brain function in healthy populations, although its clinical application has proven more challenging. Specifically, cerebrovascular reactivity (CVR), which allows the assessment of the vascular response that serves as the basis for fMRI, has been shown to be reduced in healthy aging as well as in a range of diseases, including chronic stroke. However, the timing of when this occurs relative to the stroke event is unclear. We used a breath-hold fMRI task to evaluate CVR across gray matter in a group of acute stroke patients (, Highlights • Breath-holding can be used to assess the validity of fMRI in stroke patients. • Vascular reactivity, estimated by breath-hold fMRI, was greatest in young controls. • Acute stroke patients and age-matched controls had similar vascular reactivity. • Modeling the breath-hold response on an individual basis can improve results.

FMRI BOLD responses to changes in neural activity are influenced by the reactivity of the vasculature. By complementing a task-related BOLD acquisition with a vascular reactivity measure obtained through breath-holding or hypercapnia, this unwanted variance can be statistically reduced in the BOLD responses of interest. Recently, it has been suggested that vascular reactivity can also be estimated using a resting state scan.\ud \ud This study aimed to compare three breath-hold based analysis approaches (block design, sine–cosine regressor and CO2 regressor) and a resting state approach (CO2 regressor) to measure vascular reactivity. We tested BOLD variance explained by the model and repeatability of the measures. Fifteen healthy participants underwent a breath-hold task and a resting state scan with end-tidal CO2 being recorded during both. Vascular reactivity was defined as CO2-related BOLD percent signal change/mm Hg change in CO2.\ud \ud Maps and regional vascular reactivity estimates showed high repeatability when the breath-hold task was used. Repeatability and variance explained by the CO2 trace regressor were lower for the resting state data based approach, which resulted in highly variable measures of vascular reactivity.\ud \ud We conclude that breath-hold based vascular reactivity estimations are more repeatable than resting-based estimates, and that there are limitations with replacing breath-hold scans by resting state scans for vascular reactivity assessment.

The trigeminocardiac reflex (TCR) has previously been described in the literature as a reflexive response of bradycardia, hypotension, and gastric hypermotility seen upon mechanical stimulation in the distribution of the trigeminal nerve. The diving reflex (DR) in humans is characterized by breath-holding, slowing of the heart rate, reduction of limb blood flow and a gradual rise in the mean arterial blood pressure. Although the two reflexes share many similarities, their relationship and especially their functional purpose in humans have yet to be fully elucidated. In the present review, we have tried to integrate and elaborate these two phenomena into a unified physiological concept. Assuming that the TCR and the DR are closely linked functionally and phylogenetically, we have also highlighted the significance of these reflexes in humans.

If, as postulated, the end of the steady state phase (φ2) of cardiovascular responses to apnoea corresponds to the physiological breaking point, then we may hypothesize that φ2 should become visible if exercise apnoeas are performed in pure oxygen. We tested this hypothesis on 9 professional divers by means of continuous recording of blood pressure (BP), heart rate (fH), stroke volume (QS), and arterial oxygen saturation (SpO2) during dry maximal exercising apnoeas in ambient air and in oxygen. Apnoeas lasted 45.0 ± 16.9 s in air and 77.0 ± 28.9 s in oxygen (p

Blood oxygenation level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) is a widely used technique to map brain function, and to monitor its recovery after stroke. Since stroke has a vascular etiology, the neurovascular coupling between cerebral blood flow and neural activity may be altered, resulting in uncertainties when interpreting longitudinal BOLD signal changes. The purpose of this study was to demonstrate the feasibility of using a recently validated breath-hold task in patients with stroke, both to assess group level changes in cerebrovascular reactivity (CVR) and to determine if alterations in regional CVR over time will adversely affect interpretation of task-related BOLD signal changes. Three methods of analyzing the breath-hold data were evaluated. The CVR measures were compared over healthy tissue, infarcted tissue and the peri-infarct tissue, both sub-acutely (∼2 weeks) and chronically (∼4 months). In this cohort, a lack of CVR differences in healthy tissue between the patients and controls indicates that any group level BOLD signal change observed in these regions over time is unlikely to be related to vascular alterations. CVR was reduced in the peri-infarct tissue but remained unchanged over time. Therefore, although a lack of activation in this region compared with the controls may be confounded by a reduced CVR, longitudinal group-level BOLD changes may be more confidently attributed to neural activity changes in this cohort. By including this breath-hold-based CVR assessment protocol in future studies of stroke recovery, researchers can be more assured that longitudinal changes in BOLD signal reflect true alterations in neural activity. Hum Brain Mapp 36:1755–1771, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

The use of radiation therapy has been increasing over recent years for the treatment of hepatocellular carcinoma (HCC). Proton beam therapy (PBT) has emerged as a promising treatment option for HCC patients due to its dosimetric advantages of sparing more normal liver tissue from radiation at low to moderate doses compared to photon-based treatments while still delivering high doses of radiation to tumors. The PBT therapy may be particularly beneficial in high-risk HCC cirrhotic patients with large, bulky tumors and/or vascular invasion complicated by surrounding perfusion abnormalities. We present a case of a 62-year-old male with an unresectable 13 cm diffusely infiltrative HCC tumor with main portal vein invasion and elevated alpha-feta protein (AFP) of 37,200 that was intolerant of standard sorafenib treatment. He was treated with hypofractionated PBT to 67.5 GyE in 15 fractions using a novel combination of simultaneously integrated boost intensity modulated proton therapy (SIB-IMPT), breath hold technique, and functional liver imaging with technetium-99m [99mTc] sulfur colloid single-photon emission computed tomography (SPECT/CT) to assist in the differentiation of tumor and normal liver. He had a complete radiographic and biochemical response by AFP normalization by seven months post-treatment without evidence of radiation hepatotoxicity.

Purpose/Objective Proton therapy is a highly conformal way to treat cancer. For the treatment of moving targets, scanned proton therapy delivery is a challenge, as it is sensitive to motion. The use of breath hold mitigates motion effects. Due to the treatment delivery over several fractions with delivery times extending the feasible breath hold duration, high reproducibility of breath holds is required. Active Breathing Control (ABC) is used to perform breath holds with controlled volumes. We investigated whether the lung anatomy is as reproducible as lung volumes under ABC, to consider ABC for scanned proton treatments. Material/Methods For five representative volunteers (3 male, 2 female, age: 25-58, BMI: 19 – 29) MR imaging was performed during ABC at two separate fractions. The image voxel size was 0.7x0.7x3.0 mm3. Each fraction consisted of four subsequent breath holds, resulting in a total of eight MRIs per volunteer. The interval between fractions was 1-4 weeks, keeping the same positioning. The intra-fraction reproducibility of the lung anatomy during breath hold was investigated, by comparing the MRI of the first breath hold with the three other MRIs of the same session. The inter-fraction anatomical reproducibility was investigated by comparing the first breath hold MRI of the first session with the four MRIs during the second session. To avoid any influence of setup variation, first a global rigid image registration was performed. Then the lung volume was semi-automatically segmented to define a region of interest for the deformable image registration (DIR). DIR was performed using Mirada RTx v1.2 (Mirada Medical, Ltd.), with a DIR grid resolution of 3.5x2x3 mm3. The deformation vector fields were analyzed using MATLAB v2014b. Magnitudes of the deformation vectors were calculated and combined for all five volunteers. The lung volumes were divided into six segments, to analyze the anatomical displacements on a local level. A boxplot showing the intra- and inter-fraction displacements with a schematic view of the six segments can be seen in figure 1. Results The lung volumes for all breath holds varied by 2% within and 7% between fractions. Looking at all five volunteers, up to 2 mm median intra- and inter-fraction displacements were found for all lung segments. The anatomical reproducibility decreased towards the caudal regions. Inter-fraction displacements were larger than intra-fractional displacements. Maximum displacements (99.3% of the magnitude vectors) reached 6 mm intra-fractionally and did not exceed 8 mm inter-fractionally. Conclusion While the lung volume differences were insignificant, relevant anatomical displacements were found. Moreover, a trend of increased displacements over time could be seen. ABC mitigates motion to some extent. Nevertheless, the remaining reproducibility uncertainties need to be considered during scanned proton therapy treatments. As next step, we aim to include this knowledge in a model to estimate their dosimetric influence for scanning proton therapy.

Purpose/Objective Proton therapy is a highly conformal way to treat cancer. For the treatment of moving targets, scanned proton therapy delivery is a challenge, as it is sensitive to motion. The use of breath hold mitigates motion effects. Due to the treatment delivery over several fractions with delivery times extending the feasible breath hold duration, high reproducibility of breath holds is required. Active Breathing Control (ABC) is used to perform breath holds with controlled volumes. We investigated whether the lung anatomy is as reproducible as lung volumes under ABC, to consider ABC for scanned proton treatments. Material/Methods For five representative volunteers (3 male, 2 female, age: 25-58, BMI: 19 – 29) MR imaging was performed during ABC at two separate fractions. The image voxel size was 0.7x0.7x3.0 mm3. Each fraction consisted of four subsequent breath holds, resulting in a total of eight MRIs per volunteer. The interval between fractions was 1-4 weeks, keeping the same positioning. The intra-fraction reproducibility of the lung anatomy during breath hold was investigated, by comparing the MRI of the first breath hold with the three other MRIs of the same session. The inter-fraction anatomical reproducibility was investigated by comparing the first breath hold MRI of the first session with the four MRIs during the second session. To avoid any influence of setup variation, first a global rigid image registration was performed. Then the lung volume was semi-automatically segmented to define a region of interest for the deformable image registration (DIR). DIR was performed using Mirada RTx v1.2 (Mirada Medical, Ltd.), with a DIR grid resolution of 3.5x2x3 mm3. The deformation vector fields were analyzed using MATLAB v2014b. Magnitudes of the deformation vectors were calculated and combined for all five volunteers. The lung volumes were divided into six segments, to analyze the anatomical displacements on a local level. A boxplot showing the intra- and inter-fraction displacements with a schematic view of the six segments can be seen in figure 1. Results The lung volumes for all breath holds varied by 2% within and 7% between fractions. Looking at all five volunteers, up to 2 mm median intra- and inter-fraction displacements were found for all lung segments. The anatomical reproducibility decreased towards the caudal regions. Inter-fraction displacements were larger than intra-fractional displacements. Maximum displacements (99.3% of the magnitude vectors) reached 6 mm intra-fractionally and did not exceed 8 mm inter-fractionally. Conclusion While the lung volume differences were insignificant, relevant anatomical displacements were found. Moreover, a trend of increased displacements over time could be seen. ABC mitigates motion to some extent. Nevertheless, the remaining reproducibility uncertainties need to be considered during scanned proton therapy treatments. As next step, we aim to include this knowledge in a model to estimate their dosimetric influence for scanning proton therapy.

Purpose/Objective The treatment of moving targets with scanning proton beams is challenging. By controlling lung volumes, Active Breathing Control (ABC) assists breath-holding for motion mitigation. The delivery of proton treatment fractions often exceeds feasible breath-hold durations, requiring high breath-hold reproducibility. Therefore, we investigated dosimetric consequences of anatomical reproducibility uncertainties in the lung under ABC, evaluating robustness of scanned proton treatments during breath-hold. Material/Methods T1-weighted MRIs of five volunteers were acquired during ABC, simulating image acquisition during four subsequent breath-holds within one treatment fraction. Deformation vector fields obtained from these MRIs were used to deform 95% inspiration phase CTs of 3 randomly selected non-small-cell lung cancer patients (Figure 1). Per patient, an intensity-modulated proton plan was recalculated on the 3 deformed CTs, to assess the dosimetric influence of anatomical breath-hold inconsistencies. Results Dosimetric consequences were negligible for patient 1 and 2 (Figure 1). Patient 3 showed a decreased volume (95.2%) receiving 95% of the prescribed dose for one deformed CT. The volume receiving 105% of the prescribed dose increased from 0.0% to 9.9%. Furthermore, the heart volume receiving 5 Gy varied by 2.3%. Figure 2 shows dose volume histograms for all relevant structures in patient 3. Conclusion Based on the studied patients, our findings suggest that variations in breath-hold have limited effect on the dose distribution for most lung patients. However, for one patient, a significant decrease in target coverage was found for one of the deformed CTs. Therefore, further investigation of dosimetric consequences from intra-fractional breath-hold uncertainties in the lung under ABC is needed.

Purpose/Objective The treatment of moving targets with scanning proton beams is challenging. By controlling lung volumes, Active Breathing Control (ABC) assists breath-holding for motion mitigation. The delivery of proton treatment fractions often exceeds feasible breath-hold durations, requiring high breath-hold reproducibility. Therefore, we investigated dosimetric consequences of anatomical reproducibility uncertainties in the lung under ABC, evaluating robustness of scanned proton treatments during breath-hold. Material/Methods T1-weighted MRIs of five volunteers were acquired during ABC, simulating image acquisition during four subsequent breath-holds within one treatment fraction. Deformation vector fields obtained from these MRIs were used to deform 95% inspiration phase CTs of 3 randomly selected non-small-cell lung cancer patients (Figure 1). Per patient, an intensity-modulated proton plan was recalculated on the 3 deformed CTs, to assess the dosimetric influence of anatomical breath-hold inconsistencies. Results Dosimetric consequences were negligible for patient 1 and 2 (Figure 1). Patient 3 showed a decreased volume (95.2%) receiving 95% of the prescribed dose for one deformed CT. The volume receiving 105% of the prescribed dose increased from 0.0% to 9.9%. Furthermore, the heart volume receiving 5 Gy varied by 2.3%. Figure 2 shows dose volume histograms for all relevant structures in patient 3. Conclusion Based on the studied patients, our findings suggest that variations in breath-hold have limited effect on the dose distribution for most lung patients. However, for one patient, a significant decrease in target coverage was found for one of the deformed CTs. Therefore, further investigation of dosimetric consequences from intra-fractional breath-hold uncertainties in the lung under ABC is needed.

Purpose/ObjectiveProton therapy is a highly conformal way to treat cancer. For the treatment of moving targets, scanned proton therapy delivery is a challenge, as it is sensitive to motion. The use of breath hold mitigates motion effects. Due to the treatment delivery over several fractions with delivery times extending the feasible breath hold duration, high reproducibility of breath holds is required. Active Breathing Control (ABC) is used to perform breath holds with controlled volumes. We investigated whether the lung anatomy is as reproducible as lung volumes under ABC, to consider ABC for scanned proton treatments.Material/MethodsFor five representative volunteers (3 male, 2 female, age: 25-58, BMI: 19 – 29) MR imaging was performed during ABC at two separate fractions. The image voxel size was 0.7x0.7x3.0 mm3. Each fraction consisted of four subsequent breath holds, resulting in a total of eight MRIs per volunteer. The interval between fractions was 1-4 weeks, keeping the same positioning. The intra-fraction reproducibility of the lung anatomy during breath hold was investigated, by comparing the MRI of the first breath hold with the three other MRIs of the same session. The inter-fraction anatomical reproducibility was investigated by comparing the first breath hold MRI of the first session with the four MRIs during the second session. To avoid any influence of setup variation, first a global rigid image registration was performed. Then the lung volume was semi-automatically segmented to define a region of interest for the deformable image registration (DIR). DIR was performed using Mirada RTx v1.2 (Mirada Medical, Ltd.), with a DIR grid resolution of 3.5x2x3 mm3. The deformation vector fields were analyzed using MATLAB v2014b. Magnitudes of the deformation vectors were calculated and combined for all five volunteers. The lung volumes were divided into six segments, to analyze the anatomical displacements on a local level. A boxplot showing the intra- and inter-fraction displacements with a schematic view of the six segments can be seen in figure 1.ResultsThe lung volumes for all breath holds varied by 2% within and 7% between fractions. Looking at all five volunteers, up to 2 mm median intra- and inter-fraction displacements were found for all lung segments. The anatomical reproducibility decreased towards the caudal regions. Inter-fraction displacements were larger than intra-fractional displacements. Maximum displacements (99.3% of the magnitude vectors) reached 6 mm intra-fractionally and did not exceed 8 mm inter-fractionally. ConclusionWhile the lung volume differences were insignificant, relevant anatomical displacements were found. Moreover, a trend of increased displacements over time could be seen. ABC mitigates motion to some extent. Nevertheless, the remaining reproducibility uncertainties need to be considered during scanned proton therapy treatments. As next step, we aim to include this knowledge in a model to estimate their dosimetric influence for scanning proton therapy.

Cerebrovascular reactivity (CVR) can be mapped using BOLD fMRI to provide a clinical insight into vascular health that can be used to diagnose cerebrovascular disease. Breath-holds are a readily accessible method for producing the required arterial CO2 increases but their implementation into clinical studies is limited by concerns that patients will demonstrate highly variable performance of breath-hold challenges. This study assesses the repeatability of CVR measurements despite poor task performance, to determine if and how robust results could be achieved with breath-holds in patients. Twelve healthy volunteers were scanned at 3T. Six functional scans were acquired, each consisting of 6 breath-hold challenges (10, 15, or 20 s duration) interleaved with periods of paced breathing. These scans simulated the varying breath-hold consistency and ability levels that may occur in patient data. Uniform ramps, time-scaled ramps, and end-tidal CO2 data were used as regressors in a general linear model in order to measure CVR at the grey matter, regional, and voxelwise level. The intraclass correlation coefficient (ICC) quantified the repeatability of the CVR measurement for each breath-hold regressor type and scale of interest across the variable task performances. The ramp regressors did not fully account for variability in breath-hold performance and did not achieve acceptable repeatability (ICC 0.4). Further analysis of intra-subject CVR variability across the brain (ICCspatial and voxelwise correlation) supported the use of end-tidal CO2 data to extract robust whole-brain CVR maps, despite variability in breath-hold performance. We conclude that the incorporation of end-tidal CO2 monitoring into scanning enables robust, repeatable measurement of CVR that makes breath-hold challenges suitable for routine clinical practice., Highlights • Cerebrovascular reactivity can be measured despite poor breath-hold performance. • Measuring end-tidal CO2 accounts for varying breath-hold ability and consistency. • Breath-holds can provide CVR maps with “excellent” repeatability. • Breath-holding is a robust tool for assessing vascular health in patient studies.