Knowledge of venous oxygenation (Yv) forms the cornerstone toward quantitative estimation of the brain’s oxygen extraction and consumption rate. However, measurements of these parameters are historically a niche market of Positron Emission Tomography (PET). Recently, a novel MRI pulse sequence was proposed that aims to estimate Yv via quantitative mapping of pure blood T2* in a vessel-specific manner in the presence of tissue partial voluming [1]. Despite the initial proof-of-principle, the validity of the method relative to other approaches and its sensitivity in detecting oxygenation changes are not established. In the present study, we aim to address the following issues: 1) while the previous study included both arteries and veins and did not differentiate high fidelity voxels from low ones, the present work devised an analysis pipeline that reports reliable venous voxels only in the final map; 2) while the previous study used a calibration plot based on literature, this study conducted in vitro experiments to obtain a calibration plot that matches exactly the sequence/parameter of the in vivo study; 3) we examined the sensitivity of the technique to hyperoxia challenge; 4) we validated the results with a more established TRUST MRI method [2], when evaluating global brain venous oxygenation.

Sequence and processing pipeline: This pulse sequence, T2*-Relaxation-Under-Phase-Contrast (TRUPC), was proposed recently and it is essentially a multi-echo phase-contrast sequence. It first separates out pure blood signal using phase contrast and then acquires different T2* weighted images from multiple gradient-echoes, the mono-exponential fit of which yields blood T2* even in the presence of tissue partial voluming (Figure 1). In this work, we devised the following analysis pipeline (Figure 2a) in order to provide an oxygenation map that only includes high-fidelity venous voxels. Arterial voxels will first be removed via a time-of-flight (TOF) angiogram, leaving only the venous voxels. The venous voxel mask is further refined by applying a threshold on delta R2/R2 of the fitting, weeding out voxels with poor goodness-of-fit. Finally, voxels with low S₀ were remove to further eliminate unreliable voxels from the map.

Blood calibration experiment: For the in vitro calibration, fresh bovine blood samples were scanned at 37^o using a TRUPC protocol identical to that used in humans, from which we obtained a plot of T2* dependence on both oxygenation (Y) and hematocrit (Hct).

Human experiment: Experiments were performed on a 3T (Philips). 4 subjects (2F, 26±2 yo) were studied under resting-state only but the TRUPC sequence was repeated to test the reproducibility. Another 4 subjects (3F, 25±3 yo) were recruited for the hyperoxia study. The subjects were first scanned with TRUPC under room-air breathing and again under hyperoxia state. The hyperoxic gas is expected to increase blood oxygenation. The imaging parameters for TRUPC were: 4 echoes; TR = 60ms; 1st TE/delta TE = 13ms/14ms; matrix size = 288x288x17; resolution = 0.7x0.7x5mm³; Venc = 9cm/s; flow encoding direction: anterior-posterior; acquisition time = 9:48min. For validation purposes, TRUST MRI was also performed.

Figure 2b shows the step-by-step outcome of oxygenation map using the proposed pipeline. As one can see, the original map contains both arterial and venous vessels. With the application of angiogram, many of the high-oxygenation (red), arterial voxels are eliminated. However, there is still a considerable number of red-colored voxels remaining. This is because fitting in the presence of large noise/fluctuation tends to result in high T2 values and this was verified by Monte Carlo simulations. Therefore, thresholding on delta R2/R2 and S₀ was applied and, with these additional criteria, the final remaining voxels manifested primarily venous oxygenation levels (Figure 2b), consistent with expectation. Coefficient-of-variation(CoV) of the Yv map was 6.2±0.87%, suggesting high reproducibility. Figure 3 shows the results of in vitro blood experiments, showing a strong dependence of T2* on Y but also affected by hematocrit to some extent. With results in Figure 3, venous T2* values can be converted to oxygenation. Figure 4a shows venous oxygenation maps during room air and hyperoxia from a representative subject. As expected, venous oxygenation increases globally when breathing hyperoxic gas. Across all subjects, Yv measured with TRUPC increased by 9.0±2.6% (p<0.01). Figure 4b shows a scatter plot between average Yv measured with TRUPC and global Yv measured with TRUST MRI. A strong correlation can be seen (p<0.0001) between the two measures. With the TRUPC MRI pulse sequence and the proposed analysis pipeline, it is feasible to obtain quantitative maps of venous oxygenation in the human brain.