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No description available.

No description available.

No description available.

Cerebral blood flow (CBF) is a biomarker for brain health, facilitating the advancement of studies on brain states in both healthy and diseased individuals. While there are indirect approaches of CBF based on human physiology, there is a need for technology that measures CBF directly and continuously. Laser speckle contrast imaging (LSCI) is an optical modality that measures changes in CBF by analyzing the blurring of speckle patterns. LSCI has been extensively employed to obtain two-dimensional blood flow maps in thinned-skull mouse brains and has found diverse applications in studies involving the retina, skin, and strokes. However, the effectiveness of LSCI has been limited in animal models due to the lack of depth-sensitivity. Speckle contrast optical spectroscopy (SCOS), an extension of LSCI for non-invasive human brain studies, has recently been developed to probe dynamics in deeper tissue regions by increasing the source-detector separation. But the low photon flux detected from human brain limits the usability of SCOS for brain activation measurements. To address these limitations, this thesis focuses on advancements made in laser speckle technology for improved measure of blood flow in both animal and human brains. Firstly, analytical and numerical methods have been developed for an interferometric LSCI system, which employs a heterodyne detection scheme to enhance CBF within the coherence volume in small animals. Next, a dynamic speckle model (DSM) is created to simulate the temporal evolution of the speckle patterns. DSM has been utilized to quantify the impact of noise sources on speckle contrast, particularly relevant in human brain measurements utilizing SCOS where low photon counts is a norm. Finally, a fiber-based SCOS system with a long source-detector separation has been presented to perform human brain activation studies. Through experiments involving three healthy subjects performing a mental subtraction task, changes in brain activation have been observed. Importantly, the SCOS system has demonstrated an order of magnitude improvement in the signal-to-noise ratio compared to the state-of-the-art diffuse correlation spectroscopy system.These methods serve as valuable tools to augment existing LSCI systems and promoting the widespread adoption of SCOS in human brain activation studies thus contributing to the development of future non-invasive, continuous, and cost-effective blood flow monitoring devices.

Localized pH changes have been suggested to occur in the brain during normal function. However, a lack of methods for non-invasively measuring pH with high spatial and temporal resolution limits current knowledge of brain pH dynamics. Here I report that a magnetic resonance imaging (MRI) strategy named T1 relaxation in the rotating frame (T1ρ) is sufficiently sensitive to detect widespread pH changes in the mouse and human brain evoked by systemically manipulating carbon dioxide (CO2) or bicarbonate (HCO3). Moreover, T1ρ detected changes suggesting a localized acidosis in the human visual cortex induced by a flashing checkerboard. Lactate measurements and pH-sensitive 31P spectroscopy at the same site also suggest a localized acidosis. Consistent with the established role for pH in blood flow recruitment, T1ρ correlated with blood oxygenation level dependent contrast (BOLD), although T1ρ was directly sensitive to blood oxygen content. These observations provide the strongest evidence thus far for localized pH fluctuations in the human brain during normal function. Furthermore, they suggest a novel functional imaging strategy based on pH that is independent of traditional fMRI contrast mechanisms. Possible sources of acidosis include local metabolism, which is likely to correlate with the degree of stimulation and the associated changes in local neural activity. Therefore, we hypothesized that T1ρ and pH changes would increase with increasing stimulation frequency. To test this hypothesis, we used a full-field visual flashing checkerboard and varied the frequency between 1, 4, and 7Hz. The response was imaged with T1ρ, BOLD, and 31P spectroscopy. Supporting our hypothesis, we found that increasing stimulation frequency increased responses measured by all three imaging modalities. The activation area detected by T1ρ overlapped to a large degree with that detected by BOLD, although the T1ρ response area was significantly smaller. 31P spectroscopy detected a greater acidosis with the higher stimulation frequencies. These observations suggest that, similar to the BOLD response, the magnitude of the T1ρ and pH response depends on stimulation frequency and is thus likely to be activity-dependent. Brain acidosis is the end product of energy metabolism. Metabolically active cells lower local pH, the detection of which could help pinpoint regions activated by sensory stimuli, emotion, or cognitive task. fMRI mostly relies on BOLD changes in the venous system while arterial spin labeling (ASL) enables changes in tissue perfusion resulting from local cerebral blood flow (CBF) changes. BOLD contrast can be significantly distant from the actual site of neuronal activity because it relies on changes of the local magnetic field within veins. The venous contribution results in a loss of spatial specificity and spatial resolution of the BOLD response. In addition, the hemodynamic response to brief periods of neural activity is delayed. However, ASL contrast originates predominantly from tissue and capillaries. Even though functional signal changes detected by ASL have superior spatial and temporal resolution as compared to BOLD contrast, ASL contrast still suffers from poor temporal resolution due to delays in the hemodynamic response resulting from neurovascular coupling. Therefore, the ability to measure pH dynamics may provide a more localized and direct measure of brain activity. We hypothesized that pH-sensitive T1ρ response in the visual cortex will temporally precede the hemodynamic response measured by functional imaging including BOLD and ASL contrast since local acidosis evoked by neural activity may drive the hemodynamic response. To test this hypothesis, dynamic imaging was performed using T1ρ, BOLD, and ASL while viewing a phase-encoded expanding ring stimulus which induces travelling waves of neural activity in the visual cortex. We calculated the phase maps for the eccentricity across their occipital cortices for each of functional signal and compared the T1ρ temporal resolution with the hemodynamic response. This study suggests that T1ρ signal has a higher temporal resolution as compared to the hemodynamic response. This is further evidence that the T1ρ signal is not sensitive to blood oxygenation or other blood factors that might alter T1ρ. In conclusion, T1ρ imaging has the potential to provide a new functional imaging marker that may be more specific to the area of brain activity. Therefore, it is possible that by non-invasively detecting pH dynamics in the human brain, T1ρ MRI could offer a novel, more direct approach to map brain function. A number of psychiatric and neurological disorders could potentially benefit from the ability to study dynamic pH changes.

There is a need for improved understanding of interactions between electromagnetic fields and biological tissues. In this thesis, the effects of exposure to 50 Hz magnetic fields, associated with power generation and use, and 1800 MHz fields associated with mobile phones were investigated with particular focus on the plastic processes that are involved in cognitive function. After repeated, daily exposure of young adult C57Bl/6J mice to an 1800 MHz field at 3 W/kg, very subtle changes in expression of genes involved in synaptic plasticity were found (p < 0.05). Spatial memory as measured in the water maze was not significantly affected by exposure. Exposure at 0.3 W/kg did not significantly affect any of the endpoints (p > 0.05). Indications of a greater sensitivity to exposure at 3 W/kg were seen in a senescence accelerated prone mouse model (SAMP8) compared to a resistant strain (SAMR1). However, only subtle effects of exposure were seen. Exposure of young C57Bl/6J mice to a 50 Hz field at 100 or 300 μT induced small but significant changes in expression in synaptic plasticity related genes (p < 0.05). Furthermore, repeated exposure significantly increased microglial density in the dorsal hippocampus (p < 0.05) and slightly decreased proliferation in the dorsal hippocampus (100 μT, p < 0.05). Spatial memory was not significantly affected by exposure. Acute exposure to a 50 Hz magnetic field for 30 minutes at 300 or 580 μT did not affect the adrenal response to a nocturnal white or blue light shock, while exposure at 580 μT in the absence of light significantly decreased per1 expression in the adrenal glands (p < 0.05), but not in the liver or dorsal hippocampus. Exposure at 580 μT for 24 hours had only minor transient effects on the rhythmic expression of the core clock genes. In summary, exposure to 50 Hz or 1800 MHz fields caused subtle and transient changes to some molecular mechanisms and cells involved in cognitive function and circadian rhythm control.

The analysis of hemodynamic parameters and functional reactivity of cerebral capillaries is still controversial. The detailed mapping of tissue oxygen levels on the scale of micrometers cannot be obtained by means of an experimental approach, necessitating the use of theoretical methods in this investigating field. To assess the hemodynamics and oxygen transport in the cortical capillary network, 2D and 3D generic models are constructed (non-tree like) using random voronoi tessellation in which each edge represents a capillary segment. The modelling presented here is based on morphometric parameters extracted from physiological data of the cortex in which the spatial distribution of the diameter of the capillary is based on a Modified Murray method. This method led to a proper link between the diameter topology and flow pattern such that the maximum efficiency for flowing blood is concluded in the model of cortical capillary network. The approach is capable of creating an appropriate generic, realistic model of a cerebral capillary network relating to each part of the brain cortex because its geometrical density is able to vary the capillary density. The pertinent hemodynamic parameters are obtained by numerical simulation based on effective blood viscosity as a function of hematocrit and microvessel diameter, ESL (endothelial surface layer) effect, phase separation and plasma skimming effects. Using a solution method of the Green's function, the model is numerically developed to provide different simulations of oxygen transport for varying perfusion and metabolism in a mesoscale model of the cortical capillary network, bridging smaller and larger scale phenomena. The analysis of hemodynamic parameters (blood flow rate, velocity and hematocrit) demonstrates a consistency with the experimental observation. The distribution pattern of wall shear stress (WSS) in the network model supports the physiological data which in turn represents a proper matching between the hemodynamics and morphometrics in the cerebral capillary network. The distributions of blood flow throughout the 2D and 3D models seem to confirm the hypothesis in which all capillaries in a cortical network are recruited at rest (normal condition). The predictions showed a heterogeneous distribution in the flow pathways (aspect of length and inflow) and the pertinent transit time of red blood cell (RBC) in the network model which is dependent on varying perfusion rates. The analyses of oxygen transport in the model has demonstrated that oxygen levels in the tissue are sensitively dependent on the microvascular architecture and flow distribution. Unlike the homogeneous compartmental models, the mesoscale model presented in this study led to a prediction of tissue PO2 gradients throughout the tissue and a spatial distribution of tissue PO2 on the micron-scale for varying perfusion and metabolism. The predicted nonlinear changes in the oxygen extraction fraction (OEF) of the model as a function of the perfusion rate provide a basis for the quantitative interpretation of functional magnetic resonance imaging (fMRI) studies in terms of changes in local perfusion. The model is capable of predicting the brain oxygen metabolism under both normal and disease states, particularly, local hypoxia and local ischemia caused by misery perfusion syndrome. The hypoxic states for different perfusion rates and oxygen consumption rates demonstrated that in a significant decrease in brain perfusion (as can occur in stroke), the tissue hypoxia can be avoided by a moderate reduction in oxygen consumption rate. Increasing oxygen consumption rates (a realization of spatiotemporal stimulation of neural tissue) with respect to maintaining the tissue PO2 in the model led to a predicted flow-metabolism coupling in the model which supports the experimental studies of somatosensory and visual stimulation in humans by positron emission tomography (PET) and functional MRI (magnetic resonance imaging). A disproportionately large increase in blood supply is required for a small increase in the metabolic utilization (oxygen consumption rate) which in turn, is strongly dependent on the resting OEF such that the magnitude of the blood flow increases in the higher resting OEF.

Modes of information processing were examined for 91 subjects aged between 5 years 7 months and 6 years 3 months, using A.R. Luria's model of brain function as the theoretical basis of the study. A factor analysis of the results of six psychometric tests administered to all subjects indicated the presence of two distinct factors. These were hypothesised to represent the separate contributions of simultaneous and successive synthesis. Further separate factor analyses, of the six psychometric tests and tests of M-Space (derived from the work of R. Case) and tests of standard school assessment tasks (that were also administered to the subjects), were performed. The results indicated that although both modes of synthesis are available to children of this age, simultaneous synthesis is not a potent factor in school learning. A further exploratory study was carried out using the same 91 subjects. Subjects were given a series of verbal subtraction problems requiring understanding of mathematical relationships, and randomly assigned to two presentation groups. One group received pictorial information in addition to the verbal presentation. The other group received concrete materials. A multiple regression analysis was performed on the whole group using factor scores for simultaneous and successive syntheses (derived from the factor analysis of the six psychometric tests) as independent variables and criterion test scores for the verbal subtraction problems as the dependent variable. The analysis indicated that although neither aptitude for successive synthesis nor aptitude for simultaneous synthesis had predictive value for this kind of probelm solving, simultaneous synthesis was possibly the predominant mode of information processing. Further multiple regression analyses performed on each of the presentation groups indicated an interaction between successive synthesis and the modes of presentation of information. Due to the small numbers of subjects in each presentation group this result was inconclusive.