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Establishing a foundation for physiological fMRI: How do we noninvasively quantify the human brain at work?


The development of functional magnetic resonance imaging (fMRI) caused a paradigm shift in the study of neuroscience. However, despite the boom in research, fMRI has had a much smaller impact in the clinical setting. This is due to the complexity of the blood- oxygenation level dependent (BOLD) signal and its lack of inherent physiological meaning. Instead, cerebral blood flow (CBF) and cerebral metabolism of oxygen (CMRO2) have been proposed as physiological indicators of neural activity, and noninvasive measurement of these parameters could lead to improved applicability to clinical problems. While arterial spin labeling (ASL) techniques are well-established for measuring baseline CBF and fractional changes in CBF to a stimulus, measurements of CMRO2 are more controversial. Some methods to estimate CMRO2 involve contrast injection or administration of special gases, which could potentially prevent their use in certain patient populations.

Here, the feasibility for quantitative measurements reflective of neural physiology is established. This is accomplished through a suite of tools to estimate specific physiological metrics that reflect baseline CBF and CMRO2 and their responses to a standard stimulus, without encumbering the patient. The techniques utilized are Velocity Selective Excitation and Arterial Nulling (VSEAN) to measure oxygen extraction fraction (OEF), which leads to the calculation of baseline CMRO2, and FLuid Attenuated Inversion Recovery-Gradient Echo Sampling of Spin Echo (FLAIR-GESSE) to calibrate baseline deoxyhemoglobin through R2', leading to fractional CMRO2 estimates. These, in combination with the latest BOLD/ASL acquisitions, form a toolbox that allows for full physiological quantification. Initial results demonstrate values of baseline CMRO2 that match previously reported results, as well as a close relationship between R2' data and widely-used gas method results. The toolbox is then applied to detecting changes in brain state induced by caffeine administration. Measurements in the pre- and post-caffeine states illustrate the ability of the toolbox to 1) reproduce known physiological changes due to caffeine and 2) significantly distinguish the change in brain state due to this intervention. These results demonstrate the use of physiological fMRI in providing a more detailed and reproducible picture of the human brain at work, paving the way for future clinical applications.

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