Healthy white matter in the brain and spinal cord is composed primarily of myelinated axons and glial cells. Myelinated axons transfer information between the peripheral nervous system and the central nervous system (CNS) as well as between centres within the CNS. Demyelination, a hallmark of neurodegenerative autoimmune diseases such as multiple sclerosis (MS), can cause nerve damage and degrade signal propagation. Magnetic resonance imaging (MRI) methods thought to assess myelin integrity and the structural integrity of axons are improving both the diagnosis and understanding of white matter diseases such as MS. Current methods, however, are sensitive to many different pathologies, making the interpretation of individual MRI results difficult. For this dissertation, several quantitative MRI methods were developed and compared, including single component T1 and T2 relaxometry, multicomponent T2 relaxometry, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI). These methods were tested on agarose gels, fixed rat spinal cords, healthy control mice, and the cuprizone mouse model of demyelination. Quantitative MRI measurements were correlated to ultrastructural measurements of white matter to determine the influence myelin content and axonal structure have on different MRI methods. Cellular distributions measured in electron micrographs of the corpus callosum correlated strongly to several different quantitative MRI metrics. The largest Spearman correlation coefficient varied depending on cellular type: longitudinal relaxation rates (RA/T1) vs. the myelinated axon fraction ( r = 0.90/-0.90), the qMTI-derived bound pool fraction (f) vs. the myelin sheath fraction ( r = 0.93), and the DTI-derived axial diffusivity vs. the non-myelinated cell fraction (r = 0.92). Using Pearson’s correlation coefficient, f was strongly correlated to the myelin sheath fraction (r = 0.98) with a linear equation predicting myelin content (5.37f −0.25). Of the calculated MRI metrics, f was the strongest indicator of myelin content while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure. Multiparametric MRI measurements of relaxation, diffusion, and magnetization transfer give a more complete picture of white matter integrity.

<p>In recent years, the emergence of diffusion tensor imaging (DTI) has provided a unique means via water diffusional characteristics to investigate the white matter integrity in the human brain, and its impact on neuronal functions. However, since the characterization of white matter integrity using DTI often lacks tissue specificity, most research studies report changes in anisotropy that are not explicitly correlated with particular cellular origins. To improve the utility of DTI in translational neuroimaging, it is critical to develop DTI acquisition techniques that are quantitative and tissue specific.</p><p>There are, nevertheless, existing methods for tissue specificity. For example, myelin water images can be generated using multiple echo time (TE) or magnetization transfer techniques. These techniques can detect changes in the concentration of myelin associated markers, but not in their spatial organization. Most white matter pathologies however start with early microstructural changes in the myelin sheaths during which the tissue contents remain similar and are thus not differentiable on a conventional MR image. Thus, the ability to construct a diffusion tensor that is myelin specific can have an immediate impact on our better understanding myelin physiology and pathophysiology during brain development. </p><p>Unfortunately, the myelin water signal decays rapidly because of its short transverse relaxation time constant (T2 < 50 ms), especially in DTI experiments where the echo time (TE) can be as large as 100ms. Even in special cases where the TE is shorter, the lack of myelin selectivity in conventional DTI techniques makes assessment of myelin microstructure extremely challenging. Thus we need to develop a DTI methodology that will greatly shorten the TE and allow myelin selectivity.</p><p>To address these challenges we have developed innovative DTI acquisition methodologies that can specifically assess myelin microstructural changes in white matter. To preserve more signal from myelin water we used a stimulated echo DTI implementation. In our initial approach we integrated this sequence with a magnetization transfer preparation to achieve additional differentiating sensitization to myelin water and derive a myelin water weighted (MWW) diffusion tensor. Our results indicate that, compared to the conventional DTI, myelin water diffuses along the axis of the fiber, but has the same has larger fractional anisotropy (FA) due to significantly smaller radial diffusivity. The limited specificity of MT and high radio frequency power deposition of MT-DTI restrict its applicability in clinical studies. </p><p>To obtain increased myelin specificity we implemented a robust stimulated echo DTI sequence with segmented spiral-out readout trajectory for achieving minimal TE on clinical MRI scanners. To ensure high spatial accuracy throughout the DTI scan we further develop a methodology for inherently and dynamically correcting both motion induced phase errors and off-resonance effects due to magnetic field inhomogeneities (including eddy currents) in the reconstructed image. We the used this technique to conduct an unprecedented experiment in which we collected DTI images at multiple echo times (as short as 18ms) and characterized the dependence of anisotropy on the T2 components including myelin water. The results confirmed the anisotropy characteristics of myelin water found with our initial previous approach. </p><p>Building on this new information, we designed a MWW-DTI method based on the simultaneous acquisition of DTI images at two different echo times within clinical practical durations. It is hoped that this new DTI technique sensitized myelin microanatomy will find wide applications in monitoring healthy brain development in pediatric populations, as many developmental brain disorders start with microstructural changes in white matter.</p> / Dissertation

Diffusion tensor imaging (DTI) is a specialist MRI modality that can identify microstructural changes or abnormalities in the brain. It can also be used to show fibre tract pathways. Both of these features were used in this thesis. Firstly, standard imaging analysis techniques were used to study the effects of mild, repetitive closed head injury on a group of professional boxers. Such data is extremely rare, so the findings of regions of brain abnormalities in the boxers are important, adding to the body of knowledge about more severe traumatic brain injury. The author developed a novel multivariate analysis technique which was used on the same data. This new technique proved to be more sensitive than the standard univariate methods commonly used. An important part of diagnosing and monitoring brain damage involves the use of biomarkers. A novel investigation of whether diffusion parameters obtained from DTI data could serve as bio-markers of cognitive impairment in Parkinson's disease was conducted. This also involved developing a multivariate approach, which displayed increased sensitivity compared with any of the component parameters used singly, and suggested these diffusion measures could be robust bio-markers of cognitive impairment. Fibre tract connectivity between regions of the brain is also a potentially valuable measure for diagnosis and monitoring brain integrity. The feasibility of this was investigated in a multi-modal MRI study. Functional MRI (fMRI) identifies regions of activation associated with a particular task. DTI can then find the pathway of the fibre bundles connecting these regions. The feasibility of using regional connectivity to interrogate brain integrity was investigated using a single healthy volunteer. Fibre pathways between regions activated and deactivated by a working memory paradigm were determined. Though the results are only preliminary, they suggest that this line of research should be continued.

Οι τεχνικές απεικόνισης μοριακής διάχυσης (DWI) και τανυστή διάχυσης (DTI) είναι από τις πιο δημοφιλείς τεχνικές μαγνητικής τομογραφίας (MRI) στην έρευνα του εγκεφάλου. Διάχυση (ή θερμική κίνηση Brown) είναι ένα τυχαίο φαινόμενο το οποίο περιγράφει τη μεταφορά υλικού (π.χ μόρια νερού) από μία χωρική θέση σε άλλη με την πάροδο του χρόνου. Η διάχυση του νερού σε βιολογικούς ιστούς παρατηρείται μέσα, έξω, γύρω από τις κυτταρικές δομές και είναι αποτέλεσμα της θερμικής ενέργειας των μορίων. Η κάθε τεχνική υποστηρίζεται από τον δικό της αλγόριθμο από τους οποίους προκύπτουν και οι αντίστοιχοι παραμετρικοί χάρτες. Πιο συγκεκριμένα από την τεχνική διάχυσης προκύπτει ο δείκτης της φαινόμενης σταθεράς διάχυσης (ADC-Apparent Diffusion Coefficient) , ενώ από την τεχνική του τανυστή διάχυσης προκύπτει ο δείκτης της κλασματικής ανισοτροπίας (FA-Fractional Anisotropy). Η παράμετρος ADC δείχνει πόσο διαφέρει η διάχυση στην περιοχή ενδιαφέροντος σε σχέση με την μέση τιμή διάχυσης. Η κλασματική ανισοτροπία (FA) είναι δείκτης μέτρησης του βαθμού ανισοτροπίας της διάχυσης και η τιμή της εξαρτάται άμεσα από την ακεραιότητα των νευρικών ινών. Το φάσμα εφαρμογής των δύο τεχνικών είναι ευρύ (εφαρμογή σε απομυελινωτικές νόσους, ισχαιμικά επεισόδια, εγκεφαλικοί όγκοι). Ο κύριος λόγος είναι ότι η διάχυση των μορίων νερού είναι ιδιαίτερα ευαίσθητη σε τυχόν αλλοιώσεις στη δομή των ινών της Λευκής ουσίας. Σκοπός της παρούσας ερευνητικής είναι η εφαρμογή των τεχνικών Τανυστή Διάχυσης (DTI) και Μοριακής Διάχυσης (DWI) σε τρείς κατηγορίες εγκεφαλικών όγκων (μηνιγγιώματα, γλοιώματα υψηλής και χαμηλής κακοήθειας, εγκεφαλικούς μεταστατικούς όγκους) με σκοπό τον διαχωρισμό αυτών. / The brain is a highly organized organ with a complex microstructural organization . The microstructural organization of brain tissue affects the molecular motion (diffusion) of water. Diffusion therefore reflects the structural organization of tissue. Diffusion imaging is a Magnetic Resonance (MR) imaging technique that allows the quantification to the molecular motion of water. Magnitude and directionality (anisotropy) of molecular motion of water can be described. Measurements of the magnitude of diffusion have been used to identify abnormal tissue in tumors, stroke, multiple sclerosis and status epilepticus. Diffusion tensor imaging (DTI) is a relatively new technique that allows rotationally invariant measurements of both magnitude and directionality of water diffusion. DTI sequences with calculation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) scalars allow characterization of the shape and magnitude of the diffusion ellipsoid. These parameters consequently reflect the microstructural architecture of the human brain. In addition, quantification of diffusion can be especially helpful as it may allow early diagnosis of pathology . The purpose of this study was to correlate the changes in FA and ADC between three different brain tumors and outline the probability of presurgical tumor differentiation.

Cette thèse a pour but de développer des techniques en imagerie par résonance magnétique(IRM) afin de détecter des altérations neurologiques à l’échelle microscopique dans des modèlesanimaux. Deux modèles chez la souris ont été étudiés en particulier: le modèle Glio6 de glioblastomehumain et le modèle MAP6, apparenté à la schizophrénie. Les méthodologies développées ont étécentrées autour de l’IRM du tenseur de diffusion (DTI) 3D rapide et à haute résolution spatiale pourdes applications ex vivo et in vivo chez le rongeur. Dans le modèle Glio6, la migration de cellulestumorales dans le corps calleux a été précocement détectée et quantifiée alors qu’aucun signe n’étaitvisible sur les IRM anatomiques classiques. La tractographie, imagerie des fibres de la matièreblanche, a permis d’identifier des déficits de certains tracts et de leurs connectivités dans le modèleMAP6. Des altérations inhomogènes ont été détectées, avec en particulier une réduction drastique dela voie cortico-spinale, résultats mettant en exergue le rôle primordial de la protéine MAP6 lors de laneuromorphogénèse. La méthode « Super Résolution » développée puis appliquée in vivo aux sourisMAP6, a permis d’obtenir en moins d’une heure une imagerie de tractographie comparable à celleobtenue ex vivo (en 59h), ce qui ouvre la voie à des suivis longitudinaux in vivo pour des études dudéveloppement du cerveau ou de l’évaluation de nouvelles thérapies. D’autre part, une méthode IRMcellulaire in vivo quantitative a été mise en place. Le principe repose sur la mesure combinée desrelaxivités cellulaires in vitro (pouvoir à réduire les temps de relaxation T2*, T2 et T1) pour convertir lestrois paramètres de la relaxation in vivo en concentrations cellulaires. En utilisant le modèle de gliomeU87 et des cellules U937 marquées magnétiquement, les résultats ont montré qu’une très large gammede concentrations cellulaires peut être quantifiée et que la biodistribution des cellules U937 autour dela tumeur est hétérogène, information essentielle pour étudier l’efficacité d’une thérapie cellulaire. / This thesis aims to develop magnetic resonance imaging (MRI) techniques to detectneurological damage at the microscopic level in animal models. Two mouse models were examined inparticular human glioblastoma model (Glio6) and a schizophrenia mouse model (MAP6 model). Themethodologies developed were centered around 3D fast diffusion tensor imaging (DTI) with highspatial resolution for ex vivo and in vivo applications in rodents. In Glio6 model, the migration oftumor cells in the corpus callosum was early detected and quantified while no signs were visible onconventional anatomical MRI. Tractography identified deficits of some tracts and their connectivity inthe MAP6 model. Inhomogeneous alterations were detected, especially with a drastic reduction of thecorticospinal pathway. Theses results highlight the crucial role of the MAP6 protein in the braindevelopment. The "Super Resolution" post-proccesing was developed and applied in vivo to MAP6mouse model. Tractography imaging comparable to that obtained ex vivo (in 59h) was obtained in lessthan one hour, paving the way for in vivo longitudinal studies as brain development studies orevaluation of new therapies. On the other hand, a in vivo cellular MRI method has been established.The principle is based on the combined measurement of cell relaxivities in vitro, to obtain in vivo cellconcentrations based on relaxation parameters. Using the U87 glioma model and U937 magneticallylabeled cells, the results showed that a wide range of cell concentrations can be quantified and thebiodistribution of U937 cells around the tumor is heterogeneous, information essential to study theeffectiveness of cell therapy.

Diffusion-weighted (DW) magnetic resonance imaging is an important neuroimaging technique that has successful applications in diagnosis of ischemic stroke and methods based on diffusion tensor imaging (DTI). Tensor measures have been used for detecting changes in tissue microstructure and for non-invasively tracing white matter connections in vivo. The most common image acquistion strategy is to use a DW single-shot echo-planar imaging (ss-EPI) pulse sequence, which is attractive due to its robustness to motion artefacts and high imaging speed. However, this sequence has limited achievable spatial resolution and suffers from geometric distortion and blurring artefacts. Readout-segmented echo-planar imaging (rs-EPI) is a DW sequence that is capable of acquiring high-resolution images by segmenting the acquisition of k- space into multiple shots. The fast, short readouts reduce distortion and blurring and the problem of artefacts due to motion-induced phase changes between shots can be overcome with navigator techniques. The rs-EPI sequence has two main shortcomings. (i) The method is slow to produce image volumes, which is limiting for clinical scans due to patient welfare and prevents us from acquiring very many directions in DTI. (ii) The sequence (like other diffusion techniques) is far from the optimum repetition time (TR) for acquiring data with the highest possible signal-to-noise ratio (SNR) in a given time. The work in this thesis seeks to address both of these important issues using a range of approaches. In Chapter 4 a partial Fourier extension is presented, which addresses point (i) by reducing the number of readout segments acquired and estimating the missing data. This allows reductions in scan time by approximately 40&percnt; and the reliability of the images is demonstrated in comparisons with the original images. The application of a simultaneous multi-slice scheme to rs-EPI, to address points (i) and (ii), is described in Chapter 5. Using the slice-accelerated rs-EPI sequence, tractography data were compared to ss-EPI data and high-resolution trace-weighted data were acquired in clinically relevant scan times. Finally, a 3D multi-slab extension that addresses point (i) is presented in Chapter 6. A 3D sequence could also allow higher resolution in the slice direction than 2D multi-slice methods, which are limited by the difficulties in exciting thin, accurate slices. A 3D version of rs-EPI was simulated and implemented and a k-space acquisition synchronised to the cardiac cycle showed substantial improvements in image artefacts compared to a conventional k-space acquisition.

The present study characterized two fiber pathways important for language, the superior longitudinal fasciculus/arcuate fasciculus (SLF/AF) and the frontal aslant tract (FAT), and related these tracts to speech, language, and literacy skill in children five to eight years old. We used Diffusion Tensor Imaging (DTI) to characterize the fiber pathways and administered several language assessments. The FAT was identified for the first time in children. Results showed no age-related change in integrity of the FAT, but did show age-related change in the left (but not right) SLF/AF. Moreover, only the integrity of the right FAT was related to phonology but not audiovisual speech perception, articulation, language, or literacy. Both the left and right SLF/AF related to language measures, specifically receptive and expressive language, and language content. These findings are important for understanding the neurobiology of language in the developing brain, and can be incorporated within contemporary dorsal-ventral-motor models for language.

Introdução: Os processos degenerativos vêm sendo considerados determinantes da progressão do déficit neurológico na esclerose múltipla (EM) e são associados sobretudo à perda neuronal e axonal. A patologia na substância branca (SB) manifesta-se pela quebra de membranas e perda da complexidade microestrutural dos tratos cerebrais, o que pode ser estudado indiretamente pelas alterações nos índices de fração de anisotropia (FA) e difusividade média (DM), obtidos por meio das análises das imagens por tensores de difusão (diffusion tensor imaging - DTI). Essa técnica oferece outros dois índices mais específicos, a difusividade axial () e difusividade radial (), que são associados aos processos de perda axonal e desmielinização, respectivamente. A perda neuronal na substância cinzenta (SC) pode ser avaliada pelo grau de atrofia do córtex cerebral. Este estudo tem como objetivos mensurar os índices de DTI na maior comissura cerebral, o corpo caloso (CC), e o grau e distribuição da atrofia cortical em indivíduos com EM remitente-recorrente (EMRR) e baixos escores de incapacidade funcional, correlacionando essas alterações com o volume de lesões macroscópicas e os principais parâmetros clínicos. Método: 31 indivíduos (22 mulheres, idade média 30,5 anos ± 8,7) com EMRR e um grupo controle (GC) composto por 34 indivíduos saudáveis (27 mulheres, idade média 32,3 anos ± 7,8) realizaram exames de crânio em aparelho de ressonância magnética de 3 Tesla (3T), sendo adquiridas imagens de DTI com 32 direções de gradiente, obtendo-se os índices de FA, DM, e de cinco segmentos na secção sagital do corpo caloso (CC). Através da segmentação de imagens volumétricas ponderadas em T1 foram obtidas as espessuras corticais regionais nos grupos. Esses resultados foram correlacionados com os volumes lesionais de imagens ponderadas em T1 e T2/FLAIR e os escores da escala expandida do estado de incapacidade (Expanded Disability Status Scale - EDSS), considerando-se significativos resultados com p< 0,05. Resultados: Os índices de FA, DM e do CC estavam difusamente alterados no grupo EMRR e a , alterada significativamente no esplênio, tronco médio anterior e tronco médio posterior do CC. Observou-se atrofia cortical significativa no terço anterior dos lobos temporais, bilateralmente, e nas regiões parietal inferior, insular e fronto-orbitária direitas, com uma tendência à atrofia no giro frontal superior esquerdo. As FA, DM e correlacionaram-se com os volumes lesionais T1 e, mais significativamente, com os volumes lesionais T2/FLAIR, porém não houve correlação entre os volumes lesionais e a . A espessura cortical no grupo EMRR apresentou correlações com ambos os volumes lesionais, mais significativamente com as lesões em T1. O escore médio da EDSS era 1,1 ± 0,9 (variando de 0-3), apresentando correlações com a DM e a no esplênio, tronco médio anterior e posterior do CC, com uma correlação com a no tronco médio posterior. O EDSS correlacionou-se com a espessura cortical na topografia do giro frontal superior esquerdo. Discussão e conclusão: Houve alteração difusa nos índices de FA, DM e nos segmentos do CC, com acometimento mais localizado, predominantemente médio posterior, da , o que pode sugerir desmielinização difusa do CC, porém axonopatia ou degeneração mais acentuada em algumas regiões da SB. A atrofia cortical também apresentou uma distribuição regional característica, afetando sobretudo as regiões temporais, bilateralmente, parietal inferior, insular e fronto-orbitária direitas. As correlações encontradas entre os índices de DTI e a espessura cortical e os volumes lesionais demonstraram que, ao menos em parte, as degenerações das SB e SC podem ser relacionadas à degeneração Walleriana, secundária ao acúmulo de placas lesionais. As correlações entre a DM, de alguns segmentos do CC e a espessura cortical do giro frontal superior com os escores da EDSS favoreceram à hipótese de que a degeneração tecidual na EM foi um fator preponderante na progressão do déficit neurológico na EMRR / Introduction: The degenerative processes are gaining attention as predictors of the neurological deficit in multiple sclerosis (MS), being reflected by the degree of axon loss and central nervous system atrophy. The white matter pathology (WM) is characterized by cellular membranes disruption and loss of the microstructural complexity, which can be accessed by the diffusion tensor imaging (DTI) indices of fractional anisotropy (FA) and mean diffusivity (MD). This imaging technique also offers two more specific indices: the axial diffusivity () and radial diffusivity (), which are useful to differentiate between axon loss and demyelination, respectively. The gray matter (GM) neuronal loss can be accessed by the degree of cortical atrophy. The aim of this study is to measure the DTI indices in the greatest WM commisure, the corpus callosum (CC), and the degree and distribution of cortical atrophy in patients with relapsing remitting MS (RRMS) and low disability scores, correlating them to the macroscopic lesion load and the main clinical scores. Method: 31 RRMS patients (22 women, mean age 30.5 years ± 8.7) and 34 healthy control (HC) subjects (27 women, mean age 32.3 years ± 7.8) were submitted to brain examinations in a 3T magnetic resonance image scanner. From DTI with 32 gradient encoding directions were extracted the indices of FA, MD, and , which were measured in 5 segments of the mid-sagital section of the corpus callosum (CC). The cortical thickness was obtained from the segmentation of volumetric T1 images. These results were correlated with the macroscopic lesion loads in the T1 and T2/FLAIR images and the scores in the Expanded Disability Status Scale EDSS, considering significant the results with p< 0.05. Results: The FA, MD and were diffusively abnormal in all 5 segments of the CC in the RRMS group and the was abnormal only in the splenium, anterior midbody and posterior mid-body. The anterior area of the both temporal lobes and right inferior parietal, some orbital-frontal and insular regions showed significant atrophy, with a tendency of atrophy in the superior frontal gyrus. The FA, MD and correlated with the T1 lesion load and, more significantly, with the T2/FLAIR lesion load. The cortical thickness correlated with T1 and T2/FLAIR lesion loads, more significantly with the T1 lesion load. The mean EDSS in the RRMS group was 1.1 ± 0.9 (range 0-3), correlating with the MD and of the splenium, anterior and posterior mid-body of the CC. The EDSS correlated to cortical thickness in the topography of the superior frontal gyrus. Discussion and conclusion: The FA, MD and are diffusively abnormal in the CC, with abnormalities in the , restricted to the medial and posterior segments. These results can be interpreted as signs of diffuse demyelination in the CC and a predominance of axonopathy or more advanced degeneration in some segments. The cortical atrophy also followed a characteristic regional distribution, affecting predominantly the bilateral temporal lobes, and inferior parietal, orbital-frontal and insular regions, in the right hemisphere. The correlations found between the DTI indices and the cortical thickness and the macroscopic lesion loads show that, at least partially, the WM and GM degeneration can be related to Wallerian degeneration secondary to macroscopic lesion accumulation. The correlations between the DM, , in some of the CC segments, and cortical thickness, in the superior frontal gyrus, and the EDSS scores reinforces the hypothesis that the degenerative processes in MS can play a role in the disability status of the patients

Application of Diffusion Tensor Imaging to Brain Gray and White Ma er A In the present work we explore the gray and white ma er applicability of diffusion tensor imaging (DTI). To evaluate effect of ferritin-bound iron on gray ma er contrast in DTI, we created an in vitro model consisting of agarose gel phantoms doped with ferritin, and validated our results in vivo on healthy volunteer subjects - years of age in the basal ganglia. We further explored the application of DTI to amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA); neurodegenerative diseases with gray and white ma er pathophysiological components. In the ALS study, patients and age- and sex-matched controls were recruited, while the MSA study included probable MSA subjects ( MSA-P, MSA-C) and age- and sex-matched controls. We found that ferritin-bound iron may make a signi cant contribution to DTI scalars in gray ma er regions of the brain, mediated by eigenvalue repulsion. is has important implications for DTI studies targeting gray ma er regions, especially in adolescence and in diseases associated with altered brain-iron load. In ALS, we found altered diffusion in the corona radiata and callosal body, and changes in R in the caudate nucleus and frontal white ma er. In MSA, we observed widespread white ma er changes associated...

O Transtorno de Humor Bipolar (THB) acomete até 3% dos adultos e os filhos desses pacientes constituem uma população em risco para o desenvolvimento de transtornos psiquiátricos. No entanto, faltam marcadores que permitam a identificação precoce dos indivíduos que apresentam maior vulnerabilidade para o desenvolvimento de psicopatologia. Estudos preliminares com Ressonância Magnética (RM) indicaram que alterações em substância branca estariam presentes não apenas em pacientes em episódio de alteração de humor, mas também em pacientes eutímicos e em seus familiares saudáveis, sugerindo que tais alterações poderiam constituir um endofenótipo potencial deste transtorno. A Imagem por Tensor de Difusão (Diffusion Tensor Magnetic Resonance Imaging - DT-MRI) é uma aquisição de RM que permite análise mais completa e detalhada das características da substância branca cerebral que a RM tradicional. A investigação de alterações na estrutura cerebral, particularmente de substância branca, de jovens portadores de THB não medicados e familiares saudáveis criteriosamente avaliados pode ajudar a elucidar a neurobiologia subjacente ao THB e, conseqüentemente, a identificar marcadores de vulnerabilidade ao transtorno. Objetivo: Avaliar se havia alterações em substância branca em crianças e adolescentes com THB e crianças e adolescentes filhos saudáveis de portadores de transtorno do humor bipolar quando comparados a controles saudáveis, utilizando a técnica de neuroimagem de DTMRI. Nossas hipóteses eram que jovens com THB e filhos de pacientes com THB, quando comparados a controles saudáveis, apresentariam (i) diminuição da fração de anisotropia (FA) e (ii) essas alterações seriam mais pronunciadas em crianças acometidas por THB do que em crianças saudáveis filhas de pacientes com THB. Métodos: Obtivemos imagens de DT-MRI de boa qualidade de 16 crianças e adolescentes com THB (média de idade ± D.P.= 12,7 ± 2,5 anos), 15 filhos saudáveis de pacientes com THB tipo I (média de idade ± D.P.= 13,5 ± 2,7 anos) e 15 controles saudáveis (média de idade ± D.P.= 13,5 ± 2,5 anos). Os diagnósticos foram formulados de acordo com os critérios do DSM-IV, usando as entrevistas Kiddie-SADS-PL (crianças) e Structured Clinical Interview for DSM-IV (adultos). A RM foi realizada em um scanner Philips 3,0 Tesla, com os seguintes parâmetros de aquisição: TR = 6106,0 ms, TE = 65,0ms, FOV = 224x224mm, espessura de corte = 2.0mm, sem gap, matriz de aquisição = 112x112 pixels e 3 médias, resultando em tamanho de voxel isotrópico = 2,0x2,0x2,0mm. As imagens de DTI foram pré-processadas com programas oriundos do FMRIB\'s software library (FSL), de acordo com o pipeline sugerido para o processamento de substância branca com Tract-Based Spatial Statistics (TBSS) e análise estatística com o programa Randomise (ambos integrantes do FSL). Resultados: Os grupos não diferiram em idade, gênero, grau de puberdade ou QI. Valores de FA de pacientes pediátricos com THB foram significativamente menores em relação aos de controles saudáveis (p < 0,05, corrigido para múltiplas comparações) em um cluster de 695 voxels no hemisfério direito que abrange a porção superiora da corona radiata e o corpo do corpo. Não houve diferença significativa entre pacientes com THB e filhos saudáveis de pacientes com THB, ou com filhos saudáveis de pacientes com THB e controles saudáveis. Discussão: Nossos dados corroboram a literatura de diminuição de FA em crianças e adolescentes com THB e avançam em mostrar esta alteração em pacientes não medicados. Mas nossos resultados não apoiam a hipótese de alterações em substância branca como endofenótipo de THB. Estudos de seguimento com amostras maiores e rigorosamente caracterizadas são necessários para se elucidar o papel das alterações em substância branca no THB. / Up to 3% of adults are affected with Bipolar Disorder (BD) and the offspring of these patients constitute a population at risk for the development of psychiatric disorders. Nevertheless, there are still no vulnerability markers to allow the early identification of those who are at greater risk of developing psychopathology among this population. Preliminary data indicate that white matter abnormalities may precede the disease onset and be present even in unaffected relatives - suggesting they could be further explored as an endophenotype for BD. Diffusion Tensor Magnetic Resonance Imaging (DTMRI) is an MRI acquisition that allows a thorough and detailed analysis of brain white matter characteristics. The investigation of white matter alterations in young, nonmedicated, BD patients and healthy relatives may help us understand the underlying neurobiology of BD. Objectives: evaluate white matter alterations in children at-risk and with BD using DT-MRI. Our hypothesis were that BD offspring, compared to healthy controls, would exhibit (i) reduced fractional anisotropy (FA) and (ii) these alterations would be more pronounced in children with BD than in those at-risk. Methods: We successfully scanned 16 BD patients (mean age ± S.D.= 12,7 ± 2,5 years) 15 healthy offspring with at least one parent with BD I diagnosis (mean age ± S.D.= 13,5 ± 2,7 years) and 15 healthy controls (mean age ± S.D.= 13,5 ± 2,5 years) with no history of psychiatric disorder in first-degree relatives. Psychiatric diagnosis were established according to the DSM-IV criteria, using the Kiddie-SADS-PL interview (children) and Structured Clinical Interview for DSM-IV (adults). The MRI was conducted at a 3.0 Tesla Philips scanner. Acquisition: the parameters were TR = 6106,0ms, TE = 65,0ms, FOV= 224x224mm, slice thickness = 2.0mm/no gap, matrix acquisition = 112x112 pixels, 3 averages, resulting in an isotropic voxel = 2,0x2,0x2,0 mm. DT-MRI images were preprocessed according to do FMRIB\'s software library\'s (FSL) pipeline for Tract-Based Spatial Statistics\' (TBSS) and Randomise analyses. Results: Groups did not differ in age, gender or pubertal status. Voxelwise analyses showed significant differences in FA values between BD patients and healthy controls (p < 0,05, FDR corrected for multiple comparisons) in a 695 voxels cluster comprising right corona radiata and corpus callosum . Discussion: This study was the first to evaluate a sample of non-medicated BD children and adolescents with DT-MRI and it corroborates extant literature data of lower FA in BD children compared to healthy controls. Nevertheless, our data do not support white matter alterations as an endophenotype for BD. More studies, with larger and well characterized samples are necessary to advance our understanding of the role of white matter alteration in BD.