Analysis of Brain Magnetic Resonance Images: Voxel-Based Morphometry and Pattern Classification Approaches

This thesis aims to examine two types of elaboration techniques of brain magnetic resonance imaging (MRI) data: the voxel-based morphometry (VBM) and the support vector machine (SVM) approaches. While the VBM is a standard and well-established mass-univariate method, the SVM multivariate analysis has been rarely implemented to investigate brain MRI data. An improvement of our knowledge on the pattern classication approach is necessary to be achieved, both to assess its exploratory capability and to point out advantages and disadvantages with respect to the more largely used VBM approach. Despite these methods are potentially suitable to investigate a large variety of neurological and neuropsychiatric disorders, in the present study they have been employed with the purpose of detecting neuroanatomical and gender-related abnormalities in children with autism spectrum disorders (ASD). In fact, the dierences in the neuroanatomy of young children with ASD are an intriguing and still poor investigated issue. After a description of the physical principles of nuclear magnetic resonance and an overview of magnetic resonance imaging, we specied the two algorithms that represent the object of the current study: voxel-based morphometry and support vector machines classication methods. Hence, we described the theoretical principles they are based on, pointing out schemes and procedures employed to implement these analysis approaches. Then, we examined the application of VBM and SVM methods to an opportunely chosen sample of MRI data. A total of 152 structural MRI scans were selected. Specically, our dataset was composed by 76 ASD children and 76 matched controls in the 2-7 year age range. The images were preprocessed applying the SPM8 algorithm, based on the dieomorphic anatomical registration through exponentiated lie algebra (DARTEL) procedure. The resulting grey matter (GM) segments were analyzed by applying the conventional voxel-wise two-sample t-test VBM analysis and employing the stringent family-wise error (FWE) rate correction according to random gaussian elds theory. The same preprocessed GM segments were then analyzed using the SVM pattern classication approach, that presents the advantage of intrinsically taking into account interregional correlations. Moreover, this technique would allow investigations about the predictive value of structural MRI scans. In fact, the SVM classication capability can be quantied in terms of the area under the receiver operating characteristic curve (AUC). The leave-pair-out cross- validation protocol has been adopted to evaluate the classication performance. The recursive feature elimination (RFE) procedure has been implemented both to reduce the large number of features in the classication problem and to enhance the classication capability. The SVM-RFE allows also to localize the most discriminant voxels and to visualize them in a discrimination map. However, the pattern classication method was not employed to predict the class membership of undiagnosed subjects, but as a gure of merit allowing to determine an optimal threshold on the discrimination maps, where possible between-group structural dierences are encoded. With the aim of strengthening the SVM-based methods applied to brain data and to guarantee reliability and reproducibility of the results, we set up the following tests: 1. We evaluated the consistency among all discrimination maps, each obtained from one of the SVM leave-pair-out cross-validation steps, within the chosen range of number of retained features employed. 2. We assessed the dependency on the population of the training set within the cross- validation procedure. In this way we became able to check for the stability of our statistical results with respect to the number of subjects employed during the learning phase. Furthermore, we can evaluate the classication performances for dierent cross- validation schemes. Among the results we obtained, we found that SVMs applied to GM scans correctly discriminate ASD male and female individuals with respect to controls with an AUC above the 87% with a fraction of retained voxels in the 0.4-29% range. By choosing as operative point of the system that corresponding to the lower amount of signicant voxels (0.4% of the total number of voxels) we obtained a sensitivity of 82% and a specicity of 80%. The resulting discrimination maps showed some signicant regions where an excess of GM characterizes the ASD subjects with respect to the matched control group. These regions seemed to be consistent with those obtained from the VBM analysis, nevertheless the SVM analysis highlighted a larger number of interesting gender-specic discriminating regions. Hence, multivariate methods based on the SVM could contribute not only to distinguish ASD from control children, but also to disentangle the gender specicity of ASD brain alterations, consistently with respect to the mass-univariate approach. Achieving a better AUC could make possible to employ the pattern recognition approach not only to individuate brain regions discriminating between patients and controls, but also to predict the class membership of undiagnosed subjects, thus facilitating the early diagnosis of the ASD pathology

IN VIVO DOSIMETRY AND PRE-TREATMENT QA WITH GAFCHROMIC EBT3 IN RADIOTHERAPY

The development and the spreading of complex treatment modalities in radiotherapy, such as Intensity Modulated Radiation Therapy (IMRT), Stereotactic Radiosurgery (SRS), and Volumetric Modulated Arc Therapy (VMAT), have provided great achieving in reducing dose to healthy tissues and delivering radiation targeted for very specific lesions. On the other hand, these techniques are characterized by high dose gradients and considerable time and space variations of dose rate and beam fluence, leading to an increase of the complexity of treatment planning and delivery. For these reasons, more specific dosimetric solutions are necessary to the radiotherapy treatment verification and quality assurance (QA). Among the various types of dosimeters, at present GafChromic EBT3 films represent one of the most powerful tools to perform QA with high accuracy and measure absolute dose in radiotherapy. They have very high spatial resolution, weak energy dependence in a wide photon energy range, and no angular dependence. Furthermore, radiochromic films present the advantages of easy handling, being insensitive to room light, self-developing, and they can be digitalized using a common flatbed charge couple device (CCD) scanner. The characteristics of near-tissue equivalence, effective point of measurement very close to the clinically relevant and recommended depth for skin of 70 μm (ICRP 1991; ICRU 1985) and the possiblility of being cut and positioned at various locations on the patient, allow to use EBT3 film as in vivo dosimeter and evaluate skin dose during radiotherapy treatments. This thesis aims to describe the use of GafChromic EBT3 films for pre-treatment QA applying both single channel and multichannel methods, and to report and analyse skin dose measurements using radiochromic film as in vivo dosimeter. In first place, an overview of the main principles, characteristics and applications of radiochromic films and of flatbed scanner dosimetry is provided. Secondly, the setting out of the scanning protocol and the measurements and analyses performed to characterize the scanner behaviour with differently exposed films along many positions on the scanbed are described. Then, an account of the calibration measurements, performed both at Linac and in Plesio-Röntgen therapy, is given, focusing on fit analyses performed for single channel dosimetry with red color channel. Moreover, Linac calibration has been also performed with a method that combines green and blue channels data together (Fiandra et al. 2013; McCaw et al. 2011) and using multichannel dosimetry (Pérez Azorín et al. 2014). With the purpose of validating GafChromic film dosimetry method and investigating which of the EBT3 calibration approaches better responded to the range of doses commonly used in radiotherapy, some films irradiated at Linac with different standard fields have been compared with data measured through PTW 2D-Array 729. Afterwards, pre-treatment QA measurements have been performed with EBT3, and absolute dose maps have been compared with TPS calculations using γ-analysis (Low et al. 1998). Finally, in vivo measurements performed during radiotherapy treatments are described. Skin dose was evaluated on patients undergoing helical tomotherapy treatments for different pathologies, including head and neck and sarcoma. Moreover, measurements on patients with breast cancers treated at Linac both with 3D conformal radiotherapy (3D-CRT) and VMAT, and skin lesions treated with Plesio-Röntgen therapy have been considered. Then, in vivo measurements, analysed with GafChromic dosimetry, have been compared with TPS planned doses, investigating on factors possibly related to discrepances between expected and measured doses. If compared with the other calibration approaches, multichannel method resulted the most accurate in determining the absolute dose maps regarding both validation fields and pre-treatment QA measurements, leading to a mean value of 92% for the γ(3%, 3mm) local dose pass rate. In vivo measurements showed a good reproducibility, especially regarding measuremnts performed in tomotherapy with the application of thermoplastic masks, that lead to a more reliable repositioning of the film if compared with skin measurements performed on breast treatment at Linac. Furthermore, absolute percentage differences between EBT3 reading and TPS expected dose often were higher than 10%, confirming a higher uncertainty of TPS estimated dose in the first mm of skin

A subcortical network for implicit visuo-spatial attention:Implications for Parkinson's disease

Recent studies in humans and animal models suggest a primary role of the basal ganglia in the extraction of stimulus-value regularities, then exploited to orient attentional shift and build up sensorimotor memories. The tail of the caudate and the posterior putamen both receive early visual input from the superficial layers of the superior colliculus, thus forming a closed-loop. We portend that the functional value of this circuit is to manage the selection of visual stimuli in a rapid and automatic way, once sensory-motor associations are formed and stored in the posterior striatum. In Parkinson's Disease, the nigrostriatal dopamine depletion starts and tends to be more pronounced in the posterior putamen. Thus, at least some aspect of the visuospatial attention deficits observed since the early stages of the disease could be the behavioral consequences of a cognitive system that has lost the ability to translate high-level processing in stable sensorimotor memories. (C) 2021 The Authors. Published by Elsevier Ltd

Different Roles of α- and β-Branch Xanthophylls in Photosystem Assembly and Photoprotection

Xanthophylls (oxygenated carotenoids) are essential components of the plant photosynthetic apparatus, where they act in photosystem assembly, light harvesting, and photoprotection. Nevertheless, the specific function of individual xanthophyll species awaits complete elucidation. In this work, we analyze the photosynthetic phenotypes of two newly isolated Arabidopsis mutants in carotenoid biosynthesis containing exclusively alpha-branch (chy1chy2lut5) or beta-branch (chy1chy2lut2) xanthophylls. Both mutants show complete lack of qE, the rapidly reversible component of nonphotochemical quenching, and high levels of photoinhibition and lipid peroxidation under photooxidative stress. Both mutants are much more photosensitive than npq1lut2, which contains high levels of viola- and neoxanthin and a higher stoichiometry of light-harvesting proteins with respect to photosystem II core complexes, suggesting that the content in light-harvesting complexes plays an important role in photoprotection. In addition, chy1chy2lut5, which has lutein as the only xanthophyll, shows unprecedented photosensitivity even in low light conditions, reduced electron transport rate, enhanced photobleaching of isolated LHCII complexes, and a selective loss of CP26 with respect to chy1chy2lut2, highlighting a specific role of beta-branch xanthophylls in photoprotection and in qE mechanism. The stronger photosystem II photoinhibition of both mutants correlates with the higher rate of singlet oxygen production from thylakoids and isolated light-harvesting complexes, whereas carotenoid composition of photosystem II core complex was not influential. In depth analysis of the mutant phenotypes suggests that alpha-branch (lutein) and beta-branch (zeaxanthin, violaxanthin, and neoxanthin) xanthophylls have distinct and complementary roles in antenna protein assembly and in the mechanisms of photoprotection

One-class support vector machines identify the language and default mode regions as common patterns of structural alterations in young children with autism spectrum disorders

The identification of reliable brain endophenotypes of autism spectrum disorders (ASD) has been hampered to date by the heterogeneity in the neuroanatomical abnormalities detected in this condition. To handle the complexity of neuroimaging data and to convert brain images in informative biomarkers of pathology, multivariate analysis techniques based on Support Vector Machines (SVM) have been widely used in several disease conditions. They are usually trained to distinguish patients from healthy control subjects by making a binary classification. Here, we propose the use of the One-Class Classification (OCC) or Data Description method that, in contrast to two-class classification, is based on a description of one class of objects only. This approach, by defining a multivariate normative rule on one class of subjects, allows recognizing examples from a different category as outliers. We applied the OCC to 314 regional features extracted from brain structural Magnetic Resonance Imaging (MRI) scans of young children with ASD (21 males and 20 females) and control subjects (20 males and 20 females), matched on age [range: 22-72 months of age; mean = 49 months] and non-verbal intelligence quotient (NVIQ) [range: 31-123; mean = 73]. We demonstrated that a common pattern of features characterize the ASD population. The OCC SVM trained on the group of ASD subjects showed the following performances in the ASD vs. controls separation: the area under the receiver operating characteristic curve (AUC) was 0.74 for the male and 0.68 for the female population, respectively. Notably, the ASD vs. controls discrimination results were maximized when evaluated on the subsamples of subjects with NVIQ = 70, leading to AUC = 0.81 for the male and AUC = 0.72 for the female populations, respectively. Language regions and regions from the default mode network-posterior cingulate cortex, pars opercularis and pars triangularis of the inferior frontal gyrus, and transverse temporal gyrus-contributed most to distinguishing individuals with ASD from controls, arguing for the crucial role of these areas in the ASD pathophysiology. The observed brain patterns associate preschoolers with ASD independently of their age, gender and NVIQ and therefore they are expected to constitute part of the ASD brain endophenotype

Use of contrast-enhanced ultrasonography for the characterization of tumor thrombi in seven dogs

Some neoplasia-such as adrenal and thyroid glands tumors-have been associated with "tumor thrombi" both in humans and dogs. The detection and characterization of these venous tumor thrombi is important for both surgical planning and prognosis. In human medicine, contrast-enhanced ultrasonography (CEUS) is considered an accurate diagnostic technique for differentiating malignant from benign portal vein thrombosis in hepatocellular carcinomas. Data regarding the characteristics of tumor thrombi in dogs are currently lacking. Therefore, the aim of this study was to assess the feasibility of CEUS for the characterization of malignant venous thrombosis in dogs. On the basis of our results, CEUS appeared to be useful in the detection of malignant intravascular invasion; contrast uptake of the thrombus was present in all cases. In addition, CEUS may clearly detect newly formed vessels within the thrombus, and arterial-phase enhancement and washout in the venous phase were the main features in malignant thrombosis in our dogs. As CEUS is an easy to perform, noninvasive technique, its application in the detection of malignant thrombosis in dogs may be used to improve the diagnosis in oncological canine patients. Tumors of adrenal and thyroid glands have been associated with vascular invasions-so-called tumor thrombi, both in humans and dogs. The detection and characterization of venous thrombi is an important diagnostic step in patients with primary tumors for both surgical planning and prognosis. The aim of this study was to describe the use of contrast-enhanced ultrasonography (CEUS) for the characterization of tumor thrombi. Dogs with tumor thrombus who underwent bi-dimensional ultrasound (B-mode US) and CEUS were included. Seven dogs were enrolled in this retrospective case series. On B-mode US, all thrombi were visualized, and vascular distension and thrombus-tumor continuity were seen in three and two cases, respectively. On color Doppler examination, all thrombi were identified, seemed non-occlusive and only two presented vascularity. On CEUS, arterial-phase enhancement and washout in the venous phase were observed in all cases. Non-enhancing areas were identified in the tumor thrombi most likely representing non-vascularized tissue that could potentially be embolized in the lungs after fragmentation of the tumor thrombi. On the basis of these preliminary study, CEUS appeared to be useful for the characterization of malignant intravascular invasion

A quadruple mutant of Arabidopsis reveals a β-carotene hydroxylation activity for LUT1/CYP97C1 and a regulatory role of xanthophylls on determination of the PSI/PSII ratio

<p>Abstract</p> <p>Background</p> <p>Xanthophylls are oxygenated carotenoids playing an essential role as structural components of the photosynthetic apparatus. Xanthophylls contribute to the assembly and stability of light-harvesting complex, to light absorbance and to photoprotection. The first step in xanthophyll biosynthesis from α- and β-carotene is the hydroxylation of ε- and β-rings, performed by both non-heme iron oxygenases (CHY1, CHY2) and P450 cytochromes (LUT1/CYP97C1, LUT5/CYP97A3). The Arabidopsis triple <it>chy1chy2lut5 </it>mutant is almost completely depleted in β-xanthophylls.</p> <p>Results</p> <p>Here we report on the quadruple <it>chy1chy2lut2lut5 </it>mutant, additionally carrying the <it>lut2 </it>mutation (affecting lycopene ε-cyclase). This genotype lacks lutein and yet it shows a compensatory increase in β-xanthophylls with respect to <it>chy1chy2lut5 </it>mutant. Mutant plants show an even stronger photosensitivity than <it>chy1chy2lut5</it>, a complete lack of qE, the rapidly reversible component of non-photochemical quenching, and a peculiar organization of the pigment binding complexes into thylakoids. Biochemical analysis reveals that the <it>chy1chy2lut2lut5 </it>mutant is depleted in Lhcb subunits and is specifically affected in Photosystem I function, showing a deficiency in PSI-LHCI supercomplexes. Moreover, by analyzing a series of single, double, triple and quadruple Arabidopsis mutants in xanthophyll biosynthesis, we show a hitherto undescribed correlation between xanthophyll levels and the PSI-PSII ratio. The decrease in the xanthophyll/carotenoid ratio causes a proportional decrease in the LHCII and PSI core levels with respect to PSII.</p> <p>Conclusions</p> <p>The physiological and biochemical phenotype of the <it>chy1chy2lut2lut5 </it>mutant shows that (i) LUT1/CYP97C1 protein reveals a major β-carotene hydroxylase activity <it>in vivo </it>when depleted in its preferred substrate α-carotene; (ii) xanthophylls are needed for normal level of Photosystem I and LHCII accumulation.</p

Inter-method reliability of brainstem volume segmentation algorithms in preschoolers with ASD

Introduction: The brainstem has a potential role in the pathophysiology of Autism Spectrum Disorders (ASD) (Roger, 2013). In particular, alterations in brainstem volume and their relationship with sensory/motor abnormalities have been suggested (Trevarthen & Delafield-Butt, 2013). However, the findings in volume alterations of subjects with ASD with respect to matched controls are controversial both in adults and children cohorts (Hardan, 2001; Piven, 1992; Kleiman, 1992). Moreover, the contribution to variability of brainstem volume measurements performed with different automated methods is still unclear. Methods: T1-weighted MRI brain scans of a cohort of 80 preschoolers (20 male controls, 20 male subjects with ASD, 20 female controls, 20 female subjects with ASD, mean age controls 49 months, std 12 months, mean age ASD 49 months, std 14) were processed with three different automated methods to measure the brainstem volume: Freesurfer 5.3 (Fischl, 2002), FSL-FIRST (Patenaude, 2011) and ANTs (Avants, 2011). Analysis of variance was then carried out taking into account gender and total brain volume in order to investigate potential brainstem volume differences between controls/ASD subjects for each method. A direct comparison of brainstem volume assessments in native space was then performed to assess inter-method reliability (correlation has been calculated by Pearson coefficient) and Dice similarity indexes were calculated to evaluate the segmentation agreement across methods. Results:The brainstem volume measurements are reported in scatter plots in Fig. 1 to show the agreement in terms of volume (in mm3) between different methods. The color represents the Dice similarity index (range 0-1 were 1 means total agreement) of the brainstem segmentations obtained by the methods under investigation. In Fig. 2 four examples of brainstem segmentations with the different methods are shown in sagittal view (brainstem segmentations are reported in red, green, blue for Freesurfer, FSL-FIRST and ANTs respectively). Pearson correlation coefficient between FSL-FIRST and Freesurfer brainstem volume assessments was 0.27 (p-value=0.02). It was 0.51 (p-value0.05).Conclusions:The inter-method reliability of automated algorithms for brainstem volume assessment is limited (the mean Dice similarity index barely reaches 0.8 in just one out of 3 comparisons). Inconsistencies across previous studies on brainstem and more in general the lack of evidence for brain biomarkers in ASD may in part be a result of this poor agreements in the extraction of structural features with different methods. Inter-method brainstem volume differences can be attributed to varying definitions of brainstem structure, the use of different templates (e.g. in our study only ANTs processed the brain scans by using an age-specific brain template) and the varying effects of imaging artifacts and acquisition settings. This study suggests that research on brain structure alterations should cross-validate findings across multiple methods before providing biological interpretations

Recensioni

Contiene: Ośrodki kultury dawnej Słowiańszczyzny i ich znaczenie dzie­jo­we, red. M. Kuczyńska, J. Stradomski, Kraków, Wyd. Scriptum, 2017 (V. Nosilia) ; L’Albania nell’Archivio di Propaganda Fide. Atti del Convegno In­ter­nazionale Città del Vaticano, 26-27 ottobre 2015, a cura di A. Ndreca, Città del Vaticano, Urba­nia­na University Press, 2017 (P. Lazarević) ; B. Bulatović, Oklevetana književnost: ideološki aspekti u kritič­kom sagledavanju srpske književnosti i kulture krajem 20. i početkom 21. veka, Novi Sad, Naučno udru­­ženje za razvoj srpskih studija, 2017 (P. Lazarević) ; M. Levina-Parker, Master serijnogo samosočinenija Andrej Belyj, SPb., Izd. Puš­kin­sko­go Doma/Nestor-Istorija, 2018 (G. Giuliano) ; Globalizing East European Art Histories. Past and Present, ed. by B. Hock and A. Allas, New York-London, Routledge, 2018 (M. Bertelè) ; L. Mecacci, Lev Vygotskij. Sviluppo, educazione e patologia della mente, Fi­ren­ze, Giunti, 2017 (M. Zalambani) ; N. Misler, L’arte del movimento in Russia 1920-1930, Torino, Al­le­mandi Editore, 2017 (A. Cavallaro)