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1.
Sci Rep ; 11(1): 10380, 2021 05 17.
Article in English | MEDLINE | ID: mdl-34001971

ABSTRACT

A fundamental property of mammalian hearing is the conversion of sound pressure into a frequency-specific place of maximum vibration along the cochlear length, thereby creating a tonotopic map. The tonotopic map makes possible systematic frequency tuning across auditory-nerve fibers, which enables the brain to use pitch to separate sounds from different environmental sources and process the speech and music that connects us to people and the world. Sometimes a tone has a different pitch in the left and right ears, a perceptual anomaly known as diplacusis. Diplacusis has been attributed to a change in the cochlear frequency-place map, but the hypothesized abnormal cochlear map has never been demonstrated. Here we assess cochlear frequency-place maps in guinea-pig ears with experimentally-induced endolymphatic hydrops, a hallmark of Ménière's disease. Our findings are consistent with the hypothesis that diplacusis is due to an altered cochlear map. Map changes can lead to altered pitch, but the size of the pitch change is also affected by neural synchrony. Our data show that the cochlear frequency-place map is not fixed but can be altered by endolymphatic hydrops. Map changes should be considered in assessing hearing pathologies and treatments.


Subject(s)
Brain/physiopathology , Cochlea/physiopathology , Hearing Disorders/diagnosis , Meniere Disease/physiopathology , Animals , Auditory Threshold , Disease Models, Animal , Endolymphatic Hydrops/physiopathology , Guinea Pigs , Hearing/physiology , Hearing Disorders/physiopathology , Hearing Tests , Humans , Meniere Disease/diagnosis , Sound
2.
Neuroscience ; 425: 251-266, 2020 01 15.
Article in English | MEDLINE | ID: mdl-31809731

ABSTRACT

Endolymphatic hydrops is associated with low-frequency sensorineural hearing loss, with a large body of research dedicated to examining its putative causal role in low-frequency hearing loss. Investigations have been thwarted by the fact that hearing loss is measured in intact ears, but gold standard assessments of endolymphatic hydrops are made postmortem only; and that no objective low-frequency hearing measure has existed. Yet the association of endolymphatic hydrops with low-frequency hearing loss is so strong that it has been established as one of the important defining features for Ménière's disease, rendering it critical to detect endolymphatic hydrops early, regardless of whether it serves a causal role or is the result of other disease mechanisms. We surgically induced endolymphatic hydrops in guinea pigs and employed our recently developed objective neural measure of low-frequency hearing, the Auditory Nerve Overlapped Waveform (ANOW). Hearing loss and endolymphatic hydrops were assessed at various time points after surgery. The ANOW detected low-frequency hearing loss as early as the first day after surgery, well before endolymphatic hydrops was found histologically. The ANOW detected low-frequency hearing loss with perfect sensitivity and specificity in all ears after endolymphatic hydrops developed, where there was a strong linear relationship between degree of endolymphatic hydrops and severity of low-frequency hearing loss. Further, histological data demonstrated that endolymphatic hydrops is seen first in the high-frequency cochlear base, though the ANOW demonstrated that dysfunction begins in the low-frequency apical cochlear half. The results lay the groundwork for future investigations of the causal role of endolymphatic hydrops in low-frequency hearing loss.


Subject(s)
Auditory Threshold/physiology , Cochlear Nerve/physiology , Hearing Loss/physiopathology , Hearing/physiology , Animals , Cochlea/pathology , Endolymphatic Hydrops/diagnosis , Endolymphatic Hydrops/pathology , Guinea Pigs , Hearing Loss/diagnosis , Hearing Loss, Sensorineural/pathology , Hearing Tests/methods , Meniere Disease/diagnosis , Meniere Disease/pathology
3.
J Neurophysiol ; 121(3): 1018-1033, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30673362

ABSTRACT

Little is known about the spatial origins of auditory nerve (AN) compound action potentials (CAPs) evoked by moderate to intense sounds. We studied the spatial origins of AN CAPs evoked by 2- to 16-kHz tone bursts at several sound levels by slowly injecting kainic acid solution into the cochlear apex of anesthetized guinea pigs. As the solution flowed from apex to base, it sequentially reduced CAP responses from low- to high-frequency cochlear regions. The times at which CAPs were reduced, combined with the cochlear location traversed by the solution at that time, showed the cochlear origin of the removed CAP component. For low-level tone bursts, the CAP origin along the cochlea was centered at the characteristic frequency (CF). As sound level increased, the CAP center shifted basally for low-frequency tone bursts but apically for high-frequency tone bursts. The apical shift was surprising because it is opposite the shift expected from AN tuning curve and basilar membrane motion asymmetries. For almost all high-level tone bursts, CAP spatial origins extended over 2 octaves along the cochlea. Surprisingly, CAPs evoked by high-level low-frequency (including 2 kHz) tone bursts showed little CAP contribution from CF regions ≤ 2 kHz. Our results can be mostly explained by spectral splatter from the tone-burst rise times, excitation in AN tuning-curve "tails," and asynchronous AN responses to high-level energy ≤ 2 kHz. This is the first time CAP origins have been identified by a spatially specific technique. Our results show the need for revising the interpretation of the cochlear origins of high-level CAPs-ABR wave 1. NEW & NOTEWORTHY Cochlear compound action potentials (CAPs) and auditory brain stem responses (ABRs) are routinely used in laboratories and clinics. They are typically interpreted as arising from the cochlear region tuned to the stimulus frequency. However, as sound level is increased, the cochlear origins of CAPs from tone bursts of all frequencies become very wide and their centers shift toward the most sensitive cochlear region. The standard interpretation of CAPs and ABRs from moderate to intense stimuli needs revision.


Subject(s)
Action Potentials , Cochlear Nucleus/physiology , Evoked Potentials, Auditory, Brain Stem , Animals , Female , Guinea Pigs , Male , Pitch Perception
4.
PLoS One ; 12(4): e0175236, 2017.
Article in English | MEDLINE | ID: mdl-28384320

ABSTRACT

2-Hydroxypropyl-Beta-Cyclodextrin (HPßCD) can be used to treat Niemann-Pick type C disease, Alzheimer's disease, and atherosclerosis. But, a consequence is that HPßCD can cause hearing loss. HPßCD was recently found to be toxic to outer hair cells (OHCs) in the organ of Corti. Previous studies on the chronic effects of in vivo HPßCD toxicity did not know the intra-cochlear concentration of HPßCD and attributed variable effects on OHCs to indirect drug delivery to the cochlea. We studied the acute effects of known HPßCD concentrations administered directly into intact guinea pig cochleae. Our novel approach injected solutions through pipette sealed into scala tympani in the cochlear apex. Solutions were driven along the length of the cochlear spiral toward the cochlear aqueduct in the base. This method ensured that therapeutic levels were achieved throughout the cochlea, including those regions tuned to mid to low frequencies and code speech vowels and background noise. A wide variety of measurements were made. Results were compared to measurements from ears treated with the HPßCD analog methyl-ß-cyclodextrin (MßCD), salicylate that is well known to attenuate the gain of the cochlear amplifier, and injection of artificial perilymph alone (controls). Histological data showed that OHCs appeared normal after treatment with a low dose of HPßCD, and physiological data was consistent with attenuation of cochlear amplifier gain and disruption of non-linearity associated with transferring acoustic sound into neural excitation, an origin of distortion products that are commonly used to objectively assess hearing and hearing loss. A high dose of HPßCD caused sporadic OHC losses and markedly affected all physiologic measurements. MßCD caused virulent destruction of OHCs and physiologic responses. Toxicity of HPßCD to OHC along the cochlear length is variable even when a known intra-cochlear concentration is administered, at least for the duration of our acute studies.


Subject(s)
Cochlea/drug effects , beta-Cyclodextrins/administration & dosage , 2-Hydroxypropyl-beta-cyclodextrin , Animals , Female , Guinea Pigs , Male
5.
J Neurosci Methods ; 273: 201-209, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27506463

ABSTRACT

BACKGROUND: Administering pharmaceuticals to the scala tympani of the inner ear is a common approach to study cochlear physiology and mechanics. We present here a novel method for in vivo drug delivery in a controlled manner to sealed ears. NEW METHOD: Injections of ototoxic solutions were applied from a pipette sealed into a fenestra in the cochlear apex, progressively driving solutions along the length of scala tympani toward the cochlear aqueduct at the base. Drugs can be delivered rapidly or slowly. In this report we focus on slow delivery in which the injection rate is automatically adjusted to account for varying cross sectional area of the scala tympani, therefore driving a solution front at uniform rate. RESULTS: Objective measurements originating from finely spaced, low- to high-characteristic cochlear frequency places were sequentially affected. Comparison with existing methods(s): Controlled administration of pharmaceuticals into the cochlear apex overcomes a number of serious limitations of previously established methods such as cochlear perfusions with an injection pipette in the cochlear base: The drug concentration achieved is more precisely controlled, drug concentrations remain in scala tympani and are not rapidly washed out by cerebrospinal fluid flow, and the entire length of the cochlear spiral can be treated quickly or slowly with time. CONCLUSIONS: Controlled administration of solutions into the cochlear apex can be a powerful approach to sequentially effect objective measurements originating from finely spaced cochlear regions and allows, for the first time, the spatial origin of CAPs to be objectively defined.


Subject(s)
Drug Delivery Systems , Scala Tympani/drug effects , Scala Tympani/metabolism , Acoustic Stimulation , Acoustics , Action Potentials/drug effects , Animals , Dextrans/administration & dosage , Dextrans/pharmacokinetics , Excitatory Amino Acid Agonists/administration & dosage , Female , Fluorescein-5-isothiocyanate/administration & dosage , Fluorescein-5-isothiocyanate/analogs & derivatives , Fluorescein-5-isothiocyanate/pharmacokinetics , Guinea Pigs , Kainic Acid/administration & dosage , Male , Otoacoustic Emissions, Spontaneous/drug effects , Time Factors
6.
Hear Res ; 333: 216-224, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26364824

ABSTRACT

Inhibition of cochlear amplifier gain by the medial olivocochlear (MOC) efferent system has several putative roles: aiding listening in noise, protection against damage from acoustic overexposure, and slowing age-induced hearing loss. The human MOC reflex has been studied almost exclusively by measuring changes in otoacoustic emissions. However, to help understand how the MOC system influences what we hear, it is important to have measurements of the MOC effect on the total output of the organ of Corti, i.e., on cochlear nerve responses that couple sounds to the brain. In this work we measured the inhibition produced by the MOC reflex on the amplitude of cochlear nerve compound action potentials (CAPs) in response to moderate level (52-60 dB peSPL) clicks from five, young, normal hearing, awake, alert, human adults. MOC activity was elicited by 65 dB SPL, contralateral broadband noise (CAS). Using tympanic membrane electrodes, approximately 10 h of data collection were needed from each subject to yield reliable measurements of the MOC reflex inhibition on CAP amplitudes from one click level. The CAS produced a 16% reduction of CAP amplitude, equivalent to a 1.98 dB effective attenuation (averaged over five subjects). Based on previous reports of efferent effects as functions of level and frequency, it is possible that much larger effective attenuations would be observed at lower sound levels or with clicks of higher frequency content. For a preliminary comparison, we also measured MOC reflex inhibition of DPOAEs evoked from the same ears with f2's near 4 kHz. The resulting effective attenuations on DPOAEs were, on average, less than half the effective attenuations on CAPs.


Subject(s)
Cochlea/innervation , Cochlear Nerve/physiology , Neural Inhibition , Olivary Nucleus/physiology , Reflex , Acoustic Stimulation , Auditory Pathways/physiology , Auditory Threshold , Efferent Pathways/physiology , Evoked Potentials, Auditory , Humans , Otoacoustic Emissions, Spontaneous
7.
J Acoust Soc Am ; 138(5): 2957-63, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26627769

ABSTRACT

In this report an analysis of cochlear response harmonics is developed to derive a mathematical function to estimate the gross mechanics involved in the in vivo transfer of acoustic sound into neural excitation (f(Tr)). In a simulation it is shown that the harmonic distortion from a nonlinear system can be used to estimate the nonlinearity, supporting the next phase of the experiment: Applying the harmonic analysis to physiologic measurements to derive estimates of the unknown, in vivo f(Tr). From gerbil ears, estimates of f(Tr) were derived from cochlear response measurements made with an electrode at the round window niche from 85 Hz tone bursts. Estimates of f(Tr) before and after inducing auditory neuropathy-loss of auditory nerve responses with preserved hair cell responses from neurotoxic treatment with ouabain-showed that the neural excitation from low-frequency tones contributes to the magnitude of f(Tr) but not the sigmoidal, saturating, nonlinear morphology.


Subject(s)
Cochlea/physiology , Acoustics , Action Potentials , Animals , Auditory Pathways/physiology , Cochlear Nerve/drug effects , Cochlear Nerve/physiology , Computer Simulation , Female , Gerbillinae/physiology , Hair Cells, Auditory/physiology , Mechanotransduction, Cellular , Models, Neurological , Neurotoxins/toxicity , Nonlinear Dynamics , Ouabain/toxicity
8.
J Assoc Res Otolaryngol ; 15(3): 395-411, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24515339

ABSTRACT

Measurements of cochlear function with compound action potentials (CAPs), auditory brainstem responses, and otoacoustic emissions work well with high-frequency sounds but are problematic at low frequencies. We have recently shown that the auditory nerve overlapped waveform (ANOW) can objectively quantify low-frequency (<1 kHz) auditory sensitivity, as thresholds for ANOW at low frequencies and for CAP at high frequencies relate similarly to single auditory nerve fiber thresholds. This favorable relationship, however, does not necessarily mean that ANOW originates from auditory nerve fibers innervating low-frequency regions of the cochlear apex. In the present study, we recorded the cochlear response to tone bursts of low frequency (353, 500, and 707 Hz) and high frequency (2 to 16 kHz) during administration of tetrodotoxin (TTX) to block neural function. TTX was injected using a novel method of slow administration from a pipette sealed into the cochlear apex, allowing real-time measurements of systematic neural blocking from apex to base. The amplitude of phase-locked (ANOW) and onset (CAP) neural firing to moderate-level, low-frequency sounds were markedly suppressed before thresholds and responses to moderate-level, high-frequency sounds were affected. These results demonstrate that the ANOW originates from responses of auditory nerve fibers innervating cochlear apex, confirming that ANOW provides a valid physiological measure of low-frequency auditory nerve function.


Subject(s)
Cochlea/innervation , Cochlear Nerve/physiology , Acoustic Stimulation , Action Potentials/physiology , Animals , Auditory Threshold , Female , Guinea Pigs , Male , Tetrodotoxin/pharmacology
9.
J Acoust Soc Am ; 124(4): 2174-85, 2008 Oct.
Article in English | MEDLINE | ID: mdl-19062857

ABSTRACT

The influence of noise exposure on the parameters of a convolution model of the compound action potential (CAP) was examined. CAPs were recorded in normal-hearing gerbils and in gerbils exposed to a 117 dB SPL 8 kHz band of noise for various durations. The CAPs were fitted with an analytic CAP to obtain the parameters representing the number of nerve fibers (N), the probability density function [P(t)] from a population of nerve fibers, and the single-unit waveform [U(t)]. The results showed that the analytic CAP fitted the physiologic CAPs well with correlations of approximately 0.90. A subsequent analysis using hierarchical linear modeling quantified the change in the parameters as a function of both signal level and hearing threshold. The results showed that noise exposure caused some of the parameter-level functions to simply shift along the signal level axis in proportion to the amount of hearing loss, whereas others shifted along the signal level axis and steepened. Significant changes occurred in the U(t) parameters, but they were not related to hearing threshold. These results suggest that noise exposure alters the physiology underlying the CAP, some of which can be explained by a simple lack of gain, whereas others may not.


Subject(s)
Action Potentials , Cochlear Nerve/physiopathology , Hearing Loss, Noise-Induced/physiopathology , Models, Neurological , Noise , Animals , Auditory Threshold , Gerbillinae , Linear Models , Time Factors
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