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Background Conventional air ionization chambers (ICs) exhibit ion recombination correction factors that deviate substantially from unity when irradiated with dose per pulse magnitudes higher than those used in conventional radiotherapy. This fact makes these devices unsuitable for the dosimetric characterization of beams in ultra-high dose per pulse as used for FLASH radiotherapy. Purpose We present the design, development, and characterization of an ultra-thin parallel plate IC that can be used in ultra-high dose rate (UHDR) deliveries with minimal recombination. Methods The charge collection efficiency (CCE) of parallel plate ICs was modeled through a numerical solution of the coupled differential equations governing the transport of charged carriers produced by ionizing radiation. It was used to find out the optimal parameters for the purpose of designing an IC capable of exhibiting a linear response with dose (deviation less than 1%) up to 10 Gy per pulse at 4 mu$\umu$s pulse duration. As a proof of concept, two vented parallel plate IC prototypes have been built and tested in different ultra-high pulse dose rate electron beams. Results It has been found that by reducing the distance between electrodes to a value of 0.25 mm it is possible to extend the dose rate operating range of parallel plate ICs to ultra-high dose per pulse range, at standard voltage of clinical grade electrometers, well into several Gy per pulse. The two IC prototypes exhibit behavior as predicted by the numerical simulation. One of the so-called ultra-thin parallel plate ionization chamber (UTIC) prototypes was able to measure up to 10 Gy per pulse, 4 mu$\umu$s pulse duration, operated at 300 V with no significant deviation from linearity within the uncertainties (ElectronFlash Linac, SIT). The other prototype was tested up to 5.4 Gy per pulse, 2.5 mu$\umu$s pulse duration, operated at 250 V with CCE higher than 98.6% (Metrological Electron Accelerator Facility, MELAF at Physikalisch-Technische Bundesanstalt, PTB). Conclusions This work demonstrates the ability to extend the dose rate operating range of ICs to ultra-high dose per pulse range by reducing the spacing between electrodes. The results show that UTICs are suitable for measurement in UHDR electron beams.

The free electron fraction is the fraction of electrons, produced inside the cavity of an ionization chamber after irradiation, which does not bind to gas molecules and thereby reaches the electrode as free electrons. It is a fundamental quantity to describe the recombination processes of an ionization chamber, as it generates a gap of positive charges compared to negative ones, which certainly will not undergo recombination.The free electron fraction depends on the specific chamber geometry, the polarizing applied voltage and the gas thermodynamic properties. Therefore, it is necessary to evaluate such fraction in an accurate and easy way for any measurement condition.In this paper, a simple and direct method for evaluating the free electron fraction of ionization chambers is proposed.We first model the capture process of the electrons produced inside an ionization chamber after the beam pulse; then we present a method to evaluate the free electron fraction based on simple measurements of collected charge, by varying the applied voltage. Finally, the results obtained using an Advanced Markus chamber irra-diated with a Flash Radiotherapy dedicated research Linac (ElectronFlash) to estimate the free electron fraction are presented.The proposed method allows the use of a conventional ionization chamber for measurements in ultra-high -dose -per-pulse (UHDP) conditions, up to values of dose -per-pulse at which the perturbation of the electric field due to the generated charge can be considered negligible.

Alzheimer’s disease (AD), the most common type of dementia, is an incurable brain disorder characterised by the progressive build-up of toxic amyloid-beta (Aβ) and tau protein aggregates. AD gradually inflicts cognitive functions of an individual such as memory, thinking, reasoning, and language by degrading synaptic function and the integrity of neuronal networks. It has been recently suggested that the efficacy of different brain-clearance systems like the glymphatic system (GS), involved in the removal of toxic waste and homeostatic balance, plays a key role in the pathology of AD. Moreover, the observed coupling between brain fluid movement and global brain activity implies that an alteration of the neuronal network integrity can impact brain fluid circulation throughout the brain and thereby the efficacy of the GS. Here, we investigated the dynamics of brain fluid circulation in Tet-Off APP (AD) mice, a mature-onset model of amyloidosis in which we have recently shown a deterioration of neuronal network integrity by resting-state fMRI. By utilizing dynamic contrast enhanced-MRI and gadoteric acid (Gd-DOTA) T1 contrast agent injected into the cisterna magna, we demonstrated that brain fluid exchange was significantly altered in 14-month-old AD mice compared to control littermates. More specifically, AD mice showed higher Gd-DOTA accumulation in areas proximal to the injection cite and computational modeling of time courses demonstrated significantly lower inflow time constants relative to the controls. Immunohistochemistry demonstrated abundant amyloid plaque burden in the forebrain of the AD group coinciding with extensive astrogliosis and microgliosis. The neuroinflammatory responses were also found in plaque-devoid regions, potentially impacting brain fluid circulation.

Purpose FLASH radiotherapy (RT) is an emerging technique in which beams with ultra-high dose rates (UH-DR) and dose per pulse (UH-DPP) are used. Commercially available active real-time dosimeters have been shown to be unsuitable in such conditions, due to severe response nonlinearities. In the present study, a novel diamond-based Schottky diode detector was specifically designed and realized to match the stringent requirements of FLASH-RT. Methods A systematic investigation of the main features affecting the diamond response in UH-DPP conditions was carried out. Several diamond Schottky diode detector prototypes with different layouts were produced at Rome Tor Vergata University in cooperation with PTW-Freiburg. Such devices were tested under electron UH-DPP beams. The linearity of the prototypes was investigated up to DPPs of about 26 Gy/pulse and dose rates of approximately 1 kGy/s. In addition, percentage depth dose (PDD) measurements were performed in different irradiation conditions. Radiochromic films were used for reference dosimetry. Results The response linearity of the diamond prototypes was shown to be strongly affected by the size of their active volume as well as by their series resistance. By properly tuning the design layout, the detector response was found to be linear up to at least 20 Gy/pulse, well into the UH-DPP range conditions. PDD measurements were performed by three different linac applicators, characterized by DPP values at the point of maximum dose of 3.5, 17.2, and 20.6 Gy/pulse, respectively. The very good superimposition of three curves confirmed the diamond response linearity. It is worth mentioning that UH-DPP irradiation conditions may lead to instantaneous detector currents as high as several mA, thus possibly exceeding the electrometer specifications. This issue was properly addressed in the case of the PTW UNIDOS electrometers. Conclusions The results of the present study clearly demonstrate the feasibility of a diamond detector for FLASH-RT applications.

FLASH radiation therapy is a novel technique combining ultra-high dose rates (UHDR) with very short treatment times to strongly decrease normal tissue toxicity while preserving the anti-tumoral effect. However, the radiobiological mechanisms and exact conditions for obtaining the FLASH-effect are still under investigation. There are strong indications that parameters defining the beam structure, such as dose per pulse, instantaneous dose rate and pulse repetition frequency (PRF) are of importance. UHDR irradiations therefore come with dosimetric challenges, including both dose assessment and temporal ones. In this work, a first characterization of 6 real-time point scintillating dosimeters with 5 phosphors (Al2O3:C,Mg; Y2O3:Eu; Al2O3:C; (C38H34P2)MnBr4 and (C38H34P2)MnCl4, was performed in an UHDR pulsed electron beam. The dose rate independence of the calibration was tested by calibrating the detector at conventional and UHDR. Dose rate dependence was observed, however, further investigation, including intermediate dose rates, is needed. Linearity of the response with dose was tested by varying the number of pulses and a linearity with R-2 > 0.9989 was observed up to at least 200 Gy. Dose per pulse linearity was investigated by variation of the pulse length and SSD. All point scintillators showed saturation effects up to some extent and the instantaneous dose rate dependence was confirmed. A PRF dependence was observed for the Al2O3:C,Mg and Al2O3:C- based point scintillators. This was expected as the luminescence decay time of these materials exceeds the inter-pulse time.

Radiotherapy (RT) is a fundamental tool in cancer treatment. Recent technological advances improved considerably radiotherapy techniques, allowing to obtain more precise, effective and most importantly safer treatments. However, RT is not without risks. Ionizing radiation also injures healthy cells, and there is a limit to the amount of radiation an area of the body can safely receive over the course of a lifetime. A new delivery method, called FLASH radiotherapy (FLASH-RT) has shown very promising results in in vivo studies, where a significant increase in healthy tissue sparing (FLASH effect) was observed. FLASH-RT consists in delivering the ionizing radiation therapy at dose rates much higher than the ones used in conventional radiotherapy (CONV-RT). Because of the novelty of this method, every aspect of FLASH-RT is under study, such as how the FLASH effect depends on therapy delivery parameters and what exactly are the underlining biological mechanisms. Nonetheless, dosimetry presents a challenge to overcome. The high dose rates cause significant saturation problems which render standard dosimetric equipment inadequate. Therefore, the development of online (active) dosimeters is a priority. In the short term this technology enables more efficient measurements in the experimental context, since it gives immediate feedback. In the long term it provides the basis for future studies on dosimetry in clinical practice. In this work we show the construction and characterization of online FLASH dosimeters based on scintillator materials used in integrating-mode. A GEANT4 based Monte Carlo simulation code is specifically developed to calculate the medium-equivalence correction. The simulation is validated with experimental measurements obtained with a full-fledged FLASH linear accelerator, which produces electron pulsed beams at very high dose per pulse. Measurements suggest that the proposed dosimeters have a linear response in a wide range of dose per pulse values up to 6 Gy/p, while moderate saturation can be observed up to 12.5 Gy/p.

Objective.The output of a deep learning (DL) auto-segmentation application should be reviewed, corrected if needed and approved before being used clinically. This verification procedure is labour-intensive, time-consuming and user-dependent, which potentially leads to significant errors with impact on the overall treatment quality. Additionally, when the time needed to correct auto-segmentations approaches the time to delineate target and organs at risk from scratch, the usability of the DL model can be questioned. Therefore, an automated quality assurance framework was developed with the aim to detect in advance aberrant auto-segmentations.Approach. Five organs (prostate, bladder, anorectum, femoral head left and right) were auto-delineated on CT acquisitions for 48 prostate patients by an in-house trained primary DL model. An experienced radiation oncologist assessed the correctness of the model output and categorised the auto-segmentations into two classes whether minor or major adaptations were needed. Subsequently, an independent, secondary DL model was implemented to delineate the same structures as the primary model. Quantitative comparison metrics were calculated using both models’ segmentations and used as input features for a machine learning classification model to predict the output quality of the primary model.Main results. For every organ, the approach of independent validation by the secondary model was able to detect primary auto-segmentations that needed major adaptation with high sensitivity (recall = 1) based on the calculated quantitative metrics. The surface DSC and APL were found to be the most indicated parameters in comparison to standard quantitative metrics for the time needed to adapt auto-segmentations.Significance. This proposed method includes a proof of concept for the use of an independent DL segmentation model in combination with a ML classifier to improve time saving during QA of auto-segmentations. The integration of such system into current automatic segmentation pipelines can increase the efficiency of the radiotherapy contouring workflow.

Ultra-High dose -per-pulse regimens (UHDP), necessary to trigger the "FLASH" effect, still pose serious challenges to dosimetry. Dosimetry plays a crucial role, both to significantly improve the accuracy of the radiobiological experiments necessary to fully understand the mechanisms underlying the effect and its dependencies on the beam parameters, and to be able to translate such effect into clinical practice. The standard ionization chamber in UHDP region is significantly affected by the effects of the electric field generated by the enormous density of charges produced by the dose pulse.This work describes the theory and the conceptual design of a gas chamber (the ALLS chamber) which overcomes the above-mentioned problems.

Cerebral vascular abnormalities can have a large impact on brain function and have been frequently detected as a comorbidity in various neuropathologies. The mouse is the most common pre-clinical animal model used to investigate neuropathologies and thus cerebral vascular atlases of this species are indispensable. In particular, an atlas derived from multiple animals and that can address inter-subject variability is still absent. The current study presents a mouse cerebral vascular atlas developed from MR 2D-TOF angiograms acquired from a relatively high number (N=21) of 12 weeks old male C57BL/6 mice. The vascular atlas we present depicts large arteries, veins and sinuses that are more spatially reliable across animals than smaller vessels. The atlas is available for download and contains multiple datasets: i) a cerebral vascular atlas; ii) a digital segmentation of large vessels (arteries and veins); iii) a high resolution T2 anatomical background aligned to the atlas; iv) a skeletonized vascular atlas; and v) a vascular graph model. We suggest that these components provide a very potent analysis tool for mouse fMRI data and that the atlas can be used as a template for multimodal brain imaging studies. To this end, we also demonstrate an explicit application of the atlas for the investigation of vascular influences in resting-state fMRI.

Introduction: Digitally reconstructed radiographs (DRRs) represent valuable patient-specific pretreatment training data for tumor tracking algorithms. However, using current rendering methods, the similarity of the DRRs to real X-ray images is limited, requires time-consuming measurements and/or are computationally expensive. In this study we present RealDRR, a novel framework for highly realistic and computationally efficient DRR rendering. Materials and methods: RealDRR consists of two components applied sequentially to render a DRR. First, a raytracer is applied for forward projection from 3D CT data to a 2D image. Second, a conditional Generative Adverserial Network (cGAN) is applied to translate the 2D forward projection to a realistic 2D DRR. The planning CT and CBCT projections from a CIRS thorax phantom and 6 radiotherapy patients (3 prostate, 3 brain) were split in training and test sets for evaluating the intra-patient, inter-patient and inter-anatomical region generalization performance of the trained framework. Several image similarity metrics, as well as a verification based on template matching, were used between the rendered DRRs and respective CBCT projections in the test sets, and results were compared to those of a current state-of-the-art DRR rendering method. Results: When trained on 800 CBCT projection images from two patients and tested on a third unseen patient from either anatomical region, RealDRR outperformed the current state-of-the-art with statistical significance on all metrics (two-sample t-test, p < 0.05). Once trained, the framework is able to render 100 highly realistic DRRs in under two minutes. Conclusion: A novel framework for realistic and efficient DRR rendering was proposed. As the framework requires a reasonable amount of computational resources, the internal parameters can be tailored to imaging systems and protocols through on-site training on retrospective imaging data. (C) 2020 Elsevier B.V. All rights reserved.

Background: Although effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent. Targeting a variety of MSassociated antigens by myelin antigen-presenting tolerogenic dendritic cells (tolDC) is a promising treatment strategy to re-establish tolerance in MS. Electroporation with mRNA encoding myelin proteins is an innovative technique to load tolDC with the full spectrum of naturally processed myelin-derived epitopes. Methods: In this study, we generated murine tolDC presenting myelin oligodendrocyte glycoprotein (MOG) using mRNA electroporation and we assessed the efficacy of MOG mRNA-electroporated tolDC to dampen pathogenic T cell responses in experimental autoimmune encephalomyelitis (EAE). For this, MOG35–55- immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α, 25-dihydroxyvitamin D3-treated tolDC electroporated with MOG-encoding mRNA. Mice were scored daily for signs of paralysis. At day 25, myelin reactivity was evaluated following restimulation of splenocytes with myelin-derived epitopes. Ex vivo magnetic resonance imaging (MRI) was performed to assess spinal cord inflammatory lesion load.Results: Treatment of MOG35–55-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG35–55- pulsed tolDC led to a stabilization of the EAE clinical score from the first administration onwards, whereas it worsened in mice treated with non-antigen-loaded tolDC or with vehicle only. In addition, MOG35–55-specific pro-inflammatory pathogenic T cell responses and myelin antigen epitope spreading were inhibited in the peripheral immune system of tolDC-treated mice. Finally, magnetic resonance imaging analysis of hyperintense spots along the spinal cord was in line with the clinical score. Conclusions: Electroporation with mRNA is an efficient and versatile tool to generate myelin-presenting tolDC that are capable to stabilize the clinical score in EAE. These results pave the way for further research into mRNA-electroporated tolDC treatment as a patient-tailored therapy for MS. This work was supported by the Methusalem Funding Program from the University of Antwerp, by an applied biomedical research project of the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWTTBM 140191), and by the Belgian Charcot Foundation. Furthermore, the authors received research funding from Roche Belgium. Judith Derdelinckx holds a PhD fellowship from the Research Foundation Flanders (FWO)

How do intrinsic brain dynamics interact with processing of external sensory stimuli? We sought new insights using functional magnetic resonance imaging to track spatiotemporal activity patterns at the whole brain level in lightly anesthetized mice, during both resting conditions and visual stimulation trials. Our results provide evidence that quasiperiodic patterns (QPPs) are the most prominent component of mouse resting brain dynamics. These QPPs captured the temporal alignment of anticorrelation between the default mode (DMN)- and task-positive (TPN)-like networks, with global brain fluctuations, and activity in neuromodulatory nuclei of the reticular formation. Specifically, the phase of QPPs prior to stimulation could significantly stratify subsequent visual response magnitude, suggesting QPPs relate to brain state fluctuations. This is the first observation in mice that dynamics of the DMN- and TPN-like networks, and particularly their anticorrelation, capture a brain state dynamic that affects sensory processing. Interestingly, QPPs also displayed transient onset response properties during visual stimulation, which covaried with deactivations in the reticular formation. We conclude that QPPs appear to capture a brain state fluctuation that may be orchestrated through neuromodulation. Our findings provide new frontiers to understand the neural processes that shape functional brain states and modulate sensory input processing.

Time-resolved 'dynamic' over whole-period 'static' analysis of low frequency (LF) blood-oxygen level dependent (BOLD) fluctuations provides many additional insights into the macroscale organization and dynamics of neural activity. Although there has been considerable advancement in the development of mouse resting state fMRI (rsfMRI), very little remains known about its dynamic repertoire. Here, we report for the first time the detection of a set of recurring spatiotemporal Quasi-Periodic Patterns (QPPs) in mice, which show spatial similarity with known resting state networks. Furthermore, we establish a close relationship between several of these patterns and the global signal. We acquired high temporal rsfMRI scans under conditions of low (LA) and high (HA) medetomidine-isoflurane anesthesia. We then employed the algorithm developed by Majeed etal. (2011), previously applied in rats and humans, which detects and averages recurring spatiotemporal patterns in the LF BOLD signal. One type of observed patterns in mice was highly similar to those originally observed in rats, displaying propagation from lateral to medial cortical regions, which suggestively pertain to a mouse Task-Positive like network (TPN) and Default Mode like network (DMN). Other QPPs showed more widespread or striatal involvement and were no longer detected after global signal regression (GSR). This was further supported by diminished detection of subcortical dynamics after GSR, with cortical dynamics predominating. Observed QPPs were both qualitatively and quantitatively determined to be consistent across both anesthesia conditions, with GSR producing the same outcome. Under LA, QPPs were consistently detected at both group and single subject level. Under HA, consistency and pattern occurrence rate decreased, whilst cortical contribution to the patterns diminished. These findings confirm the robustness of QPPs across species and demonstrate a new approach to study mouse LF BOLD spatiotemporal dynamics and mechanisms underlying functional connectivity. The observed impact of GSR on QPPs might help better comprehend its controversial role in conventional resting state studies. Finally, consistent detection of QPPs at single subject level under LA promises a step forward towards more reliable mouse rsfMRI and further confirms the importance of selecting an optimal anesthesia regime.