Compound Action Potential Audiograms Research Articles

Experimental estrogen-induced hyperprolactinemia results in bone-related hearing loss in the guinea pig

Our group (Horner KC, Guieu R, Magnan J, Chays A, Cazals Y. Neuropsychopharmacology 26: 135-138, 2002) has earlier described hyperprolactinemia in some patients presenting inner ear dysfunction. However, in that study, it was not possible to determine whether hyperprolactinemia was a cause or an effect of the symptoms. To investigate the effect of hyperprolactinemia on inner ear function, we first developed a model of hyperprolactinemia in estrogen-primed Fischer 344 rats and then performed functional studies on pigmented guinea pigs. Hyperprolactinemia induced, after 2 mo, a hearing loss of approximately 30-40 dB across all frequencies, as indicated by the compound action potential audiogram. During the 3rd mo, the hearing loss continued to deteriorate. The threshold shifts were more substantial in males than in females. Observations under a dissection microscope revealed bone dysmorphology of the bulla and the cochlea. Light microscopy observations of cryostat sections confirmed bone-related pathology of the bony cochlear bulla and the cochlear wall and revealed morphopathology of the stria vascularis and spiral ligament. Scanning electron microscopy revealed loss of hair cells and stereocilia damage, in particular in the upper three cochlear turns and the two outermost hair cell rows. The data provide the first evidence of otic capsule and hair cell pathology associated with estrogen-induced prolonged hyperprolactinemia and suggest that conditions such as pregnancy, anti-psychotic drug treatment, aging, and/or stress might lead to similar ear dysfunctions.

Dorsal cochlear nucleus response properties following acoustic trauma: Response maps and spontaneous activity

Recordings from single neurons in the dorsal cochlear nucleus (DCN) of unanesthetized (decerebrate) cats were done to characterize the effects of acoustic trauma. Trauma was produced by a 250 Hz band of noise centered at 10 kHz, presented at 105–120 dB SPL for 4 h. After a one-month recovery period, neurons were recorded in the DCN. The threshold shift, determined from compound action-potential audiograms, showed a sharp threshold elevation of about 60 dB at BFs above an edge frequency of 5–10 kHz. The response maps of neurons with best frequencies (BFs) above the edge did not show the typical organization of excitatory and inhibitory areas seen in the DCN of unexposed animals. Instead, neurons showed no response to sound, weak responses that were hard to tune and characterize, or “tail” responses, consisting of broadly-tuned, predominantly excitatory responses, with a roughly low-pass shape similar to the tuning curves of auditory nerve fibers with similar threshold shifts. In some tail responses whose BFs were near the edge of the threshold elevation, a second weak high-frequency response was seen that suggests convergence of auditory nerve inputs with widely separated BFs on these cells. Spontaneous rates among neurons with elevated thresholds were not increased over those in populations of principal neurons in unexposed animals.

M‐Chlorophenylpiperazine exacerbates perception of salicylate‐induced tinnitus in rats

The serotonin receptor 5-HT2c agonist m-chlorophenylpiperazine (mCPP) has been widely used to induce anxiety-like states in animals and anxiety in humans. We here addressed the effect of an intraperitoneal injection of mCPP on the perception of tinnitus in a behavioural protocol based on an active avoidance paradigm. In control saline-treated animals, mCPP did not change compound action potential audiograms or measurable tinnitus. In contrast, mCPP to animals demonstrating salicylate-induced tinnitus exacerbated tinnitus perception by nearly twofold. We went on to test whether manipulation of the peripheral generator of tinnitus (i.e. the cochlea) could extinguish this exacerbated perception by applying the N-methyl-d-aspartate (NMDA) antagonist 7-chlorokynurenate (7-CK) into cochlear fluids using a 7-CK-soaked Gelfoam ball placed on the round window of each of the animals' two ears. In addition to blocking the tinnitus induced by salicylate alone, 50 microm of 7-CK clearly abolished tinnitus in animals receiving salicylate and an injection of mCPP. The demonstration that cochlear NMDA receptor blockade abolishes the exacerbated perception of tinnitus is highly relevant in terms of treatment. In addition to psychotherapeutic treatment that may help to attenuate an individual's perception of tinnitus, targeting cochlear NMDA receptors represents a promising therapeutic strategy, even in depressed or chronically anxious patients.

Basal Forebrain Cholinergic Input Is Not Essential for Lesion-Induced Plasticity in Mature Auditory Cortex

The putative role of the basal forebrain cholinergic system in mediating lesion-induced plasticity in topographic cortical representations was investigated. Cholinergic immunolesions were combined with unilateral restricted cochlear lesions in adult cats, demonstrating the consequence of cholinergic depletion on lesion-induced plasticity in primary auditory cortex (AI). Immunolesions almost eliminated the cholinergic input to AI, while cochlear lesions produced broad high-frequency hearing losses. The results demonstrate that the near elimination of cholinergic input does not disrupt reorganization of the tonotopic representation of the lesioned (contralateral) cochlea in AI and does not affect the normal representation of the unlesioned (ipsilateral) cochlea. It is concluded that cholinergic basal forebrain input to AI is not essential for the occurrence of lesion-induced plasticity in AI.

Changes in electrovestibular brainstem responses after aminoglycoside intoxication in guinea pigs

Objective: To verify the usefulness of short-latency vestibular responses evoked by a combination of round window electrical stimulation and sinusoidal rotation (electrovestibular brainstem responses; EVBRs) as a new monitoring tool of the vestibular function in animal experiments.Methods: EVBRs were obtained before, during, and after treatment with aminoglycosides, along with compound action potential (CAP) audiograms. The changes in EVBRs were compared with morphological changes observed by scanning electron microscopy.Results: EVBR amplitudes did not change in the group of guinea pigs treated with amikacin, but markedly decreased in the streptomycin and gentamicin- treated groups. CAP audiograms indicated a significant threshold elevation in the amikacin group, a moderate elevation in the gentamicin group, and no change in the streptomycin group. Under scanning electron microscopy, the loss of the sensory hair cells observed in the cristae ampullares was slight to moderate in the amikacin group, moderate to severe in the streptomycin group, and severe in the gentamicin group.Conclusion: EVBRs reflect overall pathological changes undergone by vestibular hair cells, and support the vestibular specificity of EVBRs.

Electrical and physiological changes during short-term and chronic electrical stimulation of the normal cochlea

In the electrical stimulation (ES) of auditory pathways, the type of stimulus and the electrode/tissue interface are critical parameters for the safety and efficacy of the protocol. In this study the influence of alternate pulses, applied between round window and vertex electrodes in chronically implanted guinea pigs, and maintained during 1 and 25 daily periods of 2 h (short-term and long-term experiments, respectively), was investigated. ES consisted of monophasic current pulses of ±70 μA and 300 μs in duration at a rate of 167/s, with alternate polarity. Compound Action Potential (CAP) audiograms, amplitudes and latencies of click-evoked CAPs, amplitudes and latencies of electrically-evoked auditory responses (EARs), and electrode impedances, were measured periodically outside or during the ES periods. Short-term ES induced no change in CAP thresholds, amplitude and latency in response to clicks at 80 dB above normal threshold, but induced a slight latency increase and amplitude decrease of the EAR, correlated with an exponential decay of the electrode impedance. On a long-term basis, CAP audiograms and latencies did not change significantly, whereas CAP amplitudes and electrode impedances increased, in correlation with each other. In control guinea pigs receiving no ES, the same CAP amplitude and impedance changes were observed over the same long-term period. The EAR and CAP changes can be explained by a variation of the electrical impedance of the electrode/tissue interface. This is possibly due to a change in electrotytes around the electrode under the influence of the ES for the short-term variation, and to an electrode encapsulation by fibrous tissue independent of the ES for the long-term change. In itself, and under the conditions of this experiment, the ES demonstrated no adverse effects on the auditory function and can be safely used for inner-ear exploration.

Discharge properties of pigeon single auditory nerve fibers after recovery from severe acoustic trauma

The time course of recovery of compound action potential (CAP) thresholds was observed in individual adult pigeons after severe acoustic trauma. Each bird had electrodes implanted on the round window of both ears. One ear was exposed to a tone of 0.7 kHz at 136–142 dB SPL for 1 hr under general anesthesia. Recovery of CAP audiograms was monitored twice a week after trauma. Single unit recordings from auditory nerve fibers were made after 3 weeks and after 4 or more months of the exposure. The CAP was abolished immediately after overstimulation in all animals. Based on the temporal patters of functional recovery of the CAP three groups of animals were identified. The first group was characterized by fast functional recovery starting immediately after trauma followed by a return to pre-exposure values within 3 weeks. In the second group, slow functional recovery of threshold started 1–2 weeks after trauma followed by a return to pre-exposure values by 4–5 weeks. A mean residual hearing loss of 26.3 dB at 2 kHz remained. The third group consisted of animals that did not recover after trauma. Three weeks after the exposure, tuning curves of single auditory nerve fibers were very broad and sometimes irregular in shape. Their thresholds hovered around 120 dB SPL. Spontaneous firing rate and driven rate were much reduced. Four or more months after exposure, the thresholds and sharpness of tuning of many single units were almost completely recovered. Spontaneous firing rate and driven rate were comparable to those of control animals. In the slow recovery group neuronal tuning properties showed less recovery, especially at frequencies above the exposure frequency. Thresholds and sharpness of tuning were normal at frequencies below the exposure frequency, but were much poorer at frequencies above the exposure. Spontaneous firing rate was much reduced in fibers with high characteristic frequencies. In fast recovering animals, the papilla was repopulated with hair cells after 4 months. In slow recovering animals, short (abneural) hair cells were still missing over large parts of the papilla after 4 months of recovery. Residual short (abneural) hair cell loss was largest at two areas, one more basal and the other more apical to the characteristic place of the traumatizing frequency. The results show that, in adult birds, functional recovery from severe damage to both short (abneural) and tall (neural) hair cells occurs. However, the onset of recovery is delayed and the time course is slower than after destruction of short (abneural) hair cells alone. Also, recovery is incomplete, both functionally and morphologically. There is residual permanent hearing loss, and regeneration of short (abneural) hair cells is incomplete.

Regeneration after tall hair cell damage following severe acoustic trauma in adult pigeons: correlation between cochlear morphology, compound action potential responses and single fiber properties in single animals

The time course of recovery of compound action potential (CAP) thresholds was observed in individual adult pigeons after severe acoustic trauma. Pigeons were overstimulated with a tone of 0.7 kHz and 136–142 dB SPL presented to one ear for 1 h under general anesthesia. Recovery of CAP audiograms was monitored at regular intervals after trauma. A new semi-stereotaxic approach to the peripheral part of the auditory nerve was developed. This permitted activity from single auditory nerve fibers to be recorded over a wide range of characteristic frequencies (CFs), including high CFs, without having to open the inner ear. Single unit recordings were made after three weeks and after 4 or more months of recovery. The time course of recovery, the single unit properties, and the morphological status of the basilar papilla were correlated. The CAP was abolished in all animals after overstimulation. Three groups of animals were identified according to the functional recovery of the CAP thresholds recorded at regular intervals with implanted electrodes: Group 1: Fast functional recovery starting immediately after trauma, followed by recovery to pre-exposure values within 3 weeks. Group 2: Slow functional recovery of threshold starting 1–2 weeks after trauma and ending 4–5 weeks after trauma. A mean residual hearing loss of 26.3 dB at 2 kHz remained. Group 3: No recovery of CAP thresholds up to 8 months after trauma. Three weeks after trauma, very few responsive neurons were found in groups 2 and 3. Tuning curves were very broad and sometimes irregular in shape. Thresholds were very high, around 120 dB SPL. Spontaneous firing rate was much reduced, especially in neurons with high CFs. After 4 or more months of recovery, the response properties of single units in group 1 had only partially recovered. Thresholds and sharpness of tuning of many single units were normal; however, in general they were still poorer than in control animals. Spontaneous firing rate was comparable to control animals. Neurons from animals in group 2 showed less recovery, especially at frequencies above the exposure frequency. Thresholds and sharpness of tuning were normal at frequencies below the exposure frequency, but were much poorer at frequencies above the exposure. Spontaneous firing rate was much reduced in fibers with high CFs. The basilar papilla in animals without recovery showed total loss of the sensory epithelium. The basal lamina of the basilar membrane, however, remained intact and was covered with cuboidal cells. In fast recovering animals, the papilla was repopulated with hair cells after 4 months. In slow recovering animals, short (abneural) hair cells were still missing over large parts of the papilla after 4 months of recovery. Residual short (abneural) hair cell loss was largest at two areas, one more basal and the other more apical to the characteristic place of the traumatizing frequency. The results show that functional recovery from severe damage to both short (abneural) and tall (neural) hair cells occurs in adult birds. However, the onset of recovery is delayed and the time course is slower than after destruction of short (abneural) hair cells alone. Furthermore recovery is incomplete, both functionally and morphologically. There are residual permanent hearing losses and regeneration of short (abneural) hair cells is incomplete.

Changes in CM and CAP with sedation and temperature in the guinea pig: facts and interpretation

The influence of xylazine on the amplitude, latency and waveform of VIIIth nerve compound action potential (CAP) and cochlear microphonic (CM) in response to clicks at 95 dB SPL in normal awake preimplanted guinea pigs was investigated. The animals' temperature was monitored but no thermoregulation was exerted, except in one control experiment. Following a 0.2 ml injection of xylazine, CM showed minor variations while CAP audiograms for tone pips between 0.5 and 25 kHz remained normal. However, a progressive decrease in temperature and a strongly correlated increase in CAP amplitude and in N1 and N2 latencies were noticed. For peak N1 the changes were equivalent to linear amplitude and time expansions, and could be reproduced through CAP synthesis with convolution methods using time expanded unit response model and firing density functions. All changes were maximal after 2 h of sedation and recovered within approximately another 2 h. Whereas xylazine is known to induce hypothermia, all the changes disappeared if the animal was thermoregulated. Therefore the changes are interpreted as a result of hypothermia. The mechanism of N1 latency lengthening and increase in amplitude during hypothermia can be understood as a simultaneous increase in spike duration, hair cell/nerve synaptic delay and postsynaptic time constant. This hypothesis yielded a theoretical temperature coefficient for N1 latency (−52 μs/°C) matching that measured experimentally (−55 μs/°C). When compared with peak N1, peak N2 appeared relatively more expanded. Arguments about the origin of N2 are discussed.

The effect of a taurine modified diet on normal and hydropic ears of the guinea pig

Taurine is recognised as the major osmoregulating amino acid in the brain as well as other organs. Its possible influence on normal cochlear function and on hydropic cochleas of the guinea pig was investigated here. Normally hearing adult guinea pigs were placed on either a taurine-depleting diet (B-alanine) or a taurine-supplemented diet. At the end of 6 weeks the compound action potential audiograms (CAP) in the two groups were similar and appeared not to be different from a third control group receiving a non modified diet which suggested that a taurine-modified diet had not affected normal cochlear function. In hydropic ears the taurine-depleting diet was observed, in some cases, to moderately slow down the early phase of the characteristic progression of the CAP sensitivity loss. These data are in favor of a homeostatic role for taurine in the inner ear of the guinea pig under particular conditions such as osmoregulatory stress.

Cellular and subcellular localization of tritiated gentamicin in the guinea pig cochlea following combined treatment with ethacrynic acid

Guinea pigs (GPs) receiving one intra-muscular injection of gentamicin (GM) (150 mg/kg) in which 2 mg of tritiated GM (2 mCi) were incorporated, followed 1.5 h later by an intra-cardiac injection of ethacrynic acid (EA) (30 mg/kg) were sacrificed 25 min, 1, 4 and 24 h after the EA injection. Other GPs were treated with one injection of GM or EA alone and sacrificed 24 h later. Cochlear function was monitored by recording VIIIth nerve compound action potential (CAP) responses to clicks at 70 dB peak-equivalent Sound Pressure Level (pe SPL) and CAP audiograms. At 24 h thresholds were significantly elevated for high frequencies only in GPs treated with the GM/EA combination. GM was revealed in the cochlea and kidney by autoradiography using light and electron microscopy. In the kidney GM was already detected in the proximal tubule cells at 25 min and at 24 h. In the cochlea GM was systematically not observed at 25 min. At 1 h a weak labelling was detected in vessels of the stria vascularis and in sensory cells at the base of the cochlea. At 4 h the labelling disappeared in stria vascularis but increased in the hair cells. At 24 h GM labelling was found exclusively in hair cells, particularly outer hair cells, with a gradient from base to apex and from first to 3rd row, this distribution pattern correlating well with the pattern of threshold changes prominent at high frequencies. Inside the hair cells, labelling was diffuse in the cytoplasm at an early stage but at 24 h it was clearly localized in the hair bundle area, the cuticular plate, particularly dense on the lysosomes concentrated below the cuticular plate, and over the nucleus. This specific cellular and intracellular localization of GM, and its progressive accumulation inside the hair cell body, along with the development of functional changes, tend to indicate that the toxicity results from specific intracellular effects of the aminoglycoside molecule.

Comparison of compound action potential audiograms with distortion product otoacoustic emissions in experimentally induced hydrops

Endolymphatic hydrops was induced in a series of adult pigmented guinea pigs. Distortion product oto-acoustic emissions in general reflected the typical form of the hydropic compound action potential (CAP) audiogram, either with predominant low-frequency losses or a relatively flat audiogram. However, at certain two-tone combinations in some control ears the emissions could be smaller than expected from respective CAP audiograms, while in some hydropic ears the emissions could be larger than expected. The data presented here suggest that whilst the diagnostic value of distortion product emissions in the clinical situation might, at this time, be limited, the data from these emissions can give some insight into tonotopic hair cell function.

Contribution of Increased Endolymphatic Pressure to Hearing Loss in Experimental Hydrops

After the induction of experimental hydrops there follows a strict sequence of compound action potential (CAP) audiogram changes. Within days a low-frequency loss (below 8 kHz) is detected; within weeks a very high-frequency loss (above 8 kHz) develops; and finally within months the 8-kHz region is also affected. Following the application of excess pressure, presumably to the endolymphatic spaces, via a cannula placed in the endolymphatic duct, a sequence of CAP audiogram changes occurs that is not similar to that observed with hydrops. There is first a very high-frequency loss (above 4 kHz), then a very low-frequency loss (below 4 kHz), and finally the 4 kHz region is also affected and thresholds for all frequencies become even more raised. The data thus suggest that a slow accumulation of endolymph as induced by blockage of the endolymphatic duct does not produce the same disorder as a rapid onset of a high pressure applied at the base of the cochlea. In addition the data suggest that raised endolymphatic pressure is not likely to be significant in early stages of hydrops, but could contribute to the later high-frequency sensitivity losses.

Alterations of CAP audiogram by increased endolymphatic pressure and its relation to hydrops

Most current theories regarding the inner ear pathology of Menières disease assume that there is an augmentation of the endolymphatic pressure due to the presence of hydrops. In this study normal hearing pigmented guinea pigs were employed to investigate the effect of increased endolymphatic pressure on the compound action potential (CAP) audiogram. All animals were implanted with an electrode on the round window and the CAP audiogram was determined prior to further surgery. The endolymphatic canal was then visualised by a posterior fossa intra-dural surgical approach. A hole was pierced in the canal and a cannula inserted. The CAP audiogram was again determined before, and at frequent intervals after, the application of hydrostatic pressure (0.5–1 cm Hg). A similar sequence of CAP sensitivity losses was observed within 2 h for 0.5 cm Hg or 15 min for 1 cm Hg. There was at first a very high frequency loss, followed by a very low frequency loss and finally a mid frequency sensitivity loss rendered the audiogram flat and lying around 50 dB sound pressure level. Given that the first characteristic index for experimental hydrops is a low frequency loss the present data suggest that an increase in endolymphatic pressure, as in these experiments, is likely to be a rather late pathological feature of hydrops. Indeed we have shown that a high frequency loss develops at a second phase during the evolution of hydrops.

Laser Doppler measurements of cochlear blood flow during loud sound exposure in the guinea pig.

This investigation examined the effects of loud sound of different frequencies and intensities on cochlear blood flow as measured by the laser Doppler flowmeter. Cochlear blood flow was measured in anesthetized guinea pigs during a 1 h exposure to either a 2, 4, or 12 kHz pure tone or high-pass noise (10-40 kHz) at 90, 103, or 110 dB SPL. Cochlear function was assessed using the compound action potential audiogram before and after exposure. There was no change in blood flow in the second turn with a 2, 4, or 12 kHz tone but there was a significant (P less than 0.05) decline in flow in the first cochlear turn at the end of either the 12 kHz tone or high-pass noise exposure at 103 and 110 dB SPL. There were elevations in the thresholds of the cochlear compound action potential after all but the 90 dB exposures to 12 kHz or high-pass noise. No such changes were observed in blood flow or electrophysiology in control animals. These findings demonstrate that there is a small but significant decline in cochlear blood flow with high intensity sound exposure. However, the relationship between this change in blood flow and the development of cochlear damage is unclear.