Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) provides a critical tool to the medical and scientific communities. Despite the indispensable role of the BOLD fMRI technique in mapping human brain function, its biophysical and physiological sources are not well known because the BOLD effect has a complex dependence on many parameters including cerebral blood flow (CBF), and venous cerebral blood volume (CBV). For full utilization of the capabilities of this technique, it is imperative to investigate the origin of BOLD signals and to determine the spatial limits of fMRI. This requires an in-depth examination of the physiological basis of fMRI signals. In this application, we aim to further elucidate sources of BOLD fMRI signals, and vascular responses induced by neural activity using the well-established cortical layer model in animals at 9.4T. The hypotheses to be tested are 1) intrinsic spatial specificity of the fMRI signal is improved with spin-echo BOLD technique at high fields, 2) hemodynamic change induced by neural activity is not widespread, and 3) blood volume change induced by neural activity is dominant in arterial vascularure. Conventional gradient-echo BOLD signals are sensitive to susceptibility changes in all sizes of venous vessels, with a spatial resolution closely related to the spacing between intracortical veins. To improve spatial specificity, the spin-echo technique can be applied because it will refocus the static susceptibility effects around large vessels. The ultimate limit of spatial resolution in fMRI techniques is dictated by vascular responses induced by neural activity. Based on CBV-weighted intrinsic optical imaging studies, the CBV change is diffuse and extends far beyond the actual neuronal activation site. Poor specificity may be due to the contamination by large surface vessels and/or poor spatial specificity in regulation of CBV response. This will be examined by CBV-weighted fMRI following an injection of a long half-life contrast agent. However, it is unknown whether CBV change induced by neural activity is dominant in artery or venous vasculatures. Determination of the exact source of CBV changes is crucial because the BOLD signal is dependent on both baseline venous CBV and its changes. Further, it is imperative to determine the inter-relationship between spin-echo BOLD, CBF, arterial CBV, and total CBV in order to understand the mechanism of BOLD signals. The long-term goal of these investigations is to determine the detailed biophysical mechanisms and origins of BOLD signals, and the inherent spatial limits of BOLD and CBV-weighted fMRI. This investigation combining MR physics and physiology will provide important insight into how finely the hemodynamic response is tuned to neural activity and will help to pinpoint the characteristics of the vasculature involved in blood flow regulation.
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