Absolute cerebral blood flow quantification with pulsed arterial spin labeling during hyperoxia corrected with the simultaneous measurement of the longitudinal relaxation time of arterial blood.

There is significant interest in the use of inhaled hyperoxic gas as a contrast agent in T2*-weighted images (1,2) and T1-weighted images (3), where the respective contrast mechanisms are the modulation of the local deoxyhemoglobin (dHb) concentration (the BOLD effect) and the paramagnetic effects of molecular oxygen itself (4). Hyperoxic contrast has a range of applications, including the calibration of quantitative BOLD fMRI data (5), the quantitative measurement of regional capillary-venous cerebral blood volume (CBV) (6), the partial pressure of oxygen in body fluids (7), and the characterization of ischemic lesions (8). As a contrast agent, oxygen inhalation is attractive because it is minimally invasive, widely available, has few contraindications, and exhibits fast washout times (9). However, hyperoxic gas inhalation, through increases in the arterial partial pressure of oxygen (PaO2) and hemoglobin saturation (SaO2), exerts significant effects on the vasculature and is not physiologically inert. Many studies have shown that oxygen has reduces cerebral blood flow (CBF) due to at least one independent vasoconstrictive mechanism, including the attenuation action of nitric oxide, an endogenous vasodilator (10-13). While the vasoconstrictive effect of oxygen is well known, the degree to which CBF changes occur during hyperoxia remains the subject of ongoing research. Moreover, if inhaled oxygen is to be used as a quantitative contrast agent, precise characterization of its changes to the underlying physiology is crucial. Several studies have used arterial spin labeling (ASL) approaches to investigate the regional CBF changes during hyperoxia (9,11,12,14-16). Although it is well-known that inhaled oxygen creates a significant reduction in the T1 of arterial blood (T1a) (4,17), and that T1a has a substantial effect on CBF measurements using ASL (18), only a small number of these studies have incorporated T1a changes in their CBF calculations (9,15). For some of these studies, the T1a changes during hyperoxia were assumed from the results of prior studies of arterial blood at 100% oxygen inhalation (15). Other studies modeled the expected change in T1a during hyperoxia at intermediate hyperoxia levels, since there are no established values of T1a in the literature for various oxygen concentration levels (9). These approaches may be problematic for several reasons. First, the methods used in these studies (4,17) to measure T1a are prone to several artifacts and errors. These include the inflow of fresh, un-inverted spins from outside the transmit coil, partial-voluming, pulsatility, and motion. Second, even under equivalent conditions of hyperoxia, T1a changes may vary significantly between individuals due to physiologic variations in the blood. Third, it is not clear how to effectively model the expected T1a changes at arbitrary oxygen concentration levels, since T1a may be influenced by various factors other than the concentration of molecular oxygen in the plasma (e.g., dHb concentration). In this study, our aim was to simultaneously measure CBF and T1a in vivo during various levels of hyperoxia. This will allow for an accurate correction of CBF for T1a on a per-subject basis. In particular, we wanted to explore the finding reported in previous studies (9,15) that CBF change measured during hyperoxia is dominated by a reduction in T1a. To achieve these measurements, we implemented pulsed ASL (PASL) approaches for both the measurement of T1a (19) and CBF that were very similar in implementation. This allowed for a simultaneous measurement of these parameters in the brain without moving the subject. These measurements, however, are presented with technical challenges that complicate their implementation in human studies. These include the requirement that the transmit coil is larger than the subject to avoid the contamination of the measurement from inflowing spins (19), in addition to the long scan times inherent to inversion-recovery measurements of T1. To solve these problems, adult rats were chosen as a model organism, since they experience similar physiological responses to humans in blood and brain tissue during hyperoxia.