The ability to measure the effects of local alterations in blood flow, blood volume and oxygenation by nuclear magnetic resonance has stimulated a surge of activity in functional MRI of many organs, particularly in its application to cognitive neuroscience. However, the exact description of these effects in terms of the interrelations between the MRI signal changes and the basic physiological parameters has remained an elusive goal. We here present this fundamental theory for spin-echo signal changes in perfused tissue and validate it in vivo in the cat brain by using the physiological alteration of hypoxic hypoxia. These experiments show that high-resolution absolute blood volume images can be obtained by using hemoglobin as a natural intravascular contrast agent. The theory also correctly predicts the magnitude of spin-echo MRI signal intensity changes on brain activation and thereby provides a sound physiological basis for these types of studies.

The oxygen extraction ratio (OER) of a tissue describes the interplay between oxygen delivery and consumption and, as such, directly reflects the viability and activity of any organ. It is shown that OER can be quantified using a single magnetic resonance imaging observable, namely the relaxation time T2 of venous blood draining from the tissue. This principle is applied to study local OER changes in the brain on visual stimulation in humans, unambiguously demonstrating a mismatch between changes in blood flow and oxygen metabolism on activation.

The hypothesis was tested that hypoperfused brain regions, such as the ischemic penumbra, are detectable by reductions in absolute transverse relaxation time constant (T2) using magnetic resonance imaging (MRI). To accomplish this, temporal evolution of T2 was measured in several models of hypoperfusion and focal cerebral ischemia in the rat at 9.4 T. Occurrence of acute ischemia was determined through the absolute diffusion constant D(av) = 1/3 TraceD, while perfusion was assessed by dynamic contrast imaging. Three types of regions at risk of infarction could be distinguished: (1) areas with reduced T2 (4% to 15%, all figures relative to contralateral hemisphere) and normal D(av), corresponding to hypoperfusion without ischemia; (2) areas with both reduced T2 (4% to 12%) and D(av) (22% to 49%), corresponding to early hypoperfusion with ischemia; (3) areas with increased T2 (2% to 9%) and reduced D(av) (28% to 45%), corresponding to irreversible ischemia. In the first two groups, perfusion-deficient regions detected by bolus tracking were similar to those with initially reduced T2. In the third group, bolus tracking showed barely detectable arrival of the tracer in the region where D(av) was reduced. We conclude that T2 reduction in acute ischemia can unambiguously identify regions at risk and potentially discriminate between reversible and irreversible hypoperfusion and ischemia.

The ability of transverse nuclear magnetic resonance relaxation time, T2, to reveal acutely reduced CBF was assessed using magnetic resonance imaging (MRI). Graded reduction of CBF was produced in rats using a modification of Pulsinelli's four-vessel occlusion model. The CBF in cerebral cortex was quantified using the hydrogen clearance method, and both T2 and the trace of the diffusion tensor (Dav = 1/3TraceD) in the adjacent cortical tissue were determined as a function of reduced CBF at 4.7 T. A previously published theory, interrelating cerebral hemodynamic parameters, hemoglobin, and oxygen metabolism with T2, was used to estimate the effects of reduced CBF on cerebral T2. The MRI data show that T2 reduces in a U-shape manner as a function of CBF, reaching a level that is 2.5 to 2.8 milliseconds (5% to 6%) below the control value at CBF, between 15% and 60% of normal. This reduction could be estimated by the theory using the literature values of cerebral blood volume, oxygen extraction ratio, and precapillary oxygen extraction during compromised CBF. Dav dropped with two apparent flow thresholds, so that a small 11% to 17% reduction occurred between CBF values of 16% to 45% of normal, followed by a precipitous collapse by more than 20% at CBF below 15% of normal. The current data show that T2 can be used as an indicator of acute hypoperfusion because of its ability to indicate blood oxygenation level-dependent phenomena on reduced CBF.

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Summary:The ability of the magnetic resonance imaging transverse relaxation time, R2 = IIT2, to quantify cerebral blood volume (CBV) without the need for an exogenous con trast agent was studied in cats (n = 7) under pentobarbital anesthesia. This approach is possible because R2 is directly affected by changes in CBF, CBV, CMR02, and hematocrit (Hct), a phenomena better known as the blood-oxygenation level-dependent (BOLD) effect. Changes in CBF and CBV were accomplished by altering the carbon dioxide pressure, Paco2, over a range from 20 to 140 mm Hg. For each Paco2 value, R2 in gray and white matter were determined using MRI, and the whole-brain oxygen extraction ratio was obtained from arteriovenous differences (sagittal sinus catheter). Assuming a Recent advances in functional magnetic resonance im aging (MRI) have allowed the design of MRI techniques for quantitative determination of hemodynamic param- oxygen extraction ratio; R2, transverse relaxation time constant; R�. effective transverse relaxation time constant, equals R2 plus coherent dephasing effects owing to local field inhomogeneities and suscepti bility differences; S, signal attenuation; SE, spin echo; TE, echo time; TR, repetition time; Xlicoxy' fraction of deoxygenated hemoglobin; Yo' arterial oxygenation fraction; T, lifetime between exchanges; �w, sus ceptibility shift difference; T C PMG' delay for a single echo refocusing in a Carr-Purcell-Meiboom-Gill experiment. 809constant CMR02, the microvascular CBV was obtained from an exact fit to the BOLD theory for the spin-echo effect. The resulting CBV values at normal Paco2 and normalized to a common total hemoglobin concentration of 6.88 mmollL were 42 ± 18 fLLlg (n = 7) and 29 ± 19 fLLlg (n = 5) for gray and white matter, respectively, in good agreement with the range of literature values published using independent methodologies. The present study confirms the validity of the spin-echo BOLD theory and, in addition, shows that blood volume can be quan tified from the magnetic resonance imaging spin relaxation rate R2 using a regulated carbon dioxide experiment. Key Words: Spin-echo-BOLD-MRI-Cerebral blood volume-Carbon dioxide-Transverse relaxation rate R2.eters. Approaches to quantify cerebral blood volume (CBV) generally involve injection of a paramagnetic contrast agent (Belliveau et a!., 1990), whereas CBF quantification has used either contrast agents (Hamberg et a!., 1993; Kucharczyk et aI., 1993; Guckel et ai, 1994) or frequency labeling of arterial water nuclei Kim, 1995). Analogous to radioactive tracer methods, these new MRI techniques require either the assumption or measurement of an ar terial input function. Eliminating the need for such a function using a natural contrast agent studied under equilibrium conditions would be beneficial. Magnetic resonance imaging has the capability of doing this through the so-called blood-oxygenation-Ievel dependent (BOLD) effect (Ogawa et aI., 1990(Ogawa et aI., , 1992(Ogawa et aI., , 1993a(Ogawa et aI., , 1993bMoonen et a!., 1990;Prielmey...

Nuclear magnetic resonance imaging (MRI) was used to study dynamics of maturation and the size of ischaemic stroke lesions in rats with greatly increased activity of ornithine decarboxylase (ODC). Syngenic rats, either with or without chronic pre-ischaemic treatment with an ODC inhibitor, alpha-difluoromethylornithine (DFMO), as well as ODC-overexpressing transgenic rats were subjected either to transient middle cerebral artery (MCA) occlusion or permanent occlusion of the cortical branch of MCA. The two models were chosen to assess the role of ODC activity in damage caused by ischaemia and reperfusion, respectively. Diffusion of water was quantified by means of the trace of the diffusion tensor (D(av) = 1/3 Trace D) to assess the extent of energy failure and cytotoxic oedema, whereas the spin-spin relaxation time (T2) was used as a quantitative indicator of irreversible damage by MRI. Exposure to transient MCA occlusion resulted in significantly smaller stroke lesions in the ODC-overexpressing transgenic (246+/-14 mm3) than in syngenic (320+/-9 mm3) or DFMO-treated (442+/-63 mm3) rats as determined 48 h after the occlusion. The differences in sizes were due to smaller lesions in the cortical tissue (transgenic vs. syngenic) or both in cortical and striatal regions (transgenic vs. DFMO-treated animals). The degree of irreversible oedema was greater in DFMO-treated rats than in syngenic or transgenic animals indicating accelerated development of a permanent damage in the absence of ODC induction. Cortical infarct following permanent MCA occlusion developed faster in the DFMO-treated than in syngenic or transgenic rats as the lesion sizes at 10 h were 26.2+/-4.3 mm3, 14.2+/-2.3 mm3 and 12.3+/-1.9 mm3, respectively. However, the stroke volumes by 48 h were not statistically different in the three animal groups. The present data demonstrate that ODC activation is an endogenous neuroprotective measure in transient cerebral ischaemia.

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