Search

Background: Traumatic spinal cord injury (SCI) causes spinal cord swelling and occlusion of the subarachnoid space (SAS). SAS occlusion can change pulsatile cerebrospinal fluid (CSF) dynamics, which could have acute clinical management implications. This study aimed to characterise SAS occlusion and investigate CSF dynamics over 14 days post-SCI in the pig., Methods: A thoracic contusion SCI was induced in female domestic pigs (22-29 kg) via a weight drop apparatus (N = 5, 10 cm; N = 5, 20 cm). Magnetic resonance imaging (MRI) was performed pre-SCI and 3, 7 and 14 days post-SCI. SAS occlusion length (cranial-caudal), and injury site SAS area (cross-sectional), were measured on T2-weighted MRI. CSF dynamics, specifically peak cranial/caudal mean velocity (cm/s), and the corresponding time to peak (% of cardiac cycle), were measured on cardiac gated, axial phase-contrast MRI obtained at C2/C3, T8/T9, T11/T12 and L1/L2. Linear-mixed effects models, with a significance level of α = 0.05, were developed to assess the effect of: (1) injury group and time point on SAS occlusion measures; and (2), time point and spinal level, adjusted by injury group, on CSF dynamics., Results: For both injury groups, SAS occlusion length decreased from 3 to 7 days post-SCI, and 7 to 14 days post-SCI. The cross-sectional SAS area decreased after SCI, and increased to 14 days post-SCI, in both groups. At all spinal levels, peak cranial/caudal mean velocity and the time to peak caudal mean velocity decreased at day 3 post-SCI. From 3 to 14 days post-SCI, peak caudal mean velocity and the time to peak caudal mean velocity increased towards baseline values, at all spinal levels., Conclusions: Spinal-level specific changes to CSF dynamics, with concurrent changes to SAS occlusion, occurred after SCI in the pig, suggesting that CSF pulsatility and craniospinal compliance were altered in the sub-acute post-traumatic period. These results suggest that PC-MRI derived CSF dynamics may provide a non-invasive method to investigate functional alterations to the spinal intrathecal space following traumatic SCI., Competing Interests: Declarations. Ethics approval and consent to participate: This project was approved by the South Australian Health and Medical Research Institute Animal Ethics Committee (SAM 243 and SAM-22-031) and conducted in accordance with the Australian National Health and Medical Research Council Code of Care and Use of Animals for Scientific Purposes [54]. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The meninges, formed by dura, arachnoid and pia mater, cover the central nervous system and provide important barrier functions. Located between arachnoid and pia mater, the cerebrospinal fluid (CSF)-filled subarachnoid space (SAS) features a variety of trabeculae, septae and pillars. Like the arachnoid and the pia mater, these structures are covered with leptomeningeal or meningothelial cells (MECs) that form a barrier between CSF and the parenchyma of the optic nerve (ON). MECs contribute to the CSF proteome through extensive protein secretion. In vitro, they were shown to phagocytose potentially toxic proteins, such as α-synuclein and amyloid beta, as well as apoptotic cell bodies. They therefore may contribute to CSF homeostasis in the SAS as a functional exchange surface. Determining the total area of the SAS covered by these cells that are in direct contact with CSF is thus important for estimating their potential contribution to CSF homeostasis., Methods: Using synchrotron radiation-based micro-computed tomography (SRµCT), two 0.75 mm-thick sections of a human optic nerve were acquired at a resolution of 0.325 µm/pixel, producing images of multiple terabytes capturing the geometrical details of the CSF space. Special-purpose supercomputing techniques were employed to obtain a pixel-accurate morphometric description of the trabeculae and estimate internal volume and surface area of the ON SAS., Results: In the bulbar segment, the ON SAS microstructure is shown to amplify the MECs surface area up to 4.85-fold compared to an "empty" ON SAS, while just occupying 35% of the volume. In the intraorbital segment, the microstructure occupies 35% of the volume and amplifies the ON SAS area 3.24-fold., Conclusions: We provided for the first time an estimation of the interface area between CSF and MECs. This area is of importance for estimating a potential contribution of MECs on CSF homeostasis., (© 2023. The Author(s).)

Background: The mechanisms of cerebrospinal fluid (CSF) production by the ventricular choroid plexus (ChP) have not been fully deciphered. One prominent hypothesized mechanism is trans-epithelial water transport mediated by accumulation of solutes at the luminal ChP membrane that produces local osmotic gradients. However, this standing osmotic gradient hypothesis has not been systematically tested., Methods: To assess the plausibility of the standing gradient mechanism serving as the main driver of CSF production by the ChP, we developed a three-dimensional (3D) and a one-dimensional (1D) computational model to quantitatively describe the associated processes in the rat ChP inter-microvillar spaces and in CSF pools between macroscopic ChP folds (1D only). The computationally expensive 3D model was used to examine the applicability of the 1D model for hypothesis testing. The 1D model was employed to predict the rate of CSF produced by the standing gradient mechanism for 200,000 parameter permutations. Model parameter values for each permutation were chosen by random sampling from distributions derived from published experimental data., Results: Both models predict that the CSF production rate by the standing osmotic gradient mechanism is below 10% of experimentally measured values that reflect the contribution of all actual production mechanisms. The 1D model indicates that increasing the size of CSF pools between ChP folds, where diffusion dominates solute transport, would increase the contribution of the standing gradient mechanism to CSF production., Conclusions: The models suggest that the effect of standing osmotic gradients is too small to contribute substantially to CSF production. ChP motion and movement of CSF in the ventricles, which are not accounted for in the models, would further reduce this effect, making it unlikely that standing osmotic gradients are the main drivers of CSF production., (© 2023. The Author(s).)

Background: Detecting changes in pulsatile cerebrospinal fluid (CSF) flow may assist clinical management decisions, but spinal CSF flow is relatively understudied. Traumatic spinal cord injuries (SCI) often cause spinal cord swelling and subarachnoid space (SAS) obstruction, potentially causing pulsatile CSF flow changes. Pigs are emerging as a favoured large animal SCI model; therefore, the aim of this study was to characterise CSF flow along the healthy pig spine., Methods: Phase-contrast magnetic resonance images (PC-MRI), retrospectively cardiac gated, were acquired for fourteen laterally recumbent, anaesthetised and ventilated, female domestic pigs (22-29 kg). Axial images were obtained at C2/C3, T8/T9, T11/T12 and L1/L2. Dorsal and ventral SAS regions of interest (ROI) were manually segmented. CSF flow and velocity were determined throughout a cardiac cycle. Linear mixed-effects models, with post-hoc comparisons, were used to identify differences in peak systolic/diastolic flow, and maximum velocity (cranial/caudal), across spinal levels and dorsal/ventral SAS. Velocity wave speed from C2/C3 to L1/L2 was calculated., Results: PC-MRI data were obtained for 11/14 animals. Pulsatile CSF flow was observed at all spinal levels. Peak systolic flow was greater at C2/C3 (dorsal: - 0.32 ± 0.14 mL/s, ventral: - 0.15 ± 0.13 mL/s) than T8/T9 dorsally (- 0.04 ± 0.03 mL/s; p < 0.001), but not different ventrally (- 0.08 ± 0.08 mL/s; p = 0.275), and no difference between thoracolumbar levels (p > 0.05). Peak diastolic flow was greater at C2/C3 (0.29 ± 0.08 mL/s) compared to T8/T9 (0.03 ± 0.03 mL/s, p < 0.001) dorsally, but not different ventrally (p = 1.000). Cranial and caudal maximum velocity at C2/C3 were greater than thoracolumbar levels dorsally (p < 0.001), and T8/T9 and L1/L2 ventrally (p = 0.022). Diastolic velocity wave speed was 1.41 ± 0.39 m/s dorsally and 1.22 ± 0.21 m/s ventrally, and systolic velocity wave speed was 1.02 ± 0.25 m/s dorsally and 0.91 ± 0.22 m/s ventrally., Conclusions: In anaesthetised and ventilated domestic pigs, spinal CSF has lower pulsatile flow and slower velocity wave propagation, compared to humans. This study provides baseline CSF flow at spinal levels relevant for future SCI research in this animal model., (© 2023. The Author(s).)

Background: Disturbances in the brain fluid balance can lead to life-threatening elevation in the intracranial pressure (ICP), which represents a vast clinical challenge. Nevertheless, the details underlying the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP., Methods: Experimental rats were employed for in vivo determinations of CSF secretion rates, ICP, blood pressure and ex vivo excised choroid plexus for morphological analysis and quantification of expression and activity of various transport proteins. CSF and blood extractions from rats, pigs, and humans were employed for osmolality determinations and a mathematical model employed to determine a contribution from potential local gradients at the surface of choroid plexus., Results: We demonstrate that CSF secretion can occur independently of conventional osmosis and that local osmotic gradients do not suffice to support CSF secretion. Instead, the CSF secretion across the luminal membrane of choroid plexus relies approximately equally on the Na + /K + /2Cl - cotransporter NKCC1, the Na + /HCO 3 - cotransporter NBCe2, and the Na + /K + -ATPase, but not on the Na + /H + exchanger NHE1. We demonstrate that pharmacological modulation of CSF secretion directly affects the ICP., Conclusions: CSF secretion appears to not rely on conventional osmosis, but rather occur by a concerted effort of different choroidal transporters, possibly via a molecular mode of water transport inherent in the proteins themselves. Therapeutic modulation of the rate of CSF secretion may be employed as a strategy to modulate ICP. These insights identify new promising therapeutic targets against brain pathologies associated with elevated ICP., (© 2022. The Author(s).)

Background: Cerebrospinal fluid (CSF) protein analysis is an important element in the diagnostic chain for various central nervous system (CNS) pathologies. Among multiple existing approaches to interpreting measured protein levels, the Reiber diagram is particularly robust with respect to physiologic inter-individual variability, as it uses multiple subject-specific anchoring values. Beyond reliable identification of abnormal protein levels, the Reiber diagram has the potential to elucidate their pathophysiologic origin. In particular, both reduction of CSF drainage from the cranio-spinal space as well as blood-CNS barrier dysfunction have been suggested ρas possible causes of increased concentration of blood-derived proteins. However, there is disagreement on which of the two is the true cause., Methods: We designed two computational models to investigate the mechanisms governing protein distribution in the spinal CSF. With a one-dimensional model, we evaluated the distribution of albumin and immunoglobulin G (IgG), accounting for protein transport rates across blood-CNS barriers, CSF dynamics (including both dispersion induced by CSF pulsations and advection by mean CSF flow) and CSF drainage. Dispersion coefficients were determined a priori by computing the axisymmetric three-dimensional CSF dynamics and solute transport in a representative segment of the spinal canal., Results: Our models reproduce the empirically determined hyperbolic relation between albumin and IgG quotients. They indicate that variation in CSF drainage would yield a linear rather than the expected hyperbolic profile. In contrast, modelled barrier dysfunction reproduces the experimentally observed relation., Conclusions: High levels of albumin identified in the Reiber diagram are more likely to originate from a barrier dysfunction than from a reduction in CSF drainage. Our in silico experiments further support the hypothesis of decreasing spinal CSF drainage in rostro-caudal direction and emphasize the physiological importance of pulsation-driven dispersion for the transport of large molecules in the CSF.

Background: Postural changes are related to changes in cerebrospinal fluid (CSF) dynamics. While sitting up leads to a decrease in cranial CSF pressure, it also causes shifts in the craniospinal CSF volume and compliance distribution. We hypothesized that jugular vein collapse in upright posture is a major contributor to these shifts in CSF volume and compliance., Methods: To test this hypothesis, we implemented a mathematical lumped-parameter model of the CSF system and the relevant parts of the cardiovascular system. In this model, the CSF and the venous system are each divided into a cranial and a spinal part. The pressures in these cranial and spinal portions differ by the posture-dependent hydrostatic pressure columns in the connecting vessels. Jugular collapse is represented by a reduction of the hydrostatic pressure difference between cranial and spinal veins. The CSF pressure-volume relationship is implemented as a function of the local CSF to venous pressure gradient. This implies that an increase in CSF volume leads to a simultaneous displacement of blood from adjacent veins. CSF pulsations driven by the cardiovascular system are introduced through a pulsating cranial arterial volume., Results: In upright posture, the implemented CSF pressure-volume relationship shifts to lower cranial CSF pressures compared to the horizontal position, leading to a decrease in cranial CSF pressure when sitting up. Concurrently, the compliance of the spinal compartment decreases while the one of the cranial compartment increases. With this, in upright posture only 10% of the CSF system's compliance is provided by the spinal compartment compared to 35% in horizontal posture. This reduction in spinal compliance is accompanied by a caudal shift of CSF volume. Also, the ability of the spinal CSF compartment to compensate for cerebral arterial volume pulsations reduces in upright posture, which in turn reduces the calculated craniospinal CSF flow pulsations., Conclusion: The mathematical model enabled us to isolate the effect of jugular collapse and quantify the induced shifts of compliance and CSF volume. The good concordance of the modelled changes with clinically observed values indicates that jugular collapse can be considered a major contributor to CSF dynamics in upright posture.