Neuroinflammation creates an immune regulatory niche at the meningeal lymphatic vasculature near the cribriform plate.

Meningeal lymphatics near the cribriform plate undergo lymphangiogenesis during neuroinflammation to drain excess fluid. Here, we hypothesized that lymphangiogenic vessels may acquire an altered phenotype to regulate immunity. Using single-cell RNA sequencing of meningeal lymphatics near the cribriform plate from healthy and experimental autoimmune encephalomyelitis in the C57BL/6 model, we report that neuroinflammation induces the upregulation of genes involved in antigen presentation such as major histocompatibility complex class II, adhesion molecules including vascular cell adhesion protein 1 and immunoregulatory molecules such as programmed cell death 1 ligand 1, where many of these changes are mediated by interferon-γ. The inflamed lymphatics retain CD11c+ cells and CD4 T cells where they capture and present antigen, creating an immunoregulatory niche that represents an underappreciated interface in the regulation of neuroinflammation. We also found discontinuity of the arachnoid membrane near the cribriform plate, which provides unrestricted access to the cerebrospinal fluid. These findings highlight a previously unknown function of local meningeal lymphatics in regulating immunity that has only previously been characterized in draining lymph nodes.

Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics.

Cerebrospinal fluid (CSF) is produced by the choroid plexuses within the ventricles of the brain and circulates through the subarachnoid space of the skull and spinal column to provide buoyancy to and maintain fluid homeostasis of the brain and spinal cord. The question of how CSF drains from the subarachnoid space has long puzzled scientists and clinicians. For many decades, it was believed that arachnoid villi or granulations, outcroppings of arachnoid tissue that project into the dural venous sinuses, served as the major outflow route. However, this concept has been increasingly challenged in recent years, as physiological and imaging evidence from several species has accumulated showing that tracers injected into the CSF can instead be found within lymphatic vessels draining from the cranium and spine. With the recent high-profile rediscovery of meningeal lymphatic vessels located in the dura mater, another debate has emerged regarding the exact anatomical pathway(s) for CSF to reach the lymphatic system, with one side favoring direct efflux to the dural lymphatic vessels within the skull and spinal column and another side advocating for pathways along exiting cranial and spinal nerves. In this review, a summary of the historical and contemporary evidence for the different outflow pathways will be presented, allowing the reader to gain further perspective on the recent advances in the field. An improved understanding of this fundamental physiological process may lead to novel therapeutic approaches for a wide range of neurological conditions, including hydrocephalus, neurodegeneration and multiple sclerosis.

Cerebrospinal fluid drainage kinetics across the cribriform plate are reduced with aging.

BACKGROUND: Continuous circulation and drainage of cerebrospinal fluid (CSF) are essential for the elimination of CSF-borne metabolic products and neuronal function. While multiple CSF drainage pathways have been identified, the significance of each to normal drainage and whether there are differential changes at CSF outflow regions in the aging brain are unclear. METHODS: Dynamic in vivo imaging of near infrared fluorescently-labeled albumin was used to simultaneously visualize the flow of CSF at outflow regions on the dorsal side (transcranial and -spinal) of the central nervous system. This was followed by kinetic analysis, which included the elimination rate constants for these regions. In addition, tracer distribution in ex vivo tissues were assessed, including the nasal/cribriform region, dorsal and ventral surfaces of the brain, spinal cord, cranial dura, skull base, optic and trigeminal nerves and cervical lymph nodes. RESULTS: Based on the in vivo data, there was evidence of CSF elimination, as determined by the rate of clearance, from the nasal route across the cribriform plate and spinal subarachnoid space, but not from the dorsal dural regions. Using ex vivo tissue samples, the presence of tracer was confirmed in the cribriform area and olfactory regions, around pial blood vessels, spinal subarachnoid space, spinal cord and cervical lymph nodes but not for the dorsal dura, skull base or the other cranial nerves. Also, ex vivo tissues showed retention of tracer along brain fissures and regions associated with cisterns on the brain surfaces, but not in the brain parenchyma. Aging reduced CSF elimination across the cribriform plate but not that from the spinal SAS nor retention on the brain surfaces. CONCLUSIONS: Collectively, these data show that the main CSF outflow sites were the nasal region across the cribriform plate and from the spinal regions in mice. In young adult mice, the contribution of the nasal and cribriform route to outflow was much higher than from the spinal regions. In older mice, the contribution of the nasal route to CSF outflow was reduced significantly but not for the spinal routes. This kinetic approach may have significance in determining early changes in CSF drainage in neurological disorder, age-related cognitive decline and brain diseases.

Growth factor signaling alters the morphology of the zebrafish ethmoid plate.

Craniofacial development relies on coordinated tissue interactions that allow for patterning and growth of the face. We know a priori that the Wingless, fibroblast growth factor, Hedgehog and transforming growth factor-beta growth factor signaling pathways are required for the development of the face, but how they contribute to the shape of the face is largely untested. Here, we test how each signaling pathway contributes to the overall morphology of the zebrafish anterior neurocranium. We tested the contribution of each signaling pathway to the development of the ethmoid plate during three distinct time periods: the time of neural crest migration [10 hour post fertilization (hpf)]; once the neural crest is resident in the face (20 hpf); and finally at the time at which the cartilaginous condensations are being initiated (48 hpf). Using geometric morphometric analysis, we conclude that each signaling pathway contributes to the shape, size and morphology of the ethmoid plate in a dose-, and time-dependent fashion.

Asymmetry of the anterior skull base at the level of frontal ostium, a radioanatomical study.

BACKGROUND: Radioanatomical studies have shown that the ethmoid roof is asymmetric in 10 to 40% of individuals. The right ethmoid roof has been found on average to be lower compared to the left. The aim of this study was to extend existing results by assessing asymmetry between the right and left anterior skull base at the level of the frontal ostium. METHODOLOGY: Curved multiplanar reconstruction was used to analyse 247 consecutive paranasal sinus CT scans. The corresponding left and right parasagittal profiles of the skull base marked from the anterior ethmoidal artery to the level of the orbital roof were superimposed and compared. RESULTS: Asymmetry greater than 1 mm was found in 87% of patients, greater than 2 mm in 40.5% of patients, and greater than 3 mm in 8% of patients. The prevalence of the patients with lower skull base on the right side was greater than those with lower skull base on the left side at a ratio of more than 2:1. CONCLUSION: Skull base asymmetry in the region of the frontal ostium is observed in a large percentage of the population and may be a potential source of complications during endoscopic sinus surgery.

Quantifying the cribriform plate: influences of allometry, function, and phylogeny in Carnivora.

The small, perforated bony cup of the anterior cranial fossa called the cribriform plate (CP) is perhaps the best-preserved remnant of olfactory anatomy in fossil mammal skulls. The CP and its myriad foramina record the passage of peripheral olfactory nerves from nasal cavity to olfactory bulb. Previous work has suggested that CP surface area reflects aspects of olfactory capacity (as inferred from habitat and observed behavior) in mammals. To further explore the utility of CP as a proxy for olfactory function, we designed novel, nondestructive digital methods to quantify CP morphology from dry skulls. Using CT scans and 3-D imaging software, we quantified CP features from 42 species of Carnivora, a group that represents a wide spectrum of ecologies and sensory demands. Two metrics, CP surface area (CPSA) and cumulative CP foramina area (FXSA), scaled to skull length with negative allometry, and differed between aquatic and terrestrial species, with the former having reduced areas. Number of foramina (NF) was not correlated with skull length but tended to be greater in caniforms than feliforms. Both CPSA and FXSA are well correlated with ethmoturbinal surface area, a known osteological correlate of olfactory function. This suggests that CPSA and FXSA are useful proxies for olfactory ability, especially when studying fossils or skulls in which turbinals are not preserved. Total area of CP foramina (FXSA), an exacting measure of olfactory nerve endocasts, is tightly correlated with CPSA. Because of this, it may be desirable to use CPSA alone as a proxy given that it is easier to measure than FXSA.

Use of computational fluid dynamics to study the influence of the uncinate process on nasal airflow.

BACKGROUND: Chronic rhinosinusitis is commonly treated by functional endoscopic sinus surgery involving excision of the uncinate process and opening of the osteomeatal complex. METHODS: Computational fluid dynamics were used to compare nasal airflow after two different surgical interventions which involved opening the paranasal sinuses, excising the ethmoid sinus, and excising or preserving the uncinate process, in a cadaveric head model. Cross-sectional computed tomography images were obtained before and after the interventions. Imaging data were used to prepare computer simulations, which were used to assess the airflow characteristics of the nasal cavities and paranasal sinuses during inspiration and expiration, before and after intervention. RESULTS: Significantly larger nasal cavity airflow velocity changes were apparent following the uncinate process excising procedure. Nasal cavity airflow distribution remained relatively unchanged following the uncinate process preserving procedure. There was a significantly greater increase in airflow volume following the uncinate process excising procedure, compared with the uncinate process preserving procedure. CONCLUSION: Preservation of the uncinate process may significantly reduce the alteration of nasal cavity airflow dynamics occurring after functional endoscopic sinus surgery for chronic rhinosinusitis.

Bone-constructing cells from ethmoid bone may have multilineage differentiation potential: preliminary report.

OBJECTIVE: In order to investigate multilineage differentiation in human cultured cells from ethmoid bone, we conducted a morphological study to examine adipogenic and chondrogenic differentiation. MATERIAL AND METHODS: After reaching confluence, cells underwent terminal adipogenic differentiation by treatment with 100 microM indomethacin, 0.5 mM 1-methyl-3-isobutylxanthine, 1 microM dexamethasone (DEX), 10 microg/ml insulin and 0.3% dimethylsulfoxide in a medium supplemented with 10% fetal bovine serum. Chondrogenic differentiation was attempted by centrifuging a pelleted micromass using transforming growth factor-beta3 (TGF-beta3), DEX, ascorbic acid (AA), pyruvate acid, proline, glucose and (ITS)-plus. RESULTS: The cultured cells displayed adipocyte but not chondrogenic lineage under these conditions. Considering the possibility that some differentiation potential may be lost with in vitro culture but maintained using another chondrogenic differentiation medium containing TGF-beta1, it is possible that cultured cells may have multilineage potential, including chondrogenic differentiation ability. CONCLUSIONS: These morphological abilities of human cultured cells may indicate the possibility of the existence of mesenchymal stem cells in sinus bone. If mesenchymal stem cells exist in ethmoid bone, they may play an important role in future research on the regulation mechanisms of human bone tissue.

Pilot study of a device for measuring instrument forces during endoscopic sinus surgery.

ESS is a form of minimal access surgery that includes different tasks and manoeuvres requiring sophisticated psychomotor coordination with varying levels of force application. The avoidance of complications is partially dependent upon reducing surgical force application when operating against vital barriers such as the skull base and the medial orbital wall. The study of the surgical forces in endoscopic sinus surgery offers the potential for surgeons to identify the appropriate application of the instrument forces and torques necessary to conduct safe surgery. We have developed Sinoforce, a sinus surgery force-measuring instrument, which comprises modified Blakesley forceps fitted with specialized force sensors The instrument produces a real-time visual display of the various forces applied by the surgeon to the forceps during endoscopic ethmoidectomy. A pilot study was conducted using four cadaveric head specimens. We measured the force needed to break through the different parts of the ethmoidal bony labyrinth and skull base. Comparable forces were needed to break through the ethmoidal bulla and uncinate process. However, a force of > 2 kg, exceeding the forceps calibration, was needed to break through the different parts of the skull base. In this article we describe the new forceps, present our preliminary results and explore the potential benefits of this new instrument.

Orbital passage of pterygopalatine ganglion efferents to paranasal sinuses and nasal mucosa in man.

Parasympathetic nerves of pterygopalatine ganglion origin are considered to enter the orbit and distribute to the nasal mucosa with the anterior ethmoidal nerve. As their distribution has never been demonstrated the present study was undertaken to seek evidence of their passage and to identify their relationship with the ethmoidal nerves. The soft tissues of the pterygopalatine fossa and orbit from sixteen sides of twelve cadavers were removed in one piece and either dissected or cut coronally into slabs and prepared histologically using montages of thin resin-embedded sections at intervals suitable for nerve path tracing. Several of the rami orbitales passing mediodorsally from the ganglion enter the orbit apically, branch and enter the posterior ethmoidal foramen terminating in the lining of the paranasal sinuses and others advance to enter the anterior ethmoidal canal to reach the nasal mucosa. No junctions were made with ethmoidal nerves within the orbit or the canal. Failure of surgical lesions of the anterior ethmoidal nerve as a treatment for vasomotor rhinitis may be attributed to the sparing of the separate parasympathetic nerves. Appropriate chemical lesions, on the other hand, could ensure destruction of isolated parasympathetic nerves while limiting damage to the larger anterior ethmoidal nerve.

Blocking cerebrospinal fluid absorption through the cribriform plate increases resting intracranial pressure.

Cerebrospinal fluid (CSF) drains through the cribriform plate (CP) in association with the olfactory nerves. From this location, CSF is absorbed into nasal mucosal lymphatics. Recent data suggest that this pathway plays an important role in global CSF transport in sheep. In this report, we tested the hypothesis that blocking CSF transport through this pathway would elevate resting intracranial pressure (ICP). ICP was measured continuously from the cisterna magna of sheep before and after CP obstruction in the same animal. To block CSF transport through the CP, an external ethmoidectomy was performed. The olfactory and adjacent mucosa were removed, and the bone surface was sealed with tissue glue. To restrict our analysis to the cranial CSF system, CSF transport into the spinal subarachnoid compartment was prevented with a ligature tightened around the thecal sac between C1 and C2. Sham surgical procedures had no significant effects, but in the experimental group CP obstruction elevated ICP significantly. Mean postobstruction steady-state pressures (18.0 +/- 3.8 cmH(2)O) were approximately double the preobstruction values (9.2 +/- 0.9 cmH(2)O). These data support the concept that the olfactory pathway represents a major site for CSF drainage.

Cerebrospinal fluid outflow resistance in sheep: impact of blocking cerebrospinal fluid transport through the cribriform plate.

Recent studies in sheep suggest that a significant proportion of global cerebrospinal fluid (CSF) drainage (50% or greater) occurs through the cribriform plate into nasal mucosal lymphatics. If this is true, obstructing CSF clearance through the cribriform plate should have an impact on the ability of the intracranial pressure regulating systems to compensate for volume infusions. To test this concept, bolus infusions of artificial CSF were administered into one lateral ventricle in sheep and the intracranial pressure monitored from the contralateral side. Peak intracranial pressures (ICP) were measured and CSF outflow resistances were calculated from the pressure patterns observed in response to bolus infusions administered before and after the cribriform plate was sealed in the same animal. To obstruct the cribriform plate, a portion of nasal bone was removed to expose the nasal mucosa. The olfactory mucosa, a portion of the nasal mucosa and all soft tissue on the extracranial surface of the cribriform plate were scraped away with a curette and the bone surface sealed with bone wax. Obstruction of CSF transport through the cribriform plate increased the peak ICP after infusion (P = 0.016) and augmented the time required for ICP to return to baseline. CSF outflow resistance was elevated approximately 2.7 times (P = 0.006). When the cribriform plate was left intact (sham surgery), no significant changes in peak ICP or CSF outflow resistance were observed. We conclude that the cribriform plate represents an important site for CSF clearance. Obstruction of this pathway reduces volumetric CSF transport significantly.

Phylogenetic relationships of mormyrid electric fishes (Mormyridae; Teleostei) inferred from cytochrome b sequences.

The Mormyridae are African osteoglossomorph freshwater fishes of great interest because of their electric organs. They have become an important model in studies of electrophysiology and behavior but their phylogenetic relationships are poorly known. Phylogenetic relationships among mormyrids were determined by comparing cytochrome b sequences (588 bp) of 27 species belonging to 15 genera. Results showed that the Petrocephalus species (subfamily Petrocephalinae) are the sister-group of all other mormyrids (subfamily Mormyrinae). The monophyly of the Mormyrinae was supported, as well as three original intra-Mormyrinae clades. Three genera, Marcusenius, Pollimyrus, and Brienomyrus, were found to be polyphyletic with high support. Some of these polyphylies are tentatively explained. The results confirmed that the lateral ethmoid bone was lost several times within the Mormyrinae. These findings emphasize the necessity of systematic studies and taxonomic revision of the Mormyridae. The tree obtained from the mitochondrial data showed a single rise of each electrocyte type except for electrocyte with penetrating stalk ("Pa"). Constraining the single occurrence of electrocyte type Pa did not require an excessive number of extra steps (1.86%).

Association between the direction of orthopedic headgear force and sutural responses in the nasomaxillary complex.

This study was designed to investigate biomechanical responses of the sutures in the nasomaxillary complex to orthopedic headgear forces applied in various directions. A three-dimensional analytic model of the craniofacial complex was used for finite element analysis. A posteriorly-directed force of 1.0 Kgf was applied to the maxillary first molars in 30 degrees inferior, parallel, and 30 degrees, 52.4 degrees and 60 degrees superior directions to the functional occlusal plane. Mean principal and shear stresses were evaluated at the sphenozygomatic, temporozygomatic, sphenomaxillary, frontomaxillary and frontozygomatic sutures and lamina cribrosa. As the force direction passed closer to the center of resistance (CRe) of the complex (52.4 degrees superior direction). normal stresses approached a certain level of uniform compressive stress (-2.5 gf/mm2) with gradual decrease in shear stresses, whereas variation in these stresses produced by the forces applied in other horizontal and inferior directions was greater. It is shown that stresses in the nasomaxillary sutures are varied by the direction of headgear force. Directing the line of force closer the CRe may produce the most optimal sutural modification effective for controlling forward and downward maxillary growth.

[The human cartilaginous mesethmoid (author's transl)]. / Le mésethmoïde cartilagineux humain. Son rôle morphogénétique sur la face humaine en croissance. Applications.

The existence of a cartilaginous facial structure, the mesethmoid, has been demonstrated in the newborn human infant. This structure is the peri- and post-natal tissue developed from the embryonic cartilaginous nasal capsules. Unrecognized during facial development, the cartilaginous mesethmoid, partly because of its multidirectional growth, is responsible for frontonasomaxillary osteomembranous centrofacial morphogenesis. Practical aspects are discussed, and studies to determine the post-natal structures derived from the mesethmoid are in progress.