Auditory Ganglion Cells Research Articles

Pathophysiological mechanisms and functional hearing consequences of auditory neuropathy.

The effects of inner ear abnormality on audibility have been explored since the early 20th century when sound detection measures were first used to define and quantify 'hearing loss'. The development in the 1970s of objective measures of cochlear hair cell function (cochlear microphonics, otoacoustic emissions, summating potentials) and auditory nerve/brainstem activity (auditory brainstem responses) have made it possible to distinguish both synaptic and auditory nerve disorders from sensory receptor loss. This distinction is critically important when considering aetiology and management. In this review we address the clinical and pathophysiological features of auditory neuropathy that distinguish site(s) of dysfunction. We describe the diagnostic criteria for: (i) presynaptic disorders affecting inner hair cells and ribbon synapses; (ii) postsynaptic disorders affecting unmyelinated auditory nerve dendrites; (iii) postsynaptic disorders affecting auditory ganglion cells and their myelinated axons and dendrites; and (iv) central neural pathway disorders affecting the auditory brainstem. We review data and principles to identify treatment options for affected patients and explore their benefits as a function of site of lesion.

The spiral model of pitch: Interrelations with musical and psychoacoustic scales and with cochlear parameters

A spiral model of pitch can represent pitch chroma and pitch height. Its arclength provides the frequency-position map of the cochlea, and, when scaled by the number of auditory-ganglion cells, provides the Mel scale. Pitch-like scales fall into three groups. Group I is typified by the Cent scale, which can be expressed as a pitch spiral. Other Group-I scales are musical notation, logarithmic scales of frequency, Fechners Law for complex tones, and the pitch helix. Group II is typified by Greenwoods cochlear map, which is simply related to the arclength of the pitch spiral. Other Group-II scales are the sums of the number of (a) equivalent-rectangular bandwidths (NERBs); (b) difference limens for frequency (NDLFs); and (c) inner-hair cells (NIHCs) and are consistent with critical ratios. Group III is typified by the Mel Scale, which can be derived from the pitch spiral and the distribution of auditory-ganglion cells. Other Group-III scales are the sums of the number of (a) auditory ganglion cells (NSGCs), (b) frequency-modulation-difference limens (NFMDLs), and (c) Barks (NBARKs). The pitch spiral seems a basic concept from which other pitch-like scales can be derived.

A dominantly inherited progressive deafness affecting distal auditory nerve and hair cells.

We have studied 72 members belonging to a large kindred with a hearing disorder inherited in an autosomal dominant pattern. We used audiological, physiological, and psychoacoustic measures to characterize the hearing disorders. The initial phenotypic features of the hearing loss are of an auditory neuropathy (AN) with abnormal auditory nerve and brainstem responses (ABRs) and normal outer hair cell functions [otoacoustic emissions (OAEs) and cochlear microphonics (CMs)]. Psychoacoustic studies revealed profound abnormalities of auditory temporal processes (gap detection, amplitude modulation detection, speech discrimination) and frequency processes (difference limens) beyond that seen in hearing impairment accompanying cochlear sensory disorders. The hearing loss progresses over 10-20 years to also involve outer hair cells, producing a profound sensorineural hearing loss with absent ABRs and OAEs. Affected family members do not have evidence of other cranial or peripheral neuropathies. There was a marked improvement of auditory functions in three affected family members studied after cochlear implantation with return of electrically evoked auditory brainstem responses (EABRs), auditory temporal processes, and speech recognition. These findings are compatible with a distal auditory nerve disorder affecting one or all of the components in the auditory periphery including terminal auditory nerve dendrites, inner hair cells, and the synapses between inner hair cells and auditory nerve. There is relative sparing of auditory ganglion cells and their axons.

Pathology and physiology of auditory neuropathy with a novel mutation in the MPZ gene (Tyr145->Ser).

We studied a family with hereditary sensory motor neuropathy and deafness accompanying a missense mutation in the MPZ gene. Pathological examination of the cochlea in one of the family members revealed marked loss of auditory ganglion cells and central and peripheral auditory nerve fibres within the cochlea. The inner hair cells were of normal number with preserved morphology. The outer hair cells were normal in number except for a 30% reduction in just the apical turn. Examination of the sural nerve and the auditory nerve adjacent to the brainstem showed marked loss of fibres with evidence of incomplete remyelination of some of the remaining fibres. Studies of auditory function in surviving family members using electrophysiological and psychoacoustic methods provided evidence that the hearing deficits in this form of auditory neuropathy were probably related to a decrease of auditory nerve input accompanying axonal disease. Altered synchrony of discharge of the remaining fibres was a possible additional contributing factor.

Emerging Concepts of Hearing Loss in Paget's Disease of Bone

Hearing loss has been recognized as a clinical feature of Paget’s disease of bone since Sir James Paget’s first case report (1). Involvement of the skull is commonly associated with involvement of the temporal bones and with hearing loss in Paget’s disease (2). An older concept that hearing loss in Paget’s disease is due to multiple mechanisms is giving way to a newer concept that there is a general mechanism causing hearing loss in most cases (3). Clinical and audiometric studies of hearing loss in Paget’s disease have described high-frequency sensorineural hearing loss and a low-frequency air–bone gap in most cases (4). (An air–bone gap indicates that auditory thresholds when measured by bone conduction are better than those predicted by air conduction thresholds.) An air–bone gap is usually interpreted as indicating a conductive type of deafness. Hearing levels have been shown to progress more rapidly in untreated Paget’s disease than in uncomplicated presbycusis (5). Histologic studies in the 1960s and 1970s showed a variety of derangements, including compression and stretching of the auditory nerve, microfractures of the otic capsule, loss of auditory hair cells and ganglion cells, invasion of labyrinthine spaces, and envelopment of ossicles by pagetic bone (4,6,7). More recently, histopathologic studies have also shown atrophy of the spiral ligament and endolymphatic hydrops (8). The presence of toxic cytokines has been shown in otosclerosis and suggested in Paget’s disease. Most of these data consist of histopathologic reports of advanced cases. On the other hand, the prominent histopathologist of the temporal bone, Harold F. Schuknecht, had long held the view that such dramatic findings were not the rule. He analyzed the largest group of histopathologic cases of Paget’s disease of the temporal bone to date in 1990 (9). Using a technique of graphic analysis that compared hearing levels in the range of the speech frequencies versus the loss of auditory hair cells and ganglion cells that carry the neural place code for each of those tones, he could not demonstrate any systematic relationships. Aside from the presence of pagetic bone, the specimens were typical for the age of the subjects. There were no findings that would explain the air-bone gap, such as fixation or disruption of the auditory ossicles.

Mitosis and apoptosis in postnatal auditory system of the C3H/He strain

The mouse auditory neurons, hair cells and their supporting cells in the cochlea are considered to be generated mainly in the embryonic days and to be sustained throughout the whole life. In the present study, however, we observed that auditory ganglion cells in the spiral ganglia undergo apoptosis and mitosis in the suckling mouse (1- to 2-week-old C3H/HeJ mice) with a normal auditory system. In spiral ganglia at postnatal days 7 (P7) and 10 (P10), TUNEL (TdT-mediated dUTP nick-end labeling)-positive and morphologically apoptotic ganglion cells were found. Furthermore, by bromodeoxyuridine labeling, mitosis of auditory ganglion cells was found at P10 to P14. In a functional study of auditory brainstem response, we demonstrated that the C3H/HeJ mouse acquires the ability to hear airborne sound at P12 and this is the same time as the opening of their external acoustic meatus (EAM). These results indicate that C3H/HeJ auditory ganglion cells have the ability to proliferate even after opening of the EAM and the initial input of airborne sound. We found that postnatal apoptosis and mitosis after P7 also occurred in the greater epithelial ridge (GER) which is an important organ for maturation of the organ of Corti and is located around the inner hair cells. This indicates that GER cells are not only degenerated but also regenerated until their disappearance around P12. This is the first report on mammals to demonstrate that neuronal mitosis of spiral ganglion cells and that of GER cells occur not only in embryonic and neonatal development but also in postnatal development of the normal auditory system.

A 3-D model of membrane specializations between human auditory spiral ganglion cells.

A three-dimensional model of the cell membrane contact area was made between two large spiral ganglion cells (type 1 cells) from a cell cluster in a normal human cochlea. The freshly fixed cochlea had been removed during skull base surgery, processed, and sectioned for ultrastructural analysis. 400 consecutive serial thin sections were prepared from the apical portion where the nerve cell density is high and cell clusters are numerous. A cell cluster is defined as a conglomerate of two or more nerve cell bodies, surrounded by common Schwann cells. Direct physical contact between ganglion cell membranes (ephapse) was possible, in places where adjacent cells lacked a separating Schwann cell layer (gaps). One such gap was selected, and observed in 57 of 90 consecutive sections. Membrane specializations, observed in 36 sections, were found to be of principally three different types namely: (1) symmetrical, (2) asymmetrical, and (3) asymmetrical subplasmalemmal. The functional properties of these membrane specializations are still unknown. Asymmetrical densities were seen on one or other of the two cell membranes. A graphic model based on serial thin sections was made to illustrate the gap area. Superficially membrane specializations were seen to form small disk-like areas varying in size, the largest measuring 3 x 2 microm. It is speculated whether these unique formations between human spiral ganglion cells, which have not been observed in other species, may constitute interactive electrotonic or ephaptic transmission pathways. These may be in the low-frequency region and may increase plasticity and signal acuity related to the coding of speech.

Development of ganglion cell topography in the postnatal cochlea

In mammals, the size and number of spiral ganglion cells can vary significantly along the length of the cochlea. At present, it is unclear how these topologic differences in spiral ganglion cell morphology and density emerge during development. We addressed this issue by quantifying developmental changes in the number, density, and size of auditory ganglion cells within the cochlea of Mongolian gerbils throughout the first 3 weeks of postnatal life. In each cochlea, cells were measured at five standardized locations along the length of the spiral ganglion, as determined from serial reconstruction of Rosenthal's canal. During the first postnatal week, the total number of gerbil spiral ganglion cells decreased significantly by 27%, without further change thereafter. This brief period of neuronal cell death coincides with a major remodeling in the afferent neural projections to gerbil auditory hair cells (Echteler [1992] Proc. Natl. Acad. Sci. USA 89:6324–6327). The resulting reduction in neuronal density varied with location, being most prominent within the upper basal and lower middle turns of the cochlea. These same regions contained the smallest auditory ganglion cells found within the gerbil ear and exhibited the least amount of developmental expansion in the circumference of Rosenthal's canal. These results suggest the possibility that regional differences in auditory neuron size and number might be influenced by local extrinsic factors, such as the availability of canal space. J. Comp. Neurol. 425:436–446, 2000. © 2000 Wiley-Liss, Inc.

Development of ganglion cell topography in the postnatal cochlea

In mammals, the size and number of spiral ganglion cells can vary significantly along the length of the cochlea. At present, it is unclear how these topologic differences in spiral ganglion cell morphology and density emerge during development. We addressed this issue by quantifying developmental changes in the number, density, and size of auditory ganglion cells within the cochlea of Mongolian gerbils throughout the first 3 weeks of postnatal life. In each cochlea, cells were measured at five standardized locations along the length of the spiral ganglion, as determined from serial reconstruction of Rosenthal's canal. During the first postnatal week, the total number of gerbil spiral ganglion cells decreased significantly by 27%, without further change thereafter. This brief period of neuronal cell death coincides with a major remodeling in the afferent neural projections to gerbil auditory hair cells (Echteler [1992] Proc. Natl. Acad. Sci. USA 89:6324-6327). The resulting reduction in neuronal density varied with location, being most prominent within the upper basal and lower middle turns of the cochlea. These same regions contained the smallest auditory ganglion cells found within the gerbil ear and exhibited the least amount of developmental expansion in the circumference of Rosenthal's canal. These results suggest the possibility that regional differences in auditory neuron size and number might be influenced by local extrinsic factors, such as the availability of canal space.

Cochlear implantation: relationships with research on auditory deprivation and acclimatization.

This paper reviews research on cochlear implantation relevant to deprivation and acclimatization with acoustical hearing aids. The term "deprivation" is used in its everyday sense to refer to the bilateral absence of acoustic stimulation. Results are reviewed from several sources, with detailed evidence presented from three groups of postlingually deafened adult patients and one group of prelingually deafened child patients, all implanted at the University of Iowa. Outcomes from implantation reveal consistent effects of deprivation, evidenced by significant negative correlations between accuracy of speech perception and the duration of profound/total deafness before implantation. Outcomes also show acclimatization in the form of significant improvements in performance over time after implantation. For adult patients, the level of performance measured shortly after implantation on average is about half the level measured eventually. Individually, 80% of the adult patients implanted in Iowa show significant performance improvements with time. On average, performance reached asymptote after 30 to 40 mo of implant use, although individual differences in the rate and amount of improvement are large. Absolute accuracy of speech perception with implants by adults is believed to be related to preoperative measures in three domains: 1) the number and physiological responsiveness of auditory ganglion cells and nerve fibers, indexed by measures of hearing sensitivity, duration of deafness, and age; 2) the responsiveness of the central nervous system, indexed by measures of cognitive and linguistic ability, and possibly also by age and duration of deafness; and 3) the motivation to learn to use the implant. Preliminary analyses suggest that the measures in the first domain are more strongly associated with the immediate benefit from implantation than with the subsequent improvement in performance over time.

Central projections of cochlear nerve fibers in the alligator lizard

The auditory (cochlear) ganglion cells of the alligator lizard (Gerrhonotus multicarinatus) give rise to two types of peripheral fibers: tectorial fibers, which contact hair cells covered by a tectorial membrane, and free-standing fibers, which contact hair cells without a tectorial membrane. To determine the central projections of these fibers, we applied intracellular and extracellular injections of horseradish peroxidase (HRP) to the peripheral component of the cochlear nerve. After histological processing with diaminobenzidine, individual cochlear nerve fibers could be traced through serial sections with the aid of a light microscope and drawing tube. The projection patterns formed two morphologically distinct groups. Neurons whose peripheral processes contacted tectorial hair cells in the cochlea projected to three divisions of the cochlear nucleus: nucleus magnocellularis lateralis (NML), nucleus magnocellularis medialis (NMM), and nucleus angularis lateralis (NAL). Neurons whose peripheral processes contacted free-standing hair cells projected primarily to the nucleus angularis medialis (NAM), although some also sent a single, thin branch to the NML; these neurons never projected to NAL or NMM. Morphometric comparisons of tectorial and free-standing fibers demonstrate that tectorial fibers have a larger axonal diameter, form a greater number of terminal swellings, and make proportionally more somatic contacts. By correlating the morphologically defined groups with previously reported physiologically defined groups, we conclude that different divisions of the cochlear nucleus are associated with separate frequency ranges and that stimuli in the different frequency ranges may be processed separately in the brain.

Regeneration of the eighth nerve fibers after transection in the red-eared turtle, Chrysemys scripta elegans.

The present study examined the time sequence of degeneration and regeneration after transection of the eighth nerve in the red-eared turtle as well as the chromatolytic reaction of the turtle auditory ganglion cells. Horseradish peroxidase (HRP) transport between auditory ganglion cells and the medulla identified eighth nerve connections. The course of eighth nerve degeneration was followed with Fink and Heimer degeneration stain and HRP reaction. Cresyl-violet-stained sections through auditory ganglion cells were observed for chromatolysis. Degeneration by-product was intense in the eighth nerve and primary auditory nuclei in turtles surviving 25 and 32 days after eighth nerve transection. Turtles surviving 45 days or less after eighth nerve transection showed HRP reaction product in the eighth nerve to the point of its dorsolateral penetration into the medulla following cochlear duct injections. Acoustic tubercle injections in 50-day survivors showed HRP filling in eighth nerve and auditory ganglion cells. Cochlear duct injections in 67-day survivors demonstrated HRP filling in the eighth nerve and acoustic tubercle. Sections stained for degeneration in 67-day survivors showed little or no degeneration by-product and 80- and 90-day survivors showed none. The proportion of chromatolytic auditory ganglion cells was greatest in the 50-day postoperative turtles when compared to control turtles and other survival stages. Animals which survived longer than 50 days had reduced numbers of chromatolytic cells. Results suggest that the eighth nerve fibers are regenerated to primary brainstem auditory nuclei in experimental turtles surviving 50 days or more. Regeneration occurs between the 45th and 50th day following transection.

Dynamic effects in the input/output relationship of auditory nerve

Cyclic histograms of the responses of single auditory ganglion cells in the guinea pig were recorded during stimulation with amplitude modulated tones. Modulation frequencies ranged from 10 Hz to 800 Hz. The response histograms, phase-locked to the modulation signals, were analysed for mean action potential rate and for the amplitude of the fundamental component at the modulation frequency. Expected values for the amplitude of the modulation responses were calculated using the variation of mean firing rate with intensity. The observed responses differed from the expected responses in several ways. First, the amplitudes of the modulation responses were larger than expected. Second, the stimulus intensities at which the observed modulation responses peaked was greater by about 7–10 dB than the expected intensity for maximum response. Third, both the magnitude of the response at a given intensity and the intensity at which the response peaked increased with modulation frequency. Fourth, the responses extended to higher stimulus intensities than expected. The observed modulation responses were compared with predictions from the Schroeder and Hall model of adaptation and were found to agree with good quantitative precision. These results suggest that the observed modulation responses are another manifestation of the very rapid ( < 20 ms) adaptation seen in the onset responses of nerve fibres [(1985) Hear. Res. 17, 1–12]. It is concluded that the static input-output responses of auditory nerve are not a good predictor of the dynamic responses to fluctuating stimuli.