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Understanding the relationship between neural activity and cortical hemodynamics, or neurovascular coupling is the foundation to interpret neuroimaging signals such as functional magnetic resonance imaging (fMRI) which measure local changes in hemodynamics as a proxy for underlying neural activity. Even though the stereotypical stimulus-evoked hemodynamic response pattern with increased concentration of oxy- and total-hemoglobin and decrease in concentration of deoxy-hemoglobin has been well-recognized, the linearity of neurovascular coupling and its variances depending on brain state and tasks haven’t been thoroughly evaluated. To directly assess the cortical neurovascular coupling, simultaneous recordings of neural and hemodynamic activity were imaged by wide-field optical mapping (WFOM) over the bilateral dorsal surface of the mouse brain through a bilateral thinned-skull cranial window. Neural imaging is achieved through wide-field fluorescence imaging in animals expressing genetically encoded calcium sensor (Thy1-GCaMP). Hemodynamics are recorded via simultaneous imaging of multi-spectral reflectance. Significant hemodynamic crosstalk was found in the detected fluorescence signal and the physical model of the contamination, methods of correction as well as electrophysiological verification are presented. A linear model between neural and hemodynamic signals was used to fit spatiotemporal hemodynamics can be predicted by convolving local fluorescence changes with hemodynamic response functions derived through both deconvolution and gamma-variate fitting. Beyond confirming that the resting-state hemodynamics in the awake and anesthetized brain are coupled to underlying neural activity, the patterns of bilaterally symmetric spontaneous neural activity observed by WFOM emulate the functionally connected networks detected by fMRI. This result provides reassurance that resting-state functional connectivity has neural origins. With the access to cortical neural activity at mesoscopic level, we further explore the cortical neural representations preceding and during spontaneous locomotion.

Orientador: Newton Nunes / Coorientador: Patricia Cristina Ferro Lopes / Banca: Roberta Carareto / Banca: Vivian Fernanda Barbosa / Banc: Bruno Watanabe Minto / Resumo: Compararam-se os efeitos de diferentes frações inspiradas de oxigênio (FiO2) associado ao óxido nitroso (N2O) ou ao ar comprimido sobre a hematose, parâmetros cardiorrespiratórios, intracranianos e o índice biespectral (BIS), em leitões mantidos em ventilação espontânea ou controlada a pressão, associada ou não à PEEP (5 cmH2O). Foram utilizados 48 leitões, distribuídos em 6 grupos, submetidos à 10, 30 e 50% de ar comprimido (GA10, GA30 e GA50) ou N2O (GN10, GN30 e GN50), associadas às FiO2 de 0,9, 0,7 e 0,5, respectivamente. O GA30 mostrou maior proximidade do intervalo fisiológico da pressão parcial de oxigênio no sangue arterial. A PEEP não foi eficaz na pressão parcial de dióxido de carbono no sangue arterial, independente da FiO2, quando se utilizou o N2O. O pH, déficit base e bicarbonato no sangue arterial foram influenciados pela FiO2 e N2O. As alterações do volume corrente e volume minuto parecem correlacionadas à introdução da ventilação mecânica (VM) e PEEP. Na diferença alvéolo-arterial de oxigênio, a PEEP influenciou negativamente o GA30 e GN30 e não foi adequada para manutenção do shunt pulmonar. Já a pressão média da artéria pulmonar e pressão média capilar pulmonar apresentaram acréscimos após introdução da PEEP. A associação da PEEP com N2O (50%) ou ar comprimido (50%) parece ser a receita para desempenho inferior da variação de pressão de pulso. Para a pressão intracraniana, apenas o GN30 apresentou valor menor ao se instituir a VM quando comparado com o mome... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The effects of different fractions of inspired oxygen (FiO2) associated with compressed air or nitrous oxide (N2O) on lung oxygenation, cardiorespiratory parameters, intracranial parameters and the bispectral index (BIS) were compared in piglets maintained under spontaneous or controlled ventilation, with or without PEEP (5 cmH2O). Forty-eight piglets, distributed in six groups, were submitted to 10, 30 and 50% of compressed air (GA10, GA30 and GA50) or N2O (GN10, GN30 and GN50), associated with FiO2 of 0.9, 0.7 and 0.5, respectively. GA30 showed greater proximity to the physiological range of partial oxygen pressure in the arterial blood. When N2O was used, PEEP was ineffective in maintaining partial carbon dioxide pressure in the arterial blood, independent of FiO2. Arterial blood pH, base deficit and bicarbonate were influenced by FiO2 and N2O. Changes in tidal and minute volumes seem to correlate with the introduction of mechanical ventilation (MV) and PEEP. The difference in alveolar-arterial oxygen under PEEP negatively influenced GA30 and GN30 and was inadequate for pulmonary shunt maintenance. Mean pulmonary artery pressure and mean capillary pulmonary pressure increased following the initiation of PEEP. The association of PEEP with N2O (50%) or compressed air (50%) seems to result in lower performance of pulse pressure variation. Regarding intracranial pressure, only GN30 presented a lower value when MV was established compared with the time point when PEEP was initi... (Complete abstract click electronic access below) / Doutor

In the present study, we investigated the pathophysiological mechanisms of the hemodynamic alteration in diabetes. Glomerular hyperfiltration occurs in the early stage of diabetes mellitus and has been recognized to promote the pathogenesis of diabetic nephropathy. We determine the role of TGF response and the vascular tone of Af-Art in diabetic hyperfiltration and we found that 1) tubular high glucose directly activates NOS1 and increases NO generation in the macula densa, which inhibits TGF response and increases GFR; 2) high glucose dilates renal Af-Art through GLUT1 and mediated by NOS3-derived NO generation; 3) in diabetes, blunted TGF mediated by NOS1 in the macula densa promotes glomerular hyperfiltration. The prevalence of hypertension is much higher in diabetic subjects than non-diabetic population. We studied the potential mechanisms of blood pressure regulation in diabetes, including TGF response and renal afferent arteriolar response to vasoconstrictors, and we found that 1) inadequate NOS1 in the macula densa enhances TGF, which restricts glomerular hyperfiltration and induces hypertension in diabetes; 2) hemodynamic responses to ANG II is increased in diabetes, which is associated with increased expression and activity of AT1 receptors in the Af-Art; 3) Ang II upregulates the expression and activity of Nox2 and Nox4 in the macula densa, which enhances TGF response.

Thesis (M. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

The use of transcranial Doppler (TCD) ultrasound for the assessment of cerebral blood flow velocity (CBFV) provides an indication of cerebral blood flow assuming the diameter of the insonated vessel remains constant. Studies using TCD have traditionally described cerebrovascular hemodynamics with respect to CBFV and cerebrovascular resistance (CVRi); however, a more complete assessment of the cerebral circulation can be gleaned from the analysis of within beat characteristic of the TCD velocity waveform for the determination of cerebrovascular tone. Therefore, the general purpose of the presented studies was to assess CBFV responses and within beat characteristic for the description of cerebrovascular hemodynamics after long duration spaceflight, with sustained orthostasis, in response to changes in the partial pressure of end tidal carbon dioxide (PETCO2), and with NG stimulation. After long duration spaceflight, cerebrovascular autoregulation was found to be impaired along with a reduction in cerebrovascular CO2 reactivity (Study 1). Additionally, critical closing pressure (CrCP) was found to be increased suggesting potential remodelling of the cerebrovasculature contributing to an increase in cerebrovascular tone (Study 2). With sustained orthostasis, CBFV was found to progressively decrease and to be related to reductions in PETCO2 and increases in CrCP suggesting the contribution of changes in cerebrovascular tone leading to the development of syncope (Study 4). The CBFV reduction with the progression towards syncope was also associated with changes in waveform morphology such that the dicrotic notch point was less than the end diastolic value (Study 3). Mathematical modelling (RCKL) was used to further assess changes in cerebrovascular hemodynamics for physiological interpretation of changes in CBFV waveform morphology and found that the amplitude of the dicrotic notch and the calculation of the augmentation index were both significantly related to vascular compliance before and after stimulation with NG (Study 5). The use of quantitative assessments of common carotid artery (CCA) blood flow as an indicator of cerebral blood flow suggested the dilation of the middle cerebral artery (MCA) with NG (Study 5 and 6) and changes in MCA diameter with acute alterations in PETCO2 (Study 6). CCA and MCA velocity wave morphology were assessed showing that with changes in PETCO2, changes in CBFV velocity wave were not reflected in the CCA trace (Study 7). In addition, further assessment of the CBFV velocity trace and the calculation of CrCP and the augmentation index suggested that with changes in PETCO2 cerebrovascular compliance and cerebrovascular tension, both thought to be components of cerebrovascular tone, change independently (Study 7). Combined, the results of the presented studies suggest that changes in cerebrovascular hemodynamics can be determined from alterations in the CBFV velocity waveform morphology. However, further work is required to determine how these variations relate to specific components of cerebrovascular tone, including alterations in cerebrovascular compliance and vascular tension, and how these variables change with acute and chronic alterations in cerebrovascular hemodynamics.

ABSTRACT Purpose: The primary aim of the study (i.e. Chapter 3) was to compare the magnitude of retinal vascular reactivity in arterioles of varying diameter in healthy, young subjects. The secondary aims were to determine: a) if there are any order effects in terms of provoking vasoconstriction or vasodilation first; and b) the repeatability of the vascular reactivity measurements. An additional aim (i.e. Chapter 4) was to determine the effect of healthy aging on the relationship between retinal vascular reactivity and vessel diameter. Method: The sample comprised 10 healthy, young subjects (mean age 26.5 years, SD 4.04) and 7 healthy, older subjects (mean age 55.43 years, SD 5.41). Each subject from the young age group attended for three sessions. The first session was used to determine eligibility and select hemodynamic measurement sites. At sessions 2 and 3, O2 and CO2 were sequentially administered to the subjects using a face mask and sequential re-breathing circuit (to maintain standardized hyperoxia and hypercapnia). The order of vasoconstriction and vasodilation was varied across sessions 2 and 3. The design of the protocol was simplified for the subjects from the older age group. Each subject from the older group attended for one visit. O2 and CO2 were administered to the subjects using a face mask and sequential re-breathing circuit. The order of gas provocation was varied among the subjects (i.e. hyperoxia or hypercapnia first). For both groups, measurements of vessel diameter, centerline blood velocity and derived blood flow were acquired at each condition (i.e. baseline, during stabilized vasoconstriction, vasodilation, and recovery) at two discrete measurement sites along the supero-temporal arteriole. Results: The results of the repeated measures ANOVA showed a significant difference between the narrow and wide measurement sites for the younger group for flow (p≤ 0.0003) and a significant influence of inspired gas provocation on flow for both protocols (p<0.0001). In addition, the interaction of measurement site and inspired gas provocation was significant (p<0.0001). The magnitude of retinal vascular reactivity showed a significantly greater blood flow response for the wide measurement site (p<0.0001). O2 provocation resulted in vasoconstriction that was still present up to 10 minutes after cessation of the stimulus (order effect of O2; p≤0.046). No such order effect was apparent for CO2 provocation (order effect of CO2; p=0.352). The group mean blood flow Coefficient of Repeatability (COR) for the narrow measurement site was 0.74 µl/min (relative to group mean flow of 4.85 µl/min ± SD 1.31) and for the wide measurement site was 1.49 µl/min (relative to group mean flow of 11.29 µl/min ± SD 3.55). There was no difference between the young and the older age groups in retinal vascular reactivity for both the narrow (two-tailed Student t-test, p=0.8692) and wide (two-tailed Student t-test, p=0.2795) measurement sites. Conclusion: This study demonstrated that the magnitude of retinal vascular reactivity was greater for arteriolar measurement sites with wider baseline vessel diameters. In addition, it demonstrated that hyperoxic provocation resulted in a persistent vasoconstriction up to 10 minutes after cessation of the stimulus. The study demonstrated that the repeatability of retinal blood flow measurements in absolute terms is lower for smaller diameter vessels. Finally, this study also suggests that age does not affect the relationship between retinal vascular reactivity and vessel diameter.

Atherosclerosis is a systemic disease occurring in specific sections of the cardiovascular tree such as the carotid and the coronary arteries. Previous studies proposed a strong correlation between plaque localization and blood flow patterns in specific sections of the arteries. In order to elucidate cellular mechanisms that contribute to atherosclerosis, standard cone-and-plate devices are widely used in experiments to reproduce in vitro the effect of different hemodynamic conditions on endothelial cells. In this study, a novel computational fluid dynamic (CFD) numerical code based on the immersed boundary method is developed to simulate this microscopic flow field under different geometries and flow conditions. A comprehensive validation of the CFD code is performed. Once validated, the code is used to analyze the flow field in the cone-and-plate device simulating conditions typically employed in endothelial cell experiments. No previous studies have yet been performed on the fluid dynamics of the cone-and-plate device when surfaces representing actual endothelial cell contours are modeled on the plate surface. This represents a great opportunity to correlate the fluid dynamics in the experimental device and the biochemical properties of the cells under specific flow conditions. The challenging aspect of the problem is represented by its different length scales. While the size of the cone-and-plate device is of the order of millimeters, the endothelial cells laying on the plate surface have size of the order of microns. The goal is to obtain a spatial resolution smaller than the height of the single cell. This allows us to investigate the biological features of the endothelial cells under shear stress in different areas of their membrane surface. This feature must be incorporated in the numerical grid, representing a challenging computational problem and is expected to be a major contribution of the research.

Multiple interacting mechanisms control the formation and dissolution of clots to maintain blood in a state of delicate balance. In addition to a myriad of biochemical reactions, rheological factors also play a crucial role in modulating the response of blood to external stimuli. The broad stimuli for clot formation were laid out, more than a century ago, in, what is now referred to as, Virchow’s triad. To date, a comprehensive model for clot formation and dissolution, that takes into account the biochemical, medical and rheological factors, has not been put into place, the existing models emphasizing either one or the other of the factors. In this dissertation, a model is developed for clot formation and dissolution that incorporates many of the relevant crucial factors that have a bearing on the problem. The model, though just a first step towards understanding a complex phenomenon goes further than previous models in integrating the biochemical, medical and rheological factors that come into play. The model is tested in some simple flow situations as part of an attempt to elucidate Virchow’s triad. Extensions to the model, along with detailed numerical studies, will hopefully aid in a clearer understanding of the phenomenon, and in making relevant clinical correlations.

Thesis (M.S.)--Rutgers University, 2009. / "Graduate Program in Biomedical Engineering." Includes bibliographical references (p. 60-66).