Novel Application of MRI Technique Combined with Flow-Through Cell Dissolution Apparatus as Supportive Discriminatory Test for Evaluation of Controlled Release Formulations

Dissolution studies cannot distinguish phenomena occurring inside the dosage forms when studying formulation with similar dissolution profiles—such formulations can behave differently when considering their physical changes. The application of flow-through dissolution apparatus integrated with magnetic resonance imaging (MRI) system for discriminative evaluation of controlled release dosage forms with similar dissolution profiles was presented. Hydrodynamically balanced systems (HBS) containing l-dopa and various grades hydroxypropyl methylcelluloses were prepared. The dissolution studies of l-dopa were performed at high field (4.7 T) MR system with MR-compatible flow-through cell. MRI was done with 0.14 × 0.14 × 1-mm spatial resolution and temporal resolution of 10 min to record changes of HBS parameters during dissolution in 0.1 M HCl. Structural and geometrical changes were evaluated using the following parameters: total area of HBS cross-section, its Feret’s diameter, perimeter and circularity, area of hydrogel layer, and “dry core” area. While the dissolution profiles of l-dopa were similar, the image analysis revealed differences in the structural and geometrical changes of the HBS. The mechanism of drug release from polymeric matrices is a result of synergy of several different phenomena occurring during dissolution and may differ between formulations, yet giving similar dissolution profiles. A multivariate analysis was performed to create a model taking into account dissolution data, data from MRI, information about chemical structure, and polymer viscosity. It provided a single model for all the formulations which was confirmed to be competent. The presented method has merit as a potential Process Analytical Technology tool.     

In phantom evaluation of targeting accuracy in MRI-based brain radiosurgery

PurposeTo determine the targeting accuracy of brain radiosurgery when planning procedures employing different MRI and MRI + CT combinations are adopted.Materials and methodA new phantom, the BrainTool, has been designed and realized to test image co-registration and targeting accuracy in a realistic anatomical situation. The phantom was created with a 3D printer and materials that mimic realistic brain MRI and CT contrast using a model extracted from a synthetic MRI study of a human brain. Eight markers distributed within the BrainTool provide for assessment of the accuracy of image registrations while two cavities that host an ionization chamber are used to perform targeting accuracy measurements with an iterative cross-scan method. Two procedures employing 1.5 T MRI-only or a combination of MRI (taken with 1.5 T or 3 T scanners) and CT to carry out Gamma Knife treatments were investigated. As distortions can impact targeting accuracy, MR images were preliminary evaluated to assess image deformation extent using GammaTool phantom.ResultsMR images taken with both scanners showed average and maximum distortion of 0.3 mm and 1 mm respectively. The marker distances in co-registered images resulted below 0.5 mm for both MRI scans. The targeting mismatches obtained were 0.8 mm, 1.0 mm and 1.2 mm for MRI-only and MRI + CT (1,5T and 3 T), respectively.ConclusionsProcedures using a combination of MR and CT images provide targeting accuracies comparable to those of MRI-only procedures. The BrainTool proved to be a suitable tool for carrying out co-registration and targeting accuracy of Gamma Knife brain radiosurgery treatments.     

Design of a multimodal fibers optic system for small animal optical imaging

Small animals optical imaging systems are widely used in pre-clinical research to image in vivo the bio-distribution of light emitting probes using fluorescence or bioluminescence modalities. In this work we presented a set of simulated results of a novel small animal optical imaging module based on a fibers optics matrix, coupled with a position sensitive detector, devoted to acquire bioluminescence and Cerenkov images. Simulations were performed using GEANT 4 code with the GAMOS architecture using the tissue optics plugin. Results showed that it is possible to image a 30 × 30 mm region of interest using a fiber optics array containing 100 optical fibers without compromising the quality of the reconstruction. The number of fibers necessary to cover an adequate portion of a small animal is thus quite modest. This design allows integrating the module with magnetic resonance (MR) in order to acquire optical and MR images at the same time. A detailed model of the mouse anatomy, obtained by segmentation of 3D MRI images, will improve the quality of optical 3D reconstruction.     

Magnetic resonance imaging for the study of ovarian follicles in the mouse

Additional tools to analyze follicle development would be highly advantageous because current methods require sacrifice of animals at specific times and time-consuming sectioning of tissues for histologic analysis. Magnetic resonance imaging (MRI) may provide a less involved, faster and more cost-effective method to analyze follicles in whole ovaries. Fixed ovaries were collected at different stages of the estrus cycle and after stimulation with gonadotrophins (24 and 48 h post pregnant mares serum (PMSG), and 10 and 24 h post human chorionic gonadotrophin (hCG)) with or without administration of the contrast agent gadodiamide. The MR images were generated using a vertical-bore, 11.7 Tesla MR system. Analysis of the MR images revealed large antral follicles in fixed ovaries with the oocyte and cumulus mass identifiable within preovulatory follicles. The use of gadodiamide had no impact on the quality of MR images obtained. The fixed ovaries were paraffin embedded, sectioned, and hematoxylin stained. Follicles were counted using the MR images and the histology sections. Preovulatory follicle numbers determined using MR images were comparable to those using histology; however counts of smaller follicles were inconsistent. MRI of gonadotrophin-stimulated ovaries in situ did not reveal discernable ovarian structures. Therefore, MRI is a useful tool for studying whole fixed ovaries leaving the ovary intact for additional analyses or for selection of samples based on morphology. The MRI is also useful for identifying preovulatory follicles, although analysis of smaller follicles is not possible, and thus the potential exists for cyst analysis in mouse models of polycystic ovarian syndrome (PCOS).     

Glioblastomas and brain metastases differentiation following an MRI texture analysis-based radiomics approach

PurposeTo evaluate the potential of 2D texture features extracted from magnetic resonance (MR) images for differentiating brain metastasis (BM) and glioblastomas (GBM) following a radiomics approach.MethodsThis retrospective study included 50 patients with BM and 50 with GBM who underwent T1-weighted MRI between December 2010 and January 2017. Eighty-eight rotation-invariant texture features were computed for each segmented lesion using six texture analysis methods. These features were also extracted from the four images obtained after applying the discrete wavelet transform (88 features × 4 images). Three feature selection methods and five predictive models were evaluated. A 5-fold cross-validation scheme was used to randomly split the study group into training (80 patients) and testing (20 patients), repeating the process ten times. Classification was evaluated computing the average area under the receiver operating characteristic curve. Sensibility, specificity and accuracy were also computed. The whole process was tested quantizing the images with different gray-level values to evaluate their influence in the final results.ResultsHighest classification accuracy was obtained using the original images quantized with 128 gray-levels and a feature selection method based on the p-value. The best overall performance was achieved using a support vector machine model with a subset of 32 features (AUC = 0.896 ± 0.067, sensitivity of 82% and specificity of 80%). Naïve Bayes and k-nearest neighbors models showed also valuable results (AUC ≈ 0.8) with a lower number of features (<13), thus suggesting that these models may be more generalizable when using external validations.ConclusionThe proposed radiomics MRI approach is able to discriminate between GBM and BM with high accuracy employing a set of 2D texture features, thus helping in the diagnosis of brain lesions in a fast and non-invasive way.     

The effectiveness of gadolinium MRI to improve target delineation for radiotherapy in hepatocellular carcinoma: A comparative study of rigid image registration techniques

To achieve consistent target delineation in radiotherapy for hepatocellular carcinoma (HCC), image registration between simulation CT and diagnostic MRI was explored.Twenty patients with advanced HCC were included. The median interval between MRI and CT was 11 days. CT was obtained with shallow free breathing and MRI at exhale phase. On each CT and MRI, the liver and the gross target volume (GTV) were drawn. A rigid image registration was taken according to point information of vascular bifurcation (Method[A]) and pixel information of volume of interest only including the periphery of the liver (Method[B]) and manually drawn liver (Method[C]). In nine cases with an indefinite GTV on CT, a virtual sphere was generated at the epicenter of the GTV. The GTV from CT (V_GTV[CT]) and MRI (V_GTV[MR]) and the expanded GTV from MRI (V_+GTV[MR]) considering geometrical registration error were defined. The underestimation (uncovered V[CT] by V[MR]) and the overestimation (excessive V[MR] by V[CT]) were calculated. Through a paired T-test, the difference between image registration techniques was analyzed.For method[A], the underestimation rates of V_GTV[MR] and V_+GTV[MR] were 16.4 ± 8.9% and 3.2 ± 3.7%, and the overestimation rates were 16.6 ± 8.7% and 28.4 ± 10.3%, respectively. For V_GTV[MR] and V_+GTV[MR], the underestimation rates and overestimation rates of method[A] were better than method[C]. The underestimation rates and overestimation rates of the V_GTV[MR] were better in method[B] than method[C]. By image registration and additional margin, about 97% of HCC could be covered. Method[A] or method[B] could be recommended according to physician preference.     

Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 Tesla MRI and pathology

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by cortical and spinal motor neuron dysfunction. Routine magnetic resonance imaging (MRI) studies have previously shown hypointense signal in the motor cortex on T(2)-weighted images in some ALS patients, however, the cause of this finding is unknown. To investigate the utility of this MR signal change as a marker of cortical motor neuron degeneration, signal abnormalities on 3T and 7T MR images of the brain were compared, and pathology was obtained in two ALS patients to determine the origin of the motor cortex hypointensity. Nineteen patients with clinically probable or definite ALS by El Escorial criteria and 19 healthy controls underwent 3T MRI. A 7T MRI scan was carried out on five ALS patients who had motor cortex hypointensity on the 3T FLAIR sequence and on three healthy controls. Postmortem 7T MRI of the brain was performed in one ALS patient and histological studies of the brains and spinal cords were obtained post-mortem in two patients. The motor cortex hypointensity on 3T FLAIR images was present in greater frequency in ALS patients. Increased hypointensity correlated with greater severity of upper motor neuron impairment. Analysis of 7T T(2)(*)-weighted gradient echo imaging localized the signal alteration to the deeper layers of the motor cortex in both ALS patients. Pathological studies showed increased iron accumulation in microglial cells in areas corresponding to the location of the signal changes on the 3T and 7T MRI of the motor cortex. These findings indicate that the motor cortex hypointensity on 3T MRI FLAIR images in ALS is due to increased iron accumulation by microglia.     

Localization of motor and speech cortex in the brain with functional magnetic resonance tomography

Functional magnetic resonance imaging (MRI) can be used for non-invasive mapping of cerebral cortex. The purpose of the study was evaluation of applicability of functional MRI for studies of neurosurgical patients. 32 volunteers (mean age 37.8 +/- 20.9 years) and 16 patients with brain tumors (mean age 36.2 +/- 24.2 years) were included in the study. Statistical analysis of the data obtained was performed. Activation maps were superimposed on anatomical images and discussed with neurosurgeons. Functional MRI studies were successful in localising the motor cortex and Broca's area in 89% of cases. In 69% of cases, results of the functional MRI influenced the patients' treatment.     

Applications cliniques de l’imagerie hybride TEP-IRM

This paper reports the results of a preliminary study evaluating the feasibility and performance of a first whole body hybrid PET/MR scanner allowing sequential acquisition of co-registered MR and PET images. Sixty-two patients underwent whole body PET/MR imaging immediately after a clinical PET/CT. The hybrid device consists of a 3T MR and a time-of-flight PET scanner sharing a single bed allowing sequential acquisition of co-registered MR and PET images. Imaging protocols included a whole body MR used for attenuation correction of PET followed by high-resolution diagnostic MR. Image analysis included visual identification of radiotracer uptake in tumors and measurement of standardized uptake values (SUV) in tumoral lesions and in normal organs. PET images acquired in the PET/MR with a delay of 85 ± 22 minutes (range 49–120 minutes) showed perfect correlation and identical diagnostic quality compared to PET/CT. In 42 patients (68%), additional high-resolution MR sequences were acquired for clinical diagnosis showing excellent quality without any visually detectable artifacts. SUV measurements of tumor lesions obtained after correction with MR attenuation maps showed an excellent correlation with PET/CT (R² = 0.89 and R² = 0.95 for mean and maximum tissue uptake respectively). Due to the delay between the two studies, changes in tracer uptake biodistribution of normal tissue were observed. Our preliminary data show that whole body PET/MR is clinically applicable in oncologic patients yielding a comparable diagnostic performance as PET/CT with respect to lesion detection and localization.     

Preliminary studies on the use of magnetic resonance imaging with Gd-DTPA to monitor ovarian function in subhuman primates

These studies were initiated to explore the use of magnetic resonance imaging (MRI) to investigate follicular growth in subhuman primates. Four adult cynomolgus monkeys received an i.v. injection of a magnetic resonance (MR) contrast agent, gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA), and ovaries were removed 1-20 min later. Gd-DTPA is an extracellular fluid marker that is readily detectable in MRI. Individual ovaries were imaged using a 3-in (7.62 cm) radiofrequency surface coil and a 1.5 Tesla magnet. MR images of these ovaries provided a high resolution visualization of follicles with diameters of 1 mm and greater. Results obtained with MRI were similar to hematoxylin/eosin-stained sections of the same ovaries photographed at low magnification. These results demonstrate that MRI provides excellent resolution of ovarian follicles in macaques and thus may be suitable to monitor follicular growth and atresia in this species.     

Molecular aspects of magnetic resonance imaging and spectroscopy

Magnetic resonance imaging (MRI) is a well known diagnostic tool in radiology that produces unsurpassed images of the human body, in particular of soft tissue. However, the medical community is often not aware that MRI is an important yet limited segment of magnetic resonance (MR) or nuclear magnetic resonance (NMR) as this method is called in basic science. The tremendous morphological information of MR images sometimes conceal the fact that MR signals in general contain much more information, especially on processes on the molecular level. NMR is successfully used in physics, chemistry, and biology to explore and characterize chemical reactions, molecular conformations, biochemical pathways, solid state material, and many other applications that elucidate invisible characteristics of matter and tissue. In medical applications, knowledge of the molecular background of MRI and in particular MR spectroscopy (MRS) is an inevitable basis to understand molecular phenomenon leading to macroscopic effects visible in diagnostic images or spectra. This review shall provide the necessary background to comprehend molecular aspects of magnetic resonance applications in medicine. An introduction into the physical basics aims at an understanding of some of the molecular mechanisms without extended mathematical treatment. The MR typical terminology is explained such that reading of original MR publications could be facilitated for non-MR experts. Applications in MRI and MRS are intended to illustrate the consequences of molecular effects on images and spectra.     

A model of using magnetic resonance imaging in osteoarticular tumor lesion in case of giant cell tumors

Fifty-eight patients with giant cell tumors (GCT) underwent a comprehensive radiation diagnosis involving X-ray study and magnetic resonance imaging (MRI). The obtained MR images indicated the high efficiency of this combination of radiation diagnostic techniques in solving the problems in the visualization of osteoarticular tumor lesions. GCT is characterized by well-known primary X-ray semiotics; MR images are also rather pathognomonic of these tumors and they illustrate the process of morphogenesis of these masses. MRI made it possible to solve the specific problems facing a physician (a radiation diagnostician), to determine the site, shape, sizes, volume, and local extent of a tumor, which permitted the planning of surgical treatment policy; to assess its results, to reveal possible inflammatory complications; and to visualize a local recurrence and on-going growth of a tumor, including the signs of GCT malignancy.     

MRI denoising using nonlocal neutrosophic set approach of Wiener filtering

In this paper, a new filtering method is presented to remove the Rician noise from magnetic resonance images (MRI) acquired using single coil MRI acquisition system. This filter is based on nonlocal neutrosophic set (NLNS) approach of Wiener filtering. A neutrosophic set (NS), a part of neutrosophy theory, studies the origin, nature, and scope of neutralities, as well as their interactions with different ideational spectra. Now, we apply the neutrosophic set into image domain and define some concepts and operators for image denoising. First, the nonlocal mean is applied to the noisy MRI. The resultant image is transformed into NS domain, described using three membership sets: true (T), indeterminacy (I) and false (F). The entropy of the neutrosophic set is defined and employed to measure the indeterminacy. The ω-Wiener filtering operation is used on T and F to decrease the set indeterminacy and to remove the noise. The experiments have been conducted on simulated MR images from Brainweb database and clinical MR images. The results show that the NLNS Wiener filter produces better denoising results in terms of qualitative and quantitative measures compared with other denoising methods, such as classical Wiener filter, the anisotropic diffusion filter, the total variation minimization and the nonlocal means filter. The visual and the diagnostic quality of the denoised image are well preserved.     

Development of Bifunctional Gadolinium-Labeled Superparamagnetic Nanoparticles (Gd-MnMEIO) for In Vivo MR Imaging of the Liver in an Animal Model

Liver tumors are common and imaging methods, particularly magnetic resonance imaging (MRI), play an important role in their non-invasive diagnosis. Previous studies have shown that detection of liver tumors can be improved by injection of two different MR contrast agents. Here, we developed a new contrast agent, Gd-manganese-doped magnetism-engineered iron oxide (Gd-MnMEIO), with enhancement effects on both T1- and T2-weighted MR images of the liver. A 3.0T clinical MR scanner equipped with transmit/receiver coil for mouse was used to obtain both T1-weighted spoiled gradient-echo and T2-weighted fast spin-echo axial images of the liver before and after intravenous contrast agent injection into Balb/c mice with and without tumors. After pre-contrast scanning, six mice per group were intravenously injected with 0.1 mmol/kg Gd-MnMEIO, or the control agents, i.e., Gd-DTPA or SPIO. The scanning time points for T1-weighted images were 0.5, 5, 10, 15, 20, 25, and 30 min after contrast administration. The post-enhanced T2-weighted images were then acquired immediately after T1-weighted acquisition. We found that T1-weighted images were positively enhanced by both Gd-DTPA and Gd-MnMEIO and negatively enhanced by SPIO. The enhancement by both Gd-DTPA and Gd-MnMEIO peaked at 0.5 min and gradually declined thereafter. Gd-MnMEIO (like Gd-DTPA) enhanced T1-weighted images and (like SPIO) T2-weighted images. Marked vascular enhancement was clearly visible on dynamic T1-weighted images with Gd-MnMEIO. In addition, the T2 signal was significantly decreased at 30 min after administration of Gd-MnMEIO. Whereas the effects of Gd-MnMEIO and SPIO on T2-weighted images were similar (p = 0.5824), those of Gd-MnMEIO and Gd-DTPA differed, with Gd-MnMEIO having a significant T2 contrast effect (p = 0.0086). Our study confirms the feasibility of synthesizing an MR contrast agent with both T1 and T2 shortening effects and using such an agent in vivo. This agent enables tumor detection and characterization in single liver MRI sections.     

Detection of eggs in the living white grub beetle Dasylepida ishigakiensis (Coleoptera: Scarabaeidae) by magnetic resonance imaging

The use of magnetic resonance imaging (MRI) as a tool for in vivo detection of eggs in living Dasylepida ishigakiensis Niijima et Kinoshita, a major pest of sugarcane, was explored using females with an ovary at different developmental stages. MRI measurements of beetles were performed at 13 °C to avoid motion artifacts on the MR images. Spin–lattice relaxation time-weighted images allowed the observation of eggs at short acquisition times (2 min, 8 s). By comparing MR images with dissection data, criteria for determining mature eggs in MR images were a clear circular or ellipsoidal shape surrounded by a relatively bright rim and a size typically larger than 1.3 mm in the minor axis. Although small oocytes could not be detected, females with a developed or undeveloped ovary could be clearly distinguished based on MR images. The possibility of confusing the digestive tract as eggs in a female with a less developed ovary can be eliminated using a proton density weighted image.     

Shape (but not volume) changes in the thalami in Parkinson disease

Background  

Recent pathological studies have suggested that thalamic degeneration may represent a site of non-dopaminergic degeneration in Parkinson's Disease (PD). Our objective was to determine if changes in the thalami could be non-invasively detected in structural MRI images obtained from subjects with Parkinson disease (PD), compared to age-matched controls.     

First-in-human imaging using a MR-compatible e4D ultrasound probe for motion management of radiotherapy

PurposeRespiration-induced tumor or organ positional changes can impact the accuracy of external beam radiotherapy. Motion management strategies are used to account for these changes during treatment. The authors report on the development, testing, and first-in-human evaluation of an electronic 4D (e4D) MR-compatible ultrasound probe that was designed for hands-free operation in a MR and linear accelerator (LINAC) environment.MethodsUltrasound components were evaluated for MR compatibility. Electromagnetic interference (EMI) shielding was used to enclose the entire probe and a factory-fabricated cable shielded with copper braids was integrated into the probe. A series of simultaneous ultrasound and MR scans were acquired and analyzed in five healthy volunteers.ResultsThe ultrasound probe led to minor susceptibility artifacts in the MR images immediately proximal to the ultrasound probe at a depth of <10 mm. Ultrasound and MR-based motion traces that were derived by tracking the salient motion of endogenous target structures in the superior-inferior (SI) direction demonstrated good concordance (Pearson correlation coefficients of 0.95–0.98) between the ultrasound and MRI datasets.ConclusionWe have demonstrated that our hands-free, e4D probe can acquire ultrasound images during a MR acquisition at frame rates of approximately 4 frames per second (fps) without impacting either the MR or ultrasound image quality. This use of this technology for interventional procedures (e.g. biopsies and drug delivery) and motion compensation during imaging are also being explored.     

Correction of inhomogeneous magnetic resonance images using multiscale retinex for segmentation accuracy improvement

The purpose of this study was to improve the accuracy of tissue segmentation on brain magnetic resonance (MR) images preprocessed by multiscale retinex (MSR), segmented with a combined boosted decision tree (BDT) and MSR algorithm (hereinafter referred to as the MSRBDT algorithm). Simulated brain MR (SBMR) T1-weighted images of different noise levels and RF inhomogeneities were adopted to evaluate the outcome of the proposed method; the MSRBDT algorithm was used to identify the gray matter (GM), white matter (WM), and cerebral-spinal fluid (CSF) in the brain tissues. The accuracy rates of GM, WM, and CSF segmentation, with spatial features (G, x, y, r, θ), were respectively greater than 0.9805, 0.9817, and 0.9871. In addition, images segmented with the MSRBDT algorithm were better than those obtained with the expectation maximization (EM) algorithm; brain tissue segmentation in MR images was significantly more precise. The proposed MSRBDT algorithm could be beneficial in clinical image segmentation.     

Validation of dose distribution computation on sCT images generated from MRI scans by Philips MRCAT

AimTo evaluate calculation of treatment plans based on synthetic-CT (sCT) images generated from MRI.BackgroundBecause of better soft tissue contrast, MR images are used in addition to CT images for radiotherapy planning. However, registration of CT and MR images or repositioning between scanning sessions introduce systematic errors, hence suggestions for MRI-only therapy. The lack of information on electron density necessary for dose calculation leads to sCT (synthetic CT) generation. This work presents a comparison of dose distribution calculated on standard CT and sCT.Materials and methods10 prostate patients were included in this study. CT and MR images were collected for each patient and then water equivalent (WE) and MRCAT images were generated. The radiation plans were optimized on CT and then recalculated on MRCAT and WE data. 2D gamma analysis was also performed.ResultsThe mean differences in the majority of investigated DVH points were in order of 1% up to 10%, including both MRCAT and WE dose distributions. Mean gamma pass for acceptance criteria 1%/1 mm were greater than 82.5%. Prescribed doses for target volumes and acceptable doses for organs at risk were met in almost all cases.ConclusionsThe dose calculation accuracy on MRCAT was not significantly compromised in the majority of clinical relevant DVH points. The introduction of MRCAT into practise would eliminate systematic errors, increase patients’ comfort and reduce treatment expenses. Institutions interested in MRCAT commissioning must, however, consider changes to established workflow.     

A novel framework for spatial normalization of dose distributions in voxel-based analyses of brain irradiation outcomes

PurposeTo devise a novel Spatial Normalization framework for Voxel-based analysis (VBA) in brain radiotherapy. VBAs rely on accurate spatial normalization of different patients’ planning CTs on a common coordinate system (CCS). The cerebral anatomy, well characterized by MRI, shows instead poor contrast in CT, resulting in potential inaccuracies in VBAs based on CT alone.MethodsWe analyzed 50 meningioma patients treated with proton-therapy, undergoing planning CT and T1-weighted (T1w) MRI. The spatial normalization pipeline based on MR and CT images consisted in: intra-patient registration of CT to T1w, inter-patient registration of T1w to MNI space chosen as CCS, doses propagation to MNI.The registration quality was compared with that obtained by Statistical Parametric Mapping software (SPM), used as benchmark. To evaluate the accuracy of dose normalization, the dose organ overlap (DOO) score was computed on gray matter, white matter and cerebrospinal fluid before and after normalization. In addition, the trends in the DOOs distribution were investigated by means of cluster analysis.ResultsThe registration quality was higher for the proposed method compared to SPM (p < 0.001). The DOO scores showed a significant improvement after normalization (p < 0.001). The cluster analysis highlighted 2 clusters, with one of them including the majority of data and exhibiting acceptable DOOs.ConclusionsOur study presents a robust tool for spatial normalization, specifically tailored for brain dose VBAs. Furthermore, the cluster analysis provides a formal criterion for patient exclusion in case of non-acceptable normalization results. The implemented framework lays the groundwork for future reliable VBAs in brain irradiation studies.