Functional magnetic resonance imaging (fMRI) is an essential part of many basic neuroscience studies, providing a powerful tool for mapping patterns of activation in the working human brain. However, these techniques have been slow to move into the clinical realm, due both to a lack of sensitivity of current techniques and also to a lack of understanding of the nature and variability of the local hemodynamic response and the associated Blood Oxygenation Level Dependent (BOLD) signal response to activation. ? ? Because the hemodynamic response (HR) is the key physiological process in the brain linking neural activity with blood flow and energy metabolism, a detailed characterization of the HR has the potential to provide a powerful probe for early assessment of disease and for investigations of the pathophysiology involved. There are three problems blocking progress in the development of these clinical applications: 1) The BOLD effect is highly variable even in healthy subjects, making it difficult to detect meaningful differences between individual subjects, 2) Nonlinearities in the BOLD response introduce a strong dependence on the experimental design used, and 3) The interpretation of alterations in the BOLD response observed in a disease population is intrinsically ambiguous because the BOLD effect depends on combined changes in cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral blood volume (CBV). ? ? The basis for this proposal is the hypothesis that simultaneous measurement of the CBF response and the BOLD response using arterial spin labeling (ASL) techniques, when analyzed with a dynamic model for the HR, will greatly expand the specificity and reliability of HR measurements. To validate the feasibility of this approach we will: 1) verify that the proposed model is adequate for describing the CBF and BOLD responses by testing whether the model parameters calculated with one experimental design allow accurate prediction of the responses with a different experimental design; 2) determine the reproducibility of the HR parameter measurements in repeated studies on the same subject, and assess the variability of the parameters in young healthy adults; 3) determine the degree to which variations in resting CBF, CMRO2 changes and CBV changes contribute to the variability of the BOLD response, and 4) determine whether there is a significant variation in the HR parameters with healthy development and aging.
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