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1.  Mastoid cavity dimensions and shape: method of measurement and virtual fitting of implantable devices 
Audiology & neuro-otology  2009;14(5):308-314.
Temporal bone implants can be used to electrically stimulate the auditory nerve, to amplify sound, to deliver drugs to the inner ear and potentially for other future applications. The implants require storage space and access to the middle or inner ears. The most acceptable space is the cavity created by a canal wall up mastoidectomy and commonly access is gained through the facial recess. Detailed knowledge of the available space for implantation and pathways to access the middle and inner ears is necessary for the design of implants and successful implantation. Based on temporal bone CT scans a method for 3D reconstruction of a virtual canal wall up mastoidectomy space is described. Using Amira® software the area to be removed during such surgery is marked on axial CT slices and a 3D model of that space is created. The average volume of 31 reconstructed models is 12.6 cm3 with standard deviation of 3.69 cm3, ranging from 7.97 cm3 to 23.25 cm3. Critical distances were measured directly from the models and their averages were calculated: height 3.69cm, depth 2.43cm, length above the external auditory canal (EAC) 4.45cm and length posterior to EAC 3.16cm. These linear measurements did not correlate well with the computed volumes. The shape of the models was variable to a significant extent making the prediction of successful implantation for a given design based on linear and volumetric measurements unreliable. Hence, to assure successful implantation, preoperative assessment should include virtual fitting of an implant to the intended storage space. The above mentioned 3D models were exported from Amira® to a Solidworks application where virtual fitting was preformed. Our results are compared to other temporal bone implant virtual fitting studies. Virtual fitting has been suggested for other human applications.
PMCID: PMC2712579  PMID: 19372649
Mastoid dimension; mastoid size measurement method; implantable device
2.  Mastoid Cavity Dimensions and Shape: Method of Measurement and Virtual Fitting of Implantable Devices 
Audiology & Neuro-Otology  2009;14(5):308-314.
Temporal bone implants can be used to electrically stimulate the auditory nerve, to amplify sound, to deliver drugs to the inner ear and potentially for other future applications. The implants require storage space and access to the middle or inner ears. The most acceptable space is the cavity created by a canal wall up mastoidectomy. Detailed knowledge of the available space for implantation and pathways to access the middle and inner ears is necessary for the design of implants and successful implantation. Based on temporal bone CT scans a method for three-dimensional reconstruction of a virtual canal wall up mastoidectomy space is described. Using Amira® software the area to be removed during such surgery is marked on axial CT slices, and a three-dimensional model of that space is created. The average volume of 31 reconstructed models is 12.6 cm3 with standard deviation of 3.69 cm3, ranging from 7.97 to 23.25 cm3. Critical distances were measured directly from the model and their averages were calculated: height 3.69 cm, depth 2.43 cm, length above the external auditory canal (EAC) 4.45 cm and length posterior to EAC 3.16 cm. These linear measurements did not correlate well with volume measurements. The shape of the models was variable to a significant extent making the prediction of successful implantation for a given design based on linear and volumetric measurement unreliable. Hence, to assure successful implantation, preoperative assessment should include a virtual fitting of an implant into the intended storage space. The above-mentioned three-dimensional models were exported from Amira to a Solidworks application where virtual fitting was performed. Our results are compared to other temporal bone implant virtual fitting studies. Virtual fitting has been suggested for other human applications.
PMCID: PMC2712579  PMID: 19372649
Mastoid dimension; Mastoid size measurement method; Implantable device
3.  The Benefits of Bimodal Hearing: Effect of Frequency Region and Acoustic Bandwidth 
Audiology & neuro-otology  2014;19(3):151-163.
We examined the effects of acoustic bandwidth on bimodal benefit for speech recognition in adults with a cochlear implant (CI) in one ear and low-frequency acoustic hearing in the contralateral ear. The primary aims were to (1) replicate with a steeper filter roll-off to examine the low-pass bandwidth required to obtain bimodal benefit for speech recognition and expand results to include different signal-to-noise ratios (SNRs) and talker genders, (2) determine whether the bimodal benefit increased with acoustic low-pass bandwidth and (3) determine whether an equivalent bimodal benefit was obtained with acoustic signals of similar low-pass and pass band bandwidth, but different center frequencies. Speech recognition was assessed using words presented in quiet and sentences in noise (+10, +5 and 0 dB SNRs). Acoustic stimuli presented to the nonimplanted ear were filtered into the following bands: <125, 125–250, <250, 250–500, <500, 250–750, <750 Hz and wide-band (full, nonfiltered bandwidth). The primary findings were: (1) the minimum acoustic low-pass bandwidth that produced a significant bimodal benefit was <250 Hz for male talkers in quiet and for female talkers in multitalker babble, but <125 Hz for male talkers in background noise, and the observed bimodal benefit did not vary significantly with SNR; (2) the bimodal benefit increased systematically with acoustic low-pass bandwidth up to <750 Hz for a male talker in quiet and female talkers in noise and up to <500 Hz for male talkers in noise, and (3) a similar bimodal benefit was obtained with low-pass and band-pass-filtered stimuli with different center frequencies (e.g. <250 vs. 250–500 Hz), meaning multiple frequency regions contain useful cues for bimodal benefit. Clinical implications are that (1) all aidable frequencies should be amplified in individuals with bimodal hearing, and (2) verification of audibility at 125Hz is unnecessary unless it is the only aidable frequency.
PMCID: PMC4104148  PMID: 24556850
Bimodal hearing; Bimodal benefit; Cochlear implants; Acoustic bandwidth
4.  Availability of binaural cues for bilateral implant recipients and bimodal listeners with and without preserved hearing in the implanted ear 
Audiology & neuro-otology  2013;19(1):57-71.
The purpose of the current study was to examine the availability of binaural cues for adult, bilateral cochlear implant (CI) patients, bimodal patients and hearing preservation patients using a multiple baseline, observational study design. Speech recognition was assessed using the Bamford-Kowal-Bench Speech-In-Noise (BKB-SIN) test as well as the AzBio sentences [Spahr et al., 2012] presented in a multi-talker babble at +5 dB signal-to-noise ratio (SNR). Test conditions included speech at 0° with noise presented at 0° (S0N0), 90° (S0N90), and 270° (S0N270). Estimates of summation, head shadow (HS), squelch, and spatial release from masking (SRM) were calculated. Though none of the subject groups consistently showed access to binaural cues, the hearing preservation patients exhibited a significant correlation between summation and squelch whereas the bilateral and bimodal participants did not. That is, the two effects associated with binaural hearing—summation and squelch—were positively correlated for only the listeners with bilateral acoustic hearing. This finding provides evidence for the supposition that implant recipients with bilateral acoustic hearing have access to binaural cues which should, in theory, provide greater benefit in noisy listening environments. It is likely, however, that the chosen test environment negatively affected the outcomes. Specifically, the spatially separated noise conditions directed noise toward the mic port of the behind-the-ear (BTE) hearing aid and implant processor. Thus it is possible that in more realistic listening environments for which the diffuse noise is not directed toward the processor/hearing aid mic, hearing preservation patients have binaural hearing cues for improved speech understanding.
PMCID: PMC3932362  PMID: 24356514
5.  Gentamicin concentration gradients in scala tympani perilymph following systemic applications 
Audiology & neuro-otology  2013;18(6):383-391.
In prior studies it was shown that round window membrane (RWM) application of gentamicin produced a robust baso-apical concentration gradient in the perilymph of scala tympani (ST) with peak concentrations in the basal turn of ST. These gradients potentially contribute to the clinical efficacy and safety of intratympanic gentamicin applications for the treatment of Meniere’s disease. The present study aimed to establish the distribution of gentamicin along ST perilymph after systemic applications.
Gentamicin sulfate was applied intravenously in the amounts of 100, 300 and 600 mg/kg/bw over a period of three hours or as a 300 mg/kg/bw subcutaneous bolus injection. Three and five hours after the start of the application perilymph of ST was aspirated from the cochlea apex of the right and left cochlea, respectively. Ten sequential 1 μL-perilymph samples from the apex of each cochlea were quantitatively analyzed using a fluorescence polarization immunoassay.
In contrast to local RWM delivery, systemic application of gentamicin resulted in highest perilymph levels in the apex of the cochlea with decreasing concentrations towards the basal regions of ST. The absolute gentamicin concentrations increased with amount of drug applied and time before sampling.
While the basal-apical gradient measured after local drug applications to the RW niche is likely the result of the direct uptake of drugs into the perilymph of the ST, distribution by diffusion and a very low perilymph flow towards the cochlear apex, computer simulations suggested that the apical-basal gradient observed with these systemic applications can be explained by higher entry rates of gentamicin in the apex compared to the basal turns of the cochlea. It is also possible that gentamicin enters perilymph indirectly from blood via the endolymph. In this case the faster kinetics in apical turns could be due to the smaller cross-sectional area of scala tympani relative to endolymph in the apical turns.
PMCID: PMC3918439  PMID: 24192668
cochlea; drug delivery; gentamicin; inner ear; ototoxicity; perilymph; pharmacokinetics; guinea pig
6.  A Novel Otoferlin Splice-Site Mutation in Siblings with Auditory Neuropathy Spectrum Disorder 
Audiology & neuro-otology  2013;18(6):10.1159/000354978.
We characterize a novel otoferlin (OTOF) mutation discovered in a sibling pair diagnosed with ANSD and investigate auditory nerve function through their cochlear implants. Genetic sequencing revealed a homozygous mutation at the OTOF splice donor site of exon 28 (IVS28+1 G>T) in both siblings. Functional investigation showed that the intronic sequence between exons 28 and 29 was retained in the mutated minigenes that were expressed in 293T cells. Auditory nerve compound action potential recovery functions in the siblings demonstrated different rates of neural recovery, with sibling AN1 showing rapid recovery (1.14 ms) and AN2 showing average recovery (.78 ms) compared to subjects with sensorineural hearing loss (SNHL) (average: adults .71 ms; children .85 ms). Differences in neural recovery were consistent with speech perception differences between the siblings. Genotype information may indicate site of lesion in hearing loss; however, additional, as yet, unknown factors may impact clinical outcomes and must be considered.
PMCID: PMC3877672  PMID: 24135434
7.  Histopathology of the Clarion Cochlear Implant Electrode Positioner in a Human Subject 
Audiology & neuro-otology  2013;18(4):223-227.
A silastic electrode positioner was introduced by the Advanced Bionics Corporation in 1999 and it was designed to achieve a perimodiolar position of the stimulating electrode. The positioner was voluntarily recalled in the United States in July 2002 due to an apparent higher risk of bacterial meningitis in patients in whom the electrode positioner had been placed. A detailed histopathologic study of the positioner in the human has not previously been published. The histopathologic findings in a 74-year old woman who underwent bilateral cochlear implantation using the positioner are presented. Findings including a large track caused by the combined electrode and its positioner with considerable disruption of the basilar membrane and osseous spiral lamina. Although there was a fibrous sheath around the electrode and positioner at the cochleostomy in both ears, this fibrous sheath did not extend deeply into the cochlea except at the apical end of the electrode beyond the positioner. This resulted in a large fluid space around and between the positioner and electrode within the cochlea and presumably in fluid continuity with the CSF space. Possible clinical implications are discussed.
PMCID: PMC4189082  PMID: 23774789
Histopathology; Clarion Cochlear Implant; Positioner; Human
8.  Influence of cochleostomy and cochlear implant insertion on drug gradients following intratympanic application in guinea pigs 
Audiology & neuro-otology  2013;18(5):10.1159/000353534.
Locally-applied drugs can protect residual hearing following cochlear implantation. The influence of cochlear implantation on drug levels in scala tympani (ST) after round window application was investigated in guinea pigs using the marker trimethylphenlyammonium (TMPA) measured in real-time with TMPA-selective microelectrodes. TMPA concentration in the upper basal turn of ST rapidly increased during implantation and then declined due to cerebrospinal fluid entering ST at the cochlear aqueduct and exiting at the cochleostomy. The TMPA increase was found to be caused by the cochleostomy drilling, if the burr tip partially entered ST. TMPA distribution in the second turn was less affected by implantation procedures. These findings show that basal turn drug levels may be changed during implantation and the changes may need to be considered in the interpretation of therapeutic effects of drugs in conjunction with implantation.
PMCID: PMC3872819  PMID: 24008355
Cochleostomy; perforation; cochlear implant; electrode; pharmacokinetics; drug distribution; computational modeling
9.  Preclinical and Clinical Studies of Unrelieved Aural Fullness following Intratympanic Gentamicin Injection in Patients with Intractable Ménière’s Disease 
Audiology & neuro-otology  2013;18(5):297-306.
To clarify whether gentamicin affects vestibular dark cells in guinea pigs and relieves patients of aural fullness with intractable Ménière’s disease following intratympanic administration.
Materials and Methods
Purified gentamicin-Texas Red (GTTR) was injected intratympanically in guinea pigs that were sacrificed at 1, 3, 7, 14 and 28 days. GTTR uptake was examined in hair cells, and transitional cells and dark cells in vestibular end-organs were examined. Specific attention was paid to its distribution in dark cells under confocal microscopy, and the ultrastructure of dark cells using electron microscopy, following intratympanic injection.
Dark cells in the semicircular canals showed weak GTTR uptake at 1, 3, 7, 14 and 28 days after intratympanic injection, with no significant differences at various time points after injection. However, the adjacent transitional cells demonstrated intense GTTR uptake that was retained for at least 28 days. Ultrastructural studies demonstrated negligible characteristics associated with apoptosis or necrosis in these dark cells. The tight junctions between dark cells showed no signs of disruption at 7 or 28 days after injection.
Intratympanic gentamicin has little direct impact on vestibular dark cells.
Clinical Application
A modified low-dose titration intratympanic approach was used in 29 patients with intractable vertigo and the clinical outcomes were followed. Aural fullness following intratympanic gentamicin injection was not relieved based on our subjective scales, demonstrated by no statistically significant difference between preinjection (4.16 ± 3.08) and postinjection (3.58 ± 2.93; p > 0.05) aural fullness scores. Vertigo control was achieved in 88% of patients, with hearing deterioration identified in 16% of patients. Intratympanic gentamicin administration might not lead to relief of aural fullness in patients with intractable vertigo, although it can achieve a high vertigo control rate with some cochleotoxicity.
PMCID: PMC3962045  PMID: 24008307
Gentamicin; Intratympanic injection; Dark cells; Ménière’s disease; Aural fullness
10.  Using Temporal Modulation Sensitivity to Select Stimulation Sites for Processor MAPs in Cochlear Implant Listeners 
Audiology & neuro-otology  2013;18(4):10.1159/000351302.
Previous studies in our laboratory showed that temporal acuity as assessed by modulation detection thresholds (MDTs) varied across activation sites and that this site-to-site variability was subject specific. Using two 10-channel MAPs, the previous experiments showed that processor MAPs that had better across-site mean (ASM) MDTs yielded better speech recognition than MAPs with poorer ASM MDTs tested in the same subject. The current study extends our earlier work on developing more optimal fitting strategies to test the feasibility of using a site-selection approach in the clinical domain. This study examined the hypothesis that revising the clinical speech processor MAP for cochlear implant (CI) recipients by turning off selected sites that have poorer temporal acuity and reallocating frequencies to the remaining electrodes would lead to improved speech recognition. Twelve CI recipients participated in the experiments. We found that site selection procedure based on MDTs in the presence of a masker resulted in improved performance on consonant recognition and recognition of sentences in noise. In contrast, vowel recognition was poorer with the experimental MAP than with the clinical MAP, possibly due to reduced spectral resolution when sites were removed from the experimental MAP. Overall, these results suggest a promising path for improving recipient outcomes using personalized processor-fitting strategies based on a psychophysical measure of temporal acuity.
PMCID: PMC3874548  PMID: 23881208
Cochlear implantation; across-site differences; speech recognition; modulation detection thresholds; personalized processor fitting
11.  Long-Term Speech and Language Outcomes in Prelingually Deaf Children, Adolescents and Young Adults Who Received Cochlear Implants in Childhood 
Audiology & neuro-otology  2013;18(5):289-296.
This study investigated long-term speech and language outcomes in 51 prelingually deaf children, adolescents, and young adults who received cochlear implants (CIs) prior to 7 years of age and used their implants for at least 7 years. Average speech perception scores were similar to those found in prior research with other samples of experienced CI users. Mean language test scores were lower than norm-referenced scores from nationally representative normal-hearing, typically-developing samples, although a majority of the CI users scored within one standard deviation of the normative mean or higher on the Peabody Picture Vocabulary Test, Fourth Edition (63%) and Clinical Evaluation of Language Fundamentals, Fourth Edition (69%). Speech perception scores were negatively associated with a meningitic etiology of hearing loss, older age at implantation, poorer pre-implant unaided pure tone average thresholds, lower family income, and the use of Total Communication. Users of CIs for 15 years or more were more likely to have these characteristics and were more likely to score lower on measures of speech perception compared to users of CIs for 14 years or less. The aggregation of these risk factors in the > 15 years of CI use subgroup accounts for their lower speech perception scores and may stem from more conservative CI candidacy criteria in use at the beginning of pediatric cochlear implantation.
PMCID: PMC3895537  PMID: 23988907
cochlear implant; deafness; language; speech perception; children; prelingual hearing loss
12.  Time-Frequency Analysis of Transient-Evoked Otoacoustic Emissions in Children exposed to Carboplatin Chemotherapy 
Audiology & neuro-otology  2012;18(2):71-82.
The aims of this study were to characterize and quantify time-frequency changes in transient-evoked otoacoustic emissions (TEOAEs) recorded in children diagnosed with retinoblastoma who were receiving carboplatin chemotherapy. A signal processing technique, the wavelet transform (WT), was used to analyze TEOAE waveforms in narrow-band frequency components. Ten children (aged 3–72 months) diagnosed with unilateral or bilateral retinoblastoma were enrolled in the study. TEOAEs were acquired from the children with linear sequences of 70 dB peSPL clicks. After WT analysis, TEOAE energy, latency, and normalized energy in the narrow-band frequency components were compared before and during carboplatin (average dose 1693 mg/m2) chemotherapy treatment. On a group basis, no significant differences (p>0.05) in pre- and post-carboplatin TEOAE energy, latency, or normalized energy were observed. There were decreases in normalized energy on an individual basis in 10/18 ears in the sample. Exposure to carboplatin chemotherapy did not cause significant changes in TEOAE energy, latency, and normalized energy during treatment. However, long-term monitoring of hearing with measurements of TEOAEs is warranted given the risks of delayed hearing loss in some children receiving carboplatin chemotherapy.
PMCID: PMC3777667  PMID: 23147804
Carboplatin; Children; Cochlea; Ototoxicity; TEOAE; Wavelet
13.  Cortical Encoding of Pitch Contour Changes in Cochlear Implant Users: A Mismatch Negativity Study 
Audiology & neuro-otology  2013;18(5):10.1159/000351802.
A better understanding of melodic pitch perception in cochlear implants (CIs) may guide signal processing and/or rehabilitation techniques to improve CI patients' music perception and appreciation. In this study, the mismatch negativity (MMN) in response to infrequent changes in five-tone pitch contours was obtained in CI users and normal hearing (NH) listeners. Melodic contour identification (MCI) was also measured. Results showed that MCI performance was poorer in CI subjects than in NH subjects; The MMNs were missing in all CI subjects for the 1-semitone contours. The MMNs with the 5-semitone contours were observed in a smaller proportion of CI subjects than in NH subjects. Results suggest that encoding of pitch contour changes in CI users appears to be degraded, most likely due to the limited pitch cues provided by the CI and deafness-related compromise of brain substrates.
PMCID: PMC3823678  PMID: 23920129
cochlear implant; music perception; pitch contour; mismatch negativity; electrophysiology
14.  Hypoxia-Inducible Factor and Vascular Endothelial Growth Factor Pathway for the Study of Hypoxia in a New Model of Otitis Media with Effusion 
Audiology & neuro-otology  2012;17(6):349-356.
The hypoxia-inducible factor and vascular endothelial growth factor (HIF-VEGF) pathway in hypoxic conditions of the middle ear due to dysfunction of the eustachian tube is still unknown, but it is considered as one pathogenetic mechanism in otitis media. This study was designed to investigate the possible involvement of the HIF-VEFG pathway in otitis media with effusion induced by dysfunction of the eustachian tube. We adopted a soft palate approach to obstruct the orifice of the eustachian tube to establish otitis media in a rat model. Auditory evoked brainstem response and tympanometry were used as hearing function tests, hypoxia-related factors were examined by reverse transcriptase polymerase chain reaction (RT-PCR). The expression of hypoxia-related proteins was detected by Western blot and immunostaining. The model of otitis media with effusion was successfully induced by cauterizing the orifice of the eustachian tube. RT-PCR showed up-regulation of hypoxia-related factors in cauterized ears. Western blot and immunostaining showed that the expression of hypoxia-related proteins in cauterized ears was increased. Hypoxia-induced vascular proliferation and an increase in permeability may be one pathogenetic mechanism of otitis media due to dysfunction of the eustachian tube.
PMCID: PMC3637049  PMID: 22907120
Animal model; Dysfunction; Eustachian tube; Hypoxia-inducible factor-1 α; Vascular endothelial growth factor
15.  Effects of Lower Frequency-to-Electrode Allocations on Speech and Pitch Perception with the Hybrid Short-Electrode Cochlear Implant 
Audiology & neuro-otology  2012;17(6):357-372.
Because some users of a Hybrid short-electrode cochlear implant (CI) lose their low-frequency residual hearing after receiving the CI, we tested whether increasing the CI speech processor frequency allocation range to include lower frequencies improves speech perception in these individuals. A secondary goal was to see if pitch perception changed after experience with the new CI frequency allocation. Three subjects who had lost all residual hearing in the implanted ear were recruited to use an experimental CI frequency allocation with a lower frequency cutoff than their current clinical frequency allocation. Speech and pitch perception results were collected at multiple time points throughout the study. In general, subjects showed little or no improvement for speech recognition with the experimental allocation when the CI was worn with a hearing aid in the contralateral ear. However, all three subjects showed changes in pitch perception that followed the changes in frequency allocations over time, consistent with previous studies showing that pitch perception changes upon provision of a CI.
PMCID: PMC3519932  PMID: 22907151
short-electrode; Hybrid; electro-acoustic stimulation; cochlear implant; pitch; speech perception; plasticity
16.  The Effect of Superior Semicircular Canal Dehiscence on Intracochlear Sound Pressures 
Audiology & neuro-otology  2012;17(5):338-348.
Semicircular canal dehiscence (SCD) is a pathological opening in the bony wall of the inner ear that can result in conductive hearing loss. The hearing loss is variable across patients, and the precise mechanism and source of variability are not fully understood. Simultaneous measurements of basal intracochlear sound pressures in scala vestibuli (SV) and scala tympani (ST) enable quantification of the differential pressure across the cochlear partition, the stimulus that excites the cochlear partition. We used intracochlear sound pressure measurements in cadaveric preparations to study the effects of SCD size. Sound-induced pressures in SV and ST, as well as stapes velocity and ear-canal pressure were measured simultaneously for various sizes of SCD followed by SCD patching. Our results showed that at low frequencies (<600 Hz), SCD decreased the pressure in both SV and ST, as well as differential pressure, and these effects became more pronounced as dehiscence size was increased. Near 100 Hz, SV decreased about 10 dB for a 0.5 mm dehiscence and 20 dB for a 2 mm dehiscence, while ST decreased about 8 dB for a 0.5 mm dehiscence and 18 dB for a 2mm dehiscence. Differential pressure decreased about 10 dB for a 0.5 mm dehiscence and about 20 dB for a 2 mm dehiscense at 100 Hz. In some ears, for frequencies above 1 kHz, the smallest pinpoint dehiscence had bigger effects on the differential pressure (10 dB decrease) than larger dehiscenses (less than 10 dB decrease), suggesting larger hearing losses in this frequency range. These effects due to SCD were reversible by patching the dehiscence. We also showed that under certain circumstances such as SCD, stapes velocity is not related to how the ear can transduce sound across the cochlear partition because it is not directly related to the differential pressure, emphasizing that certain pathologies cannot be fully assessed by measurements such as stapes velocity.
PMCID: PMC3541532  PMID: 22814034
superior semicircular canal dehiscence; cochlear pressure; SCD; scala vestibuli; scala tympani; cochlea; differential pressure
17.  The Role of Vascular Endothelial Growth Factors and Fibroblast Growth Factors in Angiogenesis during Otitis Media 
Audiology & Neurotology  2011;17(3):148-154.
The middle ear response to otitis media includes transformation and hyperplasia of the mucosal epithelium and subepithelial connective tissue. Significant neovascularization is also noted, which occurs both to support the hypertrophied mucosa and to mediate the increased trafficking of leukocytes. We investigated the role of two known potent angiogenic growth factor families, the fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs), in middle ear mucosal angiogenesis. DNA microarrays were used to evaluate the expression of FGFs and VEGFs, as well as their receptors and unique signaling proteins, in the middle ears of mice undergoing a complete course of acute bacterial otitis media. In addition, a member of each family was introduced to the middle ear submucosal compartment of the normal middle ears of guinea pigs, by a continuous-release osmotic minipump system over 1 week. During the course of bacterial otitis media, a significant regulation of a number of genes important for angiogenesis was identified. Histologic evaluation of middle ear mucosa following micropump infusion of both FGF1 and VEGF-A showed significant angiogenesis at the site of infusion in comparison to control saline infusion. These results support a role for FGFs and VEGFs in the neovascularization of the middle ear mucosa during otitis media, and offer a potential avenue for therapeutic intervention.
PMCID: PMC3238030  PMID: 22104377
Angiogenesis; Otitis media; Fibroblast growth factor; Vascular endothelial growth factor
18.  Psychoacoustic Performance and Music and Speech Perception in Prelingually Deafened Children with Cochlear Implants 
Audiology & Neurotology  2012;17(3):189-197.
The number of pediatric cochlear implant (CI) recipients has increased substantially over the past 10 years, and it has become more important to understand the underlying mechanisms of the variable outcomes in this population. In this study, psychoacoustic measures of spectral-ripple and Schroeder-phase discrimination, the Clinical Assessment of Music Perception, and consonant-nucleus-consonant (CNC) word recognition in quiet and spondee reception threshold (SRT) in noise tests have been presented to 11 prelingually deafened CI users, aged 8–16 years with at least 5 years of CI experience. The children's performance was compared to the previously reported results of postlingually deafened adult CI users. The average spectral-ripple threshold (n = 10) was 2.08 ripples/octave. The average Schroeder-phase discrimination was 67.3% for 50 Hz and 56.5% for 200 Hz (n = 9). The Clinical Assessment of Music Perception test showed that the average complex pitch direction discrimination was 2.98 semitones. The mean melody score was at a chance level, and the mean timbre score was 34.1% correct. The mean CNC word recognition score was 68.6%, and the mean SRT in steady noise was −8.5 dB SNR. The children's spectral-ripple resolution, CNC word recognition, and SRT in noise performances were, within statistical bounds, the same as in a population of postlingually deafened adult CI users. However, Schroeder-phase discrimination and music perception were generally poorer than in the adults. It is possible then that this poorer performance seen in the children might be partly accounted for by the delayed maturation in their temporal processing ability, and because of this, the children's performance may have been driven more by their spectral sensitivity.
PMCID: PMC3375765  PMID: 22398954
Cochlear implant; Prelingual hearing loss; Psychophysics; Music; Speech perception
19.  Effects of computer-assisted speech training on Mandarin-speaking hearing-impaired children 
Audiology & neuro-otology  2007;12(5):307-312.
The present study investigated whether moderate amounts of computer-assisted speech training can improve the speech recognition performance of hearing-impaired children. Ten Mandarin-speaking children (3 hearing aid users and 7 cochlear implant users) participated in the study. Training was conducted at home using a personal computer for one half-hour per day, five days per week, for a period of 10 weeks. Results showed significant improvements in subjects’ vowel, consonant, and tone recognition performance after training. The improved performance was largely retained two months after training was completed. These results suggest that moderate amounts of auditory training, using a computer-based auditory rehabilitation tool with minimal supervision, can be effective in improving the speech performance of hearing-impaired children.
PMCID: PMC3580209  PMID: 17536199
20.  What Is the Site of Origin of Cochleovestibular Schwannomas? 
Audiology & Neurotology  2011;17(2):121-125.
The belief that cochleovestibular schwannomas arise from the glial-Schwann cell junction has repeatedly been quoted in the literature, although there is no published evidence that supports this statement. A systematic evaluation of the nerve of origin and the precise location of cochleovestibular schwannomas using our respective archival temporal bone collections was conducted. Forty tumors were within the internal auditory canal (IAC), while 10 were intralabyrinthine neoplasms. Of the 40 IAC schwannomas, 4 arose from the cochlear nerve, and 36 from the vestibular nerve. Twenty-one tumors clearly arose lateral to the glial-Schwann cell junction, while 16 tumors filled at least two thirds of the IAC, with the epicenter of the neoplasm located in the mid part or the lateral part of the IAC. Only 3 schwannomas were located in the medial one third of the IAC in the area of the glial-Schwann cell junction. We concluded that cochleovestibular schwannomas may arise anywhere along the course of the axons of the eighth cranial nerve from the glial-Schwann sheath junction up until their terminations within the auditory and vestibular end organs.
PMCID: PMC3221249  PMID: 21968195
Vestibular schwannoma; Histopathology, temporal bone; Origin; Obersteiner-Redlich zone; Glial-Schwann cell transition zone
21.  The Benefits of Combining Acoustic and Electric Stimulation for the Recognition of Speech, Voice and Melodies 
Audiology & neuro-otology  2007;13(2):105-112.
Fifteen patients fit with a cochlear implant in one ear and a hearing aid in the other ear were presented with tests of speech and melody recognition and voice discrimination under conditions of electric (E) stimulation, acoustic (A) stimulation and combined electric and acoustic stimulation (EAS). When acoustic information was added to electrically stimulated information performance increased by 17–23 percentage points on tests of word and sentence recognition in quiet and sentence recognition in noise. On average, the EAS patients achieved higher scores on CNC words than patients fit with a unilateral cochlear implant. While the best EAS patients did not outperform the best patients fit with a unilateral cochlear implant, proportionally more EAS patients achieved very high scores on tests of speech recognition than unilateral cochlear implant patients.
PMCID: PMC3559130  PMID: 18057874
Cochlear implant; Low-frequency hearing; Electric and acoustic stimulation
22.  Interaural Stacked Auditory Brainstem Response Measures for Detecting Small Unilateral Acoustic Tumors 
Audiology & Neurotology  2011;17(1):54-68.
The Stacked auditory brainstem response (SABR) was developed and investigated as a screening tool for small (≤1 cm) unilateral acoustic tumors (vestibular schwannomas) that were missed by standard clinical auditory brainstem response (ABR) measures [Don et al.: Am J Otol 1997;18:608–621; Audiol Neurotol 2005;10:274–290]. While the SABR measure provided much greater sensitivity than the standard ABR measures for small tumor detection, we believed that the large intersubject variability of the SABR measure compromised both the sensitivity and specificity of the measure. However, as we demonstrate in this paper, the variability between ears of a given individual is small. Thus, we introduced an interaural SABR (ISABR) amplitude difference measure to improve the sensitivity and specificity of the SABR amplitude measure to detect small unilateral acoustic tumors. Its main advantages are two-fold. First, it is somewhat immune to variables that affect the absolute SABR amplitudes because it is a relative measure. Second, it is better at assessing tumor patients with very large and non-tumor patients with very small absolute SABR amplitudes. We believe that the ISABR is a useful addition to ABR measures aimed at detecting the presence of unilateral acoustic tumors.
PMCID: PMC3169358  PMID: 21829011
Interaural Stacked auditory brainstem responses; Acoustic tumor; Vestibular schwannoma; Derived-band auditory brainstem responses; High-pass masking
23.  Infection-Mediated Vasoactive Peptides Modulate Cochlear Uptake of Fluorescent Gentamicin 
Audiology & Neurotology  2010;16(6):347-358.
Inflammatory mediators released during bacterial infection include vasoactive peptides such as histamine and serotonin, and their serum levels are frequently elevated. These peptides also modulate the vascular permeability of endothelial cells lining the blood-brain and blood-labyrinth barriers (BLB). These peptides may also modulate the permeability of the BLB to ototoxic aminoglycoside antibiotics prescribed to resolve bacterial sepsis. To test this hypothesis, we compared the effect of histamine and serotonin on the cochlear distribution of fluorescently conjugated gentamicin (GTTR) in control animals at 0.5, 1 and 3 h after injection of GTTR. The intensity of GTTR fluorescence was attenuated at 1 h in the histamine group compared to control mice, and more intense 3 h after injection (p < 0.05). In the serotonin group, the intensity of GTTR fluorescence was attenuated at 0.5 and 1 h (p < 0.05) and was increased at 3 h compared to control animals, where GTTR intensities peaked at 1 h and then plateaued or was slightly decreased at 3 h. This biphasic pattern of modulation was statistically significant in the apical turn of the cochlea. No difference in the intensity of GTTR fluorescence was observed in kidney proximal tubules. Systemic increases in serum levels of vasoactive peptides can modulate cochlear uptake of gentamicin, likely via permeability changes in the BLB. Conditions that influence serum levels of vasoactive peptides may potentiate aminoglycoside ototoxicity.
PMCID: PMC3023003  PMID: 21196726
Ototoxicity; Aminoglycosides; Gentamicin; Histamine; Serotonin; Blood-labyrinth barrier
24.  Distribution of Dexamethasone and Preservation of Inner Ear Function following Intratympanic Delivery of a Gel-Based Formulation 
Audiology & Neurotology  2010;16(5):323-335.
Intratympanic (IT) delivery of drugs to the ear is increasingly used for both clinical and research purposes. One limitation of IT delivery is that drugs are rapidly lost from the middle ear by a number of processes, so that prolonged delivery of drug is technically difficult. In the present study, the delivery characteristics of a poloxamer hydrogel formulation containing dexamethasone (dex) were evaluated. The gel is liquid at room temperature, allowing IT injection, but transitions to a gel at body temperature, providing a prolonged residence time in the middle ear. A 50-μl volume of control or dex-containing gel (dex-gel) was injected through the tympanic membrane of guinea pigs. Cochlear function was assessed with cochlear action potential and acoustic emission thresholds measured immediately, 6 or 24 h after IT gel injection. After 6- or 24-hour treatment with dex-gel, perilymph drug gradients along the cochlea were assessed by taking samples sequentially from the apex, and endolymph was sampled from the basal turn. Control gel injections caused small changes in sound field calibrations and functional measures for low-frequency stimuli, consistent with an induced conductive loss. Within 24 h, responses returned to normal. Twenty-four hours after dex-gel injection, low-frequency changes remained as the dex-gel was retained better in the middle ear, but there was no indication of high-frequency loss. While perilymph sample data showed that dex gradients were substantially lower than after single injections of dex solution, quantitative analysis of this result suggests that some dex may have entered the perilymph through the thin bone in the apical region of the cochlea. Endolymph levels of dex remained lower than those in the perilymph. This study confirms that a poloxamer hydrogel-based dex formulation provides an effective method for a prolonged delivery, providing a more uniform distribution of drug in the inner ear.
PMCID: PMC3023000  PMID: 21178339
Cochlea; Perilymph; Round window; Intratympanic drug delivery; Dexamethasone
25.  Factors Associated with Incomplete Insertion of Electrodes in Cochlear Implant Surgery: A Histopathologic Study 
Audiology & Neurotology  2010;16(2):69-81.
Atraumatic and complete insertion of the electrode array is a stated objective of cochlear implant surgery. However, it is known that obstructions within the cochlea such as new bone formation, cochlear otosclerosis, temporal bone fracture, and cochlear anomalies may limit the depth of insertion of the electrode array. In addition, even among patients without obvious clinical or radiographic indicators of obstruction, incomplete insertion may occur. The current study is a histopathologic evaluation of possible sources of resistance to insertion of the electrode array using the temporal bone collection of the Massachusetts Eye and Ear Infirmary.
Forty temporal bones from patients who in life had undergone cochlear implantation were evaluated. Temporal bones were removed at autopsy and fixed and prepared for histologic study by standard techniques. Specimens were then serially sectioned and reconstructed by 2-dimensional methods. Two electrode metrics were determined for each bone: the inserted length (IL: the distance measured from the cochleostomy site to the apical tip of the electrode) and the active electrode length (AEL: the distance between the most basal and most apical electrodes on the electrode array). The ratio of these two metrics (IL/AEL) was used to split the temporal bones into two groups: those with incomplete insertion (n = 27, IL/AEL <1.0) and those with complete insertion (n = 13, IL/AEL ≥1.0). Seven possible histopathologic indicators of resistance to insertion of the electrode due to contact with the basilar membrane, osseous spiral lamina and/or spiral ligament were evaluated by analysis of serial sections from the temporal bones along the course of the electrode tracks.
Obvious obstruction by abnormal intracochlear bone or soft tissue accounted for only 6 (22%) of the 27 partial insertions. Of the remaining 21 bones with incomplete insertions and 13 bones with complete insertions, dissection of the spiral ligament to the lateral cochlear wall was the only histopathologic indicator of insertion resistance identified with significantly higher frequency in the partial-insertion bones than in the complete-insertion bones (p = 0.003). An observed trend for the percentage of complete insertions to decrease with the number of times the electrode penetrated the basilar membrane did not reach significance. In the bones without an obvious obstruction, the most frequently observed indicator of insertion resistance was dissection of the spiral ligament (with no contact of the lateral cochlear wall) identified in 67% (14/21) of partial-insertion bones and in 92% (12/13) of complete-insertion bones.
These results are consistent with the view that (1) electrode contact with cochlear structures resulting in observable trauma to the basilar membrane, osseous spiral lamina and/or spiral ligament does not necessarily impact the likelihood of complete insertion of the electrode array and (2) once contact trauma to the spiral ligament reaches the point of dissection to the cochlear wall, the likelihood of incomplete insertion increases dramatically.
PMCID: PMC2948664  PMID: 20571258
Cochlear implant; Causes of incomplete electrode insertion; Histopathology of the human temporal bone

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