The performance of most tasks requires some interaction between the cerebral hemispheres. Despite this fact, research has focused on demonstrating that each hemisphere is specialised for certain processes and has largely neglected this interaction. ¶ Recent research has recognised the need for a better understanding of how resources are shared between the cerebral hemispheres. While these studies have shed light on factors external to the participants being tested, such as the type of task and stimuli used, presentation times, and different measurement methods, they have neglected variables that differ between individuals. The studies reported here focused on factors internal to the participants. They include sex, age, handedness, functional lateralisation, practice, attention, and hemispheric activation, which vary between individuals or within individuals across time, and have been shown to influence the structure and morphology of the corpus callosum which is the main pathway for hemispheric interactions. ¶ This thesis examines the relationship of these variables to the efficiency of hemispheric interactions. ¶ A literature review of the factors affecting hemispheric interactions and interhemispheric transfer is presented in Chapter 1, and methodological issues relating to the measurement of these variables in Chapter 2. Based upon this research, two tasks, the Poffenberger paradigm and a letter-matching task, were selected to assess interhemispheric transfer time and hemispheric interactions, respectively, and to investigate the relationship between these two variables. ¶ Chapters 3 and 4 present the findings of the principal study, using a large sample of participants and regression analysis, which demonstrate that both faster interhemispheric transfer and more extreme left-handedness are associated with greater efficiency of hemispheric interaction. Surprisingly, other factors which were expected to influence hemispheric interactions (age, sex, functional lateralisation, and attention) did not have a significant effect on this variable. ¶ A strong practice effect found in the task used in Chapters 3 and 4 is analysed in Chapter 5. Contrary to previous findings, this practice effect seems not to be due to a shift from sequential, rule-based processing to memory-retrieval, but rather, is a more general practice effect consistent with progressively more efficient use of neural resources. ¶ Chapter 6 shows that individuals with dyslexia not only demonstrate an abnormally fast interhemispheric transfer, but also attentional deficits, due probably to decreased efficiency in hemispheric interactions. Because some clinical populations, such as individuals with dyslexia, have been shown to have hemispheric interaction deficits, the study of such clinical samples can provide valuable information about the relationship between hemispheric interactions and other individual variables. ¶ In Chapter 7 it is demonstrated that both latent and induced patterns of lateralised hemispheric activation affect hemispheric interactions. This suggests that assessment of hemispheric activation is important not only in this field, but probably also more generally in neuropsychological research. These findings highlight the need for a simple, inexpensive measure of hemispheric activation that can be applied routinely in cognitive experiments. ¶ Chapter 8 presents a new technique to measure lateralised brain activation in typical psychological experiments using functional tympanic membrane thermometry (fTMT). This measure relies on the measurement of ear membrane temperature as an index of hemispheric activation. The technique is simple and inexpensive, and is shown to be suitable for the assessment of hemispheric activation patterns during typical experiments. ¶ In conclusion, individual characteristics such as the efficiency of interhemispheric transfer, handedness, functional lateralisation, attention, and hemispheric activation are important factors to consider when researching hemispheric interactions in both normal and clinical populations. Furthermore, future research will benefit from this newly developed measure, fTMT, by allowing the systematic study of the effects of hemispheric activation in brain processes.

Large scale functional brain networks, defined by synchronized spontaneous oscillations between spatially distinct anatomical regions, are essential to brain function and have been implicated in disease states, cognitive capacity, and many sensing and motor processes. In this work, we sever the corpus callosum in the rodent model to determine if structural connectivity (specifically the primary interhemispheric pathway) organizes and influences bilateral functional connectivity and brain-wide spatiotemporal dynamic activity patterns. Prior to the callosotomy work, resting state brain networks were evaluated using blood oxygen level dependent (BOLD) and cerebral blood volume (CBV) magnetic resonance imaging contrast mechanisms, and revealed that BOLD and CBV provide highly similar spatial maps of functional connectivity; however, the amplitude of BOLD connectivity was generally stronger. The effects of extended anesthetic durations on functional connectivity were also evaluated revealing extended isoflurane anesthetic periods prior to the switch to dexmedetomidine attenuates functional activity for a longer duration as compared to a shorter isoflurane paradigm. We also observed a secondary significant evolution of functional metrics occurring during long durations of dexmedetomidine use under the currently accepted and refined dexmedetomidine sedation paradigm. Taking these previous findings into account, we moved forward with the callosotomy study. Functional network integrity was evaluated in sham and full callosotomy groups using BOLD and electrophysiology. Functional connectivity analysis indicated a similar significant reduction in bilateral connectivity in the full callosotomy group as compared to the sham group across both recording modalities. Spatiotemporal dynamic analysis revealed bilaterally symmetric propagating waves of activity in the sham data, but none were present in the full callosotomy data; however, the emergence of unilateral spatiotemporal patterns became prominent following the callosotomy. This finding suggests that the corpus callosum could be largely responsible for maintaining bilateral network integrity, but non-bilaterally symmetric propagating waves occur in the absence of the corpus callosum, suggesting a possible subcortical driver of the dynamic cascading event. This work represents a robust finding indicating the corpus callosum's influence on maintaining integrity in bilateral functional networks.

A exposição a eventos traumáticos durante a infância está associada a um prejuízo na cognição, neurobiologia e morfologia cerebral. No entanto, não se sabe se o trauma está relacionado a essas mudanças em amostras que não apresentam potenciais fatores de confusão como idade avançada, cronicidade do transtorno psiquiátrico e múltiplos episódios de humor. O impacto do trauma na infância foi avaliado em duas amostras diferentes nesta tese: 1) crianças com e sem história de trauma; 2) pacientes com diagnóstico de THB logo após a recuperação do primeiro episódio de mania com e sem história de trauma na infância e controles saudáveis com e sem história de trauma na infância. Os resultados sugerem que o trauma está associado a mudanças na neurobiologia, cognição e morfologia cerebral. Crianças com trauma apresentaram aumento nos níveis de BDNF, TNF-α, IL-6 e IL-10 comparadas com crianças sem trauma. No entanto, após a exclusão de crianças com história de doença inflamatória, apenas os níveis de BDNF e TNF-α permaneceram aumentados em crianças com trauma. Na população com transtorno bipolar, a história de trauma na infância foi associada a uma diminuição no QI, atenção auditiva e memória verbal e memória de trabalho enquanto um padrão diferente foi observado nos controles saudáveis com história de abuso infantil. Pacientes com THB e trauma também apresentaram menor volume total do CC em comparação aos pacientes com THB e sem trauma, com diferenças significativas também na região anterior do CC. Por outro lado, não encontramos diferenças significativas entre o volume do CC nos pacientes com ou sem trauma em comparação aos controles saudáveis. Estes achados reforçam a extensão e gravidade do impacto negativo do trauma na infância, em diferentes etapas do desenvolvimento, afetando tanto aspectos cognitivos, como neurobiológicos e de morfologia cerebral. / Exposure to traumatic events during childhood is associated with impairment in cognition, neurobiology and brain morphology. However, it is unknown if trauma is related to these changes in samples that do not show the potential confounds of advancing age, chronicity of psychiatry disorder and multiple mood episodes. We evaluated the impact of childhood trauma in two different samples: 1) children with and without childhood trauma; 2) pacients with a BD diagnosis recently recovered from a first manic episode with and without childhood trauma and healthy controls with and without childhood trauma. The results suggest that childhood trauma is associated to changes in neurobiology, cognition and brain morphology. Children with trauma showed higher levels of BDNF, TNF-α, IL-6 e IL-10 compared to children without trauma. However, after excluding children with history of inflammatory disease, only BDNF and TNF-α levels remained increased in children with trauma. In BD patients, the childhood trauma was associated to a decreased IQ, auditory attention, verbal memory, and working memory and a different pattern was observed in healthy subjects with a history of childhood abuse. The total CC volume was found to be smaller in BD patients with trauma compared to BD patients without trauma and differences were more pronounced also in the anterior region of the CC. On the other hand, we did not find significant differences in the CC volume of patients with/without trauma compared to the healthy subjects. These findings reinforce the extent and severity of the negative impact of childhood trauma in different stages of development, affecting cognitive aspects, as well as neurobiological and brain morphology.

Introdução: O acesso ao terceiro ventrículo constitui verdadeiro desafio ao neurocirurgião. Nesse contexto, estudos anatômicos e morfométricos são úteis para estabelecer as limitações e as vantagens de determinado acesso cirúrgico. O acesso transcorioideo é versátil e promove exposição adequada da região média e posterior do terceiro ventrículo. Entretanto, a coluna do fórnice limita a exposição da região anterior do terceiro ventrículo. Há evidências de que a secção ipsilateral da coluna do fórnice tenha pouca repercussão na função cognitiva. Esta tese compara a exposição anatômica proporcionada pelo acesso transforniceal transcorioideo com o do acesso transcorioideo e realiza avaliação morfométrica de estruturas relevantes e comuns aos dois acessos. Material e métodos: A exposição anatômica proporcionada pelos acessos transcaloso transcorioideo e transcaloso transforniceal transcorioideo foram comparadas em oito cadáveres não submetidos à conservação, utilizando o sistema de neuronavegação (Artis, Brasília, Brasil), para aferir a área de trabalho, a área de exposição microcirúrgica, a exposição angular no plano longitudinal e transversal de dois alvos anatômicos (túber cinéreo e aqueduto cerebral). Adicionalmente, foram quantificados a espessura do parênquima do lobo frontal direito, a espessura do tronco do corpo caloso, o diâmetro longitudinal do forame interventricular, a distância de trabalho da superfície cortical ao túber cinéreo e a distância de trabalho da superfície cortical até o aqueduto cerebral. Os valores obtidos foram submetidos a análise de estatística utilizando o teste de Wilcoxon. Resultados: Na avaliação quantitativa, o acesso transforniceal transcorioideo proporcionou maior área de trabalho (transforniceal transcorioideo = 150,299 +/- 11,147 mm2; transcorioideo = 121,421 +/- 7,698 mm2; p < 0,05), maior área de exposição microcirúrgica (transforniceal transcorioideo = 100,920 +/- 8,764 mm2; transcorioideo = 79,944 +/- 4,954 mm2; p < 0,05), maior área de exposição angular no plano longitudinal para o túber cinéreo (transforniceal transcorioideo = 70,898 +/- 6,598 graus; transcorioideo = 63,838 +/- 5,770 graus; p < 0,05) e maior área de exposição angular no plano longitudinal para o aqueduto cerebral (transforniceal transcorioideo = 61,806 +/- 6,406 graus; transcorioideo = 54,998 +/- 5,102 graus; p < 0,05) em comparação com o acesso transcorioideo. Nenhuma diferença foi observada na exposição angular ao longo do eixo transversal para os dois alvos anatômicos (túber cinéreo e aqueduto cerebral) (p > 0,05). A espessura média do lobo frontal direito foi de 34,869 +/- 3,439 mm, a espessura do tronco caloso foi 10,085 +/- 1,172 mm, o diâmetro do forame interventricular foi de 4,628 +/- 0,474 mm, a distância da superfície cortical ao túber cinéreo foi de 69,315 +/- 4,564 mm e a distância da superfície cortical ao aqueduto cerebral foi de 75,654 +/- 4,950 mm. Na avaliação qualitativa, observamos que o acesso transforniceal transcorioideo permitiu incremento da visualização das estruturas da região anteroinferior do terceiro ventrículo. Não houve diferença quanto à exposição das estruturas da região média e posterior em ambos os acessos. Conclusões: O acesso transforniceal transcorioideo propicia maior exposição cirúrgica da região anterior do terceiro ventrículo em comparação com aquela oferecida pelo acesso transcorioideo. O estudo morfométrico estabeleceu valores médios das estruturas anatômicas comuns aos dois acessos na população estudada / Introduction: Approaches to the third ventricle constitute a formidable challenge to the neurosurgeon and, in this context, anatomical and morphometric studies are useful to establish the limitations and advantages of certain surgical approaches. The transchoroidal approach is a versatile one that promotes adequate exposure of the middle and posterior regions of the third ventricle. However, the column of fornix limits the exposure of the anterior third ventricle region. There is evidence that the ipsilateral section of the column of fornix has little effect on the cognitive function. This thesis compares the anatomical exposure using the transchoroidal transforniceal technique with the transchoroidal approach, and performs morphometric assessment of relevant structures common to both approaches. Material and methods: The anatomical exposure achieved through the transchoroidal transcallosal approach and transchoroidal transforniceal transcallosal were compared in 8 fresh cadavers using the neuronavigation system (Artis, Brasilia, Brazil), to assess the working area, microsurgical exposure area, to quantify the angular exposure in the longitudinal and cross-sectional planes to two anatomical targets (tuber cinereum and cerebral aqueduct), to measure the thickness of the right frontal lobe parenchyma, corpus callosum body thickness, longitudinal diameter of the interventricular foramen, working distance from the cortical surface to the tuber cinereum and working distance from the cortical surface to the cerebral aqueduct. The values obtained were submitted to statistical analysis using Wilcoxon\'s test. Results: In the quantitative assessment, the transchoroidal transforniceal approach provided: larger working area (transchoroidal transforniceal = 150.299 +/- 11.147 mm2; transchoroidal = 121.421 +/- 7.698 mm2; p < 0.05), larger area of microsurgical exposure (transforniceal transchoroidal = 100.920 +/- 8.764 mm2; transchoroidal = 79.944 +/- 4.954 mm2; p < 0.05), larger area of angular exposure in the longitudinal plane to the tuber cinereum (transchoroidal transforniceal = 70.898 +/- 6.598 degrees; transchoroidal = 63.838 + / - 5,770 degrees; p < 0.05) and larger area of angular exposure in the longitudinal plane to the cerebral aqueduct (transforniceal transchoroidal = 61.806 +/- 6.406 degrees; transchoroidal = 54.998 +/- 5.102 degrees; p < 0.05) when compared to the transchoroidal approach. No differences were observed in the angular exposure along the cross-sectional axis for both anatomical targets (tuber cinereum and cerebral aqueduct) (p > 0.05). The mean thickness of the right frontal lobe was 34.869 +/- 3.439 mm, the thickness of the corpus callosum body was 10.085 +/- 1.172 mm, the diameter of the interventricular foramen was 4,628 +/- 0,474 mm, the distance from the cortical surface to the tuber cinereum was 69.315 +/- 4.564 mm, and the distance from the cortical surface to the cerebral aqueduct was 75.654 +/- 4.950 mm. In the qualitative assessment, we observed that the transforniceal transchoroidal approach allowed better visualization of the structures in the anterior third ventricle region. There was no difference regarding exposure of structures in the middle and posterior regions with both access. Conclusions: The transforniceal transchoroidal approach provides greater surgical exposure of the anterior third ventricle region than that obtained with the transchoroidal approach. The morphometric study established mean values of anatomical structures that are common to both approaches in the assessed population

O corpo caloso é a maior comissura cerebral, responsável pela conexão entre os hemisférios cerebrais. Anatomicamente está localizado na profundidade da fissura inter-hemisférica e é dividido em quatro regiões: esplênio, corpo, joelho e rostro, que se continua inferiormente na lamina rostralis. A malformação do corpo caloso (MCC) representa uma desorganização na arquitetura cerebral, resultante da impossibilidade parcial ou completa das fibras da comissura calosa atravessarem a linha média. Pode estar associada a outras malformações, tanto do sistema nervoso central quanto de outros órgãos. As causas de malformações do corpo caloso são múltiplas, podendo ser ambientais, vasculares ou genéticas. As malformações do corpo caloso são comuns, principalmente entre as crianças com distúrbio do desenvolvimento neuropsicomotor ou retardo mental, mas podem também ser observada em indivíduos normais. Existem mais de 50 síndromes clínicas, autossômicas ou ligadas ao X, dominantes ou recessivas, associadas a MCC. A investigação de pacientes com malformação de corpo caloso por meio do cariótipo com bandas G identificou cerca de 20 regiões cromossômicas associadas a esta malformação. Nos últimos anos, novas técnicas de investigação cromossômica com alta resolução tornam-se disponíveis, como a hibridação comparativa do genoma em microarranjos (CGH-array). O CGH-array permite uma análise rápida de todo o genoma em alta resolução, possibilitando reconhecer variações no número de cópias de regiões genômicas com de 0,1 a 1 Mb, e desta forma detectar microdeleções ou microduplicações que não são passiveis de serem reconhecidas pelo cariótipo com bandas G, que é capaz de detectar alterações com no mínimo 4 Mb. Nesta investigação foram incluídos 21 sujeitos com MCC, associada ou não a outras malformações encefálicas ou de outros órgãos, e atraso do desenvolvimento neuropsicomotor ou retardo mental, sem etiologia definida. Estes sujeitos foram investigados com o objetivo de detectar anormalidades cromossômicas, estruturais e/ou numéricas, por meio do cariótipo com bandas G, e de variações do número de cópias de regiões genômicas, por meio do estudo com CGH-array. O cariótipo evidenciou alteração em dois dos sujeitos (9.5%): um indivíduo apresentava um derivado do cromossomo 4 [46, XX, der(4)] herdado da mãe, que apresentava translocação balanceada entre os cromossomos 4 e 10 [46, XX,t(4; 10)(q35; q23)]; e outro apresentava um rearranjo de novo, derivado do cromossomo 8, [46, XX, der(8)]. O CGH-array foi feito nestes indivíduos para delimitar a extensão e a origem do material genético presente no rearranjo. Em dois indivíduos (11%), o CGH-array evidenciou alterações cromossômicas de novo: deleção em 6q25.1-25.3, com dimensão entre 5 e 6,7 Mb, e deleção 4q25-q28.1 com 14,5 Mb. E finalmente, em quatro sujeitos (21%), o CGH-array detectou variação no número de cópias genômicas, evidente também em um dos genitores, com significado clínico incerto. Desta forma, a investigação de alterações cromossômicas nesta amostra de 21 pacientes com MCC, permitiu: (1). Diagnosticar, com o auxílio do cariótipo, anormalidades estruturais cromossômicas em dois casos; (2). Diagnosticar, com o auxílio do CGH-array, microdeleções não visualizáveis ao cariótipo em dois pacientes; (3). Caracterizar, com o auxílio do CGH-array, a extensão e origem dos rearranjos diagnosticados pelo cariótipo. A existência de translocação equilibrada em genitor de um dos pacientes com cariótipo anormal aumenta o risco de recorrência, de anormalidades, em outras gestações. Nos demais três pacientes, este risco é considerado muito baixo. Duas das alterações cromossômicas encontradas em nossos pacientes, a deleção na região 6q25.1-25.3 e a duplicação invertida no cromossomo 8 na região p23.1 - p11.21, já foram previamente descritas em MCC. Porém não há descrições envolvendo a deleção 4q25-q28 ou a deleção 4q34.3-q35.2 combinada com a duplicação 10q 23.1 - q23.6. A investigação de alterações cromossômicas em indivíduos com MCC contribui para o esclarecimento de sua etiologia e auxilia no delineamento de regiões cromossômicas que contém genes envolvidos com a formação do corpo caloso / The corpus callosum is the largest cerebral commissure and is responsible for interconnection of cerebral hemispheres. It is located in the deepest part of the interhemispheral fissure and is divided in four regions: splenium, body, genum and rostrum, which is prolonged inferiorly as lamina rostralis. Corpus callosum malformation (CCM) is a cerebral architecture disorganization caused by complete or partial failure of callosum fibers to cross the midline. It may be associated to other malformations, both from central nervous system and other organs. Many factors can contribute do CCM, including environmental, vascular and genetics. CCM are particularly common among mentally retarded or developmentally delayed children but can also be observed in cognitively normal individuals. There are more than 50 clinical syndromes associated to CCM, occurring sporadically or inherited as an autosomal or X-linked, dominant or recessive trait. Karyotype with G-banding disclosed around to 20 chromosomal regions associated to CCM. In the last few years, new techniques for high resolution chromosomal investigation, as comparative genomic hybridization array (CGH-array), became available. CGH-array allows fast analysis in high resolution of the genome, allowing the determination of copy number variations (microduplications and microdeletions) of genomic regions, with minimum size of 0, 1 to 1 Mb. This resolution is much larger than of the conventional karyotype, which is able to detect abnormalities of at least 4 Mb. This investigation included 21 subjects with CCM without defined etiology, associated or not to additional brain or other internal organ malformation and with developmental delay or mental retardation. These individuals were investigated for numeric or structural chromosomal abnormalities with karyotype with G-banding and for genomic copy number variations, using CGH-array. Karyotype disclosed abnormalities in two individuals (9.5%): one patient had a derived chromosome 4 [46, XX,der(4)], inherited from his mother, which has a balanced translocation between chromosomes 4 and 10 [46,XX,t(4;10)(q35;q23)]; and other had a de novo rearrangement, derived from chromosome 8 [46, XX,der(8)]. CGHarray analysis was conducted in these individuals to define the extension and origin of the genetic material present in the rearrangement. Among individuals with normal karyotype, CGH-array disclosed two patients (11%), with de novo abnormalities: 6q25.1-25.3 deletion, with size ranging from 5 to 6, 7 Mb, and a 14.5 deletion of 4q25-q28.1. Finally, in four subjects (21%), CGH-array detected genomic copy number variations that were also present in one of the parents, which make its clinical significance uncertain. To conclude, the investigation of chromosomal abnormalities in this sample of 21 patients with CCM, allow us to: 1. Detect two patients with chromosomal abnormalities detectable on conventional karyotype; 2. Recognize, with CGH-array technique, two additional patients with microdeletions, not seen on conventional karyotype; 3. Characterize the origin and extension of chromosomal rearrangement in the patients with abnormal karyotype. The detection of a balanced translocation in one of the parents increases the risk of occurrence of chromosomal abnormalities in future concepts of this individual. In the remaining three patients, recurrence risk is presumably very low. Two of the chromosomal abnormalities detected in our patients (6q25.1- 25.3 deletion and inverted duplication of chromosome 8 spanning p23.1 - p11.21) have been previously reported in patients with CCM. Nevertheless, chromosomal abnormalities involving chromosome 4 (deletion 4q25-q28.1) or the combined deletion 4q34.3 - q35.2 and duplication 10q 23.1 - q23.6 have not been previously reported. Investigation of chromosomal abnormalities in individuals with CCM contributes to etiology determination and helps delineation of chromosomal regions that contains gene(s) involved with corpus callosum formation.

Basische Helix-Loop-Helix (bHLH)-Proteine bilden eine diverse Gruppe evolutionär gut konservierter Transkriptionsfaktoren. Viele transaktivierende bHLH-Proteine werden zelltyp- oder gewebespezifisch exprimiert und fungieren als wichtige Schlüsselregulatoren zellulärer Determinations- und Differenzierungsprozesse. Die eng verwandten neuronalen bHLH-Gene Neurod1, Neurod2 und Neurod6 werden in differenzierenden Pyramidenneuronen des sich entwickelnden zerebralen Kortex exprimiert und stehen schon lange im Verdacht, deren Reifung zu steuern. In der Vergangenheit wurde jedes der drei Gene in Mäusen inaktiviert. Untersuchungen an den einfach-defizienten Tieren konnten jedoch keine wichtigen Funktionen in embryonalen Pyramidenneuronen identifizieren. Da die Aminosäuresequenzen und die Expressionsmuster der Faktoren sehr ähnlich sind, wurde angenommen, dass sie sich redundante Funktionalität teilen. Um dies zu überprüfen, habe ich Neurod2/6-doppel-defiziente Tiere gezüchtet und unter besonderer Berücksichtigung der Differenzierung von Pyramidenneuronen und der Konnektivität des zerebralen Kortex analysiert: Die Experimente zeigen, dass Neurod2 und Neurod6 tatsächlich mehrere bisher unbekannte gemeinsame Funktionen haben, wobei jeder Faktor für den Verlust des jeweils anderen kompensieren kann. Zumindest eines der beiden Gene ist notwendig für (1) die Kontrolle der radialen Migration eines Teils der Pyramidenneurone, (2) die frühe Regionalisierung des zerebralen Kortex und (3) die Bildung kortikaler Projektionen vom Neokortex zum Striatum, zum Thalamus und zur kontralateralen Hemisphäre. Callosale Axone bilden in Neurod2/6-doppel-defizienten Mäusen Faserbündel die tangential in den medialen Kortex einwachsen, aber noch vor Erreichen des ipsilateralen Cingulums und vor dem Kontakt mit der Mittellinie stoppen und defaszikulieren. Es resultiert eine neue Variante der callosalen Agenesie, die nahelegt, dass es bisher nicht identifizierte Wachstumssignale im medialen Kortex gibt. Die Expression von Neurod1, welche sich normalerweise auf die Subventrikularzone beschränkt, persistiert in radial migrierenden Pyramidenneuronen der Intermediärzone und der Kortikalplatte von Neurod2/6-doppel-defizienten Mäusen. Diese ektopische Neurod1-Expression kann dort den Verlust von Neurod2 und Neurod6 kompensieren. In einem weiteren Schritt habe ich konditionale Neurod1/2/6-tripel-defiziente Mäuse gezüchtet. In diesen Tieren wird das Neurod1-Gen durch selektive genetische Rekombination in all jenen Zellen, die über Neurod6-Promoteraktivität verfügen, irreversibel entfernt: Wie erwartet, teilt sich Neurod1 weitere gemeinsame Funktionen mit Neurod2 und Neurod6. Zumindest eines der drei Gene ist notwendig für die Differenzierung hippokampaler Pyramidenzellen und die Hemmung des programmierten Zelltods der unreifen Neuronen des Cornu Ammonis. Während die gemeinsame Inaktivierung von Neurod1/2/6 zur Aplasie des Hippocampus führt, überlebt ein Großteil der neokortikalen Pyramidenzellen. Die terminale neuronale Differenzierung ist jedoch auch im Neokortex gestört und die neokortikale Konnektivität sehr stark reduziert. Diese Arbeit zeigt, dass die Transkriptionsfaktoren der NeuroD-Familie gemeinsam die Differenzierung, das Überleben, die Migration und das axonale Wachstum von pyramidalen Neuronen des sich entwickelnden zerebralen Kortex steuern. Während der Embryonalentwicklung ergeben sich folgende, teils überschneidende Funktionen der NeuroD-Gene: Die Differenzierung und das Überleben von hippocampalen Körnerzellen ist abhängig von Neurod1. Die frühen Schritte der Differenzierung von hippocampalen Pyramidenneuronen und deren Überleben sind eine Funktion von wahlweise Neurod1, Neurod2 oder Neurod6. Spätere neuronale Differenzierungsschritte, die Regionalisierung des Neokortex und das gezielte Wachstum wichtiger neokortikaler Faserzüge basieren auf Funktionen von Neurod2 oder Neurod6, aber nicht von Neurod1. Der postnatale Umbau des somatosensorischen Kortex und die funktionale Integration thalamischer Afferenzen wurden bereits als strikt Neurod2-abhängig beschrieben.

A exposição a eventos traumáticos durante a infância está associada a um prejuízo na cognição, neurobiologia e morfologia cerebral. No entanto, não se sabe se o trauma está relacionado a essas mudanças em amostras que não apresentam potenciais fatores de confusão como idade avançada, cronicidade do transtorno psiquiátrico e múltiplos episódios de humor. O impacto do trauma na infância foi avaliado em duas amostras diferentes nesta tese: 1) crianças com e sem história de trauma; 2) pacientes com diagnóstico de THB logo após a recuperação do primeiro episódio de mania com e sem história de trauma na infância e controles saudáveis com e sem história de trauma na infância. Os resultados sugerem que o trauma está associado a mudanças na neurobiologia, cognição e morfologia cerebral. Crianças com trauma apresentaram aumento nos níveis de BDNF, TNF-α, IL-6 e IL-10 comparadas com crianças sem trauma. No entanto, após a exclusão de crianças com história de doença inflamatória, apenas os níveis de BDNF e TNF-α permaneceram aumentados em crianças com trauma. Na população com transtorno bipolar, a história de trauma na infância foi associada a uma diminuição no QI, atenção auditiva e memória verbal e memória de trabalho enquanto um padrão diferente foi observado nos controles saudáveis com história de abuso infantil. Pacientes com THB e trauma também apresentaram menor volume total do CC em comparação aos pacientes com THB e sem trauma, com diferenças significativas também na região anterior do CC. Por outro lado, não encontramos diferenças significativas entre o volume do CC nos pacientes com ou sem trauma em comparação aos controles saudáveis. Estes achados reforçam a extensão e gravidade do impacto negativo do trauma na infância, em diferentes etapas do desenvolvimento, afetando tanto aspectos cognitivos, como neurobiológicos e de morfologia cerebral. / Exposure to traumatic events during childhood is associated with impairment in cognition, neurobiology and brain morphology. However, it is unknown if trauma is related to these changes in samples that do not show the potential confounds of advancing age, chronicity of psychiatry disorder and multiple mood episodes. We evaluated the impact of childhood trauma in two different samples: 1) children with and without childhood trauma; 2) pacients with a BD diagnosis recently recovered from a first manic episode with and without childhood trauma and healthy controls with and without childhood trauma. The results suggest that childhood trauma is associated to changes in neurobiology, cognition and brain morphology. Children with trauma showed higher levels of BDNF, TNF-α, IL-6 e IL-10 compared to children without trauma. However, after excluding children with history of inflammatory disease, only BDNF and TNF-α levels remained increased in children with trauma. In BD patients, the childhood trauma was associated to a decreased IQ, auditory attention, verbal memory, and working memory and a different pattern was observed in healthy subjects with a history of childhood abuse. The total CC volume was found to be smaller in BD patients with trauma compared to BD patients without trauma and differences were more pronounced also in the anterior region of the CC. On the other hand, we did not find significant differences in the CC volume of patients with/without trauma compared to the healthy subjects. These findings reinforce the extent and severity of the negative impact of childhood trauma in different stages of development, affecting cognitive aspects, as well as neurobiological and brain morphology.

Early-life stress, consisting of several stressors appears to be associated with several impacts on the brain. The impacts of stress seem to be more vulnerable to the developing brain as it undergoes important changes during childhood. This thesis aims to present the association between childhood maltreatment, which is a form of early-life stress, and affected brain regions such as the hippocampus, prefrontal cortex, corpus callosum, and the amygdala. The findings in this thesis demonstrated the left hippocampus to be more vulnerable to the effects of maltreatment, corpus callosum appeared to be gender and maltreatment specific, indicating that the corpus callosum were more vulnerable to neglect in boys whereas in females the structure was more vulnerable to sexual abuse. The prefrontal cortex demonstrated a marked reduction in gray matter, and the amygdala showed increased activation in response to emotional facial expressions. Cognitive deficits as a result of earlylife stress were also discussed, showing that worse intellectual ability and the academic performance had been noted in children with exposure to early-life stress.

In general, highly hypnotizable individuals ("highs") have exhibited greater abilities to focus attention and inhibit pain than low hypnotizable individuals ("lows"). Furthermore, highs appear to have faster neural processing than lows. The present study investigated differences between lows and highs in morphological volume of some brain structures associated with inhibitory and excitatory neural processing, particularly the corpus callosum (CC). Participants were 18 healthy university students, aged 18 to 29, with no history of concussion or medical disorders. They were in a functional Magnetic Resonance Image (fMRI) study examining the neurophysiology of pain and hypnotic analgesia (Crawford, Horton, Harrington, et al., 1998; Downs et al., 1998). As assessed by the group version (Crawford & Allen, 1982) of the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C; Weitzenhoffer & Hilgard, 1962), there were eight highs (four women and four men; SHSS:C M = 11.0) and 10 lows (five men and five women; SHSS:C M = 2.1). Highs were able to successfully eliminate perception of pain and distress to experimental noxious stimuli. Their anatomical MRIs were measured to assess relationships between brain structure volume (CC, medial cortex, anterior brain regions) and hypnotizability. In comparison to lows, highs had a significantly larger CC volume in the rostrum and isthmus, inferred to reflect larger transcallosal axon diameter or greater axon myelination. For highs, but not lows, there were significant relationships between forebrain volume and the total CC, rostrum, and splenium. Findings provide support for the neuropsychophysiological model of Crawford and her associates (e.g. Crawford, 1994a, 1994b; Crawford & Gruzelier, 1992) proposing a more effective attentional system of inhibitory processes in highs than lows. Furthermore, the data suggest that the more effective systems of attentional and inhibitory processes enhanced neural processing speed, and interhemispheric transfer times seen in highs than lows, may be associated with morphological differences in certain anterior and posterior CC regions. These regions are known to be involved in the allocation of inhibitory and excitatory transfer of information between hemispheres. / Ph. D.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19270号 / 医博第4034号 / 新制||医||1011(附属図書館) / 32272 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 渡邉 大, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM