<p>    </p> <p>Cerebrovascular diseases, such as stroke, constitute the most common life-threatening neurological disease in the United States. To support normal brain function, maintaining adequate brain perfusion (i.e., cerebral blood flow (CBF)) is important. Therefore, it is crucial to assess the brain perfusion so that early intervention in cerebrovascular diseases can be applied if abnormal perfusion is observed. The goal of my study is to develop metrics to measure the brain perfusion through modeling brain physiology using resting-state and task-based blood-oxygenation-level- dependent (BOLD) functional MRI (fMRI). My first and second chapters focused on deriving the blood arrival time using the resting-state BOLD signal. In the first chapters, we extracted the systemic low-frequency oscillations (sLFOs) in the fMRI signal from the internal carotid arteries (ICA) and the superior sagittal sinus (SSS). Consistent and robust results were obtained across 400 scans showing the ICA signals leading the SSS signals by about 5 seconds. This delay time could be considered as an effective perfusion biomarker that is associate with the cerebral circulation time (CCT). To further explore sLFOs in assessing dynamic blood flow changes during the scan, in my second chapter, a “carpet plot” (a 2-dimensional plot time vs. voxel) of scaled fMRI signal intensity was reconstructed and paired with a developed slope-detection algorithm. Tilted vertical edges across which a sudden signal intensity change took place were successfully detected by the algorithm and the averaged propagation time derived from the carpet plot matches the cerebral circulation time. Given that CO₂ is a vasodilator, controlling of inhaled CO₂ is able to modulate the BOLD signal, therefore, as a follow-up study, we focused on investigating the feasibility of using a CO₂ modulated sLFO signal as a “natural” bolus to track CBF with the tool developed from the second chapter. Meaningful transit times were derived from the CO₂-MRI carpet plots. Not only the timing, the BOLD signal deformation (the waveform change) under CO₂ challenge also reveals very useful perfusion information, representing how the brain react to stimulus. Therefore, my fourth chapter focused on characterizing the brain reaction to the CO₂ stimulus to better measure the brain health using BOLD fMRI. Overall, these studies deepen our understanding of fMRI signal and the derived perfusion parameters can potentially be used to assess some cerebrovascular diseases, such as stroke, ischemic brain damage, and steno-occlusive arterial disease in addition to functional activations. </p>

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2015-07-20T18:01:54Z No. of bitstreams: 1 Suely Tomimura.pdf: 1781054 bytes, checksum: acaac7dbd088721fbe65530e5cd96c5f (MD5) / Made available in DSpace on 2015-07-20T18:01:54Z (GMT). No. of bitstreams: 1 Suely Tomimura.pdf: 1781054 bytes, checksum: acaac7dbd088721fbe65530e5cd96c5f (MD5) Previous issue date: 2013-12-17 / Due to the increasing numbers of Systemic Arterial Hypertension (HBP) patients in population and its senescence, steadily increased from 600 million in 1980 to 1.2 billion in 2008. The World Health Organization (WHO) in 2009 attributed to high blood pressure (BP) was the death cause for 9.5 million people worldwide. Currently, the hypertension has become a serious public health problem. This entity is an important risk factor for congestive heart failure, cerebrovascular disease, acute myocardial infarction, nephropathy, retinopathy and peripheral vascular insufficiency. Studies have suggested that laser photobiomulation, employing a low power, acts into the inflammatory and proliferative phases of tissue repair, by modulating the inflammatory mediators synthesis as same as the Reactive Oxygen Species (ROS). According scientific publications indicate that the inflammation component is closely related to systemic arterial hypertension as well as possibly to the oxidative stress, both participates in the Hypertension genesis. The aim of this study was to verify the long-term effects of Low Level Laser Therapy (LLLT) application in Spontaneously Hypertensive Rats-SHR (Spontaneously Hypertensive Rats) through on cardiovascular autonomic modulation and oxidative stress in the blood. The experiment consisted in 3 phases: Phase I – LLLT irradiation on SHR: The experiment's phase I consisted of animal’s irradiation, when the laser group received three times LLLT applications weekly for a 7 weeks total; the sham group received three times per week of LLLT simulation for 7 weeks and a total of 21 applications. Prospective, randomized, controlled study, with 16 SHR approximately 2 months age, randomly divided into 2 groups : Sham (n = 8) and Laser (n = 8). The animals were irradiated in a prompt, onto the tail’s dorsal area, using a Diode Laser (MMOptics, São Carlos, SP, Brazil) with a wavelength (λ) of 780 ± 2 (nm), output power at 40 mW, with a 0.04 cm2 beam area, dose of 30 J/cm2 power density of 1W/cm2 and irradiation time of 90 s. In Phase II - Hemodynamic and autonomic cardiovascular evaluation: for a period of 7 weeks, consisted in the cannulation procedure, collecting and analysis. The animals were cannulated, evaluated hemodynamically and analyzed the cardiovascular autonomic modulation. Phase III - Oxidative stress analysis, were analyzed: a) protein damage; b) cell membrane damage; c) antioxidant enzyme activity; d) nitrite concentrations. Data from phase II and III were collected and statistically analyzed applying One Way ANOVA test, followed by post hoc Student - Newman Keulls and considering the significance level of p < 0.05, equivalent to an error α 0.05. The results demonstraded hemodynamic parameters of group LLLT treated showed a BP reduction, when compared with the Sham group. In laser group the diastolic arterial pressure (DAP) showed a reduction of -14 mmHg (± 143 * 4 x 157 ± 3 mmHg Sham) and mean arterial pressure (MAP) - 13mmHg (169 ± 4 * x 182 ± 4 mmHg Sham) there were statistically significant difference. Although the value of systolic arterial pressure (SAP) (196 ± 5 x 207 ± 4 mmHg) showed no differences. There was a decreased in resting HR with a statistically significant difference in the laser group compared to Sham (312 ± 14 vs. 361 ± 13 bpm sham). The spectral reviews in the field of time and frequency showed that the Laser group decreased sympathetic activity on the heart and blood vessels while compared to the Sham group. The heart rate variation was analyzed using the DP-PI ( standard deviation of the pulse interval) VAR-PI components (pulse interval variability) and it demonstrated that LLLT was effective in diminishing variation in heart rate (HR) and sympathetic activity in heart, inducing a substantial fall in blood pressure. Lasertherapy presented a rise in spectral low-frequency component in the pulse interval (LF - IP action of the sympathetic at heart), though the sham group showed up exaggeratedly decreasing (6.77 ± 4:35 and 2:31 ± 0:16 ms ² Sham) as a function of saturation variation. Thus, there was a significant reduction in sympathetic activity after LLLT using. A high-frequency band on interval pulse HF-IP (parasympathetic activity) showed no statistically significant differences between the groups and Laser Sham group. The baroreceptor sensitivity, assessed by the alpha index, signalized a significant increase in the Laser (1:07 ± 0:23 vs. 0:45 ± 0:20 ms / mmHg Sham) group, presenting an improvement in the receptors sensitivity. The baroreflex results were associated with other relevant data, the VAR - SAP (49.55 ± 15.94 * vs 70.51 ± 13:55 mmHg² Sham) and SD -SAP (6.94 ± 1.21 * vs 8.68 ± 1.11 mmHg Sham) that proved to be diminished in the laser group, indicating baroreflex improvement sensitivity concomitantly to the positive SAP variation reduction of. There were no significant differences in baseline SAP (196 ± 5 vs. 207 ± 4 mmHg Sham) between the two groups. The results in the oxidative stress and autonomic analysis demonstrated an association between increased NO production (nitrite 0:36 ± 0:03 vs 0:26 ± 0:03 nm / mg Sham) and decreased in the vascular sympathetic (LF - SAP 7.28 ± 1.63 * vs 9.86 ± 0.47 Sham), both leading to a profound vasodilatation then a significant fall in of blood pressure. Lasertherapy shown to alter the plasma parameters such as oxidative nitrite, revealing an NO increased metabolism, as described above and, moreover, accounted for a significant reduction in carbonyl plasma concentration (vs 3.93 ± 0.24, 4.75 ± 0:26 * nm / mg Sham). Our experimental study indicate that LLLT was able to reduce the oxidative stress parameters through diminishing the damage to the proteins. The enzymatic defense was analyzed by the enzyme SOD concentration in blood plasma, denoted that no significant differences (4:42 ± 0:10 4:25 ± 0:06 vs usod / mg) between groups. Thus, low level laser therapy has shown to improve cardiovascular autonomic activity as well as oxidative parameters which resulted in steadily staggeringly reduce the blood pressure of hypertensive animals. / Em razão do aumento populacional e a senescência, o número de indivíduos com Hipertensão Arterial Sistêmica (HAS) cresceu de 600 milhões em 1980 para 1,2 bilhões (OMS 2011). Lim (2012) atribuiu que a pressão arterial (PA) elevada fosse a causa mortis de 9,5 milhões de indivíduos ao redor do mundo. Atualmente, a HAS tornou-se um grave problema de saúde pública. A hipertensão é um importante fator de risco para insuficiência cardíaca congestiva, doenças cerebrovasculares, infarto agudo do miocárdio, nefropatia, insuficiência vascular periférica e retinopatia hipertensiva. Considerando publicações científicas que demonstram que o componente da inflamação e do estresse oxidativo estão intimamente relacionados à gênese da hipertensão arterial sistêmica (HAS), e que o laser com potência baixa tem efeito positivo no estresse oxidativo e apresenta ação antiinflamatória eficaz, desta forma buscamos estudar a resposta da Laserterapia na HAS. Inúmeros estudos vêm sugerindo, ao longo de décadas, que a fotobiomulação pelo laser empregado uma potência baixa, atua durante as fases inflamatórias e proliferativas da reparação tissular, modulando síntese de mediadores inflamatórios e espécies reativas de oxigênio (ROS). O objetivo deste estudo foi analisar os efeitos da aplicação do laser de baixa intensidade em ratos espontaneamente hipertensos SHR (Spontaneously Hypertensive Rats) em longo prazo na modulação autonômica cardiovascular e no estresse oxidativo sangúineo. Estudo prospectivo, randomizado e controlado com 16 ratos SHR, divididos aleatoriamente em 2 grupos: Sham (n=8) e Laser (n=8).O experimento foi dividido em três fases: Fase I – Irradiação dos animais: constituiu-se na irradiação com laser nos animais SHR, onde o grupo Laser recebeu três aplicações semanais de LBI durante sete semanas; já no grupo Sham foram realizados três simulações de aplicação semanais de Laser de Baixa Intensidade (LBI) durante 7 semanas, totalizando 21 aplicações de LBI. Os animais foram irradiados pontualmente, na região dorsal da cauda, utilizando um Laser Diodo (MMOptics, São Carlos, SP, Brasil) com comprimento de onda de λ = 780 ± 2 (nm); potência de 40 mW, área do feixe de 0,04 cm2, densidade de energia de 30 J/cm2, densidade de potência de 1W/cm2, tempo total de irradiação de 90 s de exposição. Fase II – Avaliação hemodinâmica e autonômica cardiovascular: constituiu-se nos procedimento de canulação, registro de dados e coleta de material, teve inicio após sete semanas de irradiação. Os animais canulados foram avalidados de forma hemodinâmica, bem como analisada a modulação autonômica cardiovascular. Fase III – Análises do estresse oxidativo, foram analisadas: a) danos à proteína; b) danos à membrana celular; c) atividade enzimática; d) concentração de nitrito. Os dados da fase II e III foram coletados e analisados estatisticamente através dos testes Anova One Way, seguido de Post Hoc de Student Newman-Keulls, considerando-se o nível de significância p < 0,05, equivalendo a um erro α de 0.05. Os resultados hemodinâmicos do grupo tratado com LLLT denotaram um decréscimo significativo da PA quando comparado com o grupo Sham. A pressão arterial diastólica (PAD) do grupo Laser revelou uma redução de -14 mmHg (143± 4*vs157±3 mmHg Sham) e a pressão arterial média (PAM) -13mmHg (169±4*vs182±4 mmHg Sham), a frequência cardíaca (FC) em repouso (312±14*vs361±13 bpm Sham) revelando uma diferença estatisticamente significante, porém o valor da pressão arterial sistólica(PAS) não mostrou (196±5 x 207±4 mmHg) alterações entre os grupos. As avaliações espectrais no domínio do tempo e da frequencia demostraram que o grupo Laser reduziu a atividade simpática sobre o coração e vasos sanguíneos quando comparados ao grupo Sham. A variação frequência cardíaca foi analisada através dos componentes VAR-IP (variabilidade do intervalo de pulso) e o DP-IP (desvio do intervalo de pulso) que evidenciaram que o LBI foi eficaz no decréscimo variação da FC e da atividade simpática no coração, induzindo assim a queda das pressões arteriais. A laserterapia mostrou um incremento no componente espectral baixa frequência no intervalo de pulso (BF-IP ação do simpático no coração), porém o grupo Sham apresentou-se exacerbadamente diminuído (6.77 ± 4.35 e 2.31±0.16 ms² Sham) em função da saturação da variação desse componente que foi reduzido. Desta forma, houve um importante decréscimo da atividade simpática com o uso do LBI, significando uma importante diminuição dos níveis pressóricos. A banda de alta frequência (AF-IP atividade parassimpática cardíaca) não mostrou diferenças estatísticas significantes entre os grupos Laser e grupo Sham. A sensibilidade dos barorreceptores, avaliada pelo índice alfa, demonstrou um significativo incremento da resposta no grupo Laser (1.07 ± 0.23 vs 0.45 ± 0.20 ms/mmHg Sham), revelando uma melhora na sensibilidade destes receptores. Os resultados dos barorreflexos encontravam-se associados a outro dado relevante, o componente VAR-PAS (49.55 ± 15.94* vs 70.51 ± 13.55 mmHg² Sham) e DP-PAS (6.94 ± 1.21* vs 8.68 ± 1.11 mmHg Sham) que mostrou-se diminuído no grupo Laser, indicando que a melhora da sensibilidade barorreflexa ocorreu, concomitantemente, à redução positiva da variação da PAS. Não houve diferenças estatísticas significantes na PAS basal (196±5 vs 207 ± 4 mmHg Sham) entre os dois grupos. Já os resultados encontrados na análise do estresse oxidativo e autonômica demonstraram uma associação entre o incremento da produção do óxido nitrico (NO) (nitrito 0.36 ± 0.03 vs 0.26 ± 0.03 nm/mg Sham) e redução do simpático vascular (BF-PAS 7.28 ± 1.63* vs 9.86 ± 0.47 Sham), ambos levando a uma vasodilatação com consequente queda dos níveis pressóricos arteriais. A laserterapia mostrou alterar parâmetros oxidativos como as espécies reativas de nitrogênio (RNS reactive nitrogen species), o nitrito plasmático, revelando um aumento do metabolismo do NO, como já descrito anteriormente e denotou uma diminuição significativa da concentração de carbonilas plasmáticas (3.93 ± 0.24 * vs 4.75 ± 0.26 nm/mg Sham). A defesa enzimática foi analisada através da concentração da enzima SOD no plasma sanguíneo, que não apontou diferenças significativas (4.42 ± 0.10 vs 4.25 ± 0.06 usod/mg) entre os grupos. Evidenciamos que o LBI foi capaz de reduzir este parâmetro oxidativo, reduzindo os danos às proteínas decorrente do estresse. Desta forma, concluímos que a laserterapia demonstrou resposta positiva ao melhorar a atividade autonômica cardiovascular e parâmetros oxidativos que resultaram na redução dos níveis pressóricos dos animais hipertensos.

Electroencephalography and functional magnetic resonance are two different methods for measuring of neural activity. EEG signals have excellent time resolution, fMRI scans capture records of brain activity in excellent spatial resolution. It is assumed that the joint analysis can take advantage of both methods simultaneously. Statistical Parametric Mapping (SPM8) is freely available software which serves to automatic analysis of fMRI data estimated with general linear model. It is not possible to estimate automatic EEG–fMRI analysis with it. Therefore software EEG Regressor Builder was created during master thesis. It preprocesses EEG signals into EEG regressors which are loaded with program SPM8 where joint EEG–fMRI analysis is estimated in general linear model. EEG regressors consist of vectors of temporal changes in absolute or relative power values of EEG signal in the specified frequency bands from selected electrodes due to periods of fMRI acquisition of individual images. The software is tested on the simultaneous EEG-fMRI data of a visual oddball experiment. EEG regressors are calculated for temporal changes in absolute and relative EEG power values in three frequency bands of interest ( 8-12Hz, 12-20Hz a 20-30Hz) from the occipital electrodes (O1, O2 and Oz). Three types of test analyzes is performed. Data from three individuals is examined in the first. Accuracy of results is evaluated due to the possibilities of setting of calculation method of regressor. Group analysis of data from twenty-two healthy patients is performed in the second. Group EEG regressors analysis is realized in the third through the correlation matrix due to the specified type of power and frequency band outside of the general linear model.

The master thesis deals with the joint EEG-fMRI analysis based on a heuristic model that describes the relationship between changes in blood flow in active brain areas and in the electrical activity of neurons. This work also discusses various methods of extracting of useful information from the EEG and their influence on the final result of joined analysis. There were tested averaging methods of electrodes interest, decomposition by principal components analysis and decomposition by independent component analysis. Methods of averaging and decomposition by PCA give similar results, but information about a stimulus vector can not be extracted. Using ICA decomposition, we are able to obtain information relating to the certain stimulation, but there is the problem in the final interpretation and selection of the right components in a blind search for variability coupled with the experiment. It was found out that although components calculated from the time sequence EEG are independent for each to other, their spectrum shifts are correlated. This spectral dependence was eliminated by PCA / ICA decomposition from vectors of spectrum shifts. For this method, each component brings new information about brain activity. The results of the heuristic approach were compared with the results of the joined analysis based on the relative and absolute power approach from frequency bands of interest. And the similarity between activation maps was founded, especially for the heuristic model and the relative power from the gamma band (20-40Hz).

While task-based functional magnetic resonance imaging (fMRI) has helped us understand the functional role of many regions in the human brain, many diseases and complex behaviors defy explanation. Alternatively, if no task is performed, the fMRI signal between distant, anatomically connected, brain regions is similar over time. These correlations in “resting state” fMRI have been strongly linked to behavior and disease. Previous work primarily calculated correlation in entire fMRI runs of six minutes or more, making understanding the neural underpinnings of these fluctuations difficult. Recently, coordinated dynamic activity on shorter time scales has been observed in resting state fMRI: correlation calculated in comparatively short sliding windows and quasi-periodic (periodic but not constantly active) spatiotemporal patterns. However, little relevance to behavior or underlying neural activity has been demonstrated. This dissertation addresses this problem, first by using 12.3 second windows to demonstrate a behavior-fMRI relationship previously only observed in entire fMRI runs. Second, simultaneous recording of fMRI and electrical signals from the brains of anesthetized rats is used to demonstrate that both types of dynamic activity have strong correlates in electrophysiology. Very slow neural signals correspond to the quasi-periodic patterns, supporting the idea that low-frequency activity organizes large scale information transfer in the brain. This work both validates the use of dynamic analysis of resting state fMRI, and provides a starting point for the investigation of the systemic basis of many neuropsychiatric diseases.