No description available.

Les traumatismes infantiles (TI) sont un facteur de vulnérabilité majeur à la schizophrénie. Nous avons ici choisi d'étudier l’impact des TI sur le cerveau dans la schizophrénie.Dans notre première étude, en voxel-based morphometry (VBM) et portant sur 21 schizophrènes et 30 contrôles, la négligence émotionnelle était associée à une diminution du volume total de matière grise dans les deux groupes. Cette association était plus marquée chez les schizophrènes. Chez les patients, la négligence émotionnelle était prédictive de la densité de matière grise du cortex préfrontal dorso-latéral, elle-même prédictive de la sévérité de la désorganisation.Dans notre seconde étude, nous avons utilisé une tâche émotionnelle en IRMf pour explorer les liens entre TI et connectivité fonctionnelle PPI (psychophysiological interaction) de l’amygdale chez 21 schizophrènes et 25 contrôles. Au cours de la tâche, chez les patients, la sévérité des abus sexuels et négligences physiques été associée à une diminution de connectivité entre l’amygdale et la région du cortex cingulaire postérieur/précunéus.Enfin le résultat le plus répliqué de notre revue de la littérature (15 articles d'imagerie) est l’association forte entre TI et diminution du volume total de matière grise. Chez les schizophrènes les TI étaient associés à des diminutions de matière grise au niveau du cortex préfrontal, à des altérations de l’intégrité de la matière blanche et à des altérations de connectivité fonctionnelle.Ainsi nos résultats suggèrent que les TI, interagissant avec d'autres facteurs de vulnérabilité, pourraient modeler la psychopathologie schizophrénique via des effets cérébraux neurodéveloppementaux. / Childhood trauma (CT) is a major risk afctir for schizophrenia. The aim of this work was to question the possible impact of CT on the brain of schizophrenia patients.In our first study, using voxel-based morphometry (VBM) in 21 patients with schizophrenia and 30 controls, childhood emotional neglect was associated with decreased total grey matter volume in both groups, with a stronger association in the patients group. In schizophrenia, emotional neglect predicted grey matter decrease in dorsolateral prefrontal cortex, which in turn predicted the severity of disorganization.In our second study, we used an fMRI emotional task with PPI (psychophysiological interaction) in 21 schizophrenia patients and 25 controls. During the emotional task, in schizophrenia group, sexual abuse and physical neglect during childhood were associated with decreased connectivity between the amygdala and the precuneus/posterior cingulate region.Finaly, the most replicated result in our review is the strong association between CT and decreased total grey matter volume. In addition, CT in schizophrenia patients is related to decreased prefrontal cortex grey matter, widespread alterations of white matter integrity and alterations of functional connectivity in a network including the amygdala, the anterior cingular cortex, the precuneus/posterior cingulate region and the temporo-parietal junction.Our findings suggest that CT, in interaction with other factors, could shape the psychopathology of schizophrenia through developmental effects on the brain, with predominent alterations in the prefrontal cortex, or in stress-related circuits affecting self-consciousness and social cognition.

The brain has been one of the central foci in studies of vertebrate evolution. Work in East African cichlids and other emerging fish models like the Mexican cavefish (Astyanax mexicanus) offer new insight on the role of patterning on brain evolution. These fish can be grouped into two major categories according to habitat; for cichlids it is rock-dwelling (known locally as mbuna) and sand-dwelling (non-mbuna) lineage. The brain development of mbuna versus non-mbuna is defined by changes in gene deployment working along the dorsal/ventral (DV) and anterior/posterior (AP) neuraxes, respectively. Comparison of disparate fish ecotypes offer a new perspective of the role of patterning on brain evolution; through the slight and early modification of signal pathways working across 3-D axes, and a subsequent magnifying effect across ontogeny, evolution can generate widespread changes in the brain. To illustrate this patterning model of brain evolution, two comparative studies were done between mbuna and non-mbuna, examining the action of gene pathways that work to pattern the cichlid forebrain. The first study found that non-mbuna cichlids have a more rapid AP expansion of a gene pathway (Wingless) into the presumptive midbrain and diencephalon versus mbuna. These forebrain structures are involved in sight processing and could be of ecological benefit to vision-focused non-mbuna. The second study described a difference within the developing telencephalon. The embryonic telencephalon is split into the pallium, which processes visual signals, and the subpallium, which develops into the olfactory bulbs. Mbuna possess a larger subpallium relative to non-mbuna, which have a larger pallium. This was correlated to a more rapid expansion of another gene pathway (Hedgehog) along the DV axis. The difference in size of the pallial vs. subpallialial comparments between cichlids can be correlated to expanded olfaction in mbuna and vision in non-mbuna adult brains. Overall, East African cichlids are an excellent system to investigate the role of patterning on brain evolution because they allow for the comparison of the earliest patterning events in brain ontogeny between distinct ecotypes. These fish systems link study in brain development to the brain morphology comparisons employed in classic studies of brain evolution.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19230号 / 医博第4029号 / 新制||医||1011(附属図書館) / 32229 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邊 直樹, 教授 斎藤 通紀, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Submitted by PPG Zoologia (zoologia-pg@pucrs.br) on 2018-04-17T13:17:04Z No. of bitstreams: 1 Disserta??o_CAH_vfinal.pdf: 3985079 bytes, checksum: 6ad6a029bd9cffd5f9f47cd2432f0e7d (MD5) / Approved for entry into archive by Caroline Xavier (caroline.xavier@pucrs.br) on 2018-05-04T17:30:42Z (GMT) No. of bitstreams: 1 Disserta??o_CAH_vfinal.pdf: 3985079 bytes, checksum: 6ad6a029bd9cffd5f9f47cd2432f0e7d (MD5) / Made available in DSpace on 2018-05-04T17:35:13Z (GMT). No. of bitstreams: 1 Disserta??o_CAH_vfinal.pdf: 3985079 bytes, checksum: 6ad6a029bd9cffd5f9f47cd2432f0e7d (MD5) Previous issue date: 2018-02-22 / Conselho Nacional de Pesquisa e Desenvolvimento Cient?fico e Tecnol?gico - CNPq / Important studies have already been done regarding on paleoneurology of extinct animals due to the advancement of computed tomography techniques in recent years. This allowed more accurate studies and without the need to modify materials, especially non-mammaliaform cynodonts and basal mammals. However, these analyzes are limited by material preservation biases, often with absence of postcranium. Consequently, body mass estimations are required, which are necessary for calculations of quantitative analyzes regarding the evolution of the brain capacity of these animals. Considering this, in order to increase the data set about the evolution of the brain in Cynodontia, computed tomography of two skulls of the MCT/PUCRS (MCP 1600 PV Probelesodon kitchingi; MCP 3871 PV Massetognathus ochagaviae) were performed. We also calculated the specimens? encephalization quotients (EQ), with and without the olfactory bulbs, using two formulas of body mass estimation. When the necessary data were available in the literature, the EQs were calculated for other synapids for comparative purposes. In relation to the morphology of the endocranial casts, no differences were observed in relation to previous described for other eucinodonts, in which there is still no enlargement of the cerebral hemispheres, as well as a development of the cerebellar region. The EQs obtained for M. ochagaviae and P. kitchingi do not differ representatively from those previously calculated for other materials of the same genus. For the calculations with and without the olfactory bulbs the same was observed. However, when comparing the encephalization quotients obtained with the application of the four formulas, significant differences were observed between the results. Therefore, it is not possible to compare the EQs obtained with the different methods, and only one is required. / Importantes estudos j? foram realizados acerca da paleoneurologia de animais extintos gra?as ao avan?o das t?cnicas de tomografia computadorizada nos ?ltimos anos. Isso possibilitou estudos mais precisos e sem a necessidade de altera??o dos materiais, especialmente cinodontes n?o-mammaliaformes e mam?feros basais. Entretanto, estas an?lises s?o limitadas por vieses de preserva??o dos materiais, muitas vezes com aus?ncia de p?s-cr?nio. Consequentemente, s?o realizadas estimativas de massa corporal, necess?rias para os c?lculos de an?lises quantitativas da evolu??o da capacidade cerebral destes animais. Considerando isso, a fim de aumentar o conjunto de dados acerca da evolu??o do c?rebro em Cynodontia, foram realizadas tomografias computadorizadas de dois cr?nios do MCT/PUCRS (MCP 1600 PV Probelesodon kitchingi; MCP 3871 PV Massetognathus ochagaviae). Tamb?m foram calculados os quocientes de encefaliza??o (EQ) para os esp?cimes, com e sem os bulbos olfat?rios, aplicando-se quatro m?todos. Para as estimativas de massa corp?rea utilizou-se duas f?rmulas. Quando os dados necess?rios estavam dispon?veis na bibliografia, foram calculados os EQs para outros sinapsidos com fins comparativos. Em rela??o ? morfologia dos moldes endocranianos, n?o foram observadas diferen?as em rela??o ao descrito para outros eucinodontes, no qual ainda n?o h? um alargamento dos hemisf?rios cerebrais, assim como um desenvolvimento da regi?o cerebelar. Os EQs obtidos para M. ochagaviae e P. kitchingi n?o diferem de forma representativa dos previamente calculados para outros materiais de mesmos g?neros. O mesmo foi observado para os c?lculos com e sem os bulbos olfat?rios. Entretanto, ao analisar comparativamente os quocientes de encefaliza??o obtidos com a aplica??o das quatro f?rmulas, foram observadas diferen?as significativas entre os resultados. Portanto, n?o ? poss?vel a compara??o entre os EQs obtidos com os diferentes m?todos, sendo necess?ria a escolha de apenas um.

Abstract The duration of untreated psychosis (DUP) and its association with the course of illness in schizophrenia has been widely addressed, but the conclusions still remain essentially unclear. The studies with unselected samples and longitudinal data are few and needed. The aim of this dissertation was to study DUP and the long-term course of illness in schizophrenia in a meta-analysis and in the Northern Finland 1966 Birth Cohort (NFBC 1966). A meta-analysis of 31 original studies on the long-term association between DUP and clinical and social outcomes showed that long DUP had a small but statistically significant association with poor symptomatic, social, and global outcomes. However, there was no significant correlation between DUP and use of treatment, employment, and quality of life. In the NFBC 1966, the associations between DUP and the outcomes (n=89) were assessed with several measurements of mental and psychical state, treatment factors, education, and ability to work. In the short-term outcome, long DUP was associated with longer first hospitalization and increased risk of re-hospitalization. In the long-term, long DUP was associated only with a decreased rate of disability pension. When the association between DUP and brain structures using magnetic resonance imaging (MRI) was analyzed (n=46), long DUP correlated with decreased gray-matter density in the right hippocampus. DUP may be a modest marker of a more severe clinical phenotype regarding early outcome, but in the NFBC 1966, longer DUP seems to associate with better clinical and occupational outcomes. The relatively modest effect of DUP on outcomes indicates that shortening DUP may have positive effects on the long-term clinical course. However, it is unlikely that early intervention alone could significantly improve the overall long-term outcome of schizophrenia. Early detection of psychosis is one of the possibilities to achieve the improvement, especially in the short-term outcome of schizophrenia. / Tiivistelmä Hoitamattoman psykoosin kestoa ja sen yhteyttä skitsofrenian taudinkulkuun on tutkittu laajasti, mutta johtopäätökset asiasta ovat jääneet olennaisilta osilta epävarmoiksi. Aihetta koskevia valikoitumattomien aineistojen pitkittäisseurantoja on olemassa vain vähän. Tämän osajulkaisuväitöskirjan tavoitteena oli tutkia hoitamattoman psykoosin keston ja skitsofrenian taudinkulun pitkäaikaista yhteyttä meta-analyysin sekä Pohjois-Suomen vuoden 1966 syntymäkohorttiaineiston avulla. Meta-analyysi hoitamattoman psykoosin keston ja kliinisen ja sosiaalisen ennusteen välillä osoitti, että pidentynyt hoitamattomuus on tilastollisesti merkitsevästi yhteydessä vakavampiin oireisiin ja huonompaan sosiaaliseen toimintakykyyn sekä kokonaisennusteeseen pitkäaikaisseurannoissa. Merkitsevää yhteyttä ei ollut hoitamattoman psykoosin keston ja sairaalahoitojen määrän, työllistymisen tai elämänlaadun välillä. Pohjois-Suomen vuoden 1966 syntymäkohortissa tutkittiin hoitamattoman psykoosin yhteyttä taudinkulkuun ja ennusteeseen (n=89) ja aivojen rakenteeseen (n=46). Kahden ensimmäisen vuoden seurannassa pitkä hoitamattomuus oli yhteydessä pidempään ensimmäiseen sairaalahoitoon ja uuden sairaalahoidon kohonneeseen riskiin. Pitkäaikaisseurannassa pidentynyt hoitamattomuus oli merkitsevästi yhteydessä vähäisempään työkyvyttömyyseläkkeellä olemiseen. Kun aivojen rakennetta tutkittiin magneettikuvantamisen (MRI) avulla, löytyi yhteys pidentyneen hoitamattomuuden ja harmaan aineen pienemmän tiheyden välillä oikean hippokampuksen alueella. Hoitamattoman psykoosin keston tilastollisesti merkitsevä yhteys taudin eri ennusteisiin viittaa siihen, että psykoosin varhaisella tunnistamisella voi olla myönteisiä vaikutuksia. Muut mahdollisuudet parantaa skitsofrenian pitkäaikaisennustetta lienevät keskeisiä ja voivat tehostaa varhaisen tunnistamisen vaikutuksia.

This thesis is divided into three main parts. In the first, we discuss that, although permutation tests can provide exact control of false positives under the reasonable assumption of exchangeability, there are common examples in which global exchangeability does not hold, such as in experiments with repeated measurements or tests in which subjects are related to each other. To allow permutation inference in such cases, we propose an extension of the well known concept of exchangeability blocks, allowing these to be nested in a hierarchical, multi-level definition. This definition allows permutations that retain the original joint distribution unaltered, thus preserving exchangeability. The null hypothesis is tested using only a subset of all otherwise possible permutations. We do not need to explicitly model the degree of dependence between observations; rather the use of such permutation scheme leaves any dependence intact. The strategy is compatible with heteroscedasticity and can be used with permutations, sign flippings, or both combined. In the second part, we exploit properties of test statistics to obtain accelerations irrespective of generic software or hardware improvements. We compare six different approaches using synthetic and real data, assessing the methods in terms of their error rates, power, agreement with a reference result, and the risk of taking a different decision regarding the rejection of the null hypotheses (known as the resampling risk). In the third part, we investigate and compare the different methods for assessment of cortical volume and area from magnetic resonance images using surface-based methods. Using data from young adults born with very low birth weight and coetaneous controls, we show that instead of volume, the permutation-based non-parametric combination (NPC) of thickness and area is a more sensitive option for studying joint effects on these two quantities, giving equal weight to variation in both, and allowing a better characterisation of biological processes that can affect brain morphology.

Introdução: O transtorno bipolar (TB) é um problema crônico, de evolução cíclica, altamente prevalente na população geral e está associado a importante incapacitação dos pacientes e a déficits cognitivos e funcionais, constituindo, assim, um importante problema de saúde pública. A etiologia do TB parece ser multifatorial, resultante da interação entre fatores genéticos e ambientais; estudos apontam que a predisposição para manifestação de episódios pode advir da exposição a maus-tratos na infância (MTI), que comprometem o desenvolvimento emocional, cerebral e cognitivo das crianças e estão presentes em 30% a 60% dos portadores de TB. No TB, os MTI vem sendo associados com idade de início mais precoce, pior evolução clínica, maior incidência de comorbidades, apesar da literatura ser escassa e não conclusiva, tem sido associado também a alterações do funcionamento cognitivo e da morfologia cerebral. Objetivo: Investigar se o perfil cognitivo e a morfometria cerebral de portadores de TBI eutímicos diferencia-se com a exposição ou não a maus-tratos sofridos na infância. Método: 75 portadores de TBI eutímicos, com idades entre 18 e 45 anos, atendidos no ambulatório do Programa de Transtornos Afetivos (GRUDA) IPq-HC-FMUSP, sendo 32 sem história de MTI e 43 com história de MTI, de acordo com o ponto de corte do Childhood Trauma Questionnaire (CTQ) e 46 voluntários sadios do ponto de vista físico e mental, com idades entre 18 e 45 anos, sem história de MTI de acordo com o CTQ e sem parentes de primeiro grau com transtornos psiquiátricos foram submetidos a uma bateria de testes neuropsicológicos que avaliou as funções atencionais, mnêmicas, executivas e cognição social e a um estudo de imagem por ressonância magnética. Resultados: Os resultados apontaram para uma diferença de desempenho cognitivo entre os grupos em uma das medidas de flexibilidade mental (p=0,04), em uma de raciocínio matricial (p=0,035) e na capacidade de reconhecimento de emoções faciais de tristeza (REF, p=0,022). Em relação à morfometria cerebral, pôde-se observar que o volume do Núcleo Caudado apresentou diferença estatisticamente significativa entre os três grupos, tanto no hemisfério direito (p=0,002) como no esquerdo (0,008). No hemisfério esquerdo, a área do Órbito Frontal Medial (p=0,0466), a área do Pré-cuneo (p=0,0193) e a área do Parietal Superior (p=0,0063) apresentaram diferenças estatisticamente significativas. No hemisfério direito, a área do Órbito Frontal Medial (p=0,0200), a área do Pré-cuneo (p=0,0337), a área do Parietal Superior (p=0,0007), a espessura da Parte Triangular do Córtex Frontal (p=0,0013), a espessura do Pré-central (p=0,0307) e a espessura do Frontal Superior (p=0,0425) apresentaram diferenças estatisticamente significativas. Por fim, a partir de uma análise exploratória, pôde-se observar que no grupo de portadores de TB com MTI os resultados apontam para possíveis associações entre regiões cerebrais e desempenhos cognitivos, sendo elas: volume do Hipocampo Direito e o TMT-B (pinteração= 0,002, r = -0,40, pr=0,013), área do Giro Superior Frontal Direito e o SCWT-I (pinteração= 0,0008, r = -0,36, pr=0,0185), área do Órbito Frontal Medial Esquerdo e o FCR-cópia (pinteração= 0,004, r = 0,49, pr=0,014), espessura do Órbito Frontal Medial Direito e COWAT-total (pinteração= 0,004, r = 0,46, pr=0,003), espessura do Frontal Medial Rostral Esquerdo e WCST-erros (pinteração= 0,007, r = -0,42, pr=0,007). Conclusões: Apesar da limitação do tamanho amostral e do número de comparações estatísticas realizadas, este é o primeiro estudo a avaliar a associação entre MTI, funcionamento cognitivo e morfometria cerebral. Os resultados foram sugestivos de que a magnitude das correlações entre as características morfométricas e cognitivas podem ser moduladas pela exposição a MTI e pelo status de caso (portador de TB) / Introduction: Bipolar disorder (BD) is a chronic, cyclically-evolving problem that is highly prevalent in the general population and is associated with significant disability of the patients and cognitive and functional deficits, thus constituting an important public health problem. The etiology of BD seems to be multifactorial, resulting from the interaction between genetic and environmental factors, and studies show that the predisposition to the manifestation of episodes of BD may result from exposure to childhood maltreatment (CM), which compromises the emotional, cerebral and cognitive development and seems to be present in between 30 and 60% of BD patients. In BD, CM have been associated with earlier onset age, worse clinical course, higher incidence of comorbidities and, although the literature is scarce and not conclusive, it has also been associated with changes in cognitive function and brain morphology. Objective: To investigate whether the cognitive profile and the brain morphometry of patients with euthymic BD differ between those exposed or non-exposed to CM. Method: 75 euthymic BD patients, aged between 18 and 45 years, attended at the ambulatory of the Affective Disorders Program (GRUDA) IPq-HC-FMUSP, 32 of which had no history of CM and 43 with a positive history of CM according to the cut-off of the Childhood Trauma Questionnaire (CTQ) and 46 physically and mentally healthy volunteers, aged 18-45 years, with no history of CM according to the CTQ and no first-degree relatives with psychiatric disorders were submitted to a battery of neuropsychological tests that evaluated attentional, mnemonic, executive, and social cognition functions and a study of magnetic resonance imaging. Results: The results point to a difference in cognitive performance between groups in one of the measures of mental flexibility (p = 0.04), in one of matrix reasoning (p = 0.035) and in the ability to recognize facial emotions of sadness FER, p = 0.022). Regarding cerebral morphometry, it can be observed that the volume of the Caudate Nucleus showed a statistically significant difference between the three groups, both in the right hemisphere (p = 0.002) and in the left hemisphere (0.008). In the left hemisphere, the area of Medial Orbital Frontal (p = 0.0466), the area of Precuneus (p = 0.0193) and the area of Superior Parietal (p = 0.0063) presented statistically significant differences. In the right temisphere, the area of Medial Orbital Frontal (p = 0.0200), the area of Precuneus (p = 0.0337), the area of Superior Parietal (p = 0.0007), the thickness of Pars Triangularis (p = 0.0013), the thickness of Precentral (p = 0.0307) and the thickness of Superior Frontal (p = 0.0425) presented statistically significant differences. Finally, from this exploratory analysis, it is possible to observe that in the group of BD with CM the results point to possible associations between brain regions and cognitive performance, specifically: Right Hippocampus Volume and TMT-B (pinteraction = 0,002, r = -0,40, pr=0,013), Right Superior Frontal Area and SCWT-I (pinteraction = 0.0008, r = -0.36, pr = 0.0185), Left Medial Orbital Frontal area and FCR-copy (pinteraction= 0,004, r = 0,49, pr=0,014), Right Medial Orbital Frontal Thickness and COWAT-total (pinteraction = 0.004, r = 0.46, pr= 0.003), Left Rostral Medial Frontal Thickness and WCST-errors (pinteraction = 0.007, r = -0.42, pr = 0.007). Conclusions: Despite the limitation of the sample size and the number of statistical comparisons performed, this is the first study to evaluate the association between CM, cognitive functioning and brain morphometry. The results are suggestive of the magnitude of the correlations between the characteristics morphometric and cognitive variables can be modulated by exposure to CM and by case status (BD patients)

No description available.