Our long term goal is to understand the molecular pathology of otosclerosis and to develop better forms of therapy. Toward this goal, the current study focused on characterizing the molecular factors responsible for the unique biological features of the otic capsule: its minimal rate of remodeling, and lack of healing capacity when fractured. We compared expression levels of 62 genes involved in bone metabolism between the adult murine otic capsule and the tibia and parietal bones; the latter exemplify bones formed by endochondral and intramembranous ossification, respectively. Gene expression levels were measured using real-time quantitative RT-PCR and analyzed using tools of bioinformatics. Expression patterns of key genes were verified with in situ hybridization. The molecular profile of the otic capsule was distinctly different from that of the tibia and parietal bone. Genes found to be most characteristic of the otic capsule were: osteoprotegerin (opg), bone morphogenetic protein receptor 1b (bmpr1b) and bone morphogenetic protein 3 (bmp3). Expression levels were high for opg and bmpr1b, and minimal for bmp3 within the otic capsule. We concluded that opg and bmpr1b likely play important roles in inhibition of remodeling within the otic capsule.
Otic capsule; opg; bmpr1b; otosclerosis
Previous studies of binaural beats have noted individual variability and response lability, but little attention has been paid to the salience of the binaural beat percept. The purpose of this study was to gauge the strength of the binaural beat percept by matching its salience to that of sinusoidal amplitude modulation (SAM), and to then compare rate discrimination for the two types of fluctuation. Rate discrimination was measured for standard rates of 4, 8, 16, and 32 Hz – all in the 500-Hz carrier region. Twelve normal-hearing adults participated in this study. The results indicated that discrimination acuity for binaural beats is similar to that for SAM tones whose depths of modulation have been adjusted to provide equivalent modulation salience. The matched-salience SAM tones had relatively shallow depths of modulation, suggesting that the perceptual strength of binaural beats is relatively weak, although all listeners perceived them. The Weber fraction for detection of an increase in binaural beat rate is roughly constant across beat rates, at least for rates above 4 Hz, as is rate discrimination for SAM tones.
binaural beat; rate discrimination; amplitude modulation
The primary goal of this study was to characterize the variability in auditory-nerve temporal response patterns obtained with the electrically evoked compound action potential (ECAP) within and across a relatively large group of cochlear-implant recipients. ECAPs were recorded in response to each of 21 pulses in a pulse train for five rates (900, 1200, 1800, 2400, and 3500 pps) and three cochlear regions (basal, middle, and apical). An alternating amplitude pattern was typically observed across the pulse train for slower rates, reflecting refractory properties of individual nerve fibers. For faster rates, the alternation ceased and overall amplitudes were substantially lower relative to the first pulse in the train, reflecting cross-fiber desynchronization. The following specific parameters were examined: (1) the rate at which the alternating pattern ceased (termed stochastic rate), (2) the alternation depth and the rate at which the maximum alternation occurred, and (3) the average normalized ECAP amplitude across the pulse train (measure of overall adaptation/desynchronization). Data from 29 ears showed that stochastic rates for the group spanned the entire range of rates tested. The majority of subjects (79%) had different stochastic rates across the three cochlear regions. The stochastic rate occurred most frequently at 2400 pps for basal and middle electrodes, and at 3500 pps for apical electrodes. Stimulus level was significantly correlated with stochastic rate, where higher levels yielded faster stochastic rates. The maximum alternation depth averaged 19% of the amplitude for the first pulse. Maximum alternation occurred most often at 1800 pps for basal and apical electrodes, and at 1200 pps for middle electrodes. These differences suggest some independence between alternation depth and stochastic rate. Finally, the overall amount of adaptation or desynchronization ranged from 63% (for 900 pps) to 23% (for 3500 pps) of the amplitude for the first pulse. Differences in temporal response properties across the cochlea within subjects may have implications for developing new speech-processing strategies that employ varied rates across the array.
cochlear implant; electrically evoked compound action potential; temporal response; stochastic; stimulation rate
Humans and other animals often communicate acoustically in noisy social groups, in which the background noise generated by other individuals can mask signals of interest. When listening to speech in the presence of speech-like noise, humans experience a release from auditory masking when target and masker are spatially separated. We investigated spatial release from masking (SRM) in a free-field call recognition task in Cope’s gray treefrog (Hyla chrysoscelis). In this species, reproduction requires that females successfully detect, recognize, and localize a conspecific male in the noisy social environment of a breeding chorus. Using no-choice phonotaxis assays, we measured females’ signal recognition thresholds in response to a target signal (an advertisement call) in the presence and absence of chorus-shaped noise. Females experienced about 3 dB of masking release, compared with a co-localized condition, when the masker was displaced 90° in azimuth from the target. The magnitude of masking release was independent of the spectral composition of the target (carriers of 1.3 kHz, 2.6 kHz, or both). Our results indicate that frogs experience a modest degree of spatial unmasking when performing a call recognition task in the free-field, and suggest that variation in signal spectral content has small effects on both source identification and spatial unmasking. We discuss these results in the context of spatial unmasking in vertebrates and call recognition in frogs.
A commercially-available laser Doppler-shift velocimeter has been coupled to a compound microscope equipped with ultra-long-working-distance objectives for the purpose of measuring basilar membrane vibrations in the chinchilla. The animal preparation is nearly identical to that used in our laboratory for similar measurements using the Mössbauer technique. The vibrometer head is mounted on the third tube of the microscope’s trinocular head and its laser beam is focused on high-refractive-index glass microbeads (10–30 µm) previously dropped, through the perilymph of Scala tympani, on the basilar membrane. For equal sampling times, overall sensitivity of the laser velocimetry system is at least one order of magnitude greater than usually attained using the Mössbauer technique. However, the most important advantage of laser velocimetry vis-à-vis the Mössbauer technique is its linearity, which permits undistorted recording of signals over a wide velocity range. Thus, for example, we have measured basilar-membrane responses to clicks whose waveforms have dynamic ranges exceeding 60 dB.
Laser Doppler-shift velocimetry; Laser vibrometry; Laser heterodyne interferometry; Basilar membrane; Cochlear mechanics
The effects of low-frequency (50, 100, 200 and 400 Hz) ‘suppressor’ tones on responses to moderate-level characteristic frequency (CF) tones were measured in chinchilla auditory nerve fibers. Two-tone interactions were evident at suppressor intensities of 70–100 dB SPL. In this range, the average response rate decreased as a function of increasing suppressor level and the instantaneous response rate was modulated periodically. At suppression threshold, the phase of suppression typically coincided with basilar membrane displacement toward scala tympani, regardless of CF. At higher suppressor levels, two suppression maxima coexisted, synchronous with peak basilar membrane displacement toward scala tympani and scala vestibuli. Modulation and rate-suppression thresholds did not vary as a function of spontaneous activity and were only minimally correlated with fiber sensitivity. Except for fibers with CF < 1 kHz, modulation and rate-suppression thresholds were lower than rate and phase-locking thresholds for the suppressor tones presented alone. In the case of high-CF fibers with low spontaneous activity, excitation thresholds could exceed suppression thresholds by more than 30 dB. The strength of modulation decreased systematically with increasing suppressor frequency. For a given suppressor frequency, modulation was strongest in high-CF fibers and weakest in low-CF fibers. The present findings strongly support the notion that low-frequency suppression in auditory nerve fibers largely reflects an underlying basilar membrane phenomenon closely related to compressive non-linearity.
Auditory nerve; Biasing; Modulation; Rate suppression; Basilar membrane; Inner hair cells; Cochlea; Chinchilla
Cochlear implant performance in difficult listening situations is limited by channel interactions. It is known that partial tripolar (PTP) stimulation reduces the spread of excitation (SOE). However, the greater the degree of current focusing, the greater the absolute current required to maintain a fixed loudness. As current increases, so does SOE. In experiment 1, the SOE for equally loud stimuli with different degrees of current focusing is measured via a forward-masking procedure. Results suggest that at a fixed loudness, some but not all patients have a reduced SOE with PTP stimulation. Therefore, it seems likely that a PTP speech processing strategy could improve spectral resolution for only those patients with a reduced SOE. In experiment 2, the ability to discriminate different levels of current focusing was measured. In experiment 3, patients subjectively scaled verbal descriptors of stimuli of various levels of current focusing. Both discrimination and scaling of verbal descriptors correlated well with SOE reduction, suggesting that either technique have the potential to be used clinically to quickly predict which patients would receive benefit from a current focusing strategy.
Cochlear Implants; Current Focusing; Spread of Excitation; Monopolar; Tripolar; Psychophysics
The click-evoked auditory brainstem response (ABR) is widely used in clinical settings, partly due to its predictability and high test-retest consistency. More recently, the speech-evoked ABR has been used to evaluate subcortical processing of complex signals, allowing for the objective assessment of biological processes underlying auditory function and auditory processing deficits not revealed by responses to clicks. Test-retest reliability of some components of speech-evoked ABRs has been shown for adults and children over the course of months. However, a systematic study of the consistency of the speech-evoked brainstem response in school-age children has not been conducted. In the present study, speech-evoked ABRs were collected from 26 typically-developing children (ages 8-13) at two time points separated by one year. ABRs were collected for /da/ presented in quiet and in a 6-talker babble background noise. Test-retest consistency of response timing, spectral encoding, and signal-to-noise ratio was assessed. Response timing and spectral encoding were highly replicable over the course of one year. The consistency of response timing and spectral encoding found for the speech-evoked ABRs of typically-developing children suggests that the speech-evoked ABR may be a unique tool for research and clinical assessment of auditory function, particularly with respect to auditory-based communication skills.
electrophysiology; auditory brainstem; speech; children; test-retest reliability
Aminoglycoside antibiotics and cisplatin (CDDP) are the major ototoxins of clinical medicine due to their capacity to cause significant, as well as permanent hearing loss by targeting the mammalian sensory cells. Understanding the pathogenesis of damage is the first step in designing effective prevention of drug-induced hearing loss. In-vitro systems greatly enhance the efficiency of biochemical and molecular investigations through ease of access and manipulation. HEI-OC1, an inner ear cell line derived from the immortomouse, expresses markers for auditory sensory cells and, therefore, is a potential tool to study the ototoxic mechanisms of drugs like aminoglycoside antibiotics and CDDP. HEI-OC1 cells (and also HeLa cells) efficiently take up fluorescently tagged gentamicin and respond to drug treatment with changes in cell death and survival signaling pathways. Within hours, the C-jun N-terminal kinase pathway and the transcription factor AP-1 were activated and at later times, the “executioner caspase”, caspase-3. These responses were robust and elicited by both gentamicin and kanamycin. However, despite the initiation of apoptotic pathways and transient changes in nuclear morphology, cell death was not observed following aminoglycoside treatment, while administration of CDDP lead to significant cell death as determined by flow cytometric measurements; β-galactosidase analysis ruled out senescence in gentamicin-treated cells. The ability to withstand treatment with aminoglycosides but not with CDDP suggests that this cell line might be helpful in providing some insight into the differential actions of the two ototoxic drugs.
HEI-OC1 cell line; aminoglycoside; cisplatin; cell death; caspase-3; jun-kinase; AP-1; NF-κB; endonuclease G
The ability of an implanted ear to integrate multiple pulses, as measured by the slopes of detection threshold level (T level) versus pulse rate functions, may reflect cochlear health in the cochlea, as suggested by previous animal studies (Kang et al., 2010; Pfingst et al., 2011). In the current study, we examined the slopes of T level versus pulse rate functions in human subjects with cochlear implants. Typically, T levels decrease as a function of pulse rate, consistent with a multipulse integration mechanism. The magnitudes of the slopes of the T level versus pulse rate functions obtained from the human subjects were comparable to those reported in the animal studies. The slopes varied across stimulation sites, but did not change systematically along the tonotopic axis. This suggests that the slopes are dependent on local conditions near the individual stimulation sites. The characteristics of these functions were also similar to those found in animals in that the slopes for higher pulse rates were steeper than those for the lower pulse rates, consistent with a combined effect of multipulse integration and cumulative partial depolarization mechanisms at rates above 1000 pps. The maximum comfortable loudness level (C level) versus pulse rate functions were also examined to determine the effect of level on the slopes. Slopes of C-level functions were shallower than those for the T-level functions and were not correlated with those of the T-level functions, so the mechanisms underlying these two functions are probably not identical. The slopes of the T- or C-level functions were not dependent on stimulus-current level. Based on these results, we suggest that slopes of T level versus pulse rate functions might be a useful measure for estimating nerve survival in the cochlea in regions close to the stimulation sites.
cochlear implant; pulse rate; psychophysical detection threshold; maximum comfortable loudness level; across-site variation; human
Sharp spatial selectivity is critical to auditory performance, particularly in pitch related tasks. Most contemporary cochlear implants have employed monopolar stimulation that produces broad electric fields, which presumably contribute to poor pitch and pitch-related performance by implant users. Bipolar or tripolar stimulation can generate focused electric fields but requires higher current to reach threshold and, more interestingly, has not produced any apparent improvement in cochlear implant performance. The present study addressed this dilemma by measuring psychophysical and physiological spatial selectivity with both broad and focused stimulations in the same cohort of subjects. Different current levels were adjusted by systematically measuring loudness growth for each stimulus, each stimulation mode, and in each subject. Both psychophysical and physiological measures showed that, although focused stimulation produced significantly sharper spatial tuning than monopolar stimulation, it could shift the tuning position or even split the tuning tips. The altered tuning with focused stimulation is interpreted as a result of poor electrode-to-neuron interface in the cochlea, and is suggested to be mainly responsible for the lack of consistent improvement in implant performance. A linear model could satisfactorily quantify the psychophysical and physiological data and derive the tuning width. Significant correlation was found between the individual physiological and psychophysical tuning widths, and the correlation was improved by log-linearly transforming the physiological data to predict the psychophysical data. Because the physiological measure took only one-tenth of the time of the psychophysical measure, the present model is of high clinical significance in terms of predicting and improving cochlear implant performance.
Electric hearing; spatial tuning curve; spatial masking curve; electrically-evoked compound action potential (ECAP); electrode configuration; forward masking; loudness; dynamic range
Regrowth of peripheral spiral ganglion neuron (SGN) fibers is a primary objective in efforts to improve cochlear implant outcomes and to potentially reinnervate regenerated hair cells. Cyclic adenosine monophosphate (cAMP) regulates neurite growth and guidance via activation of protein kinase A (PKA) and Exchange Protein directly Activated by Cylic AMP (Epac). Here we explored the effects of cAMP signaling on SGN neurite length in vitro. We find that the cAMP analog, cpt-cAMP, exerts a biphasic effect on neurite length; increasing length at lower concentrations and reducing length at higher concentrations. This biphasic response occurs in cultures plated on laminin, fibronectin, or tenascin C suggesting that it is not substrate dependent. cpt-cAMP also reduces SGN neurite branching. The Epac-specific agonist, 8-pCPT-2’-O-Me-cAMP, does not alter SGN neurite length. Constitutively active PKA isoforms strongly inhibit SGN neurite length similar to higher levels of cAMP. Chronic membrane depolarization activates PKA in SGNs and also inhibits SGN neurite length. However, inhibition of PKA fails to rescue neurite length in depolarized cultures implying that activation of PKA is not necessary for the inhibition of SGN neurite length by chronic depolarization. Expression of constitutively active phosphatidylinositol 3-kinase, but not c-Jun N-terminal kinase, isoforms partially rescues SGN neurite length in the presence of activated PKA. Taken together, these results suggest that activation of cAMP/PKA represents a potential strategy to enhance SGN fiber elongation following deafness; however such therapies will likely require careful titration so as to simultaneously promote rather than inhibit nerve fiber regeneration.
protein kinase A; axon; cyclic adenosine monophosphate; phosphatidylinositol 3-kinase; c-Jun N-terminal kinase
It has been widely believed that drug entry from the middle ear into perilymph occurs primarily via the round window (RW) membrane. Entry into scala vestibuli (SV) was thought to be dominated by local, inter-scala communication between scala tympani (ST) and SV through permeable tissues such as the spiral ligament. In the present study, the distribution of the ionic marker trimethylphenylammonium (TMPA) was compared following intracochlear injections or applications to the RW niche, with or without occlusion of the RW membrane or stapes area. Perilymph TMPA concentrations were monitored either in real time with TMPA-selective microelectrodes sealed into ST and SV, or by the collection of sequential perilymph samples from the lateral semi-circular canal. Local inter-scala communication of TMPA was confirmed by measuring SV and ST concentrations following direct injections into perilymph of ST. Application of TMPA to the RW niche also showed a predominant entry into ST, with distribution to SV presumed to occur secondarily. When the RW membrane was occluded by a silicone plug, RW niche irrigation produced higher concentrations in SV compared to ST, confirming direct TMPA entry into the vestibule in the region of the stapes. The proportion of TMPA entering by the two routes was quantified by perilymph sampling from the lateral semi-circular canal. The TMPA levels of initial samples (originating from the vestibule) were markedly lower when the stapes area was occluded with silicone. These data were interpreted using a simulation program that incorporates all the major fluid and tissue compartments of the cochlea and vestibular systems. From this analysis it was estimated that 65 % of total TMPA entered through the RW membrane and 35% entered the vestibule directly in the vicinity of the stapes. Direct entry of drugs into the vestibule is relevant to inner ear fluid pharmacokinetics and to the growing field of intratympanic drug delivery.
Cochlea; Perilymph; Round Window; Intratympanic drug delivery; TMPA; Trimethylphenylammonium
Inbred strain variants of the Cdh23 gene have been shown to influence the onset and progression of age-related hearing loss (AHL) in mice. In linkage backcrosses, the recessive Cdh23 allele (ahl) of the C57BL/6J strain, when homozygous, confers increased susceptibility to AHL, while the dominant allele (Ahl+) of the CBA/CaJ strain confers resistance. To determine the isolated effects of these alleles on different strain backgrounds, we produced the reciprocal congenic strains B6.CBACa-Cdh23Ahl+and CBACa.B6-Cdh23ahl and tested 15-30 mice from each for hearing loss progression. ABR thresholds for 8 kHz, 16 kHz, and 32 kHz pure-tone stimuli were measured at 3, 6, 9, 12, 15 and 18 months of age and compared with age-matched mice of the C57BL/6J and CBA/CaJ parental strains. Mice of the C57BL/6N strain, which is the source of embryonic stem cells for the large International Knockout Mouse Consortium, were also tested for comparisons with C57BL/6J mice. Mice of the C57BL/6J and C57BL/6N strains exhibited identical hearing loss profiles: their 32 kHz ABR thresholds were significantly higher than those of CBA/CaJ and congenic strain mice by 6 months of age, and their 16 kHz thresholds were significantly higher by 12 months. Thresholds of the CBA/CaJ, the B6.CBACa-Cdh23Ahl+, and the CBACa.B6-Cdh23ahl strain mice differed little from one another and only slightly increased throughout the 18-month test period. Hearing loss, which corresponded well with cochlear hair cell loss, was most profound in the C57BL/6J and C57BL/6NJ strains. These results indicate that the CBA/CaJ-derived Cdh23Ahl+ allele dramatically lessens hearing loss and hair cell death in an otherwise C57BL/6J genetic background, but that the C57BL/6J-derived Cdh23ahl allele has little effect on hearing loss in an otherwise CBA/CaJ background. We conclude that although Cdh23ahl homozygosity is necessary, it is not by itself sufficient to account for the accelerated hearing loss of C57BL/6J mice.
age-related hearing loss; Cdh23; ahl; C57BL/6J; C57BL/6N; CBA/CaJ; inbred mouse strains; congenic mouse strains; cochleograms; ABR thresholds; hair cells
Cochlear implants electrically stimulate residual spiral ganglion neurons (SGNs) to provide auditory cues for the severe-profoundly deaf. However, SGNs gradually degenerate following cochlear hair cell loss, leaving fewer neurons available for stimulation. Providing an exogenous supply of neurotrophins (NTs) has been shown to prevent SGN degeneration, and when combined with chronic intracochlear electrical stimulation (ES) following a short period of deafness (5 days), may also promote the formation of new neurons. The present study assessed the histopathological response of guinea pig cochleae treated with NTs (brain-derived neurotrophic factor and neurotrophin-3) with and without ES over a four week period, initiated two-weeks after deafening. Results were compared to both NT alone and artificial perilymph (AP) treated animals. AP/ES treated animals exhibited no evidence of SGN rescue compared with untreated deafened controls. In contrast, NT administration showed a significant SGN rescue effect in the lower and middle cochlear turns (two-way ANOVA, p < 0.05) compared with AP-treated control animals. ES in combination with NT did not enhance SGN survival compared with NT alone. SGN function was assessed by measuring electrically-evoked auditory brainstem response (EABR) thresholds. EABR thresholds following NT treatment were significantly lower than animals treated with AP (two-way ANOVA, p = 0.033). Finally, the potential for induced neurogenesis following the combined treatment was investigated using a marker of DNA synthesis. However, no evidence of neurogenesis was observed in the SGN population. The results indicate that chronic NT delivery to the cochlea may be beneficial to cochlear implant patients by increasing the number of viable SGNs and decreasing activation thresholds compared to chronic ES alone.
deafness; neurotrophins; electrical stimulation; cochlear implant; spiral ganglion neurons; neurogenesis
The membrane glycoprotein CTL2/SLC44A2 is expressed by supporting cells in the inner ear and has been identified as a target of antibodies that may induce auto-immune hearing loss. To determine if CTL2/SLC44A2 also has roles in inner ear development and to distinguish between isoform-specific roles, we assessed age-related changes in expression of CTL2/SLC44A2 isoforms and protein in the developing murine inner ear. We determined that both isoform p1 and isoform p2 (named for the upstream p1 and proximal p2 promoters that control alternate exons 1a and 1b) were robustly expressed as early as E14 and persisted during embryonic development, but after birth the p1 isoform fell to barely detectable levels while isoform p2 levels were maintained. This trend continued and became even more apparent later in post-natal development and remained in mature ears until at least 6 weeks of age. In aged (18mo old) mice, the level of isoform p1 transcripts rose again to levels similar to the p2 isoform like that seen early in development. At the earliest stage examined, CTL2/SLC44A2 protein was expressed in both immature supporting cells and immature sensory cells, but after birth expression in the sensory cells declined in both the utricle and cochlea and by day P1 expression of CTL2/SLC44A2 was restricted to supporting cells. The changes we observed in isoform distribution are indicative of differential developmental roles and age related changes between the two isoforms of CTL2/SLC44A2 in the inner ear.
Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7 (CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes vestibular dysfunction and hearing loss. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis, and are an excellent model of CHARGE syndrome. Here we characterized Chd7 expression in mature middle and inner ears, analyzed morphological features of mutant ears and tested whether Chd7 mutant mice have altered responses to noise exposure and correlated those responses to inner and middle ear structure. We found that Chd7 is highly expressed in mature inner and outer hair cells, spiral ganglion neurons, vestibular sensory epithelia and middle ear ossicles. There were no obvious defects in individual hair cell morphology by Prestin immunostaining or scanning electron microscopy, and cochlear innervation appeared normal in Chd7Gt/+ mice. Hearing thresholds by auditory brainstem response (ABR) testing were elevated at 4 and 16 kHz in Chd7Gt/+ mice, and there were reduced distortion product otoacoustic emissions (DPOAE). Exposure of Chd7Gt/+ mice to broadband noise resulted in variable degrees of hair cell loss which inversely correlated with severity of stapedial defects. The degrees of hair cell loss and threshold shifts after noise exposure were more severe in wild type mice than in mutants. Together, these data indicate that Chd7Gt/+ mice have combined conductive and sensorineural hearing loss, correlating with changes in both middle and inner ears.
CHARGE syndrome; CHD7; inner ear; cochlea; noise exposure; middle ear
Our understanding of hereditary hearing loss has greatly improved since the discovery of the first human deafness gene. These discoveries have only accelerated due to the great strides in DNA sequencing technology since the completion of the human genome project. Here, we review the immense impact that these developments have had in both deafness research and clinical arenas. We review commonly used genomic technologies as well as the application of these technologies to the genetic diagnosis of hereditary hearing loss and to the discovery of novel deafness genes.
Massively parallel sequencing; next-generation sequencing; genomics; deafness; hearing loss; diagnostics
Recent clinical reports found a high incidence of recurrent otitis media in children suffering hyperacusis, a marked intolerance to an otherwise ordinary environmental sound. However, it is unclear whether the conductive hearing loss caused by otitis media in early age will affect sound tolerance later in life. Thus, we have tested the effects of tympanic membrane (TM) damage at an early age on sound perception development in rats. Two weeks after the TM perforation, more than 80% of the rats showed audiogenic seizure (AGS) when exposed to loud sound (120 dB SPL white noise, < 1 minute). The susceptibility of AGS lasted at least sixteen weeks after the TM damage, even the hearing loss recovered. The TM damaged rats also showed significantly enhanced acoustic startle responses compared to the rats without TM damage. These results suggest that early age conductive hearing loss may cause an impaired sound tolerance during development. In addition, the AGS can be suppressed by the treatment of vigabatrin, acute injections (250 mg/kg) or oral intakes (60 mg/kg/day for 7 days), an antiepileptic drug that inhibits the catabolism of GABA. c-Fos staining showed a strong staining in the inferior colliculus (IC) in the TM damaged rats, not in the control rats, after exposed to loud sound, indicating a hyper-excitability in the IC during AGS. These results indicate that early age conductive hearing loss can impair sound tolerance by reducing GABA inhibition in the IC, which may be related to hyperacusis seen in children with otitis media.
Otitis media; Audiogenic seizure; Acoustic startle reflex; Hyperacusis; Inferior colliculus; GABA
This study is designed to measure the degree to which spiral ganglion cell (SGC) survival in the left and right ears is similar in profoundly hearing-impaired human patients with symmetric (right/left) etiology and sensitivity. This is of interest because a small difference between ears would imply that one ear could be used as a control ear in temporal bone studies evaluating the impact on SGC survival of a medical intervention in the other ear.
Materials and Methods
Forty-two temporal bones from 21 individuals with bilaterally symmetric profound hearing impairment were studied. Both ears in each individual were impaired by the same etiology. Rosenthal’s canal was reconstructed in two dimensions and segmental and total SGCs were counted. Correlation analysis and t-tests were used to compare segmental and total counts of left and right ears. Statistical power calculations illustrate how the results can be used to estimate the effect size (right/left difference in SGC count) that can be reliably identified as a function of sample size.
Left counts (segmental and total) were significantly correlated with those in the right ears (p<0.01) and the coefficients of determination for segments 1 to 4 and total count were respectively 0.64, 0.91, 0.93, 0.91 and 0.98. The hypothesis that mean segmental and total counts of right and left are the same could not be rejected by paired t-test.
The variance in the between-ear difference across the temporal bones studied indicates that useful effect sizes can be reliably identified using subject numbers that are practical for temporal bone studies. For instance, there is 95% likelihood that an interaural difference in SGC count of approximately 1000 cells associated with a treatment/manipulation of one ear will be reliably detected in a bilaterally-symmetric profound hearing loss population of temporal bones from approximately 10 subjects.
spiral ganglion; interaural difference; profound hearing loss
The addition of background noise to an auditory signal delays brainstem response timing. This effect has been extensively documented using manual peak selection. Peak picking, however, is impractical for large-scale studies of spectrotemporally complex stimuli, and leaves open the question of whether noise-induced delays are frequency-dependent or occur across the frequency spectrum. Here we use an automated, objective method to examine phase shifts between auditory brainstem responses to a speech sound (/da/) presented with and without background noise. We predicted that shifts in neural response timing would also be reflected in frequency-specific phase shifts. Our results indicate that the addition of background noise causes phase shifts across the subcortical response spectrum (70 – 1000Hz). However, this noise-induced delay is not uniform such that some frequency bands show greater shifts than others: low-frequency phase shifts (300–500 Hz) are largest during the response to the consonant-vowel formant transition (/d/), while high-frequency shifts (720–1000 Hz) predominate during the response to the steady-state vowel (/a/). Most importantly, phase shifts occurring in specific frequency bands correlate strongly with shifts in the latencies of the predominant peaks in the auditory brainstem response, while other frequency bands do not correlate with latency shifts. This finding confirms the validity of phase shift detection as an objective measure of timing differences and reveals that this method detects noise-induced shifts in timing that may not be captured by traditional peak latency measurements.
auditory; brainstem; phase; timing; noise
Ototoxicity is a dose-limiting side effect of chemotherapeutic treatment with cisplatin. In a series of experiments on neonatal rat cochlear organotypic cultures, the extent of damage induced by a broad range of cisplatin treatment concentrations was examined. Paradoxically, it was found that hair cell loss was greater following 48 h exposure to low (10, 50 and 100 μM) versus high (400 and 1000 μM) concentrations of cisplatin; these findings indicate that hair cells possess intrinsic resistance to high levels of extracellular cisplatin. Using cisplatin conjugated to Alexa Fluor 488, it was found that cisplatin is readily taken up by hair cells at low concentrations, but is largely excluded at high concentrations. Recent studies indicate that the major influx of cisplatin into hair cells occurs via the copper transporter, Ctr1, whereas ATP7A and ATP7B are copper pumps responsible for cisplatin sequestration and efflux. Using immunolabeling procedures for these copper trafficking proteins, it was found that Ctr1 and ATP7B were localized in the hair cells, whereas ATP7A showed extensive labeling in the pillar cells in the organ of Corti. Additional experiments confirmed the protective effect of copper sulfate and cimetidine in attenuating cisplatin-induced hair cell loss. However, because neither copper sulfate nor cimetidine provided complete protection against cisplatin, and high levels of copper sulfate itself were found to be ototoxic, it is suggested that future therapeutic efforts may benefit from a combination of pharmacological treatments which seek to not only limit the uptake of cisplatin into cochlear cells but also increase its efflux.
cochlear organotypic cultures; cisplatin; outer hair cell; copper trafficking proteins; copper sulfate; cimetidine
Tamoxifen has been used extensively in the treatment of breast cancer and other neoplasms. In addition to its well-known action on estrogen receptors it is also known to acutely block chloride channels that participate in cell volume regulation. Tamoxifen’s role in preventing cochlear outer hair cell (OHC) swelling in vitro suggested that OHC swelling noted following noise exposure could potentially be a therapeutic target for Tamoxifen in its role as a chloride channel blocker to help prevent noise induced hearing loss. To investigate this possiblity, the effects of exposure to Tamoxifen on physiologic measures of cochlear function in the presence and absence of subsequent noise exposure were studied. Male Mongolian gerbils (2–4 months old) were randomly assigned to different groups. Tamoxifen at ~10 mg/kg was administered to one of the groups. Five hours later they were exposed to a one-third octave band of noise centered at 8 kHz in a sound isolation chamber for 30 minutes at 108dB SPL. Compound action potential (CAP) thresholds and distortion product otoacoustic emission (DPOAE) levels were measured 30–35 days following noise exposure. Tamoxifen administration did not produce any changes in CAP thresholds and DPOAE levels when administered by itself in the absence of noise. Tamoxifen causes a significant increase in CAP thresholds from 8–15 kHz following noise exposure compared to CAP thresholds in animals exposed to noise alone. No significant differences were seen in the DPOAE levels the f2 = 8–15 kHz frequency range where maximum noise-induced increases in CAP thresholds were seen. Contrary to our original expectation, it is concluded that Tamoxifen potentiates the degree of damage to the cochlea resulting from noise exposure.
ototoxicity; Tamoxifen; compound action potential; distortion product otoacoustic emissions; Noise induced hearing loss
The human auditory brainstem is known to be exquisitely sensitive to fine-grained spectro-temporal differences between speech sound contrasts, and the ability of the brainstem to discriminate between these contrasts is important for speech perception. Recent work has described a novel method for translating brainstem timing differences in response to speech contrasts into frequency-specific phase differentials. Results from this method have shown that the human brainstem response is surprisingly sensitive to phase-differences inherent to the stimuli across a wide extent of the spectrum. Here we use an animal model of the auditory brainstem to examine whether the stimulus-specific phase signatures measured in human brainstem responses represent an epiphenomenon associated with far field (i.e., scalp-recorded) measurement of neural activity, or alternatively whether these specific activity patterns are also evident in auditory nuclei that contribute to the scalp-recorded response, thereby representing a more fundamental temporal processing phenomenon. Responses in anaesthetized guinea pigs to three minimally-contrasting consonant-vowel stimuli were collected simultaneously from the cortical surface vertex and directly from central nucleus of the inferior colliculus (ICc), measuring volume conducted neural activity and multiunit, near-field activity, respectively. Guinea pig surface responses were similar to human scalp-recorded responses to identical stimuli in gross morphology as well as phase characteristics. Moreover, surface recorded potentials shared many phase characteristics with near-field ICc activity. Response phase differences were prominent during formant transition periods, reflecting spectro-temporal differences between syllables, and showed more subtle differences during the identical steady-state periods. ICc encoded stimulus distinctions over a broader frequency range, with differences apparent in the highest frequency ranges analyzed, up to 3000 Hz. Based on the similarity of phase encoding across sites, and the consistency and sensitivity of response phase measured within ICc, results suggest that a general property of the auditory system is a high degree of sensitivity to fine-grained phase information inherent to complex acoustical stimuli. Furthermore, results suggest that temporal encoding in ICc contributes to temporal features measured in speech-evoked scalp-recorded responses.
auditory; inferior colliculus; brainstem; midbrain; speech; phase
Improvements in speech-recognition performance resulting from the addition of low-frequency information to electric (or vocoded) signals have attracted considerable interest in recent years. An important question is whether these improvements reflect a form of constructive perceptual interaction—whereby acoustic cues enhance the perception of electric or vocoded signals—or whether they can be explained without assuming any interaction. To address this question, speech-recognition performance was measured in 24 normal-hearing listeners using lowpass-filtered, vocoded, and “combined” (lowpass + vocoded) words presented either in quiet or in a realistic background (cafeteria noise), for different signal-to-noise ratios, different lowpass-filter cutoff frequencies, and different numbers of vocoder bands. The results of these measures were then compared to the predictions of three models of cue-combination, including a “probability summation” model and two Gaussian signal-detection-theory (SDT) models—one (the “independent noises” model) involving pre-combination noises, and the other (the “late noise” model) involving post-combination noise. Consistent with previous findings, speech-recognition performance with combined stimulation was significantly higher than performance with vocoded or lowpass stimuli alone, and it was also higher than predicted by the probability-summation model. The two Gaussian-SDT models could account quantitatively for the data. Moreover, a Bayesian model-comparison procedure demonstrated that, given the data, these two models were far more likely than the probability-summation model. Since these models do not involve any constructive-interaction mechanism, this demonstrates that constructive interactions are not needed to explain the combined-stimulation benefits measured in this study. It will be important for future studies to investigate whether this conclusion generalizes to other test conditions, including real EAS, and to further test the assumptions of these different models of the combined-stimulation advantage.
combined stimulation; cue-combination; speech recognition; signal detection theory