Signal and morphological changes in the endolymph of patients with vestibular schwannoma on non-contrast 3D FLAIR at 3 Tesla.

BACKGROUND: Non-contrast FLAIR revealed increased signal within the inner ear in patients with vestibular schwannoma, which is generally assumed to occur in the perilymph; however, the majority of previous studies did not differentiate between the endolymph and perilymph. Therefore, endolymph signal changes have not yet been investigated in detail. The purpose of the present study was three-fold: (1) to assess perilymph signal changes in patients with vestibular schwannoma on heavily T2-weighted (T2W) 3D FLAIR, also termed positive perilymphatic images (PPI), (2) to evaluate signal and morphological changes in the endolymph on PPI, and (3) to establish whether vertigo correlates with the signal intensity ratios (SIR) of the vestibular perilymph or vestibular endolymphatic hydrops. METHODS: Forty-two patients with unilateral vestibular schwannoma were retrospectively recruited. We semi-quantitatively and qualitatively evaluated the perilymph signal intensity on the affected and unaffected sides. We also quantitatively examined the signal intensity of the vestibular perilymph and assessed the relationship between vertigo and the SIR of the vestibular perilymph on the affected side. We semi-quantitatively or qualitatively evaluated the endolymph, and investigated whether vestibular hydrops correlated with vertigo. RESULTS: The perilymph on the affected side showed abnormal signal more frequently (signal intensity grade: overall mean 1.45 vs. 0.02; comparison of signal intensity: overall mean 36 vs. 0 cases) and in more parts (the entire inner ear vs. the basal turn of the cochlea and vestibule) than that on the unaffected side. No significant difference was observed in the SIR of the vestibular perilymph with and without vertigo (5.54 vs. 5.51, p = 0.18). The endolymph of the vestibule and semicircular canals showed the following characteristic features: no visualization (n = 4), signal change (n = 1), or vestibular hydrops (n = 10). A correlation was not observed between vestibular hydrops and vertigo (p = 1.000). CONCLUSIONS: PPI may provide useful information on signal and morphological changes in the endolymph of patients with vestibular schwannoma. Further research is warranted to clarify the relationship between vertigo and the MR features of the inner ear.

Exploring the biomechanical responses of human cupula by numerical analysis of temperature experiments.

The vestibular receptor of cupula acts an important role in maintaining body balance. However, the cupula buried in the semicircular canals (SCCs) will be destroyed if it is detached from the relevant environment. The mechanical properties of human cupula still remain ambiguous. In this paper, we explored the cupula responses changing with temperature by experiments and numerical simulation of SCCs model. We obtained 3 volunteers' nystagmus induced by constant angular acceleration when the temperature of volunteers' SCCs was 36 °C and 37 °C respectively. The slow-phase velocity of 3 volunteers decreased by approximately 3°/s when the temperature of SCCs reduced by 1 °C, which corresponded to the reduction of cupula deformation by 0.3-0.8 µm in the numerical model. Furthermore, we investigated the effects of the variation of endolymphatic properties induced by temperature reduction on cupula deformation through numerical simulation. We found that the decrease of cupula deformation was not caused by the change of endolymphatic properties, but probably by the increase of cupula's elastic modulus. With the temperature reducing by 1 °C, the cupula's elastic modulus may increase by 6-20%, suggesting that the stiffness of cupula is enhanced. This exploration of temperature characteristic of human cupula promotes the research of alleviating vestibular diseases.

Numerical modeling and verification by nystagmus slow-phase velocity of the function of semicircular canals.

The malfunctioning of semicircular canals (SCCs) in the vestibular system results in diseases that disrupt the individual's daily life. Vestibular diseases can be treated more effectively if the functioning of the SCCs is better understood. However, the SCC is difficult to dissect, because it is a complex structure buried deep in the inner ear. To thoroughly understand the function of SCCs and provide better treatment plans for vestibular diseases, we constructed a numerical model of human SCCs and validated it experimentally. Based on the principle of the vestibulo-ocular reflex, the cupula deformation deflects embedded sensory hair cell bundles, transmitting signals to the brain and inducing a slow compensatory eye movement. The slow-phase velocity (SPV) is the characteristic of the slow compensatory eye movement. We investigated the cupula deformation in the numerical model and the SPV under different conditions. The relationship between the cupula deformation and the SPV was quantified for three volunteers. It was observed that the maximal cupula deformation is proportional to the angular acceleration, while the SPV is changing nonlinearly with the angular acceleration. For three volunteers, the relationship between the cupula deformation and the SPV can be expressed by same type function of which the parameters are dependent on individual differences. These results validate the reliability of the numerical model.

Chaotic Dynamics Enhance the Sensitivity of Inner Ear Hair Cells.

Hair cells of the auditory and vestibular systems are capable of detecting sounds that induce sub-nanometer vibrations of the hair bundle, below the stochastic noise levels of the surrounding fluid. Furthermore, the auditory system exhibits a highly rapid response time, in the sub-millisecond regime. We propose that chaotic dynamics enhance the sensitivity and temporal resolution of the hair bundle response, and we provide experimental and theoretical evidence for this effect. We use the Kolmogorov entropy to measure the degree of chaos in the system and the transfer entropy to quantify the amount of stimulus information captured by the detector. By varying the viscosity and ionic composition of the surrounding fluid, we are able to experimentally modulate the degree of chaos observed in the hair bundle dynamics in vitro. We consistently find that the hair bundle is most sensitive to a stimulus of small amplitude when it is poised in the weakly chaotic regime. Further, we show that the response time to a force step decreases with increasing levels of chaos. These results agree well with our numerical simulations of a chaotic Hopf oscillator and suggest that chaos may be responsible for the high sensitivity and rapid temporal response of hair cells.

Why the semicircular canals are not stimulated by linear accelerations.

Head accelerations are sensed by the vestibular system in the inner ear. Linear accelerations stimulate the otolith organs, while the semicircular canals (SCC) sense angular accelerations. Fluid-structure interaction (FSI) models of the cupula sensor (simulated with finite element method (FEM)) and the endolymph fluid (simulated with computational fluid dynamics (CFD)) in the semicircular canal offer the possibility to investigate why the SCC are not stimulated by linear accelerations. Two hypotheses exist in the literature. The first hypothesis focusses on the density of the cupula sensor in the SCC, while the second is based on the continuous loop of fluid in the semicircular canal. However, neither increasing the cupula density, nor disrupting the continuous fluid circulation substantially increase the cupula deformation under linear head acceleration, thereby rejecting both existing hypotheses. We propose an alternative hypothesis, based on the circular geometry of the semicircular canal. During angular head acceleration, the cupula intersects the body of endolymph and 'pushes' it forward because the cupula seals the semicircular canal like a diaphragm. This results in cupula deflection and neural stimulation. During linear head acceleration, on the other hand, a large part of the canal wall also 'pushes' the endolymph forward, which leads to hardly any cupula deflection.

Endolymphatic hydrops and ionic transporters: genetic and biohumoral aspects.

Ménière's disease (MD) is an inner ear disorder, characterized by a burden of symptoms, probably arising from the interplay of genetic and environmental factors. In this brief review, we consider the role of ion channels and transporters in the pathophysiology of MD, focusing on genetic and biohumoral aspects. Pathophysiological mechanisms related to altered concentrations of ions in the endolymph include altered osmotic pressure leading to hydrops and/or immunomodulatory effects of K+ and Endogenous Ouabain (EO) concentrations in the inner ear. Aquaporins 1-5 (AQPs) have been found in the inner ear; AQP2 is the only isoform controlled by a hormone, namely, vasopressin (antidiuretic hormone, ADH). Genetic studies on AQPs have provided inconclusive results. Recently, two genetic polymorphisms have been associated with MD: rs3746951, a missense variant (Gly180Ser) in the Salt-Inducible Kinase-1 (SIK1) gene and rs487119, an intronic variant of gene SLC8A1 coding for a Na+,Ca++ exchanger (NCX-1). EO is a hormone released by the midbrain and adrenal glands. It controls the constitutive capacity of modulating Na+,K+-ATPase activity. Higher plasma levels of EO have been found in MD subjects compared to a control group.

Asymmetric cupula displacement due to endolymph vortex in the human semicircular canal.

The vestibular system in the inner ear senses angular head manoeuvres by endolymph fluid which deforms a gelatinous sensory structure (the cupula). We constructed computer models that include both the endolymph flow (using CFD modelling), the cupula deformation (using FEM modelling), and the interaction between both (using fluid-structure interaction modelling). In the wide utricle, we observe an endolymph vortex. In the initial time steps, both the displacement of the cupula and its restorative forces are still small. As a result, the endolymph vortex causes the cupula to deform asymmetrically in an S-shape. The asymmetric deflection increases the cupula strain near the crista and, as a result, enhances the sensitivity of the vestibular system. Throughout the head manoeuvre, the maximal cupula strain is located at the centre of the crista. The hair cells at the crista centre supply irregularly spiking afferents, which are more sensitive than the afferents from the periphery. Hence, the location of the maximal strain at the crista may also increase the sensitivity of the semicircular canal, but this remains to be tested. The cupula overshoots its relaxed position in a simulation of the Dix-Hallpike head manoeuvre (3 s in total). A much faster head manoeuvre of 0.222 s showed to be too short to cause substantial cupula overshoot, because the cupula time scale of both models (estimated to be 3.3 s) is an order of magnitude larger than the duration of this manoeuvre.

Evolution of Endolymph Secretion and Endolymphatic Potential Generation in the Vertebrate Inner Ear.

The ear of extant vertebrates reflects multiple independent evolutionary trajectories. Examples include the middle ear or the unique specializations of the mammalian cochlea. Another striking difference between vertebrate inner ears concerns the differences in the magnitude of the endolymphatic potential. This differs both between the vestibular and auditory part of the inner ear as well as between the auditory periphery in different vertebrates. Here we provide a comparison of the cellular and molecular mechanisms in different endorgans across vertebrates. We begin with the lateral line and vestibular systems, as they likely represent plesiomorphic conditions, then review the situation in different vertebrate auditory endorgans. All three systems harbor hair cells bathed in a high (K+) environment. Superficial lateral line neuromasts are bathed in an electrogenically maintained high (K+) microenvironment provided by the complex gelatinous cupula. This is associated with a positive endocupular potential. Whether this is a special or a universal feature of lateral line and possibly vestibular cupulae remains to be discovered. The vestibular system represents a closed system with an endolymph that is characterized by an enhanced (K+) relative to the perilymph. Yet only in land vertebrates does (K+) exceed (Na+). The endolymphatic potential ranges from +1 to +11 mV, albeit we note intriguing reports of substantially higher potentials of up to +70 mV in the cupula of ampullae of the semicircular canals. Similarly, in the auditory system, a high (K+) is observed. However, in contrast to the vestibular system, the positive endolymphatic potential varies more substantially between vertebrates, ranging from near zero mV to approximately +100 mV. The tissues generating endolymph in the inner ear show considerable differences in cell types and location. So-called dark cells and the possibly homologous ionocytes in fish appear to be the common elements, but there is always at least one additional cell type present. To inspire research in this field, we propose a classification for these cell types and discuss potential evolutionary relationships. Their molecular repertoire is largely unknown and provides further fertile ground for future investigation. Finally, we propose that the ultimate selective pressure for an increased endolymphatic potential, as observed in mammals and to a lesser extent in birds, is specifically to maintain the AC component of the hair-cell receptor potential at high frequencies. In summary, we identify intriguing questions for future directions of research into the molecular and cellular basis of the endolymph in the different compartments of the inner ear. The answers will provide important insights into evolutionary and developmental processes in a sensory organ essential to many species, including humans.

Saccular otoconia as a cause of Ménière's disease: hypothesis based on two theories.

BACKGROUND: The cause of Ménière's disease remains enigmatic after 156 years. Schuknecht's rupture and potassium intoxication theory of attacks was based on histological studies. OBJECTIVES: This paper aimed to: present the most contemporary evidence indicating that ruptures do not usually occur, and discuss the possibility that detached saccular otoconia are the main cause of Ménière's disease; and to establish an unequivocal definition of the age of Ménière's disease onset. METHOD: The paper reviews the electrophysiological basis of the Gibson-Arenberg drainage theory used to explain vertigo attacks. The current, limited knowledge of the likely fate of detached saccular otoconia is discussed. RESULTS: Electrophysiological studies during attacks do not support endolymph ruptures, but rather endolymph flowing in one direction and then in the opposite direction. Age of onset for Ménière's disease parallels that for benign paroxysmal positional vertigo. CONCLUSION: The similarity of age of onset spectrum for Ménière's disease and benign paroxysmal positional vertigo raises the possibility that the two conditions have the same fundamental cause.

A computational framework to simulate the endolymph flow due to vestibular rehabilitation maneuvers assessed from accelerometer data.

Vertiginous symptoms are one of the most common symptoms in the world, therefore investing in new ways and therapies to avoid the sense of insecurity during the vertigo episodes is of great interest. The classical maneuvers used during vestibular rehabilitation consist in moving the head in specific ways, but it is not fully understood why those steps solve the problem. To better understand this mechanism, a three-dimensional computational model of the semicircular ducts of the inner ear was built using the finite element method, with the simulation of the fluid flow being obtained using particle methods. To simulate the exact movements performed during rehabilitation, data from an accelerometer were used as input for the boundary conditions in the model. It is shown that the developed model responds to the input data as expected, and the results successfully show the fluid flow of the endolymph behaving coherently as a function of accelerometer data. Numerical results at specific time steps are compared with the corresponding head movement, and both particle velocity and position follow the pattern that would be expected, confirming that the model is working as expected. The vestibular model built is an important starting point to simulate the classical maneuvers of the vestibular rehabilitation allowing to understand what happens in the endolymph during the rehabilitation process, which ultimately may be used to improve the maneuvers and the quality of life of patients suffering from vertigo.

Endolymph composition: paradigm or inevitability?

This review is focused on the unusual composition of the endolymph of the inner ear and its function in mechanoelectrical transduction. The role of K(+) and Ca(2+) in excitatory influx, the very low Na(+), Ca(2+) and Mg(2+) concentrations of endolymph, stereocilia structure of hair cells and some proteins involved in mechanosensory signal transduction with emphasis on auditory receptors are presented and analyzed in more details. An alternative hypothetical model of ciliary structure and endolymph with a 'normal' composition is discussed. It is concluded that the unique endolymph cation content is more than an energy saving mechanism that avoids disturbing circulatory vibrations to achieve a much better mechanosensory resolution. It is the only possible way to fulfil the requirements for a precise ciliary mechanoelectrical transduction in conditions where pressure events with quite diverse amplitudes and duration are transformed into adequate hair cell membrane depolarizations, which are regulated by a sensitive Ca(2+)-dependent feedback tuning.

An alternative 3D numerical method to study the biomechanical behaviour of the human inner ear semicircular canal.

PURPOSE: The vestibular system is the part of the inner ear responsible for balance. Vertigo and dizziness are generally caused by vestibular disorders and are very common symptoms in people over 60 years old. One of the most efficient treatments at the moment is vestibular rehabilitation, permitting to improve the symptoms. However, this rehabilitation therapy is a highly empirical process, which needs to be enhanced and better understood. METHODS: This work studies the vestibular system using an alternative computational approach. Thus, part of the vestibular system is simulated with a three dimensional numerical model. Then, for the first time using a combination of two discretization techniques (the finite element method and the smoothed particle hydrodynamics method), it is possible to simulate the transient behavior of the fluid inside one of the canals of the vestibular system. RESULTS: The obtained numerical results are presented and compared with the available literature. The fluid/solid interaction in the model occurs as expected with the methods applied. The results obtained with the semicircular canal model, with the same boundary conditions, are similar to the solutions obtained by other authors. CONCLUSIONS: The numerical technique presented here represents a step forward in the biomechanical study of the vestibular system, which in the future will allow the existing rehabilitation techniques to be improved.

Numerical modeling of the cupular displacement and motion of otoconia particles in a semicircular canal.

Balance is achieved and maintained by a balance system called a labyrinth that is composed of three semicircular canals and the otolith organs that sense linear gravity and acceleration. Within each semicircular canal, there is a gelatinous structure called the cupula, which is deformed under the influence of the surrounding endolymph. One of the balance disorders is benign paroxysmal positional vertigo, and one of the pathological conditions that have been identified as possible causes of this syndrome is canalithiasis-disturbance of the endolymph flow and cupular displacement caused by the free-moving otoconia particles within the lumen of the canal. Analysis of phenomena occurring within the semicircular canal can help to explain some balance-related disorders and the response of the vestibular system to external perturbations under various pathological conditions. Numerical simulations allow a study of the influence of a wide range of factors, without the need to perform experiments and clinical examinations. In case of canalithiasis, an accurate explanation and tracking of the motion of otoconia particles in vivo is obviously nearly impossible. In this study, a numerical model was developed to predict the motion of otoconia particles within the semicircular canal and the effect of the endolymph flow and particles on the deformation of the cupula.

Cochlear potential difference between endolymph fluid and the hair cell's interior: a retold interpretation based on the Goldman equation.

Reported cochlear potential values of near 150 mV are often attributed to endolymph itself, although membrane potentials result from ion fluxes across the adjacent semipermeable membranes due to concentration gradients. Since any two fluids separated by a semipermeable membrane develop potential due to differences in solute concentrations, a proposed interpretation here is that positive potential emanates from the Reissner membrane due to small influx of sodium from perilymph to endolymph. Basolateral hair cell membranes leak potassium into the interstitial fluid and this negative potential inside hair cells further augments the electric gradient of cochlear potential. Taken together as a sum, these two potentials are near the reported values of cochlear potential. This is based on reported data for cochlear fluids used for the calculation of Nernst and Goldman potentials. The reported positive potential of Reissner membrane can be explained almost entirely by the traffic of Na+ that enters endolymph through this membrane. At the apical membrane of hair cells, acoustic stimulation modulates stereocillia permeability to potassium. Potassium concentration gradients on the apical membrane are low (the calculated Nernst value is <+3 mV), suggesting that the potassium current is not caused by the local potassium concentration gradient, but an electric field between the positive sodium generated potential on the Reissner membrane and negative inside hair cells. Potassium is forced by this overall electric field to enter hair cells when stereocilia are permeable due to mechanical bending.

Computing simulated endolymphatic flow thermodynamics during the caloric test using normal and hydropic duct models.

CONCLUSION: The obtained simulations support the underlying hypothesis that the hydrostatic caloric drive is dissipated by local convective flow in a hydropic duct. OBJECTIVE: To develop a computerized model to simulate and predict the internal fluid thermodynamic behavior within both normal and hydropic horizontal ducts. METHODS: This study used a computational fluid dynamics software to simulate the effects of cooling and warming of two geometrical models representing normal and hydropic ducts of one semicircular horizontal canal during 120 s. RESULTS: Temperature maps, vorticity, and velocity fields were successfully obtained to characterize the endolymphatic flow during the caloric test in the developed models. In the normal semicircular canal, a well-defined endolymphatic linear flow was obtained, this flow has an opposite direction depending only on the cooling or warming condition of the simulation. For the hydropic model a non-effective endolymphatic flow was predicted; in this model the velocity and vorticity fields show a non-linear flow, with some vortices formed inside the hydropic duct.

Endolymph movement visualized with light sheet fluorescence microscopy in an acute hydrops model.

There are a variety of techniques available to investigate endolymph dynamics, primarily seeking to understand the cause of endolymphatic hydrops. Here we have taken the novel approach of injecting, via a glass micropipette, fluorescein isothiocyanate-dextran (FITC-dex) and artificial endolymph into scala media of anaesthetized guinea pigs, with subsequent imaging of the inner ear using Light Sheet Fluorescence Microscopy (LSFM) as a means to obtain highly resolved 3D visualization of fluid movements. Our results demonstrate endolymph movement into the utricle, semicircular canals and endolymphatic duct and sac when more than 2.5 µl of fluid had been injected into scala media, with no apparent movement of fluid into the perilymphatic compartments. There was no movement of endolymph into these compartments when less than 2.5 µl was injected. The remarkable uptake of the FITC-dex into the endolymphatic duct, including an absorption into the periductal channels surrounding the endolymphatic duct, highlights the functional role this structure plays in endolymph volume regulation.

Numerical simulation of the role of the utriculo-endolymphatic valve in the rotation-sensing capabilities of semicircular canals.

The utriculo-endolymphatic valve (UEV) has an uncertain function, but its opening and closure have been predicted to maintain a constant endolymphatic pressure within the semicircular canals (SCCs) and the utricle of the inner ear. Here, the study׳s aim was to examine the role of the UEV in regulating the capabilities of the 3 SCCs in sensing angular acceleration by using the finite element method. The results of the developed model showed endolymphatic flow and cupula displacement patterns in good agreement with previous experiments. Moreover, the open valve was predicted to permit endolymph exchange between the 2 parts of the membranous labyrinth during head rotation and, in comparison to the closed valve, to result in a reinforced endolymph flow in the utricle and an enhanced or weakened cupula deflection. Further, the model predicted an increase in the size of the orifice would result in greater endolymph exchange and thereby to a greater impact on cupula deflection. The model findings suggest the UEV plays a crucial role in the preservation of inner ear sensory function.

Identifying Mechanisms Behind the Tullio Phenomenon: a Computational Study Based on First Principles.

Patients with superior canal dehiscence (SCD) suffer from events of dizziness and vertigo in response to sound, also known as Tullio phenomenon (TP). The present work seeks to explain the fluid-dynamical mechanisms behind TP. In accordance with the so-called third window theory, we developed a computational model for the vestibular signal pathway between stapes and SCD. It is based on first principles and accounts for fluid-structure interactions arising between endolymph, perilymph, and membranous labyrinth. The simulation results reveal a wave propagation phenomenon in the membranous canal, leading to two flow phenomena within the endolymph which are in close interaction. First, the periodic deformation of the membranous labyrinth causes oscillating endolymph flow which forces the cupula to oscillate in phase with the sound stimulus. Second, these primary oscillations of the endolymph induce a steady flow component by a phenomenon known as steady streaming. We find that this steady flow of the endolymph is typically in ampullofugal direction. This flow leads to a quasi-steady deflection of the cupula which increases until the driving forces of the steady streaming are balanced by the elastic reaction forces of the cupula, such that the cupula attains a constant deflection amplitude which lasts as long as the sound stimulus. Both response types have been observed in the literature. In a sensitivity study, we obtain an analytical fit which very well matches our simulation results in a relevant parameter range. Finally, we correlate the corresponding eye response (vestibulo-ocular reflex) with the fluid dynamics by a simplified model of lumped system constants. The results reveal a "sweet spot" for TP within the audible sound spectrum. We find that the underlying mechanisms which lead to TP originate primarily from Reynolds stresses in the fluid, which are weaker at lower sound frequencies.

Comparison of noninvasive evaluation of endolymphatic space in healthy volunteers in different age groups using magnetic resonance imaging.

CONCLUSIONS: Noninvasive standard evaluation of normal endolymphatic space and endolymphatic hydrops using magnetic resonance imaging (MRI) in various age groups is reported for the first time. OBJECTIVE: To compare the standard evaluation of endolymphatic space in healthy volunteers in the cochlea and the vestibule among different age groups by applying noninvasive intratympanic gadolinium (Gd) perfusion through the eustachian tube and three-dimensional fluid-attenuated inversion recovery MRI (3D-FLAIR MRI). METHODS: This was a prospective study. 3D-FLAIR MRI was performed with a 3 T unit 24 h after intratympanic administration of Gd through the eustachian tube in 60 healthy volunteers aged 20-55 years. Pure-tone test and tympanometry were performed 24 h before and 1 week after Gd administration. RESULTS: There was no significant difference in the ratios of the area of the endolymphatic space to that of the fluid space in the cochlea and the vestibule between males and females, or among 20-30-, 31-44-, and 45-55-year-old healthy volunteers. In 20-55-year-old healthy volunteers, the normal value of the endolymphatic space in the cochlea ranged between 7% and 27%, and that in the vestibule was between 17% and 39%. No significant changes in pure-tone test or tympanometry were noted.

A meshless boundary method for Stokes flows with particles: application to canalithiasis.

We propose to couple the method of fundamental solutions (MFS) to the force coupling method (FCM). The resulting method is an efficient, easy to program, meshless method for flows at low Reynolds numbers with finite-size particles. In such an approach, the flow domain is extended across the solid particle phase, and the flow is approximated by a superposition of singular Stokeslets positioned outside the flow domain and finite-size multipoles collocated with the particle. To improve the efficiency of the coupling, we propose new MFS quadratures for the computation of the volume integrals required for the FCM. These are exact and do not require the expensive evaluation of Stokeslets. The proposed method has been developed in the context of investigations of the fluid dynamics of canalithiasis, that is, a pathological condition of the semicircular canals of the inner ear. Numerical examples are presented to illustrate the applicability of the method.