Rather than designing focused experiments to test individual hypotheses, scientists now commonly acquire measurements using massively parallel techniques, for post hoc interrogation. The resulting data is both high-dimensional and structured, in that observed variables are grouped and ordered into related subspaces, reflecting both natural physical organization and factorial experimental designs. Such structure encodes critical constraints and clues to interpretation, but typical unsupervised learning methods assume exchangeability and fail to account adequately for the structure of data in a flexible and interpretable way. In this thesis, I develop computational methods for exploratory analysis of structured high-dimensional data, and apply them to study gene expression regulation in Parkinson’s (PD) and Huntington’s diseases (HD). BOMBASTIC (Block-Organized, Model-Based, Tree-Indexed Clustering) is a methodology to cluster and visualize data organized in pre-specified subspaces, by combining independent clusterings of blocks into hierarchies. BOMBASTIC provides a formal specification of the block-clustering problem and a modular implementation that facilitates integration, visualization, and comparison of diverse datasets and rapid exploration of alternative analyses. These tools, along with standard methods, were applied to study gene expression in mouse models of neurodegenerative diseases, in collaboration with Dr. Myriam Heiman and Dr. Robert Fenster. In PD, I analyzed cell-type-specific expression following levodopa treatment to study mechanisms underlying levodopa-induced dyskinesia (LID). I identified likely regulators of the transcriptional changes leading to LID and implicated signaling pathways amenable to pharmacological modulation (Heiman, Heilbut et al, 2014). In HD, I analyzed multiple mouse models (Kuhn, 2007), cell-type specific profiles of medium spiny neurons (Fenster, 2011), and an RNA-Seq dataset profiling multiple tissue types over time and across an mHTT allelic series (CHDI, 2015). I found evidence suggesting that altered activity of the PRC2 complex significantly contributes to the transcriptional dysregulation observed in striatal neurons in HD.

The motivation of this study was to examine the effects of intensive speech treatment on the conversational intelligibility of Spanish speakers with Parkinson’s Disease (PD). It also aimed at investigating several acoustic variables in the speech of this population. Sixteen speakers with a medical diagnosis of PD participated in this study and their voice recordings were analyzed pre- and post-treatment. The intelligibility measures of transcription accuracy and median ease-of-understanding ratings increased significantly immediately post-treatment and gains were maintained at the one-month follow-up. The acoustic variables of vowel space and voice onset time did not change significantly pre-to-post treatment, whilst the prosodic targets of intensity and mean fundamental frequency increased significantly as a result of treatment. These findings support the implementation of intensive voice intervention to improve intelligibility in Spanish dysarthria. Clinical and theoretical considerations are discussed.

A dopamina (DA) é um neurotransmissor sintetizado nos neurônios dopaminérgicos da substância nigra, possuindo efeito importante sobre o Sistema Nervoso Central (SNC), dentre as quais a sensação de prazer e a motivação. Uma alteração nos transportadores de dopamina (DATs) se caracteriza por uma desordem progressiva do movimento devido à disfunção dos neurônios secretores de dopamina, gerando a Doença de Parkinson (DP). Por ser um distúrbio mais comum entre um espectro de doenças neurológicas, é necessário um estudo mais aprofundado para melhor diagnóstico. Esta dissertação apresenta um estudo do desempenho do filtro butterworth passa-baixa na reconstrução analítica Filtered Backprojection - FBP e reconstrução iterativa Ordered Subsets Expectation Maximization - OSEM, para garantir a qualidade da imagem de SPECT cerebral, adquirida pelo fantoma antropomórfico estriatal. Por avaliação interindividual de quatro especialistas em medicina nuclear, foram aplicadas notas para a análise visual das imagens, garantindo a qualidade da resolução espacial, contraste, ruído e diferenciação anatômica do corpo estriado. Para cada tipo de reconstrução, houve 49 imagens do corpo estriado, variando os valores das covariáveis apresentadas pelos algoritmos (iteração, subsets, ordem e frequência de corte). A fim de resultados consistentes, foram utilizados a regressão linear e o teste T-Student pareado. Os dados coletados demonstraram que é necessário utilizar um intervalo confiável de frequência de corte para FBP (0,9 a 1,6) e para OSEM (1,2 a 1,5) e variar a ordem de 0 a 10 que não influenciará a imagem. Para a reconstrução OSEM, ficou comprovado que o valor de iteração (i) e o número de subsets (s) que garantem melhor qualidade foram os mesmos que a empresa do algoritmo utilizado sugeriu (3i 8s). Esta, também, mostrou evidências de melhor qualidade da imagem, quando comparada à reconstrução FBP. Para uma imagem de qualidade, representando uma reconstrução confiável e uma análise visual segura, é necessário utilizar o intervalo de valores encontrados das covariáveis ordem e frequência de corte do filtro butterworth passa-baixa na reconstrução FBP e OSEM. Também é necessário utilizar o valor de iteração e subsets que a empresa sugeriu, e a reconstrução OSEM mostrou superioridade nas imagens comparadas à FBP, mas se o serviço não utilizar ainda este tipo de algoritmo, a imagem com FBP no intervalo proposto também garantirá a qualidade. / Dopamine is a synthesized neurotransmitter in dopaminergic neurons of the substantia nigra where it has an important effect on the central nervous system (CNS), such as the feeling of pleasure and motivation. A change in the dopamine transporters (DATs) is characterized by a progressive disorder of movement due to a dysfunction of the dopamine secreting neurons, causing Parkinson\'s Disease (PD). As it is a more common disorder among a spectrum of neurological diseases, further studies are necessary for a better diagnosis. This study presents an investigation on the performance of the low-pass butterworth filter in the Filtered Backprojection analytic reconstruction - FBP and Ordered Subsets Expectation Maximization iterative reconstruction - OSEM to ensure the quality of brain SPECT image, acquired by the anthropomorphic striatal phantom. By individual evaluation of four nuclear medicine specialists, grades were applied to the visual analysis of the images, ensuring the quality of the spatial resolution, contrast, noise and anatomical differentiation striatum. For each type of reconstruction, there were 49 pictures of the striatum, varying the values of covariates submitted by the algorithms (iteration, subsets, order and cutoff frequency). In order to obtain consistent results, we used linear regression and T-Student paired test. The collected data showed that it is necessary to use a reliable interval of cutoff frequency for both the FBP (0.9 to 1.6), and OSEM (1.2 to 1.5), and varying the order of 0 to 10, which does not influence the image. For OSEM reconstruction, it has been verified that the iteration value (i) and the number of subsets (s) ensuring best quality was the same as the company\'s algorithm suggested (3i 8s). This also showed evidence of better image quality when compared to FBP reconstruction. For an image quality, representing a reliable reconstruction and a safe visual analysis, you must use the range of values found of covariates order and cutoff frequency of the butterworth low-pass filter on the FBP and OSEM reconstruction. You must also use the iteration value and subsets that the company suggested and the OSEM reconstruction showed superiority on the images compared to FBP, but if the service does not use this type of algorithm, the image with FBP in the proposed range, also ensures quality.

O objetivo principal deste estudo foi investigar a aprendizagem de pacientes com Doença de Parkinson (DP) em 10 jogos do vídeo game Nintendo Wii Fit Plus®, com diferentes demandas motoras e cognitivas, por meio das modificações do desempenho após o treinamento, comparando-a com a aprendizagem de indivíduos saudáveis da mesma faixa etária, em um estudo clínico, longitudinal e controlado. Dezesseis pacientes em estágio inicial da DP e 11 idosos saudáveis participaram de um treinamento que compreendeu 14 sessões de exercícios de aquecimento que precederam o treino no Nintendo Wii Fit Plus®, realizadas 2 vezes por semana. Nessas sessões, duas tentativas em 5 de 10 jogos foram realizadas, sendo que nas sessões pares foram treinados 5 jogos diferentes das sessões ímpares. Uma sessão de treino e avaliação adicional foi feita sessenta dias após o final do treinamento em cada jogo, totalizando 2 sessões adicionais para treino e avaliação da retenção. Ao final do estudo foram realizadas no total 16 sessões de treino. Aprendizado foi a principal medida de resultado sendo baseada nas pontuações obtidas durante todas as sessões, nos 10 jogos. Encontrou-se que os pacientes com DP não mostraram deficiências de aprendizado em 7 dos 10 jogos, embora tenham mostrado desempenho inferior em 5 jogos, quando comparados aos idosos. Os pacientes mostraram importantes deficiências de aprendizado em 3 outros jogos, independentemente do desempenho inicial inferior. Esta deficiência pareceu estar associada às demandas cognitivas desses jogos, que requerem tomadas de decisão rápidas, inibição de resposta, atenção dividida e memória operacional. Concluiu-se que a capacidade de pacientes com DP em melhorar e reter o desempenho após o treinamento no Nintendo Wii Fit Plus® depende grandemente das demandas dos jogos envolvidos, sobretudo as demandas cognitivas, reiterando a importância da seleção adequada dos jogos com proposta de reabilitação / The main objective of this study was to investigate the learning of Parkinson´s Disease (PD) patients in 10 games of the video game Nintendo Wii Fit Plus ® with different motor and cognitive demands, through changes in performance after training, comparing it with health elderly, in a clinical, longitudinal and controlled study. Sixteen patients in early stages of PD and 11 healthy elderly subjects participated in a training program which comprised 14 warm exercises sessions that preceded the Nintendo Wii Fit Plus® training, twice a week. In these sessions, two attempts in 5 of 10 games were held, being that on even sessions were trained 5 different games of odd sessions. A training session and further evaluation was made sixty days after the end of training in each game, totaling two additional sessions to assess retention. At the end of the study were performed, in total, 16 training sessions. Learning was the main outcome measure being based on the scores obtained during all sessions, in 10 games. It was found that PD patients showed no learning impairments in 7 of 10 games, although they have shown a lower performance in 5 games, compared to the elderly. The patients showed significant deficiencies in learning in 3 other games, regardless of the initial performance lower. This deficiency appeared to be related to the cognitive demands of those games that require quick decision making, response inhibition, divided attention and working memory. It was concluded that the ability of PD patients to improve and retain the performance after training on the Nintendo Wii Fit Plus® depends greatly on the demands of the games involved, especially the cognitive demands, reiterating the importance of proper selection of games with proposed rehabilitation

Made available in DSpace on 2014-06-11T19:22:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-12Bitstream added on 2014-06-13T19:48:32Z : No. of bitstreams: 1 vieira_rcr_me_sjrp.pdf: 526975 bytes, checksum: d53edaf11f301e6857242706aa47d0e0 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Tendo como base as freqüentes hesitações nos enunciados falados de sujeitos afetados pela doença de Parkinson, predominantemente atribuídas pela literatura biomédica a limitações orgânicas impostas pela doença, nossa proposta foi investigar aspectos do funcionamento hesitativo de tais sujeitos. Extraímos os dados de uma sessão de conversação entre um sujeito parkinsoniano (NL) e um documentador (JN). Partindo da concepção de que as hesitações são marcas das negociações do sujeito com os outros constitutivos do (seu) discurso, detectamos 48 marcas hesitativas que apresentavam um aspecto peculiar: a tensão em um elemento fonético-fonológico. Pela análise dos 48 enunciados que continham as marcas, observamos, em primeiro lugar, a presença desse elemento fonético-fonológico tensionado em palavras presentes nos trechos que sucediam ou, simultaneamente, antecediam e sucediam as marcas hesitativas. Observamos, ainda, que a tensão provocada por essa repetição se mostrou fortemente vinculada a outros tipos de tensões – que remetiam tanto a elementos de outros planos da língua, além do fonético-fonológico, quanto a elementos do processo discursivo. Com relação aos planos da língua, sobretudo o semântico se mostrou vinculado com o fonético-fonológico. Já com relação ao processo discursivo, levantamos indícios de que o funcionamento hesitativo que denominamos deslizamentos em contexto fonético-fonológico recorrente escancara negociações relacionadas a diferentes elementos das condições de produção do discurso, tais como o das imagens que se fazem de si os protagonistas do processo e a dominância de objetos discursivos. Com relação aos objetos discursivos dominantes no processo analisado, identificamos: (a) doença; (b) família; (c) trabalho; e (d) estudo. Quando os dois primeiros objetos se mostravam em dominância, observamos... / Considering the frequent hesitations on the utterance of individuals with Parkinson’s disease, mainly related by the biomedical literature to organical impairment ruled by the disease, our purpose was to investigate the aspects of hesitative functioning of those individuals. Data were extracted of a conversation session between a parkinsonian individual (NL) and a documenter (JN). Thinking the hesitations as marks of the individual’s negotiations with the constructing others of (his) discourse, 48 hesitating marks were found presenting a peculiar aspect: the stress in an phonetic-phonologic element. Through the analysis of the 48 utterances that contained the marks, we observed, on first place, the presence of this phoneticphonologic element that was in stress in words that succeeded or, simultaneously, preceded and succeeded the hesitating marks. We observed, yet, that the stress caused by this repetition showed itself strongly linked to other kinds of stress – that referred to both elements of other plans of language, besides phonetic-phonologic, and to elements of the discoursive process. Regarding other plans of language, mainly the semantic one showed itself linked to the phonetic-phonologic one. But, regarding the discoursive process, we observed that the hesitative functioning we called repeteadly phonetic-phonologic context slidings highlights negotiations related to different elements of the discourse production conditions, such as the images that the protagonists of the process make of themselves and the dominance of discoursive objects. In relation to objects in the dominant discourse analysis, we identified: (a) disease, (b) family, (c) work and (d) study. When the first two objects were in dominance, it was observed that NL was predominantly through by the image of ill subject, whereas, when the objects work and study predominated, emerged... (Complete abstract click electronic access below)

Made available in DSpace on 2014-06-11T19:22:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-07-11Bitstream added on 2014-06-13T18:48:53Z : No. of bitstreams: 1 camillo_m_me_sjrp.pdf: 593366 bytes, checksum: abcc6c445f86bb0d0dc22a08bbbb3a3e (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A proposta deste estudo foi investigar em que medida se aproximam e/ou se distanciam os momentos de quebras na amarração dos significantes, mostrados por hesitações, na atividade discursiva de três sujeitos com Doença de Parkinson e de três sujeito sem lesão neurológica. Os objetivos que nortearam essa investigação foram: (a) comparar, nos dois grupos de sujeitos, as características de suas rupturas na cadeia significante; e (b) recuperar, em ambos os grupos, fatos de seus processos discursivos que possibilitariam verificar em que medida suas quebras de amarração de significantes relacionam-se à condição de parkinsoniano e a de não-parkinsoniano – já que pretendíamos levantar argumentos para problematizar o recorte que a literatura biomédica faz das questões de linguagem na Doença de Parkinson. Analisamos dados de sessões de conversação dos dois grupos de sujeitos, com sexo, faixa etária, atividade profissional, escolaridade e procedência geográfica equivalentes. No material, identificamos as marcas hesitativas – concebidas como fenômenos discursivos – correspondentes aos momentos de quebras na amarração dos significantes mostradas em situações típicas de deslizamentos. Selecionadas essas ocorrências, constatamos que a deriva, constitutiva do discurso, pode ou não ser controlada pelo sujeito e que, no caso de não ser controlada, a dispersão se materializa no discurso. Detectamos uma única maneira de a dispersão se materializar no discurso, funcionamento que caracterizamos como anacoluto. Quanto ao controle da deriva, detectamos quatro funcionamentos, os quais caracterizamos como reformulação antecipada, reformulação com paralelismo explícito, retomada e contextualização. Apoiados na contribuição de estudos discursivos e, assim, atentos ao forte laço que há entre os fatores internos e externos na construção das práticas de linguagem... / The purpose of this study was to investigate the extent to which they approach and / take distance times of significant breaks in the tie, shown by hesitations in the discursive activity of three subjects with Parkinson's disease and three subjects without neurological injury. The objectives that guided this research were: (a) to compare the two groups of subjects, the characteristics of their breaks in the signifying chain, and (b) recover in both groups, the facts of his discursive processes that make possible check to what extent breaks its mooring significant relate to the condition of parkinsonian and non-Parkinsonian - because we wanted to raise arguments to discuss the outline that the biomedical literature makes questions of language in Parkinson's disease. We analyzed data from chat sessions of two groups of subjects, sex, age, professional activity, education and geographic origin equivalent. In the material, identify the brands hesitate - conceived as discursive phenomena - corresponding to times of significant breaks in the tie shown in typical situations of landslides. Selected these instances, we found that the drift, which constitute the discourse, or cannot be controlled by the subject and, if not controlled, the dispersion is embodied in the speech. We detected only one way to materialize the dispersion in the speech, which we characterize as anacoluthon operation. Regarding the control of the drift, we detected four runs, which we characterize as early recast, recast with explicit parallelism, recovery and contextualization. Backed by the contribution of discourse studies, and thus aware of the strong bond that exists between the internal and external factors in the construction of language practices in subjects affected by degenerative diseases or not, we observe that, even with different health conditions, the two subject groups controlled... (Complete abstract click electronic access below)

Made available in DSpace on 2014-06-11T19:22:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2003-03-18Bitstream added on 2014-06-13T19:26:57Z : No. of bitstreams: 1 oliveira_ec_me_sjrp.pdf: 1211865 bytes, checksum: bbf6be8b1f37bd17293ff7675c765914 (MD5) / Este estudo teve como objetivos: (1) analisar se o modo como as pausas de início de turno são utilizadas na conversa espontânea de parkinsonianos se modifica após um intervalo significativo de tempo; em caso afirmativo (2) identificar quais aspectos da linguagem poderiam estar envolvidos nessas modificações; (3) identificar se essa modificação no uso das pausas iniciais estaria ligada a uma possível progressão da doença; (4) finalmente, propor uma mudança na metodologia utilizada pela maioria dos estudos sobre a doença de Parkinson, buscando, por meio de registros de conversa espontânea, um enfoque interacionista e discursivo para os problemas verbais destes sujeitos. Foram realizadas duas gravações de conversa espontânea de dois sujeitos parkinsonianos, com intervalo de um ano e oito meses entre elas e duração máxima de 39 minutos cada uma. Após as gravações, os dados foram transcritos e, posteriormente, digitalizados no programa computacional Multi Speech. Selecionamos e recortamos somente as pausas em início de turno e comparamos sua ocorrência na primeira e na segunda gravação. Nesta comparação, observamos: (1) freqüência de pausas e turnos conversacionais; (2) presença de pausa em turnos desenvolvidos e não desenvolvidos; (3) tipo de pausa em termos de duração que antecederam turnos desenvolvidos e não desenvolvidos; e (4) características de preenchimento acústico de pausas que antecederam turnos desenvolvidos e não desenvolvidos. Feita essa comparação, verificamos que o intervalo de tempo de um ano e oito meses foi significativo para que pudéssemos observar mudanças na ocorrência das pausas, e em suas características de duração e preenchimento. Quanto à ocorrência, observamos uma tendência à diminuição; no que se refere à duração, vimos que os sujeitos passaram a utilizar menos pausas breves e mais pausas médias e longas em sua atividade... / This study had as objectives: (1) to analyze the way how the pauses of beginning of shifts are used in spontaneous talking of parkinsonians if modify after a significant interval of time; in case of affirmative (2) to identify what aspects of language could be involved in these modifications; (3) to identify if this modification in the use of the initial pauses would be linked to a possible progression of disease; (4) finally, to propose a change in the methodology used by the most of study about a Parkinson's disease, searching, by the mean of registers of spontaneous, talking, a focus interactionist and discursive for the verbal problems of these subjects. Two recordings of spontaneous talking of two subject parkinsonians were accomplished, with interval of one year and eight months between them and maximum duration of thirty-nine minutes each one. After the recordings, the datas were transcribed and, later on, digitalized in the Multi Speech computering program. We have selected and recorded only the pauses in the beginning of shift and compared its occurrence in the first and second recording. In this comparison, we observed: (1) frequency of pauses and conversational shifts; (2) presence of pause in developed shifts and not developed shifts; (3) the kind pause in terms of duration that preceded developed shifts and not developed shifts; and (4) characteristics of acoustic fulfillment of pauses that preceded developed shifts and not developed. After making this comparison, we verified that the interval of time of one year and eight months it was significant so that we could observe changes in the occurrence of pauses, and in its characteristics of duration and fulfillment. With relationship to the occurrence, we observed a tendency to the decrease; and concerning duration, we saw that the subjects started to use less brief pauses and more pauses averages and long in its verbal activity...(Complete abstract click electronic access below)

帕金森病（PD）是一種常見的神經退行性疾病，其特徵性的癥狀是運動功能減弱，常伴有認知障礙如工作記憶缺陷。大多數癥狀源於中腦多巴胺神經元的進行性缺失。目前的治療常隨時間進展誘發嚴重的副反應，促使我們進一步研究PD的病理生理學機制。一般認為基底神經節直接和間接通路不平衡的活動導致PD的運動缺陷，但目前關於基底神經節環路突觸特性改變的研究還很少。對PD認知障礙機制的研究則更為少見。 / 本研究中，我們首先關注在對基底神經節提供主要輸入的皮質紋狀體通路。應用全細胞膜片鉗技術結合皮質刺激，并利用在D2受體表達神經元表達綠色螢光蛋白的轉基因小鼠，我們發現PD狀態下，在間接通路表達D2受體的中型多棘神經元（D2 MSN）上記到的皮質紋狀體通路AMPA受體介導電流的成對脉沖比值（PPR）以及NMDA受體介導電流的PPR均降低。此外皮質至D2 MSN突觸間隙的谷氨酸水平也增加而不伴有谷氨酸轉運體的功能異常。這些結果證明PD狀態下皮質至間接通路D2 MSN的谷氨酸釋放選擇性增加。結合基底神經節的功能環路考慮，至間接通路紋狀體投射神經元的皮質谷氨酸釋放增加可能參與了PD的運動癥狀。 / 我們接下來研究了皮質-D2 MSN通路的下游環節即紋狀體至蒼白球通路傳遞的改變。在蒼白球（GP）神經元上應用全細胞膜片鉗記錄結合紋狀體刺激，我們發現在6-羥多巴損毀之後，紋狀體蒼白球通路的PPR降低，GP神經元記到的紋狀體刺激誘發的抑制性突觸后電流（eIPSC）的變異係數降低,以及GP神經元記到的微型IPSC的頻率增加，這些結果證明紋狀體至蒼白球的GABA釋放增加。突觸前III型代謝型谷氨酸受體介導的對紋狀體蒼白球傳遞的抑制作用消失導致了紋狀體蒼白球通路GABA釋放的增加。這一增加，通過影響間接通路的下游環節，也可能參與了PD的運動癥狀。 / 為探討認知障礙的機制，我們研究了參與工作記憶功能的邊緣前皮質至伏核（NAc）的投射。應用與第一部份相似的研究方法，我們發現多巴胺受體對邊緣前皮質NAc通路的傳遞存在高度精確和補償性的調節。在邊緣前皮質-NAc D1 MSN通路，D1和D2受體突觸前分別介導對該傳遞的抑制性和易化性調節。然而，在D2 MSN相關的邊緣前皮質-NAc通路，上述作用發生了反轉。在耗竭NAc多巴胺之後，D2 MSN上誘發到的興奮性突觸后電流增加，提示邊緣前皮質-NAc D2 MSN傳遞增加。此外，在多巴胺損毀的情況下，激活D1和D2受體不再調節邊緣前皮質NAc通路的傳遞。結合邊緣環路考慮，邊緣前皮質至D2 MSN的谷氨酸釋放增加可能參與了PD的認知障礙。 / 綜上所述，PD狀態下，繼多巴胺缺失之後，多條通路發生可塑性改變，這些改變可能參與PD的運動和認知癥狀。 / Parkinson’s disease (PD) is a common neurodegenerative disease with characteristic hypokinetic motor symptoms and cognitive impairments like working memory deficits. Most of the symptoms are derived from progressive loss of dopaminergic neurons in the midbrain. Current therapies often induce severe side effects with time, which promotes us to further investigate the pathophysiological mechanism of PD. It is generally thought that the imbalanced activity between direct and indirect pathways of the basal ganglia underlies the motor deficits in PD, but little is studied about the changes in synaptic properties of the sub-circuits. Even less is known about the mechanism responsible for the cognitive dysfunctions in PD. / In our study, we first focused on the corticostriatal pathway that provides a major input to the basal ganglia. Employing whole-cell patch-clamp recordings with cortical stimulation as well as by taking advantage of transgenic mice with green fluorescent protein co-expressed in the D2 receptor-expressing neurons, we found a selective increase in cortical glutamate release onto indirect-pathway D2 receptor-expressing medium-sized spiny neurons (D2 MSNs), as indicated by reduced corticostriatal AMPA paired-pulse ratios (PPRs) and NMDA PPRs in D2 MSNs as well as increased glutamate level in cortex-D2 MSN synaptic cleft without malfunction in glutamate transporters in parkinsonian states. Considering from the functional organization of the basal ganglia circuits, the increased corticostriatal glutamate release onto indirect-pathway striatal projection neurons may contribute to the motor symptoms of PD. / We next studied whether the striatopallidal transmission, downstream to the cortex-D2 MSNs pathway, is also altered in parkinsonian states. Combining whole-cell patch-clamp recordings in globus pallidus (GP) neurons with striatal stimulation, we demonstrated that the striatopallidal GABA release was increased following 6-hydroxydopamine lesion, as indicated by decreased striatopallidal PPRs, reduced coefficient of variation of striatally evoked inhibitory postsynaptic currents (eIPSCs) and elevated frequency of miniature IPSCs in GP neurons. The loss of tonic presynaptic group III metabotropic glutamate receptors-mediated inhibition on striatopallidal transmission accounted for the increased striatopallidal GABA release. The increase in the striatopallidal GABA release, through affecting the downstream of the indirect pathway, would also contribute to the motor symptoms in PD. / To investigate the underlying mechanism of cognitive deficits, we targeted the prelimbic cortex-nucleus accumbens (NAc) projection that is critical for working memory function. Using similar approaches as the first part, we observed highly precise and complementary modulations by dopamine receptors, with D1 and D2 receptors presynaptically mediating the inhibition and facilitation of the prelimbic cortex-NAc D1 MSN transmission, respectively, and reversed effects in D2 MSN-associated pathway. Following dopamine depletion in NAc, an enhanced prelimbic cortex-NAc D2 MSN transmission was indicated by selectively increased excitatory postsynaptic current evoked in D2 MSNs. Moreover, in the dopamine-depleted state, activating D1 and D2 receptors failed to modulate the prelimbic cortex-NAc transmission. Considering from the information flow in the limbic loop, the increased prelimbic cortical glutamate release onto D2 MSNs may contribute to the cognitive impairments in PD. / In conclusion, in the parkinsonian states, multiple pathways undergo plasticity changes subsequent to dopamine depletion, which may underlie the motor and cognitive symptoms in PD. / 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. / Cui, Qiaoling. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 160-191). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Chapter Chapter 1 --- General introduction --- p.1 / Chapter 1.1 --- Parkinson’s disease --- p.1 / Chapter 1.1.1 --- Symptoms --- p.1 / Chapter 1.1.2 --- Etiology --- p.1 / Chapter 1.1.3 --- Pathology and pathophysiology --- p.2 / Chapter 1.1.4 --- Therapy --- p.5 / Chapter 1.1.4.1 --- L-DOPA and dopamine receptor agonists treatments --- p.5 / Chapter 1.1.4.2 --- Deep brain stimulation (DBS) and lesional surgery treatments --- p.6 / Chapter 1.1.4.3 --- Neural transplantation --- p.7 / Chapter 1.1.4.4 --- Treatment of nonmotor symptoms --- p.8 / Chapter 1.2 --- Basal ganglia --- p.8 / Chapter 1.2.1 --- Components of basal ganglia --- p.8 / Chapter 1.2.2 --- Pathways in basal ganglia --- p.8 / Chapter 1.2.2.1 --- Anatomical organization of the basal ganglia pathways --- p.8 / Chapter 1.2.2.2 --- Functional consequences of the basal ganglia pathways --- p.10 / Chapter 1.3 --- Striatum --- p.11 / Chapter 1.3.1 --- Anatomy of the striatum --- p.11 / Chapter 1.3.1.1 --- Cellular heterogeneity in the striatum --- p.12 / Chapter 1.3.1.1.1 --- MSNs --- p.12 / Chapter 1.3.1.1.1.1 --- Subpopulations --- p.13 / Chapter 1.3.1.1.1.2 --- Morphology --- p.13 / Chapter 1.3.1.1.1.3 --- Electrophysiological properties --- p.14 / Chapter 1.3.1.1.2 --- Cholinergic interneurons --- p.15 / Chapter 1.3.1.1.3 --- GABAergic interneurons --- p.17 / Chapter 1.3.1.2 --- Innervation of the striatum --- p.18 / Chapter 1.3.1.3 --- Output of the striatum --- p.21 / Chapter 1.3.2 --- Function of the striatum --- p.21 / Chapter 1.3.2.1 --- Function of the associative striatum --- p.22 / Chapter 1.3.2.2 --- Function of the sensorimotor striatum --- p.22 / Chapter 1.3.3 --- The corticostriatal system --- p.23 / Chapter 1.3.3.1 --- Anatomy of the corticostriatal system --- p.24 / Chapter 1.3.3.2 --- Physiology of the corticostriatal system --- p.25 / Chapter 1.3.3.3 --- Function of the corticostriatal system --- p.26 / Chapter 1.3.4 --- Striatum, corticostriatal system and PD --- p.26 / Chapter 1.4 --- GPe --- p.29 / Chapter 1.4.1 --- Anatomy of GPe --- p.29 / Chapter 1.4.1.1 --- Cellular heterogeneity in GPe --- p.29 / Chapter 1.4.1.2 --- Innervation of GPe --- p.31 / Chapter 1.4.1.3 --- Output of GPe --- p.33 / Chapter 1.4.2 --- Neurotransmission in GPe --- p.34 / Chapter 1.4.2.1 --- GABAA receptors in GPe --- p.34 / Chapter 1.4.2.2 --- GABAB receptors in GPe --- p.35 / Chapter 1.4.2.3 --- Evoked responses in GPe from direct striatal and pallidal stimulations --- p.37 / Chapter 1.4.3 --- GPe, striatopallidal system and PD --- p.38 / Chapter 1.5 --- NAc --- p.40 / Chapter 1.5.1 --- Anatomy of NAc --- p.40 / Chapter 1.5.1.1 --- Subregions --- p.40 / Chapter 1.5.1.2 --- Cell heterogeneity in NAc --- p.42 / Chapter 1.5.1.2.1 --- MSNs --- p.42 / Chapter 1.5.1.2.2 --- Interneurons --- p.42 / Chapter 1.5.1.3 --- Inervation of NAc --- p.43 / Chapter 1.5.1.4 --- Output of NAc --- p.43 / Chapter 1.5.2 --- Function of NAc --- p.43 / Chapter 1.5.3 --- The prefrontal cortex (PFC)-NAc system --- p.43 / Chapter 1.5.4 --- NAc, PFC-NAc system and PD --- p.44 / Chapter 1.6 --- Objectives --- p.45 / Chapter Chapter 2 --- General methods --- p.51 / Chapter 2.1 --- Electrophysiological experiments --- p.51 / Chapter 2.1.1 --- Slice preparation --- p.51 / Chapter 2.1.2 --- Whole-cell patch-clamp recordings --- p.52 / Chapter 2.1.3 --- Uncaging experiment --- p.54 / Chapter 2.1.4 --- Data analysis and statistics --- p.54 / Chapter 2.2 --- Dopamine depletion --- p.55 / Chapter 2.2.1 --- 6-hydroxydopamine (6-OHDA) injection into medial forebrain bundle (MFB) --- p.55 / Chapter 2.2.2 --- 6-OHDA injection into NAc --- p.56 / Chapter 2.2.3 --- Reserpine treatment --- p.56 / Chapter 2.3 --- Limb-use asymmetry test (cylinder test) --- p.57 / Chapter 2.4 --- Tyrosine hydroxylase (TH) immunohistochemistry and analysis --- p.57 / Chapter 2.4.1 --- TH immunohistochemistry of SNc and striatal slices --- p.57 / Chapter 2.4.2 --- TH immunohistochemistry and analysis of NAc slices --- p.58 / Chapter 2.5 --- Tracing study --- p.59 / Chapter 2.6 --- Genotyping and quantitative polymerase chain reaction (qPCR) --- p.60 / Chapter Chapter 3 --- Alteration of corticostriatal glutamatergic transmission onto D2 MSNs in PD models --- p.62 / Chapter 3.1 --- Summary --- p.62 / Chapter 3.2 --- Introduction --- p.63 / Chapter 3.3 --- Materials --- p.65 / Chapter 3.3.1 --- Animals --- p.65 / Chapter 3.3.2 --- Chemicals --- p.66 / Chapter 3.4 --- Results --- p.66 / Chapter 3.4.1 --- Comparison of corticostriatal paired-pulse ratios (PPRs) between hemizygotes and homozygotes of D2-EGFP BAC transgenic mice --- p.66 / Chapter 3.4.2 --- Corticostriatal AMPA PPR was specifically decreased in D2 MSNs following dopamine depletion --- p.67 / Chapter 3.4.2.1 --- Corticostriatal AMPA PPR was specifically decreased in D2 MSNs following reserpine treatment --- p.67 / Chapter 3.4.2.2 --- Corticostriatal AMPA PPR was specifically decreased in D2 MSNs following 6-OHDA lesion --- p.68 / Chapter 3.4.3 --- Increased glutamate release underlying reduction of corticostriatal PPR in D2 MSNs in parkinsonian states --- p.69 / Chapter 3.4.3.1 --- Effect of γ-DGG on the corticostriatal eEPSCs of D2 MSNs --- p.70 / Chapter 3.4.3.2 --- Effect of γ-DGG on the corticostriatal eEPSCs of D2 MSNs in the presence of CTZ --- p.70 / Chapter 3.4.3.3 --- Decay kinetics of eEPSCs of D2 MSNs in the presence of CTZ or PEPA were not consistently altered following dopamine depletion --- p.71 / Chapter 3.4.3.4 --- Corticostriatal NMDA PPR was decreased in D2 MSNs following dopamine depletion --- p.72 / Chapter 3.4.4 --- AMPA receptor occupancy was increased in D2 MSNs following dopamine depletion --- p.73 / Chapter 3.4.5 --- Increased postsynaptic AMPA receptor desensitization contributing to the reduction of corticostriatal PPR in D2 MSNs of parkinsonian states --- p.74 / Chapter 3.4.5.1 --- Effect of CTZ on the corticostriatal AMPA PPR of D2 MSNs --- p.74 / Chapter 3.4.5.2 --- Effect of PEPA on the corticostriatal AMPA PPR of D2 MSNs --- p.75 / Chapter 3.4.6 --- Loss of dopamine D2 receptor activation did not contribute to the increased corticostriatal glutamate release onto D2 MSNs in the parkinsonian states --- p.75 / Chapter 3.4.7 --- Postsynaptic Ca2+ involved in the modification of the corticostriatal transmission in D2 MSNs of parkinsonian state --- p.77 / Chapter 3.5 --- Discussion --- p.78 / Chapter 3.5.1 --- Corticostriatal glutamate release onto D2 MSNs was increased in the parkinsonian states --- p.78 / Chapter 3.5.2 --- AMPA receptor occupancy was increased in D2 MSNs following dopamine depletion --- p.80 / Chapter 3.5.3 --- Postsynaptic AMPA receptor desensitization was increased in D2 MSNs following dopamine depletion --- p.81 / Chapter 3.5.4 --- Loss of dopamine D2 receptor activation did not contribute to the increased corticostriatal glutamate release onto D2 MSNs in the parkinsonian states --- p.81 / Chapter 3.5.5 --- Postsynaptic Ca2+ involved in the modification of the corticostriatal transmission in D2 MSNs of parkinsonian state --- p.82 / Chapter 3.5.6 --- The increased corticostriatal glutamate release onto D2 MSNs and PD --- p.83 / Chapter Chapter 4 --- Alteration of striatopallidal GABAergic transmission in 6-OHDA lesioned PD model --- p.98 / Chapter 4.1 --- Summary --- p.98 / Chapter 4.2 --- Introduction --- p.99 / Chapter 4.3 --- Materials --- p.101 / Chapter 4.3.1 --- Animals --- p.101 / Chapter 4.3.2 --- Chemicals --- p.101 / Chapter 4.4 --- Results --- p.101 / Chapter 4.4.1 --- Striatopallidal paired-pulse ratio (PPR) was decreased following 6-OHDA lesion --- p.101 / Chapter 4.4.1.1 --- Striatopallidal PPR was unchanged following reserpine treatment --- p.102 / Chapter 4.4.1.2 --- Striatopallidal PPR was decreased following 6-OHDA lesion --- p.102 / Chapter 4.4.2 --- Increased striatopallidal GABA release underlying the reduction of striatopallidal PPR following 6-OHDA lesion --- p.103 / Chapter 4.4.2.1 --- CV of eIPSC1 in GP neurons was reduced following 6-OHDA lesion --- p.103 / Chapter 4.4.2.2 --- mIPSCs frequency was increased in GP neurons following 6-OHDA lesion --- p.104 / Chapter 4.4.3 --- Mechanism for the increased striatopallidal GABA release following 6-OHDA lesion --- p.105 / Chapter 4.4.3.1 --- Loss of dopamine D2 receptor activation did not contribute to the increased striatopallidal GABA release following 6-OHDA lesion --- p.105 / Chapter 4.4.3.2 --- GABAB receptor modulation did not contribute to the increased striatopallidal GABA release following 6-OHDA lesion --- p.106 / Chapter 4.4.3.3 --- Loss of presynaptic tonic group III mGluR inhibition accounted for the increased striatopallidal GABA release following 6-OHDA lesion --- p.107 / Chapter 4.5 --- Discussion --- p.109 / Chapter 4.5.1 --- Striatopallidal GABA release was increased in the parkinsonian state --- p.109 / Chapter 4.5.2 --- Mechanism underlying the increased striatopallidal GABA release in the parkinsonian state --- p.111 / Chapter 4.5.2.1 --- Loss of dopamine D2 receptor activation did not contribute to the increased striatopallidal GABA release following 6-OHDA lesion --- p.111 / Chapter 4.5.2.2 --- GABAB receptor modulation did not contribute to the increased striatopallidal GABA release following 6-OHDA lesion --- p.112 / Chapter 4.5.2.3 --- Loss of presynaptic tonic group III mGluR inhibition accounted for the increased striatopallidal GABA release following 6-OHDA lesion --- p.113 / Chapter 4.5.3 --- The increased striatopallidal GABA release and PD --- p.114 / Chapter 4.5.4 --- The striatopallidal group III mGluR system and PD --- p.116 / Chapter Chapter 5 --- Role of D1 and D2 receptors in prelimbic cortex-nucleus acumbens transmission in normal and parkinsonian states --- p.128 / Chapter 5.1 --- Summary --- p.128 / Chapter 5.2 --- Introduction --- p.129 / Chapter 5.3 --- Materials --- p.131 / Chapter 5.3.1 --- Animals --- p.131 / Chapter 5.3.2 --- Chemicals --- p.131 / Chapter 5.4 --- Results --- p.132 / Chapter 5.4.1 --- Prelimbic cortex innervated both D1 MSNs and D2 MSNs in core subregion of NAc- --- p.132 / Chapter 5.4.2 --- D1 and D2 receptors presynaptically modulated the D1 MSN-associated prelimbic cortex-NAc transmission in opposite manner --- p.133 / Chapter 5.4.3 --- D1 and D2 receptors presynaptically modulated the D2 MSN-associated prelimbic cortex-NAc transmission in a reverse manner --- p.134 / Chapter 5.4.4 --- Effects of D1 and D2 receptor antagonists on the prelimbic cortex-Nac transmission --- p.135 / Chapter 5.4.5 --- Basal synaptic transmission was enhanced in D2 MSN-associated prelimbic cortex-NAc pathway following NAc dopamine depletion --- p.136 / Chapter 5.4.6 --- D1 and D2 receptor modulation of the prelimbic cortex-NAc transmission disappeared following dopamine depletion --- p.137 / Chapter 5.5 --- Discussion --- p.138 / Chapter 5.5.1 --- Prelimbic cortex innervated both D1 MSNs and D2 MSNs in core subregion of NAc- --- p.138 / Chapter 5.5.2 --- Prelimbic cortex-NAc projections were presynaptically modulated by D1 and D2 receptors in a highly precise and complementary pattern --- p.138 / Chapter 5.5.3 --- Glutamatergic transmission was selectively enhanced in D2 MSN-associated prelimbic cortex-NAc pathway following NAc dopamine depletion --- p.140 / Chapter 5.5.4 --- D1 and D2 receptor modulation of the prelimbic cortex-NAc transmission was lost following dopamine depletion --- p.142 / Chapter Chapter 6 --- General discussion --- p.154 / Chapter 6.1 --- Enhanced corticostriatal glutamate release, enhanced striatopallidal GABA release and motor deficits in PD --- p.154 / Chapter 6.2 --- Enhanced prelimbic cortical glutamate release onto accumbal D2 MSNs and cognitive deficits in PD --- p.155 / Abbreviations --- p.158 / References --- p.160

Submitted by Leticia Nardoni Marteli (leenardoni@gmail.com) on 2019-01-24T18:58:09Z No. of bitstreams: 1 LeticiaNM_Dissertacao.pdf: 3474271 bytes, checksum: 56945aecae9563efe9206c9530e2d178 (MD5) / Approved for entry into archive by Lucilene Cordeiro da Silva Messias null (lubiblio@bauru.unesp.br) on 2019-01-25T11:47:15Z (GMT) No. of bitstreams: 1 marteli_ln_me_bauru.pdf: 3474271 bytes, checksum: 56945aecae9563efe9206c9530e2d178 (MD5) / Made available in DSpace on 2019-01-25T11:47:16Z (GMT). No. of bitstreams: 1 marteli_ln_me_bauru.pdf: 3474271 bytes, checksum: 56945aecae9563efe9206c9530e2d178 (MD5) Previous issue date: 2019-01-09 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O envelhecimento humano é cada vez mais pauta de estudos que avaliam doenças crônico-degenerativas e a interferência dessas na capacidade de execução de Atividades de Vida Diária (AVDs). A doença de Parkinson (DP) é uma patologia cujos sintomas podem agravar a qualidade da performance em atividades diárias, principalmente quanto a déficits em movimentos manuais coordenados. No que tange os aspectos de usabilidade na interação com produtos, em específico os de vestuário, percebe-se que até então pesquisas científicas não aprofundam as relações possíveis entre variáveis envolvidas nesse processo. Dentre as variáveis, pode-se destacar as características de manipulação de força e desempenho associadas à percepção de esforço e desconforto gerados no ato de vestir-despir; e, se tais variáveis interferem no gênero e situação de saúde a qual se encontram pessoas idosas. Pelo que se sabe até aqui, diferentes desenhos das interfaces podem influenciar negativamente a ação de abrir e fechar aviamentos de vestuários, limitando a autonomia em realizar essa AVD básica de forma independente. Logo, o objetivo principal do estudo foi compreender os aspectos do manejo de aviamentos de fecho, bem como a influência das perdas motoras e funcionais com base em atividades simuladas de uso, que possam esclarecer detalhes acerca da relação do usuário/atividade/produto. Com metodologia experimental, de caráter descritivo e exploratório, de natureza quantitativa e laboratorial, pode-se avaliar atividades com botões e zíperes. O estudo contou com a participação de 40 participantes em que se verificou por meio dos resultados alcançados que as variáveis de força não influenciam o desempenho de manipulação de aviamentos de fecho e que os efeitos da DP interferem na má execução da atividade coordenada, comprometendo a completude. Também foi constatado que a diminuição do desempenho em manipular aviamentos de fecho e os desenhos dos artefatos influenciam negativamente a usabilidade em fechar e abrir botões e zíperes destacáveis. Cabe ressaltar que os resultados aqui encontrados fomentam a necessidade de conscientização das empresas do setor de vestuário, em desenvolver produtos que possam promover a independência e satisfação do uso, permitindo contribuir com a vestibilidade na interação homem-atividade-produto. / The human aging is increasingly the studies that evaluate chronic degenerative diseases and the interference of those in the capacity performing Activities of Daily Life (ADLs). Parkinson's disease (PD) is a pathology that symptoms can worsen the quality of performance in daily activities, especially as the deficits in manual coordinated movements. Regarding the usability aspects on interaction with products, in particular those of clothing, that scientific research does not deepen the relationships possible between variables involved in this process. Among the variables, it can highlight the characteristics of strength and handling performance associated with the perception of effort and discomfort generated in the act of dressing-undressing; and, if these variables interfere in gender and health situation which are elderly. From what is known so far, different designs of interfaces can adversely influence the action of opening and closing trimmings of garments, limited autonomy in performing this basic ADLs independently. Soon, the main objective of the study was to understand the aspects of the management of trimmings, as well as the influence of motor and functional losses based on simulated activities, which could shed light on relationship details of user/task/product. With experimental methodology, descriptive and exploratory character, quantitative and laboratory nature one might evaluate activities with buttons and zippers. The study was attended by 40 participants that has occurred through the results achieved that force variables do not influence the performance of trimmings and handling the effects of PD interfere with bad execution of the activity coordinated, compromising the completeness. It was also noted that the decrease of performance in manipulating closures trimmings and their drawings was negatively affect the usability to open buttons and detachable zippers. It was worth noting that the results here found the need for awareness of clothing companies, developing products that can promote independence and satisfaction of use, enabling contribute with abilities of wear in human-activity-product interaction

Orientador: Lourenço Chacon Jurado Filho / Banca: Erotilde Goreti Pezatti / Banca: Maria Irma Hadler Coudry / Este estudo teve como objetivos: (1) analisar se o modo como as pausas de início de turno são utilizadas na conversa espontânea de parkinsonianos se modifica após um intervalo significativo de tempo; em caso afirmativo (2) identificar quais aspectos da linguagem poderiam estar envolvidos nessas modificações; (3) identificar se essa modificação no uso das pausas iniciais estaria ligada a uma possível progressão da doença; (4) finalmente, propor uma mudança na metodologia utilizada pela maioria dos estudos sobre a doença de Parkinson, buscando, por meio de registros de conversa espontânea, um enfoque interacionista e discursivo para os problemas verbais destes sujeitos. Foram realizadas duas gravações de conversa espontânea de dois sujeitos parkinsonianos, com intervalo de um ano e oito meses entre elas e duração máxima de 39 minutos cada uma. Após as gravações, os dados foram transcritos e, posteriormente, digitalizados no programa computacional Multi Speech. Selecionamos e recortamos somente as pausas em início de turno e comparamos sua ocorrência na primeira e na segunda gravação. Nesta comparação, observamos: (1) freqüência de pausas e turnos conversacionais; (2) presença de pausa em turnos desenvolvidos e não desenvolvidos; (3) tipo de pausa em termos de duração que antecederam turnos desenvolvidos e não desenvolvidos; e (4) características de preenchimento acústico de pausas que antecederam turnos desenvolvidos e não desenvolvidos. Feita essa comparação, verificamos que o intervalo de tempo de um ano e oito meses foi significativo para que pudéssemos observar mudanças na ocorrência das pausas, e em suas características de duração e preenchimento. Quanto à ocorrência, observamos uma tendência à diminuição; no que se refere à duração, vimos que os sujeitos passaram a utilizar menos pausas breves e mais pausas médias e longas em sua atividade...(Resumo completo, clicar acesso eletrônico abaixo) / Abstract: This study had as objectives: (1) to analyze the way how the pauses of beginning of shifts are used in spontaneous talking of parkinsonians if modify after a significant interval of time; in case of affirmative (2) to identify what aspects of language could be involved in these modifications; (3) to identify if this modification in the use of the initial pauses would be linked to a possible progression of disease; (4) finally, to propose a change in the methodology used by the most of study about a Parkinson's disease, searching, by the mean of registers of spontaneous, talking, a focus interactionist and discursive for the verbal problems of these subjects. Two recordings of spontaneous talking of two subject parkinsonians were accomplished, with interval of one year and eight months between them and maximum duration of thirty-nine minutes each one. After the recordings, the datas were transcribed and, later on, digitalized in the Multi Speech computering program. We have selected and recorded only the pauses in the beginning of shift and compared its occurrence in the first and second recording. In this comparison, we observed: (1) frequency of pauses and conversational shifts; (2) presence of pause in developed shifts and not developed shifts; (3) the kind pause in terms of duration that preceded developed shifts and not developed shifts; and (4) characteristics of acoustic fulfillment of pauses that preceded developed shifts and not developed. After making this comparison, we verified that the interval of time of one year and eight months it was significant so that we could observe changes in the occurrence of pauses, and in its characteristics of duration and fulfillment. With relationship to the occurrence, we observed a tendency to the decrease; and concerning duration, we saw that the subjects started to use less brief pauses and more pauses averages and long in its verbal activity...(Complete abstract click electronic access below) / Mestre