L'objectif de cette thèse est de fournir une chaine de traitement complète pour la reconstruction des faisceaux de la matière blanche à partir d'images pondérées en diffusion caractérisées par une faible résolution angulaire. Cela implique (i) d'inférer en chaque voxel un modèle de diffusion à partir des images de diffusion et (ii) d'accomplir une ''tractographie", i.e., la reconstruction des faisceaux à partir de ces modèles locaux. Notre contribution en modélisation de la diffusion est une nouvelle distribution statistique dont les propriétés sont étudiées en détail. Nous modélisons le phénomène de diffusion par un mélange de telles distributions incluant un outil de sélection de modèle destiné à estimer le nombre de composantes du mélange. Nous montrons que le modèle peut être correctement estimé à partir d'images de diffusion ''single-shell" à faible résolution angulaire et qu'il fournit des biomarqueurs spécifiques pour l'étude des tumeurs. Notre contribution en tractographie est un algorithme qui approxime la distribution des faisceaux émanant d'un voxel donné. Pour cela, nous élaborons un filtre particulaire mieux adapté aux distributions multi-modales que les filtres traditionnels. Pour démontrer l'applicabilité de nos outils en usage clinique, nous avons participé aux trois éditions du MICCAI DTI Tractography challenge visant à reconstruire le faisceau cortico-spinal à partir d'images de diffusion ''single-shell" à faibles résolutions angulaire et spatiale. Les résultats montrent que nos outils permettent de reconstruire toute l'étendue de ce faisceau. / The objective of this thesis is to provide a complete pipeline that achieves an accurate reconstruction of the white matter fascicles using clinical diffusion images characterized by a low angular resolution. This involves (i) a diffusion model inferred in each voxel from the diffusion images and (ii) a tractography algorithm fed with these local models to perform the actual reconstruction of fascicles. Our contribution in diffusion modeling is a new statistical distribution, the properties of which are extensively studied. We model the diffusion as a mixture of such distributions, for which we design a model selection tool that estimates the number of mixture components. We show that the model can be accurately estimated from single shell low angular resolution diffusion images and that it provides specific biomarkers for studying tumors. Our contribution in tractography is an algorithm that approximates the distribution of fascicles emanating from a seed voxel. We achieve that by means of a particle filter better adapted to multi-modal distributions than the traditional filters. To demonstrate the clinical applicability of our tools, we participated to all three editions of the MICCAI DTI Tractography challenge aiming at reconstructing the cortico-spinal tract from single-shell low angular and low spatial resolution diffusion images. Results show that our pipeline provides a reconstruction of the full extent of the CST.

<p>Uvod: Dijabetes melitus (DM) je oboljenje koje poprima karakteristike globalne epidemije. Sve ţe&scaron;&scaron;e oboljevaju pacijenti mlaŤeg ţivotnog doba. Simptomi DM tip 2 su blagi, ţesto neprimetni, te se oboljenje otkriva kada se ve&scaron; manifestuju komplikacije. Dijabetesna nefropatija (DN) je jedna od mnogobrojnih komplikacija dijabetes melitusa tip 2, koja se zavr&scaron;ava terminalnom bubreţnom insuficijencijom. DN se ţesto neblagovremeno dijagnostikuje, zbog ţega se kasno zapoţinje leţenje. Rano otkrivanje DN od kljuţnog je znaţaja, jer omogu&scaron;ava primenu terapijskih postupaka usmerenih na oţuvanje preostalih zdravih nefrona i prevenciju terminalne bubreţne slabosti. Cilj: Prikazati poreme&scaron;aj difuzije molekula vode unutar bubrega kod DN, kori&scaron;&scaron;enjem mapa prividnog koeficijenta difuzije, kvantifikacijom vrednosti prividnog koeficijenta difuzije (ADC) i frakcione anizotropije (FA). Materijal i metode: U prospektivnu studiju bilo je ukljuţeno 10 zdravih dobrovoljaca i 91 pacijent oboleo od DM tip 2. Pacijenti oboleli od DM tip 2 podeljeni su u ţetiri grupe na osnovu vrednosti procenjene jaţine glomerularne filtracije (JGF) (grupe: I JGF &ge; 90, II 89-60, III 59-30, IV &le; 29 ml/min/1,73m&sup2;). Svim ispitanicima uraŤen je MR pregled bubrega, uz primenu DWI (b=0 i b=400 s/mm&sup2;) i DTI (b=1000 s/mm&sup2;) sekvence, na aparatu jaţine 1.5T. ADC i FA vrednosti raţunate su u &scaron;est regija od interasa, po tri u korteksu i meduli svakog bubrega. Dobijene vrednosti komparirane su sa laboratorijskim parametrima bubreţne funkcije (urea, kreatinin, mokra&scaron;na kiselina) i procenjenom JGF. Rezultati: Ne postoje statistiţki znaţajne razlike ADC i FA vrednosti parenhima, korteksa i medule levog i desnog bubrega kod zdravih dobrovoljaca i DM pacijenata. Kod DM pacijenata ADC je ve&scaron;a u korteksu nego u meduli (p=0,00), a FA vrednost je ve&scaron;a u meduli nego u korteksu (p=0,284). Urea, kreatinin i cistatin C imaju negativnu korelaciju sa ADC korteksa, medule i parenhima (p&lt;0,05), a JGF ima pozitivnu korelaciju sa ADC korteksa, medule i parenhima, kao i sa FA medule (p&lt;0,05) kod DM pacijenata. Na osnovu Post hoc testa za ADC, kod DM pacijenata postoje razlike izmeŤu I i IV grupe, izmeŤu II i IV grupe i III i IV grupe (p&le;0,05). IzmeŤu godina ţivota, teţine, BMI, JGF, HbA1c, uree i &Scaron;UK-a, postoji razlika DM pacijenata i zdravih dobrovoljaca (p&lt;0,05). Niţa je vrednost FA medule DM pacijenata u odnosu na zdrave dobrovoljce (p&lt;0,05). Postoji razlika ADC korteksa, medule i parenhima izmeŤu zdravih dobrovoljaca i DM pacijenata IV grupe, kao izmeŤu DM pacijenata I i II grupe u odnosu na IV grupu. TakoŤe postoji razlika izmeŤu FA medule zdravih dobrovoljaca i DM pacijenata I i IV grupe (p&lt;0,05). Regresiona analiza pokazala je uticaj kreatinina na ADC desnog bubrega i ADC oba bubrega, dok procenjena JGF i cistatin C imaju uticaj na ADC desnog i levog bubrega, ADC oba bubrega i FA levog bubrega (p&lt;0,05). Traktografija je prikazala naru&scaron;enu arhitektoniku kod pacijenata sa o&scaron;te&scaron;enom bubreţnom funkcijom. Zakljuţak: Postoji korelacija laboratorijskih parametara bubreţne funkcije i procenjene JGF sa ADC i FA vrednostima bubrega, &scaron;to ukazuje na ulogu funkcionalnog magnetno rezonantnog imidţinga u dijagnostici dijabetesne nefropatije. Neophodna su dalja istraţivanja koja &scaron;e doprineti standardizaciji MR protokola i potvrdi znaţaja MR biomarkera u dijagnostici DN. Na osnovu na&scaron;ih rezultata vrednost FA medule osetljiviji je parametar od ADC vrednosti u otkrivanju ranog o&scaron;te&scaron;enja bubrega u sklopu dijabetes melitusa.</p> / <p>Introduction: Diabetes mellitus (DM) is a disease that takes on the characteristics of a global epidemic. Patients of younger age are more and more commonly affected. Symptoms of type 2 DM are mild, often imperceptible, and therefore the disease is usually detected when complications are already manifested. Diabetic nephropathy (DN) is one of the many complications of type 2 diabetes mellitus that leads to terminal renal failure. Diagnosis of DN is often late, causing the delay of the treatmen. Early detection of DN is crucial because it allows the application of therapeutic procedures aimed at preserving the remaining healthy nephrons and preventing terminal renal failure. Objective: To investigate a diffusion of water molecule within a kidney in DN using apparent diffusion coefficient maps, by quantification of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values in diabetic patients with DM type 2. Material and methods: The prospective study comprised 10 healthy volunteers and 91 DM type 2 patients. DM patients were divided into four groups based on the values of the estimated glomerular filtration (eGFR) (groups: I eGFR &ge; 90, II 89-60, III 59-30, IV &le; 29 ml/min/1.73m&sup2;). All subjects were scanned by 1.5T MR using DWI (b=0 and b=400 s/mm&sup2;) and DTI (b=1000 s/mm&sup2;) sequences. ADC and FA values were calculated in six regions of interest, three in cortex and three in medulla of each kidney. Obtaned values were compared to laboratory parameters of renal function (urea, creatinine, uric acid) and eGFR. Results: There were no statistically significant differences between ADC and FA values of parenchyma, cortex and medulla of the left and the right kidney in healthy volunteers and DM patients. In DM patients, the ADC value was higher in the cortex than in the medulla (p=0.00) and the FA value was higher in the medulla than in the cortex (p=0.284). The negative correlation was found between urea, creatinine and cystatin C with ADC cortex, medulla and parenchyma (p&lt;0.05), and the eGFR was positively correlated with ADC cortex, medulla and parenchyma, and with FA medulla (p&lt;0.05) in DM patients. Based on the Post hoc test for ADC, in DM patients there were differences between I and IV group, between II and IV group, III and IV group (p&le;0,05). Regarding age, weight, BMI, GFR, HbA1c, urea, and glucose in the serum, there was a difference between DM patients and healthy volunteers (p&lt;0.05). The FA of medulla in DM patients was lower than of healthy volunteers (p&lt;0.05). There were differences in ADC of cortex, medulla, and parenchyma between healthy volunteers and DM patients of IV group, as well as between DM patients of I and II group compared to IV group. There were differences of medulla FA values between healthy volunteers and group I, accompanied by healthy and IV group of DM patients (p&lt;0.05). Regression analysis showed the influence of creatinine on ADC of right kidney and ADC of both kidneys, while eGFR and cystatin C have an effect on ADC of right and left kidney, ADC of both kidneys and FA of left kidney (p&lt;0.05). The tractography showed the disturbed architectonics in patients with impaired renal function. Conclusion: There is correlation of laboratory parameters of renal function and eGFR with ADC and FA values of the kidney, indicating the role of functional magnetic resonance imaging in the diagnosis of DN. Further research that will contribute to standardizing the MR protocol and confirming the importance of MRI biomarker in the diagnosis of DN are needed. Based on our results, the values of medulla FA is more sensitive parameter than the ADC value in detecting early kidney damage in the context of diabetes mellitus.</p>

INTRODUÇÃO: O transtorno do déficit de atenção com hiperatividade (TDAH) é um transtorno do neurodesenvolvimento ainda pouco estudado na população idosa. Déficits em funções atencionais, executivas e de memória, além de anormalidades neuroanatômicas, são observados em indivíduos adultos com TDAH. Entretanto, em idosos com TDAH tais alterações ainda são pouco estudadas. OBJETIVOS: Investigar características clínicas e neuropsicológicas, alterações no volume da substância cinzenta (SC) e da substância branca (SB) cerebral, assim como alterações em microestruturas da SB em idosos com TDAH comparando com idosos sem TDAH. MÉTODOS: A amostra foi composta por 63 indivíduos, sendo 28 com TDAH (19 mulheres), diagnosticados conforme o DSM-IV e 35 controles (29 mulheres) com idade >= 65 anos. Na avaliação clínica utilizaram-se as seguintes escalas e entrevistas: Mini Mental State Examination (MMSE); Adult ADHD Self-Report Scale (ASRS-18) ; Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Version (K-SADS-PL); Inventário Beck de Ansiedade (BAI); Geriatric Depression Scale (GDS); Structural Clinical Interview for DSM-IV (SCID); Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) e o Memory Complaint Questionnaire (MAC-Q). Os instrumentos utilizados na testagem cognitiva visaram avaliar o QI estimado, as funções atencionais, executivas e de memória e, adicionalmente tempo de reação e variabilidade de respostas, funções visoespaciais/visoconstrutivas e visoperceptivas. As imagens de ressonância magnética (RM) foram adquiridas em aparelho de 1.5 T. Duas sequências de imagens foram obtidas. Uma pela técnica da volumetria baseada no voxel (VBM) para comparação de volumes da SC e SB e a outra, por imagem por tensor de difusão (DTI), para comparação dos valores de anisotropia fracionada (AF). RESULTADOS: O grupo TDAH apresentou maior frequência de repetência escolar e de vezes repetidas, menor frequência de aposentadoria formal, mais divórcios; mais sintomas de depressão e ansiedade, maior frequência de uso atual de antidepressivo. Houve uma correlação positiva entre sintomas de desatenção e hiperatividade/impulsividade e de depressão e ansiedade. Houve uma correlação negativa entre idade e sintomas de TDAH. Os grupos não se diferenciaram estatisticamente nos testes cognitivos e houve uma tendência de correlação entre sintomas de desatenção e os resultados dos testes de atenção. Sintomas de depressão influenciaram a memória operacional, memória episódica e função visoespacial. Mais sintomas de ansiedade refletiram uma maior variabilidade no tempo de respostas. Na neuroimagem, homens com TDAH apresentaram um volume total de SC menor que os homens do grupo controle. Os grupos não se diferenciaram quanto ao volume de SB. O grupo TDAH apresentou um cluster de volume de SC menor no giro frontal medial orbital direito e que se estende em direção ao giro frontal superior medial, giro frontal superior e o córtex do cíngulo anterior subgenual. Sintomas de desatenção se correlacionaram negativamente com o volume da SC do cíngulo anterior (bilateralmente) e positivamente com o volume do cerebelo esquerdo. Sintomas de Hiperatividade/impulsividade se correlacionaram negativamente com volume da SC em região do córtex órbito-frontal esquerdo. Sintomas de depressão se correlacionaram negativamente com o volume de SC do caudado (bilateralmente) e positivamente com o volume de SC na região parietal inferior direita. Os grupos não se diferenciaram quanto aos valores da AF. Sintomas de ansiedade se correlacionaram positivamente com AF nos tratos do corpo caloso e do fascículo longitudinal superior. CONCLUSÃO: O presente estudo evidenciou correlatos neurais em regiões relacionadas às funções atencionais, ao controle executivo e ao processamento afetivo no idoso com TDAH, sugerindo que prejuízos em regiões fronto-estriatal e fronto-parietal-cerebelar verificados em adultos com TDAH persistem na velhice. Os achados reforçam os conhecimentos sobre o TDAH em idosos, sugerindo um desempenho cognitivo objetivo comparável aos controles sem o transtorno, uma redução dos sintomas centrais com o aumento da idade, embora mantendo uma funcionalidade mais prejudicada e comorbidades / INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that has not yet been studied in the elderly population. Deficits in attentional, executive and memory functions, in addition to neuroanatomical abnormalities, are found in younger individuals with ADHD. However, in elderly with ADHD such changes are still poorly studied. OBJECTIVES: To investigate clinical and neuropsychological characteristics, changes in cerebral gray matter (GM) and white matter (WM) volumes, as well as alterations in WM microstructures in elderly with ADHD compared with elderly without ADHD. METHODS: The sample consisted of 63 individuals, 28 ADHD (19 women) according to DSM-IV criteria and 35 controls (29 women) aged >= 65 years. In the clinical evaluation the following scales and interviews were used: Mini Mental State Examination; Adult ADHD Self-Report Scale (ASRS-18); Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children / Present and Lifetime Version (K-SADS-PL); Beck Anxiety Inventory (BAI); Geriatric Depression Scale (GDS); Structural Clinical Interview for DSM-IV (SCID); Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and the Memory Complaint Questionnaire (MAC-Q). The neuropsychological instruments aimed to access estimated IQ, attention, executive and memory functions and, additionally, response time and response variability, visuospatial/visuoconstructive and visuoperceptive functions. Magnetic resonance imaging (MRI) was acquired in a 1.5-T equipment. Two image sequences were obtained. One by the voxel-based volumetry (VBM) technique for comparison of GM and WM volumes and the other by diffusion tensor imaging (DTI), for comparison of fractional anisotropy (FA) values. RESULTS: The ADHD group presented a higher frequency of subjects with school repetition and number of times repeated, lower frequency of formal retirement, more divorces; more depressive and anxiety symptoms, a higher frequency of current antidepressant. There was a positive correlation between inattention and hyperactivity/impulsivity symptoms and depressive and anxiety symptoms. There was a negative correlation between age and ADHD symptoms. The groups did not differ statistically in the cognitive tests and there was a tendency of correlation between symptoms of inattention and the results of the attention tests. Symptoms of depression influenced working and episodic memory and visuospatial function. More anxiety symptoms reflected on a greater variability in response time. In neuroimaging, men with ADHD had a lower total GM volume than men in the control group. The groups did not differ regarding the WM volume. The ADHD group presented a cluster of lower GM volume in the right frontal medial orbital gyrus extending towards to frontal superior medial, frontal superior and the subgenual anterior cingulate cortex. Inattention symptoms negatively correlated with GM volume in both the right and left anterior cingulate cortex and positively correlated with the left cerebellum volume. Hyperactivity/impulsivity symptoms correlated negatively with the left inferior frontal orbital gyrus. Depression symptoms correlated negatively with the caudate (bilaterally) and positively with the right inferior parietal region. The groups did not differ regarding the FA values. Anxiety symptoms correlated positively with FA in corpus callosum and superior longitudinal fasciculus tracts. CONCLUSION: The present study showed neural correlates in regions related to functions, such as attention, executive control, and affective processing, suggesting that impairments in frontostriatal and frontoparietal-cerebellar areas observed in adults with ADHD persist into old age. Our findings reinforce the knowledge about ADHD in elderly, indicating an objective cognitive performance comparable to normal controls, a reduction of central symptoms, although maintaining a more impaired functionality and comorbidities

A esquizofrenia é um transtorno mental de alta complexidade e até o presente momento nenhuma teoria conseguiu explicar completamente sua etiologia. Uma dessas teorias acredita que a transferência de informações entre os hemisférios de pacientes com esquizofrenia, que ocorre através do corpo caloso, comissura anterior e posterior, pode estar comprometida. Os objetivos do nosso estudo foram avaliar se existem alterações de conectividade inter-hemisférica (IH) e se essas alterações sofrem influência do gênero, em pacientes portadores de esquizofrenia quando comparados com seus parentes em primeiro grau e controles saudáveis, utilizando-se da imagem de ressonância magnética por tensor de difusão (IRMTD). Participaram do estudo 30 pacientes portadores de esquizofrenia, diagnosticados pelos critérios do Manual diagnóstico e estatístico das doenças mentais em sua quarta edição, os quais foram selecionados entre os pacientes do grupo de medicações atípicas do ambulatório de esquizofrenia e da enfermaria psiquiátrica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo; 30 parentes em primeiro grau desses pacientes; e 30 voluntários saudáveis. Todos os sujeitos do estudo foram submetidos a um exame de ressonância magnética, realizado no Centro de Ciências das Imagens e Física Médica de nossa instituição, onde foram adquiridas as sequências volumétricas e difusionais utilizadas em nosso estudo. Em posse das imagens de ressonância magnética dos 90 sujeitos do estudo, realizamos o pós-processamento dessas imagens, utilizando o software BrainVoyager QX® versão 2.4, com o intuito de obtermos, por meio dos dados provenientes da IRMTD, os mapas de anisotropia fracional (AF) e difusibilidade média (DM). Com esses mapas em mãos, procedemos à análise estatística do estudo, denominada de análise de covariância voxel a voxel (VANCOVA), no cérebro todo. Nessa análise, utilizamos a idade como covariável e verificamos a influência do gênero nos resultados encontrados. Nossos resultados 6 evidenciaram que os pacientes portadores de esquizofrenia apresentaram valores de AF e DM alterados em estruturas homólogas ao corpo caloso e áreas frontais adjacentes. Assim, podemos afirmar que descobrimos perda de conectividade IH nesses mesmos pacientes. Por meio de nosso estudo, descobrimos também a influência do gênero nos valores de AF e DM encontrados e então, consequentemente, podemos dizer que a conectividade IH de pacientes portadores de esquizofrenia sofreu influência do sexo. A idade também mostrou influenciar a conectividade IH de nossos pacientes. Com o atual conceito de que alterações de AF e DM podem ser encaradas como indicativos de comprometimento da mielina, e sabendo que a mielina participa diretamente das reações neuroquímicas do sistema glutamatérgico cerebral, também podemos dizer que o sistema glutamatérgico que participa da conectividade IH desses pacientes encontrava-se comprometido. / Schizophrenia is a highly complex mental disorder and no theory to date was able to fully explain the etiology of this disorder. One of the existing theories advocates that interhemispheric communication, which occurs through the corpus callosum and the anterior and posterior commissures, might be impaired in schizophrenia. Our study was designed to investigate whether there are interhemispheric connectivity (IC) alterations in schizophrenia and whether these alterations are influenced by gender through the comparison of schizophrenia patients with their first-degree relatives and healthy controls using diffusion tensor imaging (DTI). We enrolled 30 schizophrenia patients diagnosed according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders and selected from the Group of Atypical Medications of the Schizophrenia Outpatient Clinic and the psychiatric ward of the Ribeirão Preto Medical School University Hospital, 30 first-degree relatives of these patients and 30 healthy volunteers. All subjects underwent magnetic resonance imaging (MRI) scans for the acquisition of volumetric and diffusion sequences. The images were post-processed using BrainVoyager QX® version 2.4 to create fractional anisotropy (FA) and mean diffusivity (MD) maps from DTI data. The resulting data were analyzed using voxel-to- voxel analysis of covariance (VANCOVA) for the whole brain. In this analysis, we used age as a co-variable and assessed the influence of gender. Our results showed that schizophrenia patients had altered FA and MD values in structures homologous to the corpus callosum and adjacent frontal areas, suggestive of IC loss in the patients. We also found that gender influenced FA and MD values and, therefore, that IC in schizophrenia patients is influenced by gender. Age was also found to influence IC in our patients. Based on the current conception that FA and MD alterations may indicate myelin impairment and knowing that myelin participates directly in neurochemical reactions of the glutamatergic system in the brain, we can infer that the glutamatergic system, which is implicated in IC, is affected in schizophrenia and is influenced by gender.

INTRODUÇÃO: Epilepsia do lobo temporal mesial (ELTM) por esclerose hipocampal (EH) é a forma de epilepsia focal mais comum na idade adulta e a causa mais frequente de refratariedade ao tratamento clínico. Apesar de se tratar de uma patologia da substância cinzenta, alguns estudos, por meio da imagem por tensor de difusão (diffusion tensor imaging-DTI), têm demonstrado alteração da substância branca temporal e extratemporal nestes pacientes. O corpo caloso (CC) é a maior comissura cerebral conectando áreas corticais homólogas de ambos os hemisférios cerebrais e tem sido implicado na propagação da atividade epiléptica. O objetivo principal do presente estudo foi avaliar possíveis alterações no CC de pacientes com ELTM-EH pela técnica de DTI e verificar se essas dependem da lateralidade da EH e da concordância entre os exames de ressonância magnética (RM) e os exames de vídeo-eletroencefalograma (EEG). Como objetivo secundário, também avaliou-se se estas alterações se correlacionavam com alguma variável clínica ou com as medidas volumétricas do CC. MÉTODOS: 42 pacientes com ELTM-EH (idades: 20-54 anos) e 30 voluntários saudáveis como grupo controle (idades: 18-53 anos) realizaram exame de RM de crânio, sendo obtidas sequências de DTI com 32 direções de gradiente e imagens volumétricas ponderadas em T1. Os pacientes foram também divididos em subgrupos: EH à direita e EH à esquerda, e em pacientes concordantes e discordantes. Os valores de anisotropia fracionada (AF), difusividade média (DM), difusividade axial (DA), difusividade radial (DR) e os dados volumétricos foram extraídos a partir de cinco segmentos obtidos automaticamente na secção sagital do CC. Foram realizadas comparações dos parâmetros de DTI no CC entre os grupos de pacientes e controles, e entre os subgrupos de pacientes. Foram investigadas correlações entre os parâmetros do tensor de difusão e as variáveis clínicas. As alterações volumétricas no CC dos pacientes com ELTM-EH bem como a correlação dessas alterações com as anormalidades de difusão também foram avaliadas. Considerou-se um valor de p < 0,05 como estatisticamente significativo. RESULTADOS: Nas regiões anterior, médio-posterior e posterior do CC dos pacientes, observaram-se redução da AF e aumento da DM e da DR, em relação aos controles. A DA manteve-se inalterada. Não foram demonstradas diferenças nos padrões de alteração de difusão entre os pacientes com EH à direita e com EH à esquerda, nem entre pacientes concordantes e discordantes. Não foram observadas correlações significativas entre os parâmetros do tensor de difusão com a idade ao evento inicial, idade de início da epilepsia, tempo de doença, tempo de epilepsia, período de latência e frequência de crises. No entanto, pacientes que apresentaram crise febril como evento precipitante inicial exibiram maior intensidade e extensão das alterações de difusão. Observou-se redução volumétrica difusa do CC, sendo demonstrada correlação negativa significativa entre DM e DR, e o volume nos segmentos central, médio-posterior e posterior, e, ainda, entre DA e volume do segmento posterior. Nós observamos, ainda, correlação negativa significativa entre o volume e o tempo de epilepsia, e o tempo de doença. CONCLUSÕES: Houve alteração dos parâmetros de DTI em áreas específicas do CC e redução volumétrica difusa desta estrutura. Tais anormalidades parecem ser secundárias à propagação das crises epilépticas ao longo de vias específicas anatômica ou funcionalmente relacionadas aos lobos temporais promovendo alterações secundárias na substância branca cerebral. O histórico de crise febril está relacionado a maior intensidade e extensão de acometimento do CC / INTRODUCTION: Mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) is the most common form of focal epilepsy in adults and it is frequently associated with refractoriness to medical treatment. Although epilepsy is considered a grey-matter disease, abnormalities in the temporal and extra-temporal white matter have been identified in these patients with diffusion tensor imaging (DTI). The corpus callosum (CC) is the major white matter tract connecting both cerebral hemispheres and has been implicated as an important route of spread of epileptic activity. The first goal of this study was to detect DTI abnormalities in specific areas of the CC in patients with MTLE-HS and to verify if these abnormalities depend on the laterality of the HS and on the concordance between the magnetic resonance imaging (MRI) and video-electroencephalogram (EEG). As a second goal we assessed if DTI results were correlated with any clinical variable or volumetric changes of the CC. METHODS: 42 patients (age: 20-54 years) and 30 healthy controls (age:18-53 years) were submitted to brain MRI. DTI sequences with 32 gradient encoding directions and volumetric T1-weighted images were obtained. Additionally, we grouped the patients in left sided and right sided HS and in concordant and discordant HS. Mean values of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and volumetric results were extracted from five segments at the midsagittal section of the CC obtained through automatic segmentation. Comparisons of DTI parameters of the CC were performed between patients and controls and between subgroups of patients. Correlations between DTI parameters and clinical findings were calculated. We also evaluated volume abnormalities of the CC in MTLE-HS patients and the correlations between these abnormalities and DTI changes. We considered a value of p <0.05 statistically significant. RESULTS: Our study showed that, when HS patients was compared to controls, the FA was lowest in the anterior, mid-posterior and posterior subregions of the CC. MD and RD were higher in these same segments. No changes were observed in AD. No differences in the CC DTI parameters were detected between right-sided HS and left-sided HS or between concordant and discordant HS patients. Age at initial event, age at epilepsy onset, duration of disease, duration of epilepsy, latency period and seizure frequency were not significantly correlated with the DTI parameters. However, patients who had febrile seizures as initial event exhibited greater intensity and extent of DTI changes. All segments demonstrated volume reduction compared to controls. Significant negative correlation was demonstrated between MD and RD and the volume in the central, midposterior and posterior segments of the CC, and between AD and volume of the posterior segment. We also demonstrated negative correlation between volume and duration of disease and duration of epilepsy. CONCLUSIONS: This study showed diffusion abnormalities in specific areas of the CC and diffuse atrophy in patients with unilateral HS, which may be secondary to seizures propagation along specific pathways leading to secondary changes in brain white matter. The history of febrile seizure is related to greater involvement of the CC

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.

Nach einem ausführlichem Überblick über den Kenntnisstand der Genetik und Neurowissenschaft von allgemeiner Intelligenz und einer methodischen Anmerkung zur Notwendigkeit der Berücksichtigung latenter Variablen in den kognitiven Neurowissenschaften am Beispiel einer Reanalyse publizierter Ergebnisse wir das am besten etablierte Gehirnkorrelat der Intelligenz, die Gehirngröße, aus evolutionsgenetischer Perspektive neu betrachtet. Schätzungen des Koeffizienten additiv-genetischer deuten an, dass es keine rezente direktionale Selektion auf Gehirngröße gegeben hat, was ihre Validität als Proxy für Intelligenz in evolutionären Studien in Frage stellt. Stattdessen deuten Korrelationen der Gesichtssymmetrie älterer Männer mit Intelligenz und Informationsverarbeitungsgeschwindigkeit an, dass organismusweite Entwicklungsstabilität eine wichtige Grundlage von unterschieden in kognitiven Fähigkeiten sein könnte. Im zweiten Teil dieser Arbeit geht es vornehmlich um die Alterung kognitiver Fähigkeiten, beginnend mit einem allgemeinen Überblick. Daten einer Stichprobe von über 130 Individuen zeigen dann, dass die Integrität verschiedener Nervenbahnen im Gehirn hoch korreliert, was die Extraktion eines Generalfaktors der Traktintegrität erlaubt, der mit Informationsverarbeitungsgeschwindigkeit korreliert. Der einzige Trakt mit schwacher Ladung auf diesem Generalfaktor ist das Splenium des Corpus Callosum, welches mit Veränderungen der Intelligenz über 6 Jahrzehnte korreliert und den Effekt des Bet2 adrenergischem Rezeptorgens (ADRB2) auf diese Veränderung mediiert, möglicherweise durch Effekte auf neuronale Komopensationsprozesse. Schließlich wird auf Basis neuer Analyseverfahren für Magnetresonanzdaten gezeigt, dass vermehrte Eiseneinlagerungen im Gehirn, vermutlich Marker für zerebrale Mikroblutungen, sowohl mit lebenslang stabilen Intelligenzunterschieden als auch mit der altersbedingten Veränderung kognitiver Fähigkeiten assoziiert sind. / After an extensive review of what is known about the genetics and neuroscience of general intelligence and a methodological note emphasising the necessity to consider latent variables in cognitive neuroscience studies, exemplified by a re-analysis of published results, the most well-established brain correlate of intelligence, brain size, is revisited from an evolutionary genetic perspective. Estimates of the coefficient of additive genetic variation in brain size suggest that there was no recent directional selection on brain size, questioning its validity as a proxy for intelligence in evolutionary analyses. Instead, correlations of facial fluctuating asymmetry with intelligence and information processing speed in old men suggest that organism-wide developmental stability might be an important cause of individual differences in cognitive ability. The second half of the thesis focuses on cognitive ageing, beginning with a general review. In a sample of over 130 subjects it has then been found that the integrity of different white matter tracts in the brain is highly correlated, allowing for the extraction of a general factor of white matter tract integrity, which is correlated with information processing speed. The only tract not loading highly on this general factor is the splenium of the corpus callosum, which is correlated with changes in intelligence over 6 decades and mediates the effect of the beta2 adrenergic receptor gene (ADRB2) on cognitive ageing, possibly due to its involvement in neuronal compensation processes. Finally, using a novel analytic method for magnetic resonance data, it is shown that more iron depositions in the brain, presumably markers of a history of cerebral microbleeds, are associated with both lifelong-stable intelligence differences and age-related decline in cognitive functioning.

INTRODUÇÃO: O transtorno do déficit de atenção com hiperatividade (TDAH) é um transtorno do neurodesenvolvimento ainda pouco estudado na população idosa. Déficits em funções atencionais, executivas e de memória, além de anormalidades neuroanatômicas, são observados em indivíduos adultos com TDAH. Entretanto, em idosos com TDAH tais alterações ainda são pouco estudadas. OBJETIVOS: Investigar características clínicas e neuropsicológicas, alterações no volume da substância cinzenta (SC) e da substância branca (SB) cerebral, assim como alterações em microestruturas da SB em idosos com TDAH comparando com idosos sem TDAH. MÉTODOS: A amostra foi composta por 63 indivíduos, sendo 28 com TDAH (19 mulheres), diagnosticados conforme o DSM-IV e 35 controles (29 mulheres) com idade >= 65 anos. Na avaliação clínica utilizaram-se as seguintes escalas e entrevistas: Mini Mental State Examination (MMSE); Adult ADHD Self-Report Scale (ASRS-18) ; Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Version (K-SADS-PL); Inventário Beck de Ansiedade (BAI); Geriatric Depression Scale (GDS); Structural Clinical Interview for DSM-IV (SCID); Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) e o Memory Complaint Questionnaire (MAC-Q). Os instrumentos utilizados na testagem cognitiva visaram avaliar o QI estimado, as funções atencionais, executivas e de memória e, adicionalmente tempo de reação e variabilidade de respostas, funções visoespaciais/visoconstrutivas e visoperceptivas. As imagens de ressonância magnética (RM) foram adquiridas em aparelho de 1.5 T. Duas sequências de imagens foram obtidas. Uma pela técnica da volumetria baseada no voxel (VBM) para comparação de volumes da SC e SB e a outra, por imagem por tensor de difusão (DTI), para comparação dos valores de anisotropia fracionada (AF). RESULTADOS: O grupo TDAH apresentou maior frequência de repetência escolar e de vezes repetidas, menor frequência de aposentadoria formal, mais divórcios; mais sintomas de depressão e ansiedade, maior frequência de uso atual de antidepressivo. Houve uma correlação positiva entre sintomas de desatenção e hiperatividade/impulsividade e de depressão e ansiedade. Houve uma correlação negativa entre idade e sintomas de TDAH. Os grupos não se diferenciaram estatisticamente nos testes cognitivos e houve uma tendência de correlação entre sintomas de desatenção e os resultados dos testes de atenção. Sintomas de depressão influenciaram a memória operacional, memória episódica e função visoespacial. Mais sintomas de ansiedade refletiram uma maior variabilidade no tempo de respostas. Na neuroimagem, homens com TDAH apresentaram um volume total de SC menor que os homens do grupo controle. Os grupos não se diferenciaram quanto ao volume de SB. O grupo TDAH apresentou um cluster de volume de SC menor no giro frontal medial orbital direito e que se estende em direção ao giro frontal superior medial, giro frontal superior e o córtex do cíngulo anterior subgenual. Sintomas de desatenção se correlacionaram negativamente com o volume da SC do cíngulo anterior (bilateralmente) e positivamente com o volume do cerebelo esquerdo. Sintomas de Hiperatividade/impulsividade se correlacionaram negativamente com volume da SC em região do córtex órbito-frontal esquerdo. Sintomas de depressão se correlacionaram negativamente com o volume de SC do caudado (bilateralmente) e positivamente com o volume de SC na região parietal inferior direita. Os grupos não se diferenciaram quanto aos valores da AF. Sintomas de ansiedade se correlacionaram positivamente com AF nos tratos do corpo caloso e do fascículo longitudinal superior. CONCLUSÃO: O presente estudo evidenciou correlatos neurais em regiões relacionadas às funções atencionais, ao controle executivo e ao processamento afetivo no idoso com TDAH, sugerindo que prejuízos em regiões fronto-estriatal e fronto-parietal-cerebelar verificados em adultos com TDAH persistem na velhice. Os achados reforçam os conhecimentos sobre o TDAH em idosos, sugerindo um desempenho cognitivo objetivo comparável aos controles sem o transtorno, uma redução dos sintomas centrais com o aumento da idade, embora mantendo uma funcionalidade mais prejudicada e comorbidades / INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that has not yet been studied in the elderly population. Deficits in attentional, executive and memory functions, in addition to neuroanatomical abnormalities, are found in younger individuals with ADHD. However, in elderly with ADHD such changes are still poorly studied. OBJECTIVES: To investigate clinical and neuropsychological characteristics, changes in cerebral gray matter (GM) and white matter (WM) volumes, as well as alterations in WM microstructures in elderly with ADHD compared with elderly without ADHD. METHODS: The sample consisted of 63 individuals, 28 ADHD (19 women) according to DSM-IV criteria and 35 controls (29 women) aged >= 65 years. In the clinical evaluation the following scales and interviews were used: Mini Mental State Examination; Adult ADHD Self-Report Scale (ASRS-18); Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children / Present and Lifetime Version (K-SADS-PL); Beck Anxiety Inventory (BAI); Geriatric Depression Scale (GDS); Structural Clinical Interview for DSM-IV (SCID); Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and the Memory Complaint Questionnaire (MAC-Q). The neuropsychological instruments aimed to access estimated IQ, attention, executive and memory functions and, additionally, response time and response variability, visuospatial/visuoconstructive and visuoperceptive functions. Magnetic resonance imaging (MRI) was acquired in a 1.5-T equipment. Two image sequences were obtained. One by the voxel-based volumetry (VBM) technique for comparison of GM and WM volumes and the other by diffusion tensor imaging (DTI), for comparison of fractional anisotropy (FA) values. RESULTS: The ADHD group presented a higher frequency of subjects with school repetition and number of times repeated, lower frequency of formal retirement, more divorces; more depressive and anxiety symptoms, a higher frequency of current antidepressant. There was a positive correlation between inattention and hyperactivity/impulsivity symptoms and depressive and anxiety symptoms. There was a negative correlation between age and ADHD symptoms. The groups did not differ statistically in the cognitive tests and there was a tendency of correlation between symptoms of inattention and the results of the attention tests. Symptoms of depression influenced working and episodic memory and visuospatial function. More anxiety symptoms reflected on a greater variability in response time. In neuroimaging, men with ADHD had a lower total GM volume than men in the control group. The groups did not differ regarding the WM volume. The ADHD group presented a cluster of lower GM volume in the right frontal medial orbital gyrus extending towards to frontal superior medial, frontal superior and the subgenual anterior cingulate cortex. Inattention symptoms negatively correlated with GM volume in both the right and left anterior cingulate cortex and positively correlated with the left cerebellum volume. Hyperactivity/impulsivity symptoms correlated negatively with the left inferior frontal orbital gyrus. Depression symptoms correlated negatively with the caudate (bilaterally) and positively with the right inferior parietal region. The groups did not differ regarding the FA values. Anxiety symptoms correlated positively with FA in corpus callosum and superior longitudinal fasciculus tracts. CONCLUSION: The present study showed neural correlates in regions related to functions, such as attention, executive control, and affective processing, suggesting that impairments in frontostriatal and frontoparietal-cerebellar areas observed in adults with ADHD persist into old age. Our findings reinforce the knowledge about ADHD in elderly, indicating an objective cognitive performance comparable to normal controls, a reduction of central symptoms, although maintaining a more impaired functionality and comorbidities

Estudos recentes têm sugerido que as imagens de tensor de difusão podem ser úteis para diagnosticar doença de Parkinson (DP). Nosso objetivo foi estimar a exatidão diagnóstica da anisotropia fracionada da substância negra (FA-SN) para o diagnóstico de DP, em uma amostra mais próxima do cenário clínico, incluindo pacientes com tremor essencial (TE) e voluntários sadios (VS). Para uma compreensão mais profunda de nossos achados, também realizamos uma revisão sistemática da literatura e meta-análise para estimar a mudança média da FA-SN induzida pela DP e a precisão diagnóstica dessa medida. Nossa amostra consistiu de 135 pacientes: 72 pacientes com DP, 21 com TE e 42 VS. Dois exames em RM 3T foram realizados em diferentes locais. Em nossa amostra, não encontramos diferenças significativas entre os grupos e a FA-SN não foi útil para o diagnóstico. O maior componente da variabilidade foi a interação sítio-sujeito. Os resultados desta amostra foram fundidos em uma meta-análise que incluiu 1549 indivíduos compostos de 896 pacientes com DP e 653 VS. Utilizaram-se os modelos bivariados e inversos de variância inversa para resumir as medidas de acurácia diagnóstica e as diferenças de médias, respectivamente. A meta-análise estimou uma pequena diminuição nos valores médios da FA-SN na DP (0,03 menor nos pacientes com DP (IC: 0,01 - 0,06)). Apesar disso, sua capacidade discriminatória para o diagnóstico da DP foi baixa. A sensibilidade e a especificidade combinadas foram, respectivamente, 70% (IC: 65 - 74) e 63% (IC: 57 - 69). Houve alta heterogeneidade entre os resultados dos estudos (I2 = 92%). O estudo de caso-controle e a meta-análise das medidas de anisotropia fracionada na substância negra de pacientes com doença de Parkinson e voluntários sadios demonstram que o seu uso como biomarcador de DP não é confiável / Recent studies have suggested that diffusion tensor images can be useful to diagnose Parkinson\'s disease (PD). Our goal was to estimate the diagnostic accuracy of substantia nigra fractional anisotropy (SN-FA) for PD diagnosis in a sample closer to the clinical setting, including patients with essential tremor (ET) and healthy controls (HC). To a deeper understanding of our findings, we also performed a systematic literature review and meta-analysis to estimate mean change of SN-FA induced by PD, and diagnostic accuracy of this measurement. Our sample consisted of 135 subjects: 72 PD and 21 ET patients and 42 HC. Two 3T MRI scans were performed in different sites. In our sample, we did not find significant mean difference between groups and SN-FA was useless for diagnosis. The largest component of explained variability of SN-FA was site-subject interaction. MRI results of this sample were merged in a meta-analysis that included 1549 subjects composed of 896 PD patients and 653 HC. The normal bivariate and the inverse-variance random-effect models were used to summarize diagnostic accuracy measures and mean differences respectively. Meta-analysis estimated a small decrease in mean SN-FA values in PD (0.03 lower in PD patients (CI: 0.01 - 0.06)). Despite this fact, its discriminatory capability to diagnose PD was low. The pooled sensitivity and specificity was respectively 70% (CI: 65 - 74) and 63% (CI: 57 - 69). There was high heterogeneity between studies results (I2 = 92 %). This case-control study and meta-analysis of substantia nigra fractional anisotropy measurements in Parkinson\'s disease and healthy volunteers demonstrate that their use as a PD biomarker is not reliable

L’imagerie de résonance magnétique de diffusion (dMRI) est une technique très sensible pour la tractographie des fibres de substance blanche et la caractérisation de l’intégrité et de la connectivité axonale. A travers la mesure des mouvements des molécules d’eau dans les trois dimensions de l’espace, il est possible de reconstruire des cartes paramétriques reflétant l’organisation tissulaire. Parmi ces cartes, la fraction d’anisotropie (FA) et les diffusivités axiale (λa), radiale (λr) et moyenne (MD) ont été largement utilisés pour caractériser les pathologies du système nerveux central. L’emploi de ces cartes paramétriques a permis de mettre en évidence la survenue d’altérations micro structurelles de la substance blanche (SB) et de la substance grise (SG) chez les patients atteints d’une sclérose en plaques (SEP). Cependant, il reste à déterminer l’origine de ces altérations qui peuvent résulter de processus globaux comme la cascade inflammatoire et les mécanismes neurodégénératifs ou de processus plus localisés comme la démyélinisation et l’inflammation. De plus, ces processus pathologiques peuvent survenir le long de faisceaux de SB afférents ou efférents, conduisant à une dégénérescence antero- ou rétrograde. Ainsi, pour une meilleure compréhension des processus pathologiques et de leur progression dans l’espace et dans le temps, une caractérisation fine et précise des faisceaux de SB est nécessaire. En couplant l’information spatiale de la tractographie des fibres aux cartes paramétriques de diffusion, obtenues grâce à un protocole d’acquisitions longitudinal, les profils des faisceaux de SB peuvent être modélisés et analysés. Une telle analyse des faisceaux de SB peut être effectuée grâce à différentes méthodes, partiellement ou totalement non-supervisées. Dans la première partie de ce travail, nous dressons l’état de l’art des études déjà présentes dans la littérature. Cet état de l’art se focalisera sur les études montrant les effets de la SEP sur les faisceaux de SB grâce à l’emploi de l’imagerie de tenseur de diffusion. Dans la seconde partie de ce travail, nous introduisons deux nouvelles méthodes,“string-based”, l’une semi-supervisée et l’autre non-supervisée, pour extraire les faisceaux de SB. Nous montrons comment ces algorithmes permettent d’améliorer l’extraction de faisceaux spécifiques comparé aux approches déjà présentes dans la littérature. De plus, dans un second chapitre, nous montrons une extension de la méthode proposée par le couplage du formalisme “string-based” aux informations spatiales des faisceaux de SB. Dans la troisième et dernière partie de ce travail, nous décrivons trois algorithmes automatiques permettant l’analyse des changements longitudinaux le long des faisceaux de SB chez des patients atteints d’une SEP. Ces méthodes sont basées respectivement sur un modèle de mélange Gaussien, la factorisation de matrices non-négatives et la factorisation de tenseurs non-négatifs. De plus, pour valider nos méthodes, nous introduisons un nouveau modèle pour simuler des changements longitudinaux réels, base sur une fonction de probabilité Gaussienne généralisée. Des hautes performances ont été obtenues avec ces algorithmes dans la détection de changements longitudinaux d’amplitude faible le long des faisceaux de SB chez des patients atteints de SEP. En conclusion, nous avons proposé dans ce travail des nouveaux algorithmes non supervisés pour une analyse précise des faisceaux de SB, permettant une meilleure caractérisation des altérations pathologiques survenant chez les patients atteints de SEP / Diffusion Magnetic Resonance Imaging (dMRI) is a meaningful technique for white matter (WM) fiber-tracking and microstructural characterization of axonal/neuronal integrity and connectivity. By measuring water molecules motion in the three directions of space, numerous parametric maps can be reconstructed. Among these, fractional anisotropy (FA), mean diffusivity (MD), and axial (λa) and radial (λr) diffusivities have extensively been used to investigate brain diseases. Overall, these findings demonstrated that WM and grey matter (GM) tissues are subjected to numerous microstructural alterations in multiple sclerosis (MS). However, it remains unclear whether these tissue alterations result from global processes, such as inflammatory cascades and/or neurodegenerative mechanisms, or local inflammatory and/or demyelinating lesions. Furthermore, these pathological events may occur along afferent or efferent WM fiber pathways, leading to antero- or retrograde degeneration. Thus, for a better understanding of MS pathological processes like its spatial and temporal progression, an accurate and sensitive characterization of WM fibers along their pathways is needed. By merging the spatial information of fiber tracking with the diffusion metrics derived obtained from longitudinal acquisitions, WM fiber-bundles could be modeled and analyzed along their profile. Such signal analysis of WM fibers can be performed by several methods providing either semi- or fully unsupervised solutions. In the first part of this work, we will give an overview of the studies already present in literature and we will focus our analysis on studies showing the interest of dMRI for WM characterization in MS. In the second part, we will introduce two new string-based methods, one semi-supervised and one unsupervised, to extract specific WM fiber-bundles. We will show how these algorithms allow to improve extraction of specific fiber-bundles compared to the approaches already present in literature. Moreover, in the second chapter, we will show an extension of the proposed method by coupling the string-based formalism with the spatial information of the fiber-tracks. In the third, and last part, we will describe, in order of complexity, three different fully automated algorithms to perform analysis of longitudinal changes visible along WM fiber-bundles in MS patients. These methods are based on Gaussian mixture model, nonnegative matrix and tensor factorisation respectively. Moreover, in order to validate our methods, we introduce a new model to simulate real longitudinal changes based on a generalised Gaussian probability density function. For those algorithms high levels of performances were obtained for the detection of small longitudinal changes along the WM fiber-bundles in MS patients. In conclusion, we propose, in this work, a new set of unsupervised algorithms to perform a sensitivity analysis of WM fiber bundle that would be useful for the characterisation of pathological alterations occurring in MS patients