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.

Introdução: No campo do tratamento cirúrgico de Gliomas, tem se observado um interesse crescente no uso de novas tecnologias de suporte como métodos auxiliares na obtenção do equilíbrio entre radicalidade cirúrgica e preservação da funcionalidade cerebral. Na maior parte dos estudos, a localização tumoral tem sido pouco considerada e a real eficácia das tecnologias de suporte ainda está pouco investigada nos gliomas insulares. Objetivos: avaliar a eficácia da fluorescência intraoperatória com 5-ALA, monitorização neurofisiológica, neuronavegação e tractografia no grau de ressecção tumoral (GRT), escores de funcionalidade, sobrevida global e sobrevida livre de progressão em uma coorte retrospectiva de gliomas insulares. Métodos: revisamos todos os casos de tumores insulares operados no Departamento de Neurocirurgia da Universidade de Tübingen - Alemanha, entre maio de 2008 e novembro de 2013. O grau de ressecção foi avaliado por volumetria. Foram utilizados os testes de Mann Whitney, Qui-quadrado e funções de Kaplan Meier para análise do efeito de cada tecnologia nos desfechos primários e secundários. Resultados: 28 casos - 18 homens (64%) e 10 mulheres (36%); idade média 52,5 anos (12 - 59) - foram inclusos para análise. Gliomas de alto grau corresponderam a 20 casos (71%), com 8 lesões de baixo grau (29%). As tecnologias mais utilizadas foram monitorização neurofisiológica (64%) e neuronavegação (68%). 5-ALA foi a única modalidade associada a taxas de ressecção > 90% (p = 0,05). O uso de tractografia determinou melhora no KPS (50% vs 5%, p = 0,02). Houve associação positiva entre o uso de neuronavegação e sobrevida global (23 vs. 27,4 meses, p = 0,03), mas o uso de 5-ALA se associou a piora na sobrevida global (34,8 vs 21,1 meses, p = 0,01) e sobrevida livre de progressão (24,4 vs. 11,8 meses, p = 0,01). Conclusões: Considerando os gliomas insulares, o presente trabalho demonstra pioneiramente que o uso de 5-ALA tem papel na obtenção de maiores taxas de ressecção, ainda que este achado possa estar associado a piora nas sobrevidas global e livre de progressão. Tractografia e neuronavegação parecem desempenhar papel importante no tratamento dos gliomas insulares, na medida em que determinaram melhor sobrevida global e funcionalidade, respectivamente. Estudos prospectivos com uma amostra mais proeminente e análise multivariada permitirão a avaliação do benefício real destas tecnologias de suporte no tratamento dos gliomas insulares / Introduction: In the field of Glioma surgery, there has been an increasing interest in the use of assistive technologies to overcome the difficulty of preserving brain function while improving surgical radicality. In most reports, tumor localization has seldom been considered a variable and the role of intraoperative adjuncts is yet to be determined for gliomas of the insula. Objectives: to evaluate the efficacy of fluorescence-guided resection with 5-ALA, intraoperative neurophysiological monitoring (IOM), neuronavigation, and tractography in the Extent of Resection (EOR), functionality scores, overall survival (OS) and progression-free survival (PFS) in a retrospective cohort of insular gliomas. Methods: we reviewed all cases of insular tumors operated on at the Department of Neurosurgery, University Hospital of Tübingen - Germany, between May 2008 and November 2013. EOR was determined by volumetric analysis. Mann Whitney, Chi-square and Kaplan Meier functions were used for assessment of each technology\'s effect on primary and secondary outcomes. Results: 28 cases (18 men (64%) and 10 women (36%); median age at diagnosis: 52.5 years, range 12 - 59) were considered eligible for analysis. High grade and low grade gliomas accounted for 20 (71%) and 8 (29%) cases, respectively. The most used technologies were IOM (64%) and Neuronavigation (68%). 5-ALA was the only technique associated with EOR > 90% (p = 0.05). Tractography determined improvement in the Karnofsky Performance Scale (50% vs 5% cases improved, p = 0.02). There was a positive association between the use of neuronavigation and overall survival (23 vs. 27.4 months, p = 0.03), but the use of 5-ALA was associated with shorter OS (34.8 vs. 21.1 months, p = 0.01) and PFS (24.4 vs. 11.8, p = 0.01). Conclusions: we demonstrate for the first time that for insular gliomas 5-ALA plays a role in achieving higher EOR, although this technology was associated with poor OS and PFS; Also tractography and neuronavigation can be of great importance in the treatment of insular gliomas as they determined better functionality and overall survival in this study, respectively. Prospective studies with a more prominent sample and proper multivariate analysis will help determine the real benefit of these adjuncts in the setting of insular gliomas

Orientadores: Fernando Cendes, Iscia T. Lopes-Cendes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-20T13:47:21Z (GMT). No. of bitstreams: 1 Guimaraes_RachelPaes_D.pdf: 1465604 bytes, checksum: 8d25df109e02b8f6f7c12483cebf584d (MD5) Previous issue date: 2012 / Resumo: A doença de Machado Joseph (MJD) ou ataxia espinocerebelar tipo 3 (SCA3) é uma doença autossômica dominante e é o tipo de ataxia mais comum no Brasil. Os principais sintomas são ataxia, alterações de movimentação ocular, distonia, espasticidade e disfunção piramidal e fasciculações, além de disfagia e disartria. Estes usualmente tem início na idade adulta, entre os 30-40 anos. Apesar de ser frequente, existem poucos biomarcadores para a avaliação da progressão da doença. O objetivo deste estudo foi avaliar a SB cerebelar e cerebral de indivíduos com MJD/SCA3 através da técnica de Imagem por tensor de difusão (DTI) e Morfometria baseada em Vóxel (VBM), além de correlacionar os dados de duas escalas específicas para ataxia, a International Cooperative Ataxia Rating Scale (ICARS) e a Scale for the Assessment and Rating of Ataxia (SARA) com as imagens de ressonância magnética. Para tanto foram selecionados 38 pacientes com diagnóstico de MJD/SCA3, confirmado por meio de teste molecular, além de 38 indivíduos controles. Todos passaram por exame de ressonância magnética, e os acometidos pela MJD/SCA3 foram avaliados através de exame neurológico e as escalas ICARS e SARA. As análises de DTI feitas através do Tract-Based Spatial Statistics (TBSS) demonstraram redução da anisotropia fracional em tronco cerebral, lobo cerebelar anterior, mesencéfalo, lobo cerebelar posterior à direita, nódulo, culmen, núcleo denteado e fastigial. Foram encontradas também áreas com aumento de difusividade radial e axial em tronco encefálico, ponte, mesencéfalo, lobo cerebelar anterior, núcleo denteado, fastigium e tálamo. Aumento de difusividade radial também foi encontrado em lobos frontal e temporal. Não foram encontradas áreas com alteração de difusividade média. Uma correlação positiva entre os valores de anisotropia fracional extraídos da ponte com o tempo de duração da doença foi encontrada. Os resultados da VBM demonstraram atrofia de substância branca em tonsila, lobo cerebelar posterior, medula, tronco cerebral direito, ponte, culmen, declive, vermis, giro lingual, giro fusiforme, núcleo denteado, úvula e pirâmide. Foi encontrada uma correlação negativa entre densidade de SB e os escores das escalas ICARS e SARA e tempo de duração da doença. Atrofia de substância cinzenta em lobo cerebelar posterior, tonsila, medula, tronco encefálico, lóbulo semi-lunar inferior, declive, tuber e pirâmide. Correlações entre a densidade de SC e dados clínicos demonstraram correlação negativa com os escores das escalas ICARS e SARA e o tamanho da expansão CAG. O presente estudo apresenta informações relevantes sobre alterações microestruturais em SB e macroestruturais em SB e SC na MJD/SCA3. Acreditamos que esses achados contribuam para um melhor entendimento sobre o processo neuropatológico desta doença / Abstract: Machado Joseph Disease or spinocerebellar ataxia type 3 (MJD/SCA3) is an autosomal dominant ataxia and it is the most common in Brasil and in the world. The main symptoms are ataxia, extraocular movement disorders, dystonia, disfagia, spasticity, pyramidal dysfunction and fasciculation. The symptoms usually appear between 30-40 years. The objective of the present study was to assess cerebellar and cerebral white matter in MJD/SCA3 patients through Diffusion Tensor Imaging (DTI) and Voxel Based Morphometry (VBM) and to correlate clinical data obtained by two scales that are specific for ataxia, the International Cooperative Ataxia Rating Scale (ICARS) and Scale for the Assessment and Rating of Ataxia (SARA) with magnetic resonance imaging findings. For that purpose we recruited 38 patients with a confirmed molecular diagnosis of MJD/SCA3 and 38 healthy individuals as a control group. All subjects were underwent MRI scan, and patients were assessed by neurological examination, ICARS and SARA. DTI analysis with Tract-Based Statistical Analysis (TBSS) revealed fractional anisotropy (FA) reduction in the brainstem, the anterior and posterior cerebellar lobes, midbrain, culmen, dentate and fastigial. Areas with increased axial (AD) and radial diffusivity (RD) were found in brainstem, pons, midbrain, cerebellar anterior lobe and thalamus. Increased RD was also evidenced in frontal and temporal lobes. TBSS analysis revealed no alterations in mean diffusivity.A positive correlation between FA values extracted from pons and disease duration was found. VBM results demonstrated white matter atrophy at tonsil, posterior cerebellar lobe, medulla, brainstem, pons, culmen, declive, vermis, lingual gyrus, fusiform gyrus, dentate, uvula and pyramis. We found a negative correlation between white matter density and SARA, ICARS scores and disease duration. Grey matter atrophy was demonstrated at posterior cerebellar lobe, tonsil, medulla, brainstem, inferior semi-lunar lobule, declive, tuber and pyramis. A negative correlation between grey matter density, SARA and ICARS scores and CAG repeat size was found / Doutorado / Neurociencias / Mestre em Fisiopatologia Médica

Le Corps Calleux (CC), principale commissure reliant les deux hémisphères cérébraux, est d'une importance cruciale dans l'intégration des informations interhémisphériques et des fonctions cognitives supérieures. Les modifications du CC pourraient contribuer à des anomalies de connectivité susceptibles d'expliquer les dysfonctionnements des régions cérébrales impliquées dans la physiopathologie de certaines maladies psychiatriques.Toutefois notre connaissance du rôle du CC dans les troubles de l’humeur et les conduites suicidaires est encore très limitée. Nous n'avons que peu d’informations sur l’implication exacte du CC en psychopathologie et sur les facteurs pouvant altérer son intégrité. L’objectif de cette thèse était de mieux préciser les relations existant entre altération du CC, troubles de l’humeur et conduites suicidaires Nous avons montré un lien entre l’atrophie du CC et la survenue de dépression sur une période de 10 ans parmi 467 sujets sains âgés de 65 à 80 ans grâce aux IRM morphologiques de l’étude en population générale Esprit. Dans une étude clinique menée chez 121 femmes plus jeunes (18-50 ans), Nous avons mis en évidence grâce à une technique d’imagerie par tenseur de diffusion (DTI) une altération des parties antérieures du CC chez les femmes bipolaires, tandis que le splénium, la partie postérieure du CC, est atteinte uniquement chez les suicidantes. Nous soulignons également que l’altération du splénium est associée au nombre de tentatives de suicides et au score d’intentionnalité du geste suicidaire. Par ailleurs, Nous avons montré une association de type linéaire entre le niveau d’un marqueur de l’inflammation (CRP) et la réduction de la taille des portions antérieures du CC au sein de la population âgée de l’étude Esprit.Nos travaux suggèrent donc une altération de l’intégrité du CC dans les troubles de l’humeur et les comportements suicidaires à des âges différents de la vie, en population générale et en population clinique. Les études futures devraient permettre de préciser les conséquences des anomalies de communication interhémisphérique mises en évidence dans ces pathologies. / Corpus Callosum (CC), the main commissure connecting the two cerebral hemispheres, is of crucial importance in the integration of interhemispheric information and higher cognitive functions. CC alterations might contribute to abnormal interhemispheric connectivity that may underlie functional abnormalities of brain regions involved in the pathophysiology of psychiatric disorders. However, our understanding of the role of the CC in mood disorders and suicidal behaviour is still very limited. We have little information about the exact involvement of the CC in psychopathology and the factors that could affect its integrity. The objective of this thesis was to further clarify the relationship between alterations of the CC, mood disorders and suicidal behaviour.We have found an association between CC atrophy and incident depression over a 10-year follow-up period among 467 healthy subjects aged 65 to 80 years using the morphological MRI data from the epidemiological study Esprit. In a clinical study of 121 younger women (18-50 years), we have used a diffusion tensor imaging (DTI) technique to show an alteration of the anterior parts of the CC in bipolar women, while the splenium, the posterior part of the CC, is altered only in suicidal women. We have also emphasized that the alteration of splenium is associated with the number of suicide attempts and suicidal intentionality scale score. Furthermore, we showed a linear association between the level of a marker of inflammation (CRP) and a reduced size of the anterior parts of the CC within the population of the Esprit study. Our work therefore suggests impaired integrity of the CC in mood disorders and suicidal behaviours at different stages of life, in general population and in clinical population. Future studies should aim to clarify the consequences of interhemispheric communication anomalies identified in these pathologies.

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

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

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

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

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

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