The human brain is a complex and powerful organ, directing every aspect of life from somatosensory and motor function to visceral responses to higher order cognition. Neurological and psychiatric disorders often disrupt normal functioning. While the clinical symptoms of such disorders are known, their biological underpinnings are not as clearly characterized. Structural neuroimaging is a powerful, non-invasive tool that can play a critical role in finding biomarkers of these illnesses. Currently, variations in pre-processing techniques yield inconsistent and conflicting results. As neuroimaging is a nascent branch of medical research, gold standards in imaging methodologies have not yet been established. Quantitatively validating and optimizing the way these images are preprocessed is the first step towards standardization. Voxel-based morphometry (VBM) is one technique that is commonly used to compare whole-brain structural differences between groups. Statistical tests are used to compare intensities of voxels throughout all brain scans in each group. In order to ensure that comparable voxels are being tested, the images must be fitted into a common space, which is done through image preprocessing. Spatial normalization to templates is an early pre-processing step that is executed unreliably as many options for both templates and normalization algorithms exist. To determine the effect variations in template usage may cause, we utilized a VBM approach to detect simulated lesions. Template performance was analyzed by comparing the accuracy with which the lesion was detected.

This dissertation is comprised of four studies investigating the hypothesis that adults and children who stutter differ from their same-age fluent peers in the neuroanatomy and neurophysiology underlying auditory speech processing. It has been consistently reported that adults who stutter demonstrate unique functional neural activation patterns during speech production, including reduced auditory activation, relative to nonstutterers. The extent to which these functional differences are accompanied by abnormal morphology of the brain in stutterers is unclear. The first study in this dissertation examined the neuroanatomical differences in speech-related cortex between adults who do and do not stutter using magnetic resonance imaging and voxel-based morphometry analyses. Adults who stutter were found to have localized grey matter volume increases in auditory and motor speech related cortex. The second study extended this line of research to children who stutter, who were found to have localized grey matter volume decreases in motor speech related cortex. Together, these studies suggest an abnormal trajectory of regional grey matter development in motor speech cortex of people who stutter. The last two studies investigated the mechanism underlying the repeated findings of reduced auditory activation during speech in people who stutter in more detail. Magnetoencephalography was used to investigate the hypothesis that people who stutter have increased speech induced suppression of early evoked auditory responses. Adults and children who stutter demonstrated typical levels of speech induced suppression relative to fluent peers. However, adults and children who stutter showed differences from peers in the timing of cortical auditory responses. Taken together, the studies demonstrate structural and functional abnormalities in brain regions related to auditory processing and point to the possibility that people who stutter have difficulty forming the neural representations of speech sounds necessary for fluent speech production.

Submitted by PPG Letras (letraspg@pucrs.br) on 2018-04-26T17:05:23Z No. of bitstreams: 1 Tese_Sabrine Cristine Hubner.pdf: 2098756 bytes, checksum: 9b73c0fb004e2143274124c300170dee (MD5) / Approved for entry into archive by Sheila Dias (sheila.dias@pucrs.br) on 2018-05-09T12:48:28Z (GMT) No. of bitstreams: 1 Tese_Sabrine Cristine Hubner.pdf: 2098756 bytes, checksum: 9b73c0fb004e2143274124c300170dee (MD5) / Made available in DSpace on 2018-05-09T13:29:27Z (GMT). No. of bitstreams: 1 Tese_Sabrine Cristine Hubner.pdf: 2098756 bytes, checksum: 9b73c0fb004e2143274124c300170dee (MD5) Previous issue date: 2018-03-28 / Conselho Nacional de Pesquisa e Desenvolvimento Cient?fico e Tecnol?gico - CNPq / Written and oral text comprehension abilities are indispensable for human experiences. Strokes causing left hemisphere (LH) damage may impact comprehension and textual production. However, little is known about this influence at the textual/discursive level, including the comparison between oral and written modalities in this kind of lesion. This research aimed at investigating text comprehension in two modalities of presentation (read and heard) by left brain damaged individuals (LBD) and healthy controls, comparing their performance in the micro- and macro-structural levels of text comprehension to neuropsychological data and to density of the brain areas involved. In order to do that, we performed two researches, Study 1, with 18 LBD and 10 controls, and Study 2, with 10 LBD and 10 controls, with matched age and education. In both studies, neuropsychological tests assessed working memory, verbal fluency and naming abilities. Comprehension of macro- and microstructural levels was verified by means of six short narratives, presented in oral or written modality. The participants were asked to retell the stories and answer to five interpretation questions. In Study 2, the same method was used, but it included structural magnetic resonance imaging indicating the density of brain regions by voxel-based morphometry (VBM). The results of Study 1 indicated significant differences in narrative comprehension between LBD and controls. The lower performance observed at the macrostructural level of LBD compared to the micro- suggest individuals who had a stroke may face difficulties in the application of macrorules of deletion, construction and generalization, which underlie overall comprehension of a text. The data from Study 2, with a lower number of participants, indicated a tendency to confirm results found in Study 1, with statistical significant differences in benefit of controls at the macrostructural level of oral narratives. We found significant differences between groups regarding the modality of text presentation. In both Study 1 and Study 2, differences were observed between the groups in auditory word span and in naming, with an advantage to controls. The morphometry data of brain regions, related to the participants of Study 2, indicated an integration of areas from left and right hemispheres to process text comprehension in oral and written modalities. In the left hemisphere, precuneus, cerebellum white matter, superior frontal region and medial orbitofrontal region and from the right hemisphere, accumbens and superior temporal sulcus were observed. The right superior temporal sulcus, left precuneus, left cerebellar white matter and superior frontal region are positively correlated among the participants, presenting better performance as the density increases. The left medial orbitofrontal region shows a negative correlation with comprehension. The right accumbens seems to compensate LH demands, showing increased density in the LBD and reduced volume in the controls. The present study intends to contribute to deepen our understanding of the comprehension of texts presented in the oral compared to written modality in the LH lesion, related to neuropsychological and brain data. / Compreender um texto, seja ele ouvido ou lido, ? indispens?vel para as experi?ncias humanas. Acidentes vasculares cerebrais (AVCs) ocorridos em especial no hemisf?rio esquerdo (HE) podem impactar na compreens?o e na produ??o textual. No entanto, pouco ainda se sabe sobre essa influ?ncia no n?vel textual/discursivo, incluindo, por exemplo, a compara??o entre a modalidade oral e escrita na compreens?o textual/discursiva nesse tipo de les?o. Esta pesquisa teve por objetivo investigar a compreens?o de narrativas em duas modalidades de apresenta??o (lidas e ouvidas) por indiv?duos com les?o no hemisf?rio esquerdo (LHE) e controles saud?veis, comparando-se seu desempenho nos n?veis micro- e macroestruturais da compreens?o de narrativas a dados neuropsicol?gicos e ? densidade das ?reas cerebrais implicadas. Para tal, realizamos dois estudos, o Estudo 1, com 18 LHE e 10 controles, e o Estudo 2, que contemplou exames de neuroimagem, com 10 LHE e 10 controles (os mesmos do Estudo 1), com idade e escolaridade equiparadas. Em ambos os estudos, testes neuropsicol?gicos avaliaram a mem?ria de trabalho, a flu?ncia verbal e a nomea??o. A compreens?o dos n?veis macro- e microestrutural foi verificada por meio de seis narrativas curtas, divididas na modalidade oral ou escrita. Os participantes realizavam um reconto e respondiam a cinco perguntas de interpreta??o. No Estudo 2 empregou-se o mesmo m?todo, por?m com inclus?o de exame de resson?ncia magn?tica estrutural indicando a densidade das regi?es cerebrais pela morfometria baseada em voxels (VBM). Os resultados do Estudo 1 apontaram diferen?as significativas na compreens?o de narrativas entre LHE e controles. Os preju?zos observados no n?vel macroestrutural dos LHE em detrimento do micro- sugerem falhas na aplica??o das macrorregras de dele??o, constru??o e generaliza??o, subjacentes ? compreens?o global de um texto. Os dados do Estudo 2, com menor n?mero de participantes, indicaram uma tend?ncia a corroborar os resultados encontrados no Estudo 1, observando-se diferen?a significativa em benef?cio dos controles no n?vel macroestrutural das narrativas apresentadas oralmente. Foram encontradas diferen?as entre os grupos quanto ? modalidade de apresenta??o dos textos. Tanto no Estudo 1 quanto no Estudo 2 observou-se diferen?as no span auditivo de palavras e na nomea??o, com vantagem para os controles. Os dados da morfometria das regi?es cerebrais, atinentes aos participantes do segundo estudo, apontam uma integra??o de regi?es do hemisf?rio esquerdo e do direito. Do esquerdo, prec?neus, subst?ncia branca do cerebelo, regi?o frontal superior e regi?o orbitofrontal medial e do direito, accumbens e sulco temporal superior foram observadas. O sulco temporal superior direito, o prec?neus esquerdo, a subst?ncia branca cerebelar esquerda e a regi?o frontal superior correlacionam-se positivamente entre os participantes, apresentando desempenho superior ? medida que a densidade aumenta. A regi?o orbitofrontal medial esquerda apresenta correla??o negativa com a compreens?o. A regi?o do accumbens direito parece compensar as demandas do HE, apresentando sua densidade aumentada nos LHE e reduzida nos controles. O presente estudo pretende contribuir para aprofundarmos nossa compreens?o sobre a compreens?o de narrativas apresentadas na modalidade oral versus escrita na les?o de HE, relacionados a dados neuropsicol?gicos e cerebrais.

This dissertation is comprised of four studies investigating the hypothesis that adults and children who stutter differ from their same-age fluent peers in the neuroanatomy and neurophysiology underlying auditory speech processing. It has been consistently reported that adults who stutter demonstrate unique functional neural activation patterns during speech production, including reduced auditory activation, relative to nonstutterers. The extent to which these functional differences are accompanied by abnormal morphology of the brain in stutterers is unclear. The first study in this dissertation examined the neuroanatomical differences in speech-related cortex between adults who do and do not stutter using magnetic resonance imaging and voxel-based morphometry analyses. Adults who stutter were found to have localized grey matter volume increases in auditory and motor speech related cortex. The second study extended this line of research to children who stutter, who were found to have localized grey matter volume decreases in motor speech related cortex. Together, these studies suggest an abnormal trajectory of regional grey matter development in motor speech cortex of people who stutter. The last two studies investigated the mechanism underlying the repeated findings of reduced auditory activation during speech in people who stutter in more detail. Magnetoencephalography was used to investigate the hypothesis that people who stutter have increased speech induced suppression of early evoked auditory responses. Adults and children who stutter demonstrated typical levels of speech induced suppression relative to fluent peers. However, adults and children who stutter showed differences from peers in the timing of cortical auditory responses. Taken together, the studies demonstrate structural and functional abnormalities in brain regions related to auditory processing and point to the possibility that people who stutter have difficulty forming the neural representations of speech sounds necessary for fluent speech production.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18872号 / 医博第3983号 / 新制||医||1008(附属図書館) / 31823 / 京都大学大学院医学研究科医学専攻 / (主査)教授 河野 憲二, 教授 古川 壽亮, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

A polineuropatia inflamatória desmielinizante crônica (PIDC) é uma síndrome caracterizada fundamentalmente pela disfunção do Sistema Nervoso Periférico e que afeta muito a qualidade de vida dos pacientes. O envolvimento da PIDC com o Sistema Nervoso Central tem sido descrito, maiormente como sendo subclínico, porém não há estudos sobre a caracterização deste envolvimento de uma forma ampla e quantitativa. Avaliamos 11 pacientes com PIDC, todos tratados e sem sinais clínicos de alterações centrais, e 11 controles, pareados em gênero e faixa etária de 19 a 69 anos. Foram adquiridas neuroimagens em uma máquina de Ressonância Magnética de alto campo (3T) usando diferentes técnicas de imagens; volumétricas ponderadas em T1, volumétricas de inversão e recuperação com atenuação de fluidos e ponderadas em T2, relaxométricas de cinco ecos para mapas de T2, de transferência de magnetização e por tensor de difusão. As imagens foram processadas em diferentes ferramentas computacionais e foram obtidos resultados para estudos da difusibilidade, volumetria, morfometria, tratometria e conectividade cerebral, além de achados radiológicos para os pacientes. As análises de grupos foram executadas por; 1) testes paramétricos monocaudais de duas amostras pareadas para os resultados da volumetria, da tratometria e conectividade cerebral; 2) mapeamento estatístico paramétrico para os resultados da morfometria baseada em voxel e; 3) estatística espacial baseada em tratos para os resultados da difusibilidade. Foram detectas alterações em todas as comparações. Os principais achados indicam um envolvimento possivelmente caracterizado por uma perda volumétrica encefálica generalizada, sobretudo nas regiões periventriculares associadas a ventrículos proeminentes acrescido de, um aumento da difusibilidade transversa e oblíqua nos maiores tratos de substância branca e, também há uma perda de densidade na substância branca periventricular e um aumento na substância cinzenta em uma região que sinaliza para o espessamento trigeminal bilateral e, uma redução geral da conectividade cerebral estrutural. / Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a severe disease fundamentally characterized by dysfunction of the Peripheral Nervous System and affects greatly the quality of life of patients. The Central Nervous System (CNS) involvement in CIDP has not been described using recent quantitative neuroimaging techniques. We evaluated 11 patients with CIDP, all treated and without clinical signs of central alterations and 11 controls matched for gender and age group of 19 to 69 years. Magnetic Resonance Imaging were performed on a 3T scanner using different imaging techniques; structural 3D T1-weighted, fluid-attenuated inversion recovery, relaxometry with 5 echoes pulse sequence for T2 maps, magnetization transfer weighted and diffusion tensor imaging. The images were processed on different tools and were obtained results for the studies of diffusivity, volumetry, morphometry, tractometry, brain connectivity, and radiological findings of patients. Different statistical group analyses were performed in the quantitative results: 1) Parametric test for volumetry, tractometry and brain connectivity; 2) Parametric mapping for voxel morphometry; 3) Tract-based spatial statistics (TBSS) for diffusion coefficients. Changes were detected in all comparisons. In the patients, our main findings are: generalized loss brain volume more pronounced in periventricular regions associated with prominent ventricles, increased simultaneously perpendiculars and parallel diffusivity in the major tracts of the TBSS analyze, white matter density loss in the periventricular area, some bilateral trigeminal thickening, and general reduction of the brain connectivity. The CIDP affects the global brain and represents a demyelination in the CNS.