Low-frequency suppression of auditory nerve responses to characteristic frequency tones

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.     

Transient changes in cochlear potentials and DPOAEs after low-frequency tones: the 'two-minute bounce' revisited

After exposure to a loud, non-traumatic low-frequency tone, auditory thresholds are elevated. Thresholds recover to normal in a non-monotonic manner, decreasing rapidly at first before increasing again, until they finally decrease monotonically towards normal. Although the transient elevation of thresholds after the initial improvement was originally called a 'bounce' by Hirsh and Ward (1952), Kemp (1986) suggests that the initial rapid recovery is the oddity: under some conditions a low-frequency tone can produce hypersensitivity in otoacoustic emissions, psychophysical thresholds, and perceived loudness (Kemp's 'bounce') without a later elevation of threshold (Hirsh and Ward's 'bounce'). Kemp also suggested that the transient hypersensitivity was caused by changes in the sensitivity of the active process within the cochlea. We have investigated the origin of this transient hypersensitivity (Kemp's bounce) in guinea pigs, recording cochlear potentials (CM, CAP, SP and EP) and otoacoustic emissions (DPOAEs at f2-f1, 2f1-f2, 2f2-2f1 and 3f1-2f2). Our results indicate that the bounce does not require neural activity, but is probably produced by non-neural cochlear mechanisms, possibly a transient decrease in the permeability of the organ of Corti which produces a small but significant change in standing current through outer hair cells. At least part of these changes, which are reduced as the stimulation frequency increases, and absent above 2 kHz, seem due to a small and transient movement of the cochlear partition towards scala tympani, probably due to a transient osmotic imbalance.     

Comparative molecular analysis of Na+/H+ exchangers: a unified model for Na+/H+ antiport?

There is increasing evidence to suggest that free radical generation is central to a variety of pathological processes, including drug toxicity. Studies demonstrating the ability of gentamicin to facilitate the generation of radical species suggest that this process plays an important role in aminoglycoside-induced ototoxicity. Because transition metals, particularly iron, play an important role in the production of free radicals and the generation of reactive oxygen species, we sought to determine whether gentamicin-induced ototoxicity is exacerbated by increases in serum iron levels. To this end, we assessed the effects of supplemental iron administration (2 mg/kg/day and 6 mg/kg/day) on changes in auditory function induced by co-administration of gentamicin (100 mg/kg/day for 30 days). Experiments were carried out on pigmented guinea pigs initially weighing 250-300 g. Changes in cochlear function were characterized as shifts in compound action potential (CAP) thresholds, estimated every third day throughout the treatment period by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results showed that animals receiving iron in combination with gentamicin demonstrated a more rapid and profound elevation in CAP thresholds compared with animals receiving gentamicin alone. This effect occurred in a dose-dependent manner. Animals receiving supplemental iron alone maintained normal CAP thresholds throughout the treatment period. There was no statistically significant difference in serum gentamicin levels between groups receiving gentamicin alone or gentamicin plus iron. These results provide further evidence of the recently reported intrinsic role of iron in aminoglycoside ototoxicity, and highlight a potential risk of aminoglycoside administration in patients with elevated serum iron.     

Effects of K(+)-channel blockers on cochlear potentials in the guinea pig

The effects of different K+ channel blockers, 4-aminopyridine (4-AP), tetraethylammonium (TEA) and quinine, on the various cochlear potentials were observed by the means of perilymph infusion. Each of the three blockers depressed the compound action potential. However, they exerted quite different effects on other cochlear potentials, especially comparing 4-AP, a fast K(+)-channel blocker, with two other blockers. 4-AP induced a significant increase in the magnitude of summating potential, while TEA and quinine decreased it; 4-AP showed no effect on the general endocochlear potential (G-EP, the EP value recorded directly from the scala media, SM) and the negative EP component (N-EP), while TEA and Quinine increased G-EP and decreased the absolute value of N-EP. They also exerted different effects on the EP changes induced by exposure to intense noise. The results indicate the different roles of different K(+)-channels in the generation of cochlear potentials. The relationship of the two components of EP (positive and negative) and the G-EP was discussed.     

Effect of substrate-free vascular perfusion upon cochlear potentials and glycogen of the stria vascularis

The effect of vascular perfusion of the anterior inferior cerebellar artery with synthetic blood containing no metabolic substrates upon the endolymphatic potential (EP) and the cochlear microphonics (CM) was determined in the guinea pig. In substrate-free perfusion the potentials were maintained for an average of 84 min. Subsequently, the EP declined at an average rate of 1.4 mV/min until a new steady-state level was temporarily established when the potential had dropped to about 30 mV. The decline of the CM appeared to be accounted for largely by the decline of the EP. During substrate-free perfusion prior to the onset of the decline of the potentials, the level of strial glycogen remained unchanged; glycogen decreased significantly only after the potentials had started to decline. When substrate-free vascular perfusion was accompanied by simultaneous substrate-free perilymphatic perfusion, the potentials started to decline immediately. On the basis of these data, we conclude that strial glycogen plays no role in the prolonged maintenance of the EP during substrate-free perfusion; rather, the potential seems to be maintained by entry of glucose (and presumably other substrates) from perilymph into the stria vascularis.     

Continuous mannose infusion in carbohydrate-deficient glycoprotein syndrome type I

The effects on isoelectrofocusing patterns of serum glycoproteins were studied in a patient with CDG syndrome type I and phosphomannomutase deficiency during 3 weeks of continuous intravenous mannose infusion. Doses of 5.7 g/kg/day led to stable serum mannose levels up to 2.0 mmol/l and were well tolerated without signs of liver or renal toxicity. While most of the pathological glycoprotein patterns, including alpha1-antitrypsin, typical for CDG syndrome type I remained unchanged, mannose infusion led to a unique change of the isoelectrofocusing pattern of serum sialotransferrins with appearance of two extra bands after 3 weeks of treatment.     

Electrophysiological characterization of class III activity of a verapamil derivative in guinea-pig cardiac tissues

In isolated guinea-pig papillary muscle ([K+]o: 4.7 mmol/l, stimulation rate: 1 Hz) the verapamil derivative NN-bis-(3,4-dimethoxyphenethyl)-N-methylamine)-HCl (YS035; 0.3-100 mumol/l) increased the action potential duration measured at 90% repolarization level (APD90) up to 132% of control and enhanced the force of contraction (Fc) up to 125% of control while resting potential (RP) and the maximum upstroke velocity (Vmax) remained nearly unchanged. At 300 mumol/l YS 035, the membrane became depolarised and action potentials could no longer be elicited. These effects were reversed during wash-out. The increase of ADP90 was largest at 0.05 Hz, and the drug-induced effect continuously declined with an increase in stimulation frequency to 2 Hz. Control ADP90 was correlated to the absolute increase of ADP90 (r = 0.84). In atrial muscle the effect of YS 035 on APD90 was more pronounced than in papillary muscle. The Vmax of slow responses ([K+]o: 27 mmol/l, [Ba2+]o: 0.5 mmol/l) was not affected by concentrations as high as 30 mumol/l YS 035, whereas APD90 was enhanced. An increase in the stimulation rate (0.05 to 0.33 Hz) induced only a small decrease of Vmax at 100 mumol/l YS 035. According to this electrophysiological characterisation YS 035 shows Class III antiarrhythmic properties.     

Comparative anatomy of arterial vascularization of the rhinencephalon in man, cat and sheep

Although the morphological development of the fetal pancreatic B cell has been studied in considerable detail, knowledge about the functional maturation, particularly in early stages of development, is still poor. The present paper describes a method for monolayer culture of fetal rat islet cells which allows a study of the regulation of insulin biosynthesis, release and content during critical stages of embryonic and fetal development. Suspensions of pancreatic cells were prepared from rat fetuses on pregnancy day 16 and cultured for 3 days. During the initial 2 days cultures were performed in the presence of 5 or 15 mmol/l glucose. During this initial period, culture at 5 mmol/l glucose was carried out in the presence or absence of either 10 mmol/l nicotinamide (NA) or 5 or 100 ng/ml nerve growth factor (NGF). After changing the media the cells were further exposed for 24 h to either 5 or 15 mmol/l glucose or 15 mmol/l glucose plus 5 mmol/l theophylline before measuring the insulin concentration in the culture medium. Cells that had initially been cultured for 2 days in 5 mmol/l glucose showed an increased insulin release, when subsequently cultured in 15 mmol/l glucose for 24 h. Theophylline potentiated the response and caused a decrease in cellular insulin content. Cells initially cultured in the presence of 15 mmol/l glucose showed unchanged insulin release during the subsequent 24-hour exposure to 15 mmol/l glucose, irrespective of the presence or absence of theophylline. The presence of NGF (100 ng/ml) during the initial 2-day culture period increased the insulin release in the presence of 15 mmol/l glucose and theophylline during the subsequent 24-hour culture period as compared to cells cultured in the absence of NGF. When cells were first exposed to either NA or NGF followed by exposure to 5 mmol/l glucose alone in the last 24-hour culture period, there was an increased insulin content. Rates of insulin biosynthesis remained unchanged irrespective of the glucose concentration in the culture medium. It is concluded that, already in early fetal development, B cells show glucose stimulation of insulin release albeit less pronounced than in the postnatal state.     

Intermediate endocochlear potential levels induced by hypoxia

It seems that the positive potential of the scala media (endocochlear potential [EP]) and the high potassium concentration in the endolymph are generated and maintained by an electrogenic pump. In order to study its properties, the EP was measured in cats ventilated with low oxygen gas mixtures (2.25-10%). It was found that the EP could be maintained at intermediate levels which were more or less linear functions of blood oxygen tension (25-60 mmHg), showing that the pump can operate on intermediate levels. This hypoxic preparation may contribute to the study of cochlear blood flow.     

Vulnerability and adaptation of distortion product otoacoustic emissions to endocochlear potential variation

The endocochlear potential (EP) was reversibly decreased in adult gerbils by the intraperitoneal injection of furosemide, while cochlear functioning was monitored by measurement of distortion production otoacoustic emissions (DPE) at a range of stimulus intensities. Stimulus frequencies for DPEs were f1 = 6.8 and f2 = 8 kHz (f2/f1 = 1.18). Emissions monitored in the ear canal and scala media were 2f1-f2, 3f1-2f2, 2f2-f1, and f2-f1. Typically, the EP decreased smoothly, reached a minimum one-half hour after injection, then recovered slowly over several hours. Emissions at 2f1-f2 and 3f1-2f2 at low stimulus levels were particularly vulnerable to the change in EP. These vulnerable emissions showed characteristic trajectories in which the amplitudes changed little with the initial EP decrease, then dropped sharply as the EP continued to decrease. However, the amplitudes then began to recover even before the EP reached minimum, and recovered completely while the EP remained subnormal. The trajectories of the other odd order emissions were similar, but lacked the abrupt decrease. The variation of the even order (f2-f1) component was completely different, but appeared related to the odd order trajectories in a complex fashion. During the initial decrease for the vulnerable components, the decrease in emission amplitude (in dB) was found to be proportional to the square of the change in EP (in mV). The recovery with a subnormal EP was interpreted as an adaptive effect with a time constant of about 15 min.     

Human breast cancer cell line xenografts as models of breast cancer. The immunobiologies of recipient mice and the characteristics of several tumorigenic cell lines

Shifts in auditory intensity thresholds after salicylate administration were examined in postweanling and adult pigmented rats at frequencies ranging from 1 to 35 kHz. A total of 132 subjects from both age levels were tested under two-way active avoidance or one-way active avoidance paradigms. Estimated thresholds were inferred from behavioral responses to presentations of descending and ascending series of intensities for each test frequency value. Reliable threshold estimates were found under both avoidance conditioning methods, and compared to controls, subjects at both age levels showed threshold shifts at selective higher frequency values after salicylate injection, and the extent of shifts was related to salicylate dose level.     

Analysis of spontaneous activity of auditory neurones in the spiral ganglion of the guinea-pig cochlea

1. Spontaneous activity of single afferent neurones in the cochlea of the guinea-pig was studied by measurement of mean rates and computation of interspike interval histograms. 2. The shapes of interval histograms agreed with those found in cat cochlear nerve fibres. Modes of the histograms were less than 7 msec for all cells with mean rates ranging from 20 to 150 spikes/sec. 3. The distribution of mean rates showed higher maximum rates than those found in cat. Cells from animals with abnormally high thresholds showed lower mean rates than those from sensitive animals. 4. No correlation was found between mean spontaneous rate and sensitivity to acoustic stimulation. No discrete populations of cells could be discerned on any of the criteria used. 5. The simultaneous effects of hypoxia on cell thresholds, mean spontaneous rate and scala media potentials are reported. These and other results are discussed in relation to possible sites of generation of spontaneous activity in primary auditory afferents.     

Potential effects of managed care organizations in rural communities: a framework

OBJECTIVE: To define mechanisms accounting for transient deafness in three children (two siblings, ages 3 and 6, and an unrelated child, age 15) when they become febrile. DESIGN: Audiometric tests (pure-tone audiometry, speech and sentence comprehension), tympanometry, middle ear muscle reflex thresholds, otoacoustic emissions (OAEs), and electrophysiological methods (auditory brain stem responses [ABRs], sensory evoked potentials, peripheral nerve conduction velocities) were used to test the children when they were afebrile and febrile. RESULTS: ABRs, when afebrile, were abnormal with a profound delay of the IV-V and absence of waves I-III. The ABR in one of the children, tested when febrile, showed no ABR components. Measures of cochlear receptor function using OAEs were normal in both febrile and afebrile states. Cochlear microphonic potentials were present in the three children, and a summating potential was likely present in two. When afebrile, there was a mild threshold elevation for all frequencies in the 15-yr-old and a mild elevation of thresholds for just low frequencies in the two siblings. Speech comprehension in quiet was normal but impaired in noise. One of the siblings tested when febrile had a profound elevation (>80 dB) of pure-tone thresholds and speech comprehension was absent. Acoustic reflexes subserving middle ear muscles and olivocochlear bundle were absent when febrile and when afebrile. No other peripheral or cranial nerve abnormalities were found in any of the children. Sensory nerve action potentials from median nerve in one of the children showed no abnormalities on warming of the hand to 39 degrees C. CONCLUSION: These children have an auditory neuropathy manifested by a disorder of auditory nerve function in the presence of normal cochlear outer hair cell functions. They develop a conduction block of the auditory nerves when their core body temperature rises due, most likely, to a demyelinating disorder of the auditory nerve. The auditory neuropathy in the two affected siblings is likely to be inherited as a recessive disorder.     

Auditory evoked potentials and acoustically-directed behavior of nestlings

Characteristics of auditory evoked potentials (EP) were studied in 1.5 to 7.5 days old Pied Flycatchers nestlings (Ficedula hypoleuca) with chronically implanted electrodes in the field L (analogue of the mammal's auditory cortex). EPs simultaneously with behaviour were recorded in nestlings under conditions similar to natural, in response to "feeding" calls and pure tones of different frequency and intensity. It was found that EP generation thresholds do not depend on the sum total of factors which influence the organization of feeding behaviour. The EP generation threshold is by 13-36 dB (for different frequencies) below that of the appearance of feeding responses in nestling with a maximum high motivation. It is suggested that the realization of inborn behaviour with a signal basis needs not only an integration (formed in the process of embryogenesis) of a definite sensory input with a complex of structures of the "feeding centre", but also the presence of a massive modality-specific inflow.     

Membrane function and vascular reactivity

The resting potential and monovalent ions in the marginal cells and scala media were measured before and 20 min after the onset of anoxia using ion-sensitive microelectrodes. The resting potential of the marginal cells decreased from 62.7 to -2.4 mV. The K+ activity decreased from 77.7 to 53.2 mEq/l, while the Na+ activity increased from 2.6 to 24.7 mEq/l. The Cl- activity did not change significantly. In the scala media, the endocochlear potential decreased rapidly from 80.9 to -28.0 mV after the onset of anoxia. The K+ activity decreased from 119.0 to 96.5 mEq/l, the Na+ activity increased from 1.3 to 9.5 mEq/l and that of Cl- decreased from 127.0 to 115.1 mEq/l. The electrochemical gradients determined for each ion based on the ionic changes in the scala media and marginal cells, suggested the existence of an Na/K pump and Na-K-2Cl cotransport at the basolateral membrane of the marginal cells, and a rheogenic K pump and Na-K-2Cl transport at the luminal membrane of the marginal cells. The Na+ and K+ must be recycled at the basolateral membrane and luminal membrane of marginal cells, respectively.     

Extracellular adenosine 5'-triphosphate (ATP) in the endolymphatic compartment influences cochlear function

There is strong evidence for the presence of P2 purinoceptors on cochlear tissues, but the role of extracellular ATP in cochlear function is still unclear. Our previous studies have determined the presence of ATP in the cochlear fluids and indicated that the purinoceptors are substantially localized to the tissues lining the endolymphatic compartment. This implies that extracellular ATP may have an humoral role confined to the endolymphatic space. In order to study the influence of extracellular ATP in the endolymphatic space, a series of studies were undertaken in which ATP (10 microM to 10 mM) in artificial endolymph (EL) (test solution: 2-12.5 nl) was injected into the scala media and the effect on the cochlear microphonic (CM) and endocochlear potential (EP) evaluated. A double-barrelled pipette, with one barrel containing the test solution and the other artificial EL (control solution) was inserted into scala media of the third turn of the guinea-pig cochlea. A known volume (2-12.5 nl) of test or control solution was then pressure-injected into the space. ATP had a significant dose-dependent suppressive effect on both EP and CM with a threshold of approximately 2 x 10(-14) mol; the response was readily reversible, also in a dose-dependent fashion. Artificial EL of the same volume had no effect on EP and CM. The ATP effect on EP was blocked by the P2 purinoceptor antagonists suramin and reactive blue 2 (RB2). Neither adenosine (2 x 10(-13) to 2 x 10(-11) mol) nor suramin or RB2 on their own had any effect on EP and CM. This study provides the first evidence for an effect of extracellular ATP in the endolymphatic compartment on cochlear function which is mediated via P2 purinoceptors. This provides supporting evidence for an humoral role for extracellular ATP in the modulation of cochlear function.     

Recovery of the human compound action potential following prior stimulation

The recovery from prior stimulation of the compound action potential (CAP) was measured using a forward masking stimulus paradigm in four normal-hearing, human subjects. The CAP was recorded using a wick electrode placed on the tympanic membrane. The effects of a 4000-Hz, 97-dB SPL conditioning stimulus on CAP amplitude in response to a 4000-Hz probe were measured as a function of conditioner-probe interval for three probe levels. The normalized probe response amplitude was completely recovered to the control values at an average conditioner-probe interval of 1359 ms, similar to that observed in chinchilla (Relkin, E.M., Doucet, J.R., Sterns, A., 1995. Recovery of the compound action potential following prior stimulation: evidence for a slow component that reflects recovery of low spontaneous-rate auditory neurons, Hear. Res. 83, 183-189). The present results are interpreted as a consequence of the slow recovery of low spontaneous-rate (SR), high threshold neurons from prior stimulation (Relkin, E.M., Doucet, J.R., 1991. Recovery from prior stimulation. I: Relationship to spontaneous firing rates of primary auditory neurons. Hear. Res. 55, 215-222) and may provide indirect physiological evidence for the existence of a class of low-SR auditory neurons in humans.     

Longitudinal endolymph movements induced by perilymphatic injections

Endolymph movements and endocochlear potential (EP) changes were measured during disturbances of perilymphatic pressure. induced by injecting artificial perilymph into scala tympani (ST) or scala vestibuli (SV) of the guinea pig cochlea. Injections were performed either with or without an outlet made in the opposite perilymphatic scala. Injections into ST without an outlet induced large pressure changes but virtually no endolymph movement or EP change. Injection at the same rate into ST with an outlet in SV produced smaller pressure changes which were accompanied by a basally-directed displacement of endolymph and significant EP changes. The magnitude of endolymph displacements and EP changes varied as a function of injection rate. Injections into SV, either with or without an outlet in ST, produced apically-directed endolymph displacement and EP changes. For the SV injections without an outlet, the cochlear aqueduct and round window are likely to provide an outlet and compliance, permitting flow along the perilymphatic scalae to occur even when no ST outlet was provided. We conclude that endolymph movements are not dependent on the absolute pressure of the perilymph, but instead occur when small, sustained pressure gradients are present across the cochlear partition, corresponding to times when perilymph flow is induced. This study demonstrates that in the normal. sealed cochlea, endolymph and EP are insensitive to fluid injections into ST, but are sensitive to fluid injections into SV. Endolymph movements are therefore unlikely to be generated by cerebrospinal fluid pressure fluctuations (such as those produced by respiration, posture changes, coughing, sneezing, etc) which are transmitted to ST by the cochlear aqueduct.     

Hearing and vocalizations in the orange-fronted conure (Aratinga canicularis).

The auditory sensitivities of the orange-fronted conure (Aratinga canicularis) were examined in relation to the spectral characteristics of its vocalizations. Absolute thresholds, masked thresholds, frequency difference limens, and intensity difference limens for pure tones were obtained using psychoacoustic techniques. In general, hearing abilities are similar to those found in many avian auditory generalists. One exception is the unusually low critical ratio (masked threshold) between 2.0 and 4.0 kHz, similar to that previously found in the budgerigar (Melopsittacus undulatus). These auditory sensitivities were compared with average spectra for (a) contact calls and (b) a general sample of vocalizations recorded from wild birds. The spectral regions of both greatest vocal energy and best auditory sensitivity were between 2.0 and 5.0 kHz. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Attenuation of neomycin ototoxicity by iron chelation

Increasing evidence suggests that aminoglycoside ototoxicity is mediated by the formation of an aminoglycoside-iron complex and that the creation of this complex is a preliminary step in generation of free radical species and subsequent hair cell death. In this study we have assessed the ability of the iron chelator deferoxamine to attenuate the hearing loss induced by an ototoxic dose of the aminoglycoside neomycin (100 mg/kg per day for 14 days). Experiments were carried out on pigmented guinea pigs weighing 250 to 300 g. Changes in auditory sensitivity were characterized by monitoring shifts in compound action potential (CAP) thresholds, recorded through indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results show that animals receiving neomycin alone suffered a mean threshold shift exceeding 35 dB at all test frequencies (2.0, 4.0, and 8.0 kHz) 30 days after initiation of treatment. In comparison, all animals receiving cotherapy of neomycin and deferoxamine (150 mg/kg twice daily for 14 days) maintained their CAP threshold, suggesting significant protection from neomycin ototoxicity. A statistical comparison of treatment groups showed that in the animals receiving cotherapy with neomycin and deferoxamine, deferoxamine produced a significant protective effect against neomycin-induced ototoxicity (P < 0.001). These results provide further evidence of the intrinsic role of iron in aminoglycoside ototoxicity and suggest that deferoxamine may have a therapeutic role in attenuating the cytotoxic action of aminoglycoside antibiotics.