Pour répondre à des questions biologiques émergentes, l’IRM 3D in vivo est une approche de choix, mais elle souffre principalement d’une faible résolution temporelle en raison d’une faible sensibilité. Par ailleurs, l’IRM gagnerait à une meilleure sensibilité aux agents de contrastes exogènes. Il est proposé ici des développements en IRM du petit animal permettant de réduire considérablement la durée d’acquisition des images à trois dimensions chez la souris, ou la détection de très faibles quantités d’agents de contraste. Ces développements reposent sur la manipulation de l’espace-k (espace des données acquises). La première partie de ce travail a reposé sur la mise en place d’une méthode d’acquisition rapide de l’imagerie 3D permettant de conserver la qualité de l’image. Le «keyhole» 3D a été la technique choisie pour accéder à une résolution temporelle très élevée. Ainsi, le temps d’acquisition en imagerie ciné 3D cardiaque, chez la souris, a été réduit par un facteur 4 tout en conservant la qualité de l’image (SSB) et les informations extraites. Le «keyhole» 3D est aussi une méthode favorable à la mesure de prise de contraste. La biodistribution d’agent de contraste, peut être suivie en imagerie 3D à contrastes T1 et T2* dans le corps entier de la souris en quasi temps réel. La manipulation de l’espace-k permet aussi d’améliorer la qualité de l’image en réalisant une imagerie très sensible au contraste T2*. Pour cela, la correction de mouvements intrinsèques, comme ceux issus de la respiration au niveau de l’abdomen, générant un effet de perte de résolution spatiale, est indispensable. L’utilisation d’un écho navigateur permettant de détecter et de supprimer tous les signaux indésirables apporte une amélioration nette de la qualité d’image. Le seuil de détection de l’agent de contraste testé est d’ailleurs inférieur à 100 picomole de fer par kilogramme dans l’abdomen de souris. L’utilisation des propriétés de l’espace-k montre à quel point la qualité de l’image peut être améliorée et adaptée à l’information souhaitée. C’est un moyen peu couteux et efficace pour rendre l’imagerie par résonance magnétique encore plus performante en terme de résolution spatiale et de résolution temporelle. / In vivo 3D MRI is a powerful method which can be used to answer emerging biological issues. However, low temporal resolution due to intrinsic low sensitivity is one of its main drawbacks. Similarly, breakthroughs are needed to detect by MRI low-concentrated contrast agents used for molecular imaging. In this work, several methodology developments in small animals are proposed to greatly reduce acquisition times of 3D MRI and to increase contrast sensitivity to T2* agents. Both achievements were performed through the manipulation of the k-space, i.e the acquired data space in a retrospective approach. To achieve very high temporal resolution a 3D keyhole technique was chosen. This allowed the acquisition time in cardiac 3D-cine imaging in mice to be reduced by a factor 4. Image quality (signal-to-noise ratio) and the extracted functional data were preserved. Interestingly, 3D keyhole imaging also allowed the evaluation of T1 and T2* contrast enhancement and biodistribution in real time in the whole mouse body. In the last part of the work, the goal was to generate highly T2*-sensitive 3D images in mouse abdomen to detect diluted iron-oxide-based contrast agents. The use of a navigator echo enabled efficient motion correction and detection threshold of less than 100 picomol iron per kilogram. The results are discussed in a general frame of future applications and development of fast and highly-resolved 3D imaging.

Beta-talassemia é uma das doenças genéticas mais comuns no mundo, com graus variados de anemia crônica, tratados por transfusões sanguíneas rotineiras nos casos mais graves. A sobrecarga de ferro acentuada a que esses pacientes são submetidos é a principal responsável pela morbimortalidade, sendo o acúmulo de ferro no miocárdio e a doença cardíaca disso decorrente, a principal causa de morte nessa população. A ressonância magnética cardíaca (RMC) é ferramenta central no acompanhamento desses pacientes, utilizando-se da técnica T2*, capaz de determinar a presença e grau da deposição de ferro no miocárdio, modificando o tratamento da terapia quelante de ferro (TQF). Além disso, outros parâmetros volumétricos e funcionais obtidos no exame de RMC podem estar alterados nesses pacientes. Até a atualidade, inexistem estudos nacionais descrevendo uma população de pacientes beta-talassêmicos pelos parâmetros da RMC. Objetivos: 1. Caracterizar a partir dos diversos parâmetros dos exames de RMC, a população dos pacientes talassêmicos acompanhados no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto. 2. Avaliar o impacto dos diversos parâmetros da RMC com informações clinicas como mudança terapêutica, ocorrência de insuficiência cardíaca e óbito. Métodos: foram avaliados 44 pacientes com diagnóstico de beta-talassemia em seguimento no serviço de hematologia, para os quais foram solicitados exames de RMC na rotina clínica. Os exames incluíram sequências cine SSFP (steady state free precession) nos diversos planos cardíacos, incluindo uma sequência do eixo curto de ambos os ventrículos, esta utilizada para as medidas de volumes e função ventriculares. A sequência T2* utilizada foi gradiente eco com pré-pulso de saturação do sangue, com aquisição de 9 ecos consecutivos em apenas uma apneia. Sequência semelhante foi obtida para cálculo do T2* hepático. Foi feita revisão dos prontuários dos pacientes para avaliação dos dados clínicos. Resultados: 44 pacientes foram avaliados (25 do sexo masculino 56,8 %), com idade de 23,1±10,3 anos e diagnóstico de beta-talassemia maior em 30 casos (68,2 %) e talassemia intermedia em 14 casos (31,8 %). Foram descritos os volumes, massa e função para ambos os ventrículos, bem como a distribuição da medida do T2* miocárdico. Não foram observadas diferenças desses parâmetros entre os diferentes grupos de impregnação miocárdica pelo T2*. O seguimento médio do estudo foi de 4,0 (±1,1) anos com 4,7 (±1,6) exames por paciente. Foram identificados cinco pacientes com doença cardíaca e dois óbitos. Esses pacientes apresentaram redução significativa do T2* miocárdico, da fração de ejeção do ventrículo direito (VD), massa ventricular direita e esquerda e do volume sistólico final do VD, quando comparados aos indivíduos sem acometimento cardíaco reportado. Conclusão: Caracterizou-se a população de pacientes beta-talassêmicos acompanhados nesta instituição, em relação aos diversos parâmetros da RMC, salientando-se o impacto da introdução do método na mudança terapêutica. A medida do T2* miocárdico está correlacionada ao desenvolvimento de cardiopatia e pior evolução clínica, incluindo óbito. Acometimento do VD pode ser indicador precoce da impregnação miocárdica. / Beta-thalassemia is one of the most common genetic disorders worldwide, with different degrees of chronic anemia, treated with routine blood transfusions in severe cases. Morbidity and mortality is mainly related to the chronic iron overload and iron burden these patients endure. Myocardial iron overload and the development of cardiac disease remain the main cause of death for this population. Cardiac magnetic resonance (CMR) plays a central role in patient management, utilizing T2* sequences, which allows for detection and quantification of myocardial iron deposits, thus prompting changes in iron chelation therapy (ICT). Besides, there are other significant CMR volumetric and functional parameters to present abnormalities in these patients. To the present date, no national data has been published, describing a beta-thalassemia patient population from the standpoint of CMR parameters. Objectives: 1. To characterize, from the different CMR parameters, the beta-thalassemia patient population followed at a Brazilian tertiary hospital. 2. To evaluate the impact of these different CMR parameters, in relation to clinical data, such as therapeutic change, cardiac disease and death. Methods: 44 beta-thalassemia patients followed by the hematology service of this institution were evaluated, to whom CMR exams were performed in routine clinical practice. CMR exams included SSFP (steady state free precession) cine images through the different cardiac planes, including a short axis stack through both ventricles, used to calculate ventricular volumes and function. A gradient echo sequence with a dark blood pre-pulse saturation was used to calculate myocardial T2* values, with 9 consecutive echo times acquisition in one breath hold. A similar sequence was used to determine liver T2* values. Medical records were reviewed for clinical data. Results: 44 patients were evaluated (25 males, 56.8 %), with a mean age of 23,1 (±10,3) years, and diagnosis of betathalassemia major in 30 patients (68,2 %) and beta-thalassemia intermedia in 14 (31,8 %). Ventricular volumes, mass and function were described, as well as myocardial T2* distribution. There were no statistical difference observed among the different CMR parameters and the myocardial T2* degrees. Mean follow up was 4,0 (±1,1) years, with 4,7 (±1,6) exams per patient. Five patients with cardiac disease were identified with two deaths during observation. These patients showed a significantly reduced myocardial T2* and RVEF, and an elevated ventricular mass, for both ventricles, and final systolic right ventricular volume, when compared to patients without cardiac disease. Conclusion: A betathalassemia patient population was characterized through the different CMR parameters, highlighting the impact of CMR introduction to treatment decision. Myocardial T2* is related to cardiac disease development, clinical worsening and death. Right ventricular functional worsening could be an early sign of myocardial iron involvement.

Η κλασική Απεικόνιση του Μαγνητικού Συντονισμού (ΑΜΣ) βασίζεται στο φαινόμενο του πυρηνικού μαγνητικού συντονισμού όπου η κάθε λέξη ξεχωριστά μας βοηθάει να κατανοήσουμε ποια είναι η προέλευση αυτού του φαινομένου. Συγκεκριμένα, το μετρούμενο σήμα προέρχεται από τους πυρήνες των ατόμων της ύλης, η αλληλεπίδραση μεταξύ των οποίων είναι μαγνητική και το τελικό σήμα εκφρασμένο σε μορφή φασμάτων ή εικόνων λαμβάνεται χρησιμοποιώντας το φαινόμενο του πυρηνικού μαγνητικού συντονισμού. Στην κατηγορία της ποσοτικής ΑΜΣ (πΑΜΣ), όμως, μετράμε άμεσα τις ποσοτικές παραμέτρους από τις οποίες εξαρτώνται τα τελικά σήματα όπως χρόνους μαγνητικής αποκατάστασης, μοριακή διάχυση, pH, μικρο-ιξώδες κτλ. Η ρύθμιση και η βαθμονόμηση των παραμέτρων του τελικού μετρητικού συστήματος (σύστημα ΑΜΣ) παίζουν βασικό ρόλο στα τελικά αποτελέσματα των μετρήσεών μας. Για το λόγο αυτό είναι απαραίτητη η χρήση ειδικών ομοιωμάτων για τη βαθμονόμηση του μετρητικού συστήματος καθώς και για την αξιολόγηση και βελτιστοποίηση των μετρητικών μεθόδων. Τα ομοιώματα ελέγχου θα πρέπει να έχουν κάποια συγκεκριμένα βασικά χαρακτηριστικά, για να προσομοιάζουν όσο το δυνατόν καλύτερα τις μαγνητικά μετρούμενες παραμέτρους σε σχέση πάντα με εκείνες των ανθρωπίνων ιστών. Τέτοιες παράμετροι είναι κυρίως οι χρόνοι μαγνητικής αποκατάστασης (Τ1, Τ2, Τ2*) και η μοριακή διάχυση. Στα υλικά των ομοιωμάτων θα πρέπει να υπάρχει επιπλέον η δυνατότητα ανεξάρτητου ελέγχου των χρόνων μαγνητικής αποκατάστασης Τ1 και Τ2. Επίσης, θα πρέπει τα υλικά αυτά να έχουν φυσική και χημική σταθερότητα στο χρόνο και τέλος να παρασκευάζονται εύκολα και να είναι οικονομικά. Στην παρούσα εργασία παρασκευάστηκαν ειδικά ομοιώματα ενός πολυσακχαρίτη, της αγαρόζης, με πρόσμιξη μιας παραμαγνητικής ουσίας, του γαδολινίου (Gd-DTPA), σε 20 διαφορετικούς συνδυασμούς συγκεντρώσεων μεταξύ τους. Με βάση αυτά τα ομοιώματα μετρήσαμε τους χρόνους μαγνητικής αποκατάστασης Τ1, Τ2, Τ2* για οκτώ επαναλήψεις σε διάστημα τεσσάρων μηνών. Διαπιστώσαμε ότι η πιο αποτελεσματική ακολουθία για τη μέτρηση της Τ2 είναι σε μια ακολουθία πολλαπλών συμμετρικά επαναλαμβανόμενων Spin Echo (32 echo) με αρχική τιμή ΤΕ = 20ms. Με την χρήση της ακολουθίας αυτής καλύπτεται το μεγαλύτερο φάσμα μετρήσεων τιμών Τ2 για τους μαλακούς βιολογικούς ιστούς και επίσης τηρείται το 6 επιτρεπτό όριο του συντελεστή μεταβλητότητας για αυτόν τον τύπο των μετρήσεων (CV=±5%). Για τη μέτρηση της Τ1 εφαρμόσαμε δύο μεθόδους (Variable Flip Angle-VFA, Variable Time Inversion-VTI). Η πιο αποτελεσματική μέθοδος αποδείχθηκε η VTI. Η VFA υστερούσε στις μετρήσεις λόγω της αδυναμίας προσαρμογής των δεδομένων στην μαθηματική συνάρτηση περιγραφής των σημάτων λήψης Y(FA) = f (FA). Επιπλέον, διαπιστώσαμε ότι το παραμαγνητικό ιόν του γαδολινίου επηρεάζει την μέτρηση της Τ1 ανεξάρτητα από το μοριακό τύπο ή το είδος της χειλικής χημικής ένωσης στην οποία ανήκει. Τέλος, διαπιστώσαμε ότι σε όλες τις μετρήσεις η μεγαλύτερη ανομοιογένεια του τοπικού μαγνητικού πεδίου παρουσιάζεται στα πυκνά διαλύματα σε αγαρόζη και γαδολίνιο κυρίως λόγω της παραμαγνητικής ιδιότητας του γαδολινίου, η οποία επηρεάζει το τοπικό μαγνητικό πεδίο της μέτρησης. Μεγάλο συντελεστή μεταβλητότητας στις μετρήσεις της ανομοιογένειας του τοπικού μαγνητικού πεδίου παρουσιάζουν τα αραιά κολλοειδή διαλύματα και το νερό, διότι επηρεάζονται ευκολότερα από τις εξωτερικές επιδράσεις της μέτρησης (π.χ. θερμοκρασία) εξαιτίας της ασθενούς σύνδεσης μεταξύ των μορίων του υλικού τους. / The typical Magnetic Resonance Imaging (MRI) is based in the phenomenon of the nuclear magnetic resonance where each individual word, helps us understand its origin. Specifically, the measured signal is generated by the nucleus of the matter's atoms. The interaction of the latter is magnetic and the final signal is detected in the form of spectrum or images through the phenomenon of nuclear magnetic resonance. Nevertheless, in the field of quantitative MRI, we can measure quantitative parameters like magnetic relaxation time, molecular diffusion, micro-viscosity etc., on which the final signals depend. The adjustment and calibration of the parameters of the final metering systems (system MRI) are crucial for the final results. Therefore, it is essential to use special phantoms for the calibration of the metering system as well as for the valuation and optimization of the metering processes. The control phantoms need to have specific characteristics in order to simulate as much as possible the magnetically measured parameters with respect to the ones of the human tissues. Such parameters are mainly the magnetic relaxation times (T1, T2, T2*) and the molecular diffusion. The phantoms should also provide the option of individual testing of the magnetic relaxation times T1 and T2. Moreover, these materials should have the same physical and chemical stability in time and their production needs to be financially effective. In this paper, special agarose phantoms were produced, by mixing gadolinium, a paramagnetic substance, in 20 different concentrations. Based on these phantoms we measured 8 times the magnetic relaxation times Τ1, Τ2, Τ2* within a period of 4 months. We noted that the most effective sequence for measuring T2 is by symmetrically spin echo sequence with the initial time having the value of 20ms. Using this method, the widest range of T2 values is covered with regards to soft tissues. Additionally, the variation coefficient permissible figures for such measurements is respected (CV=±5%). In order to measure T1 we used two methods, Variable Flip Angle-VFA, Variable Time Inversion-VTI. The most effective one, was proven to be the VTI one. VFA method was presenting delays in the measurements due to the inability to adjust the data in the function of signal reception description Y(FA) = f (FA). Moreover, we discovered that the paramagnetic ion of gadolinium is affecting the measurement of T1 regardless the molecular type or the type of chemical ligand that this belongs to. Finally, we noted that throughout the experiments, the highest inhomogeneity of the local magnetic field is found in the dense solutions of agarose and gadolinium mainly due to the paramagnetic properties of gadolinium which affects the local magnetic field of the measurement. High variability factor of inhomogeneity of the local magnetic field demonstrated the dilute gels and water because of the poor connection between the molecules of their material.

Beta-talassemia é uma das doenças genéticas mais comuns no mundo, com graus variados de anemia crônica, tratados por transfusões sanguíneas rotineiras nos casos mais graves. A sobrecarga de ferro acentuada a que esses pacientes são submetidos é a principal responsável pela morbimortalidade, sendo o acúmulo de ferro no miocárdio e a doença cardíaca disso decorrente, a principal causa de morte nessa população. A ressonância magnética cardíaca (RMC) é ferramenta central no acompanhamento desses pacientes, utilizando-se da técnica T2*, capaz de determinar a presença e grau da deposição de ferro no miocárdio, modificando o tratamento da terapia quelante de ferro (TQF). Além disso, outros parâmetros volumétricos e funcionais obtidos no exame de RMC podem estar alterados nesses pacientes. Até a atualidade, inexistem estudos nacionais descrevendo uma população de pacientes beta-talassêmicos pelos parâmetros da RMC. Objetivos: 1. Caracterizar a partir dos diversos parâmetros dos exames de RMC, a população dos pacientes talassêmicos acompanhados no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto. 2. Avaliar o impacto dos diversos parâmetros da RMC com informações clinicas como mudança terapêutica, ocorrência de insuficiência cardíaca e óbito. Métodos: foram avaliados 44 pacientes com diagnóstico de beta-talassemia em seguimento no serviço de hematologia, para os quais foram solicitados exames de RMC na rotina clínica. Os exames incluíram sequências cine SSFP (steady state free precession) nos diversos planos cardíacos, incluindo uma sequência do eixo curto de ambos os ventrículos, esta utilizada para as medidas de volumes e função ventriculares. A sequência T2* utilizada foi gradiente eco com pré-pulso de saturação do sangue, com aquisição de 9 ecos consecutivos em apenas uma apneia. Sequência semelhante foi obtida para cálculo do T2* hepático. Foi feita revisão dos prontuários dos pacientes para avaliação dos dados clínicos. Resultados: 44 pacientes foram avaliados (25 do sexo masculino 56,8 %), com idade de 23,1±10,3 anos e diagnóstico de beta-talassemia maior em 30 casos (68,2 %) e talassemia intermedia em 14 casos (31,8 %). Foram descritos os volumes, massa e função para ambos os ventrículos, bem como a distribuição da medida do T2* miocárdico. Não foram observadas diferenças desses parâmetros entre os diferentes grupos de impregnação miocárdica pelo T2*. O seguimento médio do estudo foi de 4,0 (±1,1) anos com 4,7 (±1,6) exames por paciente. Foram identificados cinco pacientes com doença cardíaca e dois óbitos. Esses pacientes apresentaram redução significativa do T2* miocárdico, da fração de ejeção do ventrículo direito (VD), massa ventricular direita e esquerda e do volume sistólico final do VD, quando comparados aos indivíduos sem acometimento cardíaco reportado. Conclusão: Caracterizou-se a população de pacientes beta-talassêmicos acompanhados nesta instituição, em relação aos diversos parâmetros da RMC, salientando-se o impacto da introdução do método na mudança terapêutica. A medida do T2* miocárdico está correlacionada ao desenvolvimento de cardiopatia e pior evolução clínica, incluindo óbito. Acometimento do VD pode ser indicador precoce da impregnação miocárdica. / Beta-thalassemia is one of the most common genetic disorders worldwide, with different degrees of chronic anemia, treated with routine blood transfusions in severe cases. Morbidity and mortality is mainly related to the chronic iron overload and iron burden these patients endure. Myocardial iron overload and the development of cardiac disease remain the main cause of death for this population. Cardiac magnetic resonance (CMR) plays a central role in patient management, utilizing T2* sequences, which allows for detection and quantification of myocardial iron deposits, thus prompting changes in iron chelation therapy (ICT). Besides, there are other significant CMR volumetric and functional parameters to present abnormalities in these patients. To the present date, no national data has been published, describing a beta-thalassemia patient population from the standpoint of CMR parameters. Objectives: 1. To characterize, from the different CMR parameters, the beta-thalassemia patient population followed at a Brazilian tertiary hospital. 2. To evaluate the impact of these different CMR parameters, in relation to clinical data, such as therapeutic change, cardiac disease and death. Methods: 44 beta-thalassemia patients followed by the hematology service of this institution were evaluated, to whom CMR exams were performed in routine clinical practice. CMR exams included SSFP (steady state free precession) cine images through the different cardiac planes, including a short axis stack through both ventricles, used to calculate ventricular volumes and function. A gradient echo sequence with a dark blood pre-pulse saturation was used to calculate myocardial T2* values, with 9 consecutive echo times acquisition in one breath hold. A similar sequence was used to determine liver T2* values. Medical records were reviewed for clinical data. Results: 44 patients were evaluated (25 males, 56.8 %), with a mean age of 23,1 (±10,3) years, and diagnosis of betathalassemia major in 30 patients (68,2 %) and beta-thalassemia intermedia in 14 (31,8 %). Ventricular volumes, mass and function were described, as well as myocardial T2* distribution. There were no statistical difference observed among the different CMR parameters and the myocardial T2* degrees. Mean follow up was 4,0 (±1,1) years, with 4,7 (±1,6) exams per patient. Five patients with cardiac disease were identified with two deaths during observation. These patients showed a significantly reduced myocardial T2* and RVEF, and an elevated ventricular mass, for both ventricles, and final systolic right ventricular volume, when compared to patients without cardiac disease. Conclusion: A betathalassemia patient population was characterized through the different CMR parameters, highlighting the impact of CMR introduction to treatment decision. Myocardial T2* is related to cardiac disease development, clinical worsening and death. Right ventricular functional worsening could be an early sign of myocardial iron involvement.

Abstract Cartilage-related diseases such as osteoarthritis (OA) are a major cause of disability and decrease in the quality of life. Moreover OA causes a heavy economical burden on the social welfare and health care systems. Conventional magnetic resonance imaging (MRI) provides accurate noninvasive method of morphological evaluation of the articular cartilage. However, there are early degenerative changes in the articular cartilage that can be evaluated with modern quantitative MRI methods prior to the signs of cartilage loss. In this study, T2 relaxation time of the articular cartilage was further evaluated in 1.5T in vivo using clinical patients and asymptomatic volunteers. The detection of focal patellar cartilage lesions in T2 mapping as compared to standard clinical MRI was evaluated. T2 mapping showed more lesions than the clinical MRI, and in T2 maps the lesions appeared generally wider. This suggests that T2-mapping is feasible in the clinical setting and may reveal cartilage lesions not seen in the standard knee MRI. The normal topographical variation of T2 relaxation time of articular cartilage in different compartments of the knee joint and at different zones of cartilage in young healthy adults was assessed. T2 values were significantly higher in the superficial zone as compared to the deep tissue at all locations and there was remarkable variation in T2 relaxation between different locations. The normal variation in cartilage T2 within a joint is significant and should be acknowledged when pathology-related T2 changes are investigated. The short- and long-term repeatability of T2 relaxation time measurements of articular cartilage in the knee joint was assessed. The results showed mostly good repeatability, and with careful patient positioning T2 relaxation time at the different cartilage surfaces of the knee can be accurately determined. / Tiivistelmä Nivelrikko, joka usein liittyy nivelruston vaurioitumiseen, aiheuttaa merkittävää toimintakyvyn ja elämänlaadun heikentymistä ikääntyvässä väestössä. Lisäksi nivelrikosta aiheutuu merkittäviä kustannuksia sosiaali- ja terveydenhuollolle. Magneettikuvaus on tarkka kajoamaton menetelmä rustovaurioiden arvioimiseksi. Kuitenkin rustovaurion alkuvaiheessa tapahtuu ruston sisäisiä rakenteellisia ja biokemiallisia muutoksia, joita on mahdollista arvioida uusilla kvantitatiivisilla magneettikuvausmenetelmillä ennen varsinaisten rustopuutosten kehittymistä. Tässä tutkimuksessa tutkittiin ruston T2-relaksaatioaikamittausta 1.5T magneettikuvauslaitteella sekä potilasaineistossa että vapaaehtoisilla. Tutkimuksessa verrattiin paikallisten rustomuutosten havaitsemisen herk¬kyyttä T2-relaksaatioaikakartoituksen ja tavanomaisen kliinisen magneetti¬kuvauksen välillä kliinisessä potilasaineistossa. T2-relaksaatiomittaus osoitti useampia muutoksia kuin kliininen magneettikuvaus ja muutokset olivat yleensä laajempia. Voidaan olettaa, että T2-relaksaatioaikamittaus soveltuu kliiniseen käyttöön ja voi osoittaa tavanomaisessa magneettikuvauksessa näkymättömiä rustomuutoksia. Tutkimuksessa arvioitiin ruston T2-relaksaatioajan paikkakohtaista ja kerroksittaista vaihtelua polven nivelpintojen eri alueilla nuorten vapaaehtoisten aineistossa. T2-relaksaatioaika oli merkitsevästi pidempi ruston pinnallisessa kuin syvässä kerroksessa kaikilla nivelpintojen alueilla. Lisäksi T2-relaksaatioajassa oli merkittävää normaalia vaihtelua eri alueiden välillä ja tämä tulisi huomioida ruston patologisia muutoksia arvioitaessa. Tutkimuksessa arvioitiin polven ruston T2-relaksaatioajan lyhyen ja pitkän aikavälin toistettavuutta vapaaehtoisaineistossa. Tulokset osoittivat enimmäkseen hyvää toistettavuutta ja huolellisella asettelulla voidaan ruston T2-relaksaatioaika mitata luotettavasti polven nivelpintojen eri alueilla.

La technique Orthogonal Frequency Division Multiplexing (OFDM) a été adoptée par plusieurs systèmes de télécommunications et de diffusion pour sa robustesse, sa capacité à transmettre de hauts débits dans des canaux radiomobiles et pour son efficacité spectrale. Cependant, les signaux OFDM sont caractérisés par des fluctuations importantes, mesurées par le rapport de la puissance crête sur la puissance moyenne (Peak to Average Power Ratio – PAPR) du signal, qui génèrent des distorsions à la sortie de l’amplificateur non-linéaire de puissance (High Power Amplifier - HPA) et ne permettent pas de l’utiliser dans sa zone optimale afin de diminuer sa consommation énergétique. La deuxième génération de la norme Digital Video Broadcasting (DVB-T2) a notamment adopté la technique Tone Reservation (TR) de réduction du PAPR. Son principe consiste à créer un noyau, à partir d’un ensemble de sous-porteuses réservées, qui est ensuite ajouté d’une manière itérative au signal OFDM de façon à réduire les pics du signal et donc son PAPR. Dans la première partie de la thèse, différents algorithmes permettant d’améliorer les performances de cette solution TR DVT-T2 sont proposés. Un premier groupe de solutions, reposant sur la même définition du noyau, comprend : la technique Partial Oversampling and Fractional Shifted Kernels (POFSK) reposant sur un sur-échantillonnage partiel du signal, la technique Dynamic Threshold (DT) qui effectue un calcul dynamique du seuil de troncature et la technique Enhanced Peak Selection (EPS) qui améliore la sélection des pics à réduire. Le deuxième groupe de solutions comprend tout d’abord la technique Individual Carrier Multiple Peaks (ICMP) qui repose sur une nouvelle définition du noyau et utilise un calcul de phase différent permettant la réduction de plusieurs pics en même temps. La technique GICMP est une version optimisée de la technique ICMP qui, en parallélisant les opérations, permet de réduire le délai de traitement et le nombre total d’itérations. Les résultats de simulations et les mesures effectuées sur une plateforme de transmission réelle montrent que, par rapport à la version TR de DVB-T2, l’algorithme GICMP offrait notamment un gain de l’ordre de 2.5 dB en termes de Modulation Error Rate – MER ou permettait une réduction de 10 % de l’énergie consommée par l’amplificateur de puissance à performances identiques. [...] / Orthogonal Frequency Division Multiplexing (OFDM) has been adopted by many telecommunication and broadcasting systems for its robustness, high transmission rates, mobility and bandwidth efficiency. However, OFDM signals are characterized by high power fluctuations, measured by the Peak to Average Power Ratio (PAPR), which cause distortions at the output of the non-linear High Power Amplifier (HPA) and prevent the radio frequency designer to feed the signal at the optimal point of the HPA specifications in order to reduce the energy consumption. The second generation of Digital Video Broadcasting (DVB-T2) adopted two PAPR reduction techniques, one of them is Tone Reservation (TR). TR creates a Kernel from a reserved set of subcarriers. The kernel is then iteratively added to the OFDM signal in such a way to reduce its peaks thus reducing its PAPR. In the first part of the thesis, different algorithms offering better performances compared to the DVB-T2 TR solution are proposed. A first group of solutions introduces changes and enhancements to the TR algorithm adopted in DVB-T2 TR but keeps the same kernel definition. This group includes: the Partial Oversampling and Fractional Shifted Kernels (POFSK) technique which is based on a partial oversampling of the signal, the Dynamic Threshold (DT) technique which allows better algorithm convergence by dynamically computing the PAPR reduction threshold for every OFDM symbol, and the Enhanced Peak Selection (EPS) technique which provides additional PAPR reduction by choosing the appropriate signal peaks to reduce and the peaks to skip. The second group of solutions includes the Individual Carrier Multiple Peaks (ICMP) technique which is based on a special kernel definition that changes from one algorithm iteration to another and uses a different phase calculation approach that allows the reduction of multiple peaks at a time. GICMP is an optimized version of ICMP that allows the parallelization of iterations in such a way to reduce the processing delay and the number of algorithm iterations. The simulation results and real hardware platform measurements of the proposed algorithms showed that, compared to the DVB-T2 TR version, the GICMP algorithm allows a Modulation Error Rate – MER gain of up to 2.5 dB or a 10 % reduction in HPA consumed energy with the same performances.

La coopération entre les réseaux de diffusion classiques et les réseaux mobiles cellulaires pour une distribution commune de la télévision mobile est actuellement l'un des éléments clé discutés dans le cadre des nouvelles technologies de diffusion mobile; surtout l'extension mobile de la deuxième génération de diffusion de la télévision numérique terrestre (DVB-T2 Lite) et son suiveur le DVB-Next Generation Handheld (DVB-NGH).En fait, ces technologies de diffusion visent à coopérer avec la récente technologie de téléphonie mobile, connue sous le nom de Long Term Evolution (LTE) qui permet la diffusion de la TV Mobile grâce au protocole de diffusion des services multimédia dans les réseaux de téléphonie mobile (de nature unicast à priori) et connu sous le nom de enhanced-Multimedia Broadcast and Multicast Service feature (e-MBMS).Bien que la coopération entre les réseaux de diffusion DVB et ceux de téléphonie mobile n'est pas un nouveau sujet et a été étudiée avec l'introduction de la technologie de diffusion mobile précédente, connue sous le nom DVB-Handheld (DVB-H), la plupart des travaux traitants ce sujet ont considéré un scénario avec une zone de couverture commune entre le réseau de diffusion et celui cellulaire et ont évalué cette coopération en terme des gains de capacité apportés par DVB au réseau cellulaire et en terme d'amélioration de la fiabilité de transmission apportée par les réseaux cellulaire au DVB grâce à la possibilité des retransmissions unicast. / The broadcast/cellular cooperation for a common delivery of Mobile TV is at the heart of the emerging mobile broadcast technologies, namely the mobile extension of the second generation digital video broadcasting for terrestrial reception (DVB-T2 Lite) and its follower DVB-Next Generation Handheld (DVB-NGH). These broadcast technologies aim to cooperate with the Long Term Evolution (LTE), as the latter is intended to be the bearer of Mobile TV thanks to its enhanced-Multimedia Broadcast and Multicast Service feature (e-MBMS). Even though the 3GPP/DVB cooperation is not a new topic and was investigated with the introduction of the previous DVB technology, known as DVB-Handheld (DVB-H), most of the works addressing this issue considered a common service area covered by both DVB and cellular systems and focused solely on the impact of such cooperation in terms of capacity gains brought by 3GPP and error repair gains brought by DVB. This strategy was judged to be expensive since a new and very dense DVB network was needed. In order to overcome this problem and decrease as much as possible the need for a new broadcast network, we propose in this thesis a hybrid DVB/LTE network with a coverage extension strategy, where the LTE system, planned for almost a universal coverage, is used to deliver Mobile TV in areas not covered by recent DVB-T2 Lite (or eventually DVB-NGH) network. In this context, we explore two main issues:1. Mobile TV services have to share LTE resources with other higher priority services such as voice traffic. The dynamicity of the latter will impact the Quality of Service (QoS) of Mobile TV. We propose a new QoS-based planning for the hybrid DVB/LTE so as to guarantee an acceptable watching experience without over-dimensioning the LTE system. We derive using Markov chain analysis and hitting time theory, several QoS metrics pertaining to mobile TV performance, such as interruption frequency and duration.2. A new business model which clarifies the relationships between the different actors of the ecosystem namely DVB and LTE operators as well as the TV channel providers and constructs the service area from an economic point of view is needed. In fact, the absence of a clear and viable economic model that resolves the monetary conflicts between cellular and broadcast operators was one of the main drawbacks behind the failure of the first attempt of mobile TV delivery by cooperating UMTS/DVB-H. We develop in this thesis a profit sharing strategy for the cooperative network, using coalition game concept Shapley value and Nash equilibrium for a self-enforcing strategy. We further develop a new framework using real option theory coupled with coalition games for investment decision in mobile TV networks (whether an operator should enter the mobile TV market and, if yes, when to do so) and show how operators can incorporate the uncertainties related to demand and network operation costs. We propose a bi-level dynamic programming algorithm to solve numerically the developed real option game.

Magnetic resonance imaging (MRI) has become the most important modality for assessment of pathological changes in the knee cartilage. The assessment of the cartilage is usually made by a set of anatomical MRI images with different sequences. Newer techniques, that map various in MRI parameters, have been developed and allows changes in an earlier stage of the disease. One of these techniques is T2 mapping. The goal of this thesis was to compare this newer technique, T2 mapping, with the standard MRI assessment for assessment of articular cartilage on distal femur in the knee. The purpose was to assess the cartilage with these two different methods and analyze its outcomes. Eight subjects were included in this study and scanned with a 3.0 T or 1.5 T MRI machine. A specific MRI knee protocol was used for the standard MRI assessment, and a multi-echo sequence was used for the T2 mapping. The T2 map was created and analyzed in the program IntelliSpace Portal. Both the standard MRI assessment and the T2 map showed changes in the knee cartilage. The result showed either indication for damage cartilage or healthy cartilage. The standard assessment showed cartilage lesion in three subjects and no lesion in five subjects. The same outcomes were with the T2 mapping. However, not all results were equal. The T2 mapping also showed higher values in the trochlea area where no indications for changes were found in the standard assessment. This study showed similar results for both the standard assessment and the T2 map. Both methods could identify damage and is, therefore, useful for assessment of the knee cartilage. The outcomes of the different methods differ, and the assessment is therefore made in different ways. The T2 mapping can be analyzed both visual and quantitative. The outcomes were both a color map of the knee but also results in graphs and values. The standard assessment is only assessed from grayscale images. The best outcomes from the T2 mapping was when it only was changes within the cartilage and not when the cartilage lesion was adjacent to an underlying bone lesion. Based on what was examined in this work, the best result was when T2 mapping was used together with the anatomical images used in the standard assessment. The conclusion is that the standard assessment is necessary when it comes to make a damage assessment and perform damage marking as for Episurf. The T2 mapping is, however, an interesting method and will be more useful with more applications in the future. It is therefore exciting to keep an eye on the technology and its development. / Magnetisk resonanstomografi (MR) har blivit den viktigaste modaliteten vid bedömning av patologiska förändingar i knäbrosket. Bedömningen av brosket görs vanligtvis med hjälp av anatomiska MR bilder som är skannade med olika sekvenser för att få olika viktningar på bilderna. En nyare teknik, T2 mappning, som kartlägger olika MR prameterar, har utvecklats för att med hjälp av andra parametrar analysera knäbrosket. Den här tekniken har resulterat i att förändringar i brosket kan upptäckas vid ett tidigare stadie i sjukdomsförloppet. Målet med det här examensarbetet var att jämföra de olika teknikerna, T2 mappning och MR-standardbedömningen, för att bedöma ledbrosket på distala lårbenet i knäet. Syftet var att bedöma brosket utifrån dessa olika metoder samt att analysera och jämföra dess resultat. Åtta subjekt ingick i studien och skannades med en 3,0 T eller 1,5 T MR-maskin. Ett specifikt MR-knäprotokoll användes för att skanna sekvenserna som ingick i standard bedömningen och en multi-ekosekvens användes för T2 mappningen. T2-mappningen skapades och analyserades sedan i programmet IntelliSpace Portal. Både standard MR-bedömningen och T2-mappningen visade tydliga förändringar i brosket. Resultatet visade antingen indikationer på skadat eller friskt brosk. Standardbedömningen visade broskskador hos tre subjekt och inga broskskador hos fem subjekt. Samma resultat visades med T2-mappningen. Däremot skilde sig vissa resultat mellan T2 mappningen och standardbedömningen. Då denna studie visade liknande resultat för både standardbedömningen och T2-mappningen, är båda metoderna användbara för bedömning av knäbrosket. De olika metoderna har olika utfall vilket gör att bedömningen sker på olika sätt. I T2 mapping får man ut både en färgkarta över knät men också grafter och värden som kan användas. I standardbedömningen görs bedömningen bara utifrån olika gråskalebilder. T2 mappningen var mest användbar när det var tydliga förändingar i bara brosket och inte när skadan mest var i benet. Det bästa resultatet var däremot när T2 mappning användes tillsammans med standardbedömningen. Slutsatsen är att standardbedömningen är nödvändig när det kommer till att bedömma skador och göra en skademarkering så som för Episurf. T2 mapping är däremot en väldigt intressant teknik men är idag inte en vanlig teknik inom diagnostiken och saknar just nu något tydligt användningsområde. Däremot, finns det stor potential och kommer troligtvis bli vanligare och få fler användingsområden i framtiden.

Actuellement, des méthodes quantitatives de résonance magnétique nucléaire (RMN) offrent des biomarqueurs qui permettent la réalisation d’études longitudinales pour le suivi de l’évolution des maladies neuromusculaires et des essais thérapeutiques de manière non-invasive. A la différence de la dégénérescence graisseuse, les processus d’inflammation/œdème/nécrose et fibrose sont des signes d’activité des maladies et leurs quantifications constitueraient ainsi de biomarqueurs parfaitement adaptés pour le suivi thérapeutique. Ce travail de thèse a consisté à mettre en place des méthodologies quantitatives plus précises et adaptées à l’étude clinique du muscle pour : (i) détecter et quantifier des sites d’activité de maladies par la cartographie T2 de l’eau ; (ii) identifier les différents processus pathophysiologiques qui sont à l’origine des altérations du T2 ; et (iii) détecter et quantifier la fibrose musculaire. Nous avons implémenté deux méthodes pour la quantification du T2 de l’eau dans le muscle. La première est basée sur une séquence d’écho de spin du type CPMG, où les signaux provenant des protons des lipides et de l’eau sont acquis simultanément et séparés à postériori par un traitement tri-exponentiel qui exploite la différence entre les T2 qui caractérisent les signaux de l’eau et de la graisse. La deuxième technique est basée sur une séquence de « partially spoiled steady state free precession (pSSFP) ». Différemment de la première technique qui nécessite un traitement assez élaboré sur des images acquises à 17 temps d’écho différents, dans la pSSFP la cartographie T2 est extraite à partir de deux séries de données 3D. L’acquisition 3D est compatible avec des techniques de sélection spectrale de l’eau, ce qui évite la contamination par les signaux des lipides. Les deux méthodes ont été validées expérimentalement chez des malades et des sujets sains et ont démontré leur capacité à détecter et quantifier des sites d’activité de maladies. Ces deux travaux font l’objet de deux publications dans des journaux scientifiques internationaux : Azzabou, de Sousa, Araujo, & Carlier, 2014. Journal of Magnetic Resonance Imaging. DOI 10.1002/jmri.24613 (in press); et de Sousa, Vignaud, Araujo, & Carlier . 2012. Magnetic Resonance in Medicine. 67:1379-1390. Malgré le fait de permettre la détection des sites d’activité de maladies, la mesure mono-exponentielle du T2 de l’eau par imagerie reste non-spécifique vis-à-vis des processus physiologiques à l’origine de l’augmentation du T2. Il est connu que la relaxation T2 du muscle squelettique n’est pas mono-exponentielle. Cela est interprété comme une conséquence de la compartimentation anatomique de l’eau tissulaire. Nous avons mis au point une méthode pour l’acquisition localisée de données CPMG. Cette technique permet l’acquisition des données dans des conditions nécessaires pour la réalisation de traitements multi-exponentiels précis. Ce travail nous a permis d’établir un modèle de compartimentation qui explique parfaitement la relaxation T2 dans le muscle. Il a fait l’objet d’un article publié dans le « Biophysical Journal » (Araujo, Fromes & Carlier 2014. New Insights on skeletal muscle tissue compartments revealed by T2 NMR relaxometry. (In press)). Les essais réalisés chez des sujets malades suggèrent un grand potentiel pour l’application de la méthode dans des études cliniques. La formation de la fibrose commence avec une accumulation excessive de tissu conjonctif intramusculaire (TCIM). Nous avons exploité la technique « Ultrashort Time-to-Echo » (UTE) pour essayer de détecter et caractériser le signal du TCIM. Dans une première étude, nous avons caractérisé in vivo une composante à T2 court (~500 µs) dans le muscle, et nous avons trouvé des indices qui suggèrent qu’elle représente le TCIM. Dans une deuxième étude, nous avons mis au point une méthodologie qui a permis d’imager cette composante à T2 court dans le muscle pour la première fois. / Current quantitative nuclear magnetic resonance (NMR) technics offer biomarkers that allow performing non-invasive longitudinal studies for the follow up of therapeutic trials in neuromuscular disorders (NMD). In contrast to fat degeneration, the mechanisms of inflammation/oedema/necrosis and fibrosis are characteristic signs of disease activity, which makes their quantification a promising source of crucial biomarkers for longitudinal studies. This thesis work consisted on the implementation of more precise quantitative NMR methods adapted to the clinical study of skeletal muscle (SKM) for : (i) detection and quantification of sites of disease activity by T2-mapping of muscle water ; (ii) investigation of the different pathophysiological mechanisms underlying T2 alterations ; and (iii) Detection and quantification of muscle fibrosis. We implemented two methods for T2 mapping of muscle water. The first one is based on a multi-spin-echo sequence du type CPMG. In this method the 1H-NMR signals from water and lipids are acquired simultaneously. The acquired data are fitted to a tri-exponential model, in which water and fat signals are separated by exploring the T2 difference between water and fat. This method allows extraction of muscle water T2-value in the presence of fat infiltration. The second method is based on a « partially spoiled steady state free precession » (pSSFP) sequence. In contrast to the first method, which demands a sophisticated post-treatment of images acquired at 17 different echo-times, with the pSSFP a T2-mapping is extracted from two 3D data sets. 3D acquisition is compatible with spectrally selective water excitation, which eliminates signal contribution from lipids. Both methods were validated experimentally on patients and healthy subjects. The results demonstrated their capacity to detect and quantify disease activity sites. This 2 works have been published in two international journals : Azzabou, de Sousa, Araujo, & Carlier, 2014. Journal of Magnetic Resonance Imaging. DOI 10.1002/jmri.24613 (in press); et de Sousa, Vignaud, Araujo, & Carlier . 2012. Magnetic Resonance in Medicine. 67:1379-1390. Although it was shown to reveal disease activity, mono-exponential T2 of muscle water is non-specific to what concerns the mechanisms underlying its alterations. It has been long known that T2 relaxation in SKM tissue is multi-exponential. This is currently accepted to reveal anatomical compartmentation of myowater. We implemented a method for localized spectroscopic CPMG acquisition. CPMG data respect echo-time sampling and signal to noise ration limits for allowing robust multiexponential analysis. This work allowed us to establish a compartmentation model that perfectly explains the multi-exponential T2 relaxation observed in SKM tissue. This work was published in the « Biophysical Journal » (Araujo, Fromes & Carlier 2014. New Insights on skeletal muscle tissue compartments revealed by T2 NMR relaxometry. (In press)). Pilot studies performed in patients show promising results and suggest potential application of the method in clinical studies. Fibrosis starts with an excessive accumulation of intramuscular connective tissue (IMCT). We have explored the « Ultrashort time to echo » (UTE) method with the aim to detect and characterize the signal from IMCT. In a first study we characterized in vivo a short T2 component (~500 µs) in SKM, and we collected evidences suggesting that this component might reflect IMCT. Then we implemented a methodology that allowed imaging this short component in SKM tissue for the first time.

Current quantitative nuclear magnetic resonance (NMR) technics offer biomarkers that allow performing non-invasive longitudinal studies for the follow up of therapeutic trials in neuromuscular disorders (NMD). In contrast to fat degeneration, the mechanisms of inflammation/oedema/necrosis and fibrosis are characteristic signs of disease activity, which makes their quantification a promising source of crucial biomarkers for longitudinal studies. This thesis work consisted on the implementation of more precise quantitative NMR methods adapted to the clinical study of skeletal muscle (SKM) for : (i) detection and quantification of sites of disease activity by T2-mapping of muscle water ; (ii) investigation of the different pathophysiological mechanisms underlying T2 alterations ; and (iii) Detection and quantification of muscle fibrosis. We implemented two methods for T2 mapping of muscle water. The first one is based on a multi-spin-echo sequence du type CPMG. In this method the 1H-NMR signals from water and lipids are acquired simultaneously. The acquired data are fitted to a tri-exponential model, in which water and fat signals are separated by exploring the T2 difference between water and fat. This method allows extraction of muscle water T2-value in the presence of fat infiltration. The second method is based on a " partially spoiled steady state free precession " (pSSFP) sequence. In contrast to the first method, which demands a sophisticated post-treatment of images acquired at 17 different echo-times, with the pSSFP a T2-mapping is extracted from two 3D data sets. 3D acquisition is compatible with spectrally selective water excitation, which eliminates signal contribution from lipids. Both methods were validated experimentally on patients and healthy subjects. The results demonstrated their capacity to detect and quantify disease activity sites. This 2 works have been published in two international journals : Azzabou, de Sousa, Araujo, & Carlier, 2014. Journal of Magnetic Resonance Imaging. DOI 10.1002/jmri.24613 (in press); et de Sousa, Vignaud, Araujo, & Carlier . 2012. Magnetic Resonance in Medicine. 67:1379-1390. Although it was shown to reveal disease activity, mono-exponential T2 of muscle water is non-specific to what concerns the mechanisms underlying its alterations. It has been long known that T2 relaxation in SKM tissue is multi-exponential. This is currently accepted to reveal anatomical compartmentation of myowater. We implemented a method for localized spectroscopic CPMG acquisition. CPMG data respect echo-time sampling and signal to noise ration limits for allowing robust multiexponential analysis. This work allowed us to establish a compartmentation model that perfectly explains the multi-exponential T2 relaxation observed in SKM tissue. This work was published in the " Biophysical Journal " (Araujo, Fromes & Carlier 2014. New Insights on skeletal muscle tissue compartments revealed by T2 NMR relaxometry. (In press)). Pilot studies performed in patients show promising results and suggest potential application of the method in clinical studies. Fibrosis starts with an excessive accumulation of intramuscular connective tissue (IMCT). We have explored the " Ultrashort time to echo " (UTE) method with the aim to detect and characterize the signal from IMCT. In a first study we characterized in vivo a short T2 component (~500 µs) in SKM, and we collected evidences suggesting that this component might reflect IMCT. Then we implemented a methodology that allowed imaging this short component in SKM tissue for the first time.