The fundamental discovery by Ogawa and coworkers (1) of blood oxygenation level-dependent (BOLD) contrast in MRI opened up broad opportunities to study the hemodynamic properties of the brain. While the "dynamic" properties of BOLD contrast during functional activation have received much consideration, very little attention has been paid to the nature of BOLD contrast during the resting or baseline state of the brain. Raichle et al. (2) identified the baseline state of the normal human brain in terms of the brain tissue oxygen extraction fraction (OEF). OEF maps in subjects who are resting quietly with their eyes closed define a baseline level of neuronal activity. OEF maps in normal resting humans demonstrate remarkable uniformity despite substantial regional variations in CBF and CMRO 2 (3,4). Understanding brain function in the baseline state is important for understanding normal human performance because it accounts for most of the enormous energy budget of the brain, whereas evoked activity represents very small incremental changes (5). Such an understanding is also crucial for deciphering the consequences of baseline-state impairment by diseases of the brain such as stroke (6) and Alzheimer's disease (7,8). Importantly, the OEF has been shown to be an accurate predictor of subsequent stroke occurrence in patients with cerebrovascular disease (9,10). Previous studies were conducted using PET imaging techniques; however, such studies would be more available for research and clinical applications if they could be performed based on MRI methods. One such MRI approach is discussed in this article.The magnetic field inside practically any system that is put into an MRI scanner is always inhomogeneous. The relative scale of this inhomogeneity compared to an imaging voxel can be roughly divided into three categories: macroscopic, mesoscopic, and microscopic (11). These three types of inhomogeneities all affect MRI signal formation. The macroscopic scale refers to magnetic field changes that occur over distances that are larger than the dimensions of the imaging voxel. Macroscopic field inhomogeneities arise from magnet imperfections, body-air interfaces, large (compared to voxel size) sinuses inside the body, etc. These field inhomogeneities are mostly undesirable in MRI because they generally provide no information of physiologic or anatomic interest. Rather, they lead to effects such as signal loss in gradient-echo (GRE) imaging, and image spatial distortions in both GRE and spin-echo (SE) imaging. The microscopic scale refers to changes in magnetic field over distances that are comparable to atomic and molecular lengths (i.e., over distances that are orders of magnitude smaller than the imaging voxel dimensions). Fluctuating microscopic field inhomogeneities lead to the irreversible signal dephasing characterized by the T 2 relaxation time constant, as well as to the longitudinal magnetization changes characterized by the T 1 relaxation time constant. The mesoscopic scale refers to distances that are smaller th...

Recently reported contrast in phase images of human and animal brains obtained with gradient-recalled echo MRI holds great promise for the in vivo study of biological tissue structure with substantially improved resolution. Herein we investigate the origins of this contrast and demonstrate that it depends on the tissue ''magnetic architecture'' at the subcellular and cellular levels. This architecture is mostly determined by the structural arrangements of proteins, lipids, non-heme tissue iron, deoxyhemoglobin, and their magnetic susceptibilities. Such magnetic environment affects/shifts magnetic resonance (MR) frequencies of the water molecules moving/diffusing in the tissue. A theoretical framework allowing quantitative evaluation of the corresponding frequency shifts is developed based on the introduced concept of a generalized Lorentzian approximation. It takes into account both tissue architecture and its orientation with respect to the external magnetic field. Theoretical results quantitatively explain frequency contrast between GM, WM, and CSF previously reported in motor cortex area, including the absence of the contrast between WM and CSF. Comparison of theory and experiment also suggests that in a normal human brain, proteins, lipids, and non-heme iron provide comparable contributions to tissue phase contrast; however, the sign of iron and lipid contributions is opposite to the sign of contribution from proteins. These effects of cellular composition and architecture are important for quantification of tissue microstructure based on MRI phase measurements. Also theory predicts the dependence of the signal phase on the orientation of WM fibers, holding promise as additional information for fiber tracking applications. cellular architecture ͉ contrast mechanisms ͉ grey matter ͉ white matter

Quantitative evaluation of brain hemodynamics and metabolism, particularly the relationship between brain function and oxygen utilization, is important for understanding normal human brain operation as well as pathophysiology of neurological disorders. It can also be of great importance for evaluation of hypoxia within tumors of the brain and other organs. A fundamental discovery by Ogawa and co-workers of the BOLD (Blood Oxygenation Level Dependent) contrast opened a possibility to use this effect to study brain hemodynamic and metabolic properties by means of MRI measurements. Such measurements require developing theoretical models connecting MRI signal to brain structure and functioning and designing experimental techniques allowing MR measurements of salient features of theoretical models. In our review we discuss several such theoretical models and experimental methods for quantification brain hemodynamic and metabolic properties. Our review aims mostly at methods for measuring oxygen extraction fraction, OEF, based on measuring blood oxygenation level. Combining measurement of OEF with measurement of CBF allows evaluation of oxygen consumption, CMRO2. We first consider in detail magnetic properties of blood – magnetic susceptibility, MR relaxation and theoretical models of intravascular contribution to MR signal under different experimental conditions. Then, we describe a “through-space” effect – the influence of inhomogeneous magnetic fields, created in the extravascular space by intravascular deoxygenated blood, on the MR signal formation. Further we describe several experimental techniques taking advantage of these theoretical models. Some of these techniques - MR susceptometry, and T2-based quantification of oxygen OEF – utilize intravascular MR signal. Another technique – qBOLD – evaluates OEF by making use of through-space effects. In this review we targeted both scientists just entering the MR field and more experienced MR researchers interested in applying advanced BOLD-based techniques to study brain in health and disease.

Key words: OEF; BOLD; qBOLD; brain metabolism; brain hemodynamics; fMRIWhile the dynamic properties of blood oxygenation level dependent (BOLD) contrast in MRI during functional activation have received much consideration, very little attention has been paid to the nature of the BOLD contrast during the resting or baseline level of neuronal activity in the brain. Because "resting brain" is responsible for approximately 20% of total human body oxygen consumption (1,2), understanding brain functioning in the baseline state is important for understanding brain performance in health and disease. One of the important parameters defining oxygen consumption is oxygen extraction fraction (OEF) -the percent of the oxygen removed from the blood by tissue during its passage through the capillary network. Previously, Raichle et al. (2,3) used this parameter to characterize the baseline state of the normal human brain. Such a characterization is germane because OEF maps of normal human subjects, resting quietly with their eyes closed, demonstrate remarkable uniformity (2,4) despite substantial regional variations of cerebral blood flow and the cerebral metabolic rate of oxygen consumption (2,3). This uniformity of the OEF in the absence of specific goal-directed activities supports the hypothesis that an established equilibrium exists between the local metabolic requirements necessary to sustain a long term modal level of neural activity and the level of blood flow in a particular region.Thus far most quantitative imaging studies mapping tissue OEF were conducted using oxygen-15 based positron emission tomography (PET) imaging techniques (5). The advent of BOLD MR imaging initiated by Ogawa et al. (6) opened new opportunities to noninvasively study brain hemodynamics. BOLD approach capitalizes on the fact that deoxygenated blood has different magnetic susceptibility as compared to oxygenated blood (7), which in turn has magnetic susceptibility similar to the tissue (6). Due to this effect, the deoxyhemoglobin containing part of the blood vessel network in the brain creates mesoscopic field inhomogeneities in the surrounding tissue leading to more rapid MRI signal decay than from standard T2 decay alone. Because these field inhomogeneities are tissue specific, measuring the MRI signal decay rate may provide information on the tissue structure and functioning. Previously this lab has developed a theoretical model of BOLD contrast that analytically connects the BOLD signal to hemodynamic parameters such as the deoxyhemoglobincontaining blood volume (DBV), deoxyhemoglobin concentration, and OEF (8). A subsequent publication (9) quantitatively validated important features of the model in phantom studies and developed a theoretical background and experimental method (based on the Gradient Echo Sampling of Spin Echo (GESSE) sequence) that allows the separation of mesoscopic field inhomogeneity effects from both macroscopic and microscopic inhomogeneities. Such separation allows one to take full advantage of the mesoscopic, tissue...

Defining the biophysics underlying the remarkable MRI phase contrast reported in high field MRI studies of human brain would lead to more quantitative image analysis and more informed pulse sequence development. Toward this end, the dependence of water 1H resonance frequency on protein concentration was investigated using bovine serum albumin (BSA) as a model system. Two distinct mechanisms were found to underlie a water 1H resonance frequency shift: (i) a protein-concentration-induced change in bulk magnetic susceptibility, causing a shift to lower frequency, and (ii) exchange of water between chemical-shift distinct environments, i.e., free (bulk water) and protein-associated (“bound”) water, including freely exchangeable 1H sites on proteins, causing a shift to higher frequency. At 37°C the amplitude of the exchange effect is roughly half that of the susceptibility effect.