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Coupling of Flow and Oxygen Metabolism as Studied by BOLD fMRI. What Can We Measure and What Not?

 Peter C.M. van Zijl

The Russel H. Morgan Department of Radiology and Radiological Sciences, Division of MR

Research, Johns Hopkins University , Traylor Bldg. 217, 720 Rutland Ave. , Baltimore , MD USA

F.M. Kirby Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore , MD

In the last fifteen years, MRI has made much progress in providing non-invasive alternative methodologies for the quantification of physiological parameters in tissue, a field that previously was the exclusive domain of PET. It is now possible to assess cerebral blood flow (CBF), cerebral blood volume (CBV), and blood oxygenation. The ability to measure blood oxygenation using the BOLD effect has stimulated the publication of several procedures for quantifying the cerebral metabolic rate of oxygen metabolism (CMRO2 ). The mechanism of BOLD signal changes is well understood to be related to changes in the concentration of deoxyhemoglobin, which acts as a paramagnetic contrast agent in capillary and venous blood. The relative concentration of paramagnetic deoxyhemoglobin ([Hb]) to total hemoglobin ([Hbtot ]) in venous blood is:

[Hb] /[Hbtot ] 1−Yv 1−Ya OEF Ya [1].

Yv and Ya are the venous and arterial oxygen saturation fractions, respectively, and OEF is the oxygen extraction fraction, describing the ratio between oxygen consumption and delivery:

OEF  CMRO 2  CMRO 2

Ca CBF [Hbtot ] ⋅Ya CBF [2].

These equations show that the BOLD effect directly reflects the so-called “coupling” between CMRO2 and CBF and that a mismatch between these two parameters is necessary to measure this phenomenon. In addition, BOLD is very sensitive to total hemoglobin concentration,[Hbtot ], which is directly related to the hematocrit fraction (Hct). In most of the current fMRI literature, Hct is assumed to be constant during brain activation, but it is doubtful whether this is actually the case. Also, the BOLD effect depends on the arterial oxygen saturation fraction, Ya, a term necessary to properly describe hypoxia. These simple equations indicate that relative changes in CMRO2 can be measured by performing experiments in which the changes in blood flow and oxygenation are determined. However, BOLD fMRI does not measure oxygenation changes, but water signal intensity or transverse relaxation time changes, which are a function of venous oxygenation level. In addition, an imaging experiment is not just a local measurement of water signal in the venous vessels, but a measurement of water intensity in a voxel containing multiple types of tissue. In the most optimum situation, the voxel would contain only parenchyma, i.e. grey matter and microvessels (arterioles, venules, and capillaries). In practice, voxels contain parenchyma, CSF, and often some parts of larger vessels, especial draining veins. To make matters worse, when CBF changes, the blood volume (CBV) generally also changes. Furthermore, BOLD effects do not occur only inside the blood vessels (intravascular BOLD) but also around them (extravascular BOLD) and the extravascular effects are different around the microvasculature and macrovasculature and differ for T2 and T2 *. As if this is not enough, the Hct is also different between the microvasculature and large vessels. In order to be able to perform some quantification, most investigators have therefore resorted to trying to make some assumptions that seem reasonable under the particular experimental conditions and for the particular anatomy involved. A critical overview will be provided of what has been reported in the MRI literature with respect to the coupling of flow and metabolism. In addition, it will be shown that the recent availability of experiments to determine CBV changes without contrast agent provide novel information on the hemodynamic response during and following brain activation.