Quantitative cerebrovascular 4D flow MRI at rest and during hypercapnia challenge

Magnetic Resonance Imaging 34 (2016) 422–428

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Original contribution

Quantitative cerebrovascular 4D flow MRI at rest and during hypercapnia challenge J. Mikhail Kellawan a,⁎, John W. Harrell a, Eric M. Schrauben b, Carson A. Hoffman b, Alejandro Roldan-Alzate c, William G. Schrage a, Oliver Wieben b, c a b c

Department of Kinesiology, University of Wisconsin – Madison, Madison, WI, USA Department of Medical Physics, University of Wisconsin – Madison, Madison, WI, USA Department of Radiology, University of Wisconsin – Madison, Madison, WI, USA

a r t i c l e

i n f o

Article history: Received 8 October 2015 Accepted 13 December 2015 Keywords: Cerebral blood flow Hypercapnia 4D flow Phase contrast vastly-undersampled isotropic projection reconstruction (PC VIPR)

a b s t r a c t Non-invasive measurement of cerebral blood flow (CBF) in humans is fraught with technologic, anatomic, and accessibility issues, which has hindered multi-vessel hemodynamic analysis of the cranial vasculature. Recent developments in cardiovascular MRI have allowed for the measurement of cine velocity vector fields over large imaging volumes in a single acquisition with 4D flow MRI. The purpose of this study was to develop an imaging protocol to simultaneously measure pulsatile flow in the circle of Willis as well as the carotid and vertebrate arteries at rest and during increased CO2 (hypercapnia). Methods: 8 healthy adults (3 women, 26 ± 0.4 years) completed this study. Heart rate (pulse oximetry), arterial oxygen saturation (pulse oximetry), blood pressure (MAP, sphygmomanometry), and end-tidal CO2 (capnograph) were measured at rest (baseline) and during hypercapnia. Hypercapnia was induced via breathing a mixed gas of 3% CO2 and 21% O2 (balance N2) in the MR magnet. CBF and vessel cross-sectional area were quantified in 11 arteries using a 4D flow MRI scan, lasting 5–6 min with a radially undersampled acquisition and an isotropic spatial resolution of 0.7 mm. Results: Baseline total CBF was 665 ± 54 ml • min−1. Hypercapnia increased total CBF 9 ± 3% to 721 ± 61 ml • min−1. Hypercapnic increases in CBF ranged from 7 to 36% by artery, with the largest increases in the left anterior cerebral artery. Increases in artery cross-sectional area were observed in basilar and vertebral arteries. Conclusion: 4D flow MRI methods are sensitive enough to detect non-uniform changes in CBF and cross-sectional area to a mild yet clinically relevant CO2 stimulus. 4D flow MRI is a non-invasive reliable tool providing high spatio-temporal resolution in clinically feasible scan times without contrast agent. This approach can be used to interrogate regional cerebrovascular control in health and disease. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Stroke and cerebrovascular disease are the 4th leading cause of death in the United States [1], prompting considerable clinical Abbreviations: CBF, cerebral blood flow; PC VIPR, four-dimensional (4D) phase contrast vastly-undersampled isotropic projection reconstruction (PC VIPR); TCD, transcranial Doppler ultrasound; MCA, middle cerebral artery; ACA, anterior cerebral artery; VA, vertebral artery; ICA, internal carotid artery; PETCO2, end-tidal CO2; HR, heart rate; MAP, mean arterial pressure; SaO2, arterial saturation. ⁎ Corresponding author at: Integrative Human Physiology Laboratory, School of Education, Department of Kinesiology, University of Wisconsin – Madison, Office: 1141A Natatorium, 2000 Observatory Drive, Madison, WI, 53706, USA. Tel.: +1 608 263 6308; fax: +1 608 262 1656. E-mail addresses: [email protected], [email protected] (J. Mikhail Kellawan), [email protected] (J.W. Harrell), [email protected] (E.M. Schrauben), [email protected] (C.A. Hoffman), [email protected] (A. Roldan-Alzate), [email protected] (W.G. Schrage), [email protected] (O. Wieben). http://dx.doi.org/10.1016/j.mri.2015.12.016 0730-725X/© 2015 Elsevier Inc. All rights reserved.

interest in the ability to test cerebral vascular function and quantitate blood flow. However, cranial bone density and relative isolation of a complex circulation have posed significant challenges toward this goal with traditional flow sensitive measuring approaches. Four-dimensional (4D) phase contrast vastlyundersampled isotropic projection reconstruction (PC VIPR) offers a possible solution to the technologic, anatomic, and accessibility hurdles of non-invasively measuring human cerebral vascular structure and function. Knowledge of regional cerebral blood flow (CBF), vascular function and vascular structure may assist clinicians to track regional progression of neurologic or vascular diseases that affect specific brain areas, as well as determine the efficacy of interventions. To address these questions, 4D flow MRI using PC VIPR offers both angiographic and quantitative blood flow parameters in the primary and secondary branches of the proximal intracranial arteries within a single acquisition [2]. With regard to human studies, VIPR offers a

J. Mikhail Kellawan et al. / Magnetic Resonance Imaging 34 (2016) 422–428

large technical advantage over commonly used TCD methods, which typically provides blood flow velocity in single artery. Furthermore, TCD is limited by the assumption that vessel diameter is constant under conditions of physiologic stress, which was recently challenged by data indicating middle cerebral artery (MCA) diameter changes to hypercapnia [3,4]. Moreover, recent experiments provide evidence for regionally-specific responses to stressors [5,6] suggesting that vascular responses are unequal throughout the cerebral circulation. 2D flow sensitive MRI is a promising method to capture vessel caliber and flow changes through a single specific artery [3,4]. However, to assess all major cerebral arteries, an impractical number of 2D flow scans would be required. Taken together PC VIPR provides the ability to accurately quantify blood flow and artery caliber in all major cerebral arteries, generating new insights into cerebrovascular control in health and disease. Previous application of 4D flow to intracranial circulation has been limited because of the high demand for spatial and temporal resolution, providing large volumetric coverage and 3-directional velocity encoding in clinically feasible scan times. To reduce scan times, various acceleration approaches including parallel imaging, kt-acceleration, and compressed sensing have been developed and implemented [7,8]. PC VIPR [9,10] is a flow sensitive MRA sequence with a radially undersampled acquisition trajectory. Oversampling central k-space, while k-space edge undersampling, reduces scan time compared to 3D Cartesian sampling. Due to the high image contrast and sparse signal representation after background suppression, PC VIPR demonstrates benign undersampling artifacts that yield high temporal resolution capabilities, important in assessing blood velocity throughout the cardiac cycle. Most prominently, PC VIPR covers a large volume with high isotropic spatial resolution enabling volumetric angiographic images and quantitative assessment of blood flow velocities [2]. This approach has been applied to vessels of the chest [2,11], liver [12], intracranial arteries and veins [13,14] with protocols that have been validated extensively [9,13–16]. In the context of intracranial arterial measurements, the entire Circle of Willis as well as more inferior vessels may be interrogated using a single 4D flow MRI scan without the use of contrast agent. This project aimed to establish and apply an imaging protocol and post-processing method quantifying extracranial and intracranial blood flow changes in response to hypercapnia. Experiments were performed in a group of healthy, young individuals. PC VIPR MRI flow and area measurements were compared to 2D PC MR measurements during hypercapnia for corroboration.

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by-breath end-tidal CO2 (PETCO2, surrogate for arterial PCO2) were collected continuously throughout the imaging study and acquired with an MRI compatible monitor (Medrad Veris MR Vital Signs Patient Monitor, Bayer Healthcare, Whippany, NJ, USA). In addition, the subject wore a two-way non-rebreathing mouthpiece and nose clip to control the flow of air. 2.3. Hypercapnia Hypercapnic stimulus was used to increase cerebral blood flow, as systemic CO2 is commonly used to assess the cerebrovascular function [5,17–19]. The experimental protocol for the gas challenge is presented in Fig. 1. After the initial scout scans are completed within about 3 min, subjects rested quietly while breathing room air for two minutes before the acquisition of baseline 2D and PC VIPR flow MRI scans. After baseline scans, subjects breathed a hypercapnic gas mixture (3% CO2, 21% O2, and balance nitrogen) through a mouthpiece and two-way Hans-Rudolph valve. Once a steady level of hypercapnia was reached (no change in PETCO2 ~ 1 min), cerebral flow was measured with 2D PC MRI, followed by a PC VIPR flow MRI scan, and a final 2D PC MRI scan to verify steady state flow conditions. In total, five flow acquisitions were acquired and analyzed for each subject: three 2D PC and two PC VIPR flow MRI scans. 2.4. Flow imaging

2. Materials and methods

High-resolution 2D flow MRI data were acquired with a standard phase contrast sequence to assess total flow to the brain. A single axial slice was prescribed 1 cm superior to the common carotid artery bifurcation to include the left and right internal carotid arteries (ICA) and both vertebral arteries (VA). Scan parameters include: field of view (FOV) — 20 × 20 cm, 0.52 × 0.52 mm acquired in-plane resolution, 5 mm slice thickness, velocity encoding (Venc) = 100 cm/s, flip angle α = 20⁰, repetition time/echo time (TR/TE) = 7.2/3.8 ms, bandwidth = 62.5 kHz, prospective cardiac gating with 8 views per segment, scan time = 48 heart beats, and 30 reconstructed cardiac time frames. 4D flow MRI measurements were obtained with PC VIPR and the following scan parameters: imaging volume = 22 × 22 × 22 cm 3, (0.69 mm) 3 acquired isotropic resolution, scan time = 5 min 30 s, velocity encoding (Venc) = 100 cm/s, flip angle = 20⁰, TR/TE = 6.7/2.8 ms, 20 reconstructed cardiac time frames using retrospective cardiac gating and temporal view sharing [20] in an offline reconstruction that included automated background phase removal.

2.1. Subjects and informed consent

2.5. Post-processing

Eight healthy young volunteers (3 females, 26 ± 0.4 years) were enrolled. All subjects were lean (BMI: 23 ± 1 kg • m −2), normotensive (MAP: 90 ± 3 mmHg), and unmedicated, with healthy fasting blood values (glucose: 69 ± 2 mg • dl−1, LDL: 88 ± 14 mg • dl−1, HDL: 56 ± 4 mg • dl−1, triglycerides: 77 ± 8 mg • dl−1). Procedures were approved by the institutional review board and conformed to the standards set by the Declaration of Helsinki. Written informed consent was obtained before study participation.

A clinical flow analysis package (CV Flow, Version 3.3, Medis, Leiden, Netherlands) was used to process the 2D PC data through manual region-of-interest analysis in the both ICAs and VAs. The data were corrected for background phase errors and the vessel area and peak and mean flow for each of the four vessels were recorded. All PC VIPR flow MRI processing was completed using an in-house tool developed in commercial software (Matlab, The Mathworks, MA, USA). This tool has been shown to be a reliable, fast, and user-independent method for the assessment of intracranial arteries from 4D flow MRI [21]. With a centerline processing scheme, a user can interactively select a vessel position and an underlying algorithm conducts the segmentation of a vessel plane that is perpendicular to the local vessel path and one voxel width thick (0.69 mm) to provide the corresponding velocity, area, and flow measures. Flow and area parameters were averaged over 5 cross-sections to produce a 0.69 mm × 5 = 3.45 mm long segment in each artery of interest. When compared to 2D PC, the averaging of cross-sections

2.2. Instrumentation After a screening visit to determine eligibility, the imaging study was completed in a fasted state (≥ 4 h) over one visit on a clinical 3 T MRI system (Discovery MR750, GE Healthcare, Waukesha, WI, USA) using an 8-channel head coil. Heart rate (HR, pulse rate via pulse oximeter), blood pressure (MAP, by automated sphygmomanometry), arterial oxygen saturation (SaO2, pulse oximeter), and breath-

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2D

Hypercapnia Steady Level Hypercapnia

Transition to steady level

-5

Pre-Hypercapnia Baseline

0

1

2

3

4

5

4D

10

Minutes Fig. 1. Experimental timing of baseline and hypercapnia and corresponding MR acquisitions. At baseline, 2D PC MRI and 4D flow MRI (PC VIPR) data are acquired. Next the subject transitioned to hypercapnia. Once steady-state hypercapnia is reached, a second 2D PC scan ensues, followed by PC VIPR scan, and a third 2D PC MRI.

provides a more robust estimate of the flow parameters [22] especially in the presence of turbulent flow near branches. The time for processing each case was recorded. Eleven arteries of interest were assessed for each subject as shown in Fig. 2: left and right vertebral arteries (VAs), the inferior basilar artery (BA), left and right internal carotid arteries (ICAs), left and right middle cerebral arteries (MCAs), left and right posterior cerebral arteries (PCAs), and left and right anterior cerebral arteries (ACAs). VA flow was measured 4–5 mm from the junction with the basilar artery, and basilar flow was assessed in the most inferior portion near this junction. ICA measurements were performed in the straight portion of the ICA C4 segment [23]. ACA and MCA measurements were performed 4–5 mm from their junction with the ICA. PCA measures were 4–5 mm from their junction with the BA. 2.6. Statistical analysis Heart rate, PETCO2, MAP, and SaO2 at baseline were compared with measures at the end of hypercapnia using a paired Student's t-test. For this and all other statistical tests reported here, differences were considered significant at the 5% level (p b 0.05). Baseline and hypercapnia 2D PC flow and vessel cross-sectional area (ICAs and VAs) were compared with paired Student's t-test. The two 2D PC MRI scans acquired during hypercapnia before and after the PC VIPR scan were compared to assess whether steady-state hypercapnia was achieved by calculating the coefficient of variation

between the two values. Vessels cross-sectional area and flow measurements from the final 2D PC scan were used for statistical comparisons to PC VIPR measures. For the PC VIPR scans, measurements of cross-sectional area (mm 2), total flow (ml • min −1) summed over the cross-section, and peak flow (ml • s −1) over the cardiac cycle were performed. Baseline values were compared to hypercapnia values. The 2D PC slice position was selected to cover both left and right ICA and left and right VA within a single scan; this allowed for total CBF to be assessed. As a result, the 2D PC scans were performed inferior to the imaging volume for PC VIPR, which was centered over the circle of Willis. For this reason, direct comparison of flow waveforms and cross-sectional area was not possible. Therefore, to compare 2D PC results with those from PC VIPR, percent change of total flow between baseline and hypercapnia, computed as (FlowHypercapnia − FlowBaseline)/FlowBaseline × 100%, was calculated in the left/right ICA and left/right VA for all volunteers and compared with a paired Student's t-test. Correlation between 2D PC and PC VIPR was assessed using Spearman's rank correlation coefficient. 3. Results Fig. 2 provides representative angiograms from PC VIPR scans. MRI scan time varied with an individuals heart rate and averaged 300 ± 36 s. Post-processing times for the flow analysis of PC VIPR data were 474 ± 57 s. Centerline maps of the entire arterial circulation facilitat-

Fig. 2. Representative angiogram of cerebral circulation obtained using PC VIPR MR acquisitions. (A) Coronal orientation ( ) indicates measurement locations from the PC VIPR MRI scan. (B) Axial orientation of vessels of interest. (C) Sagittal orientation of vessels of interest. Numbers represent vessels in which flow was measured: 1 — left/right vertebral arteries, 2 — basilar artery, 3 — left/right internal carotid arteries, 4 — left/right middle cerebral arteries, 5 — left/right anterior cerebral arteries, and 6 — left/right posterior cerebral arteries.

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ed visualization and quantification of CBF in all major intracranial arteries simultaneously. Fig. 2A highlights approximate locations for five single voxel slices. All subjects had healthy angiograms with only one presenting P1 hypoplasia and a fetal type left PCA, which is prevalent in 15–32% of in healthy humans [24]. Table 1 summarizes hemodynamics at baseline and during hypercapnia. Hypercapnia increased HR and MAP mildly. By design PETCO2 increased from 40.6 ± 0.8 to 44.3 ± 0.7 mmHg (Δ 3.7 ± 0.6 mmHg from baseline) and was maintained throughout two 2D PC scans surrounding the PC VIPR scan during hypercapnia as shown in Fig. 3. Fig. 4 summarizes regionally specific CBF in eleven separate arteries (measured by PC VIPR at locations shown in Fig. 2 angiogram). One volunteer had no visible left VA, and a separate volunteer had no visible right VA. Blood flow through each artery at baseline and hypercapnia are shown in Table 2 and Fig. 4. Regional CBF responses to hypercapnia were not symmetrical. Hypercapnia increased CBF in all right sided arteries and only the left VA, ACA, and PCA. The relative increase in CBF was non-uniform with responses ranging from 7% (right ACA) up to 36% (left ACA) (Fig. 4). Fig. 5 illustrates the peak flow during systole at baseline and during hypercapnia across all eleven arteries. Peak systolic flow changes were significant in the right-side vessels of ICA, VA, MCA, and ACA (p b 0.05). Fig. 6 summarizes artery cross-sectional area at rest and during hypercapnia. Significant increases in cross-sectional area to hypercapnia were only observed in the left VA and basilar artery (p b 0.05), while all other changes were insignificant. Total CBF (sum of flow through ICAs and VAs) measured by PC VIPR was 665 ± 54 ml • min −1 at baseline and increased to 721 ± 61 ml • min −1 during hypercapnia (p b 0.05). Total CBF measured by 2D PC (measured proximally compared to PC VIPR) at baseline was 733 ± 39 ml • min −1. Importantly, 2D blood flow measurements during steady state hypercapnia made prior to, and immediately after PC VIPR measurements were not different (coefficient of variation = 6.0%, 754 ± 46 ml • min −1 vs. 773 ± 36 ml • min −1) indicating that blood flow was maintained at a steady state throughout ~ 300 s taken to complete PC VIPR flow scans. Fig. 7 compares the relative percent changes in 2D and 4D flow in the left/right ICA and left/right VA. Similar changes are evident for the two MRI scans and good correlation was observed across all vessels between the two MRI scans (r = 0.63, p b 0.05), indicating the same normalized magnitude increase in blood flow from baseline to hypercapnia.

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2D 4D

Fig. 3. Change in end-tidal carbon dioxide (ΔPETCO2) from baseline during MR scans. Approximate times for 2D PC scans (grey) and PC VIPR (hashed) are noted.

limitations to more common ultrasound and 2D PC approaches. For the first time in humans, we utilized a 4D flow MRI approach to measure cerebral blood flow changes during a physiological stimulus (e.g. hypercapnia,) in order to quantify global and regional cerebrovascular reactivity. As shown in Fig. 2, PC VIPR enables retrospective measurement in many arteries for comprehensive assessment of CBF changes. Prior studies on 2D PC have shown that flow analysis is feasible if the vessel diameter exceeds 5 voxels [25]. This powerful new approach has a long acquisition of around 5 min but generates a wealth of volumetric flow and cross-sectional area data to effectively interrogate cerebral artery structure and function with high spatial resolution and high-temporal resolution within the cardiac cycle. Additionally, the centerline post-processing scheme enables fast analysis of each case over many arteries of interest, and removes time-consuming and user-dependent manual placement of measurement planes that may cause reproducibility and accuracy concerns in the measured parameters. Taken together, the application of PC VIPR holds great promise for new insights into cerebrovascular function in human health and disease. Almost all arteries under investigation increased flow to hypercapnia with the exceptions of the left ICA, MCA, and right PCA. It should be noted, however, that total flow was nonsignificantly increased in these vessels (Table 2). The ~ 3% increase in total cerebral blood flow per mmHg increase in PETCO2 in the

4. Discussion This study presents a novel application for PC VIPR flow MRI to simultaneously quantify CBF and vessel area in eleven individual cerebral vessels during hypercapnia in less than 6 min without the use of MRI contrast agent. High resolution 4D flow MRI solves several

Table 1 Hemodynamic and respiratory values.

MAP (mmHg) Heart Rate (bpm) PETCO2 (mmHg) SaO2 (%)

Baseline

Hypercapnia

p

93 66 40.6 98.2

94 71 44.3 98.5

0.9 0.02 0.0001 0.13

± ± ± ±

1 3 0.8 0.4

Results are mean ± SE. ⁎ Indicates significantly greater than baseline, p b 0.05.

± ± ± ±

1 4⁎ 0.7⁎ 0.2

Fig. 4. Average total blood flow measured in each artery using PC VIPR MRI. Baseline (black) and hypercapnia (gray). Star denotes p b 0.05.

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Table 2 Quantification of total blood flow in each artery examined with PC VIPR measured in ml • min−1 and averaged over all subjects. Right

Left Baseline

VA ICA MCA ACA PCA Basilar

99.2 256.1 151.0 95.2 62.9 151.1

± ± ± ± ± ±

Hypercapnia 5.9 12.1 19.4 8.1 8.8 17.3

109.2 283.9 174.0 103.3 62.8 166.9

± ± ± ± ± ±

10.1⁎ 18.2⁎ 14.0⁎ 9.3⁎ 9.0 19.3⁎

p

Baseline

0.02 0.03 0.02 0.02 0.49 0.005

81.9 250.9 154.5 80.9 55.2

± ± ± ± ±

Hypercapnia 20.1 29.4 14.6 18.8 8.7

87.4 265.2 161.3 120.0 67.6

± ± ± ± ±

19.3⁎ 29.0 15.3 11.8⁎ 9.0⁎

p 0.01 0.07 0.12 0.003 0.04

Results are mean ± SE. ⁎ Indicates significantly greater than baseline, p b 0.05.

current study parallels with observations reported in the literature using ultrasound and 2D MR methods [6,26–29]. Changes in total flow (presented as ml • min −1) are in part due to the time-dependent contribution of the increased heart rate (at a fixed stroke volume and distribution of blood flow, more beats per minute would increase total flow per minute). This may partially explain the increase in total flow during hypercapnia. Additionally, the cerebrovasculature has been found to be specifically sensitive to changes in arterial CO2 [30], which can be observed in the large neck and intracranial arteries [6,31,32]. Our observations in the anterior cerebral circulation seemingly oppose area measurements with 2D sagittal T2-weighted black blood MRI experiments, which have reported dilation of the MCA to hypercapnia stimulus [3,4]. The differences in MCA dilation are most likely due to differences in experimental protocol. Coverdale et al. [4] and Verbree et al. [3] used much stronger CO2 stimuli (ΔPETCO2 from baseline, 7.5–15 mmHg) than the current study. The hypercapnic stimulus selected in the current study (~ 4 mmHg ΔPETCO2) was chosen for two reasons. First, this range of PETCO2 represents a typical range observed in patients with common disorders like sleep apnea [33,34], therefore, making it more clinically relevant. Second, this PETCO2 range is a more conservative approach to a new technique, so that subjects could tolerate both the hypercapnic stress and the claustrophobic feeling in the bore of the MRI. Additionally, both left and right MCAs are measured in this study and we observed flow changes in the right MCA and non-significant changes in the left MCA. The two aforementioned studies only examined a 2D slice of a single MCA, Coverdale et al. [4] examined the right MCA, while Verbree et al. [3] did not delineate subject's right versus left MCA. Therefore, 2D slice of single MCA would have not detected potential heterogeneity of

flow responses between MCA arteries. However, the constant cross-sectional area of the MCAs measured are in agreement with the non-linear model of MCA dilation in response to changes in PETCO2 proposed by Verbree et al. [3], where only larger elevations in PETCO2 elicit MCA dilation. More importantly, our data demonstrate vasoactive responses to mild hypercapnia were not uniform throughout the cerebral circulation, ranging from 7 to 36% increases in CBF by region (Fig. 4). These data indicate that CBF may be differentially regulated by region, and highlight the need to assess multiple arteries, as responses to systemic stimuli evoke diverse responses across the brain. Using high resolution 4D flow approaches such as PC VIPR meets this need. In the context of neurologic or vascular diseases that impact specific brain areas, comprehensive CBF measures may allow researchers and clinicians to track regional progression of total and regional pathophysiology as well as efficacy of interventions to improve vascular function. Conduit artery vasodilation was only evident in the left VA and basilar artery. In these vessels, total flow and cross-sectional area increased, but peak flow did not. The increased cross-sectional area likely blunted any increase in peak flow measured in these vessels. Increased flow in vessels without changes in cross-sectional area is consistent with downstream dilation of pial and parenchymal arterioles being responsible for most of the observed change in flow in the anterior cerebral circulation [28,29,35]. In addition to downstream dilation, changes in VA and basilar cross-sectional area suggest that conduit artery dilation contributed to flow changes observed in the posterior cerebral circulation. Accurate validation of non-invasive in-vivo flow measurements is particularly challenging. Studies have shown using 2D PC as the ‘gold standard’ for flow measurements is supported by both high in-vitro

Fig. 5. Peak blood flow measured in each artery using PC VIPR MRI. Baseline (black) and hypercapnia (gray). Star denotes p b 0.05.

Fig. 6. Cross-sectional area measured in each artery using PC VIPR MRI. Baseline (black) and hypercapnia (gray). Star denotes p b 0.05.

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2D 4D

25

Percent Change (%)

20

427

stimuli strength, specifically to evoke stronger responses, in order to investigate the nonlinear relationship of vessel area changes, as well as introduce other challenges such as exercise and hypoxia to assess cerebrovascular control Acknowledgements

15 We would like to thank the subjects for their time and effort. We would also like to acknowledge Cameron Rousseau, Sara John, and Jenelle Fuller for their help in data collection. These studies were supported by American Diabetes Association grant ADA 1-12-IN-39. J. Mikhail Kellawan is supported by the American Heart Association 15POST23100020.

10

5

References

0 Right ICA

Left ICA

Right VA

Left VA

Fig. 7. Percent change in total flow from baseline to hypercapnia for 2D PC (black) measured vessels compared with the results from PC VIPR (gray). No statistical differences were observed between the two MRI scans.

accuracy and precision and high in-vivo precision in larger vessels such as the aorta and ICA [36,37]. The choice of PC VIPR as a consistent measurement tool of medium to large intracranial arteries is supported by previous research [14]. This work used a conservation of mass approach at a junction of intracranial veins, with results being internally consistent (input–output flow differences) within 2.2%. Therefore, a key advantage of PC VIPR over 2D PC is the vast increase in coverage of the entire cerebral circulation – instead of a single vessel – while improving spatio-temporal resolution. Percent change as a proxy to increase in magnitude of total flow in these vessels was chosen because of the non-overlapping FOVs used for each scan. Taking 2D measurements at a more inferior location allowed for the assessment of left/right ICA, left/right VA, and left/right external carotid arteries from a single imaging slice. This further emphasizes the benefit of using PC VIPR as a volumetric assessment of all vessels of interest in this study. Despite these differences in measurement locations within the same vessels, the relative percent change in total flow calculations for the 4 vessels revealed no difference and a good correlation between the two MRI scans (Fig. 7). 5. Summary and conclusions In summary, the non-invasive PC VIPR imaging protocol and post-processing method reliably quantified intracranial blood flow of eleven individual arteries simultaneously. Within a single acquisition, PC VIPR MRI flow provides angiographic and quantitative blood flow parameters without the use of contrast agents. This approach offers an enormous opportunity for comprehensive vascular questions that until now would require an impractical number of 2D PC scans, particularly when including a physiologic stressor. Furthermore, PC VIPR is sensitive enough to quantify changes in flow induced with physiologically relevant, moderate hypercapnia in multiple cerebral arteries that TCD or 2 MRI approaches may not be able to detect. Finally, changes in artery CSA also indicate vascular resistance contribution in some of these main arteries. These methods provide clinicians and researchers an effective tool to better evaluate cerebrovascular responsiveness, interrogate specific arteries in a quantitative manner, and offer deeper insight into the physiology and pathophysiology of the brain circulation. Based on the promising results of this study, we plan to conduct follow-up studies with larger enrollment and variations in

[1] Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart disease and stroke statistics — 2014 update: a report from the American Heart Association. Circulation 2014;129:e28–92. http://dx.doi.org/10.1161/01.cir. 0000441139.02102.80. [2] Markl M, Frydrychowicz A, Kozerke S, Hope M, Wieben O. 4D flow MRI. J Magn Reson Imaging 2012;36:1015–36. http://dx.doi.org/10.1002/jmri.23632. [3] Verbree J, Bronzwaer ASGT, Ghariq E, Versluis MJ, Daemen MJ, van Buchem MA, et al. Assessment of middle cerebral artery diameter during hypocapnia and hypercapnia in humans using ultra high-field MRI. J Appl Physiol 2014;117: 1081–3. http://dx.doi.org/10.1152/japplphysiol.00651.2014. [4] Coverdale NS, Gati JS, Opalevych O, Perrotta A, Shoemaker JK. Cerebral blood flow velocity underestimates cerebral blood flow during modest hypercapnia and hypocapnia. J Appl Physiol 2014;117:1090–6. http://dx.doi.org/10.1152/ japplphysiol.00285.2014. [5] Skow RJ, MacKay CM, Tymko MM, Willie CK, Smith KJ, Ainslie PN, et al. Respiratory physiology & neurobiology. Respir Physiol Neurobiol 2013;189: 76–86. http://dx.doi.org/10.1016/j.resp.2013.05.036. [6] Willie CK, Macleod DB, Shaw AD, Smith KJ, Tzeng YC, Eves ND, et al. Regional brain blood flow in man during acute changes in arterial blood gases. J Physiol 2012;590:3261–75. http://dx.doi.org/10.1113/jphysiol.2012.228551. [7] Giese D, Wong J, Greil GF, Buehrer M, Schaeffter T, Kozerke S. Towards highly accelerated Cartesian time-resolved 3D flow cardiovascular magnetic resonance in the clinical setting. 2014;16:1–8. http://dx.doi.org/10.1186/1532-429X-16-42. [8] Tariq U, Hsiao A, Alley M, Zhang T, Lustig M, Vasanawala SS. Venous and arterial flow quantification are equally accurate and precise with parallel imaging compressed sensing 4D phase contrast MRI. J Magn Reson Imaging 2012;37: 1419–26. http://dx.doi.org/10.1002/jmri.23936. [9] Gu T, Korosec FR, Block WF, Fain SB, Turk Q, Lum D, et al. PC VIPR: a high-speed 3D phase-contrast method for flow quantification and high-resolution angiography. AJNR Am J Neuroradiol 2005;26:743–9. [10] Johnson KM, Lum DP, Turski PA, Block WF, Mistretta CA, Wieben O. Improved 3D phase contrast MRI with off-resonance corrected dual echo VIPR. Magn Reson Med 2008;60:1329–36. http://dx.doi.org/10.1002/mrm.21763. [11] Ebbers T, Wigström L, Bolger AF, Wranne B, Karlsson M. Noninvasive measurement of time-varying three-dimensional relative pressure fields within the human heart. J Biomech Eng 2002;124:288. http://dx.doi.org/10.1115/1. 1468866. [12] Frydrychowicz A, Landgraf BR, Niespodzany E, Verma RW, Roldán-Alzate A, Johnson KM, et al. Four-dimensional velocity mapping of the hepatic and splanchnic vasculature with radial sampling at 3 tesla: a feasibility study in portal hypertension. J Magn Reson Imaging 2011;34:577–84. http://dx.doi.org/ 10.1002/jmri.22712. [13] Wåhlin A, Ambarki K, Birgander R, Wieben O, Johnson KM, Malm J, et al. Measuring pulsatile flow in cerebral arteries using 4D phase-contrast MR imaging. Am J Neuroradiol 2013;34:1740–5. http://dx.doi.org/10.3174/ajnr. A3442. [14] Schrauben EM, Johnson KM, Huston J, del Rio AM, Reeder SB, Field A, et al. Reproducibility of cerebrospinal venous blood flow and vessel anatomy with the use of phase contrast-vastly undersampled isotropic projection reconstruction and contrast-enhanced MRA. Am J Neuroradiol 2014;35:999–1006. http://dx. doi.org/10.3174/ajnr.A3779. [15] Roldán-Alzate A, Frydrychowicz A, Niespodzany E, Landgraf BR, Johnson KM, Wieben O, et al. In vivo validation of 4D flow MRI for assessing the hemodynamics of portal hypertension. J Magn Reson Imaging 2012;37: 1100–8. http://dx.doi.org/10.1002/jmri.23906. [16] Frydrychowicz A, Niespodzany E, Reeder SB, Johnson KM, Wieben O, François CJ. Validation of 4D velocity mapping using 5-point PC-VIPR for blood flow quantification in the thoracic aorta and main pulmonary artery. Proceedings of the American Society of Neuroradiology 50th Annual Meeting & the Foundation of the ASNR Symposium; 2012. p. 1. [17] Markwalder TM, Grolimund P, Seiler RW, Roth F, Aaslid R. Dependency of blood flow velocity in the middle cerebral artery on end-tidal carbon dioxide partial pressure — a transcranial ultrasound Doppler study. J Cereb Blood Flow Metab 1984;4:368–72. http://dx.doi.org/10.1038/jcbfm.1984.54.

428

J. Mikhail Kellawan et al. / Magnetic Resonance Imaging 34 (2016) 422–428

[18] Ringelstein EB, Sievers C, Ecker S, Schneider PA, Otis SM. Noninvasive assessment of CO2-induced cerebral vasomotor response in normal individuals and patients with internal carotid artery occlusions. Stroke 1988;19:963–9. [19] Barnes JN, Taylor JL, Kluck BN, Johnson CP, Joyner MJ. Cerebrovascular reactivity is associated with maximal aerobic capacity in healthy older adults. J Appl Physiol 2013;114:1383–7. http://dx.doi.org/10.1152/japplphysiol.01258.2012. [20] Liu J, Redmond MJ, Brodsky EK, Alexander AL, Lu A, Thornton FJ, et al. Generation and visualization of four-dimensional MR angiography data using an undersampled 3-D projection trajectory. IEEE Trans Med Imaging 2006;25:148–57. http://dx.doi.org/10.1109/TMI.2005.861706. [21] Schrauben E, Wåhlin A, Ambarki K, Spaak E, Malm J, Wieben O, et al. Fast 4D flow MRI intracranial segmentation and quantification in tortuous arteries. J Magn Reson Imaging 2015;42:1458–64. http://dx.doi.org/10.1002/jmri.24900. [22] Schrauben E, Wåhlin A, Ambarki K, Malm J, Wieben O, Eklund A. Automated 4D flow whole vessel segmentation and quantification using centerline extraction. Milan, Italy: International Society for Magnetic Resonance in Medicine; 2014. [23] Bouthillier A, van Loveren HR, Keller JT. Segments of the internal carotid artery: a new classification. Neurosurgery 1996;38:425–32 discussion432–3. [24] Shaban A, Albright KC, Boehme AK, Martin-Schild S. Circle of Willis variants: fetal PCA. Stroke Res Treat 2013;2013:1–6. http://dx.doi.org/10.1161/STROKEAHA.110.592303. [25] Hofman MB, Visser FC, van Rossum AC, Vink QM, Sprenger M, Westerhof N. In vivo validation of magnetic resonance blood volume flow measurements with limited spatial resolution in small vessels. Magn Reson Med 1995;33:778–84. [26] Sato K, Fisher JP, Seifert T, Overgaard M, SECHER NH, Ogoh S. Blood flow in internal carotid and vertebral arteries during orthostatic stress. Exp Physiol 2012;97:1272–80. http://dx.doi.org/10.1113/expphysiol.2012.064774. [27] Kemna LJ, Posse S, Tellmann L, Schmitz T, Herzog H. Interdependence of regional and global cerebral blood flow during visual stimulation: an O-15-butanol positron emission tomography study. J Cereb Blood Flow Metab 2001;21: 664–70. http://dx.doi.org/10.1097/00004647-200106000-00004. [28] Piechnik SK, Chiarelli PA, Jezzard P. Modelling vascular reactivity to investigate the basis of the relationship between cerebral blood volume and flow under CO2

[29]

[30]

[31]

[32]

[33]

[34]

[35] [36]

[37]

manipulation. NeuroImage 2008;39:107–18. http://dx.doi.org/10.1016/j.neuroimage.2007.08.022. Mandell DM, Han JS, Poublanc J, Crawley AP, Kassner A, Fisher JA, et al. Selective reduction of blood flow to white matter during hypercapnia corresponds with leukoaraiosis. Stroke 2008;39:1993–8. http://dx.doi.org/10.1161/STROKEAHA. 107.501692. Ainslie PN, Ashmead JC, Ide K, Morgan BJ, Poulin MJ. Differential responses to CO2 and sympathetic stimulation in the cerebral and femoral circulations in humans. J Physiol 2005;566:613–24. http://dx.doi.org/10.1113/jphysiol.2005.087320. Giller CA, Bowman G, Dyer H, Mootz L, Krippner W. Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy. Neurosurgery 1993;32:737–41 discussion741–2. Wilson MH, Edsell MEG, Davagnanam I, Hirani SP, Martin DS, Levett DZH, et al. Cerebral artery dilatation maintains cerebral oxygenation at extreme altitude and in acute hypoxia—an ultrasound and MRI study. J Cereb Blood Flow Metab 2011;31:2019–29. http://dx.doi.org/10.1038/jcbfm.2011.81. Dempsey JA, Xie A, Patz DS, Wang D. Physiology in medicine: obstructive sleep apnea pathogenesis and treatment — considerations beyond airway anatomy. J Appl Physiol 2014;116:3–12. http://dx.doi.org/10.1152/japplphysiol.01054. 2013. Xie A, Skatrud JB, Dempsey JA. Effect of hypoxia on the hypopnoeic and apnoeic threshold for CO(2) in sleeping humans. J Physiol 2001;535: 269–78. Heistad DD, Kontos HA. Cerebral circulation. Compr Physiol 1983. Chatzimavroudis GP, Oshinski JN, Franch RH, Walker PG, Yoganathan AP, Pettigrew RI. Evaluation of the precision of magnetic resonance phase velocity mapping for blood flow measurements. J Cardiovasc Magn Reson 2001;3: 11–9. Wåhlin A, Ambarki K, Hauksson J, Birgander R, Malm J, Eklund A. Phase contrast MRI quantification of pulsatile volumes of brain arteries, veins, and cerebrospinal fluids compartments: repeatability and physiological interactions. J Magn Reson Imaging 2012;35:1055–62. http://dx.doi.org/10.1002/jmri.23527.