BOLD effects in MR images

Hemoglobin without bound oxygen molecules, deoxyhemoglobin, is paramagnetic because of the high spin state (S = 2) of the heme iron. In contrast, oxygen-bound hemoglobin, oxyhemoglobin, has low spin (S = 0) and is diamagnetic (Pauling &Coryl 1936). The presence of deoxyhemoglobin in red blood cells makes their magnetic susceptibility different from the diamagnetic plasma in blood and, similarly, induces a difference in magnetic susceptibility between the blood and the surrounding tissue. In the large homogenous magnetic fields used in MRI, compartmentalized susceptibility differences induce small magnetic field distortions in the blood as well as in the surrounding extra-vascular area. Water protons in these areas sense these field distortions, which are reflected in the signal decay process, characterized by T2 (spin echo) or T2*(gradient echo) relaxation. When the content of deoxyhemoglobin changes in the blood, the relaxation process of water protons is modified and one can see these changes in MRI. The image intensity that varies with deoxyhemoglobin content has been termed Blood Oxygenation Level Dependent (BOLD) and was suggested for potential use in functional study of the brain by Ogawa et al (1990). It should be noted that Thulborn et al showed, in their in vitro blood experiments, that blood water T2 varies with deoxyhemoglobin content (Thulborn et al 1982).
The era of BOLD-based functional MRI (using the endogenous contrast agent, deoxyhemoglobin) started with three papers that appeared in 1992 (Bandettini et al 1992, Kwong et al 1992, Ogawa et al 1992) (see Raichle 2000 for a historical perspective on fMRI development).
Prior to these reports, another fMRI method for detection of a functional response in the human brain was published in 1991 (Belliveau et al 1991), using an exogenous contrast agent injected into the blood stream. The measurement was only possible during the time window when the agent passed through areas of interest in the brain.