Multielectrode arrays may have several advantages compared to the traditional single macroelectrode brain electrical stimulation technique including less tissue damage due to implantation and the ability to deliver several spatio-temporal patterns of stimulation. Prior work on cell cultures has shown that multielectrode arrays are capable of completely stopping seizure-like spontaneous bursting events through a distributed asynchronous multi-site approach. In my studies, I used a similar approach for controlling seizures in a rat model of temporal lobe epilepsy. First, I developed a new method of electroplating in vivo microelectrode arrays for durably improving their impedance. I showed that microelectrode arrays electroplated through the new technique called sonicoplating, required the least amount of voltage in current controlled stimulation studies and also produced the least amplitude and duration of stimulation artifact compared to unplated, DC electroplated or pulse-plated microelectrodes. Second, using c-fos immunohistochemistry, I showed that 16-electrode sonicoplated microelectrode arrays can activate 5.9 times more neurons in the dorsal hippocampus compared to a single macroelectrodes while causing < 77% the tissue damage. Next, through open-loop multisite asynchronous microstimulation, I reduced seizure frequency by ~50% in the rodent model of temporal lobe epilepsy. Preliminary studies aimed at using the same stimulation protocol in closed-loop responsive and predictive seizure control did not stop seizures. Finally, through an internship at Medtronic Neuromodulation, I worked on developing and implementing a rapid algorithm prototyping research tool for closed-loop human deep brain stimulation applications.

Thesis (doctoral)--Universitetet i Lund. / Reprints of journal articles inserted in pocket inside back cover.

As demências Frontotemporais (DFT) compreendem 2 fenótipos clínicos: distúrbios comportamentais ou de linguagem. Coletivamente, as DFT podem ser causadas por um grupo diversas de doenças neurodegenerativas chamadas degeneração lobar frontotemporal (DLFT). Novas entidades têm sido descritas neste grupo e o conceito está em constante evolução. Parte dos mecanismos envolvidos na morte celular nas DLFTs também são observados n envelhecimento normal. Determinar as entidades e freqüência das DLFTs em uma série com utilização de imunoistoquímica. Uma série prospectiva de 833 casos avaliados prospectivamente no Centro de Pesquisas de Doença de Alzheimer da Washington University - EUA. Os casos de DFT foram selecionados por critérios clínicos e a classificação neuropatológica foi baseada em protocolos universalmente aceitos para DLFT. Dos casos de demência, 53(6,3%) atenderam aos critérios clínicos e neuropatológicos para DLFT. Outros 8 casos atenderam apenas aos critérios clínicos de DFT. As tauopatias representaram 40% dos casos. Entretanto, a maioria dos casos apresentava inclusões ubiquitina-positivas e tau-negativas. Esclerose hipocampal e alterações do tipo Doença de Alzheimer foram encontradas em 12 e 10 casos, respectivamente. Apesar da DLFT-U ter sido a entidade mais freqüente nesta série, entidades e menos comuns não incluídas nas recomendações de McKhann também podem apresentar fenótipo clínico de DFT. A inclusão destas novas entidades é mais uma evidência de que os sintomas clínicos são mais dependentes das áreas acometidas do que da entidade em si. A melhor compreensão desses mecanismos tem um grande potencial em auxiliar no desenvolvimento de medidas que possam modular ou retardar os efeitos do envelhecimento no cérebro, além é claro de trazer possibilidade de tratamento, hoje inexistente, para os pacientes acometidos. / Frontotemporal dementia (FTD) encompasses two clinical phenotypes: progressive behavioral change and language disorder. Collectively, FTD may be caused by a diverse group of neurodegenerative diseases called frontotemporal lobar degenerations (FTLDs). New entities have been described and the nosology of FTLDs continues to evolve. To determine the type and frequency of FTLDs in a series using contemporary immunohistochemical methods. Eight hundred and thirtythree dementia cases were prospectively assessed at Washington University Alzheimer Disease Research Center (WUADRC) and cases with clinical FTD were identified using existing diagnostic criteria and neuropathologic entities were ascertained using immunohistochemistry and contemporary diagnostic criteria. Of the dementia cases, 53(6.3%) met clinical criteria for FTD; 45(5.1%) fulfilled both clinical and neuropathological criteria for FTLD, and another 8 fulfilled only the clinical criteria. Forty percent of the cases were tauopathies. However, most FTLD cases were characterized by ubiquitin-positive, tau-negative inclusions. Co-existing hippocampal sclerosis and AD-type changes were observed in 12 and 10 cases, respectively. Although FTLD-MND-type is the most frequent FTLD in this prospectively assessed series, less common entities not included in the McKhann criteria, may also present clinically as FTD and should be considered as part of the neuropathologic spectrum of FTLDs that may be encountered in the dementia clinic. The better understanding of the cell death mechanisms related to those entities is likely to contribute for the development of a treatment for FTLD as well for a way of modulate brain aging.

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.

Treatment of brain diseases remains extremely challenging partly due to the fact that critical drug delivery is hindered by the blood-brain barrier (BBB), a specialized and highly selective barrier lining the brain vasculature. Focused ultrasound (FUS), combined with systematically administered microbubbles (MBs), has been established as a technique to noninvasively, locally, and transiently open the BBB. The primary mechanism for temporarily opening the BBB using FUS is microbubble cavitation, a phenomenon that occurs when the circulating microbubbles interact with the FUS beam in the brain vasculature. Over the past two decades, many preclinical and clinical applications of FUS-induced BBB opening have been developed, but certain challenges, such as drug delivery route, cavitation control, inflammation onset, and overall accessibility of the technology, have affected its efficient translation to the clinic. This dissertation focuses on optimizing three aspects of FUS-induced BBB opening for therapeutic applications. The first specific aim investigated FUS-induced BBB opening for drug delivery through the intranasal route. Optimal sonication parameters were determined and applied to FUS-enhanced intranasal delivery of neurotrophic factors in a Parkinson’s Disease mouse model. In the second specific aim, cavitation levels affecting the inflammatory response due to BBB opening with FUS were optimized. The relationship between cavitation during FUS-induced BBB opening and the local inflammation was examined, and a cavitation-based controller system was developed to modulate the inflammatory response. In the third specific aim, the devices used for FUS-induced BBB opening were streamlined. A conventional system for FUS-induced BBB opening includes two transducers: one for therapy and another for cavitation monitoring (single element) or imaging (multi-element). In this aim, a single linear array transducer capable of synchronous BBB opening and cavitation imaging was developed, creating a cost-effective and highly accessible “theranostic ultrasound” device. The feasibility of theranostic ultrasound (TUS) was demonstrated in vivo in both mice and non-human primates. In summary, the findings and methodologies in this dissertation optimized FUS-enhanced intranasal delivery across the BBB, developed a cavitation-controlled system to modulate inflammation in the brain, which has been advantageous in reducing pathology and designed a new system for theranostic ultrasound for drug delivery to the brain. Taken altogether, this thesis contributes to the efficient advancement and optimization of FUS-induced BBB opening technology, thus enhancing its clinical adoption in the fight to treat many challenging brain diseases.

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.

T1rho弛豫是旋轉坐標系中的自旋晶格弛豫，它決定橫向磁化向量在存有自旋鎖定射頻脈衝情況下的衰減，自旋鎖定脈衝與橫向磁化向量同向。T1rho磁共振成像對於低頻運動過程敏感，故可研究水與其周大分子物質環境間的交互作用，有鑒別組織內早期生化改變的潛力。 / 衰老與慢性高血壓是常見腦退行性疾病的兩個主要危險因素。但是正常腦衰老過程及慢性高血壓兩個因素與腦組織T1rho是否有相關性，尚缺乏研究。序貫性測量SD老鼠自5至15月齡、WKY（血壓正常）和SHR（患有自發性高血壓）老鼠自6至12月齡的雙側丘腦、海馬、和皮質的腦組織T1rho值。發現三組老鼠的丘腦、海馬及皮質的T1rho均隨年齡增長而增高；且SHR的顯著高於WKY老鼠。 / T1rho值與椎間盤退變等級的相關性已有報導。但相比T2值，T1rho在評價椎間盤退變方面是否優於或如何優於T2值尚缺乏研究。將椎間盤髓核及纖維環的T1rho和T2值與5級和8級椎間盤退變等級系統做比較；發現髓核的T1rho及T2與椎間盤退變等級的相關性均呈二次函數降低，且無顯著差別(P=0.40)。纖維環的T1rho及T2與椎間盤退變等級的相關性呈線性函數降低，T2降低的斜率明顯比T1rho降低的斜率要平坦(P<0.001)。故T1rho值比T2值更加適合評價纖維環退變，而兩者在評價髓核時相似。 / 肝纖維化是幾乎所有慢性肝病的常見特徵，包括大分子物質在細胞外基質的沉積。選用四氯化碳CCl4腹腔注射6周來製造肝纖維化模型。肝臟T1rho在注射後的第二天輕度上升，然後持續上升，直到注射六周後T1rho達最高值，此後T1rho隨CCl4注射停止而降低。顯示T1rho磁共振成像對於監測慢性注射CCl4誘導的肝纖維化及肝損傷有價值。當沒有明顯肝纖維化時，肝T1rho輕微受水腫及急性炎症的影響。 / 為將肝臟T1rho磁共振成像轉化到臨床使用，我們研究了其可行性，以及正常志願者肝臟T1rho值分佈範圍。發現採用六個自旋鎖定時間來測量健康志願者肝T1rho，結果有較高的可重複性和一致性，肝T1rho平均值為42.5ms，分佈範圍為38.8到46.5ms。採用三個自鎖鎖定時間點掃描，可以減少一半掃描時間，且可以得到可信的肝T1rho值，但採用兩個自旋鎖定時間點則不行。 / T1rho relaxation is spin-lattice relaxation in the rotating frame. It determines the decay of the transverse magnetization in the presence of a spin-lock radiofrequency pulse, which applied along the transverse magnetization. T1rho MRI is sensitive to low frequency motional processes, so it can be used to investigate the interaction between water molecules and their macromolecular environment. T1rho imaging is suggested to have the potential to identify early biochemical changes in tissues. / Aging and chronic hypertension are two major risk factors for common neurodegenerative disease. However, whether normal brain aging and chronic spontaneous hypertensive are associated with brain T1rho values changes were not reported. We longitudinally measured the T1rho value in rat brain of Sprague-Dawley (SD) rats from 5-month to 15-month, and spontaneous hypertensive rats (SHR) with Wistar Kyoto (WKY) rats from 6-month to 12-month. The T1rho values in three brain regions of thalamus, hippocampus, and cortices increased with aging process, and were significantly higher in SHR than WKY rats. / For intervertebral disc, the correlation between T1rho and degenerative grade has been reported. However, whether and how T1rho specifically offer better evaluation of disc degeneration compared with T2 was not studied previously. T1rho and T2 value of nucleus pulposus (NP) and annulus fibrosus (AF) was compared with reference to the five-level and eight-level semi-quantitative disc degeneration grading systems. For NP, T1rho and T2 decreased quadratically with disc degeneration grades and had no significant trend difference (P=0.40). In NP, T1rho and T2 decrease in a similar pattern following disc degeneration. For AF, T1rho and T2 decreased linearly and the slopes of T2 were significantly flatter than those of T1rho (P<0.001). Therefore, the T1rho is better suited for evaluating AF in degenerated disc than T2. / Liver fibrosis, a common feature of almost all causes of chronic liver disease, involves macromolecules accumulated within the extracellular matrix. Male Sprague-Dawley rats received intraperitoneal injection of 2 ml/kg CCl4 twice weekly for up to 6 weeks. Then CCl4 was withdrawn for recovery. The liver T1rho values increased slightly on day 2, then increased further and were highest at week 6 post CCl4 insults, and decreased upon the withdrawal of the CCl4 insult. This study demonstrated that T1rho MRI is a valuable imaging biomarker for liver injury and fibrosis induced by CCl4. Liver T1rho value was only mildly affected by edema and acute inflammation when there was no apparent fibrosis. / To translate liver T1rho MRI to clinical application, the technical feasibility of T1rho MRI in human liver was explored and the normal range of T1rho values in healthy volunteers was determined. We found it is feasible to obtain consistent liver T1rho measurement for healthy human liver with six spin-lock time (SLT) points of 1, 10, 20, 30, 40, and 50ms; the mean liver T1rho value of the healthy subjects was 42.5ms, with a range of 38.8-46.5ms. Adopting 3-SLT points of 1, 20, and 50ms for T1rho measurement could provide reliable measurement and reduce the scanning time, while 2-SLT points of 1 and 50ms do not provide reliable measurement. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhao, Feng. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 119-143). / Abstracts also in Chinese. / ABSTRACT --- p.i / ACKNOWLEDGEMENTS --- p.vi / LIST OF FIGURES --- p.viii / LIST OF TABLES --- p.xvi / LIST OF ABBREVIATIONS --- p.xvii / CONTENTS --- p.xxi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Conventional Magnetic Resonance Imaging --- p.1 / Chapter 1.1.1 --- Basic Principle of Conventional Magnetic Resonance Imaging --- p.1 / Chapter 1.1.2 --- T1 Relaxation --- p.2 / Chapter 1.1.3 --- T2 Relaxation --- p.3 / Chapter 1.2 --- T1rho Magnetic Resonance Imaging --- p.3 / Chapter 1.2.1 --- T1rho Relaxation --- p.3 / Chapter 1.2.2 --- Principle of T1rho Magnetic Resonance Imaging --- p.4 / Chapter 1.2.3 --- Radiofrequency Pulse for T1rho Magnetic Resonance Imaging --- p.5 / Chapter 1.2.4 --- T1rho-weighted Contrast Imaging and Application --- p.10 / Chapter 1.2.5 --- Quantitative T1rho Mapping and Application --- p.11 / Chapter 1.2.6 --- T1rho Dispersion and Application --- p.13 / Chapter 1.3 --- Thesis Overview --- p.14 / Chapter Chapter 2 --- T1rho MRI in brain aging of animal model --- p.19 / Chapter 2.1 --- Introduction --- p.19 / Chapter 2.2 --- Materials and Methods --- p.20 / Chapter 2.2.1 --- Animal Model of Brain Aging --- p.20 / Chapter 2.2.2 --- T1rho Data Acquisition --- p.21 / Chapter 2.2.3 --- T1rho Data Processing --- p.23 / Chapter 2.2.4 --- T1rho Measurement and Statistical Analysis --- p.24 / Chapter 2.3 --- Results --- p.27 / Chapter 2.4 --- Discussion --- p.38 / Chapter 2.5 --- Summary --- p.42 / Chapter Chapter 3 --- T1rho MRI in lumbar disc degeneration of human subjects --- p.43 / Chapter 3.1 --- Introduction --- p.43 / Chapter 3.2 --- Methods --- p.45 / Chapter 3.2.1 --- Subjects --- p.45 / Chapter 3.2.2 --- MR Image Acquisition --- p.46 / Chapter 3.2.2.1 --- T2-weighted MRI --- p.46 / Chapter 3.2.2.2 --- T2 Mapping Imaging --- p.47 / Chapter 3.2.2.3 --- T1rho MRI --- p.47 / Chapter 3.2.3 --- Data Processing --- p.49 / Chapter 3.2.4 --- Data Measurement and Statistical Analysis --- p.49 / Chapter 3.3 --- Results --- p.52 / Chapter 3.3.1 --- Range of T1rho/T2 Values for Discs --- p.52 / Chapter 3.3.2 --- The Relationship between NP T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.52 / Chapter 3.3.3 --- The Relationship between NP T1rho/T2 Values and 5-level Degeneration Grading of Discs --- p.55 / Chapter 3.3.4 --- The Relationship between AF T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.58 / Chapter 3.3.5 --- The Relationship between AF T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.61 / Chapter 3.4 --- Discussion --- p.64 / Chapter 3.5 --- Summary --- p.69 / Chapter Chapter 4 --- T1rho MRI in rat liver fibrosis model induced by CCl4 insult --- p.71 / Chapter 4.1 --- Introduction --- p.71 / Chapter 4.2 --- Materials and Methods --- p.73 / Chapter 4.2.1 --- Animal Preparation --- p.73 / Chapter 4.2.2 --- MR Image Acquisition --- p.74 / Chapter 4.2.2.1 --- T2-weighted MRI --- p.75 / Chapter 4.2.2.2 --- T1rho MRI --- p.75 / Chapter 4.2.3 --- Data Processing --- p.76 / Chapter 4.2.4 --- Data Measurement and Statistical Analysis --- p.78 / Chapter 4.2.5 --- Histology Analysis --- p.79 / Chapter 4.3 --- Results --- p.80 / Chapter 4.3.1 --- T1rho Measurement Reproducibility --- p.80 / Chapter 4.3.2 --- Rat Liver T1rho Values at Different Time Phase --- p.81 / Chapter 4.3.3 --- Relative Rat Liver Signal Intensity on T2WI at Different Time Phase --- p.83 / Chapter 4.3.4 --- Histology Results --- p.84 / Chapter 4.4 --- Discussion --- p.86 / Chapter 4.5 --- Summary --- p.91 / Chapter Chapter 5 --- T1rho MRI in liver of healthy human subjects --- p.93 / Chapter 5.1 --- Introduction --- p.93 / Chapter 5.2 --- Methods --- p.95 / Chapter 5.2.1 --- Subjects --- p.95 / Chapter 5.2.2 --- MR Image Acquisition --- p.96 / Chapter 5.2.2.1 --- T2-weighted MRI --- p.96 / Chapter 5.2.2.2 --- T1rho MRI --- p.97 / Chapter 5.2.3 --- T1rho Data Processing --- p.99 / Chapter 5.2.4 --- T1rho Measurement --- p.100 / Chapter 5.3 --- Results --- p.102 / Chapter 5.3.1 --- T1rho Measurement Reproducibility --- p.105 / Chapter 5.3.2 --- T1rho Value Agreement of the Fasting Status with Post Meal Status --- p.105 / Chapter 5.3.3 --- T1rho Value Agreement for T1rho Maps Constructed by Different Spin-lock Time Points --- p.106 / Chapter 5.3.4 --- T1rho Value Range of Healthy Human Subjects --- p.108 / Chapter 5.4 --- Discussion --- p.108 / Chapter 5.5 --- Summary --- p.113 / Chapter Chapter 6 --- General discussion and further work --- p.115 / References: --- p.119 / LIST OF PUBLICATIONS --- p.138

INTRODUÇÃO: A dosagem bioquímica do lactato no líquor (LCR) é um procedimento rotineiro e necessário na investigação diagnóstica e no acompanhamento evolutivo de várias doenças neurológicas, como, por exemplo, as doenças mitocondriais (DM). Pacientes com DM e comprometimento do sistema nervoso central frequentemente apresentam aumento do lactato no LCR. O lactato no LCR também pode ser detectado através da espectroscopia de prótons através da ressonância magnética (ERM), uma técnica não invasiva que pode ser empregada juntamente com as imagens estruturais obtidas através da ressonância magnética (RM). Nosso objetivo neste estudo é avaliar a existência ou não de correlação entre a dosagem bioquímica do lactato no LCR e no sangue e a sua quantificação através da ERM em pacientes em investigação de encefalopatia mitocondrial. Não é de nosso conhecimento a existência de estudos semelhantes in vivo na literatura médica. MÉTODOS: 22 pacientes (idades entre 9 meses e 20 anos) em investigação diagnóstica por suspeita clínica de encefalopatia relacionada a DM participara deste estudo prospectivo realizado entre novembro de 2005 a novembro de 2006. Foram comparados os valores do lactato nas dosagens séricas e liquóricas. Todos os pacientes realizaram RM e ERM e, quando presente, analisou-se o pico do lactato (PL). Os dados da quantificação do lactato obtidos nestas três modalidades foram comparados. RESULTADOS: A análise de correlação demonstrou evidências de associação entre as variáveis PL à ERM e lactato liquórico (p=0,001); não foi evidenciada correlação entre os valores do PL à ERM e as medidas sanguíneas dessa substância (p=0,736) e entre as dosagens bioquímicas liquórica e sanguínea (p=0,937). CONCLUSÕES: Este estudo demonstrou a existência de correlação entre a dosagem bioquímica do lactato no LCR e o PL obtido através de ERM. A ERM do LCR é uma técnica factível e recomendamos que a mesma seja empregada rotineiramente em pacientes com suspeita ou em seguimento de DM com comprometimento do sistema nervoso central. / INTRODUCTION: The cerebrospinal fluid (CSF) lactate biochemical dosage is a routine and a requisite procedure to evaluate and to monitor many neurological diseases, such as mitochondrial disease (MD). Patients with MD and central nervous system (CNS) involvement, usually show an increase of CSF lactate. Another choice to study the lactate instead of CSF biochemical dosage is the CSF magnetic resonance proton spectroscopy (SRM), a noninvasive technique, which can be employed as an adjunct tool with structural magnetic resonance imaging (MRI). Our objective is to study the correlation between the CSF and blood lactate dosages and the SRM lactate quantification in patients under investigation for the MD encephalopathy. To our knowledge there is no report of similar studies in vivo in the literature. METHODS: 22 patients (aging 9 months to 20 years old) under investigation for MD encephalopathy were elected for this prospective study between November 2005 and December 2006. The lactate levels were analyzed by biochemical dosages in the CSF and blood serum. Brain MRI was performed for all patients and the lactate peak (LP) obtained from SRM was analyzed. All lactate level data obtained from the three different sources were compared. RESULTS: The statistical analysis demonstrated a correlation between the LP at SRM and the CSF lactate dosage (p=0.0001); no correlation was observed between the LP and the blood lactate (p=0.736) as well the blood lactate and CSF lactate (p=0.937). CONCLUSION: Our study showed correlation between the lactate level in the CSF biochemical dosage and the LP found on SRM. The CSF SRM is tangible technique and we recommend it to be applied in the daily clinical practice to evaluate suspicious and diagnosed CNS compromised ME patients.

INTRODUÇÃO: A dosagem bioquímica do lactato no líquor (LCR) é um procedimento rotineiro e necessário na investigação diagnóstica e no acompanhamento evolutivo de várias doenças neurológicas, como, por exemplo, as doenças mitocondriais (DM). Pacientes com DM e comprometimento do sistema nervoso central frequentemente apresentam aumento do lactato no LCR. O lactato no LCR também pode ser detectado através da espectroscopia de prótons através da ressonância magnética (ERM), uma técnica não invasiva que pode ser empregada juntamente com as imagens estruturais obtidas através da ressonância magnética (RM). Nosso objetivo neste estudo é avaliar a existência ou não de correlação entre a dosagem bioquímica do lactato no LCR e no sangue e a sua quantificação através da ERM em pacientes em investigação de encefalopatia mitocondrial. Não é de nosso conhecimento a existência de estudos semelhantes in vivo na literatura médica. MÉTODOS: 22 pacientes (idades entre 9 meses e 20 anos) em investigação diagnóstica por suspeita clínica de encefalopatia relacionada a DM participara deste estudo prospectivo realizado entre novembro de 2005 a novembro de 2006. Foram comparados os valores do lactato nas dosagens séricas e liquóricas. Todos os pacientes realizaram RM e ERM e, quando presente, analisou-se o pico do lactato (PL). Os dados da quantificação do lactato obtidos nestas três modalidades foram comparados. RESULTADOS: A análise de correlação demonstrou evidências de associação entre as variáveis PL à ERM e lactato liquórico (p=0,001); não foi evidenciada correlação entre os valores do PL à ERM e as medidas sanguíneas dessa substância (p=0,736) e entre as dosagens bioquímicas liquórica e sanguínea (p=0,937). CONCLUSÕES: Este estudo demonstrou a existência de correlação entre a dosagem bioquímica do lactato no LCR e o PL obtido através de ERM. A ERM do LCR é uma técnica factível e recomendamos que a mesma seja empregada rotineiramente em pacientes com suspeita ou em seguimento de DM com comprometimento do sistema nervoso central. / INTRODUCTION: The cerebrospinal fluid (CSF) lactate biochemical dosage is a routine and a requisite procedure to evaluate and to monitor many neurological diseases, such as mitochondrial disease (MD). Patients with MD and central nervous system (CNS) involvement, usually show an increase of CSF lactate. Another choice to study the lactate instead of CSF biochemical dosage is the CSF magnetic resonance proton spectroscopy (SRM), a noninvasive technique, which can be employed as an adjunct tool with structural magnetic resonance imaging (MRI). Our objective is to study the correlation between the CSF and blood lactate dosages and the SRM lactate quantification in patients under investigation for the MD encephalopathy. To our knowledge there is no report of similar studies in vivo in the literature. METHODS: 22 patients (aging 9 months to 20 years old) under investigation for MD encephalopathy were elected for this prospective study between November 2005 and December 2006. The lactate levels were analyzed by biochemical dosages in the CSF and blood serum. Brain MRI was performed for all patients and the lactate peak (LP) obtained from SRM was analyzed. All lactate level data obtained from the three different sources were compared. RESULTS: The statistical analysis demonstrated a correlation between the LP at SRM and the CSF lactate dosage (p=0.0001); no correlation was observed between the LP and the blood lactate (p=0.736) as well the blood lactate and CSF lactate (p=0.937). CONCLUSION: Our study showed correlation between the lactate level in the CSF biochemical dosage and the LP found on SRM. The CSF SRM is tangible technique and we recommend it to be applied in the daily clinical practice to evaluate suspicious and diagnosed CNS compromised ME patients.