by Tracy Man-kiu Ma. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 48-61). / Abstract and appendix in English and Chinese. / ABSTRACT --- p.ii / ACKNOWLEDGEMENTS --- p.iii / TABLE OF CONTENTS --- p.iv / LIST OF TABLES --- p.vi / LIST OF FIGURES --- p.vii / LIST OF APPENDICES --- p.viii / Chapter CHAPTER ONE- --- INTRODUCTION / Mesial temporal lobe and its sequel of damages --- p.1 / Mesial temporal lobe pathologies --- p.2 / Memory assessment instruments and the Hong Kong List Learning Test --- p.4 / The receiver operating characteristics (ROC) analysis --- p.6 / Purpose of the present study --- p.7 / Chapter CHAPTER TWO- --- METHOD / Participants --- p.9 / Materials --- p.10 / Procedure --- p.13 / Statistical analysis --- p.15 / Chapter CHAPTER THREE - --- RESULTS / Memory Profiles of NPC Patients with bilateral temporal lobe lesions --- p.18 / Receiver operating characteristics (ROC) analysis for test performance --- p.26 / Validity and reliability --- p.33 / Chapter CHAPTER FOUR - --- DISCUSSION / The clinical utility of the blocked condition --- p.39 / Optimal cutoff scores for sensitivity and specificity --- p.40 / Memory profiles of NPC patients and its implications --- p.42 / Limitations --- p.45 / Conclusions --- p.46 / REFERENCES --- p.48 / APPENDICES --- p.62

It has been demonstrated that by using 1H NMR spectroscopy in combination with multivariate statistical modelling (PLS) it is possible, using urine samples obtained from rats, to distinguish between different types of CNS lesions. Against this background this thesis will explore whether the combination of 1H NMR and PLS modelling on biofluids can be used q-1eientify biomarkers in .. - different neurological diseases and in clinically relevant animal models of neurologic disease. The results in this thesis demonstrate that it is possible to separate sets of animals at different stages of disease in models of multiple sclerosis and to identify the presence of early brain metastasis. The same methodology was also applied to human biofluids. In MS patient cohorts (RR- MS, PP-MS and SP-MS) it was also possible to differentiate between RR-MS and SP-MS as well between MS and healthy controls. Therapy for these two stages of MS are very different and therefore a rapid test to determine a patient's stage of MS would be hugely beneficial in the clinic. Further investigation revealed that it is possible to separate MS patients from individuals with Alzheimer's disease. Metabolomics was then combined with other eo- variants in a study of cerebrospinal fluid obtained from patients with HIV associated dementia (HAD) to discover whether disease progression could be followed in this manner. The results show that it is possible to detect neurocognitive changes in patients with HAD. Indeed, the results demonstrate. that metabolomics is a far more sensitive tool for the following progression than other non-PLS biomarker techniques and should provide a useful method for early diagnosis of CNS disease and the evaluation of therapy in prospective studies.

Although the mu rhythm is traditionally defined as a normal EEG variant, recent evidence suggests that mu may have functional significance in a variety of disorders such as autism, Parkinson's disease, and multiple sclerosis. While an increasing number of articles have focused on the blocking mechanism of mu in relation to various cognitive processes and disorders, few have examined the significance of a prominent mu rhythm in the background EEG. A few studies have examined the relationship between the mu rhythm and psychological disturbance, such as attentional and affective disorders. Increasing evidence suggests that EEG and qEEG variables may be useful in classifying psychiatric disorders, presenting a neurophysiological alternative to traditional symptom-based diagnosis and classification. Thus, the intention of the present study was to examine the relationship between neuropsychological variables, gathered from multiple assessment sources, and the presence of a prominent mu rhythm in the EEG. Results did not show a statistically significant difference between individuals with and without a prominent mu rhythm on the Test of Variables of Attention (TOVA); although individuals in the mu group showed a pattern of increased impulsivity and performance decrement over time. For adults, no significant differences were observed between groups on psychological variables measured by the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). However, for children, the mu and control groups differed on several behavioral and emotional variables on the Child Behavior Checklist (CBCL). Results are examined in the context of other research and clinical implications are discussed.

Orientador: Marilisa Mantovani Guerreiro / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-08T00:49:32Z (GMT). No. of bitstreams: 1 Teixeira_KarineCoutoSarmento_M.pdf: 1612063 bytes, checksum: b67ceb8ce8a89e338f504be9b41ab015 (MD5) Previous issue date: 2006 / Resumo: Polimicrogiria é uma malformação da organização cortical que se caracteriza por múltiplos pequenos giros separados por espessos e rasos sulcos. O objetivo do presente estudo foi descrever as manifestações clínicas e eletroencefalográficas de pacientes com polimicrogiria, que têm epilepsia e/ou distúrbio específico de linguagem e dos familares dos pacientes com distúrbio específico de linguagem, correlacionando-os com a neuroimagem. Os pacientes foram submetidos a exame clínico e neurológico, com particular atenção aos sinais pseudobulbares, e realizaram eletroencefalograma de rotina com até 4 horas de duração. Quando possível, foram submetidos a vídeo-monitorização. Os dados de neuroimagem foram classificados em: polimicrogiria perisylviana (subdividida em holosylviana, parietal posterior bilateral, generalizada), polimicrogiria hemisférica e polimicrogiria frontal. Os achados eletroencefalográficos foram categorizados em: normal; anormal com atividade epileptiforme; anormal com atividade não epileptiforme; anormal com atividade epileptiforme e não epileptiforme; anormal com estado de mal elétrico (EME); anormal com atividade epileptiforme contínua e quanto à presença ou não de ativação da atividade epileptiforme pelo sono. Foram estudados 40 pacientes: 16 pacientes com polimicrogiria holosylviana, 14 com polimicrogiria parietal posterior, quatro com polimicrogiria generalizada, três com polimicrogiria hemisférica e três com polimicrogiria frontal. Observou-se nos pacientes com polimicrogiria holosylviana: sinais pseudobulbares em 11, hemiparesia em seis sendo um paciente com dupla hemiparesia. Três possuíam deficiência mental e cinco tinham epilepsia. O eletroencefalograma estava alterado em oito pacientes e atividade epileptiforme foi registrada em seis, sendo que em dois foi registrada atividade epileptiforme contínua focal. Entre os pacientes com polimicrogiria parietal posterior bilateral, cinco apresentavam sinais pseudobulbares e um possuía hemiparesia. Nenhum tinha alteração cognitiva ou epilepsia. Apenas um paciente apresentou ao eletroencefalograma atividade epileptiforme focal. Todos os pacientes com polimicrogiria generalizada tinham sinal pseudobulbar, deficiência mental e epilepsia. O quadro motor estava presente em três pacientes e apenas um deles não apresentava atividade epileptiforme no eletroencefalograma. Entre os pacientes com polimicrogiria hemisférica, todos apresentavam sinal pseudobulbar e hemiparesia, dois pacientes tinham deficiência mental e epilepsia, e um paciente atraso do desenvolvimento neuropsicomotor. Nos registros eletroencefalográficos, dois pacientes apresentaram EME focal. Os pacientes com polimicrogiria frontal não possuíam sinal pseudobulbar e em um único paciente foi detectada hemiparesia. Epilepsia estava presente em dois pacientes. No registro eletroencefalográfico, dois exames apresentaram anormalidades não-epileptiformes. Com os dados acima descritos foi possível observar que: os sinais pseudobulbares foram mais freqüentes em pacientes com idade menor ou igual a 15 anos; atividade epileptiforme e lentificação da atividade de base teve associação com epilepsia e alteração cognitiva e o distúrbio específico de linguagem apresentou uma relação inversa com estes achados eletroencefalográficos; a maioria dos nossos pacientes apresentou exame eletroencefalográfico normal; na polimicrogiria holosylviana, as atividades epileptiformes predominaram na região fronto-temporal e as atividades não epileptiformes predominaram na região fronto-centro-temporal; EME ocorreu em polimicrogiria hemisférica e atividade epileptiforme contínua focal ocorreu em polimicrogiria holosylviana bilateral assimétrica com provável displasia cortical associada; a ativação da atividade epileptiforme pelo sono foi um achado freqüente em nossa casuística; existe correlação direta entre as manifestações clínicas e anormalidades eletroencefalográficas e extensão do córtex polimicrogírico / Abstract: Polymicrogyria is a malformation of cortical organization that is characterized by multiple and small gyri. The aim of this study was do describe clinical and eletrographic features of patients with polymicrogyria, whom have epilepsia and/or developmental language disorder, and to correlate these data with neuroimaging findings. Our patients underwent clinical and neurological examination, and a routine electroencephalogram. Whenever possible, video-electroencephalographic monitoring was performed. Neuroimaging data were classified as: perisylvian polymicrogyria (subdivided as holosylvian, posterior parietal and generalized), hemispheric polymicrogyria and frontal polymicrogyria. Electrographic findings were classified as: normal; abnormal with epileptiform activity; abnormal with non-epileptiform activity; abnormal with epileptiform and non-epileptiform activities; abnormal with electrographic status (ES); abnormal with continuous epileptiform activity; sleep activation. We studied 40 patients: 16 with holosylvian polymicrogyria; 14 with posterior parietal polymicrogyria; four with generalized polymicrogyria; three with hemispheric polymicrogyria; and three with frontal polymicrogyria. Patients with holosylvian polymicrogyria showed: pseudobulbar signs in 11; hemiparesis in six one of them with double hemiparesis. Three had mental retardation and five had epilepsy. The elecgroencephalogram was abnormal in eight patients and epileptiform activity was registered in six, two of them with focal. Patients with posterior parietal polymicrogyria showed: five with pseudobulbar sign and one with hemiparesis. Cognitive delay and epilepsy was not found in this group. Only one patient had electroencephalogram with focal epileptiform discharges. Patients with generalized polymicrogyria had pseudobulbar sign, epilepsy and mental retardation. Motor deficit was found in three patients. Electroencephalogram findings showed epileptiform activity in three. Patients with hemispheric polymicrogyria had pseudobulbar sign and hemiparesis. Two of them had mental retardation and epilepsy. One had neurodevelopmental delay. Electrographic examinations showed focal ES in two patients. Patients with frontal polymicrogyria had no pseudobulbar sign and one of them had hemiparesis. Two patients had epilepsy. Electroencephalogram findings showed non-epileptiform activities in two patients. Our data demonstrated that: pseudobulbar sign are more frequent among patients under 15 years old; epilepsy and cognitive delay are both correlated with epileptiform activity and slowness of the background activity and developmental language disorder had a inverse correlation with this finds; in holosylvian polymicrogyria, epileptiform activities predominated in fronto-temporal regions and non-epileptiform activities predominated in centro-temporal regions; ES occurred in hemispheric polymicrogyria and focal continuous epileptiform activities in asymmetric bilateral holosylvian polymicrogyria with associated cortical dysplasia; sleep activation was a frequent finding; the severity of clinical and electrographic features correlated with the extent of cortical lesion / Mestrado / Neurologia / Mestre em Ciências Médicas

雖然由老化引發的腦白質病變是老年人認知障礙的一個重要誘因，其機理缺並不為人所知。最新的小樣本研究表明擴散核磁造影在很大程度上是對腦白質病變最為敏感的的成像檢測手段。加深對擴散核磁造影所給出的各種指數的理解和認知對於檢測腦白質病變的病理發展以及研發試驗療法的替代標記有重要的意義。 / 為了獲得更具有臨床價值的擴散核磁造影指數，我們首先需要重構腦白質纖維束並沿著重構出的腦白質纖維束採集數值。然而，傳統的腦白質纖維束重構技術對於腦白質病變十分敏感。此外，不同病人所重構出的腦白質纖維束間缺乏映射關係也使我們無法有效進行大樣本統計分析。 / 在這個課題裡，我們提出了一個可以解決以上問題的一個全新框架。我們將專家標註過功能區的全腦白質纖維束模板配準到各個個體的腦部。此方案可自動生成個體化的全腦白質纖維束以及纖維束的功能區標註。自由形變模型被用於在全局層面對配準進行約束。所重構纖維束的曲率被用於在局部對配準進行約束。為了減輕腦白質病變對配準的影響，我們運用了一種 魯棒的主成分分析手段來檢測被病灶所干擾的纖維束。為了指導這些被干擾纖維束的配準，我們提出了一種全新的沿纖維束的區域特徵作為替代。此外，我們也探究了通過在纖維束上建立坐標系來除去離群纖維已經提供更高相關性的辦法。 / 我們所提出的框架被運用於一個腦小血管病變的臨床研究。在64個研究對象中約半數是腦白質病變患者。試驗結果證實此算法成功地將全腦白質纖維束模板配準到了所有研究對象上。沿著特定纖維束改採集的指數與認知測試分數的相關性顯著地超越了傳統指數所給出的結果。我們同時也發現沿著不同功能區腦白質纖維改採集的指數與相應的認知測試分數統計相關。 / Although age-related white matter lesion(WML)is an important substrate for cognitive impairment in the elderly, the mechanisms whereby WML induces cognitive impairment are uncertain. Recent findings based on small studies suggested that diffusion tensor imaging (DTI) measures might be the most sensitive imaging predictors in patients with WML. Understanding the imaging predictors for such disease will be useful in monitoring disease progression and in devising surrogate marker for treatment trials. / In order to obtain DTI measurements with diagnostic significance, it is first necessary to reconstruct the white-matter fiber pathways inside the brain along which certain DTI-derived values are calculated. Nevertheless, the traditional approach of white-matter tract reconstruction, or tractography, is severely hindered by the abundant existence of lesions inside the brains of WML patients. The lack of correspondence between fiber bundles across patients also makes obtaining group statistics of individual fiber bundles dicult. / In this study, we propose a novel framework that can mitigate the aforementioned issues of traditional tractography approaches. An expert-labeled whole brain tractography template is registered onto individual patients. Fiber trajectories and anatomically meaningful fiber bundles are automatically obtained by this registration. The free-form deformations are used to regularize the transformations at the whole brain level and across fiber bundles. Fiber curvatures are penalized as the intra-fiber regularization to encourage the smoothness of transformed fibers. White matter (WM) lesion is one of the major factors affecting tractography and registration of subjects with neuro Logical disorders. The Robust Principal Component Analysis(RPCA) is used to automatically detect fiber tract segments that are affected by WM lesion and a novel along-fiber regional prior is learned from healthy subjects to facilitate the registration of these fiber tract segments. We also propose to establish bundle-wise coordinate system by utilizing low-rank constraints upon the DTI measurements. The eort elevates the summary for an anatomical bundle from a scalar statistic to a vector containing changes along the representative fiber pathway. It provides means to exclude the outlier fibers while retaining partially-complete fibers. / The proposed scheme is applied to a clinical study of cerebral small vessel diseases(SVD).Experimental results show successful registration of the whole brain tractography template onto all 64 subjects, including both healthy con¬trol subjects and SVD patients. The DTI measures measured along specific registered anatomical fiber bundles exhibit significant boost in correlation with cognitive functions as compared with traditional measures. It also shows that different anatomical WM structures correlate with multiple types of cognitive functions in different ways. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / He, Xiaotian. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 46-53). / Abstracts also in Chinese. / List of Figures --- p.ix / List of Tables --- p.xii / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Motivation --- p.1 / Chapter 1.2 --- Our Work and Contributions --- p.2 / Chapter 1.3 --- Related Work --- p.4 / Chapter 1.4 --- Thesis Organization --- p.5 / Chapter 2 --- Background --- p.6 / Chapter 2.1 --- Background of Neuroanatomy --- p.6 / Chapter 2.2 --- Background on Diffusion Tensor Magnetic Resonance Imaging (DTMRI) --- p.11 / Chapter 3 --- Free Form Fibers --- p.18 / Chapter 3.1 --- DTI Acquisition --- p.20 / Chapter 3.2 --- Fiber Model --- p.20 / Chapter 3.3 --- Fiber-to-DTI Registration --- p.21 / Chapter 3.3.1 --- Free-Form Fibers (FFFs) --- p.21 / Chapter 3.3.2 --- Tensor-Driven Fiber-to-DTI Registration --- p.23 / Chapter 3.3.3 --- Reliability Assessment by Robust Principal Component Analysis --- p.24 / Chapter 3.3.4 --- Contextual Feature --- p.26 / Chapter 3.3.5 --- Learning the Fiber Context Prior --- p.29 / Chapter 3.3.6 --- Registration Refinement Using the Fiber Context Prior --- p.29 / Chapter 4 --- Results --- p.31 / Chapter 5 --- Future Work --- p.39 / Chapter 5.1 --- Refinement on Large Bundles --- p.39 / Chapter 5.2 --- Outlier Fiber Removal in Fiber Template --- p.40 / Chapter 6 --- Conclusion --- p.44 / Bibliography --- p.46

Thesis (M. Tech. (Clinical technology )) - Central University of technology, Free State, 2013 / The incidence of epilepsy is high in sub-Saharan Africa and resource poor countries (RPCs). There are few neurologists and paediatric neurologists to manage people with epilepsy (PWE). Health care is often limited, particularly technological services, including electroencephalogram (EEG), video EEG monitoring, and Neuroradiology services. All these are important in the management of PWE. Since 2008, informal electrophysiology training has been provided at the Red Cross War Memorial Hospital, in the Department of Paediatric Neurology. The Principal Investigator (PI) elected to develop a formal teaching course on EEG interpretation at the Red Cross War Memorial Hospital. A study was designed to evaluate the practical use of a handbook entitled “Handbook of Paediatric Electroencephalography: A guide to basic paediatric electroencephalogram interpretation.” This has been developed to fulfill the need for basic understanding and interpretation of EEG amongst clinicians caring for children in sub-Saharan Africa who may not have access to, or be able to afford, training at a recognized facility or on-line. In 2008, the department of Paediatric Neurology at the Red Cross War Memorial Hospital had their first African fellow from Kenya. By 2011, seven participants had undergone EEG training. A quantitative research approach and design was used in order to evaluate the handbook in terms of the accessibility of the contents and its practical use. Quantification included the recruitment of participants who constituted the population sample, a pilot study, and the collection of data from comparative assessments of participants’ use of the handbook, and from questionnaires completed by participants. This provided the researcher with the opportunity to improve and validate her knowledge of training in EEG interpretation. The researcher was able to quantify and compare the scores of participants using the handbook, as well as to compare their evaluative responses to its content and practical use. Eleven of thirteen participants completed the study. The pre-training results showed a median percentage of 50 which increased to 70 percent post-test. A comparison of the scores of trained versus not-trained revealed that those participants who had undergone one-on-one training on site at the unit fared much better both in their interpretations, conclusions, and reporting of EEG findings. The responses from the evaluative and comparative survey between the two groups showed no significant difference across all questions, the majority of the questions on the relative usefulness of the handbook being rated ‘agree’ and ‘strongly agree’, thus supporting the finding that all participants found the handbook useful whether they had received one-on-one training or not. The post-training results in EEG interpretation showed a stronger trend towards statistical significance (p<0.06) with trained participants and with the not-trained. These findings lend support to the success and usefulness of the handbook as a basic guide to paediatric EEG interpretation. The handbook was not aimed at making the electroencephalography reader an expert at a specialist level, but rather to maximize the reliability of the reading of EEG when screening electroencephalograms for important key diagnostic markers which would alter the child’s management. This is the first published handbook on paediatric EEG in South Africa. The results of this study strongly suggest that the handbook is useful as a learning and reference tool in interpretation of paediatric EEG, both for individuals with access to one-on-one training as well as those without. It is intended that the handbook, in conjunction with one-on-one training, will form part of a post-graduate diploma course offered by the University of Cape Town on “basic electrophysiology and the management of children with epilepsy” for training neurologists and child neurologists, paediatricians and health care workers in sub-Saharan Africa.

Après un coma, certains patients restent de manière prolongée dans un état d’éveil non-répondant (éveil sans conscience) ou en état de conscience minimale (éveil et fluctuation de la conscience) (Gosseries & Bruno et al. 2011b). Des travaux antérieurs ont montré que l’évaluation comportementale aboutissait fréquemment à des erreurs diagnostiques. Des études de neuroimagerie en IRM et TEP se sont développées pour mesurer plus objectivement l’état de conscience de ces patients (Gosseries et al. 2011d). Ces techniques ne sont cependant pas encore assez sensibles pour détecter des signes de conscience au niveau individuel. Le premier objectif de ce travail est de valider de nouveaux marqueurs diagnostiques paracliniques en utilisant d’autres outils tels que l’électroencéphalographie et la stimulation magnétique transcrânnienne. D’un point de vue neuroscientifique, les théories de l’information intégrée (Tononi, 2004), de l’espace de travail neuronal global (Dehaene et al, 2006) et du syndrome de déconnexion (Laureys et al. 2005c) émettent l’hypothèse qu’un réseau neuronal largement connecté et spécialisé est requis pour l’émergence de la conscience. Ces modèles proposent un parallèle entre la connectivité au sein d’un large réseau fronto-pariéto-thalamique et le degré de conscience d’un sujet. Le second objectif de notre travail est de tester ces hypothèses, en intégrant nos résultats dans un cadre théorique général de la conscience. <p><p>Evaluation comportementale. Avant de plonger dans le vif du sujet, nous avons évalué des facteurs pronostiques à court terme de la récupération fonctionnelle après un coma. L’intervalle de temps entre la lésion cérébrale et l’admission dans un centre de réadaptation, le score à la Disability Rating Scale à l’admission et l’étiologie semblent de bons facteurs pronostiques. Nos modèles de prédiction ne peuvent cependant pas être utilisés dans le cadre des décisions cliniques individuelles, en raison d’une trop grande variabilité entre les patients (Gosseries & Whyte et al. 2009). <p><p>Evaluations électroencéphalographiques (EEG). Une mesure automatisée d’EEG-entropie a permis de discriminer entre les patients conscients et inconscients dans les stades aigus avec une très bonne sensibilité (Gosseries et al. 2011b). Les valeurs de l’EEG-entropie étaient élevées chez les patients en état de conscience minimale alors qu’elles étaient basses chez les patients en état d’éveil non-répondant, suggérant une diminution de la complexité cérébrale chez ces derniers. Cette technique, qui est facilement applicable en routine clinique, n’a par contre montré aucune valeur pronostique. Une seconde mesure a ensuite été évaluée à l’aide des potentiels évoqués auditifs combinés à des analyses spécifiques de reconstruction de source. Ces données ont montré une altération des connexions cortico-corticales (connexions rétrogrades fronto-temporales) chez les patients en état d’éveil non-répondant (Boly et al. 2011a). Ces résultats nécessitent encore une validation au niveau individuel mais soulignent l’importance des projections neuronales rétrogrades dans l’émergence de la conscience, et confirment les hypothèses de la perte de connectivité effective et du syndrome de déconnexion chez les patients en état de conscience altérée. <p><p>Stimulation magnétique transcrânienne (SMT). Nous avons ensuite utilisé la technique SMT pour mesurer les connexions cortico-spinales. Les mesures électromyographiques ont montré des résultats globalement similaires au niveau périphérique alors que les mesures corticales différaient selon le niveau de conscience. En effet, le seuil moteur, les courbes de recrutement et l’inhibition afférente à courte latence étaient altérés chez les patients, et les deux dernières mesures étaient en lien avec le niveau de conscience des patients (Gosseries & Lapitskaya et al. soumis). Ces résultats suggèrent donc une diminution de l’excitabilité et de l’inhibition cortico-spinale, ainsi qu’un syndrome de déconnexion d’origine corticale chez les patients en état de conscience altérée. Combinaison de la SMT et de l’EEG. Enfin, nous avons évalué directement l’effet de la SMT sur l’activité du cortex cérébral (Gosseries & Rosanova et al. soumis). Cette méthode a permis de différencier au niveau individuel les patients en état d’éveil non-répondant des patients en état de conscience minimale. Chez les premiers, la réponse était initialement plus forte mais s’éteignait rapidement et ne se dispersait pas au-delà du site de stimulation. Chez les patients en état de conscience minimale, une réponse initiale au site de stimulation était suivie par une séquence complexe d’ondes qui se propageaient aux aires corticales adjacentes. Les patients présentant une récupération progressive de la conscience ont quant à eux montré une résurgence d’interactions cérébrales rapides et à longue distance (Gosseries & Rosanova et al. 2012). La SMT-EEG semble être une technique sensible qui pourrait être utilisée comme marqueur diagnostique en routine clinique. Ces résultats confirment également un syndrome de déconnexion au niveau cortico-cortical et une perte de conscience liée à une altération de la connectivité effective entre les différentes aires cérébrales (perte d'intégration et de différentiation de l’activité neuronale). <p><p>Aspects psychologiques liés à la prise en charge des patients sévèrement cérébrolésés. Parallèlement aux études susmentionnées, nous avons évalué le syndrome du burnout parmi le personnel soignant prenant en charge des patients non communicants dans des centres de réadaptation et des maisons de repos. Sur 523 personnes interrogées, 18% présentaient un burnout modéré (15%) à sévère (3%). La profession (équipe infirmière), le lieu de travail (maison de repos) et le nombre d’heures passées avec les patients étaient associés à la présence de burnout (Gosseries et al. accepté). L’importance et la satisfaction de différents besoins des familles des patients ont également été évaluées. Les besoins considérés comme importants étaient le besoin d’information médicale, le soutien émotionnel et social ainsi que l’implication dans les soins. Les familles étaient insatisfaites pour les trois premiers besoins rapportés et présentaient souvent des pensées dépressives et de l’anxiété (Gosseries et al. soumis). Le burnout du personnel soignant et les besoins des familles doivent être pris en compte afin de réduire la détresse psychologique associée à la difficulté de la prise en charge de ces patients et afin de favoriser une qualité optimale des soins prodigués aux patients. Au terme de ce travail, nous proposons des perspectives de futures études sous forme de deux nouvelles approches. La première approche, multimodale et longitudinale, consiste à comparer les différents types de connectivité cérébrale (structurelle, fonctionnelle, effective) lors de la récupération de conscience. La seconde approche est d’ordre thérapeutique, et vise à établir dans quelle mesure la restauration de la connectivité effective est liée à la restauration de conscience lors de traitements pharmacologiques et de stimulation cérébrale. <p><p><p>Summary <p><p>Following a coma, some patients may stay in a chronic unresponsive wakefulness syndrome (wakefulness without awareness) or in a minimally conscious state (wakefulness and fluctuation of awareness) (Gosseries & Bruno et al. 2011b). Previous works showed that behavioral assessments frequently lead to diagnostic errors. Neuroimaging studies using MRI and PET were developed to measure more objectively the state of consciousness of these patients (Gosseries et al. 2011d). However these techniques are not sensitive enough to detect signs of consciousness at the individual level. Our first objective is to validate new diagnostic paraclinical markers using electroencephalography and transcranial magnetic stimulation. At the neuroscientific level, the information integration (Tononi, 2004), the global neuronal workspace (Dehaene et al. 2006) and the disconnection syndrome (Laureys and al, on 2005) theories postulate that activation of a widely connected and specialized neuronal network is required for consciousness to emerge. The level of consciousness can therefore be linked to the level of connectivity in a wide fronto-parieto-thalamic network. Our second objective is to test these hypotheses by integrating our results into a general theoretical frame of consciousness.<p><p>Clinical assessment. Outside the scope of our main objectives, we studied predictors of short-term outcome. The time interval post-injury and the Disability Rating Scale score at enrollment in a rehabilitation centre were predictors of early recovery. Etiology was also a good predictor in some analysis. None of these predictive models could however explain sufficient variance to allow their use in individual clinical decision making (Gosseries & Whyte et al. 2009). <p><p>EEG assessment. We investigated the usefulness of EEG in differentiating unconscious from minimally conscious patients. Automated EEG-entropy could reliably discriminate these patients in the acute setting with a good sensitivity (Gosseries et al. 2011b). EEG-entropy values were high in minimally conscious patients and low in unconscious patients, suggesting a decrease of neural network complexity in the latter. This technique, which is easily applicable in clinical routine, offered however no reliable prognosis information. In a second study, using auditory evoked potentials and specific source reconstruction analysis, we showed that the only difference between unresponsive patients and healthy controls was an impairment of backward connectivity from frontal to temporal cortices. By contrast, minimally conscious patients exhibited near-normal recurrent effective connectivity (Boly et al. 2011a). These results require further validation at the individual level but emphasize the importance of top-down projections in recurrent processing for conscious perception, and confirm the hypotheses of the loss of effective connectivity and disconnection syndrome. <p><p>Transcranial magnetic stimulation assessment (TMS). We assessed cortico-spinal excitability through the stimulation of motor cortices and electromyography recordings. Spinal measurements were globally similar whereas cortical measurements differed according to the level of consciousness. Patients revealed a higher motor threshold, narrower stimulus/response curves and a decreased short afferent inhibition (using an additional electrical stimulation on the median nerve) compared to healthy controls participants. Recruitment curves and short afferent inhibition were associated to the level of consciousness. Our findings suggest decreased cortico-spinal excitability and inhibition as well as a cortical disconnection syndrome in disorders of consciousness (Gosseries & Lapitskaya et al. submitted). <p><p>Multimodal TMS and EEG assessment. To further assess cortical excitability and effective cortico-cortical connectivity, we employed TMS combined with EEG (Gosseries & Rosanova et al. submitted). This technique allowed to reliably discriminate between unresponsive and minimally conscious patients at the individual level. In unresponsive patients, TMS triggered a stereotyped and local response whereas in minimally conscious patients, TMS triggered rapidly changing and long-lasting widespread responses. Through longitudinal measurements, we also showed that this clear-cut change in the brain’s capacity for internal communication occurred at an early stage during recovery of consciousness, before reliable communication could be established with the patient (Gosseries & Rosanova et al, 2012). TMS-EEG seems therefore a trustworthy tool which could be used as a diagnostic marker in clinical routine. These results also confirm the cortico-cortical disconnection syndrome and the loss of consciousness related to altered effective connectivity between brain areas (loss of integration and differentiation of the neuronal activity). <p><p>Psychological issues related to the management of patients with disorders of consciousness. In parallel to the above studies, we also investigated the presence of burnout among healthcare professionals working with unresponsive and minimally conscious patients in rehabilitation centres and nursing homes. Out of 523 caregivers, 18% presented a moderate (15%) to severe burnout (3%). Profession (i.e. nurse/nursing assistants), working place (i.e. nursing home) and the amount of time spent with patients were associated with burnout (Gosseries et al. accepted). We also evaluated the family needs of chronic patients with disorders of consciousness. The most important needs reported were the medical information, the social and emotional support as well as the involvement in the care. Unsatisfaction was nevertheless observed for the emotional and social support as well as for medical information, in addition to frequent depressive thoughts and anxiety (Gosseries et al. submitted). Insufficient consideration of professional workers burnout and family needs may lead to important psychological distress and may favor inadequate quality of care in patients with disorders of consciousness. <p><p>At the end of this work, we propose two new approaches in future studies. The first approach, multimodal and longitudinal, consists in comparing various types of connectivity (i.e. structural, functional and effective) during recovery of consciousness. The second approach is of therapeutic interest, and will allow to evaluate in which measure the restoration of effective connectivity is connected to the restoration of consciousness during pharmacological treatments and during brain stimulation. / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

In vivo proton magnetic resonance spectroscopy (1H MRS) is the only method available to measure small-molecule metabolites in living human tissue, including the brain, without ionizing radiation or invasive medical procedures. Despite its attendant potential for supporting clinical diagnostics in a range of neurological and psychiatric conditions, the metabolite concentration estimates produced by 1H-MRS experiments, and therefore their sensitivity and specificity to any particular biological phenomenon under study, are readily distorted by a number of confounds. These include but are not limited to static and radiofrequency field characteristics, signal relaxation dynamics, macromolecule and lipid contributions to the spectral baseline, spectral fitting artifacts, and other uncontrolled idiosyncrasies of 1H-MRS data acquisition, processing, and quantification. Using 1H-MRS data obtained via 3-Tesla and 7-Tesla magnetic resonance (MR) scanners from healthy controls, individuals with progressive and relapsing-remitting multiple sclerosis (MS), and individuals with post-traumatic stress disorder (PTSD) and/or major depressive disorder (MDD), this work therefore aims to build and apply a framework for quantifying and thereby reducing such confounds introduced to 1H-MRS estimates of in vivo metabolite concentrations at the steps of data processing and quantification, with an ultimate aim to maximizing the potential of 1H MRS for supporting sensitive and specific clinical diagnosis of neurological or psychiatric disease. The steps examined include spectral quantification by linear combination modeling (Chapter 2), absolute quantification by internal concentration referencing (Chapter 3), and cross-sectional statistical analysis of results (Chapters 4 and 5). Chapter 2 designs and implements a graphical user interface (GUI)-supported validation pipeline for measuring how data quality, spectral baseline, and baseline model affect the precision and accuracy of 1H-MR spectral quantification by linear combination modeling. This validation pipeline is then used to show that spectral data quality indices signal to noise ratio (SNR) and full width at half maximum (FWHM) interact with spectral baseline to influence not only the precision but also the accuracy of resultant metabolite concentration estimates, with fit residuals poorly indicative of true fit error and spectral baselines modeled as regularized cubic splines not significantly outperformed by those employing simulated macromolecules. A novel method for extending the commonly used spectral quantification precision estimate Cramér-Rao Lower Bound (CRLB) to incorporate considerations of continuous and piecewise polynomial baseline shapes is therefore presented, tested, and similarly integrated into a GUI-supported toolkit to improve the correspondence between estimated CRLB and metabolite fit error variability when this now empirically justified approach to spectral baseline modeling is used. In Chapter 3, age- and disease-associated differences in transverse (T2) water signal relaxation measured at 7 Tesla in the prefrontal cortex of individuals with progressive (N=21) relative to relapsing-remitting (N=26) or no (N=25) multiple sclerosis are shown to influence absolute quantification of metabolite concentrations by internal referencing to water. In Chapter 4, these findings from Chapters 2 and 3 are used to justify an evidence-based 1H-MR spectral processing and quantification protocol that focuses optimization efforts on baseline modeling approach and references metabolite concentration estimates to internal creatine instead of water. When this protocol is applied to 7-Tesla prefrontal cortex 1H-MR spectra from the aforementioned multiple sclerosis and control cohorts, it supports metabolite concentration estimates that, in the absence of any additional supporting data, inform supervised-learning-enabled identification of progressive multiple sclerosis at nearly 80% held-out validation sensitivity and specificity. Finally, in Chapter 5, the same processing, quantification, and machine-learning pipeline employed in Aim 3 is independently applied to a new set of 7-Tesla prefrontal cortex 1H-MRS raw data from an entirely different cohort of individuals with (N=20) and without (N=18) PTSD and/or comorbid or primary MDD. Here the processing, quantification, and statistics procedures designed using lessons in Chapters 2 and 3 and optimized for classifying multiple sclerosis phenotype in Chapter 4 generalize directly to metabolite-only classification of PTSD and/or MDD with sensitivity and specificity similarly near to or greater than 80%. In both Chapters 4 and 5, supervised learning avoids dimensionally reducing metabolite feature sets in order to pinpoint the specific metabolites most informative for identifying each disease group. Taken together, these findings justify the potential and continued development of 1H MRS, at least as applied in the human brain and especially as supported by multivariate approaches including supervised learning, as an auxiliary or mainstay of clinical diagnostics for neurological or psychiatric disease.

Parte da população mundial sofre com distúrbios relacionados ao controle muscular de membros superiores e inferiores que, em muitos casos, podem ter sua origem devido a interrupção da comunicação sensório-motora entre o cérebro e os grupos musculares. Estes fatores podem estar relacionados à idade, doenças neuro-degenerativas ou acidentes vasculares cerebrais (AVC). Dessa forma, devido ao gradativo envelhecimento da população, em função do aumento da expectativa de vida e consequentemente da demanda por tratamentos de reabilitação, diversos estudos da literatura utilizam equipamentos de biofeedback na reabilitação do controle muscular, não havendo, porém, uma ferramenta simples e unificada que permita a elaboração de protocolos motores para diversas patologias em uma única plataforma. Sendo assim, o objetivo deste trabalho é apresentar o desenvolvimento de uma ferramenta de biofeedback visual, baseada em plataformas de força para membros inferiores e aquisição de imagem para membros superiores. Este sistema conta com duas interfaces: a primeira, programável em alto nível, é destinada ao profissional da saúde para elaboração do treino motor conforme a necessidade do paciente; a segunda é a interface do jogo, ou serious game, com o qual o paciente interage realizando a série de atividades programadas em um jogo de exercícios, ou exergames. A proposta deste estudo é fornecer uma plataforma de reabilitação programável de acordo com a necessidade específica de cada paciente, mantendo características motivacionais e de interatividade, que proporcionem entretenimento associado às atividades, reduzindo assim a evasão dos tratamentos, que costumam ser realizados por longos períodos. Ainda, neste estudo foram apresentados alguns testes, aprovados pelo comitê de ética, com voluntários, em que é aplicado um protocolo motor a um grupo de jovens saudáveis e comparando os resultados com um grupo de voluntários idosos. Os resultados deste estudo foram obtidos a partir de duas análises: a primeira é interna à sessão, em tempo real, e diz respeito à pontuação dos voluntários no jogo; a segunda é externa à sessão, utiliza os dados armazenados ao longo de um teste estabilométrico e compara medidas posturográficas do grupo de jovens e idosos saudáveis. Ainda, para complementar a validação do equipamento desenvolvido, foi realizada uma comparação dos resultados das análises posturográficas obtidas, com os resultados obtidos a partir de um baropodômetro comercial. Os resultados demonstram que o sistema permite a obtenção da estimativa da estabilometria e atividades de serious games. / The cases of disorders related to upper and lower limbs control directly affect the population. These problems may have its origin due to interruption of sensorimotor communication between the brain and the muscle groups. These factors may be related to aging, neurodegenerative diseases or stroke. Thus, due to the gradual aging of the population, the increase in life expectancy and hence the demand for rehabilitation treatments, several studies in the literature are using biofeedback to rehabilitation of muscle control. However, there is no unified tool that allows the development of exercise protocols for several diseases in a single platform. The aim of this work is to present the development of a visual biofeedback tool, based on force platforms for lower limbs and image acquisition for upper limbs. This system has two interfaces: the first, programmable in high-level, is intended for health professionals to prepare the motor training as needed by the patient; the second is the serious game interface, with which the patient interacts performing the series of activities planned in an exercise games (exergames). The purpose of this study is to provide a programmable rehabilitation platform according to the specific needs of each patient, keeping motivational and interactive features that provide fun activities to reduce evasion of treatments, which are usually carried out for long periods. Moreover, this study shows some tests, approved by the Ethics Committee, with volunteers, applying an exercise protocol to a group of healthy young and comparing the results with a group of elderly volunteers. The results of this study are obtained from two experimental setups: the first is internal to the session in real time, and concerns the scores of volunteers in the game; the second is external to the session, uses the data stored over a stabilometry and compare posturographic data between control and study group. Furthermore, in order to complement the assessments of the developed system, the posturographic data is compared to those obtainded from a commercial baropodometer. Results show that the system is able to perform the estimative of the stabilometry and serious game activities.

Introdução: A esclerodermia é rara doença do tecido conectivo que se manifesta através da esclerose cutânea e variável acometimento sistêmico. Duas categorias de esclerodermia são conhecidas: esclerose sistêmica, caracterizada por esclerose cutânea e acometimento visceral e a esclerodermia localizada ou morfeia que classicamente apresenta evolução benigna e autolimitada, confinada a pele e/ou tecidos subjacentes. Estudos recentes demonstram que a forma localizada possa eventualmente apresentar acometimento de órgãos internos e morbidade variável. Objetivo: Neste estudo objetivamos determinar as características demográficas, a prevalência de manifestações sistêmicas e alterações laboratoriais, bem como a associação com doenças autoimunes, em pacientes com esclerodermia da face. Métodos: Pacientes com esclerodermia localizada, incluindo os casos de esclerodermia em golpe de sabre, síndrome de Parry-Romberg e morfeia em placas com acometimento facial, foram avaliados e submetidos à investigação neurológica, incluindo exame clínico neurológico e ressonância magnética de crânio, e avaliação oftalmológica. Após 3 anos, o subgrupo de pacientes disponível para seguimento foi ressubmetido à ressonância magnética. Resultados: Foram estudados 34 pacientes com esclerodermia localizada da face. Deste total, 64,7% apresentavam uma ou mais manifestações extracutâneas, sendo cefaleia a queixa mais frequente, encontrada em 61,8% dos pacientes. Dos 23 pacientes submetidos à avaliação neurológica, 56,5% apresentaram alterações neurológicas possivelmente associadas à esclerodermia. Alterações à ressonância magnética foram observadas em 50% dos casos. O achado mais frequente foi a presença de lesões parenquimatosas com alteração de sinal em 50% dos pacientes. Dos pacientes que apresentavam alteração neurológica, 80% também apresentavam alguma alteração à ressonância magnética. Doze pacientes foram ressubmetidos a novo exame após 3 anos. Em todos os pacientes os achados de imagem se mantiveram inalterados. Durante esse intervalo de 3 anos, 25% dos pacientes apresentaram sinais de atividade da esclerodermia. Quanto à avaliação oftalmológica, 67,9% dos pacientes avaliados apresentaram alteração, sendo os achados mais frequentes a ocorrência de alterações orbiculares da esclerodermia (20,6%) e xeroftalmia (10,7%). Conclusão: Pacientes com esclerodermia localizada da face apresentam alta prevalência de alterações neurológicas e oftalmológicas. Baseado nestes achados, sugerimos que todos os casos de esclerodermia localizada da face devam ser detalhadamente examinados quanto à presença de alterações sistêmicas / Introduction: Scleroderma is a rare connective tissue disease that manifests as skin sclerosis and variable systemic involvement. Two categories of scleroderma are known: systemic sclerosis, characterized by cutaneous sclerosis and visceral involvement and localized scleroderma or morphea which classically presents benign evolution and selflimited, confined to the skin and / or underlying tissue. Recent studies show that the localized form may possibly course with involvement of internal organs and variable morbidity. Objective: This study aimed to determine the demographic characteristics, the prevalence of systemic manifestations and laboratory findings, as well as the association with autoimmune diseases, in patients with scleroderma of the face. Methods: Patients with localized scleroderma, including cases of scleroderma en coup de sabre, Parry-Romberg syndrome and morphea plaque with facial involvement were evaluated and underwent neurological examination, including neurologic examination and magnetic resonance imaging, and ophthalmology evaluation. After 3 years, the subgroup of patients available for follow-up was subjected again to MRI. Results: We studied 34 patients with localized scleroderma of the face. Of this total, 64,7% had one or more extracutaneous manifestation, headache being the most frequent complaint found in 61,8% of patients. Of the 23 patients undergoing neurological evaluation, 56,5% had neurological changes possibly associated with scleroderma. MRI changes were observed in 50% of cases. The most frequent was the presence of parenchymal lesions with signal alteration in 50% of patients. Of the patients who had neurological deficits, 80% also had a change to MRI. Twelve patients were subjected again to another MRI scan after 3 years. In all patients, imaging findings were unchanged. During this interval of 3 years, 25% of patients showed signs of activity of scleroderma. As for ophthalmologic evaluation, 67,9% of patients showed abnormalities, with the most frequent findings being the occurrence of orbicular changes of scleroderma (20.6%) and xerophthalmia (10.7%). Conclusion: Patients with localized scleroderma face have a high prevalence of neurological and ophthalmological changes. Based on these findings, we suggest that all cases of localized scleroderma of the face should be thoroughly examined for the presence of systemic changes