published_or_final_version / Orthopaedics and Traumatology / Master / Master of Philosophy

La conception classique de l'organisation des réseaux cérébraux participant au langage décrit deux zones corticales, l'une frontale (Broca), l'autre temporale intervenant respectivement dans la production et la compréhension du langage, unies par un faisceau de substance blanche: le faisceau longitudinal supérieur. L'imagerie par résonance magnétique d'activation (IRMf) a rendu possible la visualisation de zones d'activation corticales, et l'imagerie en tenseur de diffusion avec la tractographie celle des faisceaux de substance blanche. Ces données nouvelles permettent de repenser l'organisation corticale et sous-corticale du langage. L'ensemble des travaux en imagerie d'activation étaye l'hypothèse d'une dissociation dorso-ventrale du traitement du langage. Les zones de traitement de l'information phonétique étant dorsales, et les centres impliqués dans le traitement sémantique plus ventraux. Imagerie d'activation, imagerie du tenseur de diffusion, stimulations corticales et sous-corticales ont permis d'aboutir à un modèle de réseau du langage impliquant une voie dorsale, essentiellement phonologique et une voie ventrale, sémantique présentant deux composantes. La première est directe, par le faisceau fronto-occipital inférieur connectant les aires temporales postérieures à la région orbito-frontale. La seconde est une voie indirecte qui connecte successivement la région occipito-temporale au pôle temporal par l'intermédiaire du faisceau longitudinal inférieur puis le pôle temporal aux aires basifrontales par le faisceau unciné. Cette dernière voie est compensée après résection ou lors des stimulations per-opératoires, suggérant la possibilité de réseaux de suppléance parallèles et bilatéraux. Dans cette vision d'une voie ventrale sémantique bilatérale, notre travail a pour objet par l'utilisation de l'imagerie fonctionnelle d'activation, d'une part, et de l'imagerie en tenseur de diffusion d'autre part, 1) de vérifier le nombre de faisceaux qui sous-tendent cette voie et en particulier de la part attribuable au faisceau longitudinal moyen; 2) de caractériser les réorganisations de la connectivité fonctionnelle du réseau du langage après une chirurgie de tumeur gliale hémisphérique gauche. Dans la première partie de ce travail, après avoir rappelé la filiation phylogénétique de l'homme et du primate non-humain, en insistant sur les dissemblances qui existent dans leur anatomie corticale et sous-corticale, nous exposons comment ces données ont permis d'aboutir à la découverte du faisceau longitudinal moyen chez l'homme. Nous confirmons la visibilité en imagerie du tenseur de diffusion de ce faisceau et nous précisons ses rapports avec les différents faisceaux de substance blanche constitutifs des voies ventrales et dorsales du langage. Enfin nous discutons ces données tractographiques à la lumière de la dissection et discutons du rôle présumé du faisceau dans le langage. Dans un deuxième temps, nous présentons les concepts de connectivité anatomique, fonctionnelle et effective. Puis nous appliquons un outil d'analyse de la connectivité fonctionnelle à des données périopératoires en tâches de fluence afin de réaliser une cartographie de la plasticité périopératoire de la composante sémantique du langage. Les résultats de cette deuxième étude suggèrent un recrutement de l'hémisphère ipsilatéral à la lésion au décours de la chirurgie. Enfin, nous évoquons la possibilité d'induire une désynchronisation (i.e. une altération de la connectivité) du réseau du mode par défaut par une stimulation peropératoire de la partie postérieure du faisceau cingulaire, induisant une sensation de dépersonnalisation, ces résultats suggérant qu'une des fonctions du noeud le plus postérieur du réseau soit de maintenir un état de conscience du monde extérieur. / According to classical conception of the anatomo-functional organization of language, there are two main cortical areas: a frontal area (Broca) and a temporal one (Wernicke) respectively involved in language production and comprehension. Functional magnetic resonance Imaging (fMRI) reveals cortical areas of activation and diffusion tensor imaging-based tractography (DTI) makes feasible the visualization of white-matter tracts in the human brain. On the basis of these techniques, a new conception of language cortical and sub-cortical organization arose, supporting the hypothesis that language processing network is dissociated in an dorso-ventral way. Dorsal areas of the brain being devoted to phonologic processing and its ventral areas to semantic processing of speech. Different techniques such as fMRI, DTI, intraoperative cortical and subcortical mapping made possible to describe two pathways involved in the language network: a dorsal stream and a ventral stream respectively involved in phonologic and semantic processing. As the dorsal route is composed of a unique pathway, the superior longitudinal fasciculus, the ventral stream appears to be composed of two different pathways. First a direct pathway, the inferior occipitofrontal fasciculus, connecting the posterior temporal areas to the orbitofrontal region. The second one, an indirect pathway, the inferior longitudinal fasciculus links the posterior occipitotemporal to the temporal pole, then relayed by the uncinate fasciculus connecting the temporal pole to the basifrontal areas. According to these observations the aim of our work is In the present work, we aim (1) to confirm that the MdLF is constantly found in control subjects and that it can be delineated from the other fiber tracts that constitute language pathways, (2) to characterize the reorganization of language network's functional connectivity follmowing surgical removal of left hemisphere low grade gliomas. In this study, we confirmed that the MdLF is constantly found in healthy volunteers and we clearly delineate the MdLF from the other fascicles that constitute language pathways, especially the ventral pathway. Considering language plasticity, our findings suggest that in the postoperative period, brain plasticity occurs with an ipsilateral recrutment and increased fonctional connectivity in the left hemisphere. Finally, we report a collaborative work observing that intraoperative electrostimulations of the white matter underlying the left posterior cingulate, while performing a naming task, systematically induced an unresponsive state for few seconds in relationship with a dream-like state. This result provides direct evidence that connectivity underlying the posterior node of the default mode network permits maintained consciousness of the external world.

Mild traumatic brain injuries (MTBI) are the leading type of head injuries with appreciable risque of sequelae leading to functional and psychological deficits. Although mild traumatic brain injuries are frequently underdiagnosed by conventional imaging modalities, rapidly evolving techniques such as diffusion tensor imaging (DTI) reveal subtle changes in white matter integrity as a result of head trauma and play an important role in refining diagnosis, therapeutic interventions and management of MTBI. In this dissertation we use diffusion tensor imaging to detect the microstructural changes induced by axonal injuries and to monitor their evolution during the recovery process. DTI data were previously acquired from 11 subjects, football players of age 19-23 years (median age 20 years). Three players had suffered a mild traumatic brain injury during the season and underwent scanning within 24 hours after the injury with follow-ups after one and two weeks. A set of diffusion indices, such as fractional anisotropy, axial, radial and mean diffusivity were derived from the diffusion tensor. Changes in diffusion indices in concussed subjects were analyzed based on two different approaches: whole brain analysis, using tract-based spatial statistics (TBSS) and region of interest analysis (ROI). In both approaches we use a voxelwise analysis to examine group differences in diffusion indices between five controls and three concussed subjects for all DTI scans. Additional statistical analysis was performed between control groups consisting of five and three non-injured players. Both analyses demonstrated that the MTBI group reveals increase in fractional anisotropy and decreases in transversal and mean diffusivity in cortical and subcortical areas within 24 hours after the injury. / No changes were detected in TBSS analysis for the follow-up data sets. Furthermore, our ROI approach revealed multiples regions with significantly different voxels, non-uniformly distributed throughout the brain, for all diffusion indices in all three scans. Three of the diffusion indices fractional anisotropy, mean and transversal diffusivity showed higher vulnerability to head trauma in subcortical and cortical areas than in regions in the lower brain. Recovery of white matter pathways occured at different locations in the brain at one and two weeks after head trauma. Strong recovery was observed in mean and transversal diffusivity in subcortical areas that correspond to the corticospinal tract. No recovery was found for fractional anisotropy and axial diffusivity in the same region. Also, decreases in fractional anisotropy and increases in transversal and axial diffusivity were observed in the spleninum of the corpus callosum. As voxelwise analysis performed on DTI data revealed white matter regions, which exhibit changes in diffusion parameters in the concussed group for all three scans, we conclude that diffusion tensor imaging is a powerful technique for early detection of axonal injuries and may serve as an important tool for monitoring microstructural changes during the recovery process. / by Angelica Hotiu. / Thesis (Ph.D.)--Florida Atlantic University, 2010. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2010. Mode of access: World Wide Web.

Esclerose Múltipla (MS) é uma doença neurodegenerativa que tem ganhado grande atenção nas últimas décadas, sendo o diagnóstico por imagens de ressonância magnética (MRI) um grande aliado para a avaliação da doença.Porém, um dos principais desafios é garantir uma maior sensibilidade e especificidade para detecção de diferentes lesões no sistema nervoso central (CNS) e assim classificar as diferentes variantes da MS, auxiliando na tomada de decisão para o tratamento farmacológico. Nas últimas décadas, a técnica de imagens ponderadas por difusão (DWI), em especial a técnica de imagem por tensor de difusão (DTI), têm sido evidenciada com grande potencial para o estudo da MS, apresentando uma melhora significativa para a detecção de lesões sutis, ainda em estágios iniciais da MS. Desta forma, as técnicas de processamento de imagens estão em constante aprimoramento para que sejam adaptados às novas modalidades de aquisição de imagens. Neste estudo focamos o desenvolvimento de uma técnica de processamento digital de imagens multimodais a fim de proporcionar uma solução viável para a rotina de diagnóstico por imagem em MS. Um conjunto de 25 pacientes de uma variante de MS foi selecionado aleatoriamente do banco de imagens do HCFMRP. Três modalidades de imagens foram coletadas para a avaliação da segmentação automatica (T1, T2-FLAIR e DTI), assim como a segmentação manual do especialista para cada paciente. Três métodos de segmentação multimodal automática de lesões foram analisados (Bayesiano, Frequentista e Agrupamento) afim de analisar a sensibilidade e especificidade de detecção de lesões na substância branca aparentemente normal (NAWM). Os resultados sugerem que o método de segmentação Bayesiano apresenta maior robustes e precisão na definição tanto de lesões visivelmente contrastantes em T1 e T2-FLAIR (i.e. lesões hipo e hiperintensas) assim como lesões da NAWM evidentes nos mapas quantitativos de DTI (FA e ADC). O erro associado à técninca automática de segmentação ficou em torno de 1.51 +- 0.51 % do volume total de lesões marcadas pelo especialista. Concluímos que o uso de ferramentas multimodais de segmentação de imagens MRI alcançou patamares razoáveis de detecção de lesões de MS, tornando assim uma ferramenta computacional hábil para uso no diagnóstico clínico. / Multiple sclerosis (MS) is a neurodegenerative disease that has gained great attention in the last decades, which magnetic resonance imaging (MRI) have shown as an important tool for the disease evaluation. However, one of the main challenges is guaranteeing greater lesion detection sensitivity and specificity in the whole central nervous system (CNS) and thus classify the different variants of MS, which aids in decision making for pharmacological treatment. In the last decades, the diffusion-weighted imaging (DWI) technique, especially the diffusion tensor imaging approach (DTI), has been evidenced with great potential for the study of MS, presenting a significant improvement for the detection of lesions even in early stages of MS. Hence, the techniques of image processing are constantly improving in order to be adapted on a multimodal image evaluation. In this study, the development of a multimodal digital image processing technique to provide a viable solution to the MS imaging routine was focused. A set of 25 patients from a MS variant was randomly selected from the HCFMRP imaging database. Three MR imaging modalities were collected for the evaluation of our automatic segmentation (T1, T2-FLAIR and DTI), as well as manual segmentation of the specialist for each patient. Three methods of automatic multimodal segmentation of MS lesions were analyzed (Bayesian, Frequentist and Clustering) in order to analyze the sensitivity and specificity of lesion detection in the apparently normal white matter (NAWM). The results suggest that the Bayesian segmentation method presented greater robustness and precision in the definition of visibly contrasting lesions in T1 and T2-FLAIR (i.e. hypo and hyperintense lesions) as well as NAWM lesions that are evident in quantitative DTI (FA and ADC). The error associated with the automatic segmentation technique was around 1.51 +- 0.51 % of the total lesion volume being evaluated by the a specialist. We conclude that the use of multimodal MRI images can be used in an automatic segmentation tools, reaching reasonable levels of MS lesion detection, thus making it a useful tool for clinical diagnosis.

Magnetic resonance imaging (MRI) has transformed the world of non-invasive imaging for diagnostic purposes. Modern techniques such as diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), and diffusion spectrum imaging (DSI) have been used to reconstruct fiber pathways of the brain - providing a graphical picture of the so-called "connectome." However, there exists controversy in the literature as to the accuracy of the diffusion tractography reconstruction. Although various attempts at histological validation been attempted, there is still no 3D histological pathway validation of the fiber bundle trajectories seen in diffusion MRI. Such a validation is necessary in order to show the viability of current DSI tractography techniques in the ultimate goal for clinical diagnostic application. This project developed methods to provide this 3D histological validation using the rhesus monkey motor pathway as a model system. By injecting biotinylated dextran amine (BDA) tract tracer into the hand area of primary motor cortex, brain section images were reconstructed to create 3D fiber pathways labeled at the axonal level. Using serial coronal brain sections, the BDA label was digitized with a high resolution digital camera to create image montages of the fiber pathway with individual sections spaced at 1200 micron intervals through the brain. An MRI analysis system, OSIRX, was then used to reconstruct these sections into a 3D volume. This is an important technical step toward merging the BDA fiber tract histology with diffusion MRI tractography of the same brain, enabling identification of the valid and inaccurate aspects of diffusion fiber reconstruction. This will ultimately facilitate the use of diffusion MRI to quantify tractography, non-invasively and in vivo, in the human brain.

OBJECTIFS : de précédentes études ont déjà démontré le potentiel de l’imagerie en tenseur de diffusion (DTI) pour détecter des anomalies médullaires dans la sclérose en plaques (SEP). L’objectif de ce travail était d’appliquer les techniques de DTI à des patients atteints de SEP et présentant une lésion médullaire symptomatique, afin de mettre en évidence une corrélation entre les variations des paramètres DTI et l’évolution clinique, et d’identifier des facteurs pronostiques prédictifs en DTI. METHODE : réalisation d’une étude prospective monocentrique chez des patients ayant une poussée médullaire de SEP traitée par corticoïdes intraveineux. Les patients étaient évalués cliniquement ainsi qu’en IRM (conventionnelle et DTI), à l’inclusion et à 3 mois. RESULTATS : seize patients ont été inclus. Lors du suivi à 3 mois, 12 patients étaient cliniquement améliorés. Tous sauf un avaient des valeurs de Fraction d’Anisotropie (FA) plus basses que les sujets normaux, au sein des lésions inflammatoires et dans la moelle apparemment normale, à l’inclusion ou lors du suivi à 3 mois. Les patients améliorés à 3 mois avaient une réduction significative de la Diffusivité Radiale (DR) (p=0,02) dans les lésions au cours du suivi. Ils avaient également une réduction significative du Coefficient de Diffusion Apparent moyen (p=0,002), de la Diffusivité Axiale (p=0,02) et de la DR (p=0,02) et une augmentation significative des valeurs de FA (p=0,02) dans la moelle apparemment normale. Les huit patients améliorés sur leur score ASIA (American Spinal Injury Association) sensitif à 3 mois avaient une FA initiale au sein des lésions inflammatoires significativement plus élevée (p=0,009) et une DR significativement plus basse (p=0,04) que les patients non améliorés. CONCLUSION : dans la SEP, l’IRM médullaire avec séquences en DTI détecte plus d’anomalies que l’IRM conventionnelle T2. Ces anomalies sont évolutives et corrélées au pronostic clinique, notamment celles observées dans la moelle épinière apparemment normale. Une diminution moins marquée des valeurs de FA initiales et plus marquée de la DR au sein des lésions inflammatoires est associée à un meilleur pronostic fonctionnel. / PURPOSE: the potential of Diffusion Tensor Imaging (DTI) to detect spinal cord abnormalities in patients with multiple sclerosis has already been demonstrated. The objective of this study was to apply DTI techniques to Multiple Sclerosis patients with a recently diagnosed spinal cord lesion, in order to demonstrate a correlation between variations of DTI parameters and clinical outcome, and to try to identify DTI parameters predictive of outcome. METHODS: a prospective single-centre study of patients with spinal cord relapse treated by intravenous steroid therapy. Patients were assessed clinically and by conventional MRI with DTI sequences at baseline and at 3 months. RESULTS: Sixteen patients were recruited. At 3 months, 12 patients were clinically improved. All but one patient had lower Fractional Anisotropy (FA) and Apparent Diffusion Coefficient (ADC) values than normal subjects in either inflammatory lesions or normal-appearing spinal cord. Patients who improved at 3 months presented a significant reduction in the Radial Diffusivity (p=0.05) in lesions during the follow-up period. They also had a significant reduction in the mean ADC (p=0.002), Axial Diffusivity (p=0.02), Radial Diffusivity (p=0.02) and a significant increase in FA values (p=0.02) in normal-appearing spinal cord. Patients in whom the American Spinal Injury Association sensory score improved at 3 months showed a significantly higher FA (p=0.009) and lower Radial Diffusivity (p=0.04) in inflammatory lesion at baseline compared to patients with no improvement. CONCLUSION: DTI MRI detects more extensive abnormalities than conventional T2 MRI. A less marked decrease in FA value and more marked decrease in Radial Diffusivity inside the inflammatory lesion were associated with better outcome.

L’IRM de diffusion est une modalité d’imagerie médicale qui suscite un intérêt croissant dans larecherche en neuro-imagerie. Elle permet de caractériser in vivo l’organisation neuronale et apportepar conséquent de nouvelles informations sur les fibres de la matière blanche. En outre, il a étémontré que chaque région corticale a une signature spécifique pouvant être décrite par des mesuresde connectivité. Notre travail de recherche a ainsi porté sur la conception d’une méthode deparcellisation du cortex entier à partir de ces métriques. En se basant sur de précédents travaux dudomaine (thèse de P. Roca 2011), ce travail propose une nouvelle analyse de groupe permettantl’obtention d’une segmentation individuelle ou moyennée sur la population d'étude. Il s’agit d’unproblème difficile en raison de la variabilité interindividuelle présente dans les données. Laméthode a été testée et évaluée sur les 80 sujets de la base ARCHI. Des aspects multimodaux ontété abordés pour comparer nos parcellisations structurelles avec d’autres parcellisations ou descaractéristiques morphologiques calculées à partir des modalités présentes dans la base de données.Une correspondance avec la variabilité de l’anatomie corticale, ainsi qu’avec des parcellisations dedonnées d’IRM fonctionnelle, a pu être montrée, apportant une première validationneuroscientifique. / Résumé anglais :Diffusion MRI is a medical imaging modality of great interest in neuroimaging research. Thismodality enables the characterization in vivo of neuronal organization and thus providinginformation on the white matter fibers. In addition, each cortical region has been shown to have aspecific signature, which can be described by connectivity measures. Our research has focused onthe design of a whole cortex parcellation method driven by these metrics. Based on the previouswork of P. Roca 2011, a new group analysis is proposed to achieve an individual or populationaveraged segmentation. This is a difficult problem due to the interindividual variability present inthe data. The method was tested and evaluated on the 80 subjects of the ARCHI database.Multimodal aspects were investigated to compare the proposed structural parcelliations with otherparcellations or morphological characteristics derived from the modalities present in the database. Aconnection between the variability of cortical anatomy and parcellations of the functional MRI datawas demonstrated, providing a first neuroscientist validation.

Objective: Following a sport related concussion (SRC) visible symptoms generally dissipate in 7-10 days post-injury. However, little is known about the cumulative effects of SRCs both in terms of structural damage to the white matter of the brain and neurocognitive performance. To address this issue, the relationship between the number of SRCs (frequency), axonal white matter (WM) damage and neurocognitive performance was examined. There were three predictions. First, increases in SRC frequency will be associated with decreases in performance on neurocognitive tests. Second, the frequency of SRC will be associated with axonal injury measured three WM tracts: the corpus callosum, the fronto-occipital fasciculus and the inferior longitudinal fasciculus. Third, less accurate and slower performance on a response inhibition task (STOP-IT) will be associated with greater axonal injury. Methods: A cross-sectional correlational design was utilised. Participants were rugby players with a history of SRC, rugby players with no history of SRC and control athletes (N=40) who completed a neurocognitive test battery and had a DTI brain scan. The neurocognitive battery consisted of the following standardised tests: Speed and Capacity of Language Processing Test, CogState Electronic Battery, Stroop Colour and Word Test, Controlled Oral Word Association Test, the Trail Making Test and the experimental test STOP-IT Electronic Test. White matter axonal injury was measured by DTI using fractional anisotropy (FA) and mean diffusivity (MD) metrics. The DTI data was processed using FSL to extract FA and MD DTI metrics in three a-priori regions of interest. Results: Spearman’s correlation analyses did not find significant associations between SRC frequency and neurocognitive performance on the FAS (rs=0.053, 95% CI [-0.27, 0.36]), TMT-A (rs=0.058, 95% CI [-0.26, 0.37]), TMT-B (rs= -0.046, 95% CI [-0.27, 0.36]) and the Stroop Interference (rs= -0.25, 95% CI [-0.07, 0.52]). Similarly, no significant Spearman’s correlations were found between SRC frequency and the computerised neurocognitive tests STOP-IT-SSRT (rs= -0.04, 95% CI [-0.28, 0.35])), STOP-IT–Accuracy (rs= -0.05, 95% CI [-0.27, 0.36]), CogState Detection subtest (rs= -0.15, 95% CI [-0.17, 0.44]), CogState Identification subtest (rs= -0.065, 95% CI [-0.26, 0.37]), CogState One card learning subtest (rs= 0.24, 95% CI [-0.08, 0.52]) or the CogState One back task subtest (rs= 0.06, 95% CI [-0.26, 0.37]). In terms of the DTI data there were no significant associations between SRC frequency and axonal injury measured by FA values in the CC (rs= 0.005, 95% CI [-0.31, 0.32]), ILF (rs= 0.028, 95% CI [-0.29, 0.34]) or FOF (rs= -0.022, 95% CI [-0.30, 0.33]). The same was pattern was found for MD values in the CC (rs= 0.081, 95% CI [-0.24, 0.39]), ILF (rs= -0.16, 95% CI [-0.16, 0.45]) or FOF (rs= -0.15, 95% CI [-0.17, 0.44]) Finally, there were no significant Spearman’s correlations between axonal injury FA values and the STOP-IT SSRT in any of the ROIs: CC (rs= 0.005, 95% CI [-0.31, 0.32]), ILF (rs= 0.028, 95% CI [-0.29, 0.34]) or FOF (rs= -0.022, 95% CI [-0.30, 0.33]). Equally, there were no significant correlations between MD values STOP-IT SSRT in the CC (rs= -0.028, 95% CI [-0.29, 0.34]), ILF (rs= -0.16, 95% CI [-0.16, 0.45]) or FOF (rs= -0.15, 95% CI [-0.17, 0.44]). Likewise, there were no significant Spearman’s correlations between accuracy on the STOP-IT and FA values and in any of the ROIs: CC (rs= 0.19, 95% CI [-0.13, 0.48]), ILF (rs= -0.045, 95% CI [-0.27, 0.35]) and FOF (rs= -0.032, 95% CI [-0.29, 0.34]), or MD values in the CC (rs= -0.11, 95% CI [-0.21, 0.41]), ILF (rs= 0.017, 95% CI [-0.30, 0.33]) or FOF (rs= 0.082, 95% CI [-0.24, 0.39]). This study did not find support for the hypothesis that cumulative SRCs are associated with poorer performance on neurocognitive tests or with axonal injury as measured by FA and MD DTI metrics. Conclusion: The null findings suggest that there are no cumulative effects of SRCs. The current findings are inconsistent with previous cross-sectional research that indicates that there are long-term changes to diffusivity measures present after single SRCs as well as cumulative effects in contact sport athletes. Likewise they are at odds with evidence suggesting that after three SRCs neurocognitive performance can be affected. The study needs to be extended to include a larger sample to ensure the results are not due to low statistical power.

The logistical complexities of performing multi-site longitudinal diffusion-weighted imaging (DWI) studies requires careful construction of analysis tools and procedures. Proposed clinical trials for therapies in neurodegenerative disease are known to re- quire several hundred subjects, thus mandating multiple site participation to obtain sufficient sample sizes. DWI is an important tool for monitoring diffusivity properties of white matter (WM) in disease progression. The multi-site nature of clinical trials requires new strategies in DWI processing and analysis to reliably measure longitudi- nal WM changes. This work describes the process of developing and validating robust analysis methodologies to process multi-site DWI data in a rare, neurodegenerative disease. Key processing components to accomplish a robust DWI processing system include: DICOM conversion, automated quality control, unbiased atlas construction, fiber tracking, and statistical analysis. Extensive validation studies were performed to characterize methodological results within and across the common confounds inherent in multi-site clinical trials. The conversion and automated quality control tools optimized for this work both enhanced the ability to reliably obtain repeat diffusion tensor image (DTI) scalar measurements in a reliability analysis of healthy controls scanned at multiple sites using multiple scanner vendors. A DTI scalar analysis performed on focused WM regions showed it was possible to detect significant mean differences of DTI scalars among separate groups of a neurodegenerative disease population. The DTI scalar analysis paved the way for an atlas-based cross-sectional fiber tracking analysis. In the cross-sectional fiber tracking analysis, multi-site data was brought into the same space, making major fiber tracts terminating in the focused WM regions of the scalar analysis from all participants comparable. Significant differences in diffusivity were found throughout each tract among separate groups of the neurodegenerative disease population. In addition, multiple neuropsychological cognitive variables that have a documented ability to track disease progression of the neurodegenerative disease, strongly correlated with many of the DTI scalars in each tract. The findings of the cross-sectional fiber tracking analysis were reinforced by similar findings produced by a longitudinal fiber tracking analysis. Collectively, these findings suggest that cogni- tive deficits seen in the neurodegenerative disease population could be explained by changes in diffusivity of the tracts explored in this work. In addition to the longi- tudinal fiber tracking analysis examining diffusivity, methods for a WM morphology analysis using parallel transport to apply longitudinal volume changes to a template was explored.

The current study investigates the effects of vascular disease on white matter health by comparing participants with atherosclerotic vascular disease (AVD) to healthy control participants (HC). The comparison between groups will help elucidate the differences between early-stage mild vascular disease and normal aging processes in terms of their effects on white matter health as measured by diffusion tensor imaging (DTI). Relationships between white matter health and depression, attention, and processing speed are studied by the application of a variety of DTI neuroimaging techniques, which will allow investigation of these relationships at the levels of global, lobe-wise, and subregional analysis. The specific subregion of interest in the depression study is Brodmann Area 25, which has shown significant relationships with depressive symptomatology in patients with treatment refractory depression, but has not been studied in the context of aging, vascular disease, or subthreshold depressive symptoms. Results indicate that there are significant differences between AVD and HC participants in global and regional FA measures. Within the AVD group, significant relationships of FA with depressive symptoms and attentional function have been observed in the current study. Several unexpected findings emerged, most important of which was the observation that there is a significant relationship between FA in Brodmann Area 25 and depressive symptoms in AVD participants which is specific to the right hemisphere. These findings have implications for the treatment of depressive symptoms in older adults and participants with vascular disease.