Validating the accuracy of real-time phase-contrast MRI and quantifying the effects of free breathing on cerebrospinal fluid dynamics.

BACKGROUND: Understanding of the cerebrospinal fluid (CSF) circulation is essential for physiological studies and clinical diagnosis. Real-time phase contrast sequences (RT-PC) can quantify beat-to-beat CSF flow signals. However, the detailed effects of free-breathing on CSF parameters are not fully understood. This study aims to validate RT-PC's accuracy by comparing it with the conventional phase-contrast sequence (CINE-PC) and quantify the effect of free-breathing on CSF parameters at the intracranial and extracranial levels using a time-domain multiparametric analysis method. METHODS: Thirty-six healthy participants underwent MRI in a 3T scanner for CSF oscillations quantification at the cervical spine (C2-C3) and Sylvian aqueduct, using CINE-PC and RT-PC. CINE-PC uses 32 velocity maps to represent dynamic CSF flow over an average cardiac cycle, while RT-PC continuously quantifies CSF flow over 45-seconds. Free-breathing signals were recorded from 25 participants. RT-PC signal was segmented into independent cardiac cycle flow curves (Qt) and reconstructed into an averaged Qt. To assess RT-PC's accuracy, parameters such as segmented area, flow amplitude, and stroke volume (SV) of the reconstructed Qt from RT-PC were compared with those derived from the averaged Qt generated by CINE-PC. The breathing signal was used to categorize the Qt into expiratory or inspiratory phases, enabling the reconstruction of two Qt for inspiration and expiration. The breathing effects on various CSF parameters can be quantified by comparing these two reconstructed Qt. RESULTS: RT-PC overestimated CSF area (82.7% at aqueduct, 11.5% at C2-C3) compared to CINE-PC. Stroke volumes for CINE-PC were 615 mm³ (aqueduct) and 43 mm³ (spinal), and 581 mm³ (aqueduct) and 46 mm³ (spinal) for RT-PC. During thoracic pressure increase, spinal CSF net flow, flow amplitude, SV, and cardiac period increased by 6.3%, 6.8%, 14%, and 6%, respectively. Breathing effects on net flow showed a significant phase difference compared to the other parameters. Aqueduct-CSF flows were more affected by breathing than spinal-CSF. CONCLUSIONS: RT-PC accurately quantifies CSF oscillations in real-time and eliminates the need for cardiac synchronization, enabling the quantification of the cardiac and breathing components of CSF flow. This study quantifies the impact of free-breathing on CSF parameters, offering valuable physiological references for understanding the effects of breathing on CSF dynamics.

Seismic response analysis of double-trough aqueduct considering fluid-structure interaction effect.

At present, the crude fluid-structure interaction analysis model cannot accurately characterize the interaction mechanism between aqueduct and water under earthquake action. In order to solve this problem, this paper analyzes the seismic response of the double-tank aqueduct under the action of earthquake by using the shaker test and the VOF (Volume of Fluid) method considering the free liquid level from the perspective of fluid-solid bidirectional coupling, explores whether the liquid movement in the double tank is consistent and the shock absorption effect of different water levels on the aqueduct, and analyzes the amplitude of free liquid level sloshing and the change of horizontal dynamic pressure caused by water level change from the generation mechanism of TLD (Liquid tuning dampers). The results show that the liquid movement in the two tanks in the double-channel aqueduct is basically the same under the action of earthquake, and the TLD effect of the liquid gradually increases with the increase of the water level in the aqueduct, and the maximum peak shock absorption rate is 63.4% at the maximum peak and 50.4% in numerical simulation. The shaking amplitude of the liquid is positively correlated with the water level height, and the magnitude of the shaking amplitude also reflects the magnitude of the moving water pressure.

Biomechanical effects of hyper-dynamic cerebrospinal fluid flow through the cerebral aqueduct in idiopathic normal pressure hydrocephalus patients.

Normal pressure hydrocephalus (NPH) is an intracranial disease characterized by an abnormal accumulation of cerebrospinal fluid (CSF) in brain ventricles within the normal range of intracranial pressure. Most NPH in aged patients is idiopathic (iNPH) and without any prior history of intracranial diseases. Although an abnormal increase of CSF stroke volume (hyper-dynamic CSF flow) in the aqueduct between the third and fourth ventricles has received much attention as a clinical evaluation index in iNPH patients, the biomechanical effects of this flow on iNPH pathophysiology are poorly understood. This study aimed to clarify the potential biomechanical effects of hyper-dynamic CSF flow through the aqueduct of iNPH patients using magnetic resonance imaging-based computational simulations. Ventricular geometries and CSF flow rates through aqueducts of 10 iNPH patients and 10 healthy control subjects were obtained from multimodal magnetic resonance images, and these CSF flow fields were simulated using computational fluid dynamics. As biomechanical factors, we evaluated wall shear stress on the ventricular wall and the extent of flow mixing, which potentially disturbs the CSF composition in each ventricle. The results showed that the relatively high CSF flow rate and large and irregular shapes of the aqueduct in iNPH resulted in large wall shear stresses localized in relatively narrow regions. Furthermore, the resulting CSF flow showed a stable cyclic motion in control subjects, whereas strong mixing during transport through the aqueduct was found in patients with iNPH. These findings provide further insights into the clinical and biomechanical correlates of NPH pathophysiology.

Parasagittal dural space and cerebrospinal fluid (CSF) flow across the lifespan in healthy adults.

BACKGROUND: Recent studies have suggested alternative cerebrospinal fluid (CSF) clearance pathways for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of these pathways is the anatomic region surrounding the superior sagittal sinus, which has been shown to have relevance to trans-arachnoid molecular passage. This so-called parasagittal dural (PSD) space may play a physiologically significant role as a distal intracranial component of the human glymphatic circuit, yet fundamental gaps persist in our knowledge of how this space changes with normal aging and intracranial bulk fluid transport. METHODS: We re-parameterized MRI methods to assess CSF circulation in humans using high resolution imaging of the PSD space and phase contrast measures of flow through the cerebral aqueduct to test the hypotheses that volumetric measures of PSD space (1) are directly related to CSF flow (mL/s) through the cerebral aqueduct, and (2) increase with age. Multi-modal 3-Tesla MRI was applied in healthy participants (n = 62; age range = 20-83 years) across the adult lifespan whereby phase contrast assessments of CSF flow through the aqueduct were paired with non-contrasted T1-weighted and T2-weighted MRI for PSD volumetry. PSD volume was extracted using a recently validated neural networks algorithm. Non-parametric regression models were applied to evaluate how PSD volume related to tissue volume and age cross-sectionally, and separately how PSD volume related to CSF flow (significance criteria: two-sided p < 0.05). RESULTS: A significant PSD volume enlargement in relation to normal aging (p < 0.001, Spearman's-[Formula: see text] = 0.6), CSF volume (p < 0.001, Spearman's-[Formula: see text] = 0.6) and maximum CSF flow through the aqueduct of Sylvius (anterograde and retrograde, p < 0.001) were observed. The elevation in PSD volume was not significantly related to gray or white matter tissue volumes. Findings are consistent with PSD volume increasing with age and bulk CSF flow. CONCLUSIONS: Findings highlight the feasibility of quantifying PSD volume non-invasively in vivo in humans using machine learning and non-contrast MRI. Additionally, findings demonstrate that PSD volume increases with age and relates to CSF volume and bi-directional flow. Values reported should provide useful normative ranges for how PSD volume adjusts with age, which will serve as a necessary pre-requisite for comparisons to persons with neurodegenerative disorders.

Cerebrospinal fluid flow in normal beagle dogs analyzed using magnetic resonance imaging.

BACKGROUND: Diseases related to cerebrospinal fluid flow, such as hydrocephalus, syringomyelia, and Chiari malformation, are often found in small dogs. Although studies in human medicine have revealed a correlation with cerebrospinal fluid flow in these diseases by magnetic resonance imaging, there is little information and no standard data for normal dogs. OBJECTIVES: The purpose of this study was to obtain cerebrospinal fluid flow velocity data from the cerebral aqueduct and subarachnoid space at the foramen magnum in healthy beagle dogs. METHODS: Six healthy beagle dogs were used in this experimental study. The dogs underwent phase-contrast and time-spatial labeling inversion pulse magnetic resonance imaging. Flow rate variations in the cerebrospinal fluid were observed using sagittal time-spatial labeling inversion pulse images. The pattern and velocity of cerebrospinal fluid flow were assessed using phase-contrast magnetic resonance imaging within the subarachnoid space at the foramen magnum level and the cerebral aqueduct. RESULTS: In the ventral aspect of the subarachnoid space and cerebral aqueduct, the cerebrospinal fluid was characterized by a bidirectional flow throughout the cardiac cycle. The mean ± SD peak velocities through the ventral and dorsal aspects of the subarachnoid space and the cerebral aqueduct were 1.39 ± 0.13, 0.32 ± 0.12, and 0.76 ± 0.43 cm/s, respectively. CONCLUSIONS: Noninvasive visualization of cerebrospinal fluid flow movement with magnetic resonance imaging was feasible, and a reference dataset of cerebrospinal fluid flow peak velocities was obtained through the cervical subarachnoid space and cerebral aqueduct in healthy dogs.

Depth relationships and measures of tissue thickness in dorsal midbrain.

Dorsal human midbrain contains two nuclei with clear laminar organization, the superior and inferior colliculi. These nuclei extend in depth between the superficial dorsal surface of midbrain and a deep midbrain nucleus, the periaqueductal gray matter (PAG). The PAG, in turn, surrounds the cerebral aqueduct (CA). This study examined the use of two depth metrics to characterize depth and thickness relationships within dorsal midbrain using the superficial surface of midbrain and CA as references. The first utilized nearest-neighbor Euclidean distance from one reference surface, while the second used a level-set approach that combines signed distances from both reference surfaces. Both depth methods provided similar functional depth profiles generated by saccadic eye movements in a functional MRI task, confirming their efficacy for delineating depth for superficial functional activity. Next, the boundaries of the PAG were estimated using Euclidean distance together with elliptical fitting, indicating that the PAG can be readily characterized by a smooth surface surrounding PAG. Finally, we used the level-set approach to measure tissue depth between the superficial surface and the PAG, thus characterizing the variable thickness of the colliculi. Overall, this study demonstrates depth-mapping schemes for human midbrain that enables accurate segmentation of the PAG and consistent depth and thickness estimates of the superior and inferior colliculi.

Connection Input Mapping and 3D Reconstruction of the Brainstem and Spinal Cord Projections to the CSF-Contacting Nucleus.

Objective: To investigate whether the CSF-contacting nucleus receives brainstem and spinal cord projections and to understand the functional significance of these connections. Methods: The retrograde tracer cholera toxin B subunit (CB) was injected into the CSF-contacting nucleus in Sprague-Dawley rats according the previously reported stereotaxic coordinates. After 7-10 days, these rats were perfused and their brainstem and spinal cord were sliced (thickness, 40 µm) using a freezing microtome. All the sections were subjected to CB immunofluorescence staining. The distribution of CB-positive neuron in different brainstem and spinal cord areas was observed under fluorescence microscope. Results: The retrograde labeled CB-positive neurons were found in the midbrain, pons, medulla oblongata, and spinal cord. Four functional areas including one hundred and twelve sub-regions have projections to the CSF-contacting nucleus. However, the density of CB-positive neuron distribution ranged from sparse to dense. Conclusion: Based on the connectivity patterns of the CSF-contacting nucleus receives anatomical inputs from the brainstem and spinal cord, we preliminarily conclude and summarize that the CSF-contacting nucleus participates in pain, visceral activity, sleep and arousal, emotion, and drug addiction. The present study firstly illustrates the broad projections of the CSF-contacting nucleus from the brainstem and spinal cord, which implies the complicated functions of the nucleus especially for the unique roles of coordination in neural and body fluids regulation.

Enhanced in vitro model of the CSF dynamics.

BACKGROUND: Fluid dynamics of the craniospinal system are complex and still not completely understood. In vivo flow and pressure measurements of the cerebrospinal fluid (CSF) are limited. Whereas in silico modeling can be an adequate pathway for parameter studies, in vitro modeling of the craniospinal system is essential for testing and evaluation of therapeutic measures associated with innovative implants relating to, for example, normal pressure hydrocephalus and other fluid disorders. Previously-reported in vitro models focused on the investigation of only one hypothesis of the fluid dynamics rather than developing a modular set-up to allow changes in focus of the investigation. The aim of this study is to present an enhanced and validated in vitro model of the CSF system which enables the future embedding of implants, the validation of in silico models or phase-contrast magnetic resonance imaging (PC-MRI) measurements and a variety of sensitivity analyses regarding pathological behavior, such as reduced CSF compliances, higher resistances or altered blood dynamics. METHODS: The in vitro model consists of a ventricular system which is connected via the aqueduct to the cranial and spinal subarachnoid spaces. Two compliance chambers are integrated to cushion the arteriovenous blood flow generated by a cam plate unit enabling the modeling of patient specific flow dynamics. The CSF dynamics are monitored using three cranial pressure sensors and a spinal ultrasound flow meter. Measurements of the in vitro spinal flow were compared to cervical flow data recorded with PC-MRI from nine healthy young volunteers, and pressure measurements were compared to the literature values reported for intracranial pressure (ICP) to validate the newly developed in vitro model. RESULTS: The maximum spinal CSF flow recorded in the in vitro simulation was 133.60 ml/min in the caudal direction and 68.01 ml/min in the cranial direction, whereas the PC-MRI flow data of the subjects showed 122.82 ml/min in the caudal and 77.86 ml/min in the cranial direction. In addition, the mean ICP (in vitro) was 12.68 mmHg and the pressure wave amplitude, 4.86 mmHg, which is in the physiological range. CONCLUSIONS: The in vitro pressure values were in the physiological range. The amplitudes of the flow results were in good agreement with PC-MRI data of young and healthy volunteers. However, the maximum cranial flow in the in vitro model occurred earlier than in the PC-MRI data, which might be due to a lack of an in vitro dynamic compliance. Implementing dynamic compliances and related sensitivity analyses are major aspects of our ongoing research.

Numerical Cerebrospinal System Modeling in Fluid-Structure Interaction.

OBJECTIVE: Cerebrospinal fluid (CSF) stroke volume in the aqueduct is widely used to evaluate CSF dynamics disorders. In a healthy population, aqueduct stroke volume represents around 10% of the spinal stroke volume while intracranial subarachnoid space stroke volume represents 90%. The amplitude of the CSF oscillations through the different compartments of the cerebrospinal system is a function of the geometry and the compliances of each compartment, but we suspect that it could also be impacted be the cardiac cycle frequency. To study this CSF distribution, we have developed a numerical model of the cerebrospinal system taking into account cerebral ventricles, intracranial subarachnoid spaces, spinal canal and brain tissue in fluid-structure interactions. MATERIALS AND METHODS: A numerical fluid-structure interaction model is implemented using a finite-element method library to model the cerebrospinal system and its interaction with the brain based on fluid mechanics equations and linear elasticity equations coupled in a monolithic formulation. The model geometry, simplified in a first approach, is designed in accordance with realistic volume ratios of the different compartments: a thin tube is used to mimic the high flow resistance of the aqueduct. CSF velocity and pressure and brain displacements are obtained as simulation results, and CSF flow and stroke volume are calculated from these results. RESULTS: Simulation results show a significant variability of aqueduct stroke volume and intracranial subarachnoid space stroke volume in the physiological range of cardiac frequencies. CONCLUSIONS: Fluid-structure interactions are numerous in the cerebrospinal system and difficult to understand in the rigid skull. The presented model highlights significant variations of stroke volumes under cardiac frequency variations only.

CSF flow patterns in the brain in patients with neuro-Behçet disease and Behçet disease.

OBJECTIVE: In the etiopathogenesis of Behcet disease (BD) and Neuro-Behcet disease (NBD), vascular eclipse occurs in both the arteries and veins. The disease affects all vascular structures. The present study evaluates the use of Phase Contrast (PC) Cerebral Spinal Fluid (CSF) Flow Magnetic Resonance Imaging (MRI), a non-invasive technique for measuring CSF dynamics, for determining the level of aqueducts that are influenced in BD and NBD. PATIENTS AND METHODS: The quantitative evaluation of CSF flow in BD and NBD was performed using images obtained at the level of the cerebral aqueduct on the semi-axial plane. The PC-MRI angiography technique was used. RESULTS: There is no distinctive difference between BD and NBD that can be distinguished by the aqueduct diameters of both conditions. A clear increase in aqueduct diameter occurred BD and NBD group when compared to the control group. While there were no differences found between the BD group and the control group regarding peak velocity, average velocity, forward flow, reverse flow, net forward flow, and flow, there were distinctive increases in these various factors in the NBD group. CONCLUSIONS: Using the non-invasive PC-MRI technique, this study found that in BD and NBD patients, changes occurred in CSF flow figures. Increases in CSF parameters were also observed in NBD patients, a finding which may be helpful for future distinction between BD and NBD during diagnosis.

Neurocomputational Consequences of Evolutionary Connectivity Changes in Perisylvian Language Cortex.

The human brain sets itself apart from that of its primate relatives by specific neuroanatomical features, especially the strong linkage of left perisylvian language areas (frontal and temporal cortex) by way of the arcuate fasciculus (AF). AF connectivity has been shown to correlate with verbal working memory-a specifically human trait providing the foundation for language abilities-but a mechanistic explanation of any related causal link between anatomical structure and cognitive function is still missing. Here, we provide a possible explanation and link, by using neurocomputational simulations in neuroanatomically structured models of the perisylvian language cortex. We compare networks mimicking key features of cortical connectivity in monkeys and humans, specifically the presence of relatively stronger higher-order "jumping links" between nonadjacent perisylvian cortical areas in the latter, and demonstrate that the emergence of working memory for syllables and word forms is a functional consequence of this structural evolutionary change. We also show that a mere increase of learning time is not sufficient, but that this specific structural feature, which entails higher connectivity degree of relevant areas and shorter sensorimotor path length, is crucial. These results offer a better understanding of specifically human anatomical features underlying the language faculty and their evolutionary selection advantage.SIGNIFICANCE STATEMENT Why do humans have superior language abilities compared to primates? Recently, a uniquely human neuroanatomical feature has been demonstrated in the strength of the arcuate fasciculus (AF), a fiber pathway interlinking the left-hemispheric language areas. Although AF anatomy has been related to linguistic skills, an explanation of how this fiber bundle may support language abilities is still missing. We use neuroanatomically structured computational models to investigate the consequences of evolutionary changes in language area connectivity and demonstrate that the human-specific higher connectivity degree and comparatively shorter sensorimotor path length implicated by the AF entail emergence of verbal working memory, a prerequisite for language learning. These results offer a better understanding of specifically human anatomical features for language and their evolutionary selection advantage.

Cerebrospinal fluid and blood flow patterns in idiopathic normal pressure hydrocephalus.

OBJECTIVES: Increased aqueduct cerebrospinal fluid (CSF) flow pulsatility and, recently, a reversed CSF flow in the aqueduct have been suggested as hallmarks of idiopathic normal pressure hydrocephalus (INPH). However, these findings have not been adequately confirmed. Our objective was to investigate the flow of blood and CSF in INPH, as compared to healthy elderly, in order to clarify which flow parameters are related to the INPH pathophysiology. MATERIALS AND METHODS: Sixteen INPH patients (73 years) and 35 healthy subjects (72 years) underwent phase-contrast magnetic resonance imaging (MRI). Measurements included aqueduct and cervical CSF flow, total arterial inflow (tCBF; i.e. carotid + vertebral arteries), and internal jugular vein flow. Flow pulsatility, net flow, and flow delays were compared (multiple linear regression, correcting for sex and age). RESULTS: Aqueduct stroke volume was higher in INPH than healthy (148±95 vs 90±50 mL, P<.05). Net aqueduct CSF flow was similar in magnitude and direction. The cervical CSF stroke volume was lower (P<.05). The internal carotid artery net flow was lower in INPH (P<.05), although tCBF was not. No differences were found in internal jugular vein flow or flow delays. CONCLUSIONS: The typical flow of blood and CSF in INPH was mainly characterized by increased CSF pulsatility in the aqueduct and reduced cervical CSF pulsatility. The direction of mean net aqueduct CSF flow was from the third to the fourth ventricle. Our findings may reflect the altered distribution of intracranial CSF volume in INPH, although the causality of these relationships is unclear.

Evaluation of aqueductal cerebrospinal fluid flow dynamics with phase-contrast cine magnetic resonance imaging in normal pediatric cases.

PURPOSE: This study aimed to determine differences according to age groups and gender in the parameters of aqueductal cerebrospinal fluid (CSF) flow in childhood using phase-contrast cine magnetic resonance imaging (MRI) method. MATERIALS AND METHODS: This prospective study included 47 boys and 36 girls for a total of 83 healthy children. The cases were divided into three groups depending on age as infants (1-12 months), children (12-120 months), and adolescents (120-204 months). To quantitatively evaluate CSF flow, images in the transverse plane were taken at the cerebral aqueduct level using the phase-contrast MR angiography technique in a 1.5-T MR unit. Peak and average velocity (cm/s), cranial direction, caudal direction and net volume (ml), and aqueduct area (mm2) were calculated. To assess differences between the groups, a one-way analysis of variance and least significant difference tests were used. RESULTS: A statistically significant difference was determined between children and adolescents in peak velocity and caudal direction volume (P=.012 and P=.039, respectively) and between infants and children in cranial direction volume (P=.036). Peak velocity, cranial direction, and net volume were higher in boys (P=.050, P=.016, and P=.029, respectively). There were no differences by age and gender in the aqueduct area. CONCLUSION: In conclusion, this study determined the normal values for the CSF flow parameters of velocity, volume, and aqueduct area using phase-contrast MRI in healthy children. Velocity and volume parameters varied according to age and sex and were not affected in the aqueductal area.

Inspiration is the major regulator of human CSF flow.

The mechanisms behind CSF flow in humans are still not fully known. CSF circulates from its primary production sites at the choroid plexus through the brain ventricles to reach the outer surface of the brain in the subarachnoid spaces from where it drains into venous bloodstream and cervical lymphatics. According to a recent concept of brain fluid transport, established in rodents, CSF from the brain surface also enters the brain tissue along para-arterial routes and exits through paravenous spaces again into subarachnoid compartments. This unidirectional flow is mainly driven by arterial pulsation. To investigate how CSF flow is regulated in humans, we applied a novel real-time magnetic resonance imaging technique at high spatial (0.75 mm) and temporal (50 ms) resolution in healthy human subjects. We observed significant CSF flow exclusively with inspiration. In particular, during forced breathing, high CSF flow was elicited during every inspiration, whereas breath holding suppressed it. Only a minor flow component could be ascribed to cardiac pulsation. The present results unambiguously identify inspiration as the most important driving force for CSF flow in humans. Inspiratory thoracic pressure reduction is expected to directly modulate the hydrostatic pressure conditions for the low-resistance paravenous, venous, and lymphatic clearance routes of CSF. Furthermore, the experimental approach opens new clinical opportunities to study the pathophysiology of various forms of hydrocephalus and to design therapeutic strategies in relation to CSF flow alterations.

A novel method to study cerebrospinal fluid dynamics in rats.

BACKGROUND: Cerebrospinal fluid (CSF) flow dynamics play critical roles in both the immature and adult brain, with implications for neurodevelopment and disease processes such as hydrocephalus and neurodegeneration. Remarkably, the only reported method to date for measuring CSF formation in laboratory rats is the indirect tracer dilution method (a.k.a., ventriculocisternal perfusion), which has limitations. NEW METHOD: Anesthetized rats were mounted in a stereotaxic apparatus, both lateral ventricles were cannulated, and the Sylvian aqueduct was occluded. Fluid exited one ventricle at a rate equal to the rate of CSF formation plus the rate of infusion (if any) into the contralateral ventricle. Pharmacological agents infused at a constant known rate into the contralateral ventricle were tested for their effect on CSF formation in real-time. RESULTS: The measured rate of CSF formation was increased by blockade of the Sylvian aqueduct but was not changed by increasing the outflow pressure (0-3cm of H2O). In male Wistar rats, CSF formation was age-dependent: 0.39±0.06, 0.74±0.05, 1.02±0.04 and 1.40±0.06µL/min at 8, 9, 10 and 12 weeks, respectively. CSF formation was reduced 57% by intraventricular infusion of the carbonic anhydrase inhibitor, acetazolamide. COMPARISON WITH EXISTING METHODS: Tracer dilution methods do not permit ongoing real-time determination of the rate of CSF formation, are not readily amenable to pharmacological manipulations, and require critical assumptions. Direct measurement of CSF formation overcomes these limitations. CONCLUSIONS: Direct measurement of CSF formation in rats is feasible. Our method should prove useful for studying CSF dynamics in normal physiology and disease models.

Conditional N-WASP knockout in mouse brain implicates actin cytoskeleton regulation in hydrocephalus pathology.

Cerebrospinal fluid (CSF) is produced by the choroid plexus and moved by multi-ciliated ependymal cells through the ventricular system of the vertebrate brain. Defects in the ependymal layer functionality are a common cause of hydrocephalus. N-WASP (Neural-Wiskott Aldrich Syndrome Protein) is a brain-enriched regulator of actin cytoskeleton and N-WASP knockout caused embryonic lethality in mice with neural tube and cardiac abnormalities. To shed light on the role of N-WASP in mouse brain development, we generated N-WASP conditional knockout mouse model N-WASP(fl/fl); Nestin-Cre (NKO-Nes). NKO-Nes mice were born with Mendelian ratios but exhibited reduced growth characteristics compared to their littermates containing functional N-WASP alleles. Importantly, all NKO-Nes mice developed cranial deformities due to excessive CSF accumulation and did not survive past weaning. Coronal brain sections of these animals revealed dilated lateral ventricles, defects in ciliogenesis, loss of ependymal layer integrity, reduced thickness of cerebral cortex and aqueductal stenosis. Immunostaining for N-cadherin suggests that ependymal integrity in NKO-Nes mice is lost as compared to normal morphology in the wild-type controls. Moreover, scanning electron microscopy and immunofluorescence analyses of coronal brain sections with anti-acetylated tubulin antibodies revealed the absence of cilia in ventricular walls of NKO-Nes mice indicative of ciliogenesis defects. N-WASP deficiency does not lead to altered expression of N-WASP regulatory proteins, Fyn and Cdc42, which have been previously implicated in hydrocephalus pathology. Taken together, our results suggest that N-WASP plays a critical role in normal brain development and implicate actin cytoskeleton regulation as a vulnerable axis frequently deregulated in hydrocephalus.

Aqueductal cerebrospinal fluid pulsatility in healthy individuals is affected by impaired cerebral venous outflow.

PURPOSE: To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius (AoS) in chronic cerebrospinal venous insufficiency (CCSVI)-positive and -negative healthy individuals using cine phase contrast imaging. MATERIALS AND METHODS: Fifty-one healthy individuals (32 CCSVI-negative and 19 age-matched CCSVI-positive subjects) were examined using Doppler sonography (DS). Diagnosis of CCSVI was established if subjects fulfilled ≥2 venous hemodynamic criteria on DS. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and routine 3T MRI outcomes. RESULTS: CCSVI was associated with increased CSF pulsatility in the AoS. Net positive CSF flow was 32% greater in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.008). This was accompanied by a 28% increase in the mean aqueductal characteristic signal (ie, the AoS cross-sectional area over the cardiac cycle) in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.021). CONCLUSION: CSF dynamics are altered in CCSVI-positive healthy individuals, as demonstrated by increased pulsatility. This is accompanied by enlargement of the AoS, suggesting that structural changes may be occurring in the brain parenchyma of CCSVI-positive healthy individuals.

Cerebral aqueduct block attenuates cardio-renal injuries in post-DOCA-NaCl-hypertensive Dahl R rats.

The systemic and/or local effects of the hydrocephalic brain were investigated in DOCA-NaCl-hypertensive Dahl R rats induced by 250 mg kg(-1) DOCA in silicone and 1% saline water. After a 1-week recovery with 0.3% NaCl chow and tap water, one group had the aqueduct of Sylvius blocked with silicone and epoxy materials with a control sham group matching mean blood pressure (BP) and body weight. The 4-week-postsurgery BP on the 0.3% NaCl diet averaged 161±3.2 in the sham group and 146±2.3 mm Hg in the blocked group (P<0.0001). Both groups were then given an 8% NaCl diet and after 4 weeks, the sham group's BP was increased further with markedly increased mortality: 186 mm Hg vs. 154 mm Hg (P<0.0001); 12 sham rats died after 11 weeks, while all the blocked rats survived (P<0.0001). A transient change in plasma Na levels was observed in the blocked group after 48 h on the 8% NaCl diet. At 14 weeks, 0 sham rats survived, compared with 10 out of 16 blocked rats (P<0.0001). After 11 weeks on 8% NaCl, the average tail venous pressure in the sham group was significantly higher than that of the blocked rats (P<0.0001) indicating the end stage of renal and heart failure. The hearts and kidneys weighed significantly more in the sham vs. the blocked rats (P<0.0001 for both groups). These results indicate that the aqueduct block prevents post-DOCA hypertension and cardio-renal injuries, suggesting that centralized third ventricular brain signaling has a role in salt-genetic hypertension.

Simple patient-based transmantle pressure and shear estimate from cine phase-contrast MRI in cerebral aqueduct.

From measurements of the oscillating flux of the cerebrospinal fluid (CSF) in the aqueduct of Sylvius, we elaborate a patient-based methodology for transmantle pressure (TRP) and shear evaluation. High-resolution anatomical magnetic resonance imaging first permits a precise 3-D anatomical digitalized reconstruction of the Sylvius's aqueduct shape. From this, a very fast approximate numerical flow computation, nevertheless consistent with analytical predictions, is developed. Our approach includes the main contributions of inertial effects coming from the pulsatile flow and curvature effects associated with the aqueduct bending. Integrating the pressure along the aqueduct longitudinal centerline enables the total dynamic hydraulic admittances of the aqueduct to be evaluated, which is the pre-eminent contribution to the CSF pressure difference between the lateral ventricles and the subarachnoidal spaces also called the TRP. The application of the method to 20 healthy human patients validates the hypothesis of the proposed approach and provides a first database for normal aqueduct CSF flow. Finally, the implications of our results for modeling and evaluating intracranial cerebral pressure are discussed.