O processo de envelhecimento é acompanhado por um declínio nas funções cognitivas, principalmente, de funções fluidas ou de processamento. Essas diminuições são pelo menos, em parte, devido a alterações estruturais e funcionais do sistema nervoso central. Uma abordagem para estudar as mudanças funcionais é a medição da utilização metabólica regional da glicose, ou, alternativamente, um parâmetro físico correlacionado ao metabolismo cerebral e à atividade funcional local, como o fluxo sanguíneo cerebral (CBF). Neste contexto, em Imagens por Ressonância Magnética (IRM), a técnica de Marcação dos Spins Arteriais (ASL) surge como uma importante ferramenta não invasiva para análises perfusionais. Seu uso não só permite avaliar a perfusão sanguínea cerebral, gerando mapas quantitativos de CBF, mas também fornecer uma alternativa para estudar a conectividade funcional (FC), um parâmetro importante para descrição da topologia e funcionalidade cerebral. Sessenta e três indivíduos saudáveis, na faixa etária entre dezoito à setenta e dois anos, foram recrutados para participar deste estudo. Análises estatísticas mostram uma diminuição de CBF em várias regiões cerebrais, especialmente nos lobos frontal e temporal, que acompanham o processo de envelhecimento. As medidas de FC foram obtidas em análises por regiões de interesse e teoria de grafos; estas também demostraram uma diminuição, com o avanço da idade, em regiões presentes nos lobos frontal e temporal, mas também relataram um maior número de regiões prejudicadas no lobo parietal. Portanto, usando uma técnica de imagem não invasiva, foi possível observar déficits de CBF além de alterações de aspectos da organização funcional, oferecendo valores quantitativos que podem ajudar na melhor descrição dos efeitos do envelhecimento na hemodinâmica cerebral. / Aging process is accompanied by a decline in cognitive functions foremost comprise fluid or processing-based functions. These decreases are at least partly due to structural and functional deteriorating changes of the central nervous system. One approach to study these functional changes is the measurement of the regional metabolic utilization of glucose, or, alternatively, a physical quantity correlated to cerebral metabolism and local functional activity, such as the cerebral blood flow (CBF). In this context, Arterial spin labeling (ASL) emerges as a noninvasive Magnetic Resonance Imaging (MRI) perfusion technique. Its use not only allows assessing cerebral perfusion, by generating CBF values, but also can provide an alternative to study functional connectivity (FC), which is an important parameter that describes the brain topology and functionality. Sixty-three healthy subjects, from age eighteen to seventy-two years, were recruited to participate in this study. ASL-CBF maps showed a decrease in several brain regions, especially in frontal and temporal lobes that follows aging process. FC measures were assessed with regions of interest (ROI-to-ROI) and graph theory analysis, also showing a decrease in regions present in frontal and temporal lobes, and also more impaired regions in the parietal lobe. Therefore, using a noninvasive imaging technique it was possible to observe CBF deficits besides alteration in aspects on functional organization, offering quantitative values that can help to describe better the aging effects on cerebral hemodynamics.

Esta tese apresenta um novo método para analisar dados de ressonância magnética funcional (FMRI) durante o estado de repouso denominado Análise de Componentes Esparsos Locais (LSCA). A LSCA é uma especialização da Análise de Componentes Esparsos (SCA) que leva em consideração a informação espacial dos dados para reconstruir a informação temporal de fontes bem localizadas, ou seja, fontes que representam a atividade de regiões corticais conectadas. Este estudo contém dados de simulação e dados reais. Os dados simulados foram preparados para avaliar a LSCA em diferentes cenários. Em um primeiro cenário, a LSCA é comparada com a Análise de Componentes Principais (PCA) em relação a capacidade de detectar fontes locais sob ruído branco e gaussiano. Em seguida, a LSCA é comparada com o algoritmo de Maximização da Expectativa (EM) no quesito detecção de fontes dinâmicas locais. Os dados reais foram coletados para fins comparativos e ilustrativos. Imagens de FMRI de onze voluntários sadios foram adquiridas utilizando um equipamento de ressonância magnética de 3T durante um protocolo de estado de repouso. As imagens foram pré-processadas e analisadas por dois métodos: a LSCA e a Análise de Componentes Independentes (ICA). Os componentes identificados pela LSCA foram comparados com componentes comumente reportados na literatura utilizando a ICA. Além da comparação direta com a ICA, a LSCA foi aplicada com o propósito único de caracterizar a dinâmica das redes de estado de repouso. Resultados simulados mostram que a LSCA é apropriada para identificar fontes esparsas locais. Em dados de FMRI no estado de repouso, a LSCA é capaz de identificar as mesmas fontes que são identificadas pela ICA, permitindo uma análise mais detalhada das relações entre regiões dentro de e entre componentes e sugerindo que muitos componentes identificados pela ICA em FMRI durante o estado de repouso representam um conjunto de componentes esparsos locais. Utilizando a LSCA, grande parte das fontes identificadas pela ICA podem ser decompostas em um conjunto de fontes esparsas locais que não são necessariamente independentes entre si. Além disso, as fontes identificadas pela LSCA aproximam muito melhor o sinal temporal observado nas regiões representadas por seus componentes do que as fontes identificadas pela ICA. Finalmente, uma análise mais elaborada utilizando a LSCA permite estimar também relações dinâmicas entre os componentes previamente identificados. Assim, a LSCA permite identificar relações clássicas bem como relações causais entre componentes do estado de repouso. As principais implicações desse resultado são que diferentes premissas permitem decomposições aproximadamente equivalentes, entretanto, critérios menos restritivos tais como esparsidade e localização permitem construir modelos mais compactos e biologicamente mais plausíveis. / This thesis presents Local Sparse Component Analysis (LSCA), a new method for analyzing resting state functional magnetic resonance imaging (fMRI) datasets. LSCA, a extension of Sparse Component Analysis (SCA), takes into account data spatial information to reconstruct temporal sources representing connected regions of significant activity. This study contains simulation data and real data. The simulated data were prepared to evaluate the LSCA in different scenarios. In the first scenario, the LSCA is compared with Principal Component Analysis (PCA) for detecting local sources under Gaussian white noise. Then, LSCA is compared with the expectation maximization algorithm (EM) for detecting the dynamics of local sources. Real data were collected for comparative and illustrative purposes. FMRI images from eleven healthy volunteers were acquired using a 3T MRI scanner during a resting state protocol. Images were preprocessed and analyzed using LSCA and Independent Components Analysis (ICA). LSCA components were compared with commonly reported ICA components. In addition, LSCA was applied for characterizing the dynamics of resting state networks. Simulated results have shown that LSCA is suitable for identifying local sparse sources.For real resting state FMRI data, LSCA is able to identify the same sources that are identified using ICA, allowing detailed functional connectivity analysis of the identified regions within and between components. This suggests that ICA resting state networks can be further decomposed into local sparse components that are not necessarily independent from each other. Moreover, LSCA sources better represent local FMRI signal oscillations than ISCA sources. Finally, brain connectivity analysis shows that LSCA can identify both instantaneous and causal relationships between resting state components. The main implication of this study is that independence and sparsity are equivalent assumptions in resting state FMRI. However, less restrictive criteria such as sparsity and source localization allow building much more compact and biologically plausible brain connectivity models.

Orientador: Roberto Jose Maria Covolan / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin / Made available in DSpace on 2018-08-11T17:50:31Z (GMT). No. of bitstreams: 1 Ozelo_HelkaFabbriBroggian_D.pdf: 3528702 bytes, checksum: 523c7cd6259312cc27664736508c3c69 (MD5) Previous issue date: 2008 / Resumo: Neste trabalho, uma técnica multimodal envolvendo eletroencefalografia (EEG) e imagens funcionais por Ressonância Magnética (fMRI) foi implementada a fim de realizar estudos sobre memória operacional em um grupo de indivíduos, incluindo controles e pacientes com epilepsia do lobo temporal mesial (ELTM) associada à atro½a hipocampal esquerda. Para isso, uma série de testes de memória foram implementados. Estes testes foram baseados em um paradigma em blocos dividido em períodos de codificação e retenção de memória, otimizados com relação ao tempo de duração para que se adequassem tanto à análise de EEG quanto para a análise de fMRI. O paradigma foi apresentado aos indivíduos no primeiro momento durante a aquisição de EEG e posteriormente durante a aquisição de fMRI. Os dados de EEG indicaram a presença de oscilações theta (4-8 Hz) na região do córtex frontal e oscilações alfa (9-12 Hz) na região do córtex parieto-occipital, em ambos os grupos durante todo o período de codi.cação. No entanto, durante a retenção só foi observada a presença do ritmo alfa nas regiões mais posteriores, envolvendo principalmente as áreas temporo-parietais. Diferentemente do que é encontrado na literatura, foram estabelecidas correlações entre esses ritmos e respostas BOLD tanto positivas quanto negativas, envolvendo diferentes regiões cerebrais. No entanto, estas áreas de ativação e de desativação não eram concorrentes, mas sim vizinhas ou contralaterais. Embora ambos os grupos, controles e pacientes, tenham apresentado um desempenho semelhante na realização dos testes, houve discrepâncias entre os dois grupos com relação às estruturas corticais envolvidas na tarefa. Durante a codi.cação, o grupo controle apresentou a predominância de áreas de ativação no hemisfério cerebral esquerdo, enquanto que no grupo de pacientes a ativação foi igualmente distribuída entre os dois hemisférios. Esse achado sugere o fenômeno de neuroplasticidade, no qual áreas corticais adicionais seriam recrutadas para compensar as estruturas afetadas pela atrofia / Abstract: In this work, a multimodal approach involving electroencefalography (EEG) and functional Magnetic Resonance Imaging (fMRI) was implemented in order to perform studies on working memory in a group of subjects including controls and patients with mesial temporal lobe epilepsy (MTLE) associated with left hippocampal atrophy. In order to do that, a series of memory tests were implemented. These tests were based on a block paradigm containing epochs of memory codification and memory retention, optimized with respect to the time to fit both analysis of EEG and fMRI. The paradigm was presented to subjects for the first time during EEG acquisition and later during fMRI acquisition. EEG data indicated the presence of theta oscillations (4-8 Hz) in the frontal region and alpha oscillations (9-12 Hz) in the parieto-occipital region, in both groups. In the retention period, it was only observed the presence of the alpha rhythm in the posterior region, involving mainly the temporo-parietal regions. Diÿerently from what is found in the literature, correlations were established among these rhythms and both, positive and negative BOLD responses, but in diÿerent regions. Activation and deactivation zones were detected for all epochs. The deactivation zones were found not only in the neighborhood of the activation regions, but frequently in the homologous regions. Although both groups, controls and patients, presented similar performance for the memory tests, there were discrepancies between these groups in terms of the cortical structures involved in the memory task. In the control group, it was found predominance of activation at the left hemisphere whereas for the patient group activation was predominantly lateralized to the right, probably due to damage in the mesial temporal lobe structures. Such a finding is suggestive of the neuroplasticity phenomenon by which additional cortical areas would be recruited to compensate the structures affected by atrophy / Doutorado / Física Médica / Doutor em Ciências

INTRODUÇÃO: O processamento emocional pelo cérebro humano tem sido atualmente investigado através do uso de ressônancia magnética funcional (RMf). A RMf possibilita o estudo in vivo e não invasivo de mudanças na atividade cerebral regional em voluntários humanos saudáveis. O processamento emocional pode ser modulado através do uso de antidepressivos que influenciam sistemas neurais relacionados ao processamento emocional, através da modulação da ação de neurotransmissores como a serotonina e a noradrenalina. A clomipramina, um antidepressivo tricíclico, tem sido relacionada com efeitos de resposta clínica mesmo em voluntários saudáveis. Estudos utilizando a RMf permitem a investigação do efeito de antidepressivos nos sistemas neurais envolvidos no processamento emocional em indivíduos saudáveis que apresentam resposta ao uso destes medicamentos comparados a sujeitos que não apresentam resposta ao tratamento. MÉTODOS: Nesta tese, dezoito voluntários saudáveis foram investigados em relação a mudanças de atividade neural em resposta à indução emocional através da apresentação de fotografias do International Affective Pictures System (IAPS). Foram estudadas particularmente as emoções de raiva, felicidade e medo. Os voluntários foram submetidos ao tratamento prolongado com doses baixas de clomipramina por quatro semanas. A amostra foi subdividida em respondedores (n=6) e não respondedores (n=12) ao tratamento com clomipramina. A atividade neural foi estimada com o uso da RMf, através da mensuração do efeito blood oxygenation level dependent (BOLD). As imagens foram processadas e analisadas usando o programa Statistical Parametric Mapping (SPM). Indivíduos não respondedores foram comparados sob o efeito e na ausência de efeito da clomipramina, através de comparações planejadas utilizando t-teste pareado. Indivíduos respondedores foram comparados com os não respondedores sob o efeito da clomipramina através de t-teste não pareado. RESULTADOS: Nos voluntários não respondedores à clomipramina, a comparação entre os estados medicado versus não medicado evidenciou menor atividade neural na região da amídala quando sob efeito da clomipramina em resposta a estímulos de valência negativa. Demonstramos ainda, em paradigmas de valência positiva e negativa, diminuição da atividade neural no giro do cíngulo anterior, na ínsula e no putâmen na vigência da medicação. Quando foram comparados os indivíduos respondedores com os não respondedores sob efeito de clomipramina, um aumento consistente de atividade cerebral foi observado nos voluntários respondedores na região da ínsula. CONCLUSÕES: O uso prolongado de doses baixas de clomipramina apresentou ação em regiões cerebrais envolvidas com o processamento emocional. Quando indivíduos não respondedores foram comparados sob o efeito e sem o efeito da clomipramina, foi observada menor atividade amidalar durante o tratamento em resposta a estímulos de valência negativa, possivelmente devido à menor demanda neural na avaliação inicial do estímulo de valência negativa. Também foi observada menor ativação no giro do cingulo anterior, na ínsula e no putâmen na vigência do uso da clomipramina, possivelmente em associação a uma diminuição do mapeamento cortical de funções interoceptivas em resposta a estímulos emocionais positivos e negativos. Quando indivíduos respondedores foram comparados com os não respondedores ao tratamento prolongado com doses baixas de clomipramina, foi observada maior ativação insular nos indivíduos respondedores quando estavam sob efeito de clomipramina; estes resultados indicam que possivelmente os indivíduos que respondem ao tratamento antidepressivo são os que percebem mais as alterações de seu estado corporal durante o processamento emocional. / INTRODUCTION: The emotional processing by the human brain has now been investigated through the use of functional magnetic resonance imaging (fMRI). The fMRI technique allows the noninvasive study of in vivo changes in regional brain activity in healthy human volunteers. The emotional processing may be modulated through the use of antidepressants that influence neural systems linked to emotional processing, by modulating the action of neurotransmitters such as serotonin and norepinephrine. Clomipramine, a tricyclic antidepressant, has been reported to elicit clinical response even in healthy volunteers. Studies using fMRI allow the investigation of the effect of antidepressants on neural systems involved in emotional processing in healthy subjects showing response to the use of antidepressant drugs compared to subjects who do not respond to treatment. METHODS: In this thesis, eighteen healthy volunteers were investigated in relation to changes in neural activity in response to emotional induction through the presentation of photos of the International Affective Picture System (IAPS). We studied especially the emotions of anger, happiness and fear. The volunteers were subjected to prolonged treatment with low doses of clomipramine for four weeks. The sample was divided into responders (n = 6) and non-responders (n = 12) to treatment with clomipramine. The neural activity was estimated by using fMRI, by measuring the blood oxygenation level dependent effect (BOLD). Images were processed and analyzed using the Statistical Parametric Mapping (SPM) program. Non-responders were compared under two conditions: when using clomipramine, and after drug washout, using paired t-tests. Individuals who responded to clomipramine treatment were compared with non-responders under the effect of the drug by independent t-test. RESULTS: In volunteers not responding to clomipramine, a comparison between the non-medicated versus medicated states showed less neural activity in the region of the amygdala when under effect of clomipramine in response to stimuli of negative valence. We also demonstrated, both in the paradigms of positive and negative valence, decreased neural activity in the anterior cingulate gyrus, insula and putamen during the medicated state. When responders were compared with non-responders under the effect of clomipramine, a consistent increase in brain activity was observed in the former group in the insula. CONCLUSIONS: The prolonged use of low doses of clomipramine induced activity changes in brain regions involved in emotional processing. When non-responders were compared under the influence and without the effect of clomipramine, the amygdala displayed lower activity during treatment in response to stimuli of negative valence, possibly due to lower demand in the initial evaluation of stimuli of negative valence. There was less activation in the anterior cingulate gyrus, insula and putamen during the use of clomipramine, possibly in association with a decrease in the cortical mapping of interoceptive changes in response to positive and negative emotional stimuli. When responders were compared with non-responders after prolonged treatment with low doses of clomipramine, insular activation was greater in responders when individuals were under the effect of clomipramine. These results indicate that individuals who respond to antidepressant treatment are those who perceive more changes in their bodily state during emotional processing.

Abstract The purpose of the present study was to gain more insight into the blood oxygen level-dependent (BOLD)-contrast functional MRI (fMRI) in the brain and its connection to EEG, both in global and local scales of their temporal and spatial relations. BOLD signal changes were studied during hyperventilation (HV) induced EEG reactivity of intermittent rhythmic delta activity (IRDA). The BOLD signal in gray matter decreased 30% more in subjects with IRDA (N = 4) than in controls (N = 4), during the first two minutes of HV. This difference disappeared during IRDA in EEG. BOLD signal changes may provide additional information about dynamic hemodynamic changes relative to HV induced EEG reactivity. BOLD signal changes were investigated during sudden deepening of thiopental anesthesia into EEG burst-suppression level in pigs (N = 5). Positive (6–8%) or negative (-3– -8%) group average BOLD signal changes correlated to the thiopental bolus injection were seen. Positive and negative responses covered 1.6% and 2.3% of the brain voxels, respectively. BOLD signal changes in brain are associated with sudden deepening of thiopental anesthesia into EEG burst-suppression level, but they are spatially inconsistent and scarce. Somatosensory BOLD response was studied in brain before and after globally induced methotrexate (MTX) exposition in pigs (N = 4). After the MTX exposure, reduced (from 2–4% to 0–1%) or negative (-2% to -3%) BOLD responses were detected. Somatosensory BOLD-contrast response shows a slight difference in brain before and after globally induced MTX exposition. An experimental epilepsy model for development of simultaneous EEG and BOLD-contrast fMRI in the localization of epilepsy was developed and tested. Dynamic penicillin induced local epilepsy was applied in deep isoflurane anesthesia in pigs (N = 6). Relatively high (10–20%) and localized BOLD signal increase was found. The dynamic penicillin induced focal epilepsy model in deep isoflurane anesthesia with simultaneous EEG and BOLD-contrast fMRI is feasible for the development of these methods for localization of epileptic focus or foci. In conclusion, with careful experimental design and analysis, BOLD-contrast fMRI with EEG provides a potential tool for monitoring and localising functional changes in the brain.

Predicting who will benefit from what in the treatment of psychiatric disorders is incremental to future development of psychological treatments. In the current study functional magnetic resonance imaging (fMRI) data from participants with social anxiety disorder (SAD) was used to elucidate whether neural responses to negative evaluation could predict treatment response in SAD. Nine weeks prior to Internet- delivered Cognitive Behaviour Therapy (ICBT) onset, participants viewed negative social stimuli directed either at themselves or an significant other during fMRI scanning. Regression analyses including the differential activations for other-referential criticism in contrast to self-referential criticism in the posterior mid cingulate cortex (pMCC) and the lingual gyrus (LG) predicted 34% of treatment change as measured by residual gain scores on the Liebowitz Social Anxiety Scale Self-Report (LSAS-SR) in our sample. The final regression model, combining these measures with behavioural measures, which by themselves explained 27% of the variance, resulted in a model explaining 50% of the variance regarding treatment response. This lends additional support to the notion that further elucidating the neurobiological underpinnings of core processes in SAD, as well as the neural correlates of treatment response to CBT, would be of great value in predicting treatment outcome.

Abstract Brain activity fluctuations occur in multiple spatial and temporal scales. Functional magnetic resonance imaging (fMRI) has shown that infra slow fluctuations (ISF) of blood oxygen level-dependent signal (BOLD) are organized into well-defined areas called resting state networks (RSN). ISFs have also been detected in full-band EEG (fbEEG) data and in recent years, many have combined these two modalities to enable more accurate measurements of brain fluctuations. In simultaneous EEG-fMRI measurements the ISFs of BOLD signal have been found to be correlated with amplitude envelopes of faster electrophysiological data, suggesting the same underlying neuronal dynamics. Also direct correlations have been found in task related studies but not previously in resting state studies. Understanding the relation between EEG and BOLD signal in resting state might prove beneficial in the research of baseline activity fluctuations of the brain. Functional connectivity (FC) of the RSNs has been found to vary in different tasks and in some diseases, but also in resting state in healthy people. Despite numerous studies, no clear cause for these variations has yet been found. To research these open questions we performed simultaneous fbEEG-fMRI studies. The measurements from both modalities were analyzed with independent component analysis to improve the comparability of these results. Correlation analysis revealed that the EEG ISFs correlate with BOLD signal both temporally and spatially. These correlations showed spatiotemporal variability that was related to the strength of RSN functional connectivity. These results indicate that the ISFs of EEG and BOLD reflect a common source of fluctuations. The understanding of the correlations between ISFs in EEG and fMRI BOLD signals gives basic information of brain dynamics and of the variables that affect it. A better understanding of the background of brain activity helps in the development of more effective treatments for various neurological diseases as the knowledge of the mechanisms behind them grows. The ability to measure RSN activity with EEG more accurately can help in the development of new methods for early diagnosis of diseases. / Tiivistelmä Aivojen toiminta vaihtelee monissa avaruudellisissa ja ajallisissa mittakaavoissa. Toiminnallisissa magneettikuvauksissa (TMK) on havaittu, että veren happipitoisuudesta riippuvan (engl. BOLD) signaalin erittäin hitaat vaihtelut ovat järjestäytyneet hyvin määriteltyihin alueisiin, joita kutsutaan lepotilahermoverkostoiksi. Erittäin hitaita vaihteluita on havaittu myös täysikaistaisesta aivosähkökäyrästä (fbEEG). Viime vuosina nämä kaksi menetelmää on usein yhdistetty tarkemman mittaustuloksen aikaansaamiseksi. Samanaikaisissa EEG-TMK-mittauksissa BOLD signaalin erittäin hitaiden vaihteluiden on huomattu korreloivan nopeampien elektrofysiologisten värähtelyjen amplitudien verhokäyrien kanssa, mikä viittaa samaan perustana olevaan neuraaliseen dynamiikkaan. Myös suoria korrelaatioita on löydetty tehtäviin liittyvissä tutkimuksissa, mutta ei aiemmin lepotilatutkimuksissa. Lepotilan EEG:n ja BOLD-signaalin suhteen ymmärrys voi osoittautua hyödylliseksi aivojen perustilan aktiivisuuden vaihteluiden tutkimisessa. Hermoverkostojen toiminnallisen liittyvyyden on todettu huojuvan tietyissä tehtävissä ja joissain sairauksissa, mutta myös lepotilassa terveillä henkilöillä. Runsaasta tutkimuksesta huolimatta ei liittyvyyden huojunnalle ole vielä löytynyt selkeää aiheuttajaa. Näiden avoimien kysymysten tutkimiseksi suoritimme yhdenaikaisia fbEEG-TMK-mittauksia. Kummankin modaliteetin mittaustuloksia analysoitiin itsenäisten komponenttien analyysillä tulosten vertailtavuuden parantamiseksi. Korrelaatioanalyysit osoittivat, että EEG:n erittäin hitaat vaihtelut korreloivat ajallisesti ja avaruudellisesti TMK:n BOLD-signaalin kanssa. Näissä korrelaatioissa esiintyi sekä paikkaan että aikaan liittyvää huojuntaa, joka oli yhteydessä lepotilahermoverkostojen toiminnallisen liittyvyyden vahvuuteen. Nämä tulokset viittaavat siihen, että samat tekijät tuottavat EEG:n ja TMK:n BOLD-signaalien hitaat vaihtelut. EEG:n ja TMK:n signaalien erittäin hitaiden vaihteluiden välisen korrelaation ymmärtäminen antaa perustason tietoa aivojen toiminnan dynamiikasta sekä siihen vaikuttavista tekijöistä. Parempi ymmärrys aivotoiminnan taustoista auttaa kehittämään tehokkaampia hoitoja neurologisiin sairauksiin, kun tieto mekanismeista niiden takana tarkentuu. Mahdollisuus mitata lepotilahermoverkostojen toimintaa EEG:llä aiempaa tarkemmin voi auttaa kehittämään uusia menetelmiä sairauksien varhaiseen diagnostiikkaan.

Abstract The purpose of the present work was to investigate whether children with non-lesional temporal lobe epilepsy (TLE) have deficits in neuropsychological performance and whether the possible deficits can be investigated using functional magnetic resonance imaging (fMRI). In this population-based study, 21 children aged 8-15 with non-lesional TLE and a normal intelligence quotient were evaluated and compared with 21 healthy, age- and gender-matched controls. Neuropsychological assessments, clinical examinations, electroencephalography (EEG) and structural and functional MRI were performed on all the subjects. Three fMRI methods were used: resting-state regional homogeneity, resting-state functional connectivity and task-induced blood oxygenation level-dependent activation. The patients with non-lesional TLE showed good neuropsychological performance on average, although the girls were found to have significant problems in several neuropsychological tests. The deficits were not restricted to elements of performance involving the classical temporal lobe memory system but were also found in tests requiring frontal and parietal lobe functioning. Early onset of epilepsy and duration of epilepsy had significant negative effects on neuropsychological performance. All the fMRI methods detected significant functional differences between the TLE patients and the healthy controls, not only in the temporal lobes but also in broad networks extending to the frontal, parietal and thalamic areas. These differences seemed to differ markedly in location between the TLE patients depending on the interictal EEG findings. Neuropsychological performance results were supported by the fMRI findings, implying that TLE should be regarded as a widespread disruption of the brain networks and not just malfunction of a single region in the brain within these networks. This needs to be taken into consideration when evaluating learning abilities among TLE patients even at an early stage in epilepsy. / Tiivistelmä Tutkimuksen tarkoituksena oli selvittää onko lapsilla, jotka sairastavat tuntemattomasta syystä aiheutuvaa ohimolohkoepilepsiaa, neuropsykologisia ongelmia ja aiheuttavatko mahdolliset ongelmat aivojen toiminnallisessa magneettikuvauksessa nähtäviä muutoksia. Tähän väestöpohjaiseen tutkimukseen otettiin 21 tuntemattomasta syystä ohimolohkoepilepsiaa sairastavaa normaaliälyistä 8-15-vuotiaista lasta ja verrattiin heitä 21 terveeseen, ikä- ja sukupuolivakioituun kontrollihenkilöön. Kaikille tutkimukseen osallistuneille tehtiin neuropsykologinen tutkimus, kliininen tutkimus, aivosähkökäyrä sekä rakenteellinen ja toiminnallinen aivojen magneettikuvaus. Toiminnallisessa magneettikuvauksessa käytettiin veren happipitoisuudesta riippuvaista (engl. blood oxygenation level-dependent) kontrastia kuvantamaan levossa aivojen paikallista homogeniteettia (engl. regional homogeneity) ja toiminnallista kytkennällisyyttä (engl. functional connectivity) sekä kognitiivisten tehtävien herättämiä aktivaatio-vasteita. Tuntemattomasta syystä ohimolohkoepilepsiaa sairastavien lasten neuropsykologinen suoriutuminen oli keskimäärin hyvää, vaikkakin tytöillä oli nähtävillä tilastollisesti merkitseviä ongelmia useissa eri testeissä. Ongelmat eivät rajoittuneet pelkästään klassisiin ohimolohkoalueen muistitoimintoihin, vaan niitä havaittiin myös otsa- ja päälakilohkojen toimintoja edellyttävissä testeissä. Varhainen sairastumisikä ja epilepsian kesto heikensivät suoriutumista tilastollisesti merkitsevästi osatesteissä, joissa tarvittiin näönvaraisen hahmottamisen taitoja, psykomotorista nopeutta ja työmuistia. Ohimolohkoepilepsiaa sairastavien ja terveiden kontrollien aivoissa löydettiin toiminnallisia eroja kaikilla toiminnallisen magneettikuvauksen menetelmillä. Eroja ei todettu ainoastaan ohimolohkoissa, vaan niitä löytyi myös otsa- ja päälakilohkoon sekä tyvitumakealueelle ylettyvissä laaja-alaisissa hermoverkostoissa. Epilepsiapotilailla erojen paikantuminen riippui kohtaustenvälisestä aivosähkökäyrälöydöksestä. Neuropsykologisen suoriutumisen tulokset tukevat toiminnallisen magneettikuvauksen löydöksiä kuvastaen temporaaliepilepsian olevan laaja-alainen hermoverkostojen häiriö eikä pelkästään tietyn aivoalueen toiminnan häiriö. Tämä tulee huomioida arvioitaessa ohimolohkoepilepsiaa sairastavien lasten oppimiskykyä jo epilepsian alkuvaiheessa.

La fatigue post-accident vasculaire cérébral (FPAVC) est fréquente et invalidante. Pour autant, elle reste à ce jour un phénomène mal connu et reconnu. Dans ce travail de thèse, nous avons réalisé une synthèse exhaustive de la littérature scientifique sur les facteurs associés à la FPAVC. Il en ressort qu’elle est fréquemment reliée aux symptômes dépressifs et anxieux mais que ses mécanismes physiopathologiques sont encore peu compris. Nous avons conduit une étude de la FPAVC sur 153 patients de la cohorte hospitalière STROKDEM (NCT01330160) ayant été suivis 6 mois après leur AVC ischémique. Dans une première étude, nous avons montré que la FPAVC n’était pas un effet secondaire des médicaments utilisés par les patients à la sortie de l’hôpital et à 6 mois. Elle reflèterait plutôt la présence de troubles fréquemment observés après un AVC comme la dépression, l’anxiété et les troubles du sommeil. Dans une deuxième étude, nous avons mis au jour une association forte entre FPAVC et plaintes cognitives subjectives des patients qui contrastait avec l’absence d’association avec les performances cognitives objectives lors de l’évaluation neuropsychologique, quel que soit le domaine cognitif considéré. Dans une troisième étude, nous avons exploré les mécanismes neuronaux sous-jacents à la FPAVC. Avec une analyse exploratoire et sans a priori, nous n’avons pas montré de différence de connectivité fonctionnelle au repos entre les patients avec ou sans FPAVC. L’ensemble de ces données nous apporte des éléments permettant d’avancer dans la compréhension du phénomène complexe qu’est la FPAVC. / Post-stroke fatigue (PSF) is frequent and debilitating. However, PSF is up to date a poorly understood and unrecognized phenomenon. In this thesis, we have done an exhaustive synthesis of scientific literature on factors associated with PSF. It indicates that PSF is frequently related with depressive and anxious symptoms but there is a lack of understanding of its physiopathological mechanisms. We conducted a study of PSF on 153 patients from the hospital-based cohort study STROKDEM (NCT01330160), followed-up for 6 months after an ischemic stroke. In a first study, we have shown that PSF was not a side effect of drugs use. PSF more reflects presence of disturbances frequently observed after stroke such as depression, anxiety, or sleep disturbances. In a second study, we have observed a strong association between PSF and subjective cognitive complaints that contrasted with the absence of association with objective cognitive performances during the neuropsychological evaluation, regardless of the considered cognitive domain. In a third study, we explored neuronal mechanisms underlying PSF. With an exploratory analysis, without a priori, we did not demonstrate any difference in functional connectivity at rest between patients with or without PSF. As a whole, these data give us pieces to progress in the understanding of the complex phenomenon named PSF.

[pt] A memória de trabalho fonológica pode ser definida como um grupo de processos mentais usados para codificar, guardar, manter, manipular e recuperar informações auditivas. É o alicerce de outras funções cognitivas superiores e mais complexas como o planejamento, mudança do foco da tarefa, raciocínio lógico e abstrato e linguagem. Algumas evidências mostram a relação entre o desenvolvimento da memória de trabalho fonológica e mais tarde a aquisição da linguagem e inteligência global fluida. A antropologia contemporânea discute o papel da memória de trabalho como uma forma rudimentar de pensamento e suas consequências para o desenvolvimento de ferramentas e cultura entre os hominídeos. Têm sido aceito que a expansão da região frontal do crânio abre espaço para novas formações corticais no cérebro, especialmente no lobo frontal. Crê-se que o córtex pré-frontal tem um importante papel em tarefas de memória de trabalho. Ao mesmo tempo, a memória de trabalho é uma descoberta psicológica recente e diversos autores sugerem diferentes modelos teóricos para explicá-la. Dentre os mais importantes, Alan Baddeley, Nelson Cowan e Adele Diamond são aqueles cujas teorias são as mais estudadas e implementadas pelos pesquisadores que testam suas teorias. Estudar a base neural da memória de trabalho fonológica pode ajudar a lançar luz sobre ambos os pontos: o papel do córtex pré-frontal na evolução humana especialmente no funcionamento da memória de trabalho, e qual modelo teórico é o mais confiável dentro de uma perspectiva neuropsicológica. Para fazer isso, conduzimos uma meta-análise usando o método de estimação de verossimilhança das ativações e discutimos os resultados alicerçados na psicologia evolutiva e cognitiva modernas. / [en] Phonological working memory can be defined as a set of mental processes that encode, store, maintain, manipulate, and retrieve auditory information. It is the foundation for other complex and higher cognitive functions, such as planning, task switching, logical and abstract reasoning, and language. Some evidence shows a relationship between the development of phonological working memory and further language acquisition and general fluid intelligence. Current neuroscience discusses the networks and brain regions that account for working memory. Working memory relies on a parietal-frontal network that is divided according to memory and attention. It has been hypothesized that the prefrontal cortex plays an important role in working memory tasks. Working memory is a relatively recent psychological discovery, and several authors suggest different theoretical models to explain it. Among the most important are those proposed by Alan Baddeley, Nelson Cowan, and Adele Diamond, which have been the most studied and implemented in attempts to test their hypotheses. Studying the neural basis of phonological working memory will help shed light on the organization and location of mnemonic and attentional functions in the brain. The present study comprised a meta-analysis of functional magnetic resonance imaging studies on phonological working memory that were published between 2000 and 2014. The results showed that one region in the temporal lobe and another region in the fronto-polar cortex were clustered intersections of phonological working memory, suggesting that these brains regions may account for sensorial memory and the central executive, respectively.