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This study examined the external morphology and morphometry of the human embryonic inner ear membranous labyrinth and documented its three-dimensional position in the developing embryo using phase-contrast X-ray computed tomography and magnetic resonance imaging. A total of 27 samples between Carnegie stage (CS) 17 and the postembryonic phase during trimester 1 (approximately 6-10 weeks after fertilization) were included. The otic vesicle elongated along the dorso-ventral axis and differentiated into the end lymphatic appendage and cochlear duct (CD) at CS 17. The spiral course of the CD began at CS18, with anterior and posterior semicircular ducts (SDs) forming prominent circles with a common crus. The spiral course of the CD comprised more than two turns at the postembryonic phase, at which time the height of the CD was evident. A linear increase was observed in the length of anterior, posterior, and lateral SDs, in that order, and the length of the CD increased exponentially over the course of development. Bending in the medial direction was observed between the cochlear and vestibular parts from the latero-caudal view, with the angle decreasing during development. The position of the inner ear was stable throughout the period of observation on the lateral to ventral side of the rhombencephalon, caudal to the pontine flexure, and adjacent to the auditory ganglia. The plane of the lateral semicircular canal was approximately 8.0°-14.6° with respect to the cranial caudal (z-)axis, indicating that the orientation of the inner ear changes during growth to adulthood., (© 2015 Wiley Periodicals, Inc.)

The human brain constructs verticality perception by integrating vestibular, somatosensory, and visual information. Here we investigated whether galvanic vestibular stimulation (GVS) has an effect on verticality perception both during and after application, by assessing the subjective verticals (visual, haptic and postural) in healthy subjects at those times. During stimulation the subjective visual vertical and the subjective haptic vertical shifted towards the anode, whereas this shift was reversed towards the cathode in all modalities once stimulation was turned off. Overall, the effects were strongest for the haptic modality. Additional investigation of the time course of GVS-induced changes in the haptic vertical revealed that anodal shifts persisted for the entire 20-min stimulation interval in the majority of subjects. Aftereffects exhibited different types of decay, with a preponderance for an exponential decay. The existence of such reverse effects after stimulation could have implications for GVS-based therapy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Vertigo in and around magnetic resonance imaging (MRI) machines has been noted for years [1, 2]. Several mechanisms have been suggested to explain these sensations [3, 4], yet without direct, objective measures, the cause is unknown. We found that all of our healthy human subjects developed a robust nystagmus while simply lying in the static magnetic field of an MRI machine. Patients lacking labyrinthine function did not. We use the pattern of eye movements as a measure of vestibular stimulation to show that the stimulation is static (continuous, proportional to static magnetic field strength, requiring neither head movement nor dynamic change in magnetic field strength) and directional (sensitive to magnetic field polarity and head orientation). Our calculations and geometric model suggest that magnetic vestibular stimulation (MVS) derives from a Lorentz force resulting from interaction between the magnetic field and naturally occurring ionic currents in the labyrinthine endolymph fluid. This force pushes on the semicircular canal cupula, leading to nystagmus. We emphasize that the unique, dual role of endolymph in the delivery of both ionic current and fluid pressure, coupled with the cupula's function as a pressure sensor, makes magnetic-field-induced nystagmus and vertigo possible. Such effects could confound functional MRI studies of brain behavior, including resting-state brain activity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Na(+) concentrations in endolymph must be controlled to maintain hair cell function since the transduction channels of hair cells are cation-permeable, but not K(+)-selective. Flooding or fluctuations of the hair cell cytosol with Na(+) would be expected to lead to cellular dysfunction, hearing loss and vertigo. This review briefly describes cellular mechanisms known to be responsible for Na(+) homeostasis in each compartment of the inner ear, including the cochlea, saccule, semicircular canals and endolymphatic sac. The influx of Na(+) into endolymph of each of the organs is likely via passive diffusion, but these pathways have not yet been identified or characterized. Na(+) absorption is controlled by gate-keeper channels in the apical (endolymphatic) membrane of the transporting cells. Highly Na(+)-selective epithelial sodium channels (ENaCs) control absorption by Reissner's membrane, saccular extramacular epithelium, semicircular canal duct epithelium and endolymphatic sac. ENaC activity is controlled by a number of signal pathways, but most notably by genomic regulation of channel numbers in the membrane via glucocorticoid signaling. Non-selective cation channels in the apical membrane of outer sulcus epithelial cells and vestibular transitional cells mediate Na(+) and parasensory K(+) absorption. The K(+)-mediated transduction current in hair cells is also accompanied by a Na(+) flux since the transduction channels are non-selective cation channels. Cation absorption by all of these cells is regulated by extracellular ATP via apical non-selective cation channels (P2X receptors). The heterogeneous population of epithelial cells in the endolymphatic sac is thought to have multiple absorptive pathways for Na(+) with regulatory pathways that include glucocorticoids and purinergic agonists., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Ontogeny, or the development of an individual from conception to death, is a major source of variation in vertebrate morphology. All anatomical systems are affected by ontogeny, and knowledge of the ontogenetic history of these systems is important to understand when formulating biological interpretations of evolutionary history and physiology. The present study is focused on how variation affects the bony labyrinth across a growth series of an extant mammal after ossification of the inner ear chambers. Digital endocasts of the bony labyrinth were constructed using CT data across an ontogenetic sequence of Monodelphis domestica, an important experimental animal. Various aspects of the labyrinth were measured, including angles between the semicircular canals, number of turns of the cochlea, volumes of inner ear constituents, as well as linear dimensions of semicircular canals. There is a strong correlation between skull length and age, but from 27 days after birth onward, there is no correlation with age among most of the inner ear measurements. Exceptions are the height of the arc of the lateral semicircular canal, the angular deviation of the lateral canal from planarity, the length of the slender portion of the posterior semicircular canal, and the length of the canaliculus cochleae. Adult dimensions of several of the inner ear structures, such as the arcs of the semicircular canals, are achieved before the inner ear is functional, and the non-ontogenetic variation in the bony labyrinth serves as an important source for behavioral, physiological, and possibly phylogenetic information.

The effects of microgravity on frog semicircular canals have been studied by electrophysiological and morphological approaches. Reduced gravity (microG) was simulated by a random positioning machine (RPM), which continually and randomly modified the orientation in space of the anesthetized animal. As this procedure stimulates the semicircular canals, the effect of altered gravity was isolated by comparing microG-treatment with an identical rotary stimulation in the presence of normal gravity (normoG). Electrophysiological experiments were performed in the isolated labyrinth, extracted from the animals after the treatment, and mounted on a turntable. Junctional activity was measured by recording quantal events (mEPSPs) and spikes from the afferent fibers close to the junction, at rest and during rotational stimulation. MicroG-treated animals displayed a marked decrease in the frequency of resting and evoked mEPSP discharge, vs. both control and normoG (mean decrease approximately 50%). Spike discharge was also depressed: 57% of microG-treated frogs displayed no spikes at rest and during rotation at 0.1 Hz, vs. 23-31% of control or normoG frogs. Among the firing units, during one cycle of sinusoidal rotation at 0.1 Hz microG-treated units emitted an average of 41.8 + or - 8.06 spikes, vs. 77.2 + or - 8.19 in controls. Patch-clamp analysis on dissociated hair cells revealed altered Ca(2+) handling, after microG, consistent with and supportive of the specificity of microG effects. Marked morphological signs of cellular suffering were observed after microG, mainly in the central part of the sensory epithelium. Functional changes due to microgravity were reversible within a few days.

Objective: There exist 3 communication routes between the intracranial space and the inner ear, the vestibular aqueduct, the cochlear aqueduct, and the internal auditory canal. They possess a key role in inner ear pressure regulation and fluid homeostasis and are related to inner ear diseases., Review Methods: Relevant literature was reviewed, and the current knowledge of the anatomy, physiologic importance, and relations to inner ear diseases were described. Pathologic communication routes such as semicircular canal dehiscence syndrome were highlighted as well., Conclusion: Abnormalities in all 3 communication routes may predispose or be the cause of distinct inner ear pathologic condition and involved in other cochlear and vestibular syndromes, in which their role is not completely clear. The increasing knowledge of the underlying mechanisms encourages promising approaches for possible intervention in the future.

We investigated the possible contribution of signals carried by vestibular-nerve afferents to long-term processes of vestibular compensation after unilateral labyrinthectomy. Semicircular canal afferents were recorded from the contralesional nerve in three macaque monkeys before [horizontal (HC) = 67, anterior (AC) = 66, posterior (PC) = 50] and 1-12 mo after (HC = 192, AC = 86, PC = 57) lesion. Vestibular responses were evaluated using passive sinusoidal rotations with frequencies of 0.5-15 Hz (20-80 degrees /s) and fast whole-body rotations reaching velocities of 500 degrees /s. Sensitivities to nonvestibular inputs were tested by: 1) comparing responses during active and passive head movements, 2) rotating the body with the head held stationary to activate neck proprioceptors, and 3) encouraging head-restrained animals to attempt to make head movements that resulted in the production of neck torques of < or =2 Nm. Mean resting discharge rate before and after the lesion did not differ for the regular, D (dimorphic)-irregular, or C (calyx)-irregular afferents. In response to passive rotations, afferents showed no change in sensitivity and phase, inhibitory cutoff, and excitatory saturation after unilateral labyrinthectomy. Moreover, head sensitivities were similar during voluntary and passive head rotations and responses were not altered by neck proprioceptive or efference copy signals before or after the lesion. The only significant change was an increase in the proportion of C-irregular units postlesion, accompanied by a decrease in the proportion of regular afferents. Taken together, our findings show that changes in response properties of the vestibular afferent population are not likely to play a major role in the long-term changes associated with compensation after unilateral labyrinthectomy.

Programmed cell death is known to be an essential process for accurate ontogeny during the normal development of the inner ear. The inner ear is a complex sensory organ responsible for equilibrium and sound detection in vertebrates. In all vertebrates, the inner ear develops from a single ectodermic patch on the surface of the embryo's head, which undergoes a series of morphological changes to give rise to the complex structure of the adult inner ear. Enlargement and morphogenesis of the inner ear primordium is likely to depend on cellular division, growth, migration, differentiation and apoptosis. Here we describe the regions of programmed cell death that contribute to the final morphological aspect of the adult inner ear. The few studies that focus on the molecules that control this process during inner ear development indicate that the molecules and intracellular signaling pathways activated during the apoptotic response in the inner ear are similar to the previously described for the nervous system. In this review, we will describe some of the growth factors and key pathways that regulate pro- and anti-apoptotic signals and how they cross talk to determine the apoptotic or survival fate of cells in the development of the inner ear.

Understanding the development and function of the inner ear requires knowledge of the genes expressed and the pathways involved. Such knowledge is also essential for the development of therapeutic approaches for a wide range of inner ear diseases affecting millions of people. The completion of the Human Genome Project and emergence of genomics-based technologies have made it possible to analyze the expression patterns of the inner ear genes at the whole genome level, generating an unprecedented amount of information on gene expression patterns. This review will discuss the current status of work using genomics, in particular the functional genomics approach, to study different aspects of inner ear genes. It will also illustrate how the approach can help to identify and characterize deafness genes, as well as contributing to work related to hair cell regeneration.

Gaze is stabilized during head movements primarily by the vestibuloocular reflex (VOR). After a unilateral canal plug, the VOR's response is reduced. Recovery of the VOR may be brought about by changes in the efficacy of brain stem synapses or by other mechanisms. We measured the responses of horizontal secondary vestibular neurons (HSNs) to stimulation of the contralateral labyrinth. HSN responses in normal alert cats were compared with those in cats that had recovered from unilateral horizontal semicircular canal (HSCC) plugs. After recovery, excitatory commissural inputs to HSNs on the plugged side elicited significantly smaller responses than in normal cats with no change in mean discharge rates. However, mean discharge rates tended to be higher after recovery for cells receiving inhibitory commissural inputs. The change in resting rate invalidates any direct comparison of inhibitory inputs. These results are interpreted in terms of possible mechanisms for recovery from unilateral vestibular loss by the VOR neural network. We conclude that after unilateral HSCC plugs, changes in brain stem excitatory synapses and/or excitability of secondary vestibular neurons may participate in the restoration of normal vestibular reflexes.

Whole membranous labyrinths of bullfrogs were used in order to replicate the human vestibule. The posterior semicircular canals (PSCs) were exposed, leaving the remaining membranous labyrinth encapsulated in the otic capsule. Vibration was applied to the surface of the bony capsule using a conventional surgical drill in order to dislodge the otoconia from the utricle. The position of the preparation was controlled so that the dislodged otoconia were attached to the cupular surface. This was regarded as a cupulolithiasis model. The action potentials changed instantaneously according to the gravitational force on the cupula. When the otoconia were dislodged and held within the PSC lumen, the position of the whole preparation was changed so that the otoconia moved back and forth within the canal lumen. This is a model of canalolithiasis. The action potentials changed in combination with the otoconial movement after a latent period. Both cupulolithiasis and canalolithasis are potentially valid mechanisms of benign paroxysmal positional vertigo (BPPV). However, canalolithiasis is the most likely mechanism of BPPV, which is usually characterized by nystagmus of short duration and long latency. A vibratory stimulus was able to detach the otoconia from the utricle, suggesting that mechanical insult could be a possible etiology of BPPV.

A CT study was performed on 8 foetuses aged between 20 and 38 weeks. In foetuses at the 20th week the semicircular canals, the spiral canal of the cochlea and the initial (labyrinthine) part of the facial canal are visible. At week 24 the tympanic part of the facial canal is observed. In the 31st week the cochlea is divided into 2 compartments, and in the 38th week the vestibular aqueduct and osseous labyrinth are seen.

Objective: To give a historical perspective of Antonio Scarpa's contributions to otology, specifically the discovery of the inner ear organs as the foundation for the experimental work that followed., Background/method: Scarpa's original descriptions of the human inner ear were translated from the Latin text, and his illustrations were analyzed and compared with current knowledge., Conclusions: Antonio Scarpa's anatomic and clinical studies place him among the great scientists of the eighteenth century. His discoveries about the inner ear established the limit of what could be learned without advanced histologic techniques and provided the foundation for the work that eventually led to the modern understanding of ear physiology.

An outstanding challenge in developmental biology is to reveal the mechanisms underlying the morphogenesis of complex organs. A striking example is the developing inner ear of the vertebrate, which acquires a precise three-dimensional arrangement of its constituent epithelial cells to form three semicircular canals, a central vestibule and a coiled cochlea (in mammals). In generating a semicircular canal, epithelial cells seem to 'disappear' from the center of each canal. This phenomenon has been variously explained as (i) transdifferentiation of epithelium into mesenchyme, (ii) absorption of cells into the expanding canal or (iii) programmed cell death. In this study, an in situ DNA-end labeling technique (the TUNEL protocol) was used to map regions of cell death during inner ear morphogenesis in the chicken embryo from embryonic days 3.5-10. Regions of cell death previously identified in vertebrate ears have been confirmed, including the ventromedial otic vesicle, the base of the endolymphatic duct and the fusion plates of the semicircular canals. New regions of cell death are also described in and around the sensory organs. Reducing normal death using retrovirus-mediated overexpression of human bcl-2 causes abnormalities in ear morphogenesis: hollowing of the center of each canal is either delayed or fails entirely. These data provide new evidence to explain the role of cell death in morphogenesis of the semicircular canals.

Mechanical properties of the semicircular canals of guinea pigs, frogs and water fishes, and of human membranous labyrinths were tested. Tensile strength of the semicircular canals of guinea pig, frog and water fish was greater in the order of guinea pig, frog and fish. In the human membranous labyrinth, the saccular membrane was the weakest, followed by Reissner's membrane, the utricular membrane and the semicircular canal. These values were converted from tensile strength to breakage pressure. The breakage pressure of the saccular membrane was 64.0 mmHg.

Selective labyrinthine lesions were made to study the origin of excitation in the labyrinth during off-vertical axis rotation. Plugging the semicircular canals abolishes the response to rotation about a vertical axis, but optokinetic after-nystagmus (OKAN) and the sustained horizontal nystagmus induced by off-vertical axis rotation (OVAR) are maintained. After cutting the nerves of the lateral semicircular canals, neither horizontal OKAN nor the continuous horizontal nystagmus associated with off-axis rotation can be induced, although vertical OKN, OKAN and vestibular nystagmus are intact. This supports the theory that labyrinthine activity responsible for the nystagmus induced by OVAR arises in the otolith organs and couples to the oculomotor system through the velocity storage mechanism.

Compensatory (slow phase) eye movements elicited by sinusoidal oscillation on a torsion swing were measured in rabbits, 6 months after destruction of the left labyrinth. A range of combinations of stimulus frequencies (0.048-1.8 Hz) and amplitudes (1-25 degrees) were used. Gain (amplitude of cumulative slow phase eye movement/amplitude of swing), phase (eye position vs. swing position - 180 degrees) and directional asymmetry were calculated from averaged records. With eyes covered, gain was much less than half of normal and phase lead was increased by at least 20 degrees. Spontaneous drift was minimal or absent; a slight asymmetry of reactions (preponderance of smooth movements to the intact side) was found. In the presence of vision, reactions were slightly improved, but only for low stimulus velocities. It is concluded that although the acute effects of unilateral labyrinthectomy in rabbits subside and a static equilibrium is achieved, dynamic performance of vestibular reactions remains much below normal.

1. The horizontal sinusoidal frequency response and the problem of vestibular receptor convergence in Purkinje cells (P-cells) of the auriculum, dorsal rim and corpus cerebelli were studied in curarized frogs with natural stimulation. 2. Primarily "simple" but also "complex" spikes were evoked by sinusoidal stimulation of the horizontal canals. P-cell "simple" spike activity could be grouped into types I-IV. Type I and II responses were directionally sensitive and thus were evoked at the stimulus frequency. Type III (and IV) cells, on the other hand, had response waveforms double that of the input frequency, with peak increases (or decreases) in discharge inphase with head velocity in the mid-frequency range. Except in the cerebellar midline regions where type III response waveforms were symmetrical, ipsilateral sinusoidal responses were larger in magnitude than those evoked during contralateral rotation. Despite the differences in magnitudes, ipsi- and contralateral response phase angles for one cell were approximately equal. "Complex" spikes were evoked with ipsi (type I) or contralateral (type II) horizontal rotation. Generally only 1-2 spikes were evoked per cycle with short (0-60 degrees) or long (120-150 degrees) phase-lags following acceleration. 3. A Bode analysis of type I "simple" spike activity in yaw indicates a slightly greater phase-lag and a 10-15 fold smaller P-cell gain in the range 0.05-0.5 Hz when compared to peripheral horizontal canal neurons. 4. Stimulation of the vertical canals and otolith organs also evoked "simple" and, to a lesser extent, "complex" P-cell spikes. "Simple" spikes were in most cases (85%) evoked by stimulation of several canal and/or otolithic receptors thus demonstrating a high degree of receptor convergence. "Complex" spikes, however, were only evoked by stimulation of one canal or otolith receptor. 5. Otolithic input to P-cells, examined statically and with low level constant velocity rolls, was mainly phasic or phasic-tonic in nature.

In axolotls (Ambystoma mexicanun) the labyrinths and the associated parts of the medulla were doubled artificially. In these so-called tandem-heads the vestibular afferent fibres from both labyrinths on one side united within the medulla to form common bundles. The head-turning reflexes following impulse acceleration and during long-lasting acceleration were measured quantitatively and compared with those for normal animals. The form and the time-course of the reactions were almost identical in both groups. Tandem-heads showed a linear relationship between stimulus intensity and reaction strength, parallel to that in normal animals but with a greater reaction for a given stimulus. Consequent to this shift in the relationship, there was a significant decrease in the reaction threshold. The removal of one horizontal semicircular canal in tandem-heads proved that both pairs of labyrinths were functionally connected with the brain. It was suggested that during ontogenesis there exists a kind of specificity in the connexion of vestibular fibres. From the parallel shift of the intensity functions it was concluded that the input from both pairs of labyrinths in tandem-heads is not simply accumulate but compared with a reference parameter, which is also double in tandem-heads.

For the experiments 39 cats were used. Selective sectioning of either the anterior or the posterior vertical ampullar nerves was performed bilaterally. Additionally in some cats the utricular nerves were cut, or the saccule extirpated on one or both sides. The otolith organs were stimulated by tilting around the bitemporal axis of the animals. Bilateral sectioning of the anterior ampullar nerve induced vertical nystagmus upwards, which disappeared, if the animals were tilted upside down. When the posterior ampullar nerves were cut bilaterally a vertical nystagmus downwards was obtained, and if the animals were tilted upside down there was a large increase in nystagmus frequency. After unilateral extirpation of the saccule, vertical nystagmus downwards was observed in 50 percent of these experiments. This nystagmus was modulated by tilting. However, if the saccules on both sides were extirpated, no nystagmus could be elicited. The cause of these results is discussed.

A combined morphological and physiological study on the effect of saccus obliteration on the cochlea and the vestibular labyrinth of the rat is presented. Endolymphatic hydrops was successfully induced in 49% of the animals. It was frequently associated with fistulae of the membranous wall and degenerative changes in the organ of Corti and spiral ganglion. In hydropic ears electrocochleography revealed a CAP threshold increase only in those cases where hydrops was associated with loss of hair cells and ganglion cells. In two of these animals also an increased negative SP was present. Static otolith reflexes were found to be normal in all hydropic ears despite severe lesions of the saccule in some of these. Abnormal canal reflexes measured by electronystagmography and cupulometry were established in animals with hydrops of the semicircular canals and in one animal with a fistula of the saccule.

The results of studies of the vestibular function and spatial perception function in crewmembers of long-term (96- and 140-day) space missions aboard Salyut-6 are presented. Similar changes and individual variations are revealed. All the cosmonauts have shown the following changes: increased reactivity of the otolith organ, decreased sensitivity of the cupular system, asymmetry of most parameters studied, and illusory reactions inflight, individual reactions are as follows: level of changes, dynamics and time of recovery, development of vestibulo-vegetative symptomocomplex during early adaptation to zero-g, signs of decline in vestibulo-vegetative tolerance postflight, and changes in reciprocal relations between the otolith organ and semicircular canals.

Brainstem neurons projecting to the anterior, lateral and posterior semicircular canal ampullae (vestibular efferent neurons) were identified in guinea pigs using retrograde labelling with fluorescent primuline. Two bilateral groups of such neurons located dorsally and ventrally of the facial nerve trajectory were found.

A differential equation is proposed for describing how the brain compromises between a sensation of rotation about a particular axis (derived from the semicircular canals) and a sensation of gravity perpendicular to this axis (derived from the otolith organs). It is shown that this differential equation, with suitably chosen and reasonable values of the parameters and initial conditions, will satisfactorily explain the experimental results of Lansberg, Guedry, and Graybiel (7).

The influence of the efferent vestibular system being eliminated, the spontaneous activity of single afferent fibres of the ampullary nerves of the horizontal and vertical anterior semicircular canals was recorded in the frog. By stimulating electrically the nerves of the vertical posterior canal, lagena or saccule as well as by sectioning these nerves and then using statistical methods, it is shown that the receptor-receptor fibres arising from the above mentioned receptors have generally an inhibitory influence on the afferent activity from the horizontal and vertical anterior canals.