Nondeterministic nature of sensorineural outcomes following noise trauma.

Over 1.1 billion individuals are at risk for noise induced hearing loss yet there is no accepted therapy. A long history of research has demonstrated that excessive noise exposure will kill outer hair cells (OHCs). Such observations have fueled the notion that dead OHCs underlie hearing loss. Therefore, previous and current therapeutic approaches are based on preventing the loss of OHCs. However, the relationship between OHC loss and hearing loss is at best a modest correlation. This suggests that in addition to the death of OHCs, other mechanisms may regulate the type and degree of hearing loss. In the current study, we tested the hypothesis that permanent noise-induced-hearing loss is consequent to additional mechanisms beyond the noise dose and the death of OHCs. Hooded male rats were randomly divided into noise and control groups. Morphological and physiological assessments were conducted on both groups. The combined results suggest that beyond OHC loss, the surviving cochlear elements shape sensorineural outcomes, which can be nondeterministic. These findings provide the basis for individualized ototherapeutics that manipulate surviving cellular elements in order to bias cochlear function towards normal hearing even in the presence of dead OHCs.

[Effect of melatonin on expression of Prestin protein in the inner ear of mice following radiotherapy].

Objective: To investigate the effect of melatonin on the expression of prestin protein in the inner ear of mice following a single dose radiation therapy, so as to provide the basis for the mechanism study of radiation induced inner ear injury and its prevention. Methods: Sixty 4-week-old male mice were randomly divided into six groups, including the control group (A group), 50 mg/kg MLT group (B group), 5 mg/kg MLT group (C group), 50 mg/kg MLT + radiotherapy group (D group), 5 mg/kg MLT+ radiotherapy group (E group), and 16 Gy radiotherapy group (F group). Each experimental group was randomly subdivided into two subgroups, which were killed to harvest the cochlea on the 3rd and 7th days following 16 Gy radiation. The specimens were used for immunostaining and Western blot to detect the expression of prestin protein. SPSS 19.0 software was used for statistical analysis. Results: Prestin protein mainly distributed in the lateral membrane above the outer hair cell nucleus. When compared with A, B and C group, the expression of prestin protein in the inner ear was significantly up-regulated in F group (P<0.05). However, D and E group reduced the abnormal expression of prestin following radiotherapy when compared with F group, the difference was statistically significant (P<0.05), and the effect of D group was more significant than E group (P<0.05). Conclusions: The prestin protein of cochlea is mainly distributed in the lateral membrane above the outer hair cell nucleus. Following the high-dose radiotherapy, the prestin expression is upregulated, and melatonin can control the abnormal expression of prestin protein induced by radiotherapy with dose dependent.

Severe hearing loss and outer hair cell death in homozygous Foxo3 knockout mice after moderate noise exposure.

Noise induced hearing loss (NIHL) is a disease that affects millions of Americans. Identifying genetic pathways that influence recovery from noise exposure is an important step forward in understanding NIHL. The transcription factor Foxo3 integrates the cellular response to oxidative stress and plays a role in extending lifespan in many organisms, including humans. Here we show that Foxo3 is required for auditory function after noise exposure in a mouse model system, measured by ABR. Absent Foxo3, outer hair cells are lost throughout the middle and higher frequencies. SEM reveals persistent damage to some surviving outer hair cell stereocilia. However, DPOAE analysis reveals that some function is preserved in low frequency outer hair cells, despite concomitant profound hearing loss. Inner hair cells, auditory synapses and spiral ganglion neurons are all present after noise exposure in the Foxo3KO/KO fourteen days post noise (DPN). We also report anti-Foxo3 immunofluorescence in adult human outer hair cells. Taken together, these data implicate Foxo3 and its transcriptional targets in outer hair cell survival after noise damage. An additional role for Foxo3 in preserving hearing is likely, as low frequency auditory function is absent in noise exposed Foxo3KO/KOs even though all cells and structures are present.

Effects of Intratympanic Dexamethasone on High-Dose Radiation Ototoxicity In Vivo.

BACKGROUND: Stereotactic radiosurgery for lateral skull base tumors can cause hearing loss when the cochleae are exposed to high doses of single-fraction radiation. Currently, there are no known nondosimetric preventative treatments for radiation-induced ototoxicity. HYPOTHESIS: Intratympanic (IT) dexamethasone (DXM), a synthetic steroid, protects against radiation-induced auditory hair cell (HC) and hearing losses in rats in vivo. METHODS: Seven rats received radiation (12 Gy) to both cochleae. In irradiated rats and six nonirradiated rats, IT DXM was randomized to one ear, while tympanic puncture without DXM was performed on the contralateral ear. Baseline and 4-week postradiation auditory-evoked potential tests were performed. The cochleae were processed for HC viability. RESULTS: Cochleae exposed to radiation demonstrated more outer HC (OHC) loss in all turns than nonirradiated ears (p <0.05). OHCs were more susceptible to radiation injury than inner HCs in the middle and basal turns (p <0.05). In irradiated cochleae, there was a nonsignificant trend for less OHC loss with IT DXM in the basal turn when compared with placebo. IT DXM did not improve radiation-induced hearing threshold shifts; however, a high rate of tympanic membrane perforations occurred with irradiated ears which may contribute to this finding. CONCLUSION: Radiation induced loss of OHCs in all turns of the cochlea. IT DXM reduced OHC loss in the basal turn of irradiated ears; however, this finding did not achieve statistical significance. Although IT DXM did not affect radiation-induced hearing threshold shifts in adult rats in vivo, this may be due to a high rate of tympanic membrane perforations.

[The study on the targets of the optical evoked auditory brainstem response on the cochlea of guinea pig stimulating by infrared laser].

Objective: To identify the targets of the infrared laser stimulating on the cochlea of guinea pig which evoked auditory brainstem response (oABR), and explore the mechanisms of the infrared neurostimulation. Methods: A polished optical fiber with 200 µm diameter (NA=0.22) was planted into the scala tympani of guinea pigs to stimulate the cochlea of both the normal hearing and acute deafened guinea pigs. The direction of the fiber distal was changed to radiate different regions of the scala tympani, recording the oABR respectively. Differences of energy thresholds and amplitudes of oABR between normal hearing and acute deafened animals was concerned, and different responses were recorded as the optical path of laser fiber being changed to investigate the targets of the infrared laser stimulation. Immunofluorescence was used to detect the changes of inner and outer hair cells, and spiral ganglion neurons 7 days post-deafening, to looking for the probable association with the oABR changes at the same stimulus. SPSS 18.0 software was used to analyze the data. Results: Inner and outer hair cells were damaged in basal and middle turn, butresidual hair cells were observed in apical turn.Only when the optical fiber pointed to Rosenthal's canal stimulated the spiral ganglion region directly could the oABR be evoked. No response was recorded while the fiber pointed to other directions. Conclusion: Infrared laser stimulates cochlea evoked oABR generats from the response of spiral ganglion directly, the spiral ganglion neurons are the target of infrared stimulation.

Methylprednisolone use during radiotherapy extenuates hearing loss in patients with nasopharyngeal carcinoma.

OBJECTIVES/HYPOTHESIS: To investigate the hearing protective effects of methylprednisolone use during radiotherapy in patients with nasopharyngeal carcinoma. STUDY DESIGN: Prospective, controlled clinical study. METHODS: Fifty-three patients with nasopharyngeal carcinoma (106 ears). Twenty-five patients (50 ears) received radiotherapy with intravenous methylprednisolone for 14 days, and another 28 patients (56 ears) received radiotherapy alone. Pure tone audiometry, distortion product otoacoustic emission (DPOAE), and auditory brainstem responses (ABR) results were reviewed before and 1 year after radiotherapy. RESULT: One year after radiotherapy, the air-and-bone conduction pure tone hearing thresholds increased, and the DPOAE levels decreased in the control group. There was no difference in the ABR wave I, III, and V latencies and the I to V interwave latencies before and 1 year after radiotherapy. The pure tone air conduction thresholds decreased, and the DPOAE levels increased in the treatment group compared with the control group. CONCLUSION: Early sensorineural hearing loss after radiotherapy primarily affected the outer hair cells. The use of methylprednisolone during radiotherapy can extenuate early sensorineural hearing loss caused by irradiation.

Low-level laser therapy for prevention of noise-induced hearing loss in rats.

Noninvasive low-level laser therapy (LLLT) is neuroprotective, but the mechanism of this effect is not fully understood. In this study, the use of LLLT as a novel treatment for noise-induced hearing loss (NIHL) is investigated. Sprague-Dawley rats were exposed to intense noise and their right ears were irradiated with an 808nm diode laser at an output power density of 110 or 165mW/cm(2) for a 30min period for 5 consecutive days. Measurement of the auditory brainstem response revealed an accelerated recovery of auditory function in the groups treated with LLLT compared with the non-treatment group at days 2, 4, 7 and 14 after noise exposure. Morphological observations also revealed a significantly higher outer hair cell survival rate in the LLLT groups. Immunohistochemical analyses for inducible nitric oxide synthase (iNOS) and cleaved caspase-3 were used to examine oxidative stress and apoptosis. Strong immunoreactivities were observed in the inner ear tissues of the non-treatment group, whereas these signals were decreased in the LLLT group at 165mW/cm(2) power density. Our findings suggest that LLLT has cytoprotective effects against NIHL via the inhibition of iNOS expression and apoptosis.

Light-induced vibration in the hearing organ.

The exceptional sensitivity of mammalian hearing organs is attributed to an active process, where force produced by sensory cells boost sound-induced vibrations, making soft sounds audible. This process is thought to be local, with each section of the hearing organ capable of amplifying sound-evoked movement, and nearly instantaneous, since amplification can work for sounds at frequencies up to 100 kHz in some species. To test these fundamental precepts, we developed a method for focally stimulating the living hearing organ with light. Light pulses caused intense and highly damped mechanical responses followed by traveling waves that developed with considerable delay. The delayed response was identical to movements evoked by click-like sounds. This shows that the active process is neither local nor instantaneous, but requires mechanical waves traveling from the cochlear base toward its apex. A physiologically-based mathematical model shows that such waves engage the active process, enhancing hearing sensitivity.

Localization of prestin and expression in the early period after radiation in mice.

This study aimed to examine expression and microstructural distribution of prestin in outer hair cells, and the effect of dose and time of radiation on prestin expression in the BALB/c mouse. We also investigated the molecular biological characteristics of prestin and possible mechanisms of sensorineural hearing loss caused by radiation. Seventy 4-week-old mice were randomly divided into four groups, including one control group and three experimental groups. Each experimental group was randomly divided into two groups, which were killed to collect specimens of the cochlea on the 3rd and 7th days after exposure to different doses of 8, 12, and 16 Gy radiation. These cochleas were embedded in paraffin, and then cut into sections. The sections were immunostained with anti-prestin antibodies. The distribution of prestin was observed under optical microscopy and the density of prestin-positive expression was quantitatively calculated by Image-Pro Plus. Prestin had high expression in the lateral membrane and low expression in the cytoplasm of outer hair cells above the nucleus. The density of prestin protein expression of the basal turn was not significantly different after exposure to the different doses of radiation compared with the control group, but up-regulation occurred after radiation in the apex turn. We conclude that prestin protein is mainly expressed in the lateral membrane above the nucleus. Prestin protein may be responsible for the mechanism of injury to the inner ear caused by radiation.

Low frequency electromagnetic radiation and hearing.

OBJECTIVE: To analyse the possible impact of low and extremely low frequency electromagnetic fields on the outer hairs cells of the organ of Corti, in a guinea pig model. MATERIALS AND METHODS: Electromagnetic fields of 50, 500, 1000, 2000, 4000 and 5000 Hz frequencies and 1.5 microT intensity were generated using a transverse electromagnetic wave guide. Guinea pigs of both sexes, weighing 100-150 g, were used, with no abnormalities on general and otic examination. Total exposure times were: 360 hours for 50, 500 and 1000 Hz; 3300 hours for 2000 Hz; 4820 hours for 4000 Hz; and 6420 hours for 5000 Hz. One control animal was used in each frequency group. The parameters measured by electric response audiometer included: hearing level; waves I-IV latencies; wave I-III interpeak latency; and percentage appearance of waves I-III at 90 and 50 dB sound pressure level intensity. RESULTS: Values for the above parameters did not differ significantly, comparing the control animal and the rest of each group. In addition, no significant differences were found between our findings and those of previous studies of normal guinea pigs. CONCLUSION: Prolonged exposure to electromagnetic fields of 50 Hz to 5 KHz frequencies and 1.5 microT intensity, produced no functional or morphological alteration in the outer hair cells of the guinea pig organ of Corti.

No effects of UMTS exposure on the function of rat outer hair cells.

UMTS communication devices are becoming common in everyday use. This could raise public concern about their possible detrimental effects on human health. The aim of this study, in the framework of the EMF nEAR Project, was to evaluate possible influence of UMTS electromagnetic fields (EMF) exposure on cochlear outer hair cells' (OHCs) functionality in laboratory animals. Forty-eight male Sprague-Dawley rats were locally exposed (right ear) or sham-exposed to a controlled UMTS EMF, frequency of 1946 MHz, at SAR level of 10 W/kg, 2 h a day, 5 days a week, for 4 weeks. A group of 12 rats treated with kanamycin (KM) was also included as positive control. Rats were tested by recording Distortion Product Otaoacoustic Emissions (DPOAEs), a non-invasive test capable of assessing the status of the OHCs in the inner ear. DPOAEs were performed before, during (one or three times a week) and after (1-week) exposure to the EMF. The analysis of the data shows that no statistically significant differences were found between the audiological signals recorded from the different experimental groups. The ototoxic effect of KM has been confirmed.

Fast cholinergic efferent inhibition in guinea pig outer hair cells.

Hair cells of inner ear are suggested to be inhibited by the activation of the alpha9-containing nicotinic acetylcholine (ACh) receptors (alpha9-containing nAChRs). Several studies have suggested that the native nicotinic-like ACh receptors (nAChRs) in hair cells display a significant permeability of Ca(2+) ions and unusual pharmacological properties. The activation of native nAChRs will initiate the hyperpolarization of hair cells by activation of the small conductance, Ca(2+)-activated K(+) channels (SK). In this work, the properties of the ACh-sensitive potassium current (IK(ACh)) in outer hair cells (OHCs) of guinea pigs were investigated by employing whole-cell patch-clamp. Followed by perfusion of ACh, OHCs displayed a rapid desensitized current with an N-shaped current-voltage curve (I-V) and a reversal potential of - 66 +/- 7 mV. The IK(ACh) was still present during perfusion of either iberiotoxin (IBTX, 200 nM) or TEA (5 mM) but was potently inhibited by apamin (1 muM), TEA (30 mM). The IK(ACh) demonstrated a strong sensitivity to alpha-bungarotoxin (alpha-BgTx), bicuculline and strychnine. These results suggested that OHCs display the well-known SK current, which might be gated by the alpha9-containing nAChRs. Two important changes were present after lowering the Ca(2+) concentration in the external conditions from 2 mM to 0.2 mM: one was a flattened N-shape I-V relationship with a maximum shifted toward hyperpolarized potentials from -20 approximately -30 mV approximately -40 to -50 mV, the other was a significant reduction in the agonist maximal response (percentage of maximal response 10.5 +/- 5.4). These results indicated that native nAChRs are both permeable to and modulated by extracellular Ca(2+) ions. Taken together, this work provides direct evidences that SK channels in OHCs of guinea pigs are gated by alpha9-containing nAChRs, which play an important role in the fast cholinergic efferent inhibition. This fast inhibition is both potently dependent on the permeability of Ca(2+) ions through the native nAChRs and modulated by Ca(2+) ions.

[Electromechanical transduction: influence of the outer hair cells on the motion of the organ of Corti]. / Elektromechanische Transduktion: Einfluss der äusseren Haarsinneszellen auf das Bewegungsmuster des Corti-Organs.

BACKGROUND: The somatic electromotility of the outer hair cells can be induced by an extracellular electrical field. This enables us to investigate the electromechanically induced motion of the organ of Corti. METHODS: The electrically induced motion of the guinea-pig organ of Corti was measured with a laser Doppler vibrometer in three cochlear turns at ten radial positions on the reticular lamina (RL) and six on each of the upper and lower surfaces of the tectorial membrane (TM). RESULTS AND CONCLUSIONS: We found a complex vibration pattern of the RL and TM, leading to a stimulus synchronous modulation of the depth of the subtectorial space in the region of the inner hair cells (IHCs). This modulation causes radial fluid motion inside the space up to at least 3 kHz. This motion is capable of deflecting the IHC stereocilia and provides an amplification mechanism additional to that associated with basilar-membrane motion.

Depolarization of cochlear outer hair cells evokes active hair bundle motion by two mechanisms.

There is current debate about the origin of mechanical amplification whereby outer hair cells generate force to augment the sensitivity and frequency selectivity of the mammalian cochlea. To distinguish contributions to force production from the mechanotransducer (MET) channels and somatic motility, we have measured hair bundle motion during depolarization of individual outer hair cells in isolated rat cochleas. Depolarization evoked rapid positive bundle deflections that were reduced by perfusion with the MET channel blocker dihydrostreptomycin, with no effect on the nonlinear capacitance that is a manifestation of prestin-driven somatic motility. However, the movements were also diminished by Na salicylate and depended on the intracellular anion, properties implying involvement of the prestin motor. Furthermore, depolarization of one outer hair cell caused motion of neighboring hair bundles, indicating overall motion of the reticular lamina. Depolarization of solitary outer hair cells caused cell-length changes whose voltage-activation range depended on the intracellular anion but were insensitive to dihydrostreptomycin. These results imply that both the MET channels and the somatic motor participate in hair bundle motion evoked by depolarization. It is conceivable that the two processes can interact, a signal from the MET channels being capable of modulating the activity of the prestin motor.

Effectiveness, active energy produced by molecular motors, and nonlinear capacitance of the cochlear outer hair cell.

Cochlear outer hair cells are crucial for active hearing. These cells have a unique form of motility, named electromotility, whose main features are the cell's length changes, active force production, and nonlinear capacitance. The molecular motor, prestin, that drives outer hair cell electromotility has recently been identified. We reveal relationships between the active energy produced by the outer hair cell molecular motors, motor effectiveness, and the capacitive properties of the cell membrane. We quantitatively characterize these relationships by introducing three characteristics: effective capacitance, zero-strain capacitance, and zero-resultant capacitance. We show that zero-strain capacitance is smaller than zero-resultant capacitance, and that the effective capacitance is between the two. It was also found that the differences between the introduced capacitive characteristics can be expressed in terms of the active energy produced by the cell's molecular motors. The effectiveness of the cell and its molecular motors is introduced as the ratio of the motors'active energy to the energy of the externally applied electric field. It is shown that the effectiveness is proportional to the difference between zero-strain and zero-resultant capacitance. We analyze the cell and motor's effectiveness within a broad range of cellular parameters and estimate it to be within a range of 12%-30%.

Investigation of potential effects of cellular phones on human auditory function by means of distortion product otoacoustic emissions.

Outer hair cells (OHC) are thought to act like piezoelectric transducers that amplify low sounds and hence enable the ear's exquisite sensitivity. Distortion product otoacoustic emissions (DPOAE) reflect OHC function. The present study investigated potential effects of electromagnetic fields (EMF) of GSM (Global System for Mobile Communication) cellular phones on OHCs by means of DPOAEs. DPOAE measurements were performed during exposure, i.e., between consecutive GSM signal pulses, and during sham exposure (no EMF) in 28 normally hearing subjects at tone frequencies around 4 kHz. For a reliable DPOAE measurement, a 900-MHz GSM-like signal was used where transmission pause was increased from 4.034 ms (GSM standard) to 24.204 ms. Peak transmitter power was set to 20 W, corresponding to a specific absorption rate (SAR) of 0.1 W/kg. No significant change in the DPOAE level in response to the EMF exposure was found. However, when undesired side effects on DPOAEs were compensated, in some subjects an extremely small EMF-exposure-correlated change in the DPOAE level (< 1 dB) was observed. In view of the very large dynamic range of hearing in humans (120 dB), it is suggested that this observation is physiologically irrelevant.

Evidence of piezoelectric resonance in isolated outer hair cells.

Our results demonstrate high-frequency electrical resonances in outer hair cells (OHCs) exhibiting features analogous to classical piezoelectric transducers. The fundamental (first) resonance frequency averaged f(n) approximately 13 kHz (Q approximately 1.7). Higher-order resonances were also observed. To obtain these results, OHCs were positioned in a custom microchamber and subjected to stimulating electric fields along the axis of the cell (1-100 kHz, 4-16 mV/80 microm). Electrodes embedded in the side walls of the microchamber were used in a voltage-divider configuration to estimate the electrical admittance of the top portion of the cell-loaded chamber (containing the electromotile lateral wall) relative to the lower portion (containing the basal plasma membrane). This ratio exhibited resonance-like electrical tuning. Resonance was also detected independently using a secondary 1-MHz radio-frequency interrogation signal applied transversely across the cell diameter. The radio-frequency interrogation revealed changes in the transverse electric impedance modulated by the axial stimulus. Modulation of the transverse electric impedance was particularly pronounced near the resonant frequencies. OHCs used in our study were isolated from the apical region of the guinea pig cochlea, a region that responds exclusively to low-frequency acoustic stimuli. In this sense, electrical resonances we observed in vitro were at least an order of magnitude higher (ultrasonic) than the best physiological frequency of the same OHCs under acoustic stimuli in vivo. These resonance data further support the piezoelectric theory of OHC function, and implicate piezoelectricity in the broad-band electromechanical behavior of OHCs underlying mammalian cochlear function.

Is cochlear outer hair cell function affected by mobile telephone radiation?

Mobile telephones emit high-frequency pulsed electromagnetic fields (PEMF). These are known to have measurable biological effects, and possible effects on the auditory system. Otoacoustic emissions give an indication of the functional state of the auditory system. Otoacoustics are known to be highly specific for the individual when the test pulse is identical. In this way, subtle changes in the ear can be detected. We investigated whether there is a measurable effect on Otoacoustic emissions from PEMF radiation. A total of 12 volunteers were recruited who had normal hearing; confirmed by pure tone audiometry. An Otoacoustic emission trace was obtained. The test subjects were exposed to a mobile telephone that was placed over the test ears mastoid process. The subjects had Otoacoustic emissions measured without the telephone and again on receive and transmit. There was no change in the trace signature during the test. There was no statistically significant change in the trace figures. This would indicate that PEMF from commonly available hand held mobile telephones have no measurable effect on the outer hair cell function during the time of use.

Mouse outer hair cells lacking the alpha9 ACh receptor are motile.

Efferent nerve fibers form chemical synapses at the bases of outer hair cells (OHC), with acetylcholine (ACh) being their principal neurotransmitter. The activation of ACh receptors on OHCs is known to influence cochlear function. These efferent effects exhibit an unusual pharmacology and are generally known to be inhibitory. Recent evidence suggests that an ACh receptor subunit, known as alpha9, plays a dominant role in mediating the olivocochlear neurotransmission to OHCs. In this investigation, we attempt to determine the possible role(s) of the alpha9 subunit in regulating OHC function by examining OHC electromotility and compound action potentials (CAP) in mice carrying a null mutation for the alpha9 gene. Results indicate that cochlear sensitivity, based on CAP thresholds, is similar for homozygous mutant and wild-type mice. Electromotility is also present in OHCs, independent of whether the alpha9 subunit is present or absent.

[Delayed damage of ionizing radiation on the inner ear].

To investigate the feature and mechanism of delayed effect of ionizing radiation on the inner ear, the function and structure of the inner ear of the guinea pigs were observed during 8 month's period after exposure to fractional doses of gamma radiation (2 Gy per day) with a total dose of 60 Gy. Morphological study was performed using light microscopy, transmission and scanning electron microscopy while the function was measured with electrocochleography (ECochG) and electronystagmography (ENG). The results showed that the mean CAP response threshold was 35.67 +/- 6.78 dB before radiation, and 41.17 +/- 7.76 dB, 47.00 +/- 8.82 dB and 71.00 +/- 7.63 dB at 1st day, 3rd month and 8th months after completion of treatment, respectively. No significant change was demonstrated in the auditory responses at the 1st day of radiation (P > 0.05), but there was obvious hearing loss at 3rd and 8th month (P < 0.01). The nystagmus duration induced by ice water (ENG) was 40.00 +/- 5.44 seconds before radiation, 22.71 +/- 7.93 seconds at 8th month after radiation (P < 0.01). Histologic examination at 8th month after radiation revealed atrophy and degeneration of stria vascularis, a reduced number of capillaries, degeneration of endotheliocyte in vessels, outer hair cell and supporting cell of Corti's organ. The percentage of damaged hair cells in basal turn of the cochlea was significantly higher than those of the upper turn. Degeneration of vestibular hair cell was found. It is suggested that radiation from routine radiotherapy doses may result in a delayed impairment of the inner ear. The main mechanism of the radiation damage may be interference of oxygen supply and metabolism of the inner ear by radiation vascular lesion.