Ensemble Kalman inversion for magnetic resonance elastography.

Magnetic resonance elastography (MRE) is an MRI-based diagnostic method for measuring mechanical properties of biological tissues. MRE measurements are processed by an inversion algorithm to produce a map of the biomechanical properties. In this paper a new and powerful method (ensemble Kalman inversion with level sets (EKI)) of MRE inversion is proposed and tested. The method has critical advantages: material property variation at disease boundaries can be accurately identified, and uncertainty of the reconstructed material properties can be evaluated by consequence of the probabilistic nature of the method. EKI is tested in 2D and 3D experiments with synthetic MRE data of the human kidney. It is demonstrated that the proposed inversion method is accurate and fast.

In silicoevaluation and optimisation of magnetic resonance elastography of the liver.

Objective.Magnetic resonance elastography (MRE) is widely adopted as a biomarker of liver fibrosis. However,in vivoMRE accuracy is difficult to assess.Approach.Finite element model (FEM) simulation was employed to evaluate liver MRE accuracy and inform methodological optimisation. MRE data was simulated in a 3D FEM of the human torso including the liver, and compared with spin-echo echo-planar imaging MRE acquisitions. The simulated MRE results were compared with the ground truth magnitude of the complex shear modulus (∣G*∣) for varying: (1) ground truth liver ∣G*∣; (2) simulated imaging resolution; (3) added noise; (4) data smoothing. Motion and strain-based signal-to-noise (SNR) metrics were evaluated on the simulated data as a means to select higher-quality voxels for preparation of acquired MRE summary statistics of ∣G*∣.Main results.The simulated MRE accuracy for a given ground truth ∣G*∣ was found to be a function of imaging resolution, motion-SNR and smoothing. At typical imaging resolutions, it was found that due to under-sampling of the MRE wave-field, combined with motion-related noise, the reconstructed simulated ∣G*∣ could contain errors on the scale of the difference between liver fibrosis stages, e.g. 54% error for ground truth ∣G*∣ = 1 kPa. Optimum imaging resolutions were identified for given ground truth ∣G*∣ and motion-SNR levels.Significance.This study provides important knowledge on the accuracy and optimisation of liver MRE. For example, for motion-SNR ≤ 5, to distinguish between liver ∣G*∣ of 2 and 3 kPa (i.e. early-stage liver fibrosis) it was predicted that the optimum isotropic voxel size is 4-6 mm.

MR elastography to measure the effects of cancer and pathology fixation on prostate biomechanics, and comparison with T 1, T 2 and ADC.

MRI is under evaluation for image-guided intervention for prostate cancer. The sensitivity and specificity of MRI parameters is determined via correlation with the gold-standard of histopathology. Whole-mount histopathology of prostatectomy specimens can be digitally registered to in vivo imaging for correlation. When biomechanical-based deformable registration is employed to account for deformation during histopathology processing, the ex vivo biomechanical properties are required. However, these properties are altered by pathology fixation, and vary with disease. Hence, this study employs magnetic resonance elastography (MRE) to measure ex vivo prostate biomechanical properties before and after fixation. A quasi-static MRE method was employed to measure high resolution maps of Young's modulus (E) before and after fixation of canine prostate and prostatectomy specimens (n = 4) from prostate cancer patients who had previously received radiation therapy. For comparison, T 1, T 2 and apparent diffusion coefficient (ADC) were measured in parallel. E (kPa) varied across clinical anatomy and for histopathology-identified tumor: peripheral zone: 99(±22), central gland: 48(±37), tumor: 85(±53), and increased consistently with fixation (factor of 11 ± 5; p < 0.02). T 2 decreased consistently with fixation, while changes in T 1 and ADC were more complex and inconsistent. The biomechanics of the clinical prostate specimens varied greatly with fixation, and to a lesser extent with disease and anatomy. The data obtained will improve the precision of prostate pathology correlation, leading to more accurate disease detection and targeting.

Evaluation of wave delivery methodology for brain MRE: Insights from computational simulations.

PURPOSE: MR elastography (MRE) of the brain is being explored as a biomarker of neurodegenerative disease such as dementia. However, MRE measures for healthy brain have varied widely. Differing wave delivery methodologies may have influenced this, hence finite element-based simulations were performed to explore this possibility. METHODS: The natural frequencies of a series of cranial models were calculated, and MRE-associated vibration was simulated for different wave delivery methods at varying frequency, using simple isotropic viscoelastic material models for the brain. Displacement fields and the corresponding brain constitutive properties estimated by standard inversion techniques were compared across delivery methods and frequencies. RESULTS: The delivery methods produced widely different MRE displacement fields and inversions. Furthermore, resonances at natural frequencies influenced the displacement patterns. Consequently, some delivery methods led to lower inversion errors than others, and the error on the storage modulus varied by up to 11% between methods. CONCLUSION: Wave delivery has a considerable impact on brain MRE reliability. Assuming small variations in brain biomechanics, as recently reported to accompany neurodegenerative disease (e.g., 7% for Alzheimer's disease), the effect of wave delivery is important. Hence, a consensus should be established on a consistent methodology to ensure diagnostic and prognostic consistency. Magn Reson Med 78:341-356, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

T1 Relaxation Time in Lungs of Asymptomatic Smokers.

PURPOSE: Interest in using T1 as a potential MRI biomarker of chronic obstructive pulmonary disease (COPD) has recently increased. Since tobacco smoking is the major risk factor for development of COPD, the aim for this study was to examine whether tobacco smoking, pack-years (PY), influenced T1 of the lung parenchyma in asymptomatic current smokers. MATERIALS AND METHODS: Lung T1 measurements from 35 subjects, 23 never smokers and 12 current smokers were retrospectively analyzed from an institutional review board approved study. All 35 subjects underwent pulmonary function test (PFT) measurements and lung T1, with similar T1 measurement protocols. A backward linear model of T1 as a function of FEV1, FVC, weight, height, age and PY was tested. RESULTS: A significant correlation between lung T1 and PY was found with a negative slope of -3.2 ms/year (95% confidence interval [CI] [-5.8, -0.6], p = 0.02), when adjusted for age and height. Lung T1 shortens with ageing among all subjects, -4.0 ms/year (95%CI [-6.3, -1.7], p = 0.001), and among the never smokers, -3.7 ms/year (95%CI [-6.0, -1.3], p = 0.003). CONCLUSIONS: A correlation between lung T1 and PY when adjusted for both age and height was found, and T1 of the lung shortens with ageing. Accordingly, PY and age can be significant confounding factors when T1 is used as a biomarker in lung MRI studies that must be taken into account to detect underlying patterns of disease.

Technical Note: Method to correlate whole-specimen histopathology of radical prostatectomy with diagnostic MR imaging.

PURPOSE: Validation of MRI-guided tumor boundary delineation for targeted prostate cancer therapy is achieved via correlation with gold-standard histopathology of radical prostatectomy specimens. Challenges to accurate correlation include matching the pathology sectioning plane with the in vivo imaging slice plane and correction for the deformation that occurs between in vivo imaging and histology. A methodology is presented for matching of the histological sectioning angle and position to the in vivo imaging slices. METHODS: Patients (n = 4) with biochemical failure following external beam radiotherapy underwent diagnostic MRI to confirm localized recurrence of prostate cancer, followed by salvage radical prostatectomy. High-resolution 3-D MRI of the ex vivo specimens was acquired to determine the pathology sectioning angle that best matched the in vivo imaging slice plane, using matching anatomical features and implanted fiducials. A novel sectioning device was developed to guide sectioning at the correct angle, and to assist the insertion of reference dye marks to aid in histopathology reconstruction. RESULTS: The percentage difference in the positioning of the urethra in the ex vivo pathology sections compared to the positioning in in vivo images was reduced from 34% to 7% through slicing at the best match angle. Reference dye marks were generated, which were visible in ex vivo imaging, in the tissue sections before and after processing, and in histology sections. CONCLUSIONS: The method achieved an almost fivefold reduction in the slice-matching error and is readily implementable in combination with standard MRI technology. The technique will be employed to generate datasets for correlation of whole-specimen prostate histopathology with in vivo diagnostic MRI using 3-D deformable registration, allowing assessment of the sensitivity and specificity of MRI parameters for prostate cancer. Although developed specifically for prostate, the method is readily adaptable to other types of whole tissue specimen, such as mastectomy or liver resection.

Magnetic resonance elastography of the brain: An in silico study to determine the influence of cranial anatomy.

PURPOSE: Magnetic resonance elastography (MRE) of the brain has demonstrated potential as a biomarker of neurodegenerative disease such as dementia but requires further evaluation. Cranial anatomical features such as the falx cerebri and tentorium cerebelli membranes may influence MRE measurements through wave reflection and interference and tissue heterogeneity at their boundaries. We sought to determine the influence of these effects via simulation. METHODS: MRE-associated mechanical stimulation of the brain was simulated using steady state harmonic finite element analysis. Simulations of geometrical models and anthropomorphic brain models derived from anatomical MRI data of healthy individuals were compared. Constitutive parameters were taken from MRE measurements for healthy brain. Viscoelastic moduli were reconstructed from the simulated displacement fields and compared with ground truth. RESULTS: Interference patterns from reflections and heterogeneity resulted in artifacts in the reconstructions of viscoelastic moduli. Artifacts typically occurred in the vicinity of boundaries between different tissues within the cranium, with a magnitude of 10%-20%. CONCLUSION: Given that MRE studies for neurodegenerative disease have reported only marginal variations in brain elasticity between controls and patients (e.g., 7% for Alzheimer's disease), the predicted errors are a potential confound to the development of MRE as a biomarker of dementia and other neurodegenerative diseases. Magn Reson Med 76:645-662, 2016. © 2015 Wiley Periodicals, Inc.

Effect of material property heterogeneity on biomechanical modeling of prostate under deformation.

Biomechanical model based deformable image registration has been widely used to account for prostate deformation in various medical imaging procedures. Biomechanical material properties are important components of a biomechanical model. In this study, the effect of incorporating tumor-specific material properties in the prostate biomechanical model was investigated to provide insight into the potential impact of material heterogeneity on the prostate deformation calculations. First, a simple spherical prostate and tumor model was used to analytically describe the deformations and demonstrate the fundamental effect of changes in the tumor volume and stiffness in the modeled deformation. Next, using a clinical prostate model, a parametric approach was used to describe the variations in the heterogeneous prostate model by changing tumor volume, stiffness, and location, to show the differences in the modeled deformation between heterogeneous and homogeneous prostate models. Finally, five clinical prostatectomy examples were used in separately performed homogeneous and heterogeneous biomechanical model based registrations to describe the deformations between 3D reconstructed histopathology images and ex vivo magnetic resonance imaging, and examine the potential clinical impact of modeling biomechanical heterogeneity of the prostate. The analytical formulation showed that increasing the tumor volume and stiffness could significantly increase the impact of the heterogeneous prostate model in the calculated displacement differences compared to the homogeneous model. The parametric approach using a single prostate model indicated up to 4.8 mm of displacement difference at the tumor boundary compared to a homogeneous model. Such differences in the deformation of the prostate could be potentially clinically significant given the voxel size of the ex vivo MR images (0.3  ×  0.3  ×  0.3 mm). However, no significant changes in the registration accuracy were observed using heterogeneous models for the limited number of clinical prostatectomy patients modeled and evaluated in this study.

Feasibility assessment of using oxygen-enhanced magnetic resonance imaging for evaluating the effect of pharmacological treatment in COPD.

OBJECTIVES: Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests. MATERIALS AND METHODS: COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9µg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9µg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function. RESULTS: OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies. CONCLUSIONS: In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a ß2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.

Quasi-static magnetic resonance elastography at 7 T to measure the effect of pathology before and after fixation on tissue biomechanical properties.

Evaluation of imaging for cancer detection and localization can be achieved by correlation of gold-standard histopathology with imaging data. Usage of a 3D biomechanical-based deformable registration for correlation of the histopathology of whole-tissue specimens with ex vivo imaging necessitates measurement of the distribution of biomechanical properties in the ex vivo tissue specimen and changes that occur during pathology fixation. To measure high-resolution 3D distributions of Young's modulus (E) prefixation and postfixation, a quasi-static magnetic resonance elastography method was developed at 7 T. Use of echo-planar imaging allowed for shorter imaging times, in line with limited time frames allowable for pathology specimens. The finite element modeling algorithm produced voxel-wise E measures, and mechanical indentation was used for comparison. An initial preclinical evaluation with canine prostate specimens (n = 5) demonstrated a consistent increase in E with fixation (P < 0.002) by a factor of 4 (± 1). Increases were a function of distance from the tissue edge and correlated with fixation time (ρ = 1, P < 0.02). The technique will be used to generate population-averaged data of E from clinical ex vivo specimens prefixation and postfixation to inform registration of whole-mount histopathology with in vivo imaging.

Biomechanical model-based deformable registration of MRI and histopathology for clinical prostatectomy.

A biomechanical model-based deformable image registration incorporating specimen-specific changes in material properties is optimized and evaluated for correlating histology of clinical prostatectomy specimens with in vivo MRI. In this methodology, a three-step registration based on biomechanics calculates the transformations between histology and fixed, fixed and fresh, and fresh and in vivo states. A heterogeneous linear elastic material model is constructed based on magnetic resonance elastography (MRE) results. The ex vivo tissue MRE data provide specimen-specific information for the fresh and fixed tissue to account for the changes due to fixation. The accuracy of the algorithm was quantified by calculating the target registration error (TRE) by identifying naturally occurring anatomical points within the prostate in each image. TRE were improved with the deformable registration algorithm compared to rigid registration alone. The qualitative assessment also showed a good alignment between histology and MRI after the proposed deformable registration.

Measurement of arterial plasma oxygenation in dynamic oxygen-enhanced MRI.

Inhaled oxygen can be used as a contrast agent for magnetic resonance imaging, due to the T(1) shortening effect of the oxygen dissolved in blood and tissue water. In this study, blood T(1) was measured dynamically in 14 volunteers (seven smokers, seven never-smokers) as the inhaled gas was switched from medical air to 100% oxygen and back to medical air. These T(1) values were converted to changes in partial pressure of oxygen, which were found to be in agreement with literature values. There were differences in curve shape and curve height between the smoker and never-smoker groups, suggesting differences in lung function due to smoking-related damage. These curves could be used as an input function for modeling of oxygen uptake in tissues. The differences between groups highlight the importance of measuring such an input function for each individual rather than relying on an assumed measurement.

Tracer kinetic analysis of dynamic contrast-enhanced MRI and CT bladder cancer data: A preliminary comparison to assess the magnitude of water exchange effects.

The purpose of this study was to determine the impact of water exchange on tracer kinetic parameter estimates derived from T(1)-weighted dynamic contrast-enhanced (DCE)-MRI data using a direct quantitative comparison with DCE-CT. Data were acquired from 12 patients with bladder cancer who underwent DCE-CT followed by DCE-MRI within a week. A two-compartment tracer kinetic model was fitted to the CT data, and two versions of the same model with modifications to account for the fast exchange and no exchange limits of water exchange were fitted to the MR data. The two-compartment tracer kinetic model provided estimates of the fractional plasma volume (v(p)), the extravascular extracellular space fraction (v(e)), plasma perfusion (F(p)), and the microvascular permeability surface area product. Our findings suggest that DCE-CT is an appropriate reference for DCE-MRI in bladder cancers as the only significant difference found between CT and MR parameter estimates were the no exchange limit estimates of v(p) (P = 0.002). These results suggest that although water exchange between the intracellular and extravascular-extracellular space has a negligible effect on DCE-MRI, vascular-extravascular-extracellular space water exchange may be more important.

Technical note: fiducial markers for correlation of whole-specimen histopathology with MR imaging at 7 tesla.

PURPOSE: There is increasing interest in the registration of 3-D histopathology with 3-D in vivo imaging, for example, to validate tumor boundary delineation for targeted radiation cancer therapy. However, accurate correlation is compromised by tissue distortion induced by histopathological processing. Reference landmarks that are visible in both data sets are required. In this study, two iridescent acrylic paints, "Bronze" (containing iron oxide coated mica particles) and "Stainless Steel" (containing iron, chromium, and nickel), were evaluated for creating MRI-visible and histology-visible fiducial markers at 7 T, where resolution is more similar to histology, but artifacts are accentuated. Furthermore, a straight-line paint-track fiducial method was developed to assist in registration and 3-D histopathology reconstruction. METHODS: First, the paints were injected into ex vivo porcine tissue samples, which were MR imaged prefixation and postfixation, and subsequently prepared for hematoxylin and eosin staining to verify stability through histopathological processing. Second, the severity of marker susceptibility artifacts produced was compared while using spin-echo and gradient-echo MRI pulse sequences. Finally, multiple paint tracks were injected prefixation through an ex vivo canine prostate sample to validate the potential for line-based registration between MR images of prefixation and postfixation tissue and whole mount histology slides. RESULTS: The Stainless Steel paint produced excessive susceptibility artifacts and image distortion, while the Bronze paint created stable and appropriate markers in MRI and histology. The Bronze paint produced artifacts approximately three times larger in gradient-echo than in spin-echo MR images. Finally, the paint-track fiducials were visible in the prefixation and postfixation MRI and on whole mount histology. CONCLUSIONS: The Bronze iridescent acrylic paint is appropriate for fiducial marker creation in MRI at 7 T. The straight-line paint-track fiducials may assist 3-D histopathology reconstruction and can provide important information on the deformation effects of fixation, and hence may improve registration accuracy.

Comparison of model-based arterial input functions for dynamic contrast-enhanced MRI in tumor bearing rats.

When using tracer kinetic modeling to analyze dynamic contrast-enhanced MRI (DCE-MRI) it is necessary to identify an appropriate arterial input function (AIF). The measured AIF is often poorly sampled in both clinical and preclinical MR systems due to the initial rapid increase in contrast agent concentration and the subsequent large-scale signal change that occurs in the arteries. However, little work has been carried out to quantify the sensitivity of tracer kinetic modeling parameters to the form of AIF. Using a preclinical experimental data set, we sought to measure the effect of varying model forms of AIF on the extended Kety compartmental model parameters (K(trans), v(e), and v(p)) through comparison with the results of experimentally acquired high temporal resolution AIFs. The AIF models examined have the potential to be parameterized on lower temporal resolution data to predict the form of the true, higher temporal resolution AIF. The models were also evaluated through application to the population average AIF. It was concluded that, in the instance of low temporal resolution or noisy data, it may be preferable to use a bi-exponential model applied to the raw data AIF, or when individual measurements are not available a bi-exponential model of the average AIF.

Preliminary study of oxygen-enhanced longitudinal relaxation in MRI: a potential novel biomarker of oxygenation changes in solid tumors.

PURPOSE: There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) longitudinal relaxation rate (R(1)). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status. METHODS AND MATERIALS: Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R(1) while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced DeltaR(1). RESULTS: DeltaR(1) showed significant increases of 0.021 to 0.058 s(-1) in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the DeltaR(1) curve (consistent with minimal increase in oxygen concentration). CONCLUSIONS: These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.

Comparison of normal tissue R1 and R*2 modulation by oxygen and carbogen.

Magnetic resonance imaging has shown promise for evaluating tissue oxygenation. In this study differences in the tissue longitudinal relaxation rate (R(1)) and effective transverse relaxation rate (R(*)(2)), induced by inhalation of pure oxygen and carbogen, were evaluated in 10 healthy subjects. Significant reductions in R(1) were demonstrated following both oxygen and carbogen inhalation in the spleen (both P < 0.001), liver (P = 0.002 air vs. oxygen; P = 0.001 air vs. carbogen), skeletal muscle (both P < 0.001), and renal cortex (P = 0.005 air vs. oxygen; P = 0.008 air vs. carbogen). No significant change in R(*)(2) occurred following pure oxygen in any organ. However, a significant increase in R(*)(2) was observed in the spleen (P < 0.001), liver (P = 0.001), skeletal muscle (P = 0.026), and renal cortex (P = 0.001) following carbogen inhalation, an opposite effect to that observed in many studies of tumor pathophysiology. Changes in R(1) and R(*)(2) were independent of the gas administration order in the spleen and skeletal muscle. These findings suggest that the R(1) and R(*)(2) responses to hyperoxic gases are independent biomarkers of oxygen physiology.

Oxygen-induced changes in longitudinal relaxation times in skeletal muscle.

The objective was to measure the effect of 100% oxygen inhalation on T1 relaxation times in skeletal muscle. Healthy volunteers were scanned using three different MRI protocols while breathing medical air and 100% oxygen. Measurements of T1 were made from regions of interest (ROIs) within various skeletal muscle groups. Dynamic data of subjects breathing a sequence of air-oxygen-air allowed the calculation of characteristic wash-in and -out times for dissolved oxygen in muscle. Contrary to previous findings, a statistically significant decrease in T1 in skeletal muscle was observed due to oxygen inhalation. We report approximate baseline characteristic values for the response of skeletal muscle to oxygen inhalation. This measurement may provide new biomarkers for evaluation of oxygen delivery and consumption in normal and diseased skeletal muscle.

Organ-specific effects of oxygen and carbogen gas inhalation on tissue longitudinal relaxation times.

Molecular oxygen has been previously shown to shorten longitudinal relaxation time (T1) in the spleen and renal cortex, but not in the liver or fat. In this study, the magnitude and temporal evolution of this effect were investigated. Medical air, oxygen, and carbogen (95% oxygen/5% CO2) were administered sequentially in 16 healthy volunteers. T1 maps were acquired using spoiled gradient echo sequences (TR=3.5 ms, TE=0.9 ms, alpha=2 degrees/8 degrees/17 degrees) with six acquisitions on air, 12 on oxygen, 12 on carbogen, and six to 12 back on air. Mean T1 values and change in relaxation rate were compared between each phase of gas inhalation in the liver, spleen, skeletal muscle, renal cortex, and fat by one-way analysis of variance. Oxygen-induced T1-shortening occurred in the liver in fasted subjects (P<0.001) but not in non-fasted subjects (P=0.244). T1-shortening in spleen and renal cortex (both P<0.001) were greater than previously reported. Carbogen induced conflicting responses in different organs, suggesting a complex relationship with organ vasculature. Shortening of tissue T1 by oxygen is more pronounced and more complex than previously recognized. The effect may be useful as a biomarker of arterial flow and oxygen delivery to vascular beds.