Functional and structural connectivity in patients with focal epilepsy

Orientadores: Fernando Cendes, Ana Carolina CoanTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: 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 dadosAbstract: 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 proceduresDoutoradoFisiopatologia MédicaDoutor em Ciência

Does side of onset influence the pattern of cerebral atrophy in Parkinson's disease?

Imaging studies have revealed widespread neurodegeneration in Parkinson's disease (PD), but only a few considered the issue of asymmetrical clinical presentations. To investigate if the side of onset influences the pattern of gray matter (GM) atrophy in PD. Sixty patients (57.87 +/- 10.27 years) diagnosed with idiopathic PD according to the U.K. Brain Bank criteria, 26 with right-sided disease onset (RDO) and 34 with left-sided disease onset (LDO), were compared to 80 healthy controls (HC) (57.1 +/- 9.47 years). We acquired T1-weighted images on a 3 T scanner. Images were processed and analyzed with VBM8 (SPM8/Dartel) on Matlab R2012b platform. Statistic assessments included a two-sample test (family-wise error p < 0.05) with extent threshold of 20 voxels. Compared to HC, LDO patients had GM atrophy in the insula, putamen, anterior cingulate, frontotemporal cortex, and right caudate, while the RDO group showed atrophy at the anterior cingulate, insula, frontotemporal, and occipital cortex. This study revealed widespread GM atrophy in PD, predominantly in the left hemisphere, regardless of the side of onset. Future investigations should also consider handedness and side of onset to better characterize cerebral involvement and its progression in PD7CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP74873/2010-22012/05286-

Cognitive Reserve Relates to Functional Network Efficiency in Alzheimer’s Disease

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

Análise de atividade epileptiforme com uso simultâneo de eletrencefalografia e ressonância magnética funcional

The use of multimodal neuroimaging techniques has been helpful in the investigation of epileptogenic zone in patients with refractory epilepsies. This work aims to describe an ictal event during EEG-fMRI performed simultaneously in a 39-year-old man with refractory epilepsy. The EEG data were recorded at a sampling rate of 5 kHz, using a BrainAmp (BrainProducts, München, Germany) amplifier, with 64 MR (magnetic resonance) compatible Ag/AgCl electrodes. MR images were acquired using a 3T scanner in 3 sequences of 6 minutes of echo-planar images (EPIs), with TR = 2s, being the last sequence stopped after the ictal event. The EEG was corrected for gradient and pulse artifacts using the Brain Vision Analyzer2 software (BrainProducts), and the functional images were realigned, slice-timing corrected, normalized and smoothed. The start of the ictal changes was used for the evaluation of the BOLD response in MR images, using a t-test with a minimum cluster of 5 voxels, p 2.5). The patient had a partial complex seizure, as noted by neurologist. The fMRI data showed positive BOLD responses (activation) in dysplastic areas, but showed the most significant activation outside the lesion, in areas compatible with secondary spread of the epileptic focus, probably caused by motor reaction also observed during the seizure. As a conclusion, we note that the technique of EEG-fMRI can detect the epileptogenic zone in patients with refractory epilepsy, but areas of dissemination of primary epileptogenic focus may show significant activation, introducing additional difficulties to the interpretation of the resultsO uso de técnicas de neuroimagem multimodais tem auxiliado na investigação da zona epileptogênica em pacientes com epilepsias refratárias. Este trabalho visa descrever o registro de um evento ictal durante EEG-fMRI realizados simultaneamente em paciente já diagnosticado com epilepsia, um homem de 39 anos com epilepsia refratária. O EEG foi adquirido a uma taxa de sampleamento de 5kHz, utilizando o amplificador BrainAmp (BrainProducts, München, Alemanha) com 64 eletrodos Ag/AgCl compatíveis com Ressonância Magnética (RM). Aquisição foi feita concomitantemente a exame de RM realizado em aparelho de 3T, com 3 sequências de 6 minutos de imagens eco-planares (EPIs) com TR=2s, sendo a última sequência interrompida após a constatação de um evento epiléptico. O EEG foi corrigido para artefatos de gradiente e de batimento cardíaco através do programa Vision Analyzer2 (BrainProducts), e as imagens de fMRI foram realinhadas, corrigidas devido ao tempo de aquisição de cada fatia, normalizadas e suavizadas. O instante de início das alterações ictais no traçado foi utilizado para avaliação da resposta BOLD nas imagens de RM, com uso de “teste t” com limite inferior de 5 voxels, p2,5. O paciente apresentou crise parcial complexa, conforme observado por neurologista. A técnica fMRI revelou resposta BOLD positiva (ativação) em áreas com lesão displásica já conhecida do paciente, porém evidenciou resposta de ativação mais significativa em áreas sem lesão, compatíveis com áreas de propagação secundária do foco epiléptico, provavelmente causada por reação motora também observada no momento de crise. Como conclusão observa-se que técnica de EEG-fMRI pode detectar zona epileptogênica em pacientes com epilepsia refratária, porém áreas de difusão do foco epileptogênico primário podem apresentar ativação significativa, introduzindo dificuldades adicionais na interpretação dos resultado

Analisys of the hemodynamic responses in patients with temporal lobe epilepsy by using simultaneous acquisitions of electroencephalography and functional magnetic resonance imaging

Orientador: Fernando CendesDissertação (Mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Introdução: A técnica multimodal de eletroencefalografia (EEG) acoplada à ressonância magnética (RM) funcional (RMf) apresenta características físicas complementares. Este método permite não só avaliar atividades neurais fisiológicas, mas também a dinâmica de neuropatologias como a epilepsia. Dentro do grupo das epilepsias, as epilepsias de lobo temporal (ELT) são particularmente importantes pela sua elevada prevalência e morbidade. Objetivo: Investigar e comparar os padrões de alterações hemodinâmicas associados a descargas epilépticas interictais (DEIs) em pacientes com ELT com (ELT-EH) ou sem (ELT-NL) sinais de esclerose hipocampal em exames de RM, através do uso combinado das técnicas de EEG e RMf (EEG-RMf). Métodos: Foram submetidos a exames de EEG-RMf, 25 pacientes com diagnóstico de ELT, sendo 12 ELT-NL e 13 ELT-EH. As imagens de RM foram adquiridas em aparelho de 3T e o EEG amostrado com 64 eletrodos compatíveis com RM. O tempo das DEIs foi utilizado para avaliar as respostas BOLD positivas (BOLDpos) e negativas (BOLDneg). Foram realizadas análises de EEG-RMf individuais e para grupos, além de análise estrutural, com o software SPM8-VBM8. As análises funcionais foram realizadas com pico da função resposta hemodinâmicas (FRH) em 0 segundo (precoce) e 5 segundos (tardio) após as DEIs. Resultados: Os mapas BOLDpos no grupo ELT-EH mostraram alterações hemodinâmicas precoces no lobo temporal ipsilateral, ínsula e giro precentral contralateral, e tardia no putâmem ipsilateral, cíngulo anterior bilateral, ínsula e lobos temporais. No grupo ELT-NL, BOLDpos precoce difuso foi observado, com alterações mais significativas no giro medial frontais ipsilateral, enquanto BOLDpos tardio foi observado na ínsula ipsilateral e giro temporal superior. Em ambos os grupos a análise estrutural mostrou redução significativa de substância cinzenta em áreas que se estendem além do lobo temporal, porém sem sobreposição significativa com áreas de BOLDpos. Em ambos os grupos de pacientes, BOLDneg foi observado em áreas compatíveis com default mode network (DMN). Interpretação: As redes funcionais relacionadas às DEIs diferem entre ELT-EH e ELT-NL. As regiões com atrofia mais significativa de substância cinzenta não coincidem com estas redes funcionais. Há possível supressão da atividade em áreas da DMN relacionadas com as DEIs em pacientes com ELT com ou sem sinais de EHAbstract: Introduction: The multimodal technique of electroencephalography (EEG) coupled to functional magnetic resonance imaging (fMRI) presents additional physical characteristics. This method allows not only evaluating physiological neural activities, but also the dynamics of neuropathologies as epilepsy. Within the group of epilepsy, temporal lobe epilepsy (TLE) is particularly important due to its high prevalence and morbidity. Objective: To investigate and compare the patterns of hemodynamic changes associated with interictal epileptiform discharges (IEDs) in patients with TLE with (TLE-HS) or without (TLE-NL) signs of hippocampal sclerosis in MRI, through the combined use of EEG and fMRI techniques (EEG-fMRI). Methods: Twenty five patients diagnosed with TLE underwent EEG-fMRI scans, 12 with TLE-NL and 13 TLE-HS. MR images were acquired on a 3T scanner and EEG recorded with 64 electrodes compatible with MRI. The time for IED was used to assess the BOLD positive (BOLDpos) and negative (BOLDneg) responses. Analysis of EEG-fMRI MRI structural analyses were performed with SPM8-VBM8 software. The functional analyses were performed with the peak of the hemodynamic response function (HRF) in 0 second (early) and 5 seconds (late) after IED. Results: The BOLDpos maps in TLE-HS group showed early hemodynamic changes in ipsilateral temporal lobe, contralateral insula and precentral gyrus and late hemodynamic changes in ipsilateral putamen, bilateral anterior cingulate, insula and temporal lobes. In TLE-NL, diffuse early BOLDpos was observed, with the most significant changes in the ipsilateral medial frontal gyrus, while late BOLDpos was observed in the ipsilateral insula and superior temporal gyrus. In both groups the structural analysis showed significant reduction of gray matter in areas that extend beyond the temporal lobe, but with no significant overlap with areas of BOLDpos. In both groups of patients BOLDneg was observed in areas consistent with default mode network (DMN). Interpretation: The functional networks related to the IED differ in TLE-HS and TLE-NL. The regions with the most significant gray matter atrophy do not coincide with these functional networks. There is possible suppression of activity in the DMN areas related to IED in TLE patients with or without signs of HSMestradoFisiopatologia MédicaMestre em Ciência

Amygdala Enlargement in Patients with Mesial Temporal Lobe Epilepsy without Hippocampal Sclerosis

Purpose: Patients with mesial temporal lobe epilepsy (MTLE) without MRI abnormalities (MTLE-NL) represent a challenge for definition of underlying pathology and for presurgical evaluation. In a recent study we observed significant amygdala enlargement in 14% of MTLE patients with MRI signs of HS. Areas of gray matter volume (GMV) increase could represent structural abnormalities related to the epileptogenic zone or part of a developmental abnormality. Our objective was to look for undetected areas of increased GMV in MTLE-NL using post processing MRI techniques to better understand the pathophysiology of this condition.Methods: We evaluated 66 patients with MTLE-NL on visual analysis and 82 controls. Voxel-based morphometry (VBM) group analysis was performed with VBM8/SPM8 looking for areas of increased GMV. We then performed automatic amygdala volumetry using Freesurfer software and T2 relaxometry to confirm VBM findings.Results: VBM group-analysis demonstrated increased amygdala volume in the MTLE-NL group compared to controls. Individual volumetric analysis confirmed amygdala enlargement (AE) in eight (12%) patients. Overall, from all patients with AE and defined epileptic focus, four (57%) had the predominant increased volume ipsilateral to the epileptic focus. These results were cross-validated by a secondary VBM analysis including subgroups of patients according to the volumetric data. T2 relaxometry demonstrated no amygdala hyperintense signal in any individual with significant amygdala enlargement. There were no clinical differences between patients with and without AE.Discussion: This exploratory study demonstrates the occurrence of AE in 12% of patients with MTLE-NL. This finding supports the hypothesis that there might be a subgroup of patients with MTLE-NL in which the enlarged amygdala could be related to the epileptogenic process. Further studies are necessary but this finding could be of great importance in the understanding of MTLE-NL

Large-scale brain networks are distinctly affected in right and left mesial temporal lobe epilepsy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Mesial temporal lobe epilepsy ( MTLE) with hippocampus sclerosis ( HS) is associated with functional and structural alterations extending beyond the temporal regions and abnormal pattern of brain resting state networks ( RSNs) connectivity. We hypothesized that the interaction of large-scale RSNs is differently affected in patients with right-and left-MTLE with HS compared to controls. We aimed to determine and characterize these alterations through the analysis of 12 RSNs, functionally parceled in 70 regions of interest ( ROIs), from resting-state functional-MRIs of 99 subjects ( 52 controls, 26 right-and 21 left-MTLE patients with HS). Image preprocessing and statistical analysis were performed using UF 2 C-toolbox, which provided ROI-wise results for intranetwork and internetwork connectivity. Intranetwork abnormalities were observed in the dorsal default mode network ( DMN) in both groups of patients and in the posterior salience network in right-MTLE. Both groups showed abnormal correlation between the dorsal-DMN and the posterior salience, as well as between the dorsal-DMN and the executive-control network. Patients with left-MTLE also showed reduced correlation between the dorsal-DMN and visuospatial network and increased correlation between bilateral thalamus and the posterior salience network. The ipsilateral hippocampus stood out as a central area of abnormalities. Alterations on left-MTLE expressed a low cluster coefficient, whereas the altered connections on right-MTLE showed low cluster coefficient in the DMN but high in the posterior salience regions. Both right-and left-MTLE patients with HS have widespread abnormal interactions of largescale brain networks; however, all parameters evaluated indicate that left-MTLE has a more intricate bihemispheric dysfunction compared to right-MTLE. (C) 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.Mesial temporal lobe epilepsy ( MTLE) with hippocampus sclerosis ( HS) is associated with functional and structural alterations extending beyond the temporal regions and abnormal pattern of brain resting state networks ( RSNs) connectivity. We hypothesize37931373152FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)2013/00099-7; 2013/07559-3; 2014/15918-6Mesial temporal lobe epilepsy ( MTLE) with hippocampus sclerosis ( HS) is associated with functional and structural alterations extending beyond the temporal regions and abnormal pattern of brain resting state networks ( RSNs) connectivity. We hypothesiz

Structural Connectivity Of The Default Mode Network And Cognition In Alzheimer׳s Disease.

Disconnectivity between the Default Mode Network (DMN) nodes can cause clinical symptoms and cognitive deficits in Alzheimer׳s disease (AD). We aimed to examine the structural connectivity between DMN nodes, to verify the extent in which white matter disconnection affects cognitive performance. MRI data of 76 subjects (25 mild AD, 21 amnestic Mild Cognitive Impairment subjects and 30 controls) were acquired on a 3.0T scanner. ExploreDTI software (fractional Anisotropy threshold=0.25 and the angular threshold=60°) calculated axial, radial, and mean diffusivities, fractional anisotropy and streamline count. AD patients showed lower fractional anisotropy (P=0.01) and streamline count (P=0.029), and higher radial diffusivity (P=0.014) than controls in the cingulum. After correction for white matter atrophy, only fractional anisotropy and radial diffusivity remained significantly lower in AD compared to controls (P=0.003 and P=0.05). In the parahippocampal bundle, AD patients had lower mean and radial diffusivities (P=0.048 and P=0.013) compared to controls, from which only radial diffusivity survived for white matter adjustment (P=0.05). Regression models revealed that cognitive performance is also accounted for by white matter microstructural values. Structural connectivity within the DMN is important to the execution of high-complexity tasks, probably due to its relevant role in the integration of the network.22315-2

Depression and anxiety symptoms are associated to disruption of default mode network in subacute ischemic stroke

Depression and anxiety symptoms are common after stroke and associated to reduction in quality of life and poor physical and social outcomes. The Default Mode Network (DMN) plays an important role in the emotional processing. We investigated whether these symptoms are associated to a disruption of DMN functional connectivity in the first month after stroke. Thirty-four subacute ischemic stroke patients were submitted to: 1) behavioral assessment through Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Structured Clinical Interview for DSM Disorders; 2) neuropsychological assessment using Mini Mental State Examination and Montreal Cognitive Assessment; 3) resting state functional magnetic resonance imaging acquisition using a 3 T scanner (Philips Achieva). Patients with depression and/or anxiety symptoms showed an increased DMN functional connectivity in left inferior parietal gyrus and left basal nuclei, when compared to stroke controls. Specific correlation between BDI/BAI scores and DMN functional connectivity indicated that depression symptoms are correlated with increased functional connectivity in left inferior parietal gyrus, while anxiety symptoms are correlated with increased functional connectivity in cerebellum, brainstem and right middle frontal gyrus. Our study provides new insights into the underlying mechanisms of post stroke depression and anxiety, suggesting an alternate explanation other than regional structural damage following ischemic event, that these psychiatric symptoms are related to brain network dysfunction11615711580FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2013/07559-3; 2013/23183-3; 2015/06163-