EEC hearing impairment programme: collaboration in Europe, 1974-1988.

The Commission of the European Communities funds a 'concerted action' programme in the area of hearing impairment. The programme does not fund research directly, but is intended to provide funds for coordination of research in different countries. Previous projects funded by the programme include a comprehensive study of the prevalence of childhood deafness in the European Community, and meetings on cochlear implants, human temporal bone histopathology, diagnostic techniques and hearing impairment in children. The programme is currently concerned with new technologies for communication in the hearing impaired and activities in 1988 will include workshops on signal processing hearing aids and early diagnosis in children.

Mixed conductive and sensorineural hearing loss in LP/J mice.

Air and bone conduction thresholds for the detection of a compound action potential response were measured in mice of the LP/J inbred strain, which has been proposed as a possible model for human otosclerosis. Thresholds were compared with control data from CBA/Ca mice. Evidence of a mixed sensorineural and conductive hearing loss was obtained in LP/J mice. Few signs of hair cell degeneration or middle-ear bony lesions were found in 20-day old mice, although they generally showed raised thresholds to both air and bone conducted stimuli. The reason for the observed sensorineural component of the hearing loss at this age is not clear, since endocochlear potentials were normal in mice of this strain. By 225 days of age, hair cell loss was extensive and there was clearly excess bone growth in all middle-ear specimens studied, particularly on the incus and the cochlear wall facing the middle ear. Microbiological analysis of LP/J specimens revealed no evidence of a middle-ear infection specific to these mice which might explain the pathology.

Strial dysfunction in mice with cochleo-saccular abnormalities.

Most viable dominant spotting (Wv/Wv) mutant mice, which show cochleo-saccular degeneration, were found to have an endocochlear potential (EP) around zero together with a structurally abnormal stria vascularis. Inner hair cells were well preserved, but outer hair cells in the basal half of the cochlea were degenerating, possibly as a result of primary strial dysfunction. Thresholds for the detection of a compound action potential were raised to around 100 dB SPL in the mutants with no EP, and there was little if any cochlear microphonic at the round window. Of the 20 Wv/Wv mice studied, five partially escaped the effects of the mutation and had measurable positive potentials (15-86 mV) in scala media in the basal turn; responses in these animals were intermediate between control responses and those of mutants with no EP. These findings confirm that the pathological processes in this mutant, with cochleo-saccular abnormalities, are fundamentally different from the pathological processes in animals with neuroepithelial abnormalities reported previously [see Steel and Bock (1983) Arch. Otolaryngol. 109, 22-29, for references].

Distortion product otoacoustic emissions in hearing-impaired mutant mice.

The acoustic intermodulation distortion product (2f1-f2) was recorded in the ear canal of two different types of normally hearing mice and in four different types of hearing-impaired mutant mice. In the normally hearing animals, primary tones at levels of 60- to 100-dB SPL evoked distortion product emissions (DP's) at 20-50 dB below the primary levels. In the hearing-impaired mutants the level was dependent on the particular type of auditory dysfunction associated with the mutation. In both the deafness and the viable dominant spotting mutants, where either the whole organ of Corti or the stria vascularis is affected by the mutation, no DP's could be detected. The quivering mutant has a central auditory dysfunction associated with the nuclei of the superior olivary complex and the lateral lemniscus, with apparently normal cochlear function. DP's at levels and thresholds similar to those in normally hearing animals were recorded in quivering mice. The Bronx Waltzer mutant has a full complement of outer hair cells but only about of 20%-25% inner hair cells. DP's of small amplitude were recorded but the thresholds were raised by about 30 dB. The data suggest that the 2f1-f2 emission can be used as a noninvasive monitor of cochlear function.

Combined electrophysiological and autoradiographic delimitation of retrocochlear dysfunction in a mouse mutant.

The hereditary retrocochlear dysfunction in the quivering (qv) mouse was investigated with autoradiography and single unit recordings. Whilst the cochlea appears to function normally, earlier studies had indicated some single unit dysfunction detectable at the level of the cochlear nucleus (CN) and abnormality of auditory evoked potentials recorded at the inferior colliculus (IC). The present study investigated the possibility of progressive deterioration of function at successive higher levels in the auditory system. The 2-deoxyglucose technique illustrated auditory activity in the CN of quivering mice similar to that seen in normally-hearing control animals. There was only a slight increment in metabolic activity detectable at the level of the IC. Electrophysiology demonstrated that this minimal IC activity was the result of abnormally raised thresholds associated with all single units recorded, rather than of activity in a few normally responding cells. There was no evidence from autoradiography for any enhanced auditorily evoked metabolic activity in either the superior olivary complex or the lateral lemniscus. This study suggests that the retrocochlear dysfunction in quivering mice is due to a specific abnormality at a low stage in the auditory pathway rather than being non-specific and cumulative over stages.

Genetic factors affecting hearing development.

Both genetic background and single gene mutations may affect the development of the auditory system. A classification system is presented for those single gene mutations causing hearing impairment. The new feature of this classification is the inclusion of a category for hereditary deafness of central origin. The other categories involve peripheral abnormalities and are: morphogenetic defects, in which the overall structure of the labyrinth is deformed; neuroepithelial degeneration, in which the primary defect appears to occur in the organ of Corti; and cochleo-saccular degeneration, where the stria vascularis is abnormal and Reissner's membrane collapses, leading to further degeneration.

Electrical stimulation of the auditory system in animals profoundly deaf from birth.

Animals homozygous for the recessive deafness gene (dn/dn) have been used to study central responses to modiolar or round window electrical stimulation. Inferior colliculus evoked responses to contralateral constant current pulses are larger in mutants than in controls. In mutants, responses are largest in animals aged 5-7 months, compared with animals aged 42-50 days or 13.5-19 months. The spiral ganglion cell density is normal in the youngest group, but decreases significantly in older animals. Electrical stimulation of the round window is less effective than modiolar stimulation. Single unit recordings suggest that the larger evoked responses in deafness mice are produced by stronger discharges in neurones, rather than greater synchrony of discharge. The deafness mutation appears to provide a useful animal model for studying electrical stimulation of a central pathway which has never received stimulus-related input.

The effects of paracetamol on frusemide ototoxicity.

Paracetamol (acetaminophen) is currently one of the most widely used drugs. In large doses, paracetamol is both nephrotoxic and hepatotoxic, and this toxicity may arise through the production of free radicals. Recently, there has been a revival of interest in the hypothesis that aminoglycoside antibiotics are ototoxic because they facilitate free-radical production. Aminoglycosides interact strongly with loop diuretics, producing enhanced ototoxicity. The object of the present study was to determine whether paracetamol would also interact with a loop diuretic. Pigmented guinea pigs received a dose of 500 or 1000 mg/kg paracetamol via an intragastric cannula. Compound action potentials (CAP) were recorded every 10 min for 2 h. Paracetamol alone had no effect on CAP thresholds, but significantly enhanced the CAP decrement induced by frusemide given intraperitoneally 1 h after paracetamol. This enhancement was larger in animals receiving 1000 mg/kg paracetamol. Repetition of these drug doses in recovery experiments indicated that all threshold shifts recovered within 7 days.

Brainstem responses in the quivering mutant mouse.

The recessive quivering gene in mice produces general neurological abnormalities and deafness. Previous work indicated that cochlear responses (microphonics and compound action potentials) were normal in the quivering (qv/qv) mouse, but inferior colliculus evoked potentials had poor thresholds and abnormal latencies. The object of the present study was to record evoked potentials from the cochlear nucleus (CN) in quivering and control mice, and also to record surface responses. The CN evoked response in control mice consisted of two prominent positive peaks. The first peak appeared normal in the quivering CN, resulting in normal thresholds for detection of the response. However, the second peak in mutants was smaller and of longer latency. Surface responses in quivering showed a normal first wave followed by an abnormal wave pattern. It was concluded that the input from auditory nerve to CN in quivering is probably normal and that the central deficit in quivering is evident at the level of CN.

Electrically-evoked responses in animals with progressive spiral ganglion degeneration.

The deafness (dn/dn) mouse has an hereditary cochlear dysfunction throughout its development, and spiral ganglion cell density decreases progressively over the three age groups we examined. We have used this mutant to examine inferior colliculus evoked responses to modiolar electrical stimulation as a function of spiral ganglion degeneration. No differences were found between mutants and control mice or between ages in either threshold for detection of the response or latency of the response. However, peak-to-peak amplitudes of the response were larger in the mutants than in the controls in the young and intermediate age groups. There was a poor correlation between spiral ganglion degeneration and size of the evoked response: for example, mutants in the old age group had similar amplitudes of response as controls while spiral ganglion cell density was reduced to 21% of the value in young mice, and mutants in the intermediate age group with 50% spiral ganglion degeneration showed response amplitudes more than double that in controls. These data may be relevant to the significant numbers of people with hereditary deafness among the hearing-impaired human population.

Inferior colliculus single unit responses to peripheral electrical stimulation in normal and congenitally deaf mice.

We have investigated the single unit response in the inferior colliculus of the mouse to electrical pulse stimulation at the auditory periphery. The experimental animals were deafness mutant mice (dn/dn), which have hereditary congenital peripheral pathology. The control animals were normal littermates (+/dn). Monopolar electrical pulses were applied either to the modiolus or the round window and the evoked single unit activity was recorded in the contralateral inferior colliculus (IC). Two types of single unit response were observed: a single-spike response, and a multiple-spike response. There was a predominance of the former in the control animals and of the latter in the mutants. For both modes of stimulation the group mean threshold of response was lower in mutants compared to controls, whilst the maximum number of evoked spikes per 50 presentations was higher in mutants than control animals. The mutant response pattern was similar to that seen in animals with experimentally induced auditory deprivation. The suitability of the deafness mutant as a model for the investigation of coding strategies for cochlear implants is discussed.

Use of albino animals for auditory research.

Since Hearing Research commenced publication, 51% of reports involving the use of guinea pigs provide no information on whether the animals used were albino or pigmented. Recent evidence creates a strong suspicion that the albino mutation can influence both peripheral and central auditory function. It is concluded that information on pigmentation should always be provided in reports of auditory experiments on guinea pigs, and that the only justification for using albino animals in auditory research is to study effects of the albino mutation on hearing.

Single unit responses in the cochlear nucleus of the deaf quivering mouse.

Mice homozygous for the autosomal recessive gene quivering do not have a classical Preyer reflex and appear to be deaf. Round window recordings including both cochlear microphonics and compound action potentials failed to reveal any abnormality. However, auditory-evoked potentials recorded from the inferior colliculus (IC) are small with long latencies, and the thresholds are at least 50 dB higher than those recorded in controls. This suggests that the auditory deficit arises in the auditory pathway between the cochlear nerve and IC and underlines the need for a description of the functioning of the cochlear nucleus (CN). Single units were recorded extracellularly from the CN in 9 mutants (qv/qv) and 11 control animals (+/qv, or +/+) in the age range 60-120 days. The spike response pattern in mutant animals was broadly similar to that in the controls: a sustained response with monotonic rate-intensity functions. In addition the mean Q10dB for units in the mutants was similar to that of the controls. However, in mutants the group mean threshold at the characteristic frequency was higher and the latency to the first evoked spike at 20 dB above threshold was longer than in controls. Some unit responses in the mutants were similar to those of the controls. Nevertheless, in the quivering mouse, evidence now exists of single unit dysfunction in the cochlear nucleus.

The quivering mutant mouse: hereditary deafness of central origin.

Mice homozygous for the recessive quivering gene are largely unresponsive to sound, although their cochleas appear normal by light microscopy and cochlear hair cells do not degenerate with age. Cochlear potentials and inferior colliculus evoked responses were recorded in quivering mice (qv/qv) and in littermate controls (+/qv or +/+). There were no significant differences between mutants and controls in cochlear microphonic amplitudes or compound action potential thresholds, amplitudes and latencies. However, inferior colliculus evoked responses in mutants were small in amplitude and abnormal in waveform. Latencies were long and thresholds were elevated by at least 50 dB at all frequencies tested. These data suggest that the genetic hearing impairment in quivering mice is retrocochlear.

Electrical stimulation of the cochlear nerve in deafness mice.

The deafness mouse mutant provides a useful animal model for studying the central consequences of complete auditory deprivation during development. The object of this study was to record inferior colliculus-evoked potentials in mutant and control mice, using short electrical pulses to stimulate either the whole cochlea or the cochlear nerve directly. In both experiments, evoked potentials were readily recorded in the mutant and control mice, indicating that some central connections are functional, even though the auditory pathway has received no stimulus-related input throughout development. The results are relevant to the clinical problem of restoring auditory function in the profoundly deaf using peripheral electrical stimulation.

Inner ear pathology in the deafness mutant mouse.

A distinctive cochlear pathology was found in deafness mutant mice. There was a delay in the formation of the fluid-filled Nuel and tunnel spaces in the organ of Corti, the hair cells were distorted and degenerate, and there was poor maintenance of synapses. No hair cells appeared normal by TEM, but SEM revealed some areas where stereocilia appeared relatively normal, suggesting that SEM of the surface of the organ of Corti is not necessarily a good indicator of hair cell pathology in hereditary hearing impairment. Mutant mice show normal development of endocochlear potential, but have no measurable cochlear microphonics or compound action potential. The data suggest that the deafness gene affects the organ of Corti and that cochlear hair cells in deafness mice are never functional.

Cochlear dysfunction in the jerker mouse.

Surface preparations show that the jerker (je/je) mutant mouse has a normal total number of cochlear hair cells when young but that these progressively degenerate with increasing age. However, no gross 8th nerve action potentials or cochlear microphonics could be detected at the round window in 12-20-day-old mutants, although many hair cells still appear to be intact at these ages. Light microscopy of surface preparations is apparently a poor indicator of the functional state of hair cells, at least in genetically determined inner ear defects. The endocochlear potential (EP) was significantly higher in the mutants than in controls during the maturation of the cochlea. During anoxia induced in adults, EP fell to a significantly less negative value in mutants than in control mice. This abnormality in the anoxia potential probably reflects an organ of Corti abnormality.

A method for monitoring end-tidal CO2 during neurophysiological experiments on small laboratory animals.

The Hewlett Packard Model 47210A Capnometer, intended for monitoring expired CO2 in human patients, can be modified for use in acute neurophysiological studies on small animals. The airway adaptor which would normally be attached to an endotracheal tube is modified and its internal volume is reduced to 0.2 ml, and is incorporated into a guinea pig head-holder. We have verified that the modification does not alter the Capnometer's accuracy. There is no significant increase in resistance in the airway when the adaptor is in place, and the waveform of instantaneous CO2 shows rapid changes on inspiration and expiration with well-resolved peaks and troughs. Measurement of arterial pCO2 suggests that the Capnometer and modified airway adaptor form an accurate system for obtaining a continuous record of end-tidal CO2 in small guinea pigs.

Hereditary inner-ear abnormalities in animals. Relationships with human abnormalities.

A classification scheme for inner-ear abnormalities is defined, based on animals with hereditary inner-ear defects. Three major groups are (1) morphogenetic abnormalities, involving gross structural deformities of the labyrinth; (2) neuroepithelial abnormalities, in which there appears to be a primary organ of Corti defect and Reissner's membrane remains in its normal position; and (3) cochleosaccular abnormalities, showing collapse of Reissner's membranes and restriction of vestibular abnormalities to the saccule. Recent experimental findings in hearing-impaired animal mutants are taken into account. The relevance of the classification of scheme to conditions in humans is discussed. It is suggested that the Mondini and Michel deformities in humans are best considered together in the morphogenetic group. Some cases of inner-ear abnormality in humans might be considered as belonging to the neuroepithelial group.