Cancer accounts for nearly 1 out of every 4 deaths in the United States, and because conventional treatments are limited by morbidity and off-target toxicities, improvements in cancer management are needed. This thesis further develops nanoparticle-assisted photothermal therapy (NAPT) as a viable treatment option for cancer patients. NAPT enables localized ablation of disease because heat generation only occurs where tissue permissive near-infrared (NIR) light and absorbing nanoparticles are combined, leaving surrounding normal tissue unharmed. Two principle approaches were investigated to improve the specificity of this technique: multimodal imaging and molecular targeting. Multimodal imaging affords the ability to guide NIR laser application for site-specific NAPT and more holistic characterization of disease by combining the advantages of several diagnostic technologies. Towards the goal of image-guided NAPT, gadolinium-conjugated gold-silica nanoshells were engineered and demonstrated to enhance imaging contrast across a range of diagnostic modes, including T1-weighted magnetic resonance imaging, X-Ray, optical coherence tomography, reflective confocal microscopy, and two-photon luminescence in vitro as well as within an animal tumor model. Additionally, the nanoparticle conjugates were shown to effectively convert NIR light to heat for applications in photothermal therapy. Therefore, the broad utility of gadolinium-nanoshells for anatomic localization of tissue lesions, molecular characterization of malignancy, and mediators of ablation was established. Molecular targeting strategies may also improve NAPT by promoting nanoparticle uptake and retention within tumors and enhancing specificity when malignant and normal tissue interdigitate. Here, ephrinA1 protein ligands were conjugated to nanoshell surfaces for particle homing to overexpressed EphA2 receptors on prostate cancer cells. In vitro, successful targeting and subsequent photothermal ablation of prostate cancer cells was achieved with negligible nanoshell binding to normal cells. In vivo however, ephrinA1-nanoshells did not promote enhanced therapeutic outcomes in mice bearing subcutaneous prostate cancer tumors treated with NAPT compared to nontargeted particles. Nonetheless, both treatment groups demonstrated effective ablation of prostate tumors, as evidenced by tumor tissue regression. Further investigation is warranted to overcome probable protein immunogenicity that offsets ephrinA1 targeting in vivo. With future study, photothermal therapy with multimodal gadolinium-conjugated and molecularly targeted nanoshells may offer a viable treatment option for cancer patients in the clinic.

Les bactéries sont des microorganismes capables de se développer et de proliférer indépendamment les uns des autres en milieu liquide. Mais dès qu’une surface se présente, biotique ou abiotique, les bactéries privilégient un « mode de vie en communauté » pour se protéger des agressions externes et survivre aux environnements hostiles. Ces biostructures, appelées biofilms, sont présentes dans tous les environnements naturels, y compris chez l’Homme où elles peuvent être à l’origine d’infections chroniques lorsqu’elles hébergent des germes pathogènes. Il est aujourd’hui admis que de tels édifices biologiques perdurent sous l’action des antibiotiques. Outre le très médiatique phénomène de résistance qui trouve son origine dans des mutations génétiques bactériennes, la tolérance, quant à elle, provient des spécificités de la structure et de la physiologie des bactéries organisées en biofilms. C’est dans ce contexte que s’inscrit ce travail de thèse qui vise à mieux comprendre les mécanismes sous-jacents au manque d’efficacité d’antibiotiques (vancomycine,daptomycine, rifampicine) vis-à-vis des biofilms de S. aureus, en s’appuyant notamment sur des techniques innovantes d’imagerie à résolution micro-nanométrique. Nous avons mis au point un modèle d’infections sur prothèse vasculaire implantable chez la souris qui a permis une toute première visualisation par imagerie de fluorescence de biofilms formés in vivo et soumis à l’action des antibiotiques mais aussi de montrer leur activité limitée. Nous nous sommes ensuite attachés à une meilleure compréhension de la tolérance aux antibiotiques de biofilms bactériens de S. aureus. Pour ce faire, nos études ont porté, d’une part, sur le rôle de la matrice extracellulaire et, d’autre part, sur le rôle de la physiologie des bactéries incluses en biofilm. Il a ainsi été mis en évidence le rôle crucial de la fluidité membranaire. Ces travaux nous ont alors permis de dégager des pistes pour améliorer l’antibiothérapie disponible mais aussi développer des alternatives à ce type de traitement. / Bacteria are microorganisms capable of growing independently in liquid media. However, as soon as they encounter a surface, either biotic or abiotic, bacteria favour a "community living" to protect themselves from external aggressions and survive in hostile environments. These bacterial communities, named biofilms, are present in all natural environments, including humans where they can cause severe infections when hosting pathogenic germs. It is now accepted that such biological edifices persist under antibiotics action. In addition to antibiotic 'resistance', which is associated with genetic mutations of bacteria, 'tolerance' is related with the specific structure and physiology of bacteria organized in biofilms. In this context, we took benefit from innovative high-resolution imaging techniques to better understand the mechanisms underlying antibiotics (vancomycin, daptomycin, rifampicin) (in)efficacy within S. aureus biofilms. In addition, we developed a model for prosthetic vascular graft infections in mice that allowed the visualization by fluorescence imaging of biofilms formed in vivo and subjected to the action of antibiotics. Considering the very limited antibiotics efficacy observed, we then focused on a better understanding of S. aureus bacterial biofilms tolerance towards antibiotics. To this purpose, our work was focused on the role of both the extracellular matrix and the physiology of bacteria included in biofilms. The crucial role of membrane fluidity was then demonstrated. This work allowed us to identify paths for the improvement of antibiotic therapy and to develop alternatives to this type of treatment.

Gas filled microbubbles (MBs) stabilized by a shell (e.g. lipids) are commonly used as ultrasound (US) contrast agents. Attaching biomolecules to the surface of MBs allows for molecular US imaging of various diseases. With the increased interest in targeted US imaging, new platforms to prepare disease-targeted MBs are necessary. Furthermore, attaching signaling agents to MBs creates multi-modal imaging opportunities, enhancing visualization and quantification of disease biomarkers. In this thesis, MBs labeled with 99mTc and/or rhodamine dye by taking advantage of the strong interaction between biotin and streptavidin are reported. Radiolabeling of MBs was achieved in good radiochemical yield (~ 30%). 99mTc-labeled MBs were targeted to vascular endothelial growth factor receptor 2 (VEGFR2) using an anti-VEGFR2 antibody and to prostate specific membrane antigen (PSMA) using small-molecule based PSMA inhibitors. In vitro evaluations showed successful binding of MBs to the target while in vivo targeting assessments were unsuccessful. New strategies to target MBs to the site of interest were then developed through the use of the bioorthogonal reaction between tetrazine (Tz) and trans-cyclooctene (TCO). A biotinylated derivative of Tz was loaded on streptavidin coated MBs to create a Tz-derivatized MB (MBTz). Targeting MBTz to extracellular markers of cancer such as VEGFR2, PSMA and urokinase plasminogen activator receptor (uPAR) in vitro was achieved using TCO-conjugated antibodies. In vivo targeting was successful for VEGFR2 and PSMA, but not uPAR. Translating the new strategy to other US contrast agents was then investigated. Gas vesicles (GVs) produced in halobacteria were conjugated with TCO using amide-coupling chemistry. A 99mTc-labeled derivative of Tz was loaded on TCO-GVs (RCY= 59%) and their distribution assessed by SPECT/CT imaging and ex vivo tissue counting. Having established a convenient platform to conjugate molecules to GVs and MBs, future work focuses on developing a new generation of human compatible molecular US imaging probes. / Dissertation / Doctor of Philosophy (PhD)

<p>Optical coherence tomography (OCT) is a noninvasive three-dimensional interferometric imaging technique capable of achieving micrometer scale resolution. It is now a standard of care in ophthalmology, where it is used to improve the accuracy of early diagnosis, to better understand the source of pathophysiology, and to monitor disease progression and response to therapy. In particular, retinal imaging has been the most prevalent clinical application of OCT, but researchers and companies alike are developing OCT systems for cardiology, dermatology, dentistry, and many other medical and industrial applications. </p><p>Adaptive optics (AO) is a technique used to reduce monochromatic aberrations in optical instruments. It is used in astronomical telescopes, laser communications, high-power lasers, retinal imaging, optical fabrication and microscopy to improve system performance. Scanning laser ophthalmoscopy (SLO) is a noninvasive confocal imaging technique that produces high contrast two-dimensional retinal images. AO is combined with SLO (AOSLO) to compensate for the wavefront distortions caused by the optics of the eye, providing the ability to visualize the living retina with cellular resolution. AOSLO has shown great promise to advance the understanding of the etiology of retinal diseases on a cellular level.</p><p>Broadly, we endeavor to enhance the vision outcome of ophthalmic patients through improved diagnostics and personalized therapy. Toward this end, the objective of the work presented herein was the development of advanced techniques for increasing the imaging speed, reducing the form factor, and broadening the versatility of OCT and AOSLO. Despite our focus on applications in ophthalmology, the techniques developed could be applied to other medical and industrial applications. In this dissertation, a technique to quadruple the imaging speed of OCT was developed. This technique was demonstrated by imaging the retinas of healthy human subjects. A handheld, dual depth OCT system was developed. This system enabled sequential imaging of the anterior segment and retina of human eyes. Finally, handheld SLO/OCT systems were developed, culminating in the design of a handheld AOSLO system. This system has the potential to provide cellular level imaging of the human retina, resolving even the most densely packed foveal cones.</p> / Dissertation

Functional brain images are extraordinarily rich data sets that reveal distributed brain networks engaged in a wide variety of cognitive operations. It is a substantial challenge both to create models of cognition that mimic behavior and underlying cognitive processes and to choose a suitable analytic method to identify underlying brain networks. Most of the contemporary techniques used in analyses of functional neuroimaging data are based on univariate approaches in which single image elements (i.e. voxels) are considered to be computationally independent measures. Beyond univariate methods (e.g. statistical parametric mapping), multivariate approaches, which identify a network across all regions of the brain rather than a tessellation of regions, are potentially well suited for analyses of brain imaging data. A multivariate method (e.g. partial least squares) is a computational strategy that determines time-varying distributed patterns of the brain (as a function of a cognitive task). Compared to its univariate counterparts, a multivariate approach provides greater levels of sensitivity and reflects cooperative interactions among brain regions. Thus, by considering information across more than one measuring point, additional information on brain function can be revealed. Similarly, by considering information across more than one measuring technique, the nature of underlying cognitive processes become well-understood. Cognitive processes have been investigated in conjunction with multiple neuroimaging modalities (e.g. fMRI, sMRI, EEG, DTI), whereas the typical method has been to analyze each modality separately. Accordingly, little work has been carried out to examine the relation between different modalities. Indeed, due to the interconnected nature of brain processing, it is plausible that changes in one modality locally or distally modulate changes in another modality. This thesis focuses on multivariate and multimodal methods of image analysis applied to various cognitive questions. These methods are used in order to extract features that are inaccessible using univariate / unimodal analytic approaches. To this end, I implemented multivariate partial least squares analysis in study I and II in order to identify neural commonalities and differences between the available and accessible information in memory (study I), and also between episodic encoding and episodic retrieval (study II). Study I provided evidence of a qualitative differences between availability and accessibility signals in memory by linking memory access to modality-independent brain regions, and availability in memory to elevated activity in modality-specific brain regions. Study II provided evidence in support of general and specific memory operations during encoding and retrieval by linking general processes to the joint demands on attentional, executive, and strategic processing, and a process-specific network to core episodic memory function. In study II, III, and IV, I explored whether the age-related changes/differences in one modality were driven by age-related changes/differences in another modality. To this end, study II investigated whether age-related functional differences in hippocampus during an episodic memory task could be accounted for by age-related structural differences. I found that age-related local structural deterioration could partially but not entirely account for age-related diminished hippocampal activation. In study III, I sought to explore whether age-related changes in the prefrontal and occipital cortex during a semantic memory task were driven by local and/or distal gray matter loss. I found that age-related diminished prefrontal activation was driven, at least in part, by local gray matter atrophy, whereas the age-related decline in occipital cortex was accounted for by distal gray matter atrophy. Finally, in study IV, I investigated whether white matter (WM) microstructural differences mediated age-related decline in different cognitive domains. The findings implicated WM as one source of age-related decline on tasks measuring processing speed, but they did not support the view that age-related differences in episodic memory, visuospatial ability, or fluency were strongly driven by age-related differences in white-matter pathways. Taken together, the architecture of different aspects of episodic memory (e.g. encoding vs. retrieval; availability vs. accessibility) was characterized using a multivariate partial least squares. This finding highlights usefulness of multivariate techniques in guiding cognitive theories of episodic memory. Additionally, competing theories of cognitive aging were investigated by multimodal integration of age-related changes in brain structure, function, and behavior. The structure-function relationships were specific to brain regions and cognitive domains. Finally, we urged that contemporary theories on cognitive aging need to be extended to longitudinal measures to be further validated.

Le cancer de la prostate est le cancer le plus fréquent chez l'homme en France et aux pays occidentaux. Il est la troisième cause de décès liés au cancer, étant responsable d'environ 10% des morts. La curiethérapie, une technique de radiothérapie, est liée à une meilleure qualité de vie après le traitement, par rapport aux autres méthodes de traitement. La curiethérapie de la prostate consiste à insérer des sources radioactives dans la prostate afin de délivrer une dose d'irradiation localisée à la tumeur tout en protégeant les tissus sains environnants. L'imagerie multimodale est utilisée afin d'améliorer la précision du traitement. Les images Tomodensitométriques préopératoires, appelées Computed Tomography (CT), peuvent être utilisées pour calculer une distribution personnalisée et plus précise de dose. Pendant l'intervention, le chirurgien utilise un système de guidage temps-réel par l'Ultrason Transrectale, Transrectal Ultrasound (TRUS), pour placer correctement les sources radioactives dans leurs positions souhaitées. Par conséquent, si les positions des sources sont déterminées sur l'image CT, elles doivent être transférées à l'image US. Cependant, un recalage US/CT direct et robuste est difficilement envisageable parce que les tissus mous, telle que la prostate, offrent peu de contraste en CT et en US. En revanche, l'Imagerie par Résonance Magnétique (IRM) fournit un meilleur contraste et peut, potentiellement, améliorer le traitement en améliorant la visualisation. Donc, ces trois modalités (IRM, CT et US) doivent être correctement alignées. Pour compenser les déformations de la prostate, due au changement de taille et forme entre les différentes acquisitions, un recalage non-rigide est nécessaire. Une méthode de recalage entièrement automatique est nécessaire, afin de faciliter son intégration au bloc opératoire. Nous proposons dans un premier temps un recalage IRM/CT basé sur la maximisation de l'information mutuelle en combinaison avec un champ de déformation paramétré par B-Splines. Nous proposons de contraindre le recalage sur des volumes d'intérêt (VOIs) afin d'améliorer la robustesse et le temps de calcul. L'approche proposée a été validée sur des jeux de données cliniques. Une évaluation quantitative a montré que l'erreur de recalage est égale à 1.15±0.20 mm; qui répond à la précision clinique souhaitée. Ensuite, nous proposons un deuxième recalage US/IRM, où nous utilisons une approche multi-résolution pour éviter les minima locaux et améliorer le temps de calcul. Un critère de similarité, qui met en corrélation l'intensité de l'image US avec l'intensité ainsi que le gradient de l'image IRM, a été utilisé afin de trouver la transformation qui aligne les deux images. Cette méthode a été validée sur un fantôme de prostate dans un premier temps pour évaluer sa faisabilité. Ensuite, elle a été validée sur des jeux de données cliniques en utilisant des critères qualitatives et quantitatives. La distance Hausdorff a montré que l'erreur de recalage est égale à 1.44±0.06 mm. L'approche proposée dans ce travail permet d'aller vers un protocole de curiethérapie guidée par l'imagerie multimodale qui puisse améliorer la précision globale de cette procédure. Malgré ces résultats plutôt encourageants, les travaux futurs impliqueront une évaluation plus approfondie sur plus de jeux de données afin d'évaluer la fiabilité et l'efficacité de cette méthode avant de l'intégrer au bloc opératoire. / Prostate cancer is the most common cancer in men in France and western countries. It is the third leading cause of death from cancer, being responsible for around 10% of deaths. Brachytherapy, a radiotherapy technique, is associated with a better health-related quality of life after the treatment, compared to other treatment techniques. Prostate brachytherapy involves the implantation of radioactive sources inside the prostate to deliver a localized radiation dose to the tumor while sparing the surrounding healthy tissues. Multi-modal imaging is used in order to improve the overall accuracy of the treatment. The pre-operative Computed Tomography (CT) images can be used to calculate a personalized and accurate dose distribution. During the intervention, the surgeon utilizes a real-time guiding system, Trasnrectal Ultrasound (TRUS), to accurately place the radioactive sources in their desired pre-planned positions. Therefore, if the positions of the sources were determined on CT, they need to be transferred to US. However, a robust and direct US/CT registration is hardly possible since they both provide low soft tissue contrast. Magnetic Resonance Imaging (MRI), on the other hand, has a superior contrast and can potentially improve the treatment planning and delivery by providing a better visualization. Thus, these three modalities (MRI, US and CT) need to be accurately registered. To compensate for prostate deformations, caused by changes in size and form between the different acquisitions, non-rigid registration is essential. Fully automatic registration methodology is necessary in order to facilitate its integration in a clinical workflow. At first, we propose a registration between pre-operative MR and CT images based on the maximization of the mutual information in combination with a deformation field parameterized by cubic B-Splines. We propose to constrain the registration to volumes of interest (VOIs) in order to improve the robustness and the computational efficiency. The proposed approach was validated on clinical patient datasets. Quantitative evaluation indicated that the overall registration error was of 1.15±0.20 mm; which satisfies the desired clinical accuracy. Then, we propose a second intra-operative US/MRI registration, where a multi-resolution approach is implemented to reduce the probability of local minima and improve the computational efficiency. A similarity measure, which correlates intensities of the US image with intensities and gradient magnitude of the MRI, is used to determine the transformation that aligns the two images. The proposed methodology was validated on a prostate phantom at first to assess its feasibility. Subsequently, the method was validated on clinical patient datasets and evaluated using qualitative and quantitative criteria, resulting in a registration error of 1.44±0.06 mm. The approach proposed in this work allows going towards a multimodal protocol for image-guided brachytherapy which can improve the overall accuracy of this procedure. Despite such encouraging results, future work will involve further evaluation on a larger number of datasets in order to assess the reliability and the efficiency of this methodology before integrating it in a clinical workflow.

Cette thèse traite du développement de nanoparticules d'imagerie multimodale vectorisées pour détecter spécifiquement des dépôts amyloïdes ou certains récepteurs cellulaires. Ces nanoparticules, dénommées AGuIX (Activation et Guidage de l'Irradiation par rayonnement X), sont composées d'un squelette de polysiloxane fonctionnalisées par des chélates de DOTAGA(Gd3+). Une fois marquées par un fluorophore organique ou des radioisotopes, ces Nps permettent de combiner jusqu'à trois techniques d'imagerie : l'IRM, qui présente une excellente résolution spatiale, et la scintigraphie et l'imagerie optique qui présentent toutes deux une excellente sensibilité. De par leur diamètre hydrodynamique inférieur à 5 nm, ces Nps sont efficacement éliminées par voie rénale et les différents tests in vivo réalisés n'ont pas révélé de toxicité de ces objets. Ainsi, les Nps AGuIX sont particulièrement indiquées dans le cadre d'un diagnostic précis et précoce de différentes pathologies. L'objectif de la thèse consiste donc à greffer à la surface de ces Nps des vecteurs ciblants (i) les fibres amyloïdes ; (ii) les récepteurs asialoglycoprotéines des cellules hépatocytes du foie. Selon la nature du vecteur à greffer (i.e. molécule organique, peptide, fragment d'anticorps, …) différentes stratégies ont été mises en place. Nous avons donc dans un premier temps optimisé les synthèses des Nps vectorisées, pour ensuite évaluer leur affinité pour leurs cibles respectives in vitro et/ou in vivo / The goal of this PhD is to develop multimodal imaging nanoparticles vectorized for the detection of amyloid deposit or specific cells receptors. These Nps, called AGuIX (Activation and Guidance of XRay Irradiation) are composed of a polysiloxane network surrounded by DOTAGA(Gd3+) chelates. One labeled with an organic dye or a radioisotope, these Nps could combine three imaging techniques such as MRI, known for its outstanding spatial resolution, and optical imaging and scintigraphy, known for their strong sensitivity. Thanks to their hydrodynamic diameter below 5 nm, they are efficiently eliminated from the body though renal clearance. Thus, these Nps are particularly indicated for earlier and more accurate diagnosis of a wide range of pathologies. To target amyloid deposits or asialoglycoproteins receptors we optimized the grafting several ligands (i.e. small molecules, peptides, antibody fragments, …). Then, we evaluated their affinity of their respective targets in vitro and/or in vivo

Optical coherence tomography (OCT) and Photoacoustic microscopy (PAM) are two noninvasive, high-resolution, three-dimensional, biomedical imaging modalities based on different contrast mechanisms. OCT detects the light backscattered from a biological sample either in the time or spectral domain using an interferometer to form an image. PAM is sensitive to optical absorption by detecting the light-induced acoustic waves to form an image. Due to their complementary contrast mechanisms, OCT and PAM are suitable for being combined to achieve multimodal imaging. In this dissertation, an optical coherence photoacoustic microscopy (OC-PAM) system was developed for in vivo multimodal retinal imaging with a pulsed broadband NIR light source. To test the capabilities of the system on multimodal ophthalmic imaging, the retina of pigmented rats was imaged. The OCT images showed the retinal structures with quality similar to conventional OCT, while the PAM images revealed the distribution of melanin in the retina since the NIR PAM signals are generated mainly from melanin in the posterior segment of the eye. By using the pulsed broadband light source, the OCT image quality highly depends on the pulse-to-pulse stability of the light source without averaging. In addition, laser safety is always a concern for in vivo applications, especially for eye imaging with a pulsed light source. Therefore, a continuous wave (CW) light source is desired for OC-PAM applications. An OC-PAM system using an intensity-modulated CW superluminescent diode was then developed. The system was tested for multimodal imaging the vasculature of a mouse ear in vivo by using Gold Nanorods (GNRs) as contrast agent for PAM, as well as excised porcine eyes ex vivo. Since the quantitative information of the optical properties extracted from the proposed NIR OC-PAM system is potentially able to provide a unique technique to evaluate the existence of melanin and lipofuscin specifically, a phantom study has been conducted and the relationship between image intensity of OCT and PAM was interpreted to represent the relationship between the optical scattering property and optical absorption property. It will be strong evidence for practical application of the proposed NIR OC-PAM system.

Imaging techniques have become much more in demand in modern medicine, especially in fields of disease prognosis, diagnosis and therapeutics. This is because a better understanding of different diseases, characteristics of each patient and further optimizing treatment planning, are all enhanced by advanced imaging techniques. Since each imaging modality has its own merits and intrinsic limitations, combining two or more complementary imaging modalities has become an interesting research area. In this study, gadolinium (Gd3+) doped CdTe quantum dots (QDs) were synthesized and used as multimodal imaging probes of two highly complementary imaging modalities: optical imaging and magnetic resonance imaging. The new imaging probes were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), UV-vis absorbance spectra, fluorescence spectra (FL) and magnetic resonance imaging (MRI). The optical / MRI imaging probes were further functionalized by conjugating with the axonal tracer dextran amine (10 kDa) for non-invasive axonal tracing observations. Biocompatibility and MRI contrast effect of prepared multimodal imaging probes were investigated by in vitro cell experiments and MRI scanner. Ultimately, it is hoped that this imaging probe will help us better understand the regeneration mechanisms in real time without sacrificing animals at intervening time-points.

A l'adolescence, la maturation cérébrale implique des changements anatomiques globaux et régionaux subtils, et estimer la morphologie exacte de certaines structures au cours du développement post-pubertaire est par conséquent difficile. L'effet du dimorphisme sexuel sur la maturation cérébrale n'a été que très peu exploré de façon prospective par l'imagerie par résonance magnétique. Dans ce contexte, ce travail de thèse est consacré à l'étude longitudinale des effets du sexe sur la maturation cérébrale à l'aide de deux méthodes pour contrôler et analyser les variations de positionnement spatial des images acquises à différents intervalles de temps. Dans une première étude utilisant une approche multimodale, notre objectif était d'examiner si le dimorphisme sexuel dans la maturation cérébrale du système limbique pouvait expliquer les différences émotionnelles entre les filles et les garçons pendant l'adolescence. Nous avons adapté pour cela une méthode de traitement longitudinal sur des images anatomiques et de diffusion de 335 adolescents sains entre 14 et 16 ans. Nous avons mis en évidence des différences sexuelles dans la maturation cérébrale du système limbique avec une maturation plus tardive des garçons par rapport aux filles. Ces changements avaient un rôle médiateur sur les différences sexuelles dans la régulation émotionnelle, illustrée par une augmentation des traits de personnalité positifs chez les garçons et une diminution chez les filles. Dans une deuxième étude utilisant une approche originale de recalage, notre objectif était d'estimer et extrapoler des trajectoires de maturation en fonction du dimorphisme sexuel. Nous avons mis en évidence des trajectoires divergentes entre les filles et les garçons entre 14 et 16 ans, illustrant une différenciation des vitesses de maturation croissante à cette période, spécifiquement dans le cortex préfrontal. Ces trajectoires différentielles ont permis d'estimer une avance de maturation de 5 mois chez les filles dans le cortex préfrontal. L'ensemble de ces résultats apporte des informations utiles à une meilleure compréhension des différences de maturation cérébrale entre les filles et les garçons, et de leurs liens avec la dérégulation du système émotionnel et donc la vulnérabilité à la dépression à l'adolescence. / In adolescence, brain maturation involves subtle global and regional anatomical changes, and estimating the exact morphology of some structures during post-pubertal development is therefore difficult. Effect of sexual dimorphism on brain maturation has been under-explored prospectively by magnetic resonance imaging. In this context, this work is focused on the longitudinal study of the effects of sex on brain maturation using two methods to control and analyze the spatial positioning variations of images acquired at different time points. In a first study using a multimodal approach, our goal was to examine sexual dimorphism in brain maturation of the limbic system to explain the emotional differences between girls and boys during adolescence. We adapted a method of longitudinal processing on anatomical and diffusion images of 335 healthy adolescents between 14 and 16 years. We highlighted sexual differences in brain maturation of the limbic system with a later maturation of boys compared to girls. These changes mediated sexual differences in emotional regulation, illustrated by an increase in positive personality traits in boys and a decrease in girls. In a second study using an original registration approach, our objective was to estimate and extrapolate maturation trajectories based on sexual dimorphism. We highlighted divergent trajectories between girls and boys between 14 and 16, illustrating a differentiation in maturation rates that increased during this period, specifically in the prefrontal cortex. These differential trajectories made it possible to estimate a maturational advance of 5 months in girls in the prefrontal cortex. All these results provide useful information for a better understanding of the differences in brain maturation between girls and boys, and their links with the emotional system dysregulation and therefore the vulnerability to depression in adolescence.