Fluids and Barriers of the CNS

Journal: Fluids and Barriers of the CNS

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Fluids Barriers CNS

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BioMed Central

ISSN

2045-8118

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Publications 1 - 10 of 12

VIEshunt: towards a ventricular intelligent and electromechanical shunt for hydrocephalus therapy
Flürenbrock, Fabian; Korn, Leonie; Schulte, Dominik; et al. (2025)
Fluids and Barriers of the CNS
Background Shunt systems for hydrocephalus therapy are commonly based on passive mechanical pressure valves that are driven by the intracranial, intra-abdominal, and hydrostatic pressure. The differential pressure acting on the valve determines the drainage rate of cerebrospinal fluid (CSF) but is not a gauge of the physiological condition of the patient. Internal and external influences can cause over- or underdrainage and lead to pathological levels of intracranial pressure (ICP). Methods The first prototype of a ventricular intelligent and electromechanical shunt (VIEshunt) is developed, tested, and compared with previous efforts towards the development of a smart shunt. Its key components are a micro pump, a flow meter, a pressure sensor, an inertial measurement unit, a wireless communication interface, and a microcontroller. The VIEshunt prototype was tested in vitro using a hardware-in-the-loop (HiL) test bench that runs real-time patient simulations involving changes in intracranial and intra-abdominal pressure, as well as changes in posture ranging between supine and upright position. The prototype was subsequently tested in an in vivo pilot study based on an acute ovine animal model (n=1) with infusions of artificial CSF. Results During 24 h in vitro testing, the prototype detected the simulated posture changes of the patient and automatically adapted the controller reference. The posture-specific ICP references of 12 mmHg for supine and —3 mmHg for upright position were tracked without offset, thus preventing adverse over- and underdrainage during the investigated HiL test scenario. During acute in vivo testing, the prototype first regulated the mean ICP of a sheep from 22 mmHg down to 20 mmHg. Each of the three subsequent intraventricular bolus infusions of 1 mL saline solution increased mean ICP by approximately 11 mmHg. While natural absorption alone decreased ICP by only 5 mmHg within 9 min, the prototype was able to regulate ICP back to the pre-bolus pressure value within 5 min. Conclusion The developed VIEshunt prototype is capable of posture-dependent ICP regulation and CSF drainage control. Smart shunt systems based on VIEshunt could improve patient monitoring and enable optimal physiologic therapy by adapting to the individual patient. To derive statistically relevant conclusions for the performance of VIEshunt, future work will focus on the development of a next generation prototype for use in pre-clinical studies.
Towards an automated identification of typical walking patterns in NPH patients using wearable sensors
Stieglitz, Lennart Henning; Dias, Sandra; Graf, Christina; et al. (2023)
Fluids and Barriers of the CNS ~ Abstracts from Hydrocephalus 2022 - The Fourteenth Meeting of the Hydrocephalus Society
Introduction: An experienced physician may tell the likelihood of iNPH from the walking pattern alone. However, the challenge is to provide the benefits of a “diagnostic view” to as many patients as possible to improve iNPH identification and treatment rates. We therefore performed a prospective controlled study using wear- able inertia measurement units (IMUs) to identify typical walking patterns in preparation of a future automated patient identification system. Methods: Five wearable inertial measurement units were placed in 20 iNPH patients, 20 elderly age- and gender-matched healthy con- trols (EHCs) and 20 young healthy controls (YHCs) for data collection in their home environment during 72 h, as well as 6 months after shunt implantation in case of the iNPH patients. Results: There was a significant difference for most of the gait parameters when YHC, EHC and iNPH patients were compared. Post- operatively, iNPH patients showed an improvement of the swing phase (p = 0.039). In gait velocity, stance to swing ratio, stance phase, cycle time and cadence, a significant difference was observed for patients with a good VP-shunt response (NPH RR ≥ 5). A receiver operating characteristic analyses showed a good sensitivity for stride length ≥ 0.44 m, gait velocity≥ 0.39 m/s and cadence≥ 0.81 steps/min. Conclusions: The walking-pattern characteristics in iNPH patients are far more evident in the home environment than during a physi- cal examination. It can be used to distinguish patients from healthy persons and to predict response to VP shunt therapy.
Intercompartmental communication between the cerebrospinal and adjacent spaces during intrathecal infusions in an acute ovine in-vivo model
Podgoršak, Anthony; Trimmel, Nina Eva; Oertel, Markus Florian; et al. (2022)
Fluids and Barriers of the CNS
Introduction: The treatment of hydrocephalus has been a topic of intense research ever since the first clinically successful use of a valved cerebrospinal fluid shunt 72 years ago. While ample studies elucidating different phenomena impacting this treatment exist, there are still gaps to be filled. Specifically, how intracranial, intrathecal, arterial, and venous pressures react and communicate with each other simultaneously. Methods: An in-vivo sheep trial (n = 6) was conducted to evaluate and quantify the communication existing within the cranio-spinal, arterial, and venous systems (1 kHz sampling frequency). Standardized intrathecal infusion testing was performed using an automated infusion apparatus, including bolus and constant pressure infusions. Bolus infusions entailed six lumbar intrathecal infusions of 2 mL Ringer’s solution. Constant pressure infusions were comprised of six regulated pressure steps of 3.75 mmHg for periods of 7 min each. Mean pressure reactions, pulse amplitude reactions, and outflow resistance were calculated. Results: All sheep showed intracranial pressure reactions to acute increases of intrathecal pressure, with four of six sheep showing clear cranio-spinal communication. During bolus infusions, the increases of mean pressure for intrathecal, intracranial, arterial, and venous pressure were 16.6 ± 0.9, 15.4 ± 0.8, 3.9 ± 0.8, and 0.1 ± 0.2 mmHg with corresponding pulse amplitude increases of 2.4 ± 0.3, 1.3 ± 0.3, 1.3 ± 0.3, and 0.2 ± 0.1 mmHg, respectively. During constant pressure infusions, mean increases from baseline were 14.6 ± 3.8, 15.5 ± 4.2, 4.2 ± 8.2, and 3.2 ± 2.4 mmHg with the corresponding pulse amplitude increases of 2.5 ± 3.6, 2.5 ± 3.0, 7.7 ± 4.3, and 0.7 ± 2.0 mmHg for intrathecal, intracranial, arterial, and venous pulse amplitude, respectively. Outflow resistances were calculated as 51.6 ± 7.8 and 77.8 ± 14.5 mmHg/mL/min for the bolus and constant pressure infusion methods, respectively—showing deviations between the two estimation methods. Conclusions: Standardized infusion tests with multi-compartmental pressure recordings in sheep have helped capture distinct reactions between the intrathecal, intracranial, arterial, and venous systems. Volumetric pressure changes in the intrathecal space have been shown to propagate to the intraventricular and arterial systems in our sample,and to the venous side in individual cases. These results represent an important step into achieving a more complete quantitative understanding of how an acute rise in intrathecal pressure can propagate and influence other systems.
Finite state machine for position dependent hydrocephalus shunt therapy
Iselin, David; Chomarat, Joris; Holzer, Caroline; et al. (2023)
Fluids and Barriers of the CNS ~ Abstracts from Hydrocephalus 2022 - The Fourteenth Meeting of the Hydrocephalus Society
Introduction: Intracranial pressure (ICP) being strongly position- dependent complicates pressure-based shunt control as a reliable therapy approach for hydrocephalus patients. An algorithm using state detection and position-specific ICP reference selection imple- mented on a novel mechatronic shunt platform enables regulation towards a physiological ICP in any patient’s posture. Methods: A finite state machine (FSM) was developed. Two states rep- resent pressure-control for positions of known reference pressures, namely supine and upright. A third state represents flow-control for positions with unknown reference pressures and positional changes. The FSM switches cases by tracking the torso inclination of the patient every second, using an increasing counter when leaving a certain case-dependent angular interval and changing case when reaching a predefined counter threshold. Results: During hardware-in-the-loop tests, position-dependent pres- sure references of physiological ICP could be tracked without offset during sequences of postural changes. The case-dependent thresh- olds improved robustness against sensor noise and patient motion. Increasing threshold values for changes from flow to pressure-based cases and decreasing values vice versa improved the controller stabil- ity. Flow-based regulation using averaged empirical flows as reference allowed for physiological cerebrospinal fluid drainage even during intervals of severe ICP fluctuations and disturbances. Conclusions: FSM posture detection proves to be an efficient exten- sion to pressure-based shunt control. The implementation of case- dependent threshold values allows for a trade-off between fast and robust system response and will be a central aspect of future research. Possibilities arising from the FSM enable the extension to further posi- tion and activity states, rendering the controller personalised for every patient.
Human CD4+ T cell subsets differ in their abilities to cross endothelial and epithelial brain barriers in vitro
Nishihara, Hideaki; Soldati, Sasha; Mossu, Adrien; et al. (2020)
Fluids and Barriers of the CNS
Background The brain barriers establish compartments in the central nervous system (CNS) that significantly differ in their communication with the peripheral immune system. In this function they strictly control T-cell entry into the CNS. T cells can reach the CNS by either crossing the endothelial blood–brain barrier (BBB) or the epithelial blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP). Objective Analysis of the cellular and molecular mechanisms involved in the migration of different human CD4+ T-cell subsets across the BBB versus the BCSFB. Methods Human in vitro models of the BBB and BCSFB were employed to study the migration of circulating and CNS-entry experienced CD4+ T helper cell subsets (Th1, Th1*, Th2, Th17) across the BBB and BCSFB under inflammatory and non-inflammatory conditions in vitro. Results While under non-inflammatory conditions Th1* and Th1 cells preferentially crossed the BBB, under inflammatory conditions the migration rate of all Th subsets across the BBB was comparable. The migration of all Th subsets across the BCSFB from the same donor was 10- to 20-fold lower when compared to their migration across the BBB. Interestingly, Th17 cells preferentially crossed the BCSFB under both, non-inflamed and inflamed conditions. Barrier-crossing experienced Th cells sorted from CSF of MS patients showed migratory characteristics indistinguishable from those of circulating Th cells of healthy donors. All Th cell subsets could additionally cross the BCSFB from the CSF to ChP stroma side. T-cell migration across the BCSFB involved epithelial ICAM-1 irrespective of the direction of migration. Conclusions Our observations underscore that different Th subsets may use different anatomical routes to enter the CNS during immune surveillance versus neuroinflammation with the BCSFB establishing a tighter barrier for T-cell entry into the CNS compared to the BBB. In addition, CNS-entry experienced Th cell subsets isolated from the CSF of MS patients do not show an increased ability to cross the brain barriers when compared to circulating Th cell subsets from healthy donors underscoring the active role of the brain barriers in controlling T-cell entry into the CNS. Also we identify ICAM-1 to mediate T cell migration across the BCSFB.
Influence of head-over-body and body-over-head posture on craniospinal, vascular, and abdominal pressures in an acute ovine in-vivo model
Podgoršak, Anthony; Trimmel, Nina Eva; Flürenbrock, Fabian; et al. (2023)
Fluids and Barriers of the CNS
Introduction Optimal shunt-based hydrocephalus treatments are heavily influenced by dynamic pressure behaviors between proximal and distal ends of shunt catheters. Posture-dependent craniospinal, arterial, venous, and abdominal dynamics thereby play an essential role. Methods An in-vivo ovine trial (n = 6) was conducted to evaluate communication between craniospinal, arterial, venous, and abdominal dynamics. Tilt-testing was performed between –13° and + 13° at 10-min intervals starting and ending at 0° prone position. Mean pressure, pulse pressure, and Pearson correlation (r) to the respective angle were calculated. Correlations are defined as strong: |r|≥ 0.7, mild: 0.3 <|r|< 0.7, and weak: |r|≤ 0.3. Transfer functions (TFs) between the arterial and adjacent compartments were derived. Results Strong correlations were observed between posture and: mean carotid/femoral arterial (r = − 0.97, r = − 0.87), intracranial, intrathecal (r = −0.98, r = 0.94), jugular (r = − 0.95), abdominal cranial, dorsal, caudal, and intravesical pressure (r = − 0.83, r = 0.84, r = − 0.73, r = 0.99) while mildly positive correlation exists between tilt and central venous pressure (r = 0.65). Only dorsal abdominal pulse pressure yielded a significant correlation to tilt (r = 0.21). TFs followed general lowpass behaviors with resonant peaks at 4.2 ± 0.4 and 11.5 ± 1.5 Hz followed by a mean roll-off of − 15.9 ± 6.0 dB/decade. Conclusions Tilt-tests with multi-compartmental recordings help elucidate craniospinal, arterial, venous, and abdominal dynamics, which is essential to optimize shunt-based therapy. Results motivate hydrostatic influences on mean pressure, with all pressures correlating to posture, with little influence on pulse pressure. TF results quantify the craniospinal, arterial, venous, and abdominal compartments as compliant systems and help pave the road for better quantitative models of the interaction between the craniospinal and adjacent spaces.
Characterization of the blood–brain barrier in genetically diverse laboratory mouse strains
Schaffenrath, Johanna; Huang, Sheng-Fu; Wyss, Tania; et al. (2021)
Fluids and Barriers of the CNS
Background Genetic variation in a population has an influence on the manifestation of monogenic as well as multifactorial disorders, with the underlying genetic contribution dependent on several interacting variants. Common laboratory mouse strains used for modelling human disease lack the genetic variability of the human population. Therefore, outcomes of rodent studies show limited relevance to human disease. The functionality of brain vasculature is an important modifier of brain diseases. Importantly, the restrictive interface between blood and brain—the blood–brain barrier (BBB) serves as a major obstacle for the drug delivery into the central nervous system (CNS). Using genetically diverse mouse strains, we aimed to investigate the phenotypic and transcriptomic variation of the healthy BBB in different inbred mouse strains. Methods We investigated the heterogeneity of brain vasculature in recently wild-derived mouse strains (CAST/EiJ, WSB/EiJ, PWK/PhJ) and long-inbred mouse strains (129S1/SvImJ, A/J, C57BL/6J, DBA/2J, NOD/ShiLtJ) using different phenotypic arms. We used immunohistochemistry and confocal laser microscopy followed by quantitative image analysis to determine vascular density and pericyte coverage in two brain regions—cortex and hippocampus. Using a low molecular weight fluorescence tracer, sodium fluorescein and spectrophotometry analysis, we assessed BBB permeability in young and aged mice of selected strains. For further phenotypic characterization of endothelial cells in inbred mouse strains, we performed bulk RNA sequencing of sorted endothelial cells isolated from cortex and hippocampus. Results Cortical vessel density and pericyte coverage did not differ among the investigated strains, except in the cortex, where PWK/PhJ showed lower vessel density compared to NOD/ShiLtJ, and a higher pericyte coverage than DBA/2J. The vascular density in the hippocampus differed among analyzed strains but not the pericyte coverage. The staining patterns of endothelial arteriovenous zonation markers were similar in different strains. BBB permeability to a small fluorescent tracer, sodium fluorescein, was also similar in different strains, except in the hippocampus where the CAST/EiJ showed higher permeability than NOD/ShiLtJ. Transcriptomic analysis of endothelial cells revealed that sex of the animal was a major determinant of gene expression differences. In addition, the expression level of several genes implicated in endothelial function and BBB biology differed between wild-derived and long-inbred mouse strains. In aged mice of three investigated strains (DBA/2J, A/J, C57BL/6J) vascular density and pericyte coverage did not change—expect for DBA/2J, whereas vascular permeability to sodium fluorescein increased in all three strains. Conclusions Our analysis shows that although there were no major differences in parenchymal vascular morphology and paracellular BBB permeability for small molecular weight tracer between investigated mouse strains or sexes, transcriptomic differences of brain endothelial cells point to variation in gene expression of the intact BBB. These baseline variances might be confounding factors in pathological conditions that may lead to a differential functional outcome dependent on the sex or genetic polymorphism.
VIEshunt: towards a smart shunt system for hydrocephalus patients
Flürenbrock, Fabian; Korn, Leonie; Schulte, Dominik; et al. (2023)
Fluids and Barriers of the CNS ~ Abstracts from Hydrocephalus 2022: the Fourteenth Meeting of the Hydrocephalus Society
Is posture‐related craniospinal compliance shift caused by jugular vein collapse? - A theoretical analysis
Gehlen, Manuel; Kurtcuoglu, Vartan; Schmid Daners, Marianne (2017)
Fluids and Barriers of the CNS
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.
The influence of upright posture on craniospinal, arteriovenous, and abdominal pressures in a chronic ovine in-vivo trial
Podgoršak, Anthony; Trimmel, Nina Eva; Oertel, Markus Florian; et al. (2023)
Fluids and Barriers of the CNS
Introduction Most investigations into postural influences on craniospinal and adjacent physiology have been performed in anesthetized animals. A comprehensive study evaluating these physiologies while awake has yet been completed. Methods Six awake sheep had telemetric pressure sensors (100 Hz) implanted to measure intracranial, intrathecal, arterial, central venous, cranial, caudal, dorsal, and ventral intra-abdominal pressure (ICP, ITP, ABP, CVP, IAPcr, IAPcd, IAPds, IAPve, respectively). They were maneuvered upright by placing in a chair for two minutes; repeated 25 times over one month. Changes in mean and pulse pressure were calculated by comparing pre-chair, P0, with three phases during the maneuver: P1, chair entrance; P2, chair halftime; P3, prior to chair exit. Statistical significance (p ≤ .05) was assessed using repeated measures ANOVA. Results Significant mean pressure changes of (P1 − P0) and (P3 − P0) were measured at − 12.1 ± 3.1 and − 14.2 ± 3.0(p < .001), 40.8 ± 10.5 and 37.7 ± 3.5(p = .019), 9.7 ± 8.3 and 6.2 ± 5.3(p = .012), 22.3 ± 29.8 and 12.5 ± 12.1(p = .042), and 11.7 ± 3.9 and 9.0 ± 5.2(p = .014) mmHg, for ICP, ITP, IAPds, IAPcr, IAPca, respectively. For pulse pressures, significant changes of (P1 − P0) and (P3 − P0) were measured at − 1.3 ± 0.7 and − 2.0 ± 1.1(p < .001), 4.7 ± 2.3 and 1.4 ± 1.4(p < .001), 15.0 ± 10.2 and 7.3 ± 5.5(p < .001), − 0.7 ± 1.8 and − 1.7 ± 1.7(p < .001), − 1.3 ± 4.2 and − 1.4 ± 4.7(p = .006), and 0.3 ± 3.9 and − 1.0 ± 1.3(p < .001) mmHg, for ICP, ITP, ABP, IAPds, IAPcr, IAPca, respectively. Conclusions Pressures changed posture-dependently to differing extents. Changes were most pronounced immediately after entering upright posture (P1) and became less prominent over the chair duration (P2-to-P3), suggesting increased physiologic compensation. Dynamic changes in IAP varied across abdominal locations, motivating the abdominal cavity not to be considered as a unified entity, but sub-compartments with individual dynamics.

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Journal: Fluids and Barriers of the CNS

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