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ALL CENTRAL NERVOUS SYSTEM (CNS) NEURO- AND VASCULAR-COMMUNICATION CHANNELS ARE SURROUNDED WITH CEREBROSPINAL FLUID (CSF)
Lara M Fahmy1, Yongsheng Chen2, Stephanie Xuan3, E Mark Haacke3, Jiani M Hu3, and Quan Jiang4
1Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States, 2Neurology, Wayne State University School of Medicine, Detroit, MI, United States, 3Radiology, Wayne State University School of Medicine, Detroit, MI, United States, 4Neurology, Henry Ford Health System, Detroit, MI, United States

Synopsis

It's well-established that the CNS is completely submerged in CSF; but to what extent is this true regarding the finer spaces within the CNS itself? We used MRI to simultaneously map the presence of CSF within all peri-neural and peri-vascular spaces in vivo in humans. Our findings indicated that all peri-neural spaces surrounding cranial and spinal nerves, as well as all peri-vascular spaces, were filled with CSF. These findings suggest that anatomically, substance exchange between the brain parenchyma and outside tissues (i.e. lymphatics) can only occur through CSF, warranting further investigation into its cerebral waste clearance and immunomodulation implications.

Introduction

CSF penetrates and interacts with the brain parenchyma through the glymphatic pathway.1 Dysfunctions of this glymphatic pathway have been associated with a broad range of neurological diseases including, but not limited to, Alzheimer’s disease and stroke.2-10 Therefore, it has become apparent that gaining a complete understanding of CSF physiology is an essential prerequisite to understanding the pathophysiology underlying neurological disease.
It is already very well-established that the CNS is completely submerged in CSF on the outside; but to what extent is this true regarding the finer spaces within the CNS itself? Most studies have asynchronously investigated these spaces and these investigations have been mainly conducted in animals and human cadavers.11-25 Moreover, although CSF-filled peri-vascular spaces in several brain regions have been illustrated in several studies, to our knowledge, there is no systematic study focusing on whether all cerebral vasculature (with the exception of capillaries) are surrounded with CSF, and this can only be revealed using in vivo imaging methods. Therefore, the objective of this study was to use MRI to simultaneously map the presence of CSF within all peri-neural (cranial and spinal nerves) and peri-vascular spaces in vivo in humans.

Methods

Upon IRB approval, we performed four types of experiments, each with 5 participants, using a 3T magnet to image the CSF in the brain and spinal cord. The first experiment employed a 3D T2-weighted (T2W) ‘Sampling Perfection with Application optimized Contrasts using different flip angle Evolution’ (T2W-SPACE) sequence to image the CSF and cranial nerves with hyperintense CSF signal and hypointense signal for cranial nerves and blood vessels. For the second experiment, in order to image CSF in peri-vascular spaces and to demonstrate that all MRI-visible cerebral blood vessels were surrounded by CSF, we used high-resolution ‘STrategically Acquired Gradient Echo’ (STAGE) imaging to simultaneously obtain bright-blood and dark-blood images.26-28 The STAGE imaging included a proton density weighted (PDW) scan and a T1-weighted (T1W) scan. Both images were fully flow compensated with bright blood signal. By subtracting the PDW from the inverted T1W image, one could obtain a synthetic T2W dark-blood image (sT2W) presenting bright-CSF and uniform grey matter and white matter intensities. In addition, we acquired a pure CSF image by using a 3D turbo-spin echo (TSE) sequence. The third experiment was performed on the cervical spinal cord at the C4/C5 level. A 2D T2* weighted spoiled gradient echo sequence (Multiple Echo Data Image Combination, MEDIC) was used to acquire images with hyperintense CSF and blood vessels, and hypointense nerves. The fourth experiment was performed on the lumbar spinal nerves at L3/L4 level. A regular T2W-TSE sequence was used.

Results

Images from the first experiment were used to visualize all 12 pairs of the cranial nerves (Fig. 1-2). As illustrated, the cranial nerves were hypointense, while the peri-neural spaces surrounding the cranial nerves were hyperintense, indicating the presence of CSF within these spaces. The spinal nerves were visualized on the images from the third and fourth experiments (Fig. 3). Similarly, the spinal nerves were hypointense, while the peri-neural spaces surrounding the spinal nerves were hyperintense, indicating the presence of CSF. The high-resolution (in the order of 100 µm) sT2W (Fig. 4A, bright CSF and dark blood) and T1W (Fig. 4B, bright blood and dark CSF) derived from STAGE imaging demonstrated that all MRI-visible vasculature were surrounded with CSF. By comparing these two images, we found that all MRI-visible vasculature were indeed surrounded by CSF. Moreover, in order to further confirm these findings, we used a T2W-TSE image acquired with a very long echo time to generate “pure” CSF images, with bright CSF and dark blood (Fig. 4C-D). Once again, all MRI-visible vasculature were indeed surrounded with CSF.

Discussion

To our knowledge, this is the first study to simultaneously and systematically verify that all 12 pairs of cranial nerves, all MRI-visible vasculature and spinal nerves are surrounded with CSF in vivo in humans; as opposed to previous studies that have asynchronously investigated this, mainly in animals and human cadavers. Our findings indicate that all brain parenchyma and spinal cord communication channels, both neuro- and vascular-communication channels, are encased in CSF. Therefore, it logically follows that CSF must play a critical role in substance exchange between the brain parenchyma/spinal cord and its communication channels as well as its surrounding environment/tissue—a role that has been historically underestimated and understudied. Our findings are consistent with previous literature that have asynchronously investigated CSF-filled peri-neural spaces, mostly in the context of CWC lymphatic-associated CSF outflow pathways, as well as peri-vascular spaces.2,29-32

Acknowledgements

This work was supported by the following NIH grants: R01-NS108491, RF1-AG057494 and R01-NS108463.

References

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Figures

Figure 1. CSF-filled peri-neural spaces surrounding the first five cranial nerves (CN I-CN V). A) Olfactory nerves (CN I); B) Optic nerves (CN II); C) Oculomotor nerves (CN III); D) Right trochlear nerve (CN IV); E) Left CN IV; and F) Trigeminal nerves (CN V). Space within the yellow lines: respective nerve (hypointense signal). Space between the red and yellow lines: peri-neural space (hyperintense signal). Space between the blue lines: CN V (hypointense signal). All images were generated from the first experiment as described in the method section.

Figure 2. CSF-filled peri-neural spaces surrounding the cranial nerves 6 to 12 (CN VI-CN XII). A) Abducens nerves (CN VI); B) Facial nerves (CN VII); C) Vestibulocochlear nerves (CN VIII); D) Glossopharyngeal nerves (CN IX); E) Vagus nerves (CN X); F) Accessory nerves (CN IX); G) Right hypoglossal nerve (CN XII); and Left CN XII. Space between the red and yellow lines: peri-neural space (hyperintense signal). All images were generated from the first experiment as described in the method section.

Figure 3. CSF-filled peri-neural spaces surrounding spinal nerves. A) Cervical spinal nerves (brachial plexus). Cervical nerves 4 are pointed with red arrows (hypointense signal), and the space surrounding the nerves is the CSF-filled peri-neural space (hyperintense signal). Multiple lymph nodes are detected from MRI (white arrowhead). B) Lumbar spinal nerves (red arrows, hypointense signal) surrounded with CSF-filled peri-neural space (hyperintense signal). Images were generated from the third and the fourth experiments as described in the method section.

Figure 4. Illustration showing that all MRI-visible vasculature were surrounded by CSF. A) sT2W image with bright CSF and dark blood; B) T1W with bright blood signal but dark CSF signal; C) CSF-only images, acquired by T2-TSE sequence with TE = 345ms at 3T; D) a 3D rendering of the CSF-only images. A) and B) were results from the high-resolution STAGE scans. The enlarged image in C) shows several MRI-visible vasculature (dark curves) surrounded by bright CSF. Images were generated from the second experiment as described in the method section.

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)
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