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Cyclic Intracerebral Coherent Motion on Peripheral-Pulse-Gated Ultra-Low VENC MRI: Noninvasive Depiction of Glymphatic Flow?
Robert Y Shih1,2, J Kevin DeMarco1,2, J Kent Werner1,2, Justin E Costello1,2, Isabelle Heukensfeldt Jansen3, Luca Marinelli3, Thomas K Foo3, and Vincent B Ho1,2
1Uniformed Services University of the Health Sciences, Bethesda, MD, United States, 2Walter Reed National Military Medical Center, Bethesda, MD, United States, 3GE Global Research, Niskayuna, NY, United States

Synopsis

A combination of pressure gradients from arterial pulsatility, respiratory cycles, and resistance changes is thought to drive convective influx of CSF into paraarterial spaces for rapid exchange with ISF, followed by efflux into paravenous spaces toward arachnoid granulations, meningeal lymphatics, or cranial nerves. Visualization of this phenomenon was attempted with peripheral-pulse-gated phase contrast sequences at VENC = 5 mm/s (gradient echo) and 0.24 mm/s (spin echo) in four healthy adults using an ultra-high-performance MAGNUS gradient coil. Very slow intracerebral coherent motion was depicted, cerebropetal during systole, cerebrofugal during diastole, possibly reflecting bulk flow in paravascular spaces of the glymphatic system.

Introduction

The glymphatic system is a clearance pathway for extracellular proteins and waste products in the mammalian brain; it depends on astrocytic AQP4 channel-mediated exchange between the extracellular interstitial fluid (ISF) and paravascular cerebrospinal fluid (CSF) compartments.(1) A combination of pressure gradients from arterial pulsatility, respiratory cycles, and resistance changes is thought to drive convective influx of CSF into paraarterial spaces for rapid exchange with ISF, followed by efflux into paravenous spaces toward arachnoid granulations, meningeal lymphatics, or cranial nerves.(2-3)

In vivo studies have tracked the movement of intrathecally administered tracers from CSF into ISF over the course of minutes to hours, using fluorescent tracers in mice or gadolinium-based contrast agents in mice and humans.(4-8) It would be beneficial to be able to assess changes in glymphatic flow without invasive procedures or extended imaging. While one human study has purported to use ultra-fast <100 ms whole-brain 3D BOLD fMRI to visualize cerebral glymphatic pulsations,(9) we propose ultra-low VENC MRI as an alternative noninvasive method.

Methods

Under an IRB-approved protocol, four awake healthy adult volunteers were imaged in 3T MRI with a MAGNUS (Microstructure Anatomy Gradient for Neuroimaging with Ultrafast Scanning) insert, which is a head-only ultra-high-performance gradient coil that can deliver simultaneous 200 mT/m and 500 T/m/s on each axis.(10) While designed primarily for benefits in high b-value low TE diffusion weighted imaging, it can also be applied to phase contrast imaging with shorter TE at ultra-low VENC, beyond what is normally feasible on a commercial 3T scanner.

Two peripheral-pulse-gated motion-sensitive sequences of the brain were acquired: 1) a fast gradient echo phase contrast sequence with VENC = 5 mm/s (TE=7.2 ms; TR = 13.1 ms) and 2 views per segment (ΔT = 52 ms) at 27-29 time points over the cardiac cycle and 2) a modified DTI sequence using a phase sensitive reconstruction with VENC = 0.24 mm/s (b = 2000 s/mm2) at 8 time points over the cardiac cycle. Because velocity-encoding gradients serve as diffusion-encoding gradients for the magnitude reconstruction, the latter sequence will be called SCIMI (Simultaneous Coherent-Incoherent Motion Imaging).

Results

On the peripheral-pulse-gated low VENC (5 mm/s) phase contrast sequence, coherent motion is seen in the lateral ventricles which is directed toward the brain parenchyma in the early cardiac cycle and away from the brain parenchyma in the late cardiac cycle (see Figure 1). Fainter signal or phase shifts in the brain parenchyma is consistent with very slow sub-mm/s flow.

On the peripheral-pulse-gated ultra-low VENC (0.24 mm/s) SCIMI sequence, coherent motion is depicted in the cerebral parenchyma, which is directed away from the ventricles and CSF spaces in the early cardiac cycle then toward the ventricles and CSF spaces in the late cardiac cycle (see Figures 2-5). This bulk flow is on the order of 0.1 mm/s and highest in the central/ventral brain.

Discussion

To the best of our knowledge, this is the first depiction of cardiac cyclic intracerebral coherent motion using ultra-low VENC phase contrast MRI. This may represent visualization of pulsatile bulk flow in the paravascular spaces, cerebropetal in systole and then cerebrofugal in diastole. Unilateral internal carotid arterial ligation studies in mice as well as mathematical modeling of paravascular-interstitial flow and resistance have shown the importance of arterial pulsation in driving glymphatic peristalsis as steady pressure-driven flow is not sufficient.(11-12) Regarding glymphatic flow in the interstitial space, which has been postulated to represent a combination of coherent (convection) and incoherent (diffusion) motion, an analysis of data from real-time iontophoresis experiments in mice/rats suggested an upper limit for superficial convective bulk flow velocity of 50 μm/min (0.0008 mm/s), which may remain undetectable, even with VENC = 0.24 mm/s.(13)

We do not believe that SCIMI is visualizing cardiac cyclic cerebral parenchymal deformation or displacement, which has been shown to be oriented in the opposite direction (i.e. expansion or cerebrofugal in systole and contraction or cerebropetal in diastole) by previous studies utilizing cardiac-gated phase contrast, pencil-excitation M-mode , and 3D DENSE MRI techniques.(14-16) We also do not believe that SCIMI is visualizing cardiac cyclic intravascular movement, because our velocity range is well below expected values for cerebral arteriolar (2.4 mm/s) and capillary (0.8 mm/s) blood flow,(17) yet we do not see evidence of aliasing. In the end, measurements of differences between wakefulness and slow wave sleep are needed to prove the utility of SCIMI in the noninvasive assessment of glymphatic flow. If successful, animal scanners may be used to replicate mouse experiments based on injected tracers: awake versus asleep, young versus old, adrenergic blockade, anesthetic use, loss of perivascular AQP4 localization.(18-20)

Conclusion

Phase sensitive reconstruction of a modified DTI sequence (SCIMI) with ultra-low VENC = 0.24 mm/s and peripheral pulse gating in four healthy adult volunteers depicted very slow cardiac cyclic intracerebral coherent motion on the order of 0.1 mm/s. The streamlines were oriented cerebropetal during systole and cerebrofugal during diastole, which may reflect pulsatile bulk flow in the paravascular spaces of the glymphatic system. Our plans for further study include quantification and comparison of this finding during wakefulness versus slow wave sleep, as well as animal models of impaired glymphatic clearance (e.g. AQP4 knockout mice).

Acknowledgements

The views expressed in this abstract are those of the authors and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, the Department of Defense, or the U.S. Government.

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Figures

Axial peripheral-pulse-gated low VENC (5 mm/s) gradient echo phase contrast MRI at the level of the basal ganglia in early (left), middle, and late (right) cardiac cycle for Volunteer A. Coherent motion is seen in the atria/trigones of the lateral ventricles, which is directed toward the brain parenchyma in the early cardiac cycle and away from the brain parenchyma in the late cardiac cycle (white is toward patient right, black is toward patient left).

Axial peripheral-pulse-gated ultra-low VENC (0.24 mm/s) SCIMI sequence at the level of lateral ventricles (upper) and third ventricle (lower) in the early (left), middle, and late (right) cardiac cycle for Volunteer A. Intracerebral coherent motion or bulk flow is directed away from the ventricles and CSF spaces (cerebropetal) in the early cardiac cycle and toward the ventricles and CSF spaces (cerebrofugal) in the late cardiac cycle.

Axial peripheral-pulse-gated ultra-low VENC (0.24 mm/s) SCIMI sequence at the level of lateral ventricles (upper) and third ventricle (lower) in the early (left), middle, and late (right) cardiac cycle for Volunteer B. Intracerebral coherent motion or bulk flow is directed away from the ventricles and CSF spaces (cerebropetal) in the early cardiac cycle and toward the ventricles and CSF spaces (cerebrofugal) in the late cardiac cycle.

Axial peripheral-pulse-gated ultra-low VENC (0.24 mm/s) SCIMI sequence at the level of lateral ventricles (upper) and third ventricle (lower) in the early (left), middle, and late (right) cardiac cycle for Volunteer C. Intracerebral coherent motion or bulk flow is directed away from the ventricles and CSF spaces (cerebropetal) in the early cardiac cycle and toward the ventricles and CSF spaces (cerebrofugal) in the late cardiac cycle.

Axial peripheral-pulse-gated ultra-low VENC (0.24 mm/s) SCIMI sequence at the level of lateral ventricles (upper) and third ventricle (lower) in the early (left), middle, and late (right) cardiac cycle for Volunteer D. Intracerebral coherent motion or bulk flow is directed away from the ventricles and CSF spaces (cerebropetal) in the early cardiac cycle and toward the ventricles and CSF spaces (cerebrofugal) in the late cardiac cycle.

Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)
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