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Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The p.Ile369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue p.Val241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmx1a is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmx1a mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs; however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment.

While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss.

Congenital inner ear malformations affecting both the osseous and membranous labyrinth can have a devastating impact on hearing and language development. With the exception of an enlarged vestibular aqueduct, non-syndromic inner ear malformations are rare, and their underlying molecular biology has thus far remained understudied. To identify molecular factors that might be important in the developing inner ear, we adopted a family-based trio exome sequencing approach in young unrelated subjects with severe inner ear malformations. We identified two previously unreported de novo loss-of-function variants in GREB1L [c.4368G>T;p.(Glu1410fs) and c.982C>T;p.(Arg328*)] in two affected subjects with absent cochleae and eighth cranial nerve malformations. The cochlear aplasia in these affected subjects suggests that a developmental arrest or problem at a very early stage of inner ear development exists, e.g., during the otic pit formation. Craniofacial Greb1l RNA expression peaks in mice during this time frame (E8.5). It also peaks in the developing inner ear during E13-E16, after which it decreases in adulthood. The crucial function of Greb1l in craniofacial development is also evidenced in knockout mice, which develop severe craniofacial abnormalities. In addition, we show that Greb1l -/- zebrafish exhibit a loss of abnormal sensory epithelia innervation. An important role for Greb1l in sensory epithelia innervation development is supported by the eighth cranial nerve deficiencies seen in both affected subjects. In conclusion, we demonstrate that GREB1L is a key player in early inner ear and eighth cranial nerve development. Abnormalities in cochleovestibular anatomy can provide challenges for cochlear implantation. Combining a molecular diagnosis with imaging techniques might aid the development of individually tailored therapeutic interventions in the future.

Background: Distortion product otoacoustic emissions (DPOAEs) and transient-evoked otoacoustic emissions (TEOAEs) are sound waves generated as byproducts of the cochlear amplifier. These are measurable in the auditory canal and represent an objective method for diagnosing functional disorders of the inner ear. Conventional DPOAE and TEOAE methods permit detection of hearing impairment, but with less than desirable accuracy., Objective: By accounting for DPOAE generation mechanisms, the aim is to improve the accuracy of inner-ear diagnosis., Methods: DPOAEs consist of two components, which emerge at different positions along the cochlea and which may cause artifacts due to mutual interference. Here, the two components are separated in the time domain using short stimulus pulses. Optimized stimulus levels facilitate the acquisition of DPOAEs with maximum amplitudes. DPOAE and Békésy audiograms were recorded from 41 subjects in a clinically relevant frequency range of 1.5-6 kHz., Results: The short stimulus pulses allowed artifact-free measurement of DPOAEs. Semilogarithmic input-output functions yielded estimated distortion product thresholds, which were significantly correlated with the subjectively acquired Békésy thresholds. In addition, they allowed detection of hearing impairment from 20 dB HL, with 95% sensitivity and only a 5% false-positive rate. This accuracy was achieved with a measurement time of about 1-2 min per frequency., Conclusion: Compared to conventional DPOAE and TEOAE methods, separation of DPOAE components using short-pulse DPOAEs in combination with optimized stimulus parameters considerably enhances the accuracy of DPOAEs for diagnosing impairment of the cochlear amplifier.

Background: High-intensity noise exposure from impulse and blast noise events often leads to acute hearing loss and may cause irreversible permanent hearing loss as a long-term consequence. Here, a treatment regime was developed to limit permanent damage based on a preclinical animal model of acute noise trauma., Aim: To develop clinical trials for the treatment of acute noise traumas using approved drugs. The otoprotective potential of glucocorticoids applied locally to the inner ear was examined., Materials and Methods: A series of experiments with different impulse noise exposures were performed. Permanent hearing loss and hair cell density were assessed 14 days after exposure. Hearing and hair cell preservation were investigated as a function of the glucocorticoid dose., Results: After impulse noise exposure, local application to the round window of the cochlea of high-dose prednisolone (25 mg/ml) or methylprednisolone (12.5 mg/ml) resulted in a statistically significant reduction in hearing loss compared with the control group., Conclusion: The local application of high doses of the drugs to the round window of the cochlea appears to be an effective treatment for acute noise trauma.

Sensorineural hearing impairment is caused by pathologies within the cochlear portion of the inner ear or the central auditory pathway. Within the last decade, tremendous progress has been made in inner ear biology, thus greatly increasing our understanding of congenital and acquired inner ear pathologies. Moreover, the discovery of hair cell regeneration and the presence of neuronal stem cells in the cochlea has raised hopes of being able to treat the causes of sensorineual hearing impairment in the mid-term future. To do so, the regenerated cells will have to be reinnervated through the peripheral axons of the spiral ganglion neurons (SGNs). So far, most factors with the potential to guide peripheral axons of SGNs have been investigated in the developing cochlea of rodent models but not in humans. Remaining SGNs can already be directly stimulated electrically by cochlear implants, electrode arrays surgically inserted into the cochlea, providing effective treatment for severe cochlear hearing impairment.

Dysfunctions of the inner ear such as hearing impairment due to noise exposure or presbycusis and vertigo are often caused by loss of hair cells in the sensory epithelium. There is still no specific therapy, just technical aids. Options for protecting and regenerating hair cells are explained here. The inhibition of apoptosis via caspases is presently the main target of research. They are involved in damage caused by aminoglycosides, cisplatin, or noise exposure. Bcl-2, growth factors, and oxidative stress are discussed. In regeneration the transdifferentiation of supporting cells to hair cells is explained. This can be achieved with local gene therapy using math1. Approach and media for the application are discussed, while viral vectors such as the adenovector seem the most promising in research.

Hearing impairment is the most common form of human sensory deficit. The most frequent form, sensorineural hearing loss (SNHL), which accounts for approximately 70% of cases, encompasses various pathologies in both the inner ear and the auditory nerve. The individual hearing impairment and its outcome following aiding with hearing devices critically depend on the underlying disorder. Here recent progress in our understanding of the cellular mechanisms of SNHL in genetically engineered mouse models is reviewed. First, insights gained from models for specific defects in cochlear sound amplification and ion homeostasis are discussed followed by a focus on disorders of the inner hair cell synapses (auditory synaptopathy) and the auditory nerve (auditory neuropathy). Both nosological entities have also attracted substantial clinical interest in recent years and share an impaired temporal processing of auditory stimuli. This results in poor speech recognition, often out of proportion to the pure tone threshold. Hearing loss can range from mild variants with exclusive deficits of temporal processing to complete deafness. At least initially, signs of normal outer hair cell function such as evoked otoacoustic emissions can be found. In summary, well-characterized animal models allow us to refine our pathophysiological understanding of SNHL and offer invaluable help in defining toolboxes for investigating the mechanism(s) underlying the SNHL of affected individuals. Together, this will contribute to custom-tailored diagnostics and rehabilitation of SNHL patients.

We investigated whether the expression of glycinergic receptor (GLYR) subunits of gephyrin and of their mRNAs in the medial vestibular nuclei are affected following unilateral labyrinthectomy. Specific radioactive oligonucleotide probes recognizing the sequences encoding alpha1-3 and ss subunits of GLYR and the anchoring protein gephyrin were used to probe sections of vestibular nuclei. Signals in these in situ hybridization experiments were detected with film or by emulsion photography. Animals were killed at various times following the lesion: 5 h, 1, 3, 8, 30 and 60 days. Specific monoclonal GLYR and gephyrin antibodies were also used to determine GLYR and gephyrin immunoreactivity in control and operated rats (5 h, 1, 3 and 8 days post-lesion). In normal animals, several brainstem regions including the lateral, medial, superior and inferior vestibular nuclei contained mRNAs for gephyrin and the alpha1 and beta subunits of GLYR, and expressed the GLYR and gephyrin polypeptides. In unilaterally labyrinthectomized rats, no asymmetry was detected on autoradiographs between the two medial vestibular nuclei with any of the oligonucleotide probes used, or at any time following the lesion. No difference in the immunofluorescence staining was observed between the intact and deafferented medial vestibular nuclei of lesioned animals or between the vestibular nuclei of lesioned and controls rats. Thus, deafferentation of the vestibular nuclei did not affect the expression of gephyrin, of the various GLYR subunits, or of their mRNAs in the deafferented and intact medial vestibular nuclei. It is therefore unlikely that GLYR and gephyrin modulation contribute significantly to the recovery of the resting discharge of the deafferented medial vestibular neurons and consequently to the restoration of a normal posture and eye position.

Eye-head coordination during saccadic gaze shifts normally relies on vestibular information. A vestibulo-saccadic reflex (VSR) is thought to reduce the eye-in-head saccade to account for current head movement, and the vestibulo-ocular reflex (VOR) stabilizes postsaccadic gaze while the head movement is still going on. Acute bilateral loss of vestibular function is known to cause overshoot of gaze saccades and postsaccadic instability. We asked how patients suffering from chronic vestibular loss adapt to this situation. Eye and head movements were recorded from six patients and six normal control subjects. Subjects tracked a random sequence of horizontal target steps, with their heads (1) fixed in primary position, (2) free to move, or (3) preadjusted to different head-to-target offsets (to provoke head movements of different amplitudes). Patients made later and smaller head movements than normals and accepted correspondingly larger eye eccentricities. Targeting accuracy, in terms of the mean of the signed gaze error, was better in patients than in normals. However, unlike in normals, the errors of patients exhibited a large scatter and included many overshoots. These overshoots cannot be attributed to the loss of VSR because they also occurred when the head was not moving and were diminished when large head movements were provoked. Patients' postsaccadic stability was, on average, almost as good as that of normals, but the individual responses again showed a large scatter. Also, there were many cases of inappropriate postsaccadic slow eye movements, e.g., in the absence of concurrent head movements, and correction saccades, e.g., although gaze was already on target. Performance in patients was affected only marginally when large head movements were provoked. Except for the larger lag of the head upon the eye, the temporal coupling of eye and head movements in patients was similar to that in normals. Our findings show that patients with chronic vestibular loss regain the ability to make functionally appropriate gaze saccades. We assume, in line with previous work, three main compensatory mechanisms: a head movement efference copy, an active cervico-ocular reflex (COR), and a preprogrammed backsliding of the eyes. However, the large trial-to-trial variability of targeting accuracy and postsaccadic stability indicates that the saccadic gaze system of patients does not regain the high precision that is observed in normals and which appears to require a vestibular head-in-space signal. Moreover, this variability also permeates their gaze performance in the absence of head movements.

A modified rotatory chair test is reported in which radial acceleration, generated by eccentric displacement of the subject during constant angular velocity, is exploited as a unilateral stimulation to the otolith organs. During constant angular rate rotation, the test subject is displaced laterally on the rotating turntable by 3.5 cm, so that one labyrinth becomes aligned with the rotatory axis while the second - eccentric - labyrinth is solely exposed to the altered gravito-inertial acceleration (GIA). Previously reported results showed that the direction of the response is independent of the direction of turntable rotation, ruling out any canal influence, and indicated that in a normal population the response, measured in one eye, was symmetrical for displacement of the left and right labyrinths. This mode of stimulus thus appears to elicit a unilateral otolith-ocular response (OOR). Examination of this unilateral OOR was extended in the present study; comparative testing with head-tilt to gravity, i.e. involving bilateral stimulation to the otolith organs, was carried out. Movements of both eyes were recorded (by three-dimensional video-oculography), in order to examine response conjugacy. To verify the specificity of the unilateral stimulus, tests were performed with patients who had previously undergone unilateral section of the vestibular nerve as treatment for acoustic neuroma. The eccentric displacement profile (EDP) and head-tilt stimulus each included ten cycles of left-right oscillation in order to permit signal averaging. In the normal subjects (n=12) the torsional component of the OOR proved to be both labyrinth-symmetrical and conjugate, during both bilateral and unilateral otolith stimulation. OOR gain (ocular torsion/GIA tilt) was higher for bilateral than unilateral stimulation. Bilateral OORs, obtained from three of the five unilaterally deafferented patients, proved less symmetrical and conjugate than in the normals. Unilateral OORs in all five patients were characteristically asymmetrical, with little or no response during stimulation of the diseased labyrinth.

This study examined retrospectively the spontaneous recovery of patients with an acute peripheral vestibular deficit in order to determine whether the caloric test response and with it vestibular function improves over time. The caloric bithermal was tested three times on 79 patients who were hospitalised with an acute deficit. The first test was recorded on emergency admission by observing nystagmus beats under the Frenzel glasses. Two to five days later a complete electronystagmus (ENG) examination was performed. A second ENG was performed, on average, 4 months later. 46% of the patients recovered a normal caloric canal paresis value (less than 32%). By comparing the canal paresis values in the first and second ENG an improvement exceeding 30% was demonstrated in 50% of the patients and there was no correlation between the extent of the canal paresis deficit and the amount of recovery. A simultaneous cochlear deficit had no influence on the recovery of vestibular function.

Although lightning injuries are quite common, lightning-induced damage to the middle or inner ear and to the vestibular nerve has been reported in only a very few cases. Two case reports are presented: a 22-year-old woman and a 26-year-old man who experienced lightning injuries to several body parts including the ear. Pathophysiology, diagnostic criteria and treatment are discussed.

Inner ear physiology has largely contributed to clinical progress in otolaryngology within the last decade. The cell biological knowledge of basic properties of outer hair cells and their motility in particular helped to explain the unique sharp frequency dispersion in the cochlea and other mechanisms of hearing. Further important aspects with a clinical impact have been e.g. the description of the cellular mechanism in aminoglycoside ototoxicity, a pathophysiological concept of Ménière's disease and the application of otoacoustic emissions in audiological testing of infants.

An endolymphatic hydrops was induced in the left ear of each of 32 guinea pigs by obliteration of the endolymphatic sac. Both the hydropic ear and the control ear were examined by electrocochleography 1, 2, 4 or 8 months after obliteration of the sac using electrodes on the apex and near the round window. One month after obliteration, the threshold of the compound action potential (AP) and the increase of the AP amplitude with sound pressure level (SPL) were the same as the results recorded from the control ears despite the presence of a histologically confirmed hydrops. In the 2-month group, small AP threshold differences (10-20 dB) were recorded, increasing up to 10-40 dB in the 4- and 8-month groups. In the latter animals we also found a more rapid increase of the AP amplitude with SPL, a finding suggestive of recruitment. In the 1-month group we recorded an enhanced negative SP for 2- and 4 kHz stimuli when the electrode was placed near the apex. The same was recorded for 4-kHz stimuli in the 2-month group. In the 4- and 8-month groups there was a tendency towards a decrease in the negative SP. The SP-AP ratio recorded from the apical position showed the same pattern as the SP amplitude, an increase after 1 month and a tendency to decrease in the following months. Near the round window there was no significant effect of hydrops on the SP amplitude or on the SP-AP ratio. A deviation in the AP-SP wave form was recorded in 69% (22/32) of the guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the effects of blood pressure on the blood flow in the inner ear as compared with other organs in normotensive rats (NR), spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). The cardiac output and the regional blood flow were measured by a radioactive microsphere technique in conscious rats. The haemodynamics of the inner ear and other organs and the effects of a converting-enzyme inhibitor (SA-446) on the regional blood flow were compared among NR, SHR, and RHR, the blood pressure being 107, 152, and 185 mm Hg, respectively. With the exception of the heart, the organ blood flow was lower in SHR than in NR in all organs, including the inner ear. It was also lower in RHR than in SHR. The blood pressure dropped after i.v. injection of SA-446, while the regional blood flow increased. The effect was strongest in RHR, followed by SHR and finally NR.

Correlations were made between the detection thresholds of evoked otoacoustic emissions (EOAEs), subjective click thresholds, and mean audiometric thresholds in 240 normal and hearing-impaired ears. EOAEs have never been observed when subjective click thresholds or mean audiometric thresholds were equal to or greater than 35 dB HL. EOAEs were always found when click thresholds were equal to or lower than 15 dB HL and when mean audiometric thresholds were equal to or lower than 22 dB HL. The incidence of EOAEs decreased and EOAE thresholds increased with increasing click or mean audiometric thresholds.

The influence of sorbitol was studied by recording the microphonic potentials (MP) of 10 guinea-pigs whose internal ears had been noise-damaged immediately before. Neither the rise of MP 10 sec after the start of noise exposure nor the total rise of MP showed any changes after the intraperitoneal injection of 2 ml of a 40% sorbitol solution.

Recent clinical results show that electrical excitation of hearing sensations with implanted electrodes in the inner ear can be successful in suitable deaf persons. A critical literature review shows that some results have been described too vaguely and that there still exist numerous methodical and technical deficiencies. Even with multichannel stimulation, true tonotopical hearing could not be achieved. Periodicity hearing alone is not sufficient for the discrimination of one-syllable words. However, most deaf persons fitted with surgically implanted electrodes judged the new hearing sensations as being agreeable and quite useful. There seem to be no long term harmful effects of these implants upon the state of the acoustic nerve. However there are still a series of basic questions in auditory physiology pending which can only be solved through intensive collaboration of the clinical disciplines involved.

A short introduction to motion sickness is followed by a historical survey of the various theories, with special reference to those concerning the inner ear. The symptomatology and the consequences of the disease are discussed. Prevention and therapy are considered.