Biomedical subjects

R J Mount

Publications and source records attributed to R J Mount.

At least 37 records · Page 2Linked to original sources

PubMed1996

Recording from the inferior colliculus following cochlear inner hair cell damage.

The anti-cancer drug carboplatin has been used to generate inner hair cell (IHC) lesions in the cochleae of chinchilla. This model has provided a valuable physiological tool for the study of the auditory system, particularly concerning the relative roles of IHCs and outer hair cells (OHCs). We recorded responses to contralateral sound stimuli of single units (SU) in the central nucleus (CN) of the inferior colliculus (IC) from normal and carboplatin treated animals. Normal single unit thresholds and frequency tuning curves (FTCs) were found, despite gross IHC damage within the cochleae of carboplatin treated animals. No evoked afferent responses could be detected in CN regions which represented cochlear loci where total IHC loss had occurred. Normal frequency selectivity in the auditory system is possible with small numbers of surviving IHCs provided OHCs remain normal.

Animals↗

PubMed1996

The neonatal chinchilla cochlea: morphological and functional study.

The developmental time scale of the cochlea varies from species to species. We investigate here the condition of the neonatal cochlea in the chinchilla, a species increasingly used in auditory research. We have examined the morphology of cochlear hair cells using scanning microscopy, and the development of auditory function during the first postnatal month by monitoring auditory brainstem evoked responses (ABR). We find that although there were some outer hair cell kinocilia present in middle and apical areas, the hair cells otherwise were mature at 24 hours after birth. Furthermore, cochlear auditory thresholds are adult-like at birth. However, whilst there was little change in ABR thresholds over one month, there is evidence of continued maturation of the central auditory system as shown by the shortening of the PI-P5 latency from 9.1 ms to 7.7 ms.

Animals↗

PubMed1995

Effects of chronic cochlear damage on threshold and frequency tuning of neurons in AI auditory cortex.

We describe the effects of long-term cochlear lesions on the frequency response properties of AI cortical neurons in the cat. Young animals were treated with amikacin to produce bilateral, basal to mid-turn cochlear lesions. After 12-24 months the response properties of single neurons or small unit clusters in primary auditory cortex were recorded in anesthetized animals. Responses to stimulus frequency and intensity were mapped in detail and frequency threshold curves (FTCs) and Q10dB values were derived. Subsequent to recording experiments, scanning electron microscopy of the sensory epithelium was used to characterize the degree and extent of the cochlear damage. In normal control animals, Q10dB values were, on average, lower than those derived by others from cochlear nerve fibre recordings in the same species. In amikacin-treated animals, deterioration was evident in the threshold and tuning properties of cortical neurons, particularly in those cells whose input originated in damaged cochlear regions. Often, neurons associated with 'normal' cochlear areas (as assessed by scanning microscopy) also had poor frequency tuning compared with controls. As an animal model of sensorineural hearing loss, we consider the cat with long-term cochlear lesions to be more appropriate than animals with acute or short-term pathology. We also suggest that in making physiological-psychophysical correlations, neural responses from the central auditory system (e.g. cortex) should perhaps be given more consideration than data derived at the cochlear level.

Amikacin↗

PubMed1995

Carboplatin ototoxicity in the chinchilla: lesions of the vestibular sensory epithelium.

Carboplatin (cis-Diammine-1,1-cyclobutane dicarboxylate platinum II; CBDCA) is a second generation platinum analog with less nephrotoxicity and cochlear ototoxicity than cisplatin, the first generation platinum chemotherapeutic agent. Studies in many animal species have indicated that carboplatin ototoxicity is expressed as damage to cochlear outer hair cells. The lesion is similar, though less severe, than that resulting from cisplatin intoxication. Recent investigations by our laboratory have demonstrated a species-specific ototoxicity of carboplatin in the chinchilla cochlea. Contrary to other animal models, the inner hair cells are the focus of damage; the outer hair cells often sustain little or no damage. Clinical evidence points to vestibular dysfunction in some patients treated with platinum-containing anti-tumoural agents. However, no morphological studies have shown degeneration of the sensory cells in the vestibular labyrinth resulting from carboplatin treatment. The objective of the present study was to determine whether, in view of its unique toxicity in the chinchilla, carboplatin has any toxic effect on the vestibular end organs. Preliminary investigations of the vestibule by light and scanning electron microscopy indicate that sensory cell cilia became exfoliated or deformed in the crista, utricle and in one instance in the saccule. In general the pattern of damage is similar to that caused by other known ototoxic agents including aminoglycosides and cisplatin.

Animals↗

PubMed1994

Cochlear function after selective inner hair cell degeneration induced by carboplatin.

The ototoxicity of carboplatin, a second generation anti-cancer agent, was examined using the chinchilla as an animal model. In animals treated with a clinical therapeutic dose (400 mg/m2), the dominant degenerative change is to inner hair cells (IHCs). This is in sharp contrast to most other ototoxic agents, which damage primarily the outer hair cells (OHCs). Functional changes to the cochlea have been evaluated in carboplatin treated subjects by recording cochlear action potentials (CAP) and cochlear microphonics (CM); cochlear lesions were evaluated using scanning electron microscopy. In carboplatin treated animals, CAP thresholds to tone-pip stimuli were elevated in proportion to IHC damage in corresponding cochlear regions. In contrast, CM amplitudes and 'thresholds' remained close to normal in most cases, reflecting the preservation of OHCs in the basal turn. These results indicate a high degree of independence between the inner and outer hair cell systems in the cochlear transduction mechanism. We suggest that this species-specific preparation with selective IHC loss will provide a valuable tool for studying, separately, the role of OHCs in both afferent and efferent cochlear function.

Acoustic Stimulation↗

PubMed1994

Induction of selective inner hair cell damage by carboplatin.

Carboplatin (diammine [1,1 cyclobutane dicarboxylato (2)-0,0'] platinum) is an anti-cancer agent which can be toxic to the inner ear. We have explored the nature of this ototoxicity in the chinchilla. In this species, initial degenerative changes appear to be restricted to the inner hair cell (IHC) regions of the organ of Corti. This finding is intriguing and unusual since all other known ototoxic drugs, such as aminoglycosides, are predominantly associated with outer hair cell damage. In the present study, the mechanism of ototoxicity was investigated by comparing two different routes of carboplatin administration. Carboplatin was administered either intravenously (i.v.) or intraperitoneally (i.p.). The mode of administration influenced electrophysiological and morphological changes. Hearing thresholds were elevated in the i.v. group significantly more than in the i.p. group at all tested frequencies. The degree of hair cell damage was evaluated by scanning electron microscopy at four frequency regions in each cochlea. IHC damage in the i.v. group was significantly more severe than in the i.p. group. Carboplatin effects on a different species, the guinea pig, were also determined to clarify interspecies differences. In the guinea pig, outer hair cell damage occurred sporadically and inner hair cells remained intact. In contrast, chinchilla inner hair cells are susceptible to the ototoxic effects of carboplatin. The degree of hair cell damage appears to be dependent on the peak level of carboplatin rather than on the total dose. This animal model provides a new tool for the investigation of inner and outer hair cell function.

Animals↗

PubMed1993

Auditory evoked potentials in cats with neonatal high frequency hearing loss. Evidence of abnormal frequency representation in the midbrain.

We have recorded auditory evoked potentials, of both neurogenic and myogenic origin, in cats having neonatal high frequency cochlear hearing loss. Using frequency specific stimuli (tone pips) and by measuring responses near to threshold, we have probed tonotopic (or cochleotopic) representation within the brainstem-midbrain auditory pathway. At stimulus frequencies corresponding to the high frequency cut-off of the cats' audiograms we have observed enhanced amplitudes of both auditory brainstem evoked responses (ABR) and postauricular myogenic (PAM) potentials. We interpret our findings as evidence of a larger than normal population of neurons tuned to this frequency region. We suggest that such abnormal frequency representation results from a long-term sensory deficit caused by lesions to the basal, high frequency region of the cochleas.

Animals↗

PubMed1993

The MRL-lpr/lpr mouse: a potential model of autoimmune inner ear disease.

Most attempts at developing a model of autoimmune inner ear disease have focused on the immunization of healthy animals with cochlear tissue. We have chosen an alternate route of studying this entity utilizing the MRL-lpr/lpr (Lupus) mouse, an animal known to spontaneously develop multisystemic, organ nonspecific autoimmune disease. We report on the auditory pathology found in animals at early stages of this systemic disease. At the onset of clinical signs of illness (cachexia, weight loss, lethargy) animals were sacrificed and their cochleas and kidney prepared for morphologic analysis. Significant pathology was seen in the MRL/lpr animals involving the basal and middle turns of the cochlea which could not be correlated with the presence or degree of glomerulonephritis. Findings included outer and inner haircell degeneration, strial edema and degeneration, and an acellular infiltrate in the tunnel of Corti. Cochlear pathology was not found in control animals. Thus, at early stages of systemic disease, MRL/lpr mice manifest significant cochlear pathology not seen in control animals. The implications of these results with regard to the pathogenesis of these lesions as well as their clinical relevance are discussed.

Animals↗

PubMed1993

Neonatal cochlear hearing loss results in developmental abnormalities of the central auditory pathways.

We have used animal models of long term neonatal cochlear hearing loss to study developmental plasticity of the central auditory pathways. Newborn chinchilla pups and feline kittens were treated with the ototoxic drug amikacin, so as to induce basal lesions in the cochlea. At maturity these animals were used in single unit electrophysiological mapping studies, in which the cochleotopic organization of primary auditory cortex (of the cat) and the inferior colliculus of the midbrain (in the chinchilla) were mapped. We have observed, both in the midbrain and auditory cortex, massive reorganization of frequency representation. Most striking were the presence of large monotonic regions (i.e. large areas in which all neurons have similar tuning properties). Cochlear lesions which involve inner hair cells clearly modify the normal development of cochleotopic representation in the midbrain and cortical regions. We suggest that similar abnormal patterns of frequency representation will exist in human subjects with long term neonatal hearing loss.

Amikacin↗

PubMed1993

Damage to cochlear efferents following AF64A intoxication.

Damage to cochlear efferents in chinchillas was assessed using transmission electron microscopy following unilateral treatment with the cholinotoxin ethylcholine mustard aziridinium ion (AF64A). AF64A was diluted in artificial perilymph to concentrations ranging from 0.5 to 100 microM. Survival times ranged from 1 to 12 weeks. At concentrations above 10 microM, widespread damage was noted to efferent fibers within the inner spiral bundle (ISB), tunnel spiral bundle (TSB), tunnel radial fibers (TRF) and efferent terminals at the base of OHCs. This damage included degeneration of fibers and terminals, delamination of mitochondria, vacuolization, and loss of cell membrane. However, at high concentrations, non-specific damage was also noted as thinnings or discontinuities of the membrane of OHCs and afferent fibers. At concentrations between 3 and 10 microM, selective damage was observed to efferent fibers within the ISB, TSB, TRF, and to terminals at the base of the OHCs, with all other structures appearing normal. At concentrations of 0.5 and 1 microM, damage was limited to efferent fibers within the TSB and ISB below the inner hair cells. In general, insult was greatest to middle- and basal-turn efferents, and longer survival times did not produce greater damage to, or loss of, efferents. These data suggest that at low concentrations, AF64A produces a partial yet selective degeneration of cochlear efferents within both the medial and lateral tracts, and that at the lowest concentrations used in these studies, AF64A produces a preferential insult on lateral olivocochlear efferents.

Animals↗

PubMed1993

Three-dimensional cytoskeletal structures of the chinchilla organ of Corti: scanning electron microscopy application of the polyethylene glycol method.

We describe the application of a polyethylene glycol (PEG) embedding technique to examine the sensory and supporting structures of the inner ear. The chinchilla organ of Corti was exposed by cracking PEG embedded cochleas. A range of PEG molecular weights (2000-8000) were utilized; PEG 2000, with a melting point of 57 degrees C was preferred. After removal of the PEG, the three-dimensional aspects of intracellular structures were observed using scanning electron microscopy. Filamentous elements in the hair cell cuticular plate and in the supporting cells were clearly observed, as was the meshwork of cross-linked actin filaments in the cuticular portion of sensory hair cells. Microtubule and microfilament alignment patterns in pillar and Deiters cells were also clearly demonstrated. Characteristic structures in the outer hair cell synaptic region, such as the post-synaptic cistern and synaptic body, were well preserved using the PEG method.

Actin Cytoskeleton↗

PubMed1993

The effects of long-term cochlear hearing loss on the functional organization of central auditory pathways.

We have developed an animal model of neonatal high-frequency cochlear hearing loss to investigate the long-term effects on the central auditory pathways. Specifically, we have induced basal cochlear lesions in newborn kittens using the ototoxic aminoglycoside, amikacin. We have monitored the consequent auditory threshold elevations using auditory brainstem evoked responses (ABR) to tone pip stimuli. In the mature animal we have mapped tonotopic (cochleotopic) representation in primary auditory cortex (AI) using standard micro-electrode recording techniques, and we show that this map becomes massively re-organized. In particular, one frequency area that corresponds to the high frequency cut-off slope of the subject's audiogram appears to become greatly expanded, in some cases to take up 75% of AI surface. In general, the development of normal cochleotopic or tonotopic representation in cortex appears to depend upon the integrity of ascending sensory input from the cochlea particularly during early stages of development. With the clinician in mind, we discuss our findings in relation to practical issues.

Acoustic Stimulation↗

PubMed1991

Reorganization of auditory cortex after neonatal high frequency cochlear hearing loss.

Cochleotopic representation in cortex (AI) is extensively reorganized in cats having neonatal, bilateral high frequency cochlear hearing loss. Anterior areas of AI, normally devoted to high frequencies, contain neurons which are almost all tuned to one lower frequency. This frequency corresponds, at the level of the cochlea, to the border between normal and damaged haircell regions.

Amikacin↗

PubMed1991

Morphological changes to the cochlea in an animal model of profound deafness.

We have used systemic application of the ototoxic drug amikacin, to induce total cochlear haircell loss in the chinchilla, in order to create an animal model of profound deafness. We have produced models of both neonatal deafness (by treatment of new-born pups), as well as of acquired total hearing loss (by treatment of mature animals). We present a description of our techniques for producing cochlear lesions and for evoked potential monitoring of the resulting threshold elevations. We also give a qualitative description of cochlear haircell damage as viewed by scanning electron microscopy, and a quantitative assessment of the spiral ganglion cell survival after total haircell loss.

Amikacin↗

PubMed1991

Cytoarchitecture of cochlear nucleus in the chinchilla.

The morphology of the cochlear nucleus in the normal, adult chinchilla, as demonstrated by Nissl staining, was examined. The cytoarchitecture was determined from sections viewed at the light microscope level. The chinchilla cochlear nucleus was found to possess most of the features reported in other mammalian cochlear nuclei. It could easily be divided into dorsal and ventral components due to an intervening layer of granule cells, and most cell types previously reported in mammals were also found in the chinchilla cochlear nucleus. A distinct distribution pattern of cell types exists within each part.

Animals↗

PubMed1991

Effects of total cochlear haircell loss on integrity of cochlear nucleus. A quantitative study.

In cochleas of chincillas treated with amikacin, cochlear sensory cells were totally destroyed in all new-born animals. In animals treated as adults some occasional haircells remained in apical turns. In the neonatally treated animals, the resulting auditory deprivation significantly affected the volume of the ventral cochlear nucleus and large-dark spherical cell area. The density of large-dark spherical cells increased significantly from normal in both neonatally and adult treated groups. Our results suggest that the VCN is more dependent on auditory stimulation for proper development than the DCN. In adult chinchillas treated with amikacin there was a significant change in large-dark spherical cell density without a change in total cell numbers or large-dark spherical cell area volume. Our study indicates that the mature cochlear nucleus is much more resistant to the effects of auditory deprivation than the developing cochlear nucleus and that the maintenance of the mature auditory system is not as dependent on auditory stimulation. Studies such as this examining the morphological effects of profound cochlear deafness on higher levels of the auditory system are essential in cochlear implant research.

Amikacin↗

PubMed1991

Three dimensional intracellular structure of the cochlea using the A-O-D-O method.

We have observed the three-dimensional intracellular structure of the organ of Corti and the spiral ganglion of the chinchilla using the aldehyde osmium-DMSO-osmium (A-O-D-O) method, and compared our findings with previous studies in the guinea pig. In cells of the spiral ganglion and the organ of Corti, microtubules and other cytoplasmic filaments were digested by OsO4 during processing to provide a clear view of membranous structures such as mitochondria, endoplasmic reticulum and Golgi apparatus. The appropriate digestion time with 0.1% OsO4 solution was found to be 60-80 hrs for the organ of Corti and 70-90 hrs for the spiral ganglion. The A-O-D-O method has been especially useful to show the organization of the endoplasmic reticulum of the outer hair cells. We have made a further characterization of the apical cistern, a reticular network which appears to link the basal body of the (vestigial) kinocilium to both Hensen's body and the subsurface cisternae.

Animals↗

PubMed1991

Correlation of cochlear pathology with auditory brainstem and cortical responses in cats with high frequency hearing loss.

Newborn kittens were treated with the aminoglycoside amikacin to produce a bilateral high frequency cochlear hearing loss. The degree and stability of hearing loss were confirmed by recording auditory brainstem evoked potentials (ABR audiograms). After maturation, cochleotopic frequency representation within primary auditory cortex (AI) was mapped using standard microelectrode recording techniques. The cochlear sensory epithelium was assessed with SEM and the pattern of damage compared with the ABR audiograms and cortical frequency maps. Amikacin treatment resulted in various patterns of haircell damage towards the base of the cochlea. A relatively abrupt transition between damaged and undamaged haircell regions resulted in an ABR audiogram with normal threshold to low frequencies and a high frequency elevation with a steep cut-off slope. In the cortical map, low frequency representation was normal, but anterior areas contained only neurons tuned to a common frequency which corresponded to the frequency-place position of the boundary of the haircell lesion and to the cut-off frequency of the audiogram. A large transitional zone of the cochlear lesion correlated with a gradual cut-off slope to the audiogram and again a remapping of the anterior and normally high frequency area to a common lower frequency. Haircell loss or damage (i.e. disarray of stereocilia) in lower frequency regions of the cochlea correlated with a significant reorganization of the lower frequency bands in the cortical map. We conclude from this study that the pattern of cochleotopic organization of the cortex is dependent on the pattern of activity in the ascending sensory pathway during early stages of development.

Amikacin↗