L'évolution des connaissances dans le domaine de la neurochirurgie fonctionnelle, la neuroradiologie et les études de traçage neuronal par virus neurotropes ont permis d'étudier les circuits sous-tendant l'expression clinique de plusieurs syndromes neurologiques. La stimulation cérébrale profonde (SCP) du globus pallidus interne (GPi) est une thérapie validée dans les syndromes dystono-dyskinétiques (SDD) isolés. L'extension des indications vers des SDD secondaires ou hérédo-dégénératifs nous confronte à la nécessité d'améliorer notre compréhension des mécanismes de réorganisation fonctionnelle du circuit moteur et de l'intégrité résiduelle des connexions anatomiques. L'efficacité de la SCP dans les SDD complexes est déterminée par la préservation relative de la voie pyramidale, les interactions du circuit cortico-striato-pallido-thalamique et cérébello-thalamo-cortical et la réorganisation du réseau moteur au niveau cortical. Ce travail de thèse a essayé d’évaluer différentes composantes du réseau moteur in vivo chez l’homme à travers de l’étude de trois pathologies du mouvement associées à un SDD complexe. L’application de la SCP à la maladie de Huntington (MH) est un modèle d'étude du réseau moteur dans le contexte d’un SDD associé à une dégénérescence des neurones striato-pallidaux. Nous avons fait une étude prospective pour évaluer l'efficacité à long terme de la SCP du GPi sur les symptômes moteurs de la MH. Sept patients ayant une chorée sévère réfractaire au traitement pharmacologique ont été inclus dans l'étude. Nous avons observé une réduction significative de la chorée chez tous les patients avec un effet maintenu dans le temps (suivi médian de 3 ans). La bradykinésie et la dystonie ont montré une tendance (non significative) à une aggravation progressive. L'analyse anatomo-fonctionnelle du réseau moteur résiduel sous-tendant un SDD secondaire (dû à une lésion cérébrale acquise) a été abordée par deux techniques de neuroimagerie avancée. La réorganisation du circuit moteur dans le cadre d’une hémidystonie a été évaluée par IRM fonctionnelle. Les objectifs principaux ont été: 1) l’évaluation des régions activées par l'exécution d’une tâche motrice chez un groupe de patients hémidystoniques par rapport à un groupe de sujets témoins; 2) l’identification des profils d'activation selon le phénotype clinique (hypo/hyperkinétique) ou radiologique (lésion localisée en amont ou en aval du GPi) (des critères qui orientent l’éligibilité pour la SCP pallidale). Les études individuelles des patients ont montré des profils d'activation hétérogènes avec une activation bilatérale possible malgré le caractère unilatéral des lésions. En comparaison avec les sujets témoins, les patients ont présenté une réduction de l'activation au niveau thalamique, pallidal et temporal médial du côté ipsilatéral à la lésion. Les patients atteints d'une hémidystonie hypokinétique ont montré un profil d'activation bi-hémisphérique, désorganisé, ce qui pourrait expliquer le manque de réponse à la SCP observée dans cette présentation clinique. L'imagerie du tenseur de diffusion (DTI) a été appliquée à l'étude de la distribution topographique et la gravité des lésions de la substance blanche d'un groupe de patients atteints d'un SDD secondaire à une encéphalopathie anoxique néonatale par rapport à un groupe témoin. L'étude TBSS (tract based spatial statistics) a identifié la présence d'anomalies diffuses de la microstructure de la substance blanche (diminution de la fraction d’anisotropie (FA)) chez les patients. La technique de tractographie probabiliste a été utilisée pour reconstruire les faisceaux corticospinaux (CS) et thalamocorticaux (TC) (les voies efférentes du circuit moteur) et pour obtenir des paramètres quantitatifs DTI moyens pour chaque faisceau. La FA moyenne des faisceaux TC est diminuée chez les patients. Nous avons étudié la corrélation entre les paramètres cliniques et neurophysiologiques et les paramètres DTI du groupe de patients. / Advances in the field of functional neurosurgery, neuroradiology and virus neuronal tracing studies have enabled to deepen our knowledge of the circuits underlying the clinical expression of several neurologic syndromes. Globus pallidus internus (GPi) deep brain stimulation (DBS) is a validated technique for the treatment of isolated (primary) dystonia-dyskinesia syndromes (DDS). Broadening indications for DBS therapy to complex DDS (secondary and heredodegenerative disorders) require further understanding of motor circuit functional reorganization mechanisms and residual anatomic connections integrity. The efficacy of neuromodulation in these complex dystonia syndromes is determined by the relative preservation of pyramidal pathway, the interactions between cortico-striato-pallido-thalamic and cerebello-thalamo-cortical circuits and motor network reorganization at the cortical level. This thesis has tried to evaluate the different components of human motor network in vivo through the study of three different movement disorders associated with complex dystonia. The application of DBS to Huntington’s disease (HD) is a model for the study of the motor network in the context of this heredodegenerative DDS associated with striatal neuron degeneration in the cortico-striato-pallido-thalamic loop. We have conducted a prospective study to evaluate long-term motor outcome of GPi DBS in HD. Seven patients with severe chorea refractory to medical treatment were included in the study. Significant and sustained reduction of chorea was observed for all patients until last follow-up visit (median follow-up was 3 years). Bradykinesia and dystonia showed a non-significant trend towards progressive worsening. Anatomic and functional assessment of the motor circuit following brain injury (secondary DDS) has been approached by two different advanced neuroimaging techniques. We have studied motor circuit reorganization underlying hemidystonia in functional magnetic resonance imaging (fMRI). The main objectives of this study were: 1) to evaluate activation regions associated with motor task execution in a group of hemidystonic patients compared with another group of healthy control subjects; 2) to identify activation patterns related to clinical (hypo or hyperkinetic) or radiological (prepallidal or postpallidal) phenotypes (following clinical criteria relevant for DBS therapy eligibility). Activation patterns associated with motor-task execution were heterogeneous in single-subject studies. Despite the unilateral distribution of lesions leading to dystonia, bilateral activation was found in several subjects. Compared with healthy control group, hemidystonic patients showed reduced brain activation in ipsilesional thalamus, globus pallidus and medial temporal areas. Hypokinetic hemidystonic subgroup showed widespread bilateral overactivity involving both hemispheres. Poor clinical outcome associated with this clinical presentation could be explained by DBS therapy inability to modulate a highly disorganized network. Diffusion tensor imaging (DTI) has been applied to the study of the topographic distribution and severity of white matter lesions in a group of patients with a DDS secondary to neonatal anoxic encephalopathy in comparison with a healthy control group. TBSS (tract based spatial statistics) found widespread areas of abnormal white matter microstructure (decreased fractional anisotropy (FA)) in the corpus callosum, corona radiata and posterior limb of the internal capsule in the group of patients. After running probabilistic tractography to reconstruct corticospinal and thalamocortical tracts (motor circuit output pathways), mean quantitative tract-derived DTI parameters were calculated for each single tract. This study found decreased mean FA in thalamocortical tracts in the group of patients as compared to healthy controls. Clinical scores and neurophysiological measures were also analyzed and correlated with DTI parameters.

Si l’imagerie par résonance magnétique (IRM) montre la charge lésionnelle qui reflète le caractère inflammatoire de la sclérose en plaques (SEP), il n’existe pas de marqueur permettant de prédire son évolution ou de caractériser les phénomènes de neurodégénérescence. Par conséquent, cette étude a pour objectif premièrement d’identifier des marqueurs de l’intégrité tissulaire par IRM de tenseur de diffusion (DTI), permettant de détecter les dommages tissulaires de type inflammatoire et/ou dégénératif, et deuxièmement de caractériser leur évolution par une analyse longitudinale, chez des patients de différentes formes cliniques. A cette fin, nous avons proposé une première approche régionale des substances blanche (SB) et grise (SG) sous-corticale et une deuxième approche statistique globale analysant par TBSS les variations d’anisotropie de la SB et par VBM la densité de la SG. Les résultats obtenus dans la SB montrent des variations de la fraction d’anisotropie (FA), et des diffusivités radiales et axiales reflétant respectivement une atteinte myélinique et une atteinte axonale alors que la SG présente une augmentation de la FA suggérant une atteinte dendritique neuronale. L’analyse par TBSS et VBM montre des anomalies touchant plutôt les régions sous-corticales chez les patients rémittents qui s’étendent aux régions corticales chez les patients de forme progressive. Longitudinalement, on retrouve essentiellement des changements de FA dans la SB et d’atrophie de la SG chez les patients rémittents. Ces travaux montrent que la DTI constitue une méthode sensible pour une meilleure détection et compréhension des altérations cérébrales et de leur évolution dans la SEP. / If magnetic resonance imaging (MRI) shows the inflammatory nature of multiple sclerosis (MS) lesions, there is no marker capable of predicting its evolution or characterizing neurodegeneration. Therefore, the aim of this work was first, to identify markers of tissue integrity by diffusion tensor MRI (DTI) for the detection of inflammatory and/or degenerative tissue damages, and second, to characterize their changes with time using a longitudinal analysis of patients with different clinical forms. To this end, we first proposed a regional approach based on several white (WM) and gray (GM) matter regions of interest, and second, a statistical approach for the analysis of global WM anisotropy changes (TBSS) and GM density changes (VBM). WM analysis showed variations of the fractional anisotropy (FA), and radial and axial diffusivities, reflecting myelin and axonal damage respectively, while the GM analysis showed increased FA suggesting neuronal dendritic loss. TBSS and VBM analysis showed abnormalities affecting mostly subcortical regions in patients with relapsing-remitting (RR) MS which extended to cortical regions in patients with progressive MS. Longitudinally, we mainly observed WM FA changes and GM atrophy in RR patients. This work showed that DTI is a sensitive method for the detection and a better understanding of brain alterations and their progression in MS

Thesis named Calculation of advanced diffusion parameters in brain grey matter from DKI MRI images deals with processing of diffusion-weighted images from DKI. The thesis contains review of literature on principle of diffusion, influence of diffusion on MRI, calculation of DTI and DKI parameters and clinical application of diffusion-weighted maps with focus on grey matter. The thesis focuses on software tools for processing and pre-processing DTI and DKI. The practical part consisted of two sections. Two different softwares were used to calculate maps of diffusion parameters. Diffusion parameters from anatomical structure sunstantia nigra were compared between group of healthy controls and patients with Parkinson’s disease. This comparison did not show any statisticaly significant difference. In the second step, a script for creating diffusion maps in software Diffusinal Kurtosis Estimator was made.

<p>While radiation therapy is a standard treatment modality for managing primary and metastatic brain tumors, it causes irreversible and progressive long-term side effects that decrease the quality of life for pediatric brain tumor survivors. These side effects, known as radiation-induced brain injury (RIBI) and which occur at least 6 months post-treatment, create challenges in education, employment, and social relationships throughout the patients’ lifetime. With the prognosis for pediatric cancer patients constantly improving, long-term side effects such as RIBI pose a major clinical problem for post-treatment care. To create and evaluate treatments for this clinical injury, it is critical to understand how this condition forms and develops. However, this cannot be done in patients due to the invasive nature of cranial biopsies. The current scientific understanding behind the pathophysiology of these late-delayed forms of RIBI is therefore built upon studies of pre-clinical animal models. Such experimental models, typically of healthy rodents, are not currently capable of accurately replicating the radiological and histological changes seen in human patients. This inconsistency limits the efficacy of preclinical discoveries when translated to clinical trials. To address this issue, we chose to establish a mini-pig model for RIBI using a standard clinical approach of radiation delivery and follow-up imaging. Our hypothesis is that cranial irradiation of the mini-pig brain will elucidate the clinical magnetic resonance imaging (MRI) signatures of RIBI, which will then correspond to characteristic changes in diffusion properties, metabolite profiles, immune constituents, and glial and neuronal cell subpopulations as evidenced by advanced MRI techniques and histopathology. As such, results from Aim 1 have highlighted not only incongruencies between rodent models and clinical findings, but also various inconsistencies in current assessment techniques of late-delayed RIBI in patients. Additionally, results from Aim 2 have established the feasibility of a mini-pig model of RIBI based on the current clinical standard of diagnosis. Finally, results from Aim 3 describe characteristic changes in diffusion properties and histological appearances as well as novel changes in metabolite concentrations within our mini-pig model late-delayed RIBI. In conclusion, this intermediate animal model of RIBI can replicate the clinical condition and may ultimately provide valuable insight into the pathophysiology of RIBI. </p>

Introduction: Bone loss, fractures, and declining physical performance are associated with muscle atrophy and fat infiltration. Muscle structure and composition differences may be apparent between women with and without osteoporosis (OP). Purpose: To: 1) evaluate the effect of a time period spent in supine on magnetic resonance imaging (MRI) measures of muscle size and diffusion properties in young and older women; 2) assess the feasibility of applying three MRI scanning methods to evaluate macrostructural and microstructural properties of leg muscles in older women; and 3) compare musculoskeletal tissue structure and composition between older women with and without OP, and to determine the relationships between bone, muscle, fat, and physical performance. Methods: Sixteen young and older women had their legs scanned with MRI at baseline and after 30 and 60 minutes of supine resting. Feasibility of recruitment, participant tolerance to scanning, and image acquisition and analysis protocols were assessed. Thirty-five moderately active, older women with and without OP underwent MRI and peripheral quantitative computed tomography scanning of the leg and performed physical performance tests. Results: In young and older women, muscle size did not change with time spent supine, but water diffusivity decreased in some muscle regions. It is feasible to perform a single session of three MRI scanning techniques in older women. Women with and without OP had similar musculoskeletal structure that showed fat infiltration is associated with reduced bone strength and slower gait speed. Conclusions: In young and older women, muscle size is unaffected by a period of supine rest, but time spent in supine may modify water diffusivity measures. It is feasible to use a combination of MRI scanning techniques to evaluate leg muscle structure in older women. MRI improves our understanding of the relationships among muscle, fat, bone, and physical performance. / Dissertation / Doctor of Science (PhD)

Recently there has been considerable attention directed towards the increased risk for head injuries that athletes face while participating in high impact sports. Furthermore, there is also heightened interest in the asymptomatic sport related sub-concussive blows, commonly experienced during play, that possibly lead to long term neurological deficits. Purpose: The goal of this study was to investigate retired professional athletes of the Canadian Football League with a history of sport-related concussions, using several advanced MRI methods. The ultimate goal being the identification of any potential synergistic effects between a history of sport-related concussions, and exacerbated cognitive decline later on in life. Materials and Methods: Twenty former professional athletes of the Canadian Football League were scanned using a GE Discovery MR750 3T MRI with a 32-channel RF-coil. Axial FSPGR-3D images were used to define rs-BOLD and DTI scans. Seed based network analysis of the DMN was performed on rs-BOLD data. Voxel-wise tensor fitting of DTI data provided the means for estimating several tensor metrics. Results were normalized through comparison with a database of healthy controls. Potential associations between functional connectivity, white matter integrity, and cortical thickness measures were correlated with retired athlete position and years of professional play. Results: We found widespread cortical thinning in retired CFL subjects, alongside significant increases in axial and mean diffusivity in the corona radiata and splenium and genu of the corpus callosum compared to controls. Seed based correlation analysis of the DMN network revealed interrupted connectivity in retired athletes. Athlete age, po- sition, and number of years played appear to be factors in overall core white matter microstructural integrity. Conclusions: When compared to an age and sex matched control population, differences were observed both in functional and structural con- nectivity, suggesting that even years after retiring the brains of these former athletes still exhibit signs of damage. / Thesis / Master of Applied Science (MASc) / Sport-related concussions affect millions of athletes on a yearly basis in the United States alone. Concussions are often accompanied by short-lived neurological impairments, such as confusion, headaches, dizziness, nausea and memory loss. In addition, there is the potential for development of long term mental health and cognitive impairment. The goal of this work was to identify any neurological changes present in retired athletes of the Canadian Football League, through the use of advanced magnetic resonance imaging techniques evaluating thickness of brain structures, changes in brain activity, and alterations in core microstructure of the brain. Analyzing the results of these techniques revealed changes in a number of brain regions within the retired professional athlete population. These results suggest that a career of high impact sports may lead to short term, in addition to long-term neurological consequences.

People suffering from congenital anosmia show normal brain architecture although they do not have functional sense of smell. Some studies in this regard point to the changes in secondary olfactory cortex, orbitofrontal cortex (OFC), in terms of gray matter volume increase. However, diffusion tensor imaging has not been explored so far. We included 13 congenital anosmia subjects together with 15 controls and looked into various diffusion parameters like FA. Increased FA in bilateral OFC confirms the earlier studies reporting increased gray matter thickness. However, it is quite difficult to interpret FA in terms of gray matter volume. Increased FA has been seen with recovery after traumatic brain injury. Such changes in OFC point to the plastic nature of the brain.

Thesis (MScMedSc (Biomedical Sciences. Medical Physiology))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: HIV/AIDS is a global epidemic that accounts for a large percentage of the mortality in South Africa every year. Since the implementation of anti-retroviral treatment, HIV positive individuals have been living longer, and the cognitive impairment associated with the disease is becoming increasingly apparent. During the initial systemic infection of HIV, the virus migrates through the blood-brain barrier and inflicts axonal injury by causing upregulation of cytokines and neurotoxic proteins. HIV-associated dementia is a neuropsychological classification of cognitive impairment in HIV and a variety of symptoms have been classified as a part of the dementia complex. One of these is apathy, which is thought to be a precursor for dementia in HIV patients. Three groups of individuals have been recruited and scanned using magnetic resonance imaging (MRI) to examine changes in the brain. These are an HIV non-apathetic cohort, an HIV apathetic cohort and a healthy control cohort. Diffusion tensor imaging (DTI) is an MRI technique used to quantitatively assess white matter (WM) integrity using metrics such as fractional anisotropy (FA). Voxel-based analysis, tract-based spatial statistics (TBSS) and tractography are three established DTI analysis methods that have been applied in numerous studies. However, there are certain methodological strengths and limitations associated with each technique and therefore all three of these techniques were used to compare WM differences across groups. The frontal-subcortical pathways are known to be abnormal in apathy, and this has been demonstrated in a number of imaging studies. Most of these studies have examined apathy in the context of neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s. However, to our knowledge this is the first DTI study in HIV apathetic patients. With the tractography method, the anterior thalamic radiation and the corpus callosum were reconstructed for each individual to determine whether there were any global changes in these tracts. No significant changes were found. However, a variety of regions in the WM were significantly abnormal in the HIV cohorts when comparing the data at a voxel-based level and using TBSS. This included areas such as the genu and splenium of the corpus callosum, the internal capsule and corona radiata. Changes in frontal WM for the HIV apathy group are an indication of dysfunction in the frontal-striatal circuits, and previous literature has implicated these circuits in the neuropathology of apathy in a variety of central nervous system (CNS) disorders. / AFRIKAANSE OPSOMMING: MIV/VIGS is `n wêreldwye epidemie wat verantwoordelik is vir `n hoë sterftesyfer in Suid- Afrika elke jaar. Sedert die inleiding van anti-retrovirale behandeling, het die MIV-positiewe populasie se lewensduur verleng. Tesame met langer lewensduur, het die kognitiewe verswakking wat geassosieer word met die siekte ook meer prominent na vore gekom. Gedurende die beginstadium van sistemiese infeksie in MIV is daar `n migrasie van die virus deur die bloed-breinskans. MIV kan indirek verantwoordelik wees vir aksonale beskadiging deur verhoging van neurotoksiese proteine en sitokinien te induseer. MIV-geassosieerde demensie is `n neurosielkundige klassifikasie van kognitiewe verswakking in MIV en verskeie simptome is al geïdentifiseer as deel van die demensie kompleks. Een van die simptome is apatie en daar word gespekuleer dat dit `n voorloper is vir demensie in MIV pasiënte. Drie groepe individue was gewerf vir die studie en geskandeer deur magnetiese resonansie beeldvorming (MRB) om sodoende veranderinge in die brein te ondersoek. Die groepe was onderskeidelik `n HIV nie-apatiese kohort, `n HIV apatiese kohort en `n gesonde kontrole kohort. Diffusie tensor beelding (DTB) is `n MRB tegniek wat toegepas word om witstof integriteit te meet deur gebruik te maak van maatstawwe soos fraksionele anisotropie (FA). “Voxel-based analysis”, “tract-based spatial statistics (TBSS)” en “tractography” is drie gevestigde DTB analitiese metodes wat al in talle studies toegepas was. Daar is egter sekere metodologiese voordele en beperkings verbonde aan elke tegniek en daarom is al drie tegnieke gebruik om witstof verskille tussen groepe te vergelyk. Die frontale-subkortikale roetes in die brein is bekend vir abnormaliteite in apatie en dit was ook al gedemonstreer in verskeie studies. Die meeste van die studies het apatie ondersoek in die konteks van neurodegeneratiewe siektes soos Alzheimer se siekte en Parkinson se siekte. Maar sover ons weet is hierdie die eerste DTB studie in MIV pasiënte met apatie. Met die “tractography” metode was die anterior thalamic radiation en corpus callosum herbou vir elke individu. Dit was om te bepaal of daar enige globale veranderinge is in hierdie gebiede, maar geen beduidende veranderinge is gevind nie.`n Verskeidenheid van gebiede in die witstof was beduidend abnormaal in die MIV kohorte wanneer die data vergelyk was met “TBSS” en “voxel-based analysis.” Dit het gebiede ingesluit soos die genu en splenium van die corpus callosum, die internal capsule en die corona radiata. Veranderinge in die frontale witstof vir die MIVapatie groep is `n aanduiding van disfunksie in die frontale-striatale bane. Vorige literatuur impliseer dat hierdie bane betrokke is in die neuro-patologie van apatie in verskeie sentrale senuweestelsel (SS) steurings.

L’Imagerie par résonance magnétique (IRM) est un outil fondamental pour l’exploration in vivo du développement du cerveau chez le fœtus, le bébé et l’enfant. Elle fournit plusieurs paramètres quantitatifs qui reflètent les changements des propriétés tissulaires au cours du développement en fonction de différents processus de maturation. Cependant, l’évaluation fiable de la maturation de la substance blanche est encore une question ouverte: d'une part, aucun de ces paramètres ne peut décrire toute la complexité des changements sous-jacents; d'autre part, aucun d'eux n’est spécifique d’un processus de développement ou d’une propriété tissulaire particulière. L’implémentation d’approches multiparamétriques combinant les informations complémentaires issues des différents paramètres IRM devrait permettre d’améliorer notre compréhension du développement du cerveau. Dans ce travail de thèse, je présente deux exemples de telles approches et montre leur pertinence pour l'étude de la maturation des faisceaux de substance blanche. La première approche fournit une mesure globale de la maturation basée sur la distance de Mahalanobis calculée à partir des différents paramètres IRM (temps de relaxation T1 et T2, diffusivités longitudinale et transverse du tenseur de diffusion DTI) chez des nourrissons (âgés de 3 à 21 semaines) et des adultes. Cette approche offre une meilleure description de l’asynchronisme de maturation à travers les différents faisceaux que les approches uniparamétriques. De plus, elle permet d'estimer les délais relatifs de maturation entre faisceaux. La seconde approche vise à quantifier la myélinisation des tissus cérébraux, en calculant la fraction de molécules d’eau liées à la myéline (MWF) en chaque voxel des images. Cette approche est basée sur un modèle tissulaire avec trois composantes ayant des caractéristiques de relaxation spécifiques, lesquelles ont été pré-calibrées sur trois jeunes adultes sains. Elle permet le calcul rapide des cartes MWF chez les nourrissons et semble bien révéler la progression de la myélinisation à l’échelle cérébrale. La robustesse de cette approche a également été étudiée en simulations. Une autre question cruciale pour l'étude du développement de la substance blanche est l'identification des faisceaux dans le cerveau des enfants. Dans ce travail de thèse, je décris également la création d'un atlas préliminaire de connectivité structurelle chez des enfants âgés de 17 à 81 mois, permettant l'extraction automatique des faisceaux à partir des données de tractographie. Cette approche a démontré sa pertinence pour l'évaluation régionale de la maturation de la substance blanche normale chez l’enfant. Pour finir, j’envisage dans la dernière partie du manuscrit les applications potentielles des différentes méthodes précédemment décrites pour l’étude fine des réseaux de substance blanche dans le cadre de deux exemples spécifiques de pathologies : les épilepsies focales et la leucodystrophie métachromatique. / Magnetic Resonance Imaging (MRI) is a fundamental tool for in vivo investigation of brain development in newborns, infants and children. It provides several quantitative parameters that reflect changes in tissue properties during development depending on different undergoing maturational processes. However, reliable evaluation of the white matter maturation is still an open question: on one side, none of these parameters can describe the whole complexity of the undergoing changes; on the other side, neither of them is specific to any particular developmental process or tissue property. Developing multiparametric approaches combining complementary information from different MRI parameters is expected to improve our understanding of brain development. In this PhD work, I present two examples of such approaches and demonstrate their relevancy for investigation of maturation across different white matter bundles. The first approach provides a global measure of maturation based on the Mahalanobis distance calculated from different MRI parameters (relaxation times T1 and T2, longitudinal and transverse diffusivities from Diffusion Tensor Imaging, DTI) in infants (3-21 weeks) and adults. This approach provides a better description of the asynchronous maturation across the bundles than univariate approaches. Furthermore, it allows estimating the relative maturational delays between the bundles. The second approach aims at quantifying myelination of brain tissues by calculating Myelin Water Fraction (MWF) in each image voxel. This approach is based on a 3-component tissue model, with each model component having specific relaxation characteristics that were pre-calibrated in three healthy adult subjects. This approach allows fast computing of the MWF maps from infant data and could reveal progression of the brain myelination. The robustness of this approach was further investigated using computer simulations. Another important issue for studying white matter development in children is bundles identification. In the last part of this work I also describe creation of a preliminary atlas of white matter structural connectivity in children aged 17-81 months. This atlas allows automatic extraction of the bundles from tractography datasets. This approach demonstrated its relevance for evaluation of regional maturation of normal white matter in children. Finally, in the last part of the manuscript I describe potential future applications of the previously developed methods to investigation of the white matter in cases of two specific pathologies: focal epilepsy and metachromatic leukodystrophy.

Les lésions de la moelle épinière ont un impact significatif sur la qualité de la vie car elles peuvent induire des déficits moteurs (paralysie) et sensoriels. Ces déficits évoluent dans le temps à mesure que le système nerveux central se réorganise, en impliquant des mécanismes physiologiques et neurochimiques encore mal connus. L'ampleur de ces déficits ainsi que le processus de réhabilitation dépendent fortement des voies anatomiques qui ont été altérées dans la moelle épinière. Il est donc crucial de pouvoir attester l'intégrité de la matière blanche après une lésion spinale et évaluer quantitativement l'état fonctionnel des neurones spinaux. Un grand intérêt de l'imagerie par résonance magnétique (IRM) est qu'elle permet d'imager de façon non invasive les propriétés fonctionnelles et anatomiques du système nerveux central. Le premier objectif de ce projet de thèse a été de développer l'IRM de diffusion afin d'évaluer l'intégrité des axones de la matière blanche après une lésion médullaire. Le deuxième objectif a été d'évaluer dans quelle mesure l'IRM fonctionnelle permet de mesurer l'activité des neurones de la moelle épinière. Bien que largement appliquées au cerveau, l'IRM de diffusion et l'IRM fonctionnelle de la moelle épinière sont plus problématiques. Les difficultés associées à l'IRM de la moelle épinière relèvent de sa fine géométrie (environ 1 cm de diamètre chez l'humain), de la présence de mouvements d'origine physiologique (cardiaques et respiratoires) et de la présence d'artefacts de susceptibilité magnétique induits par les inhomogénéités de champ, notamment au niveau des disques intervertébraux et des poumons. L'objectif principal de cette thèse a donc été de développer des méthodes permettant de contourner ces difficultés. Ce développement a notamment reposé sur l'optimisation des paramètres d'acquisition d'images anatomiques, d'images pondérées en diffusion et de données fonctionnelles chez le chat et chez l'humain sur un IRM à 3 Tesla. En outre, diverses stratégies ont été étudiées afin de corriger les distorsions d'images induites par les artefacts de susceptibilité magnétique, et une étude a été menée sur la sensibilité et la spécificité de l'IRM fonctionnelle de la moelle épinière. Les résultats de ces études démontrent la faisabilité d'acquérir des images pondérées en diffusion de haute qualité, et d'évaluer l'intégrité de voies spinales spécifiques après lésion complète et partielle. De plus, l'activité des neurones spinaux a pu être détectée par IRM fonctionnelle chez des chats anesthésiés. Bien qu'encourageants, ces résultats mettent en lumière la nécessité de développer davantage ces nouvelles techniques. L'existence d'un outil de neuroimagerie fiable et robuste, capable de confirmer les paramètres cliniques, permettrait d'améliorer le diagnostic et le pronostic chez les patients atteints de lésions médullaires. Un des enjeux majeurs serait de suivre et de valider l'effet de diverses stratégies thérapeutiques. De telles outils représentent un espoir immense pour nombre de personnes souffrant de traumatismes et de maladies neurodégénératives telles que les lésions de la moelle épinière, les tumeurs spinales, la sclérose en plaques et la sclérose latérale amyotrophique. / Spinal cord injury has a significant impact on quality of life since it can lead to motor (paralysis) and sensory deficits. These deficits evolve in time as reorganisation of the central nervous system occurs, involving physiological and neurochemical mechanisms that are still not fully understood. Given that both the severity of the deficit and the successful rehabilitation process depend on the anatomical pathways that have been altered in the spinal cord, it may be of great interest to assess white matter integrity after a spinal lesion and to evaluate quantitatively the functional state of spinal neurons. The great potential of magnetic resonance imaging (MRI) lies in its ability to investigate both anatomical and functional properties of the central nervous system non invasively. To address the problem of spinal cord injury, this project aimed to evaluate the benefits of diffusion-weighted MRI to assess the integrity of white matter axons that remain after spinal cord injury. The second objective was to evaluate to what extent functional MRI can measure the activity of neurons in the spinal cord. Although widely applied to the brain, diffusion-weighted MRI and functional MRI of the spinal cord are not straightforward. Various issues arise from the small cross-section width of the cord, the presence of cardiac and respiratory motions, and from magnetic field inhomogeneities in the spinal region. The main purpose of the present thesis was therefore to develop methodologies to circumvent these issues. This development notably focused on the optimization of acquisition parameters to image anatomical, diffusion-weighted and functional data in cats and humans at 3T using standard coils and pulse sequences. Moreover, various strategies to correct for susceptibility-induced distortions were investigated and the sensitivity and specificity in spinal cord functional MRI was studied. As a result, acquisition of high spatial and angular diffusion-weighted images and evaluation of the integrity of specific spinal pathways following spinal cord injury was achieved. Moreover, functional activations in the spinal cord of anaesthetized cats was detected. Although encouraging, these results highlight the need for further technical and methodological development in the near-future. Being able to develop a reliable neuroimaging tool for confirming clinical parameters would improve diagnostic and prognosis. It would also enable to monitor the effect of various therapeutic strategies. This would certainly bring hope to a large number of people suffering from trauma and neurodegenerative diseases such as spinal cord injury, tumours, multiple sclerosis and amyotrophic lateral sclerosis.