Expression of Oligodendrocyte Marker during Peripheral-Central Transitional Zone Formation of the Postnatal Mouse Cochlear Nerve.

Objective To better understand oligodendrocyte protein expression along the mouse cochlear nerve in postnatal mice. Study Design In vivo murine study. Setting Research laboratory. Subjects and Methods Swiss Webster mice used at multiple postnatal days (0, 1, 3, 5, 7, 8, 10, 14, 30, and 60). There were 5 replicates at each postnatal day. Cryosection was done to produce sections that included the cochlear nucleus, cochlear nerve, and cochlea in a single sample. Differential interference contrast (DIC) microscopy and immunofluorescence with antibodies specific to the oligodendrocyte protein Olig2 were used to study the cochlear nerve of Swiss Webster mice at postnatal days. Results The myelination of central nervous system projections initiates in close proximity to the peripheral nervous system-central nervous system transitional zone (PCTZ), and oligodendrocytes in neonatal mice are seen with immunohistochemistry peripheral to the DIC-PCTZ interface. Conclusions As the PCTZ migrates from the brain to the cochlea, oligodendrocytes are a part of peripheral extension of central nervous system tissue along the cochlear nerve. Expression of oligodendrocyte marker Oligo2 was observed peripherally to the formation of PCTZ, as determined by DIC microscopy.

Changes in Properties of Auditory Nerve Synapses following Conductive Hearing Loss.

Auditory activity plays an important role in the development of the auditory system. Decreased activity can result from conductive hearing loss (CHL) associated with otitis media, which may lead to long-term perceptual deficits. The effects of CHL have been mainly studied at later stages of the auditory pathway, but early stages remain less examined. However, changes in early stages could be important because they would affect how information about sounds is conveyed to higher-order areas for further processing and localization. We examined the effects of CHL at auditory nerve synapses onto bushy cells in the mouse anteroventral cochlear nucleus following occlusion of the ear canal. These synapses, called endbulbs of Held, normally show strong depression in voltage-clamp recordings in brain slices. After 1 week of CHL, endbulbs showed even greater depression, reflecting higher release probability. We observed no differences in quantal size between control and occluded mice. We confirmed these observations using mean-variance analysis and the integration method, which also revealed that the number of release sites decreased after occlusion. Consistent with this, synaptic puncta immunopositive for VGLUT1 decreased in area after occlusion. The level of depression and number of release sites both showed recovery after returning to normal conditions. Finally, bushy cells fired fewer action potentials in response to evoked synaptic activity after occlusion, likely because of increased depression and decreased input resistance. These effects appear to reflect a homeostatic, adaptive response of auditory nerve synapses to reduced activity. These effects may have important implications for perceptual changes following CHL. SIGNIFICANCE STATEMENT: Normal hearing is important to everyday life, but abnormal auditory experience during development can lead to processing disorders. For example, otitis media reduces sound to the ear, which can cause long-lasting deficits in language skills and verbal production, but the location of the problem is unknown. Here, we show that occluding the ear causes synapses at the very first stage of the auditory pathway to modify their properties, by decreasing in size and increasing the likelihood of releasing neurotransmitter. This causes synapses to deplete faster, which reduces fidelity at central targets of the auditory nerve, which could affect perception. Temporary hearing loss could cause similar changes at later stages of the auditory pathway, which could contribute to disorders in behavior.

Maturation of suprathreshold auditory nerve activity involves cochlear CGRP-receptor complex formation.

In adult animals, the neuropeptide calcitonin gene-related peptide (CGRP) is contained in cochlear efferent fibers projecting out to the cochlea, and contributes to increased suprathreshold sound-evoked activity in the adult auditory nerve. Similarly, CGRP applied to the lateral-line organ (hair cell organ) increases afferent nerve activity in adult frogs (post-metamorphic day 30), yet this increase is developmentally delayed from post-metamorphic day 4-30. In this study, we discovered that there was also a developmental delay in increased suprathreshold sound-evoked activity auditory nerve between juvenile and adult mice similar to what had been observed previously in frog. Moreover, juvenile mice with a targeted deletion of the αCGRP gene [CGRP null (-/-)] did not show a similar developmental increase in nerve activity, suggesting CGRP signaling is involved. This developmental delay is not due to a delay in CGRP expression, but instead is due to a delay in receptor formation. We observed that the increase in sound-evoked nerve activity is correlated with increased formation of cochlear CGRP receptors, which require three complexed proteins (CLR, RAMP1, RCP) to be functional. CGRP receptor formation in the cochlea was incomplete at 1 month of age (juvenile), but complete by 3 months (adult), which corresponded to the onset of suprathreshold enhancement of sound-evoked activity in wild-type animals. Taken together, these data support a model for cochlear function that is enhanced by maturation of CGRP receptor complexes.

Temporal coupling between specifications of neuronal and macular fates of the inner ear.

The inner ear is a complex organ comprised of various specialized sensory organs for detecting sound and head movements. The timing of specification for these sensory organs, however, is not clear. Previous fate mapping results of the inner ear indicate that vestibular and auditory ganglia and two of the vestibular sensory organs, the utricular macula (UM) and saccular macula (SM), are lineage related. Based on the medial-lateral relationship where respective auditory and vestibular neuroblasts exit from the otic epithelium and the subsequent formation of the medial SM and lateral UM in these regions, we hypothesized that specification of the two lateral structures, the vestibular ganglion and the UM are coupled and likewise for the two medial structures, the auditory ganglion and the SM. We tested this hypothesis by surgically inverting the primary axes of the otic cup in ovo and investigating the fate of the vestibular neurogenic region, which had been spotted with a lipophilic dye. Our results showed that the laterally-positioned, dye-associated, vestibular ganglion and UM were largely normal in transplanted ears, whereas both auditory ganglion and SM showed abnormalities suggesting the lateral but not the medial-derived structures were mostly specified at the time of transplantation. Both of these results are consistent with a temporal coupling between neuronal and macular fate specifications.

Stochastic resonance in the synaptic transmission between hair cells and vestibular primary afferents in development.

The stochastic resonance (SR) is a phenomenon of nonlinear systems in which the addition of an intermediate level of noise improves the response of such system. Although SR has been studied in isolated hair cells and in the bullfrog sacculus, the occurrence of this phenomenon in the vestibular system in development is unknown. The purpose of the present study was to explore for the existence of SR via natural mechanical-stimulation in the hair cell-vestibular primary afferent transmission. In vitro experiments were performed on the posterior semicircular canal of the chicken inner ear during development. Our experiments showed that the signal-to-noise ratio of the afferent multiunit activity from E15 to P5 stages of development exhibited the SR phenomenon, which was characterized by an inverted U-like response as a function of the input noise level. The inverted U-like graphs of SR acquired their higher amplitude after the post-hatching stage of development. Blockage of the synaptic transmission with selective antagonists of the NMDA and AMPA/Kainate receptors abolished the SR of the afferent multiunit activity. Furthermore, computer simulations on a model of the hair cell - primary afferent synapse qualitatively reproduced this SR behavior and provided a possible explanation of how and where the SR could occur. These results demonstrate that a particular level of mechanical noise on the semicircular canals can improve the performance of the vestibular system in their peripheral sensory processing even during embryonic stages of development.

Maturation of NaV and KV Channel Topographies in the Auditory Nerve Spike Initiator before and after Developmental Onset of Hearing Function.

Auditory nerve excitation and thus hearing depend on spike-generating ion channels and their placement along the axons of auditory nerve fibers (ANFs). The developmental expression patterns and native axonal locations of voltage-gated ion channels in ANFs are unknown. Therefore, we examined the development of heminodes and nodes of Ranvier in the peripheral axons of type I ANFs in the rat cochlea with immunohistochemistry and confocal microscopy. Nodal structures presumably supporting presensory spiking formed between postnatal days 5 (P5) and P7, including Ankyrin-G, NaV1.6, and Caspr. These immature nodal structures lacked low-voltage-activated KV1.1 which was not enriched at juxtaparanodes until approximately P13, concurrent with the developmental onset of acoustic hearing function. Anatomical alignment of ANF spike-initiating heminodes relative to excitatory input from inner hair cell (IHC) ribbon synapses continued until approximately P30. High-voltage-activated KV3.1b and KV2.2 were expressed in mutually exclusive domains: KV3.1b was strictly localized to nodes and heminodes, whereas KV2.2 expression began at the juxtaparanodes and continued centrally along the first internode. At spike-initiating heminodes in the distal osseous spiral lamina, NaV1.1 partly overlapped NaV1.6 and ankyrin-G. ANFs displayed KV7.2 and KV7.3 at heminodes, nodes, internodes, and the unmyelinated synaptic terminal segments beneath IHCs in the organ of Corti. In response to sound, spikes are initiated at the heminode, which is tightly coupled to the IHC ribbon synapse ∼20-40 µm away. These results show that maturation of nodal alignment and ion channel content may underlie postnatal improvements of ANF excitability and discharge synchrony. SIGNIFICANCE STATEMENT: Acoustic and electrical hearing depends on rapid, reliable, and precise spike generation in auditory nerve fibers. A limitation of current models and therapies is a lack of information on the identities and topographies of underlying ion channels. We report the developmental profile of the auditory nerve spike generator with a focus on NaV1.1, NaV1.6, KV1.1, KV2.2, KV3.1b, KV7.2, and KV7.3 in relation to the scaffold ankyrin-G. Molecular anatomy of the spike generator matures in the weeks after developmental onset of hearing function. Subcellular positioning of voltage-gated ion channels will enable multicompartmental modeling of auditory nerve responses elicited by afferent chemical neurotransmission from hair cells and modulated by efferent neurotransmitters or evoked by extracellular field stimulation from a cochlear implant.

Cochlear afferent innervation development.

Sound signal is detected by sensory hair cells located in the cochlear region of the inner ear, and transmitted to the central nervous system by the spiral ganglion neurons (SGNs). These bipolar neurons develop long peripheral processes to connect hair cells, forming ribbon synapses, specialised for the precision and speed required to process auditory information. The establishment of a complex innervation pattern relies on specific signals, intrinsic to SGNs or provided by neighbouring cells, which are tightly controlled in time and space. In this paper, we review recent advances about stepwise development of afferent auditory neuronal circuitries, from neuron specification within the early otic vesicle to definitive synaptic connections with target cells. We especially focus on the cellular and molecular developmental changes involved in fibre outgrowth and extension to the sensory epithelium, specific afferent targeting to hair cells, and synaptic pruning.

Concurrent maturation of inner hair cell synaptic Ca2+ influx and auditory nerve spontaneous activity around hearing onset in mice.

Hearing over a wide range of sound intensities is thought to require complementary coding by functionally diverse spiral ganglion neurons (SGNs), each changing activity only over a subrange. The foundations of SGN diversity are not well understood but likely include differences among their inputs: the presynaptic active zones (AZs) of inner hair cells (IHCs). Here we studied one candidate mechanism for causing SGN diversity-heterogeneity of Ca(2+) influx among the AZs of IHCs-during postnatal development of the mouse cochlea. Ca(2+) imaging revealed a change from regenerative to graded synaptic Ca(2+) signaling after the onset of hearing, when in vivo SGN spike timing changed from patterned to Poissonian. Furthermore, we detected the concurrent emergence of stronger synaptic Ca(2+) signals in IHCs and higher spontaneous spike rates in SGNs. The strengthening of Ca(2+) signaling at a subset of AZs primarily reflected a gain of Ca(2+) channels. We hypothesize that the number of Ca(2+) channels at each IHC AZ critically determines the firing properties of its corresponding SGN and propose that AZ heterogeneity enables IHCs to decompose auditory information into functionally diverse SGNs.

Formation of the peripheral-central transitional zone in the postnatal mouse cochlear nerve.

OBJECTIVES: Determine the formation of peripheral and central nervous system (CNS and PNS) transitional zone (PCTZ) along the postnatal mouse cochlear nerve. STUDY DESIGN: Prospective, basic science. SETTING: Research laboratory. SUBJECTS AND METHODS: A novel cryosection model of cochlea-cochlear nerve-brainstem was used in this study. The sections were harvested from a total of 45 mice in 9 groups of postnatal-day-0 to postnatal-day-60 mice (n = 5). Differential interference contrast microscopy and immunofluorescence were used to study the formation of PCTZ along the cochlear nerve of the postnatal mouse. RESULTS: The CNS tissue extended peripherally along the cochlear nerve from postnatal-day-0 to postnatal-day-7 and then stably located at the level of the spiral lamina of the basal cochlear turn. The PCTZ reached a mature pattern along the cochlear nerve after postnatal-day-7. A long segment of the CNS tissue extended along the cochlear nerve in the postnatal mouse. CONCLUSION: In the early postnatal days, the PCTZ extended peripherally toward the cochlea and obtains a mature pattern along the neonatal mouse cochlear nerve.

Emergence of coordinated plasticity in the cochlear nucleus and cerebellum.

Synapses formed by one cell type onto another cell type tend to show characteristic short-term plasticity, which varies from facilitating to depressing depending on the particular system. Within a population of synapses, plasticity can also be variable, and it is unknown how this plasticity is determined on a cell-by-cell level. We have investigated this in the mouse cochlear nucleus, where auditory nerve (AN) fibers contact bushy cells (BCs) at synapses called "endbulbs of Held." Synapses formed by different AN fibers onto one BC had plasticity that was more similar than would be expected at random. Experiments using MK-801 indicated that this resulted in part from similarity in the presynaptic probability of release. The similarity was not present in immature synapses but emerged after the onset of hearing. In addition, the phenomenon occurred at excitatory synapses in the cerebellum. This indicates that postsynaptic cells coordinate the plasticity of their inputs, which suggests that plasticity is of fundamental importance to synaptic function.

Iron deficiency disrupts axon maturation of the developing auditory nerve.

Iron is critical in multiple aspects of CNS development, but its role in neurodevelopment--the ability of iron deficiency to alter normal development--is difficult to dissociate from the effects of anemia. We developed a novel dietary restriction model in the rat that allows us to study the effects of iron deficiency in the absence of severe anemia. Using a combination of auditory brainstem response analyses (ABR) and electron microscopy, we identified an unexpected impact of nonanemic iron deficiency on axonal diameter and neurofilament regulation in the auditory nerve. These changes are associated with altered ABR latency during development. In contrast to models of severe iron deficiency with anemia, we did not find consistent or prolonged defects in myelination. Our data demonstrate that iron deficiency in the absence of anemia disrupts normal development of the auditory nerve and results in altered conduction velocity.

Electrophysiologic and behavioral outcomes of cochlear implantation in children with auditory nerve hypoplasia.

OBJECTIVES: Hypoplasia of the auditory nerve (AN) refers to significant narrowing of the VIIIth cranial nerve which could compromise stimulation of the nerve by electrical pulses delivered from a cochlear implant (CI), thereby hindering activity in other parts of the auditory pathways. To compensate, high current levels or increased charge may be required to elicit auditory perception causing current to spread to other cranial nerves and potentially resulting in unwanted myogenic responses. Deficits in central auditory activity could reduce perception of speech and language. In the present study, we measured auditory brainstem responses in children with and without hypoplasia of the AN to answer the following questions. In children with hypoplastic ANs, (a) can CI stimulation evoke typical patterns of activity from the AN and brainstem?, (b) do brainstem responses change with CI experience?, (c) are evoked responses dependent on the size of the AN pathway?, and (d) does auditory development measured by behavioral tests of speech perception develop more slowly than in peers with normal AN diameter? DESIGN: Of 807 children using CIs in our program, 20 (2.5%) were identified as having AN hypoplasia using high-resolution computed tomographic scan and/or magnetic resonance imaging. An age-matched control group of children using CIs with normal AN diameter were recruited to compare electrophysiological and behavioral measures. Radiologic imaging was used to measure the diameter of the internal auditory canal (IAC), auditory nerve canal (ANC), and AN. Electrophysiological testing of the evoked compound action potential and auditory brainstem response was performed at CI activation and every 3 mo after initial testing up to 2 yr. Peak latency and waveform morphology were compared between study and control groups. Tests of speech perception and discrimination were attempted every 12 mo after device activation up to 10 yr. RESULTS: : Hypoplastic AN was identified as moderate to critical stenosis of the IAC, ANC, and AN. Initial electrically evoked compound action potential responses were mostly absent in children with AN hypoplasia. In the time window when electrically evoked auditory brainstem responses would be expected, some responses included single amplitude peaks at normal wave eV latencies, but the majority were abnormal, with peaks at atypical latencies or with no observable wave peaks. All evoked responses were inconsistent over time and did not reflect a typical pattern of auditory brainstem development. Speech perception scores were significantly poorer in the study group compared with controls and did not improve with CI experience. The type of abnormal evoked waveform response was independent of IAC, ANC, or AN diameter and also independent of behavioral outcome measures. CONCLUSIONS: : Evoked responses recorded in CI children with AN hypoplasia indicate a high incidence of nonauditory activity with CI use. The range of abnormal responses was not predicted by the severity of the hypoplastic AN or associated structures. This, along with poorer auditory development compared with peers with normal AN diameters, suggests that children with hypoplasia of the AN are poor candidates for cochlear implantation.

Postnatal development of cochlear microphonic and compound action potentials in a precocious species, Chinchilla lanigera.

The development of sound-evoked responses in Chinchilla lanigera was studied from postnatal ages P0-1 (first 24 h) to adult. Cochlear microphonic (CMs) and compound action potentials (CAPs), representing ensemble sound-evoked activities of hair cells and auditory nerve fibers, respectively, were present as early as age P0-1. The data indicate that CM thresholds and sensitivities were generally adult-like (i.e., fall into adult ranges) at birth, but suprathreshold CM amplitudes remained below adult ranges through P28. CAP thresholds reached adult-like values between P7-P14, but the suprathreshold CAP amplitude continued to increase until ∼P28. The results confirm the auditory precociousness of the chinchilla.

Effect of the dopant anion in polypyrrole on nerve growth and release of a neurotrophic protein.

The dopant anion in polypyrrole plays a critical role in determining the physical and chemical properties of these conducting polymers. Here we demonstrate an additional effect on the ability to incorporate and release a neurotrophic protein - neurotrophin-3. The multi-faceted role of the dopant is critical in ensuring optimal performance of polypyrroles in their use as platforms for nerve growth. In this paper, the effect of changing the co-dopant used in electrochemical polypyrrole synthesis on the compatibility with primary auditory nerve tissue is considered and compared to some of the physical properties of the films. Significant differences in the controlled-release properties of the films were also observed. The ability of the polymers to enhance nerve growth and survival in vitro with neurotrophin-3 release was also studied, which is a function of both compatibility with the neural tissue and the ability of the polymer to release sufficient neurotrophic protein to affect cell growth. A small synthetic dopant, para-toluene sulphonate, was found to perform favourably in both aspects and ultimately proved to be the most suitable material for the application at hand, which is the delivery of neurotrophins for inner-ear therapies.

Formation and maturation of the calyx of Held.

Sound localization requires precise and specialized neural circuitry. A prominent and well-studied specialization is found in the mammalian auditory brainstem. Globular bushy cells of the ventral cochlear nucleus (VCN) project contralaterally to neurons of the medial nucleus of the trapezoid body (MNTB), where their large axons terminate on cell bodies of MNTB principal neurons, forming the calyces of Held. The VCN-MNTB pathway is necessary for the accurate computation of interaural intensity and time differences; MNTB neurons provide inhibitory input to the lateral superior olive, which compares levels of excitation from the ipsilateral ear to levels of tonotopically matched inhibition from the contralateral ear, and to the medial superior olive, where precise inhibition from MNTB neurons tunes the delays of binaural excitation. Here we review the morphological and physiological aspects of the development of the VCN-MNTB pathway and its calyceal termination, along with potential mechanisms that give rise to its precision. During embryonic development, VCN axons grow towards the midline, cross the midline into the region of the presumptive MNTB and then form collateral branches that will terminate in calyces of Held. In rodents, immature calyces of Held appear in MNTB during the first few days of postnatal life. These calyces mature morphologically and physiologically over the next three postnatal weeks, enabling fast, high fidelity transmission in the VCN-MNTB pathway.

KCNQ5 reaches synaptic endings in the auditory brainstem at hearing onset and targeting maintenance is activity-dependent.

Kv7.5/KCNQ5, a voltage-dependent potassium channel that generates a subthreshold K+ current (also called M-current), is localized in excitatory endings of auditory brainstem nuclei in the adult rat. Here, we focus on how specific targeting develops from birth to adulthood in the rat. We first analyzed by immunocytochemistry the distribution of KCNQ5 during postnatal development of neurons in the anteroventral cochlear nucleus (AVCN) and their targets in the medial nucleus of the trapezoid body (MNTB). From postnatal days (P) 0 to 12, KCNQ5 immunoreactivity was restricted to cell bodies, whereas from P13 onward a shift in labeling pattern was seen, with KCNQ5 immunoreactivity becoming confined to synaptic endings in both the AVCN and MNTB. The developmental synaptic targeting was also accompanied by a downregulation of KCNQ5 transcripts in the cochlear nucleus from P13 onward, as seen with quantitative reverse transcriptase polymerase chain reaction. We further tested whether auditory nerve activity at hearing onset (approximately P12) regulates synaptic targeting of the channel. Cochleae were removed at P10, before hearing onset. In the MNTB, 3 days after cochlear ablation, at P13, KCNQ5 immunoreactivity was seen in calyces of Held, as in normal age-matched controls. However, immunolabeling virtually disappeared from MNTB calyces 40 days after cochlear ablation but reappeared in the somata of neurons in AVCN. These findings suggest that synaptic targeting of KCNQ5 in brainstem auditory neurons occurs around the time of hearing onset, regardless of auditory nerve activity. However, long-term synaptic localization after hearing onset depends on peripheral input.

Conducting polymers, dual neurotrophins and pulsed electrical stimulation--dramatic effects on neurite outgrowth.

In this study the synergistic effect of delivering two neurotrophins simultaneously to encourage neuron survival and neurite elongation was explored. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) were incorporated into polypyrrole (PPy) during electrosynthesis and the amounts incorporated and released were determined using iodine-125 ((125)I) radio-labelled neurotrophins. Neurite outgrowth from cochlear neural explants grown on the conducting polymer was equivalent to that on tissue culture plastic but significantly improved with the incorporation of NT-3 and BDNF. Neurite outgrowth from explants grown on polymers containing both NT-3 and BDNF showed significant improvement over PPy doped only with NT-3, due to the synergistic effect of both neurotrophins. Neurite outgrowth was significantly improved when the polymer containing both neurotrophins was electrically stimulated. It is envisaged that when applied to the cochlear implant, these conducting and novel polymer films will provide a biocompatible substrate for storage and release of neurotrophins to help protect auditory neurons from degradation after sensorineural hearing loss and encourage neurite outgrowth towards the electrodes.

The maturational process of the auditory system in the first year of life characterized by brainstem auditory evoked potentials.

UNLABELLED: The study of brainstem auditory evoked potentials (BAEP) allows obtaining the electrophysiological activity generated in the cochlear nerve to the inferior colliculus. In the first months of life, a period of greater neuronal plasticity, important changes are observed in the absolute latency and inter-peak intervals of BAEP, which occur up to the completion of the maturational process, around 18 months of life in full-term newborns, when the response is similar to that of adults. OBJECTIVE: The goal of this study was to establish normal values of absolute latencies for waves I, III and V and inter-peak intervals I-III, III-V and I-V of the BAEP performed in full-term infants attending the Infant Hearing Health Program of the Speech-Language Pathology and Audiology Course at Bauru School of Dentistry, Brazil, with no risk history for hearing impairment. MATERIAL AND METHODS: The stimulation parameters were: rarefaction click stimulus presented by the 3ª insertion phone, intensity of 80 dBnHL and a rate of 21.1 c/s, band-pass filter of 30 and 3,000 Hz and average of 2,000 stimuli. A sample of 86 infants was first divided according to their gestational age in preterm (n=12) and full-term (n=74), and then according to their chronological age in three periods: P1: 0 to 29 days (n=46), P2: 30 days to 5 months 29 days (n=28) and P3: above 6 months (n= 12). RESULTS: The absolute latency of wave I was similar to that of adults, generally in the 1st month of life, demonstrating a complete process maturity of the auditory nerve. For waves III and V, there was a gradual decrease of absolute latencies with age, characterizing the maturation of axons and synaptic mechanisms in the brainstem level. CONCLUSION: Age proved to be a determining factor in the absolute latency of the BAEP components, especially those generated in the brainstem, in the first year of life.

The maturational process of the auditory system in the first year of life characterized by brainstem auditory evoked potentials

The study of brainstem auditory evoked potentials (BAEP) allows obtaining the electrophysiological activity generated in the cochlear nerve to the inferior colliculus. In the first months of life, a period of greater neuronal plasticity, important changes are observed in the absolute latency and inter-peak intervals of BAEP, which occur up to the completion of the maturational process, around 18 months of life in full-term newborns, when the response is similar to that of adults. OBJECTIVE: The goal of this study was to establish normal values of absolute latencies for waves I, III and V and inter-peak intervals I-III, III-V and I-V of the BAEP performed in full-term infants attending the Infant Hearing Health Program of the Speech-Language Pathology and Audiology Course at Bauru School of Dentistry, Brazil, with no risk history for hearing impairment. MATERIAL AND METHODS: The stimulation parameters were: rarefaction click stimulus presented by the 3ª insertion phone, intensity of 80 dBnHL and a rate of 21.1 c/s, band-pass filter of 30 and 3,000 Hz and average of 2,000 stimuli. A sample of 86 infants was first divided according to their gestational age in preterm (n=12) and full-term (n=74), and then according to their chronological age in three periods: P1: 0 to 29 days (n=46), P2: 30 days to 5 months 29 days (n=28) and P3: above 6 months (n= 12). RESULTS: The absolute latency of wave I was similar to that of adults, generally in the 1st month of life, demonstrating a complete process maturity of the auditory nerve. For waves III and V, there was a gradual decrease of absolute latencies with age, characterizing the maturation of axons and synaptic mechanisms in the brainstem level. CONCLUSION: Age proved to be a determining factor in the absolute latency of the BAEP components, especially those generated in the brainstem, in the first year of life.

Topography of auditory nerve projections to the cochlear nucleus in cats after neonatal deafness and electrical stimulation by a cochlear implant.

We previously reported that auditory nerve projections from the cochlear spiral ganglion (SG) to the cochlear nucleus (CN) exhibit clear cochleotopic organization in adult cats deafened as neonates before hearing onset. However, the topographic specificity of these CN projections in deafened animals is proportionately broader than normal (less precise relative to the CN frequency gradient). This study examined SG-to-CN projections in adult cats that were deafened as neonates and received a unilateral cochlear implant at approximately 7 weeks of age. Following several months of electrical stimulation, SG projections from the stimulated cochleae were compared to projections from contralateral, non-implanted ears. The fundamental organization of SG projections into frequency band laminae was clearly evident, and discrete projections were always observed following double SG injections in deafened cochleae, despite severe auditory deprivation and/or broad electrical activation of the SG. However, when normalized for the smaller CN size after deafness, AVCN, PVCN, and DCN projections on the stimulated side were broader by 32%, 34%, and 53%, respectively, than projections in normal animals (although absolute projection widths were comparable to normal). Further, there was no significant difference between projections from stimulated and contralateral non-implanted cochleae. These findings suggest that early normal auditory experience may be essential for normal development and/or maintenance of the topographic precision of SG-to-CN projections. After early deafness, the CN is smaller than normal, the topographic distribution of these neural projections that underlie frequency resolution in the central auditory system is proportionately broader, and projections from adjacent SG sectors are more overlapping. Several months of stimulation by a cochlear implant (beginning at approximately 7 weeks of age) did not lessen or exacerbate these degenerative changes observed in adulthood. One clinical implication of these findings is that congenitally deaf cochlear implant recipients may have central auditory system alterations that limit their ability to achieve spectral selectivity equivalent to post-lingually deafened subjects.