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Agradecimentos: We would like to thank Coordination for the Improvement of Higher Education Personnel (CAPES—Brazil—Financing Code 001) and Sáo Paulo Research Foundation (FAPESP—Brazil—Processes 2013-07559-3 and 2017-25795-7) for financial support Abstract: Over the last decade, several methods for analysis of epileptiform signals in electroencephalography (EEG) have been proposed. These methods mainly use EEG signal features in either the time or the frequency domain to separate regular, interictal, and ictal brain activity. The aim of this work was to evaluate the feasibility of using functional connectivity (FC) based feature extraction methods for the analysis of epileptiform discharges in EEG signals. These signals were obtained from EEG-fMRI sessions of 10 patients with mesial temporal lobe epilepsy (MTLE) with unilateral hippocampal atrophy. The connectivity functions investigated were motif synchronization, imaginary coherence, and magnitude squared coherence in the alpha, beta, and gamma bands of the EEG. EEG signals were sectioned into 1-s epochs and classified according to (using neurologist markers): activity far from interictal epileptiform discharges (IED), activity immediately before an IED and, finally, mid-IED activity. Connectivity matrices for each epoch for each FC function were built, and graph theory was used to obtain the following metrics: strength, cluster coefficient, betweenness centrality, eigenvector centrality (both local and global), and global efficiency. The statistical distributions of these metrics were compared among the three classes, using ANOVA, for each FC function. We found significant differences in all global (p < 0.001) and local (p < 0.00002) graph metrics of the far class compared with before and mid for motif synchronization on the beta band; local betweenness centrality also pointed to a degree of lateralization on the frontotemporal structures. This analysis demonstrates the potential of FC measures, computed using motif synchronization, for the characterization of epileptiform activity of MTLE patients. This methodology may be helpful in the analysis of EEG-fMRI data applied to epileptic foci localization. Nonetheless, the methods must be tested with a larger sample and with other epileptic phenotypes COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP Aberto

Agradecimentos: We thank ER, GF, and LS for technical assistance. This work was supported by funding provided by the Fundação de Amparo a Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, grants from the Trust in Science Initiative from Glaxo-Smithkline, UK, and the National Institutes of Health (DK089036, DK098466; EAS). The Laboratories of Cell Signaling and Experimental Endocrinology belong to the Obesity and Comorbidities Research Center and the National Institute of Science and Technology—Diabetes and Obesity Abstract: Background/Objectives Hypothalamic neurons play a major role in the control of body mass. Obese subjects present radiologic signs of gliosis in the hypothalamus, which may reflect the damage or loss of neurons involved in whole-body energy homeostasis. It is currently unknown if hypothalamic gliosis (1) differs between obese nondiabetic (ND) and obese diabetic subjects (T2D) or (2) is modified by extensive body mass reduction via Roux-n-Y gastric bypass (RYGB). Subjects/Methods Fifty-five subjects (all female) including lean controls (CT; n = 13), ND (n = 28), and T2D (n = 14) completed at least one study visit. Subjects underwent anthropometrics and a multi-echo MRI sequence to measure mean bilateral T2 relaxation time in the mediobasal hypothalamus (MBH) and two reference regions (amygdala and putamen). The obese groups underwent RYGB and were re-evaluated 9 months later. Analyses were by linear mixed models. Results Analyses of T2 relaxation time at baseline showed a group by region interaction only in the MBH (P < 0.0001). T2D had longer T2 relaxation times compared to either CT or ND groups. To examine the effects of RYGB on hypothalamic gliosis a three-way (group by region by time) mixed effects model adjusted for age was executed. Group by region (P < 0.0001) and region by time (P = 0.0005) interactions were significant. There was a reduction in MBH relaxation time by RYGB, and, although the T2D group still had higher T2 relaxation time overall compared to the ND group, the T2D group had significantly lower T2 relaxation time after surgery and the ND group showed a trend. The degree of reduction in MBH T2 relaxation time by RYGB was unrelated to clinical outcomes. Conclusion T2 relaxation times, a marker of hypothalamic gliosis, are higher in obese women with T2D and are reduced by RYGB-induced weight loss FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ Fechado

Functional and structural changes in the brain have been associated with regular aerobic exercise and expertise in several sports. A variety of neuroimaging techniques have revealed changes in brain activation with increased exercise intensity; however, how expertise modulates neural activation is still unclear for some sports, like cycling. Using an adapted cycling MRI ergometer, we compared the neural patterns of cycling experts and non-cyclists during cycling periods of different intensities. 22 participants were divided into two groups: 12 healthy adults who performed physical activity 4-6 h/week and 10 trained cyclists (>2 yrs of training and competitive experience, cycling 4-6 days/week for ˜60 min). The participants performed an incremental test on an adapted cycling MRI ergometer while whole-brain activity was recorded with functional MRI. Using a one-sample t-test (p11.1), while the cerebellum and insular cortex were activated only in cyclists (ts>6.83). In addition, both groups had inhibition of prefrontal cortical areas (ts>7.44) during cycling, but the non-cyclists had larger areas of the prefrontal cortex inhibited (ts>7.52). ycling expertise impacts the modulation of subcortical and prefrontal brain areas during cycling. We believe that these findings suggest that regular practice of cycling may enhance the neural regulation of cognitive, motor and homeostatic resources during exercise at different intensities, which may explain the higher performance of cycling athletes Fechado

Ratings of perceived exertion (RPE) during exercise is processed in the brain, however, the modulation of the associated areas at different intensities levels remains unclear. To verified the brain modulation while RPE processing immediately after cycling exercise performed at different intensities. 24 healthy adults (77.6±9.4 kg; 176±7.2 cm; 25.9±5.9 years old) performed an incremental load test on an adapted cycling ergometer attached to a MRI scanner. The workload started at 25 W and increased 25W after every four blocks of 30 s of cycling and 30 s rest. At the end of each block, participants had four seconds to report their RPE based on the 6-20 Borg scale presented on a screen. The RPE processing periods for RPE responses from 6 to 12 were labeled as LOW intensity while those from 13 to 18 were considered as HIGH intensity. To identify the common areas associated to RPE processing, the one sample t-test was used for each condition (all RPE, LOW and HIGH intensities). The statistical threshold established was family-wise error corrected (FWE

Agradecimentos: The study was supported by Fundacão de Amparo à Pesquisa do Estado de São Paulo (FAPESP; São Paulo Research Foundation), grants #2015/06163-4, #2013/07559-3 and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, National Council for Scientific and Technological Development) #304442/2015-1. We thank the GraphVar group for all the help with statistical analyses Abstract: Alzheimer's disease (AD) is the most common form of dementia, with no means of cure or prevention. The presence of abnormal disease-related proteins in the population is, in turn, much more common than the incidence of dementia. In this context, the cognitive reserve (CR) hypothesis has been proposed to explain the discontinuity between pathophysiological and clinical expression of AD, suggesting that CR mitigates the effects of pathology on clinical expression and cognition. fMRI studies of the human connectome have recently reported that AD patients present diminished functional efficiency in resting-state networks, leading to a loss in information flow and cognitive processing. No study has investigated, however, whether CR modifies the effects of the pathology in functional network efficiency in AD patients. We analyzed the relationship between CR, pathophysiology and network efficiency, and whether CR modifies the relationship between them. Fourteen mild AD, 28 amnestic mild cognitive impairment (aMCI) due to AD, and 28 controls were enrolled. We used education to measure CR, cerebrospinal fluid (CSF) biomarkers to evaluate pathophysiology, and graph metrics to measure network efficiency. We found no relationship between CR and CSF biomarkers; CR was related to higher network efficiency in all groups; and abnormal levels of CSF protein biomarkers were related to more efficient networks in the AD group. Education modified the effects of tau-related pathology in the aMCI and mild AD groups. Although higher CR might not protect individuals from developing AD pathophysiology, AD patients with higher CR are better able to cope with the effects of pathology-presenting more efficient networks despite pathology burden. The present study highlights that interventions focusing on cognitive stimulation might be useful to slow age-related cognitive decline or dementia and lengthen healthy aging FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ Aberto

O uso de carboidrato (CHO) como suplemento nutricional está relacionado com melhor rendimento esportivo. Alguns estudos observaram relação entre consumo e ativação cerebral que influenciam o rendimento. Assim, o objetivo desse estudo foi avaliar a influência do consumo de CHO na ativação de determinadas áreas cerebrais durante exercício físico, realizado juntamente à aquisição de ressonância magnética funcional (RMf). Dez homens ciclistas (32,1 ± 4,1 anos, peso 76,8 ± 14,6 kg) realizaram um protocolo de exercício de pedalada, com alta intensidade (Escala de Borg), em cicloergômetro acoplado à ressonância magnética (RM) e, ingeriram 50g de CHO ou de placebo no intervalo de duas séries de exercício. A ingestão de CHO apresentou influência nas áreas cerebrais durante o exercício, ativando áreas relacionadas à tomada de decisões (insula) e motivação (sistema límbico) e desativando principalmente áreas motoras (lobo frontal) e de introspecção (precuneos). Com o consumo de placebo, também houve ativação de áreas importantes relacionadas à motivação do individuo (cíngulo posterior). Além disso, as áreas relacionadas com a iniciação e manutenção de movimento, localizadas no lobo frontal e cerebelo, apresentaram-se ativas. Com o CHO, áreas importantes para a manutenção do exercício foram ativadas (BOLD positivo), mostrando que a suplementação pode ter influência na ativação cerebral durante o exercício de forma que melhore o rendimento esportivo., Motricidade, Vol 12 No 1 (2016)

Resumo: O uso de carboidrato (CHO) como suplemento nutricional está relacionado com melhor rendimento esportivo. Alguns estudos observaram relação entre consumo e ativação cerebral que influenciam o rendimento. Assim, o objetivo desse estudo foi avaliar a influência do consumo de CHO na ativação de determinadas áreas cerebrais durante exercício físico, realizado juntamente à aquisição de ressonância magnética funcional (RMf). Dez homens ciclistas (32,1 ± 4,1 anos, peso 76,8 ± 14,6 kg) realizaram um protocolo de exercício de pedalada, com alta intensidade (Escala de Borg), em cicloergômetro acoplado à ressonância magnética (RM) e, ingeriram 50g de CHO ou de placebo no intervalo de duas séries de exercício. A ingestão de CHO apresentou influência nas áreas cerebrais durante o exercício, ativando áreas relacionadas à tomada de decisões (insula) e motivação (sistema límbico) e desativando principalmente áreas motoras (lobo frontal) e de introspecção (precuneos). Com o consumo de placebo, também houve ativação de áreas importantes relacionadas à motivação do individuo (cíngulo posterior). Além disso, as áreas relacionadas com a iniciação e manutenção de movimento, localizadas no lobo frontal e cerebelo, apresentaram-se ativas. Com o CHO, áreas importantes para a manutenção do exercício foram ativadas (BOLD positivo), mostrando que a suplementação pode ter influência na ativação cerebral durante o exercício de forma que melhore o rendimento esportivo Abstract: The use of carbohydrate (CH) as a nutritional supplement is related to better sports performance. Some studies have noted a relationship between consumption and brain activation influencing the performance. The objective of this study was to evaluate the influence of CH consumption in the activation of certain brain areas during exercise, performed simultaneously the acquisition of functional magnetic resonance imaging (fMRI). Ten men cyclists (32.1 ± 4.1 years, weight 76.8 ± 14.6 kg) performed a pedaling exercise protocol, with high intensity (Borg Scale), on a cycleergometer coupled to magnetic resonance (MR) and ingested 50g CH or placebo in the range of two sets of exercise. The CH ingestion showed influence on brain areas during exercise, activating areas related to decision-making (insula) and motivation (limbic system) and mainly disabling motor areas (frontal lobe) and introspection (precuneus). With the use of placebo, there was also activation of important areas in the motivation of the individual (posterior cingulate). In addition, areas associated with the initiation and maintenance of movement, located on the front lobe and cerebellum, was active. With the use of CH, areas important for maintenance of the exercise have been activated showing that supplementation can influence the brain activation during exercise to improve the sport performance Fechado

Orientadores: Fernando Cendes, Ana Carolina Coan Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: Introdução: Estudos recentes demonstram que as epilepsias são doenças relacionadas a alterações de redes neuronais. Técnicas de neuroimagem funcional e de difusão aliadas a avançados métodos de pós-processamento computacional permitem avaliações de conectividade funcional e estrutural do cérebro fornecendo informações sobre os padrões organizacionais das redes associadas. Este estudo visa avaliar a conectividade estrutural e funcional em pacientes com epilepsias focais, caracterizando as alterações de pacientes com epilepsia de lobo temporal mesial (ELTM) associada à esclerose hipocampal (EH) e comparando com outras epilepsias focais. Métodos: Instrumentações de software foram desenvolvidas para as análises realizadas: 1- de conectividade estrutural e 2- de conectividade funcional. Para avaliação da conectividade estrutural, foram selecionados três grupos de pacientes (ELTM-EH, ELT-não lesional [NL] e epilepsia de lobo frontal associada a displasia cortical focal [ELF-DCF]) e um grupo controle. Metodologia de tractografia semiautomática avaliou a anisotropia fracionada (FA), difusividade radial (RD) e axial (AD) de quatro fascículos: 1-uncinado; 2-fórnix; 3-fronto-occiptal inferior; 4-cíngulo. As análises de conectividade funcional foram realizadas comparando pacientes de ELTM-EH com lateralização à direita (D-ELTM) e à esquerda (E-ELTM) e um grupo controle. Setenta regiões de interesse representando 12 redes funcionais foram usadas para análise de criação das matrizes de adjacência. O segundo nível foi realizado comparando pacientes e controles. Resultados: Análise macroestrutural de substancia branca (SB) mostrou alterações (principalmente ipsilaterais) para ELTM-EH e ELF-DCF. A análise microstrutural mostrou alterações em parâmetros de difusão para os mesmos grupos. Os pacientes ELT-NL não apresentaram alterações em nenhuma das análises de integridade estrutural. Comparados ao grupo controle, os grupos D-ELTM e E-ELTM apresentaram alterações de conectividade funcional. Das 12 redes, apenas auditory e visual não apresentaram alterações em ambos os grupos. Para D-ELTM, a anterior salience e a sensorimotor também foram preservadas. Pacientes de E-ELTM apresentaram alterações mais difusas, afetando os dois hemisférios de forma mais evidente. Discussão e conclusão: Pacientes com epilepsias focais apresentam alterações de conectividade funcional e estrutural. Pacientes com ELTM-EH apresentaram piores resultados de alterações estruturais e vasta rede de alterações quando comparados a frontais ou não lesionais. Adicionalmente, apresentam complexa rede de alterações funcionais. Pacientes com E-ELTM apresentaram pior padrão de alterações funcionais comparados aos com D-ELTM. O desenvolvimento de toolboxes para as modalidades metodológicas propostas possibilitaram padronização e melhor eficiência da análise dos dados Abstract: Introduction: Recent studies has shown that epilepsies are diseases related to neuro networks alterations. Functional and diffusion neuroimaging techniques explored by advanced computational methodologies, allows the functional and structural brain connectivity evaluation providing information regarding the brain networks behavior. This project aim to evaluate the functional and the structural connectivity in patients with temporal lobe epilepsy comparing its alteration patterns with other focal epilepsies. Methods: We developed software resources to perform the analysis: 1- Structural connectivity and 2- functional connectivity. For structural evaluations, three groups of patients were included (mesial temporal lobe epilepsy [MTLE] associated to hipocampal sclerosis [HS], non-lesional temporal lobe epilepsy [TLE-NL] and frontal lobe epilepsy associated to focal cortical dysplasia [FLE-FCD]) and a control group. We performed a semi-automatic tractography procedure to evaluate the fractional anisotropy (FA), the radial diffusivity (RD) and the axial diffusivity (AD) of four anatomic relevant fasciculi: uncinate, body of fornix, inferior fronto-occipital and body of cingulum. We performed functional connectivity analysis comparing patients with left and right MTLE-HS and controls. We used 70 regions of interest (ROIs) from 12 functional networks to compute the connectivity adjacency matrices and performed a second level analysis to compare patients and controls groups. Results: The macrostructural white matter (WM) analysis showed alterations (manly ipsilateral) on MTLE-HS and FLE-FCD. The microstructural WM analysis presented alterations on diffusion parameters for the same groups. Patients with TLE-NL showed no changes for both structural analysis. Compared to the control group, the R-MTLE and L-MTLE groups showed functional connectivity alterations. From the 12 studied networks, only the auditory and the visual networks were preserved on both groups. For the R-MTLE patients, the anterior salience and the sensorimotor networks were also not affected. Patients with L-MTLE showed more diffuse alterations, more evidently affecting both hemispheres. Discussion and conclusion: The study and the proposal methodology were effective for the identifications and characterization of functional and structural connectivity alterations in patients with focal epilepsies. The MTLE-HS showed worse widespread structural alterations compared to the FLE and TLE-NL. Additionally, they presented complex and widespread functional networks abnormalities. Patients with L-MTLE demonstrated worse and more bilaterally affected pattern of alterations when compared to R-MTLE. The development of toolboxes to perform the proposal methodology enabled the standardization and high data analysis efficiency, throughout clear procedures Doutorado Fisiopatologia Médica Doutor em Ciências

Agradecimentos: This work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. Funding was also received from the Central and East London NIHR CLRN. ACC and BMC were supported by São Paulo Research Foundation (FAPESP), grants 2009/54552–9 and 2011/03477–7, respectively. SV is supported by Swiss National Science Foundation grants SNSF 141165 and 140332 (SPUM Epilepsy). The authors thank Rachel C Thornton and Catherine A Scott for their help in collecting some of the data Abstract: Objective Drug-resistant temporal lobe epilepsy (TLE) often requires thorough investigation to define the epileptogenic zone for surgical treatment. We used simultaneous interictal scalp EEG-fMRI to evaluate its value for predicting long-term postsurgical outcome. Methods 30 patients undergoing presurgical evaluation and proceeding to temporal lobe (TL) resection were studied. Interictal epileptiform discharges (IEDs) were identified on intra-MRI EEG and used to build a model of haemodynamic changes. In addition, topographic electroencephalographic correlation maps were calculated between the average IED during videoEEG and intra-MRI EEG, and used as a condition. This allowed the analysis of all data irrespective of the presence of IED on intra-MRI EEG. Mean follow-up after surgery was 46 months. International League Against Epilepsy (ILAE) outcomes 1 and 2 were considered good, and 3-6 poor, surgical outcome. Haemodynamic maps were classified according to the presence (Concordant) or absence (Discordant) of Blood Oxygen Level-Dependent (BOLD) change in the TL overlapping with the surgical resection. Results The proportion of patients with good surgical outcome was significantly higher (13/16, 81%) in the Concordant than in the Discordant group (3/14, 21%) (chi(2) test, Yates correction, p=0.003) and multivariate analysis showed that Concordant BOLD maps were independently related to good surgical outcome (p=0.007). Sensitivity and specificity of EEG-fMRI results to identify patients with good surgical outcome were 81% and 79%, respectively, and positive and negative predictive values were 81% and 79%, respectively. Interpretation The presence of significant BOLD changes in the area of resection on interictal EEG-fMRI in patients with TLE retrospectively confirmed the epileptogenic zone. Surgical resection including regions of haemodynamic changes in the TL may lead to better postoperative outcome FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP Fechado

Mild cognitive impairment (aMCI) is a clinical condition, with high risk to develop Alzheimer’s disease. Physical exercise may have positive effect on cognition and brain structure in older adults. However, it is still under research whether these influences are true on aMCI subjects with low Ab_42 and high total tau in cerebrospinal fluid (CSF), which is considered a biomarker for AD. Therefore, we aimed to investigate a possible relation between aerobic fitness (AF) and gray matter (GM) volume and AF and white matter (WM) integrity in aMCI with a CSF biomarker. Twenty-two participants with aMCI acquired the images on a 3.0-T MRI. AF was assessed by a graded exercise test on a treadmill. Voxel-based morphometry and tract-based spatial statistic methods were used to analyze the GM volume and WM microstructural integrity, respectively. We correlated AF and GM volume and WM integrity in aMCI (p < 0.05, FWE corrected, cluster with at least five voxels). There was a positive relation between AF and GM volume mostly in frontal superior cortex. In WM integrity, AF was positively correlated with fractional anisotropy and negatively correlated with mean diffusivity and radial diffusivity, all in the same tracts that interconnect frontal, temporal, parietal, and occipital areas (longitudinal fasciculus, fronto-occipital fasciculus, and corpus callosum). These results suggest that aerobic fitness may have a positive influence on protection of brain even in aMCI CSF biomarker, a high-risk population to convert to AD Fechado

Objective To evaluate white matter (WM) integrity of distinct groups of patients with antiepileptic drug (AED)-resistant localization-related epilepsies. Methods We used diffusion tensor imaging (DTI) fiber-tractography and voxel-based morphometry (VBM) to investigate differences of WM micro- and macrostructural integrity in patients with different drug-resistant localization-related epilepsies: 17 with temporal lobe epilepsy with magnetic resonance imaging (MRI) signs of hippocampal sclerosis (TLE-HS), 17 with TLE and normal MRI (TLE-NL), 14 with frontal lobe epilepsy and subtle MRI signs of focal cortical dysplasia (FLE-FCD), and 112 healthy controls. We performed fiber-tractography using a semiautomatic deterministic method to yield average fractional anisotropy (FA), axial (AD), and radial (RD) diffusivity ipsilateral and contralateral to the epileptogenic zone of the following tracts based on their functional and anatomic relevance: body of fornix (BoF), body of cingulum (BoC), inferior frontal occipital (IFO), and uncinate fasciculi (UF). In addition, we performed VBM of the WM maps to assess macrostructural integrity differences among groups. Results TLE-HS had ipsilateral and contralateral decreased FA and increased RD for all tracts. VBM showed WM alterations mainly in the ipsilateral parahippocampal region and contralateral superior temporal gyrus. FLE-FCD showed bilateral FA decreases only in the BoC and ipsilateral RD increases also in the BoC. VBM showed WM reduction mainly in the ipsilateral precuneus and posterior and anterior cingulum. No significant WM alterations were found in the TLE-NL in DTI or VBM analysis. Significance WM abnormalities differ in distinct AED-resistant localization-related epilepsies. The diverse distribution of the WM damage in these patients suggests that the localization of the epileptic networks may play a role in the WM burden. However, the distinct degree of this damage, more accentuated in TLE-HS, also suggests that the underlying cause of the epilepsy is probably an additional factor to explain this WM damage FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP Aberto

Orientador: Leticia Rittner Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação Resumo: A espectroscopia por ressonância magnética (MRS), apesar de ser uma técnica recente, vem sendo bastante utilizada para estudar alterações metabólicas em tumores cerebrais e outras doenças do cérebro em geral. Porém ainda não existem métodos que explorem bem as informações contidas na região da imagem de ressonância magnética de onde o conjunto de espectros foi adquirido. Conhecer essas informações é importante, pois permite que a quantificação dos metabólitos seja mais precisa. O presente trabalho tem como objetivo apresentar um método capaz de analisar a região da imagem de ressonância magnética de onde foi coletado o conjunto de espectros, identificando os tipos de tecidos: substância branca (WM - White matter), substância cinzenta (GM - Gray matter) e fluido cerebroespinal (CSF - Cerebrospinal fluid) e/ou estrutura cerebral (hipocampo, corpo caloso, etc.), nela contidos e, posteriormente, possibilitar a seleção de um subconjunto de espectros de interesse. Essa abordagem torna possível analisar melhor os dados adquiridos através da técnica de MRSI, agrupando espectros provenientes de regiões semelhantes, como tecidos (GM, WM e CSF) ou estruturas (estruturas cerebrais, tumores ou lesões). A partir deste agrupamento é possível criar subconjuntos de espectros de interesse e realizar a quantificação dos metabólitos em cada um dos espectros isoladamente ou todos os espectros do subconjunto Abstract: Magnetic Resonance Spectroscopy (MRS) although a recent technique, has been widely used to study metabolic changes in brain tumors and other diseases of the brain in general. Currently there are no good methods that exploit the information contained in the region of the magnetic resonance image, from where the set of spectra was acquired. This information is important to allow a more accurate quantification of metabolites. This study aims to present a method to analyze the region of the magnetic resonance image from where the set of spectra was collected, identifying the types of tissue (white matter, gray matter and cerebrospinal fluid) and/or brain structure (hippocampus, corpus callosum, etc.) contained, and consequently allowing the selection of a set of the spectra of interest. This approach makes it possible to better analyze the data acquired through the MRSI, grouping spectra from similar regions, such as tissues (GM, WM and CSF) or structures (brain structures, tumors or lesions). From this grouping it is possible to create subsets of spectra of interest and execute the quantification of the metabolites in each spectrum alone or in all the spectra of the subset Mestrado Engenharia de Computação Mestre em Engenharia Elétrica FAPESP

Orientador: Wu Shin-Ting Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação Resumo: A ressonância magnética ponderada em difusão (DWI) é uma modalidade de imageamento que mensura a difusão de fluidos. Aplicada ao cérebro, o DWI é único no que diz respeito à quantificação deste fenômeno na água em tecido vivo. Na substância branca do cérebro, a difusão de água tem a mesma direção preferencial das fibras do cérebro, o que possibilita a inferência da sua arquitetura in-vivo e de forma não-invasiva. Para este fim, há métodos de imageamento que modelam este fenômeno, sendo o imageamento por tensor de difusão (Diffusion Tensor Imaging, DTI) o mais conhecido e difundido clinicamente. Os sinais de difusão são mapeados em um tensor de segunda ordem e a partir de métricas derivadas, como informações referentes à direção preferencial de difusão, possibilitam a inferência da arquitetura da substância branca e tornam viável estudos e diagnósticos baseados na conectividade do cérebro. No entanto, o modelo utilizado no DTI falha na resolução do comportamento da difusão em regiões de substância branca onde há duas ou mais populações de fibras localizadas no mesmo voxel. Face a este problema, grupos de pesquisa passaram a propor tensores de ordem superior a 2 para modelar a difusão com o objetivo de superar o problema do DTI e possibilitar a estimativa da arquitetura da substância branca de forma mais precisa. Este trabalho tem como objetivo a integração de um tensor de alta ordem em um ambiente de visualização multimodal interativo e a proposição de um novo algoritmo para visualização da difusão intravóxel em glifos. Apresentamos uma introdução aos tensores de alta ordem e detalhamos a implementação computacional do método Amostragem Generalizada no Espaço-Q (Generalized Q-Space Imaging, GQI) para processamento de tensores de alta ordem, mais especificamente dos dados do imageamento de difusão de alta resolução angular (High Angular Resolution Diffusion Imaging, HARDI). A fim de proporcionar uma visão tridimensional dos dados pós-processados, desenvolvemos um algoritmo interativo acelerado por GPU que mapeia os tensores de alta ordem em glifos. Integramos o algoritmo num ambiente de visualização multimodal para validação. Os resultados demonstraram que os glifos propiciam a inferência da trajetória de fibras subjacentes e avaliação dos dados gerados, que é fundamental para pesquisa na área Abstract: Diffusion-weighted magnetic resonance (DWI) is an imaging modality that measures fluid diffusion. Applied to the brain, DWI is unique in quantifying this phenomenon in water in living tissue. In the white matter of the brain, the diffusion has the preferential direction of its fibers, which allows the inference of their architecture in-vivo and noninvasively. Imaging methods were proposed to model this phenomenon, and the diffusion tensor imaging (DTI) is the most well-known and clinically disseminated. The diffusion signals are mapped to a second-order tensor. From the tensor metrics, such as information regarding the preferred direction of diffusion, it is possible to infer the white matter architecture and make studies and diagnoses viable. However, the model used in DTI cannot resolve regions of white matter where there are two or more fiber populations in the same voxel. Facing this problem, research groups have proposed higher-order tensors to model a diffusion to improve the white matter architecture inference. This work aims to integrate a high-order tensor in an interactive multimodal visualization environment and a novel rendering algorithm to the visualization of intravoxel diffusion in glyphs. We present an introduction to high-order tensors and detail the computational implementation of the Generalized Q-Sampling Imaging for processing higher-order tensors from High Angular Resolution Diffusion Imaging (HARDI) data. We developed an interactive GPU-accelerated algorithm that maps high-order tensors data into glyphs to provide a three-dimensional view of the post-processed data. The results demonstrate that the glyphs allow inferring the underlying fiber trajectory and evaluating the generated data, which are of great use for research in the area Mestrado Engenharia de Computação Mestre em Engenharia Elétrica CNPQ 132790/2019-0

Orientador: Leticia Rittner Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação Resumo: O corpo caloso (CC) é a principal comissura interhemisférica do cérebro e, devido às suas fibras altamente organizadas, é frequentemente estudado em imagens de tensores de difusão (diffusion tensor images, ou DTI). DTI, uma modalidade de ressonância magnética, é um método não invasivo para mapear a difusão de água nos tecidos, o que o torna útil para mapear fibras, permitindo a quantificação de tratos in vivo. Os estudos do CC em DTI geralmente dependem de sua segmentação - determinação das bordas da estrutura - e parcelamento - divisão da estrutura em diferentes partes, de acordo com as regiões corticais com as quais estão interligadas. No entanto, essas tarefas apresentam dificuldades que podem prejudicar a qualidade da pesquisa. As imagens de difusão geralmente apresentam baixa resolução espacial, baixa relação sinal-ruído e contraste, e imagens adquiridas em diferentes scanners também podem apresentar variabilidade de intensidade. Embora alguns métodos de segmentação e de parcelamento do CC em imagens de difusão tenham sido propostos, poucos são completamente automáticos e a maioria não tem implementação disponível. Considerando este contexto, o presente trabalho propõe uma ferramenta de código aberto, portável e interativa para análise do corpo caloso em DTI individualmente ou em grupos, implementando diferentes técnicas disponíveis para segmentação e parcelamento e propondo métricas relevantes para comparação e avaliação da qualidade desses procedimentos em uma aplicação web. Também propõe diferentes tipos de visualizações interativas das informações extraídas do DTI, para permitir a exploração e visualização destes dados. A ferramenta desenvolvida é uma aplicação web open-source, portável e pode ser usada nos principais sistemas operacionais – Linux, além de Windows e Mac usando Docker –, disponível em . Este trabalho apresenta também um estudo de caso aplicando a ferramenta a um estudo sobre Lupus Eritomastoso Sistêmico a partir de DTI, onde são discutidos os impactos da ferramenta proposta nas conclusões do estudo Abstract: The corpus callosum (CC) is the main interhemispheric commissure and, due to its highly organized fibers, is frequently studied in diffusion tensor images. Diffusion tensor imaging (DTI), a type of magnetic ressonance imaging, is a non-invasive method for mapping the diffusion of water in tissues, which makes it useful for mapping tracts, allowing in-vivo tract quantification. Studies of the CC using DTI usually depend on its segmentation – determination of the CC borders – and parcellation – division of the structure in different parts, according with the cortical regions with which they are interconnected, but these tasks present difficulties that can jeopardise research quality. Diffusion images usually present low resolution, definition and contrast, and images acquired in different scanners might also present intensity variability. Although several diffusion CC segmentation and parcellation methods have been proposed, few are automatic and most have no implementation available. Considering this context, the present work proposes an open-source, portable, tool for analysis of the corpus callosum in diffusion tensor images individually or in groups, implementing different techniques available for segmentation and parcellation and proposing relevant metrics for comparison and quality evaluation of these procedures in a graphical interface. It also proposes different types of interactive visualizations of extracted information from the DTI, to allow data exploration. The developed tool is an open-source, web-based application, portable and can be used in the most used operating systems - Linux, in addition to Windows and Mac using Docker -, available at . This work also presents a case study applying the tool to a study on Systemic Lupus Erythemastous from DTI, where the impacts of the proposed tool on the study conclusions are discussed Mestrado Engenharia de Computação Mestra em Engenharia Elétrica CAPES 313598/2020-7

Orientador: Enrico Ghizoni, Andrei Fernandes Joaquim Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: Introdução: Neoplasias neuroepiteliais de baixo grau associadas à epilepsia (LEATs ¿ "low-grade epilepsy-associated neuro-epithelial tumors") representam um amplo grupo de neoplasias gliais e/ou glioneuronais associado à epilepsia crônica, de início precoce, e frequentemente fármaco-resistente. Apesar desse grupo de neoplasias geralmente apresentar comportamento biológico benigno e indolente, com reduzido risco de transformação maligna, ele está associado às consequências relacionadas à epilepsia e suas complicações como comprometimento cognitivo e morte súbita associada à epilepsia ("sudden unexpected death in epilepsy" ¿ SUDEP). O manejo desse grupo particular de tumores deve contemplar aspectos oncológicos e o controle da epilepsia. A cirurgia é o principal tratamento de pacientes portadores de LEATs. O propósito desse estudo foi descrever nossa experiência no tratamento desses tumores, as abordagens cirúrgicas empregadas, resultados histopatológicos e controle das crises epilépticas. Métodos: Realizamos um estudo retrospectivo observacional envolvendo a análise de registros médicos de pacientes apresentando neoplasias gliais e/ou glioneuronais e uma história prévia de epilepsia associada, que foram submetidos a tratamento cirúrgico em nossos serviços entre os anos de 2002 e 2017. Todos os pacientes incluídos apresentavam avaliação pré e pós-operatória completas incluindo exames eletroencefalográficos e ressonância magnética nuclear. O estudo enfatizou dados epidemiológicos, abordagens cirúrgicas, achados histopatológicos e controle das crises epilépticas segundo a classificação de Engel. Foi empregada a análise estatística descritiva dos dados obtidos, análise univariada e análise multivariada segundo modelos de regressão de Cox e regressão logística. O estudo foi aprovado pelos Comitês de Ética das instituições participantes. Resultados: Foram incluídos 56 pacientes, a idade média do primeiro episódio epiléptico foi de 9,83 anos (variação de 0,5 a 5; 9,24DP); o intervalo médio entre a primeira crise epiléptica e a cirurgia foi de 7,11 anos (variação de 0,03 a 48 anos; 9,58DP), a idade média dos pacientes no momento da cirurgia foi de 16,8 anos (variação de 1 a 63; 13,2DP). Acometimento de lobo temporal esteve presente em 73% dos casos. A lesionectomia foi a abordagem cirúrgica de escolha para os tumores extra temporais; lesionectomia ou lobectomia temporal anterior incluindo as estruturas mesiais temporais foram as abordagens selecionadas para os tumores com envolvimento temporal. Gangliogliomas (29 casos; 51,7%) e DNETs (8 casos; 14,2%) foram os achados histopatológicos mais frequentes. Quatro pacientes (7,1%) apresentaram displasia cortical focal tipo IIIb associada. Após um ano do procedimento cirúrgico 48 pacientes (85,7%) encontravam-se livres de crises incapacitantes (Engel I); 43 desses (76,7%) encontravam-se completamente livres de crises (Engel Ia). Onze pacientes (19,6%) foram reoperados devidos à recidiva tumoral ou controle insatisfatório de crises. Tivemos três óbitos relacionados à progressão para formas anaplásicas. Não tivemos complicações maiores ou óbitos relacionados às cirurgias. Ao final do estudo 42 pacientes (75%) continuavam completamente livre de crises (Engel Ia). Conclusão: Nossos resultados evidenciam que a cirurgia é uma modalidade de tratamento segura, efetiva e potencialmente curativa para os pacientes com neoplasias gliais e/ou glioneuronais associadas à epilepsia. A lobectomia anterior incluindo estruturas mesiais mostrou-se superior à lesionectomia nos tumores temporais Abstract: Introduction: Low-grade epilepsy-associated neuro-epithelial tumors (LEATs) describes a wide group of glial and glioneuronal tumors associated with early-onset, chronic and often pharmaco-resistant focal epilepsy. Despite of LEATs often present benign and indolent biological behavior, a reduced risk of malignant transformation, they are associated with all conditions related to epilepsy and its complications including cognitive impairment and sudden unexpected death in epilepsy (SUDEP). The management of this specific group of tumors should address the oncological aspects and the epilepsy control. Surgery is the main treatment of patients presenting LEATs. The purpose of this study was to describe our experience treating these tumors, the surgical approaches, pathological findings and outcomes. Methods: The authors performed a retrospective observational review of medical reports of patients presenting glial and/or glioneuronal tumors and a previous history of associated epilepsy who underwent to surgical treatment in our services between 2002 and 2017. All patients had a complete pre- and postoperative evaluation including electroencephalography (EEG) and MRI investigation. The study focused on epidemiology, surgical approach, histological findings and outcomes according to Engel classification. We employed descriptive statistics, univariate analysis and multivariate Cox proportional hazards regression and logistic regression models. The present study was approved by the Ethical Committee of our institution. Results: Fifty-six patients were included, average age of first seizure episode was 9,83 years (range, 0,5 ¿ 55, SD 9,24); the average interval between first seizure episode and surgery was 7,11 years (range, 0,03 ¿ 48, SD 9,58), the average age of the patients at time of surgery was 16,8 years (range, 1 ¿ 63, SD 13,2). Temporal involvement was present in seventy-three percent of cases. Lesionectomy was the chosen approach for extra-temporal lesions; lesionectomy or anterior temporal lobectomy including medial temporal region resection for temporal ones. Gangliogliomas (51,7%) and DNETs (14,2%) were the most often pathologic findings. Four patients (7,1%) also presented focal cortical dysplasia type IIIb associated. One year after the surgery forty-eight patients (85,7%) were free of disabling seizures (Engel I); forty-three of them (76,7%) were completely free of seizures (Engel Ia). Eleven patients (19,6%) had a second surgery because of tumoral recurrence or because of disabling seizures recurrence. There were three deaths related to grade progression. We had no deaths or major complications related to surgical procedures. At the end of the study forty-two patients (75%) continued completely free of seizures (Engel Ia). Conclusion: Our results confirm that surgical treatment is safe, effective and potentially a curative modality of treatment for patients harboring LEATs. The anterior lobectomy including mesial structures were superior to lesionectomy in temporal tumors Mestrado Neurologia Mestre em Ciências CAPES 001

Orientador: Marcondes Cavalcante França Junior Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: Introdução: As neuronopatias sensitivas (NS) constituem um subgrupo de doenças do sistema nervoso periférico cuja característica mais marcante é a degeneração primária dos gânglios da raiz dorsal, gerando déficits de sensibilidade em muitos pontos do corpo. Pelo mesmo motivo, observa-se a perda da coordenação plena dos movimentos, ainda que áreas cerebrais motoras permaneçam intactas. Além disso, a doença pode se antecipar aos sintomas da enfermidade subjacente (como o câncer de pulmão), e, portanto, o diagnóstico precoce das NSs é fundamental para guiar a conduta médica. Por ser um quadro de déficit quase exclusivamente sensorial, torna-se um modelo valioso no estudo da integração sensório-motora. Objetivos: Avaliar o padrão de alteração no cérebro e na medula espinal destes pacientes utilizando a técnica de MRI, almejando identificar novas ferramentas diagnósticas e entender os mecanismos envolvidos com a doença. Métodos: Foram adquiridas imagens estruturais (difusão, T1 e T2) e funcionais (T2*) de 36 pacientes com NS (52±11 anos; 17 mulheres) definida de acordo com critérios clínico-eletrofiosiológicos. Para avaliar os efeitos da deaferentação sensitiva sobre o cérebro, foram feitas análises estruturais estratificadas em substância cinzenta (VBM e volumetria baseada na segmentação "multi-atlas" - SMA) e substância branca (TBSS e análise de parâmetros baseados na SMA). Paralelamente, investigamos alterações no padrão de ativação motora utilizando um paradigma em bloco de finger-tapping. Para identificar um novo marcador diagnóstico, foi feita uma análise dos parâmetros de DTI no funículo posterior da medula espinal, comparando pacientes com NS, com polineuropatia sensitiva (PN) e controles. Resultados: Nos pacientes com NS crônica (duração ? 4 anos) identificamos aumento volumétrico simétrico dos núcleos caudados e redução de volume na porção posterior do bulbo. Em termos microestruturais, houve alterações em tratos que conectam tálamo e gânglios da base. Em relação às alterações funcionais, os resultados relacionados à tarefa motora apontaram uma diferença na ativação cerebral como consequência da falta de propriocepção, especificamente nas regiões parietais posteriores e nas áreas mediais do cerebelo. Os pacientes com NS tiveram redução significativa da anisotropia fracional média no funículo posterior da medula espinal comparado com controles e indivíduos com PN (p=0,027). Este parâmetro de imagem foi capaz de discriminar entre os grupos com uma sensibilidade de 86% e uma especificidade de 71% (área sob a curva = 0.838) Discussão e conclusão: A análise do DTI de medula cervical parece ser uma ferramenta poderosa para auxiliar o diagnóstico das NSs, e poderia ser adicionada ao conjunto de investigações realizadas nos pacientes. Os achados estruturais reforçam a hipótese de uma plasticidade neuronal nos núcleos da base do cérebro cronicamente deaferentado, ressaltado pela hipertrofia do núcleo caudado. Além disso, alterações de substância branca vizinhas ao caudado e ao tálamo parecem corroborar a hipótese de dano na circuitaria que envolve os núcleos da base. Estas informações nos induziram a sugerir que uma via recentemente identificada entre o tálamo e o estriado tivesse papel inibitório, dentro de um esquema de integração sensório-motor Abstract: Introduction: Sensory neuronopathies (NS) constitute a subgroup of diseases of the peripheral nervous system, whose most striking feature is the primary degeneration of the dorsal root ganglia, yielding sensory deficits in many points of the body. For the same reason, there is loss of full coordination of movements, even though motor brain areas remain intact. In addition, the disease can anticipate symptoms of the underlying cause (such as lung cancer), and therefore early diagnosis of SNs is critical. Since it is an almost exclusively sensory disease, it is also a valuable model in the study of sensorimotor integration. Objectives: To evaluate the pattern of alteration in the brain and spinal cord of these patients using the MRI technique, in order to identify new diagnostic tools and understand the mechanisms involved with the disease. Methods: Structural (T1-weighted and T2-weighted) and functional (T2-weighted) images of 36 NS patients (52±11 years old; 17 women) defined according to clinical and electrophysiological criteria were acquired. To evaluate the effects of sensory deafferentation in the brain, stratified structural analyzes on gray matter (VBM and volumetry based on "multi-atlas" segmentation - SMA) and white matter (TBSS and SMA-based parameter analysis) were performed. In parallel, we investigated changes in motor activation pattern using a finger-tapping paradigm. To identify a new diagnostic marker, we performed an analysis of the DTI parameters in the posterior funiculus of the spinal cord, comparing SN patients with sensory polyneuropathy patients (PN) and controls. Results: In patients with chronic SNs (duration ? 4 years), we identified symmetrical volumetric increase of the caudate nuclei and volumetric reduction in the posterior portion of the medulla. In the microstructural domain, there were alterations in tracts that connect the thalamus and basal ganglia. Regarding functional alterations, task-related results pointed to a difference in cerebral activation as a consequence of lack of proprioceptive input, specifically in the posterior parietal regions and in medial areas of the cerebellum. SN patients had a significant reduction of mean fractional anisotropy in the posterior funiculi compared to controls and PN patients (p = 0.027). This image parameter was able to discriminate the groups with a sensitivity of 86% and a specificity of 71% (area under the curve = 0.838) Discussion and Conclusion: DTI analysis of the spinal cord seems to be a powerful tool to aid in the diagnosis of SNs, and could be part of the diagnostic work up. Structural findings reinforce the hypothesis that neuronal plasticity takes place in the basal nuclei of the chronically deafferented brain, highlighted by caudate hypertrophy. In addition, white matter alterations surrounding the caudate and thalami favor the hypothesis of damage to circuitries involving the basal nuclei. These findings led us to suggest that a recently identified pathway between the thalamus and the striatum may have an inhibitory role within a sensorimotor integration scheme Doutorado Fisiopatologia Médica Doutor em Ciências FAPESP 2014/15918-6 CAPES