Die KE-Familie ist das am ausführlichsten untersuchte Beispiel für eine angeborene spezifische Sprachstörung. Die Sprachstörung in dieser Familie wird durch eine heterozygote Punktmutation im FoxP2-Gen hervorgerufen, die R553H-Mutation. Die betroffenen Mitglieder der Großfamilie haben Defizite beim Erlernen komplexer orofazialer Bewegungsabläufe als Grundlage des fließenden Sprechens und zeigen Störungen beim Sprachverständnis und beim Schreiben. Untersuchungen an der KE-Familie und an Knockout-Tieren hatten Hinweise auf eine Beteiligung des Kleinhirns an der Sprachstörung der KE-Familie geliefert. Entsprechend war zu erwarten, dass genauere Kenntnisse über den Einfluss vom FoxP2-Gen auf Entwicklung und Funktion des Kleinhirns helfen könnten, die Funktion von FoxP2 und seine Rolle bezüglich dieser Sprachstörung, aber auch in Hinblick auf die Sprachfähigkeit des Menschen weiter aufzuschlüsseln. Die Experimente, die der vorliegenden Promotionsarbeit zu Grunde liegen, erforschten erstmals den Einfluss der KE-Mutation im FoxP2-Gen auf synaptischer Ebene durch Untersuchungen am in der Literatur ausführlich beschriebenen erregenden Schaltkreis im Kleinhirnkortex von heterozygoten R552H-Mäusen. Elektrophysiologische Messungen dienten dazu, die Verschaltung der Parallelfasern und Kletterfasern auf die Purkinjezelle auf Veränderungen der Übertragungseigenschaften zu prüfen. Durch Induktion von Langzeitdepression und Paarpulsbahnung an der Parallelfaser-Purkinjezell-Synapse sollte die synaptische Plastizität untersucht werden. Es zeigten sich eine intakte Verschaltung der erregenden Eingänge auf die Purkinjezelle, jedoch Veränderungen der Langzeit- und der Kurzzeitplastizität: Nach Induktion von Langzeitdepression entwickelte sich diese signifikant schneller. Die Paarpulsbahnung war bei kurzen Interstimulusintervallen signifikant verstärkt. Die Befunde sprechen für einen Einfluss des FoxP2-Gens auf die synaptischen Eigenschaften im Kleinhirnkortex. Die Aufschlüsselung dieses Einflusses und seine Bedeutung für die Sprachstörung der KE-Familie und die Sprachentwicklung beim Menschen ist Gegenstand weiterer Forschung.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Thèse de doctorat présentée en vue de l'obtention du doctorat en psychologie - recherche intervention, option neuropsychologie clinique (Ph.D) / Les oscillations endogènes cérébrales sont associées à des fonctions cognitives spécifiques et jouent un rôle important dans la communication entre les différentes régions corticales et sous-corticales. Les rythmes alpha (8-12 Hz) et bêta (13-30 Hz) ont été observés de façon dominante dans les aires sensorimotrices, avec des moyennes de fréquence autour de 10 et 20 Hz, et jouent un rôle dans les fonctions motrices. Ces oscillations cérébrales peuvent être entrainées par une stimulation externe, notamment par la stimulation électrique transcrânienne par courant alternatif (SEtCA). Ainsi, la SEtCA de 10 et 20 Hz a un effet sur certaines mesures physiologiques comme l’excitabilité corticospinale et la puissance des oscillations via la stimulation magnétique transcrânienne (SMT) et l’électroencéphalogramme (EEG), respectivement. Toutefois, les effets post-stimulation sont variables et parfois incohérents. De plus, à ce jour, aucune étude n’a mesuré les effets physiologiques d’une stimulation bilatérale sensorimotrice tant sur l’activité locale que sur l’interaction entre les deux aires sensorimotrices. Les articles composant le présent ouvrage visent à explorer les effets post-stimulation de deux fréquences de stimulation, soit 10 Hz et 20 Hz, sur les régions sensorimotrices à l’aide d’un montage SEtCA bilatéral. Ce travail de recherche s’est effectué à travers une revue de la littérature ainsi que deux études avec des paramètres méthodologiques relativement similaires, mais avec des mesures différentes et complémentaires de SMT et d’EEG. L’article 1 sert d’assise à la pertinence de l’évaluation de la connectivité entre le cortex moteur et les différentes aires du cerveau. Cet excursus recense et décrit les différents protocoles de stimulation magnétique pairée qui ont été développés au cours des dernières années afin d’évaluer la connectivité effective entre les aires sensorimotrices du cerveau. L’article 2 montre que la SEtCA bilatérale à 10 Hz a permis de réduire l’excitabilité corticospinale via la SMT après la stimulation. La fréquence bêta de 20 Hz n’a cependant mené à aucun changement. De plus, la SEtCA n’a pas modulé de façon significative les mesures d’interaction entre les régions sensorimotrices, telles l’inhibition interhémisphérique et les mouvements miroirs physiologiques. Dans l’article 3, les résultats démontrent que la SEtCA bilatérale à 10 et 20 Hz appliquée sur les aires sensorimotrices peut modifier la puissance des oscillations alpha et bêta après la stimulation. Notons que les résultats étaient associés à une variabilité interindividuelle qui est également rapportée dans la littérature. Ces résultats peuvent avoir des implications dans la conception de protocoles visant à induire des changements persistants dans l'activité cérébrale. / Endogenous brain oscillations are associated with specific cognitive functions and are known to have an important role in regimenting communication between cortical and subcortical areas. Alpha (8-12 Hz) and beta (13-30 Hz) rhythms have been observed predominantly in sensorimotor areas, with averages around 10 and 20 Hz, and are believed to play a role in motor functions. These cerebral oscillations can be entrained by external stimulation, in particular by transcranial alternating current stimulation (tACS). Thus, tACS has shown an impact on certain physiological measures such as corticospinal excitability and the power of oscillations via transcranial magnetic stimulation (TMS) and electroencephalogram (EEG), respectively. However, the after-effects are variable and incoherent. In addition, to date no study has measured the physiological effects of a bilateral sensorimotor stimulation montage on both local activity and the interaction between the two sensorimotor areas. Thus, the studies included in the present thesis aim to explore the after-effects of two stimulation frequencies, 10 Hz and 20 Hz, on sensorimotor regions using a bilateral montage. This research was carried out through a review of the literature as well as two methodological studies with relatively similar parameters, but using different and complementary measures of TMS and EEG. Article 1 provides a basis for the relevance of assessing the connectivity between the motor cortex and different areas of the brain. This excursus identifies and describes the different paired magnetic stimulation protocols that have been developed in recent years to assess the effective connectivity between sensorimotor areas of the brain. Study 2 shows that bilateral 10 Hz tACS significantly reduced corticospinal excitability via TMS after stimulation. However, the 20 Hz frequency did not lead to any change. In addition, tACS did not significantly modulate measures of interaction between sensorimotor regions, such as interhemispheric inhibition and physiological mirror movements. In study 3, the results failed to demonstrate reliably that bilateral tACS at 10 and 20 Hz administered over sensorimotor areas could modulate offline alpha and beta oscillations power at the stimulation site. Note that the results were associated with inter-individual variability, which is also reported in the literature. These findings may have implications for the design and implementation of future protocols aiming to induce sustained changes in brain activity.

We study unconventional superconductivity in two-dimensional systems. Unbiased numerical calculations within two-dimensional Hubbard models have found no evidence for long-range superconducting order. Most of the two-dimensional theories suggest that the superconducting state can be obtained by destabilizing an antiferromagnetic or spin-liquid insulating state. An antiferromagnet is a half-filled system because each site has one electron or hole. However, in anisotropic triangular lattices, numerical calculation finds pairing enhancement at quarter-filling but no long-range superconducting order. Many organic superconductors are dimerized in nature. Such a dimer lattice is effectively half-filled because each dimer has one electron or hole. Some theories suggest that magnetic fluctuation in such a system can give superconductivity. However, at zero temperature, we performed density matrix renormalization group (DMRG) calculations in such a system, and we find no superconducting long-range order. We also find that the antiferromagnetic order is not necessary to get a superconducting state. Failure in explaining superconductivity in two-dimensional systems suggests that only repulsive interactions between electrons are not sufficient, and other interactions are required. The most likely candidate is the electron-phonon interaction. However, existing theories of superconductivity emphasize either electron-electron or electron-phonon interactions, each of which tends to cancel the effect of the other. We present direct evidence from quantum Monte Carlo calculations of cooperative, as opposed to competing, effects of electron-electron and electron-phonon interactions within the frustrated Hubbard Hamiltonian, uniquely at the band-filling of one-quarter. Bond-coupled phonons and the onsite Hubbard U cooperatively reinforce d-wave superconducting pair-pair correlations at this filling while competing with one another at all other densities. Our work further gives new insight into how intertwined charge-order and superconductivity appear in real materials.

<p dir="ltr">My research projects focuses on the dual targeting of small molecules to abrogate aberrant α-syn, tau (2N4R), and p-tau (1N4R) aggregation and to reduce the spread of AD and related dementias. Not very many drug discovery programs focus on the specific isoforms of the tau protein. We established two series of compounds: aminoindole compounds connected by a carboxamide and triazine compounds connected by a triazine linker. Using biophysical methods we evaluated the effectiveness of both series of compounds in decreasing the amount of misfolded α-syn and tau protein in order to explore their anti-aggregation potential.</p><p><br></p>

The prediction of a company's financial health is of critical importance to a variety of stakeholders ranging from auditors, creditors, customers, employees, financial institutions and investors through to management. There has been considerable research in this field, ranging from the univariate dichotomous approach of Beaver (1966) to the multivariate multi-state approaches of Lau (1987) and Ward (1994). All of the South African studies namely, Strebel and Andrews (1977), Daya (1977), De La Rey (1981), Clarke et al (1991) and Court et al (1999), and even, Lukhwareni's (2005) four separate models, were dichotomous in nature providing either a "Healthy" or a "Failed" state; or a "Winner" or "Loser" as in the latter case. Notwithstanding, all of these models would be classified as first stage, initial screening models. This study has focused on following a two stage approach to identifying (first stage) and analysing (second stage) the States of Health in a company. It has not adopted the rigid "Healthy" or "Failed" dichotomous methodology. For the first stage, three-state models were developed classifying a company as Healthy, Intermittent or Distressed. Both three year and five year Profit after Tax (PAT) averages for Real Earnings Growth (REG) calculations were used to determine the superior definition for the Intermittent state; with the latter coming out as superior. Models were developed for the current year (Yn), one (Yn-1), two (Yn-2) and three years (Yn-3) forward using a Test sample of twenty companies and their predictive accuracy determined by using a Holdout sample of twenty-two companies and all their data points or years of information. The statistical methods employed were a Naïve model using the simple Shareholder Value Added (SVA) ratio, CHAID and MDA, with the latter providing very disappointing results - for the Yn year (five year average), the Test sample results were 100%, 95% and 95%, respectively; with the Holdout sample results being 81.3%, 83.8% and 52.5%, respectively. The Yn-1 to Yn-3 models produced very good results for the Test sample but somewhat disappointing Holdout sample results. The best two Yn models namely, the Naïve and the CHAID models, were modified so as to enable a comparison with the notable, dichotomous De La Rey (1981) model. As such, three different approaches were adopted and in all cases, both the modified Naïve (100%, 81.3%, 100%) and the modified CHAID (100%, 85.9%, 98%) produced superior results to the De La Rey model (84.8%, 62.6%, 75.3%). For the second stage, a Financial Risk Analysis Model (FRAM) using ratios in the categories of Growth, Performance Analysis, Investment Analysis and Financial Status were used to provide underlying information or clues, independent of the first stage model, so as to enable the stakeholder to establish a more meaningful picture of the company. This would pave the way for the appropriate strategy and course of action to be followed, to take the company to the next level; whether it be taking the company out of a Distressed State (D) or further improving on its Healthy status (H). / Business Management / D. BL.

Seres humanos com danos nos corpos mamilares exibem prejuízos no funcionamento da memória episódica. O presente estudo investigou a possível participação do núcleo mamilar medial (MM), estrutura densamente inervada por fibras imunorreativas ao hormônio concentrador de melanina (MCH) potencialmente envolvida no comportamento alimentar, em processos de evocação de memórias sobre locais em que alimento foi previamente encontrado, em ratos. Investigou-se ainda seu envolvimento na memória espacial motivada aversivamente, por meio do labirinto aquático de Morris, e em processos de ansiedade, por meio do labirinto em cruz elevado. Descreve-se uma tarefa comportamental envolvendo busca alimentar orientada por memória espacial em ratos, funcionalmente análoga ao teste de aprendizagem de pares associados, utilizado para avaliar memória episódica em seres humanos. Ratos treinados a escavar numa arena para obter alimento foram expostos ao pareamento de um determinado sabor, e.g., amendoim, com um local da arena e, numa segunda tentativa, ao pareamento de um outro sabor, e.g., avelã, com um local diferente da mesma arena. Antes de uma terceira tentativa, ainda na caixa de espera, os animais receberam uma amostra de amendoim ou avelã. Então, inseridos na arena para uma terceira tentativa, deveriam procurar e escavar por alimento enterrado no local sinalizado pela amostra. As associações sabor-local, a seqüência das associações, os locais do pareamento e a amostra oferecida antes da terceira tentativa, variaram quase aleatoriamente a cada dia. O treinamento dos animais para a aquisição da tarefa foi prolongado. O número de visitas e o tempo de permanência no local da arena sinalizado pela amostra foram significativamente maiores em relação aos parâmetros correspondentes ao local pareado com alimento mas não sinalizado pela amostra, quando o intervalo de tempo entre a 2ª e 3ª tentativas foi 60 ou 120 minutos; Testes de Avaliação sem oferta de alimento na arena na 3ª tentativa, permitiram excluir a hipótese de que os animais desempenharam essa tarefa com base em estímulos olfativos, levando à conclusão que o fizeram com base na memória das associações sabor-local. Ratos com danos seletivos do MM, induzidos pela aplicação tópica, micro-iontoforética, de N-Metil-D-Aspartato (NMDA), testados na tarefa de pares associados sabor-local, não exibiram prejuízo de desempenho em relação aos animais controle. Análises adicionais revelaram que houve uma redução da busca por alimento em ambos os grupos (lesado e controle) nos testes pós-operatórios, em relação ao seu próprio desempenho nos testes pré-operatórios; porém, essa redução foi mais acentuada em relação ao local sinalizado pela amostra, particularmente nos animais do grupo lesado. Estes resultados, embora não conclusivos, podem representar indícios em favor da idéia de que o MM estaria envolvido numa circuitaria relacionada à memória espacial voltada à busca alimentar. Mais estudos seriam necessários para avaliar essa possibilidade. Além disso, esses animais não exibiram qualquer prejuízo no teste de memória de referência espacial no labirinto aquático de Morris e no paradigma do teste e re-teste no labirinto em cruz elevado, sugerindo que esse tipo de lesão não leva a deficiência no funcionamento da memória espacial motivada por estimulação aversiva, na memória aversiva por espaços abertos ou nos mecanismos responsáveis pela ansiedade. / Human beings with damage to the mammillary bodies exhibit episodic memory disruption. This study investigated the potential participation of the medial mammillary nucleus (MM), a structure that receives a high density of melaninconcentrating hormone immunoreactive fibers (MCH) potentially involved in food intake, in processes of retrieval of memory about places where food was previously found, in rats. In addition, we investigated the possible involvement of this brain structure in both aversively motivated spatial memory, using the Morris´ water maze, and in anxiety, using the elevated plus maze. A behavioral task involving search for food guided by spatial memory, in rats, functionally analogous to the paired-associate learning task used for studying episodic memory in humans, was described. Rats trained to dig for food in an arena were exposed both to the pairing of a taste, peanut, with a specific place in the arena and, in a second trial, to the pairing of another taste, hazelnut, with another place in the arena. Immediately before a third trial, while still in the waiting box, the animals received a sample of either peanut or hazelnut. Then, they were inserted into the arena for a third trial and could search and dig for food buried in the place previously associated with the sample. The taste-place associations, sequence of associations, pairing places and sample offered before the third trial, were all varied quasi-randomly every day. The animals took extensive training to learn this task. It was found that the number of visits and the time spent in the place indicated by the sample were significantly greater as compared to the corresponding parameters of the place previously associated with a taste but not indicated by the sample, when the time interval between the second and the third trials was both 60 and 120 min; probe tests with no food in the arena in the third trial allowed to exclude the hypothesis that the rats were performing the task relying on olfactory cues, leading to the conclusion that the animals performed the task relying on the memory for the associations tastefood. Rats with selective damage to the MM, induced by topic, microiontophoretic, injections of N-Methyl-D-Aspartate (NMDA), tested in the taste-place pairedassociate learning task, did not exhibit any disruption of performance relative to the controls. Additional analyses revealed that both MM and control subjects exhibited a reduction of food search during the post-operatory tests as compared to their own performance in pre-operatory tests; however, this reduction was stronger towards the place indicated by the sample, particularly for the animals subjected to MM damage. Even though not conclusive, these results may suggest that the MM might be involved in search for food guided by spatial memory. More studies would be required to evaluate this possibility. Further, these rats did not exhibit any disruption of performance in the reference memory test in the water maze and in the test/re-test elevated plus maze, suggesting that this type of damage does not disrupt aversively motivated spatial memory, open-space aversive memory and anxiety.

Seres humanos com danos nos corpos mamilares exibem prejuízos no funcionamento da memória episódica. O presente estudo investigou a possível participação do núcleo mamilar medial (MM), estrutura densamente inervada por fibras imunorreativas ao hormônio concentrador de melanina (MCH) potencialmente envolvida no comportamento alimentar, em processos de evocação de memórias sobre locais em que alimento foi previamente encontrado, em ratos. Investigou-se ainda seu envolvimento na memória espacial motivada aversivamente, por meio do labirinto aquático de Morris, e em processos de ansiedade, por meio do labirinto em cruz elevado. Descreve-se uma tarefa comportamental envolvendo busca alimentar orientada por memória espacial em ratos, funcionalmente análoga ao teste de aprendizagem de pares associados, utilizado para avaliar memória episódica em seres humanos. Ratos treinados a escavar numa arena para obter alimento foram expostos ao pareamento de um determinado sabor, e.g., amendoim, com um local da arena e, numa segunda tentativa, ao pareamento de um outro sabor, e.g., avelã, com um local diferente da mesma arena. Antes de uma terceira tentativa, ainda na caixa de espera, os animais receberam uma amostra de amendoim ou avelã. Então, inseridos na arena para uma terceira tentativa, deveriam procurar e escavar por alimento enterrado no local sinalizado pela amostra. As associações sabor-local, a seqüência das associações, os locais do pareamento e a amostra oferecida antes da terceira tentativa, variaram quase aleatoriamente a cada dia. O treinamento dos animais para a aquisição da tarefa foi prolongado. O número de visitas e o tempo de permanência no local da arena sinalizado pela amostra foram significativamente maiores em relação aos parâmetros correspondentes ao local pareado com alimento mas não sinalizado pela amostra, quando o intervalo de tempo entre a 2ª e 3ª tentativas foi 60 ou 120 minutos; Testes de Avaliação sem oferta de alimento na arena na 3ª tentativa, permitiram excluir a hipótese de que os animais desempenharam essa tarefa com base em estímulos olfativos, levando à conclusão que o fizeram com base na memória das associações sabor-local. Ratos com danos seletivos do MM, induzidos pela aplicação tópica, micro-iontoforética, de N-Metil-D-Aspartato (NMDA), testados na tarefa de pares associados sabor-local, não exibiram prejuízo de desempenho em relação aos animais controle. Análises adicionais revelaram que houve uma redução da busca por alimento em ambos os grupos (lesado e controle) nos testes pós-operatórios, em relação ao seu próprio desempenho nos testes pré-operatórios; porém, essa redução foi mais acentuada em relação ao local sinalizado pela amostra, particularmente nos animais do grupo lesado. Estes resultados, embora não conclusivos, podem representar indícios em favor da idéia de que o MM estaria envolvido numa circuitaria relacionada à memória espacial voltada à busca alimentar. Mais estudos seriam necessários para avaliar essa possibilidade. Além disso, esses animais não exibiram qualquer prejuízo no teste de memória de referência espacial no labirinto aquático de Morris e no paradigma do teste e re-teste no labirinto em cruz elevado, sugerindo que esse tipo de lesão não leva a deficiência no funcionamento da memória espacial motivada por estimulação aversiva, na memória aversiva por espaços abertos ou nos mecanismos responsáveis pela ansiedade. / Human beings with damage to the mammillary bodies exhibit episodic memory disruption. This study investigated the potential participation of the medial mammillary nucleus (MM), a structure that receives a high density of melaninconcentrating hormone immunoreactive fibers (MCH) potentially involved in food intake, in processes of retrieval of memory about places where food was previously found, in rats. In addition, we investigated the possible involvement of this brain structure in both aversively motivated spatial memory, using the Morris´ water maze, and in anxiety, using the elevated plus maze. A behavioral task involving search for food guided by spatial memory, in rats, functionally analogous to the paired-associate learning task used for studying episodic memory in humans, was described. Rats trained to dig for food in an arena were exposed both to the pairing of a taste, peanut, with a specific place in the arena and, in a second trial, to the pairing of another taste, hazelnut, with another place in the arena. Immediately before a third trial, while still in the waiting box, the animals received a sample of either peanut or hazelnut. Then, they were inserted into the arena for a third trial and could search and dig for food buried in the place previously associated with the sample. The taste-place associations, sequence of associations, pairing places and sample offered before the third trial, were all varied quasi-randomly every day. The animals took extensive training to learn this task. It was found that the number of visits and the time spent in the place indicated by the sample were significantly greater as compared to the corresponding parameters of the place previously associated with a taste but not indicated by the sample, when the time interval between the second and the third trials was both 60 and 120 min; probe tests with no food in the arena in the third trial allowed to exclude the hypothesis that the rats were performing the task relying on olfactory cues, leading to the conclusion that the animals performed the task relying on the memory for the associations tastefood. Rats with selective damage to the MM, induced by topic, microiontophoretic, injections of N-Methyl-D-Aspartate (NMDA), tested in the taste-place pairedassociate learning task, did not exhibit any disruption of performance relative to the controls. Additional analyses revealed that both MM and control subjects exhibited a reduction of food search during the post-operatory tests as compared to their own performance in pre-operatory tests; however, this reduction was stronger towards the place indicated by the sample, particularly for the animals subjected to MM damage. Even though not conclusive, these results may suggest that the MM might be involved in search for food guided by spatial memory. More studies would be required to evaluate this possibility. Further, these rats did not exhibit any disruption of performance in the reference memory test in the water maze and in the test/re-test elevated plus maze, suggesting that this type of damage does not disrupt aversively motivated spatial memory, open-space aversive memory and anxiety.

睡眠是否能鞏固陳述性記憶目前尚無定論。過去研究一致較支持睡眠能增進相關字詞配對的學習，但睡眠是否能增進無關字詞配對的學習，目前仍存在不一致的發現。造成該差異的原因可能是：過去研究多採用的行為測量指標，或許無法充分反映出睡眠促進記憶新聯結（new association）產生的效果。事件關聯電位（Event-related potential, ERP）的N400反映出語意記憶系統內每個字詞彼此的相關程度，因此本研究使用N400來探討睡眠強化無關字詞配對形成新聯結的電生理歷程。30名健康受試者（15位男性與15位女性，平均年齡為20.7歲） 隨機分派至睡眠組或清醒組，第一晚在學習80組無關字詞配對後，接受第一次再認記憶測驗，同時進行ERP的記錄。隨後睡眠組接受睡眠記錄（PSG），清醒組則接受整晚的睡眠剝奪，兩組受試者皆在第二晚給予8小時的躺床時間，使他們有機會充足睡眠以恢復精神，於第三天早上接受第二次再認記憶測驗及ERP記錄。在記憶測驗時，無關字詞配對分別組成促發字（prime）與目標字（target）先後出現，受試者需判斷先後出現的字詞是否為先前學過的完整配對，在測試階段同時記錄腦電波訊號。行為測量結果顯示睡眠過後，再認表現的正確率顯著提高且反應時間明顯縮短，但在睡眠剝奪後則顯示相反的結果。電生理測量發現睡眠組的N400振幅在睡眠過後較清醒組明顯降低。另外，睡眠組較清醒組有較高的正確率與較短的反應時間。睡眠組再認測驗的進步量與慢波睡眠呈現負相關，而慢波睡眠與第一次再認測驗的正確率呈現正相關，根據二階段睡眠記憶鞏固理論，慢波睡眠涉及重新組織記憶的歷程（系統性固化），因此學習表現較佳的受試者出現較多的深度睡眠，可能反應其經歷系統性固化。本研究結果顯示睡眠對於產生新聯結有明顯的增強效果，而且慢波睡眠可能參與了記憶表徵重新分配的歷程。 / The effect of sleep on declarative memory remains contradictory. Prior studies show that sleep benefits the learning of related word pairs consistently, while the learning of unrelated word pairs, however, show mixed results. It is possible that the behavioral measures used in previous studies are not sensitive enough to reveal subtle effects of sleep on new associations. N400, an event-related potential (ERP) component reflecting relatedness among words in semantic memory, was used in the present study to investigate the effect of sleep on the physiological process underlying new associations of unrelated word pairs. Participants were randomly assigned to either a Sleep group or a Wakefulness group. In the learning phase, participants were asked to memorize 80 visually presented unrelated word-pairs, followed by a pre-test phase with a recognition task. The participants then underwent either a night of nocturnal sleep (Sleep group) or sleep deprivation (Wakefulness group). A post-test was conducted after subjects had one night of recovery sleep. During both pre-test and post-test sessions, prime and target words were presented successively for the subjects to judge whether they were among the original pairs or new pairs. ERPs were recorded during both test phases. The behavioral data show that differences in improvement of recognition and decreases in reaction time from pre-test to post-test are significant between Sleep and Wakefulness groups. N400 peak amplitude attenuated significantly after sleep but not after wakefulness. The improvement of recognition negatively correlates with slow wave sleep (SWS). The number of word-pairs acquired in the learning phase, however, correlates positively with SWS. According to the two-stage memory consolidation theory of sleep, SWS involves in redistribution of memory (systematic consolidation). Therefore, that the participants with high performance showed more SWS may reflect the process of systematic consolidation. These results suggest that the sleep has an enhancing effect on the formation of novel association, and SWS may be involved in the process of redistributing memory representations.

The field of medicine is regularly faced with the challenge of utilizing information that is complicated or difficult to characterize. Physicians often must use their best judgment in reaching decisions or recommendations for treatment in the clinical setting. The goal of this thesis is to use innovative statistical tools in tackling three specific challenges of this nature from current healthcare applications. The first aim focuses on developing a novel approach to meta-analysis when combining binary data from multiple studies of paired design, particularly in cases of high heterogeneity between studies. The challenge is in properly accounting for heterogeneity when dealing with a low or moderate number of studies, and with a rarely occurring outcome. The proposed approach uses a Rasch model for translating data from multiple paired studies into a unified structure that allows for properly handling variability associated with both pair effects and study effects. Analysis is then performed using a Bayesian hierarchical structure, which accounts for heterogeneity in a direct way within the variances of the separate generating distributions for each model parameter. This approach is applied to the debated topic within the dental community of the comparative effectiveness of materials used for pit-and-fissure sealants. The second and third aims of this research both have applications in early detection of breast cancer. The interpretation of a mammogram is often difficult since signs of early disease are often minuscule, and the appearance of even normal tissue can be highly variable and complex. Physicians often have to consider many important pieces of the whole picture when trying to assess next steps. The final two aims focus on improving the interpretation of findings in mammograms to aid in early cancer detection. When dealing with high frequency and irregular data, as is seen in most medical images, the behaviors of these complex structures are often difficult or impossible to quantify by standard modeling techniques. But a commonly occurring phenomenon in high-frequency data is that of regular scaling. The second aim in this thesis is to develop and evaluate a wavelet-based scaling estimator that reduces the information in a mammogram down to an informative and low-dimensional quantification of the innate scaling behavior, optimized for use in classifying the tissue as cancerous or non-cancerous. The specific demands for this estimator are that it be robust with respect to distributional assumptions on the data, and with respect to outlier levels in the frequency domain representation of the data. The final aim in this research focuses on enhancing the visualization of microcalcifications that are too small to capture well on screening mammograms. Using scale-mixing discrete wavelet transform methods, the existing detail information contained in a very small and course image will be used to impute scaled details at finer levels. These "informed" finer details will then be used to produce an image of much higher resolution than the original, improving the visualization of the object. The goal is to also produce a confidence area for the true location of the shape's borders, allowing for more accurate feature assessment. Through the more accurate assessment of these very small shapes, physicians may be more confident in deciding next steps.