Influence of the lateral ventricles and irregular skull base on brain kinematics due to sagittal plane head rotation

Two-dimensional physical models of the human head were used to investigate how the lateral ventricles and irregular skull base influence kinematics in the medial brain during sagittal angular head dynamics. Silicone gel simulated the brain and was separatedfrom the surrounding skull vessel by paraffin that provided a slip interface between the gel and vessel. A humanlike skull base model (HSB) included a surrogate skull base mimicking the irregular geometry of the human. An HSBV model added an elliptical inclusion filled with liquid paraffin simulating the lateral ventricles to the HSB model. A simplified skull base model (SSBV) included ventricle substitute but approximated the anterior and middle cranial fossae by a flat and slightly angled surface. The models were exposed to 7600 rad/s2 peak angular acceleration with 6 ms pulse duration and 5 deg forced rotation. After 90 deg free rotation, the models were decelerated during 30 ms. Rigid body displacement, shear strain and principal strains were determined from high-speed video recorded trajectories of grid markers in the surrogate brains. Peak values of inferior brain surface displacement and strains were up to 10.9X (times) and 3.3X higher in SSBV than in HSBV. Peak strain was up to 2.7X higher in HSB than in HSBV. The results indicate that the irregular skull base protects nerves and vessels passing through the cranial floor by reducing brain displacement and that the intraventricular cerebrospinal fluid relieves strain in regions inferior and superior to the ventricles. The ventricles and irregular skull base are necessary in modeling head impact and understanding brain injury mechanisms.     

Dynamic response of the brain with vasculature: a three-dimensional computational study

To date, the influence of the vasculature on the dynamic response of the brain has not been studied with a complete three-dimensional (3D) finite element head model. In this study, short duration rotational (10,000 rad/s(2) with a duration of 5 ms) and translational (100G with a duration of 5 ms) acceleration impulses were applied to the 3D finite element models to study the dynamic response of the brain. The hypothesis of this study was that due to the convoluted organization and non-linear material properties of cerebral vasculature, the difference in maximum principle strain between models with and without vasculature should be minimal. The effects of non-linear material properties and the convoluted structure of the vasculature were examined by comparing the results from the 3D finite element models. The peak average strain reduction in a model with non-linear elastic vasculature and a model with linear elastic vasculature compared to a model without vasculature was 2% and 5%, respectively, indicating that the influence of the vasculature on the dynamic response of the brain is minimal.     

3D Modeling of the Lateral Ventricles and Histological Characterization of Periventricular Tissue in Humans and Mouse

The ventricular system carries and circulates cerebral spinal fluid (CSF) and facilitates clearance of solutes and toxins from the brain. The functional units of the ventricles are ciliated epithelial cells termed ependymal cells, which line the ventricles and through ciliary action are capable of generating laminar flow of CSF at the ventricle surface. This monolayer of ependymal cells also provides barrier and filtration functions that promote exchange between brain interstitial fluids (ISF) and circulating CSF. Biochemical changes in the brain are thereby reflected in the composition of the CSF and destruction of the ependyma can disrupt the delicate balance of CSF and ISF exchange. In humans there is a strong correlation between lateral ventricle expansion and aging. Age-associated ventriculomegaly can occur even in the absence of dementia or obstruction of CSF flow. The exact cause and progression of ventriculomegaly is often unknown; however, enlarged ventricles can show regional and, often, extensive loss of ependymal cell coverage with ventricle surface astrogliosis and associated periventricular edema replacing the functional ependymal cell monolayer. Using MRI scans together with postmortem human brain tissue, we describe how to prepare, image and compile 3D renderings of lateral ventricle volumes, calculate lateral ventricle volumes, and characterize periventricular tissue through immunohistochemical analysis of en face lateral ventricle wall tissue preparations. Corresponding analyses of mouse brain tissue are also presented supporting the use of mouse models as a means to evaluate changes to the lateral ventricles and periventricular tissue found in human aging and disease. Together, these protocols allow investigations into the cause and effect of ventriculomegaly and highlight techniques to study ventricular system health and its important barrier and filtration functions within the brain.     

The effects of the interthalamic adhesion position on cerebrospinal fluid dynamics in the cerebral ventricles

The interthalamic adhesion is a unique feature of the third ventricle in the brain. It differs in shape and size and its location varies between individuals. In this study, computational fluid dynamics was performed on 4 three-dimensional models of the cerebral ventricular system with the interthalamic adhesion modeled in different locations in the third ventricle. Cerebrospinal fluid (CSF) was modeled as incompressible Newtonian fluid and flow was assumed laminar. The periodic motion of CSF flow as a function of the cardiac cycle starting from diastole was prescribed as the inlet boundary condition at the foramen of Monroe. Results from this study show how the location of the interthalamic adhesion influences the pattern of pressure distribution in the cerebral ventricles. In addition, the highest CSF pressure in the third ventricle can vary by ～50% depending on the location of the interthalamic adhesion. We suggest that the interthalamic adhesion may have functional implications on the development of hydrocephalus and it is important to model this anatomical feature in future studies.     

Distribution of 1-14C palmitic acid in brain tissue after intraventricular injection in the conscious cat]

The distribution of (1-14C) palmitic acid in the brain tissue following the injection into the cerebral ventricles of conscious cats was investigated. The radioactive material was found in the brain tissue surrounding the cerebral ventricles and in the cerebral cortex, but in varying amounts : the smallest amounts were found in the cerebral cortex, while the highest in the thalamus and in the hippocampus. Radioactive material was also found in the peripheral venous blood. The amount of the radioactive material in the grey matter lining the cerebral ventricles as well as in the cerebral cortex was time-dependant. The labelled material in the structures surrounding the cerebral ventricles and in the cerebral cortex increased within first four hours after its intraventricular administration. Thereafter, throughout subsequent 48 hours either it slowly disappeared in the caudate nucleus and in the thalamus, or it was retained in the hypothalamus and in the floor of the IV ventricle.     

Three-dimensional systolic kinematics of the right ventricle

The right ventricle (RV) of the heart is responsible for pumping blood to the lungs. Its kinematics are not as well understood as that of the left ventricle (LV) due to its thin wall and asymmetric geometry. In this study, the combination of tagged MRI and three-dimensional (3-D) image-processing techniques was used to reconstruct 3-D RV-LV motion and deformation. The reconstructed models were used to quantify the 3-D global and local deformation of the ventricles in a set of normal subjects. When compared with the LV, the RV exhibited a similar twisting pattern, a more longitudinal strain pattern, and a greater amount of displacement.     

Computational modeling of the mechanical behavior of the cerebrospinal fluid system

A computational fluid dynamics (CFD) model of the cerebrospinal fluid system was constructed based on a simplified geometry of the brain ventricles and their connecting pathways. The flow is driven by a prescribed sinusoidal motion of the third ventricle lateral walls, with all other boundaries being rigid. The pressure propagation between the third and lateral ventricles was examined and compared to data obtained from a similar geometry with a stenosed aqueduct. It could be shown that the pressure amplitude in the lateral ventricles increases in the presence of aqueduct stenosis. No difference in phase shift between the motion of the third ventricle walls and the pressure in the lateral ventricles because of the aqueduct stenosis could be observed. It is deduced that CFD can be used to analyze the pressure propagation and its phase shift relative to the ventricle wall motion. It is further deduced that only models that take into account the coupling between ventricles, which feature a representation of the original geometry that is as accurate as possible and which represent the ventricle boundary motion realistically, should be used to make quantitative statements on flow and pressure in the ventricular space.     

Systemic site of action for pressor effect of angiotensin II injected into the fourth cerebral ventricle of rats?

Angiotensin II (ANG II) causes a systemic pressor effect when injected into the cerebral ventricles. In the rat fourth ventricle, the effective doses for the ANG II pressor effect are over 100 times larger than in the systemic circulation. Considering the discrepancy of doses, the possibility that ANG II may reach the systemic circulation and promote pressor effects, following injection into the fourth ventricle, was investigated. The effects on blood pressure of different vasoactive peptides that produce pressor responses when injected into the central nervous system were compared. Dose-response curves were obtained for intravenous or fourth cerebroventricular injections of ANG II, lysyl-vasopressin (LVP), bradykinin (BK), or endothelin-1 (ET-1). The ED50 ratios for intracerebroventricular/intraveneous injections were 110 for ANG II, 109 for LVP, 0.01 for BK, and approximately 0.4 for ET-1. In cross-circulation preparations, pressor responses occurred in the donor rat following injection into the fourth cerebral ventricle of the recipient animal, showing that effective doses of ANG II, administered to the fourth cerebral, reach the systemic circulation. The same results were obtained for the microinjection of 4 nmol of LVP into the fourth cerebral ventricle of recipient animals. High-performance reverse-phase liquid chromatography analyses of arterial blood showed that approximately 1% of the [125I]ANG II injected into the fourth cerebral ventricle may be recovered from the systemic circulation a few seconds after the microinjection. The systemic administration of the ANG II receptor antagonist losartan blocked the response to ANG II injected into the fourth ventricle whereas antagonist administration in the same ventricle did not. Angiotensin injections into the lateral ventricle produced pressor responses that were reduced by antagonist administration to the same ventricle but not by systemic administration of the antagonist. The data suggest that the pressor effect resulting from ANG II or LVP injections into the fourth cerebral ventricle may be due to the action of this peptide in the systemic circulation. On the other hand, the pressor effect due to ANG II microinjection into the lateral ventricle apparently results from the direct stimulation of central periventricular structures.     

The effect of ventricular volume increase in the amplitude of intracranial pressure

We study the impact of vascular pulse in the cerebrospinal fluid (CSF) pressure measured on the lateral cerebral ventricles, as well as its sensitivity with respect to ventricular volume change. Recent studies have addressed the importance of the compliance capacity in the brain and its relation to arterial pulse abortion in communicating hydrocephalus. Nevertheless, this mechanism is not fully understood. We propose a fluid-structure interaction (FSI) model on a 3?D idealized geometry based on realistic physiological and morphological parameters. The computational model describes the pulsatile deformation of the third ventricle due to arterial pulse and the resulting CSF dynamics inside brain pathways. The results show that when the volume of lateral ventricles increases up to 3.5 times, the amplitudes of both average and maximum pressure values, computed on the lateral ventricles surface, substantially decrease. This indicates that the lateral ventricles expansion leads to a dumping effect on the pressure exerted on the walls of the ventricles. These results strengthen the possibility that communicant hydrocephalus may, in fact, be a natural response to reduce abnormal high intracranial pressure (ICP) amplitude. This conclusion is in accordance with recent hypotheses suggesting that communicant hydrocephalus is related to a disequilibrium in brain compliance capacity.     

Brain abnormalities induced by murine cytomegalovirus injected into the cerebral ventricles of mouse embryos exo utero

Murine cytomegalovirus (MCMV) was injected into the cerebral ventricle of mouse embryos on day 13 of gestation after exposing the embryos out of the uterus in the abdominal cavity of the mother. The embryos were allowed to develop to day 18 of gestation, then taken out from the abdominal cavity. Macroscopically, there were four expanded and three distorted brains out of 19 surviving embryos, whereas no brain abnormality was noticed in 13 embryos injected with culture medium instead of MCMV in the same way. Histopathological examination showed hydrocephalic lesions with strong dilatation of the ventricles and atrophy of the cerebral cortex, and inflammatory lesions with granulomatous proliferation of the ventricular walls with disappearance of the cortical zonation. Immunohistochemically, MCMV-induced nuclear antigen-positive cells were frequently observed in the wall of the ventricles and occasionally scattered in the cerebral cortex, white matter, and the nucleus basalis. Some fetuses injected with MCMV in the same way were recovered from the abdominal cavities on day 18 of gestation and transferred to foster nurse mothers. They showed massive cerebral necrosis after feeding for 9 days after birth. Brain abnormalities of mouse embryos after intraventricular injection with MCMV may provide an experimental model of brain damage induced by congenital cytomegalovirus infection.     

Design and numerical implementation of a 3-D non-linear viscoelastic constitutive model for brain tissue during impact

Finite Element (FE) head models are often used to understand mechanical response of the head and its contents during impact loading in the head. Current FE models do not account for non-linear viscoelastic material behavior of brain tissue. We developed a new non-linear viscoelastic material model for brain tissue and implemented it in an explicit FE code. To obtain sufficient numerical accuracy for modeling the nearly incompressible brain tissue, deviatoric and volumetric stress contributions are separated. Deviatoric stress is modeled in a non-linear viscoelastic differential form. Volumetric behavior is assumed linearly elastic. Linear viscoelastic material parameters were derived from published data on oscillatory experiments, and from ultrasonic experiments. Additionally, non-linear parameters were derived from stress relaxation (SR) experiments at shear strains up to 20%. The model was tested by simulating the transient phase in the SR experiments not used in parameter determination (strains up to 20%, strain rates up to 8s(-1)). Both time- and strain-dependent behavior were predicted accurately (R2>0.96) for strain and strain rates applied. However, the stress was overestimated systematically by approximately 31% independent of strain(rate) applied. This is probably caused by limitations of the experimental data at hand.     

Measurement of strain in physical models of brain injury: a method based on HARP analysis of tagged magnetic resonance images (MRI)

Two-dimensional (2-D) strain fields were estimated non-invasively in two simple experimental models of closed-head brain injury. In the first experimental model, shear deformation of a gel was induced by angular acceleration of its spherical container In the second model the brain of a euthanized rat pup was deformed by indentation of its skull. Tagged magnetic resonance images (MRI) were obtained by gated image acquisition during repeated motion. Harmonic phase (HARP) images corresponding to the spectral peaks of the original tagged MRI were obtained, following procedures proposed by Osman, McVeigh and Prince. Two methods of HARP strain analysis were applied, one based on the displacement of tag line intersections, and the other based on the gradient of harmonic phase. Strain analysis procedures were also validated on simulated images of deformed grids. Results show that it is possible to visualize deformation and to quantify strain efficiently in animal models of closed head injury.     

An anatomically detailed and personalizable head injury model: Significance of brain and white matter tract morphological variability on strain

Finite element head (FE) models are important numerical tools to study head injuries and develop protection systems. The generation of anatomically accurate and subject-specific head models with conforming hexahedral meshes remains a significant challenge. The focus of this study is to present two developmental works: first, an anatomically detailed FE head model with conforming hexahedral meshes that has smooth interfaces between the brain and the cerebrospinal fluid, embedded with white matter (WM) fiber tracts; second, a morphing approach for subject-specific head model generation via a new hierarchical image registration pipeline integrating Demons and Dramms deformable registration algorithms. The performance of the head model is evaluated by comparing model predictions with experimental data of brain–skull relative motion, brain strain, and intracranial pressure. To demonstrate the applicability of the head model and the pipeline, six subject-specific head models of largely varying intracranial volume and shape are generated, incorporated with subject-specific WM fiber tracts. DICE similarity coefficients for cranial, brain mask, local brain regions, and lateral ventricles are calculated to evaluate personalization accuracy, demonstrating the efficiency of the pipeline in generating detailed subject-specific head models achieving satisfactory element quality without further mesh repairing. The six head models are then subjected to the same concussive loading to study the sensitivity of brain strain to inter-subject variability of the brain and WM fiber morphology. The simulation results show significant differences in maximum principal strain and axonal strain in local brain regions (one-way ANOVA test, p < 0.001), as well as their locations also vary among the subjects, demonstrating the need to further investigate the significance of subject-specific models. The techniques developed in this study may contribute to better evaluation of individual brain injury and the development of individualized head protection systems in the future. This study also contains general aspects the research community may find useful: on the use of experimental brain strain close to or at injury level for head model validation; the hierarchical image registration pipeline can be used to morph other head models, such as smoothed-voxel models.

     

Comparison of the Relationship between Cerebral White Matter and Grey Matter in Normal Dogs and Dogs with Lateral Ventricular Enlargement

Large cerebral ventricles are a frequent finding in brains of dogs with brachycephalic skull conformation, in comparison with mesaticephalic dogs. It remains unclear whether oversized ventricles represent a normal variant or a pathological condition in brachycephalic dogs. There is a distinct relationship between white matter and grey matter in the cerebrum of all eutherian mammals. The aim of this study was to determine if this physiological proportion between white matter and grey matter of the forebrain still exists in brachycephalic dogs with oversized ventricles. The relative cerebral grey matter, white matter and cerebrospinal fluid volume in dogs were determined based on magnetic-resonance-imaging datasets using graphical software. In an analysis of covariance (ANCOVA) using body mass as the covariate, the adjusted means of the brain tissue volumes of two groups of dogs were compared. Group 1 included 37 mesaticephalic dogs of different sizes with no apparent changes in brain morphology, and subjectively normal ventricle size. Group 2 included 35 brachycephalic dogs in which subjectively enlarged cerebral ventricles were noted as an incidental finding in their magnetic-resonance-imaging examination. Whereas no significant different adjusted means of the grey matter could be determined, the group of brachycephalic dogs had significantly larger adjusted means of lateral cerebral ventricles and significantly less adjusted means of relative white matter volume. This indicates that brachycephalic dogs with subjective ventriculomegaly have less white matter, as expected based on their body weight and cerebral volume. Our study suggests that ventriculomegaly in brachycephalic dogs is not a normal variant of ventricular volume. Based on the changes in the relative proportion of WM and CSF volume, and the unchanged GM proportions in dogs with ventriculomegaly, we rather suggest that distension of the lateral ventricles might be the underlying cause of pressure related periventricular loss of white matter tissue, as occurs in internal hydrocephalus.     

Initial formation of zebrafish brain ventricles occurs independently of circulation and requires the nagie oko and snakehead/atp1a1a.1 gene products

The mechanisms by which the vertebrate brain develops its characteristic three-dimensional structure are poorly understood. The brain ventricles are a highly conserved system of cavities that form very early during brain morphogenesis and that are required for normal brain function. We have initiated a study of zebrafish brain ventricle development and show here that the neural tube expands into primary forebrain, midbrain and hindbrain ventricles rapidly, over a 4-hour window during mid-somitogenesis. Circulation is not required for initial ventricle formation, only for later expansion. Cell division rates in the neural tube surrounding the ventricles are higher than between ventricles and, consistently, cell division is required for normal ventricle development. Two zebrafish mutants that do not develop brain ventricles are snakehead and nagie oko. We show that snakehead is allelic to small heart, which has a mutation in the Na+K+ ATPase gene atp1a1a.1. The snakehead neural tube undergoes normal ventricle morphogenesis; however, the ventricles do not inflate, probably owing to impaired ion transport. By contrast, mutants in nagie oko, which was previously shown to encode a MAGUK family protein, fail to undergo ventricle morphogenesis. This correlates with an abnormal brain neuroepithelium, with no clear midline and disrupted junctional protein expression. This study defines three steps that are required for brain ventricle development and that occur independently of circulation: (1) morphogenesis of the neural tube, requiring nok function; (2) lumen inflation requiring atp1a1a.1 function; and (3) localized cell proliferation. We suggest that mechanisms of brain ventricle development are conserved throughout the vertebrates.     

Linear acceleration-evoked cardiovascular responses in awake rats.

It has been well documented that vestibular-mediated cardiovascular regulation plays an important role in maintaining stable blood pressure (BP) during postural changes. But the underlying neural mechanisms remain to be elucidated. In particular, because the vestibular stimulation employed in previous animal studies activated both semicircular canals and otolith organs, the contributions of the otolith system has not been studied selectively. The goal of the present study was to characterize cardiovascular responses to natural otolith stimulation in awake rats that were subjected to pure linear motion. In any of the four directions tested, transient linear motion produced a short-latency ( approximately 520 ms) increase in mean BP with a peak of 8.27 +/- 0.66 mmHg and was followed by a decrease in BP. There was an initial small biphasic response in heart rate (HR) that was followed by a longer duration increase. The short-latency increase in BP was absent in rats that were pentobarbital sodium anesthetized or that were labyrinthectomized bilaterally, but it was unaffected by baroreceptor denervation, indicating that it was of otolith origin. The increase in BP was linear acceleration intensity dependent and was not affected by absence of visual cues. Furthermore, the BP response was attenuated by inactivation of the medial and inferior vestibular nuclei by microinjections of muscimol, indicating that the otolith-driven cardiovascular responses are mediated by the neurons in these areas. These results not only demonstrate the otolith specific influences on the cardiovascular system but also they establish the first rodent model for examining the neural mechanisms underlying the otolith-mediated cardiovascular regulation.     

心肺复苏后脑缺血再灌注损伤治疗理念及相关动物模型研究进展

心肺复苏后脑缺血再灌注损伤是一个复杂的病理生理变化过程,由多种损伤机制共同参与。自心肺复苏后系统性综合治疗和亚低温治疗在临床上广泛应用后,目前已有多种治疗理念在不同的动物实验和动物模型基础上被提出,包括缺血预处理、药物预处理、缺血后处理、和药物后处理,而后吸入麻醉药对心肺复苏后脑缺血再灌注损伤的保护作用受到了人们的重视,而七氟烷后处理已经成为目前研究的热点之一。为了指导临床上的心肺复苏,人们一直在利用不同动物模型,探究不同保护方法,寻找有效的脑保护药物。而各种治疗理念的提出均是建立在动物实验和动物模型的基础上,窒息性心肺复苏模型模拟围术期气道梗阻,能较贴切的复制临床上由窒息引起的心肺复苏后脑损伤,对将来指导临床复苏具有重大意义。     

Evaluation of threshold stress for bone resorption around screws based on in vivo strain measurement of miniplate

The purpose of this study is to investigate the critical threshold stress causing bone resorption evaluated from strain measurement in vivo, comparing the various finite element models. In this study strains of miniplates used for mandibular fractures were measured once a week until the strains reduced. The maximum bite force for each patient was applied in the incisal, right molar and left molar region. The strains increased and reached a peak level at 2-4 weeks, whereas the bite forces increased during the period of measurements. A 3-D osteosynthesis model using finite element method showed that the compressive stresses of the bone surrounding screws ranged within approximately -40 MPa under the condition generating the same amounts of strains measured in the miniplates. Furthermore, various finite element models simulating mandibular reconstruction using the fibular graft were constructed. The models for reconstruction using single strut fibula showed distinct stress concentration in the cortical bone surrounding screws, and the peak stress levels were 2 to 3 times as strong as that of the fracture model. We conclude that critical threshold for bone resorption should be approximately -50 MPa (3600 micro strain).     

Immunocytochemical and autoradiographic research on the growth of serotoninergic fibers to the cerebral ventricles in the perinatal period in rats

Anatomical relationships between serotoninergic (5-HT) fibers and cerebral ventricles were studied in rats from the 16th fetal day until the 9th postnatal day with immunocytochemistry and radioautography. In the latter case, 5-HT neuronal elements were detected according to their specific uptake of intraventricularly injected 3H-5-HT. On the 16th fetal day, occasional 5-HT fibers first spread from the main place of their origin in the raphe nuclei to the dorsocaudal portion of the 3rd ventricle and aqueduct. Two days later, a more extensive network of 5-HT fibers appeared around the dorsal portion of the 3rd ventricle, whereas fibers only rarely penetrated fibers became noticeable in the lateral and 3rd ventricles. The functional significance of hypothalamic and ventricular 5-HT is discussed from the standpoint of its being either a modulator of growth and differentiation of the developing brain, or a factor involved in some specific neuroendocrine functions.